339
WE CLAIM:
1. A compound of formula I':
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
A and B, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety which
contains one or more O, C (R1)2, S (O)p, N, NR1, or NR5 atoms;
V is CH, S, or N;
X is O, CH2 or S;
m is 0 or 1;
G is
<IMGS>
R1 is independently hydrogen, C1-C9 straight or
branched chain alkyl, or C2-C9 straight or branched chain
alkenyl or alkynyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, a
carboxylic acid or carboxylic acid isostere, N (R4)n, Ar1,
Ar4, a bridged ring moiety, or K-L, wherein said alkyl,
cycloalkyl, cycloalkenyl, alkynyl, alkenyl, Ar1, Ar4, or
bridged ring moiety, is optionally substituted with one or
more substituent(s) independently selected from the group
consisting of:
2-furyl, 2-thienyl, pyridyl, phenyl, C3-C6
cycloalkyl wherein said furyl, thienyl, pyridyl,
phenyl or cycloalkyl group optionally is
340
substituted with C1-C4 alkoxy, (Ar1) n, halo, halo-
C1-C6-alkyl, carbonyl, thiocarbonyl, C1-C6
thioester, cyano, imino, COOR6 in which R6 is
independently C1-C9 straight or branched chain
alkyl or alkenyl, hydroxy, nitro,
trifluoromethyl, C1-C6 alkoxy, C2-C4 alkenyloxy,
C1-C6 alkylaryloxy C1-C6 aryloxy, aryl- (C1-C6) -
alkyloxy, phenoxy, benzyloxy, thio- (C1-C6) -alkyl,
C1-C6-alkylthio, sulfhydryl, sulfonyl, amino,
(C1-C6)-mono- or di-alkylamino, amino- (C1-C6) -
alkyl, aminocarboxy, C3-C8 cycloalkyl, C1-C6
straight or branched chain alkyl, C2-C6 straight
or branched chain alkenyl optionally substituted
with (Ar1)n, C3-C8 cycloalkyl, C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched
chain alkenyl substituted with C3-C8 cycloalkyl,
C3-C8 cycloalkyl, and Ar2, and, wherein any
carbon atom of an alkyl or alkenyl group may
optionally replaced with O, NR5, or S(O)p;
Ar1 or Ar2, independently, is an alicyclic
or aromatic, mono-, bi- or tricyclic, carbo- or
heterocyclic ring, wherein the ring is
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl,
C3-C8 cycloalkyl, C5-C7 cycloalkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and
amino; wherein the individual ring contains 5-8
members; and wherein the heterocyclic ring
contains 1-6 heteroatom(s) independently
selected from the group consisting of O, N, and
S, and, wherein any aromatic or tertiary
341
alkylamine is optionally oxidized to a
corresponding N-oxide;
or, R1 is independently a moiety of the formula:
<IMG>
wherein:
R3 is independently C1-C9 straight
or branched chain alkyl which is
optionally substituted with C3-C8
cycloalkyl, a bridged ring moiety, or
Ar1;
X2 is O or NR6, wherein R6 is
independently selected from the group
consisting of hydrogen, C1-C6 straight
or branched chain alkyl, and C2-C6
straight or branched chain alkenyl;
R4 is independently selected from
the group consisting of phenyl,
benzyl, C1-C5 straight or branched
chain alkyl, C2-C5 straight or
branched chain alkenyl, C1-C5 straight
or branched chain alkyl substituted
with phenyl, C2-C5 straight or
branched chain alkenyl substituted
with phenyl, and a bridged ring
moiety;
R2 is independently C1-C9 straight or
branched chain alkyl, C2-C9 straight or branched
chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, a bridged ring moiety, or Ar1,
342
wherein said alkyl, alkenyl, cycloalkyl,
cycloalkenyl, or bridged ring moiety, is
optionally substituted with one or more
substituents selected from the group consisting
of C1-C6 straight or branched chain alkyl,C2-C6
straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, (Ar1)n and
hydroxy: or,
R2 is independently either hydrogen or P;
Y is either oxygen or CH-P, provided that
if R2 is hydrogen, then Y is CH-P, or if Y is
oxygen then R2 is P:
P is hydrogen, O- (C1-C4 straight
or branched chain alkyl), O- (C2-C4
straight or branched chain alkenyl),
C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched
chain alkenyl, C2-C6 cycloalkyl, C5-C7
cycloalkenyl substituted with C1-C4
straight or branched chain alkyl or
C2-C4 straight or branched chain
alkenyl, (C1-C4 alkyl or C2-C4
alkenyl) -Ar5, or Ar5;
U is either 0 or N, provided that:
when U is O, then R' is a lone
pair of electrons and R" is selected
from the group consisting of Ar4, a
bridged ring moiety, C3-C8 cycloalkyl,
C1-C9 straight or branched chain
alkyl, and C2-C9 straight or branched
chain alkenyl, wherein said alkyl or
alkenyl is optionally substituted with
one or more substituent(s)
independently selected from the group
343
consisting of Ar4 and C3-C8 cycloalkyl;
and
when U is N, then R' and R" are,
independently, selected from the group
consisting of hydrogen, Ar4, a
bridged ring moiety, C3-C10 cycloalkyl,
a C7-C12 bi- or tri-cyclic carbocycle,
C1-C9 straight or branched chain
alkyl, and C2-C9 straight or branched
chain alkenyl, wherein said alkyl or
alkenyl is optionally substituted with
one or more substituent(s)
independently selected from the group
consisting of Ar4 and C3-C8 cycloalkyl;
or R' and R'' are taken together to
form a heterocyclic 5- or 6-membered
ring selected from the group
consisting of pyrrolidine,
imidazolidine, pyrazolidine,
piperidine, and piperazine.
W and Y, independently, are O, S, CH2 or H2;
Z is C (R1) 2, O, S, a direct bond or NR1; or,
Z-R1 is independently
<IMGS>
wherein:
C and D are, independently, hydrogen, a
bridged ring moiety, Ar4, Ar1, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl; wherein said alkyl or
344
alkenyl is optionally substituted with one or
more substituent(s) independently selected from
the group consisting of C3-C8 cycloalkyl, C5-C7
cycloalkenyl, hydroxy, carbonyl oxygen, Ar1 and
Ar4; wherein said alkyl, alkenyl, cycloalkyl or
cycloalkenyl is optionally substituted with C1-C6
alkyl, C2-C6 alkenyl, hydroxy, amino, halo,
haloalkyl, thiocarbonyl, C1-C6 ester, C1-C6
thioester, C1-C6 alkoxy, C1-C6 alkenoxy, cyano,
nitro, imino, C1-C6 alkylamino, amino- (C1-
C6) alkyl, sulfhydryl, thio- (C1-C6) alkyl, or
sulfonyl; wherein any carbon atom of said alkyl
or alkenyl is optionally substituted in one or
more position(s) with oxygen to form a carbonyl;
or wherein any carbon atom of said alkyl or
alkenyl is optionally replaced with O, NR5, or
(SO)p;
C' and D' are independently hydrogen, a
bridged ring moiety, Ar5, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl, wherein said alkyl or
alkenyl is optionally substituted with C5-C7
cycloalkyl, C5-C7 cycloalkenyl, or Ar5, wherein,
one or two carbon atom(s) of said alkyl or
alkenyl may be substituted with one or two
heteroatom(s) independently selected from the
group consisting of oxygen, sulfur, SO, and SO2
in chemically reasonable substitution patterns,
or
<IMG>
wherein
345
Q is hydrogen, C1-C6 straight or
branched chain alkyl, or C2-C6
straight or branched chain alkenyl;
and
T is Ar5 or C5-C7 cycloalkyl
substituted at positions 3 and 4 with
substituents independently selected
from the group consisting of hydrogen,
hydroxy, O- (C1-C4 alkyl), O-(C2-C4
alkenyl), and carbonyl,
J is O, NR1, S, or (CR1)2;
K is a direct bond, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl; wherein said alkyl or
alkenyl is optionally substituted with one or
more substituent(s) independently selected from
the group consisting of C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched
chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, a bridged ring moiety, hydroxy,
carbonyl oxygen, and Ar3; wherein said alkyl,
alkenyl, cycloalkyl, cycloalkenyl or Ar3, is
optionally substituted with C1-C4 alkyl, C2-C4
alkenyl, hydroxy, or carbonyl oxygen; wherein
any carbon atom of said alkyl, alkenyl,
cycloalkyl, cycloalkenyl or Ar3, is optionally
replaced with O, NR''', or S(O)p,
wherein R''' is selected from the
group consisting of hydrogen, C1-C4
straight or branched chain alkyl, C3-
C4 straight or branched chain alkenyl
or alkynyl, a bridged ring moiety,
and C1-C4 bridging alkyl wherein a
bridge is formed between the nitrogen
346
and a carbon atom of said alkyl or
alkenyl chain containing said
heteroatom to form a ring, wherein
said ring is optionally fused to an
Ar3 group;
K' is a direct bond, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl, wherein any carbon atom
of said alkyl or alkenyl is optionally
substituted in one or more position(s) with
amino, halo, haloalkyl, thiocarbonyl, ester,
thioester, alkoxy, alkenoxy, cyano, nitro,
imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, sulfonyl, or oxygen to form a
carbonyl, or wherein any carbon atom of said
alkyl or alkenyl is optionally replaced with O,
NR5, S(O)p;
K'' is C(R1)2, O, S, a direct bond or NR1;
L is an aromatic amine or a tertiary amine
oxidized to a corresponding N-oxide; said
aromatic amine being selected from the group
consisting of pyridyl, pyrimidyl, quinolinyl,
and isoquinolinyl, said aromatic amine being
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl,
C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy,
benzyloxy, and amino; and wherein said tertiary
amine is NR x R y R z, wherein R k, R y, and R z are
independently selected from the group consisting
of C1-C6 straight or branched chain alkyl and C2-
C6 straight or branched chain alkenyl; wherein
347
said alkyl or alkenyl is optionally substituted
with one or more substituent(s) independently
selected from the group consisting of C1-C6
straight or branched chain alkyl, C2-C6 straight
or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, hydroxy, carbonyl oxygen, a
bridged ring moiety, and Ar3; wherein said
alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar3
is optionally substituted with C1-C9 alkyl, C2-C4
alkenyl, hydroxy, or carbonyl oxygen; wherein
any carbon atom of said alkyl, alkenyl,
cycloalkyl, cycloalkenyl, or Ar3 is optionally
replaced with O, NR', S(O)p;
L' is a direct bond, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl, wherein any carbon atom
of said alkyl or alkenyl is optionally
substituted in one or more position(s) with
amino, halo, haloalkyl, thiocarbonyl, ester,
thioester, alkoxy, alkenoxy, cyano, nitro,
imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, sulfonyl, or oxygen to form a
carbonyl, or wherein any carbon atom of said
alkyl or alkenyl is optionally replaced with O,
NR5, S(O)p:
n is 1 or 2;
p is 0, 1, or 2;
t is 0, 1, 2, 3, or 4;
Ar3 is independently selected from the group
consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl,
pyridazyl, quinolinyl, and isoquinolinyl;
Ar4 is independently an alicyclic or aromatic, mono-,
bi- or tricyclic, carbo- or heterocyclic ring, wherein the
ring is optionally substituted with one or more
348
substituent(s) independently selected from the group
consisting of alkylamino, amido, amino, aminoalkyl, azo,
benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9
alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain
alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl,
carboxy, cyano, diazo, ester, formanilido, halo,
haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo,
nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy,
thio, thioalkyl, thiocarbonyl, thiocyano, thioester,
thioformamido, trifluoromethyl, and carboxylic and
heterocyclic moieties: wherein the individual alicyclic or
aromatic ring contains 5-8 members and wherein said
heterocyclic ring contains 1-6 heteroatom(s) independently
selected from the group consisting of O, N, and S; and
wherein any aromatic or tertiary alkyl amine is optionally
oxidized to a corresponding N-oxide;
Ar5 is independently selected from the group
consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-
thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and
phenyl, monocyclic and bicyclic heterocyclic ring systems
with individual ring sizes being 5 or 6 which contain in
either or both rings a total of 1-4 heteroatom(s)
independently selected from the group consisting of
oxygen, nitrogen and sulfur; wherein Ar5 optionally
contains 1-3 substituent(s) independently selected from
the group consisting of hydrogen, halo, hydroxy,
hydroxymethyl, nitro, CF3, trifluoromethoxy, C1-C6 straight
or branched chain alkyl, C2-C6 straight or branched chain
alkenyl, O-(C1-C4 straight or branched chain alkyl), O-(C2-
C4 straight or branched chain alkenyl), O-benzyl, O-phenyl,
amino, 1,2-methylenedioxy, carbonyl, and phenyl; and
R5 is independently selected from the group consisting
of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6
straight or branched chain alkenyl or alkynyl, a bridged
349
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar4 or
Ar1 group.
2. The compound of claim 1, wherein the compound is
formula I
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
A and B, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety containing
one or more heteroatom(s) independently selected from the
group consisting of O, S, SO, SO2, N, NH, and NR2;
X is either O or S;
Z is either S, CH2, CHR1 or CR1R3;
W and Y are independently O, S, CH2 or H2;
R1 and R3 are independently C1-C6 straight or branched
chain alkyl, C2-C6 straight or branched chain alkenyl, or
a bridged ring moiety, wherein said alkyl or alkenyl is
substituted with one or more substituent(s) independently
selected from the group consisting of (Ar1)n, C1-C6 straight
or branched chain alkyl or C2-C6 straight or branched chain
alkenyl substituted with (Ar1)n, C3-C8 cycloalkyl, C1-C6
350
straight or branched chain alkyl or C2-C6 straight or
branched chain alkenyl substituted with C3-C8 cycloalkyl,
a bridged ring moiety, and Ar2;
n is 1 or 2;
R2 is independently C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar1, wherein said alkyl, alkenyl, cycloalkyl or
cycloalkenyl is either unsubstituted or substituted with
one or more substituent(s) independently selected from the
group consisting of C1-C4 straight or branched chain alkyl,
C2-C4 straight or branched chain alkenyl, a bridged ring
moiety, and hydroxy; and
Ar1 and Ar2 are independently an alicyclic or
aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic
ring, wherein said ring is either unsubstituted or
substituted with one or more substituent(s) independently
selected from the group consisting of halo, hydroxyl,
nitro, trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
wherein the individual ring size is 5-8 members; and
wherein the heterocyclic ring contains 1-6 heteroatom(s)
independently selected from the group consisting of O, N,
and S.
3. The compound of claim 2, wherein the compound is
formula II:
351
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
n is 1 or 2;
Br is a heterocylic bridged ring moiety, wherein any
two or more atoms of the pyrrolidine ring (when n=1) or
the piperidine ring (when n=2) are bonded to each other
through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
X is O or S;
Z is selected from the group consisting of S, CH2,
CHR1, and CR1R3:
R1 and R3 are independently selected from the group
consisting of C1-C5 straight or branched chain alkyl, C2-C5
straight or branched chain alkenyl, a bridged ring moiety,
and Ar1, wherein said alkyl, alkenyl or Ar1 is
unsubstituted or substituted with one or more
substituent(s) independently selected from the group
consisting of halo, nitro, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, a bridged
ring moiety, hydroxy, C1-C4 alkoxy, C2-C4 alkenyloxy,
phenoxy, benzyloxy, amino, and Ar1;
R2 is independently selected from the group consisting
of C1-C9 straight or branched chain alkyl, C2-C9 straight or
352
branched chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, a bridged ring moiety, and Ar1; and
Ar1 is independently phenyl, benzyl, pyridyl,
fluorenyl, thioindolyl or naphthyl, wherein said Ar1 is
unsubstituted or substituted with one or more
substituent(s) independently selected from the group
consisting of halo, trifluoromethyl, hydroxy, nitro, C1-C6
straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy,
phenoxy, benzyloxy, and amino.
4. The compound of claim 2, wherein the compound is
formula III:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
A, B, and C are independently CH2, O, S, SO, SO2, NH
or NR2;
Br is a heterocylic bridged ring moiety, wherein any
two or more of A, B, and C are bonded to each other
through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
X is O or S;
Z is S, CH2, CHR, or CR1R3;
R1 and R3 are independently C1-C6 straight or branched
353
chain alkyl, C2-C6 straight or branched chain alkenyl, or
a bridged ring moiety, wherein said alkyl or alkenyl is
substituted with one or more substituent(s) independently
selected from the group consisting of (Ar1)n, a bridged
ring moiety, C1-C6 straight or branched chain alkyl or C2-C6
straight or branched chain alkenyl substituted with (Ar1)n,
C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl or
C2-C6 straight or branched chain alkenyl substituted with
C3-C8 cycloalkyl, and Ar2;
n is 1 or 2;
R2 is independently C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar1, wherein said alkyl, alkenyl, cycloalkyl or
cycloalkenyl is either unsubstituted or substituted with
one or more substituent(s) independently selected from the
group consisting of C1-C4 straight or branched chain alkyl,
C2-C4 straight or branched chain alkenyl, a bridged ring
moiety, and hydroxyl; and
Ar1 and Ar2 are independently an alicyclic or
aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic
ring, wherein said ring is either unsubstituted or
substituted with one or more substituent(s) independently
selected from the group consisting of halo, hydroxyl,
nitro, trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
wherein the individual ring size is 5-8 members; and
wherein the heterocyclic ring contains 1-6 heteroatom(s)
independently selected from the group consisting of O, N,
and S.
5. The compound of claim 2, wherein the compound is
formula IV:
354
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
A, B, C and D are independently CH2, O, S, SO, SO2, NH
or NR2;
Br is a heterocylic bridged ring moiety, wherein any
two or more of A, B, C and D are bonded to each other
through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
X is O or S;
Z is S, CH2, CHR1 or CR1R3;
R1 and R3 are independently C1-C6 straight or branched
chain alkyl, C2-C6 straight or branched chain alkenyl, or
a bridged ring moiety, wherein said alkyl or alkenyl is
substituted with one or more substituent(s) independently
selected from the group consisting of (Ar1)n, C1-C6 straight
or branched chain alkyl or C2-C6 straight or branched chain
alkenyl substituted with (Ar1)n, C3-C8 cycloalkyl, C1-C6
straight or branched chain alkyl or C2-C6 straight or
branched chain alkenyl substituted with C3-C8 cycloalkyl,
a bridged ring moiety, and Ar2;
n is 1 or 2;
R2 is independently C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, C3-C8
355
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar1, wherein said alkyl, alkenyl, cycloalkyl or
cycloalkenyl is either unsubstituted or substituted with
one or more substituent(s) independently selected from the
group consisting of C3-C8 cycloalkyl, C1-C4 straight or
branched chain alkyl, C2-C4 straight or branched chain
alkenyl, a bridged ring moiety, and hydroxyl; and
Ar1 and Ar2 are independently an alicyclic or
aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic
ring, wherein said ring is either unsubstituted or
substituted with one or more substituent(s) independently
selected from the group consisting of halo, hydroxyl,
vitro, trifluoro-methyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
wherein the individual ring size is 5-8 members; and
wherein the heterocyclic ring contains 1-6 heteroatom(s)
independently selected from the group consisting of O, N,
and S.
6. The compound of claim 1, wherein the compound is
formula V:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
V is CH, N, or S;
A and B, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
356
heterocylic or carbocyclic bridged ring moiety containing
one or more heteroatom(s) independently selected from the
group consisting of O, S, SO, SO2, N, NH, and NR4;
X is either O or S;
Z is either S, CH2, CHR1 or CR1R3;
W and Y are independently O, S, CH2 or H2;
R1 and R3 are independently C1-C6 straight or branched
chain alkyl, C2-C6 straight or branched chain alkenyl, or
a bridged ring moiety, wherein said alkyl or alkenyl is
substituted with one or more substituent(s) independently
selected from the group consisting of (Ar1)n, C1-C6 straight
or branched chain alkyl or C2-C6 straight or branched chain
alkenyl substituted with (Ar1)n, C3-C6 cycloalkyl, C1-C6
straight or branched chain alkyl or C2-C6 straight or
branched chain alkenyl substituted with C3-C6 cycloalkyl,
a bridged ring moiety, and Ar2;
n is 1 or 2;
R2 is independently C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar1, wherein said alkyl, alkenyl, cycloalkyl or
cycloalkenyl is either unsubstituted or substituted with
one or more substituent(s) independently selected from the
group consisting of C1-C4 straight or branched chain alkyl,
C2-C4 straight or branched chain alkenyl, a bridged ring
moiety, and hydroxy;
R4 is independently either C1-C9, straight ar branched
chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar3, wherein R4 is either unsubstituted or substituted with
one or more substituent(s) independently selected from the
group consisting of halo, halo-C1-C6-alkyl, carbonyl,
carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched chain
357
alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy,
thio-C1-C6-alkyl, C1-C6-alkylthio, sulfhydryl, amino, C1-C6-
alkylamino, amino-C1-C6-alkyl, aminocarboxyl, a bridged
ring moiety, and Ar4; and
Ar3 and Ar4 are independently an alicyclic or
aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic
rings wherein the individual ring size is 5-8 members;
wherein said heterocyclic ring contains 1-6 heteroatom(s)
independently selected from the group consisting of O, N,
and S.
7. The compound of claim 1, wherein the compound is
formula VI:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
A and B, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety containing
one or more heteroatom(s) independently selected from the
group consisting of O, S, SO, SO2, N, NH, and NR1;
X is O or S;
Z is O, NH or NR1;
W and Y are independently O, S, CH2 or H2;
R1 is independently C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, or a
bridged ring moiety, which is substituted with one or more
358
substituent(s) independently selected from the group
consisting of (Ar1)n, C1-C6 straight or branched chain alkyl
or C2-C6 straight or branched chain alkenyl substituted
with (Ar1)n, C3-C8 cycloalkyl, C1-C6 straight or branched
chain alkyl or C2-C6 straight or branched chain alkenyl
substituted with C3-C8 cycloalkyl, a bridged ring moiety,
and Ar2;
n is 1 or 2;
R2 is independently either C1-C9 straight or branched
chain alkyl, C2-C9 straight or branched chain or alkenyl,
C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety,
or Ar1, wherein said alkyl, alkenyl, cycloalkyl or
cycloalkenyl is either unsubstituted or substituted with
one or more substituent(s) independently selected from the
group consisting of C1-C4 straight or branched chain alkyl,
C2-C4 straight or branched chain alkenyl, a bridged ring
moiety, and hydroxyl; and
Ar1 and Ar2 are independently an alicyclic or
aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic
ring, wherein the ring is either unsubstituted or
substituted with one or more substituent(s) independently
selected from the group consisting of halo, hydroxyl,
vitro, trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
wherein the individual ring size is 5-8 members; and
wherein the heterocyclic ring contains 1-6 heteroatom(s)
independently selected from the group consisting of O, N,
and S.
8. The compound of claim 7, wherein the compound is
formula VII:
359
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
A, B and C are independently CH2, O, S, SO, SO2, NH or
NR1;
Br is a heterocylic bridged ring moiety, wherein any
two or more of A, B and C are bonded to each other through
either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
R1 is C1-C5 straight or branched chain alkyl, C2-C5
straight or branched chain alkenyl, or a bridged ring
moiety, which is substituted with one or more
substituent(s) independently selected from the group
consisting of (Ar1)n and C1-C6 straight or branched chain
alkyl or C2-C6 straight or branched chain alkenyl
substituted with (Ar1)n;
n is 1 or 2;
R2 is independently either C1-C9 straight or branched
chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar1; and
Ar1 is independently an alicyclic or aromatic, mono-,
bi- or tricyclic, carbo- or heterocyclic ring, wherein the
ring is either unsubstituted or substituted with one or
more substituent(s) independently selected from the group
360
consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6
straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy,
phenoxy, benzyloxy, and amino; wherein the individual ring
size is 5-8 members; and wherein the heterocyclic ring
contains 1-6 heteroatom(s) independently selected from the
group consisting of O, N, and S.
9. The compound of claim 8, wherein the compound is
formula:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
Br is a heterocylic bridged ring moiety, wherein any
two or more of A, B and C are bonded to each other through
either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure.
10. The compound of Claim 8, wherein:
A is CH2;
B is CH2 or S;
C is CH2 or NH;
R1 is selected from the group consisting of 3-
phenylpropyl and 3-(3-pyridyl)propyl; and
R2 is selected from the group consisting of 1,1-
361
dimethylpropyl, cyclohexyl, and tert-butyl.
11. The compound of claim 7, wherein the compound is
formula VIII:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
A, B, C and D are independently CH2, O, S, SO, SO2, NH
or NR1;
Br is a heterocylic bridged ring moiety, wherein any
two or more of A, B, C and D are bonded to each other
through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
R1 is independently C1-C5 straight or branched chain
alkyl, C2-C5 straight or branched chain alkenyl, or a
bridged ring moiety, wherein said alkyl or alkenyl is
substituted with one or more substituent(s) independently
selected from the group consisting of (Ar1)n and C1-C6
straight or branched chain alkyl or C2-C6 straight or
branched chain alkenyl substituted with (Ar1)n;
n is 1 or 2;
R2 is independently either C1-C9 straight or branched
chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
362
Ar1; and
Ar1 is independently an alicyclic or aromatic, mono-,
bi- or tricyclic, carbo- or heterocyclic ring, wherein the
ring is either unsubstituted or substituted with one or
more substituent(s) independently selected from the group
consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6
straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy,
phenoxy, benzyloxy, and amino; wherein the individual ring
size is 5-8 members; and wherein the heterocyclic ring
contains 1-6 heteroatom(s) independently selected from the
group consisting of O, N, and S.
12. The compound of Claim 11, wherein:
A is CH2;
B is CH2;
C is S, O or NH;
D is CH2;
R1 is selected from the group consisting of 3-
phenylpropyl and (3,4,5-trimethoxy)phenylpropyl; and
R2 is selected from the group consisting of 1,1-
dimethylpropyl, cyclohexyl, tert-butyl, phenyl, and 3,4,5-
trimethoxyphenyl.
13. The compound of claim 1, wherein the compound is
formula IX:
<IMG>
363
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
V is CH, N, or S;
A and B, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety containing
one or more heteroatom(s) independently selected from the
group consisting of O, S, SO, SO2, N, NH, and NR;
R is independently C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, C3-C9
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar3, wherein R is independently either unsubstituted or
substituted with one or more substituent(s) independently
selected from the group consisting of halo, halo-C1-C6-
alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl,
C1-C6 straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy,
phenoxy, benzyloxy, thio-C1-C6-alkyl, C1-C6-alkylthio,
sulfhydryl, amino, C1-C6-alkylamino, amino-C1-C6-alkyl,
aminocarboxyl, a bridged ring moiety, and Ar4;
Ar3 and Ar4 are independently an alicyclic or
aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic
ring; wherein the individual ring size is 5-8 members;
wherein said heterocyclic ring contains 1-6 heteroatom(s)
independently selected from the group consisting of O, N,
and S; and
X is O or S;
Z is O, NH or NR1;
W and Y are independently O, S, CH2 or H2;
R1 is independently C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, or a
bridged ring moiety, wherein said alkyl or alkenyl is
substituted with one or more substituent(s) independently
selected from the group consisting of (Ar1)n, C1-C6 straight
364
or branched chain alkyl or C2-C6 straight or branched chain
alkenyl substituted with (Ar1)n, C3-C8 cycloalkyl, C1-C6
straight or branched chain alkyl or C2-C6 straight or
branched chain alkenyl substituted with C3-C8 cycloalkyl,
and Ar2;
n is 1 or 2;
R2 is independently C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain or alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar1, wherein said alkyl, alkenyl, cycloalkyl or
cycloalkenyl is either unsubstituted or substituted with
one or more substituent(s) independently selected from the
group consisting of C1-C4 straight or branched chain alkyl,
C2-C4 straight or branched chain alkenyl, and hydroxyl; and
Ar1 and Ar2 are independently an alicyclic or
aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic
ring, wherein the ring is either unsubstituted or
substituted with one or more substituent(s) independently
selected from the group consisting of halo, hydroxyl,
nitro, trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
wherein the individual ring size is 5-8 members; and
wherein the heterocyclic ring contains 1-6 heteroatom(s)
independently selected from the group consisting of O, N,
and S.
14. The compound of claim 1, wherein the compound is
formula X:
365
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
A and B, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety containing
one or more heteroatom(s) independently selected from the
group consisting of O, S, SO, SO2, N, NH, and NR1;
W is O, S, CH2, or H2;
R is independently C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar1, which is optionally substituted with one or more
substituent(s) independently selected from the group
consisting of C1-C4 alkyl, C2-C4 alkenyl, hydroxy, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, and
Ar2;
Ar1 and Ar2 are independently selected from the group
consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl,
2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-
pyridyl, 4-pyridyl and phenyl, having one or more
substituent(s) independently selected from the group
consisting of hydrogen, halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-
C6 straight or branched chain alkenyl, C2-C4 alkenyloxy,
phenoxy, benzyloxy, and amino;
X is O, NH, NR1, S, CH, CR1, or CR1R3;
366
Y is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl; wherein
said alkyl or alkenyl is optionally substituted with one
or more substituent(s) independently selected from the
group consisting of C1-C6 straight or branched chain alkyl,
C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl,
C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar;
wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or
Ar is optionally substituted with C1-C4 alkyl, C2-C4
alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon
atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or
Ar is optionally replaced with O, NH, NR2, S, SO, or SO2;
R2 is independently selected from the group consisting
of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar
group;
Z is an aromatic amine or a tertiary amine oxidized
to a corresponding N-oxide;
said aromatic amine is selected from the group
consisting of pyridyl, pyrimidyl, quinolinyl, or
isoquinolinyl, which is either unsubstituted or
substituted with one or more substituent(s) independently
selected from the group consisting of halo, hydroxy,
nitro, trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
said tertiary amine is NR4R5R6, wherein R4, R5, and R6
are independently selected from the group consisting of a
bridged ring moiety, or C1-C6 straight or branched chain
alkyl or C2-C6 straight or branched chain alkenyl
367
optionally substituted with one or more substituent(s)
independently selected from the group consisting of C1-C6
straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl
oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl,
cycloalkenyl, or Ar is optionally substituted with C1-C4
alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein
any carbon atom of said alkyl, alkenyl, cycloalkyl,
cycloalkenyl, or Ar is optionally replaced with O, NH, NR1,
S, SO, or SO2;
Ar is independently selected from the group
consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl,
pyridazyl, quinolinyl, and isoquinolinyl; and
R1 and R3 are independently hydrogen, C1-C4 straight or
branched chain alkyl, C3-C4 straight or branched chain
alkenyl or alkynyl, a bridged ring moiety, or Y-Z.
15. The compound of claim 14, wherein the compound
is formula XI:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
E, F, G and J are independently CH2, O, S, SO, SO2, NH
or NR1;
Br is a heterocylic bridged ring moiety, wherein any
two or more of E, F, G and J are bonded to each other
through either
a chemical bond or
368
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
W is O, S, CH2, or H2;
R is independently C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar1, which is optionally substituted with one or more
substituent(s) independently selected from the group
consisting of C1-C4 alkyl, C2-C4 alkenyl, hydroxy, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, and
Ar1;
Ar1 is independently selected from the group
consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl,
2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-
pyridyl, 4-pyridyl, and phenyl, having one or more
substituent(s) independently selected from the group
consisting of hydrogen, halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-
C6 straight or branched chain alkenyl, C2-C4 alkenyloxy,
phenoxy, benzyloxy, and amino;
X is O, NH, NR1, S, CH, CR1, or CR1R3;
Y is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl; wherein
said alkyl or alkenyl is optionally substituted with one
or more substituent(s) independently selected from the
group consisting of C1-C6 straight or branched chain alkyl,
C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl,
C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar;
wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or
Ar is optionally substituted with C1-C4 alkyl, C2-C4
alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon
atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or
Ar is optionally replaced with O, NH, NR2, S, SO, or SO2;
369
R2 is independently selected from the group consisting
of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar
group;
Z is an aromatic amine or a tertiary amine oxidized
to a corresponding N-oxide;
said aromatic amine is pyridyl, pyrimidyl,
quinolinyl, and isoquinolinyl, which is either
unsubstituted or substituted with one or more
substituent(s) independently selected from the group
consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6
straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl, C1-C4 alkoxy, C2-C9 alkenyloxy,
phenoxy, benzyloxy, and amino;
said tertiary amine is NR4R5R6, wherein R4, R5, and R6
are independently selected from the group consisting of C1-
C6 straight or branched chain alkyl, a bridged ring moiety,
and C2-C6 straight or branched chain alkenyl; wherein said
alkyl or alkenyl is optionally substituted with one or
more substituent(s) independently selected from the group
consisting of C1-C6 straight or branched chain alkyl, C2-C6
straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl
oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl,
cycloalkenyl, or Ar is optionally substituted with C1-C4
alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein
any carbon atom of said alkyl, alkenyl, cycloalkyl,
cycloalkenyl, or Ar is optionally replaced with O, NH, NR1,
S, SO, or SO2;
Ar is independently selected from the group
370
consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl,
pyridazyl, quinolinyl, and isoquinolinyl; and
R1 and R3 are independently hydrogen, C1-C4 straight or
branched chain alkyl, C3-C4 straight or branched chain
alkenyl or alkynyl, a bridged ring moiety, or Y-Z.
16. The compound of claim 14, wherein the compound
is formula XII:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
E, F, and G are independently CH2, O, S, SO, SO2, NH
or NR1;
Br is a heterocylic bridged ring moiety, wherein any
two or more of E, F, and G are bonded to each other
through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
W is O, S, CH2, or H2;
R is independently C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar1, which is optionally substituted with one or more
substituent(s) independently selected from the group
consisting of C1-C4 alkyl, C2-C4 alkenyl, hydroxy, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, and
Ar1;
371
Ar1 is independently selected from the group
consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl,
2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-
pyridyl, 4-pyridyl and phenyl, having one or more
substituent(s) independently selected from the group
consisting of hydrogen, halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-
C6 straight or branched chain alkenyl, C2-C4 alkenyloxy,
phenoxy, benzyloxy, and amino;
X is O, NH, NR1, S, CH, CR1, or CR1R3;
Y is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl; wherein
said alkyl or alkenyl is optionally substituted with one
or more substituent(s) independently selected from the
group consisting of C1-C6 straight or branched chain alkyl,
C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl,
C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar;
wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or
Ar is optionally substituted with C1-C4 alkyl, C2-C4
alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon
atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or
Ar is optionally replaced with O, NH, NR1, S, SO, or SO2;
R2 is independently selected from the group consisting
of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar
group;
Z is an aromatic amine or a tertiary amine oxidized
to a corresponding N-oxide;
said aromatic amine is pyridyl, pyrimidyl,
quinolinyl, or isoquinolinyl, which is either
372
unsubstituted or substituted with one or more
substituent(s) independently selected from the group
consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6
straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy,
phenoxy, benzyloxy, and amino;
said tertiary amine is NR4R5R6, wherein R4, R5, and R6
are independently selected from the group consisting of C1-
C6 straight or branched chain alkyl,a bridged ring moiety,
and C2-C6 straight or branched chain alkenyl; wherein said
alkyl or alkenyl is optionally substituted with one or
more substituent(s) independently selected from the group
consisting of C1-C6 straight or branched chain alkyl, C2-C6
straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl
oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl,
cycloalkenyl, or Ar is optionally substituted with C1-C4
alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein
any carbon atom of said alkyl, alkenyl, cycloalkyl,
cycloalkenyl, or Ar is optionally replaced with O, NH, NR1,
S, SO, or SO2;
Ar is independently selected from the group
consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl,
pyridazyl, quinolinyl, and isoquinolinyl; and
R1 and R3 are independently hydrogen, C1-C4 straight or
branched chain alkyl, C3-C4 straight: or branched chain
alkenyl or alkynyl, a bridged ring moiety, or Y-Z.
17. The compound of claim 14, wherein the compound
is formula XIII:
373
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
n is 1, 2, or 3, forming a 5-7 member heterocyclic
ring;
Br is a heterocylic bridged ring moiety, wherein any
two or more atoms of the primary ring (when n is 1, 2, or
3) are bonded to each other through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
W is O, S, CH2, or H2;
R is independently C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar1, which is optionally substituted with one or more
substituent(s) independently selected from the group
consisting of C1-C4 alkyl, C2-C4 alkenyl, hydroxy, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, and
Ar1;
Ar1 is independently selected from the group
consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl,
2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-
pyridyl, 4-pyridyl and phenyl, having one or more
substituent(s) independently selected from the group
consisting of hydrogen, halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-
379
C6 straight or branched chain alkenyl, C2-C4 alkenyloxy,
phenoxy, benzyloxy, and amino;
X is O, NH, NR1, S, CH, CR1, or CR1R3;
Y is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl; wherein
said alkyl or alkenyl is optionally substituted with one
or more substituent(s) independently selected from the
group consisting of C1-C6 straight or branched chain alkyl,
C2-C6 straight or branched .chain alkenyl, C3-C8 cycloalkyl,
C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar;
wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or
Ar is optionally substituted with C1-C4 alkyl, C2-C4
alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon
atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or
Ar is optionally replaced with O, NH, NR2, S, SO, or SO2;
R2 is independently selected from the group consisting
of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar
group;
Z is an aromatic amine or a tertiary amine oxidized
to a corresponding N-oxide;
said aromatic amine is pyridyl, pyrimidyl,
quinolinyl, or isoquinolinyl, which is either
unsubstituted or substituted with one or more
substituent(s) independently selected from the group
consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6
straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy,
phenoxy, benzyloxy, and amino
said tertiary amine is NR4R5R6, wherein R4, R5, and R6
375
are independently selected from the group consisting of C1-
C6 straight or branched chain alkyl, a bridged ring moiety,
and C2-C6 straight or branched chain alkenyl; wherein said
alkyl or alkenyl is optionally substituted with one or
more substituent(s) independently selected from the group
consisting of C1-C6 straight or branched chain alkyl, C2-C6
straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl
oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl,
cycloalkenyl, or Ar is optionally substituted with C1-C4
alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein
any carbon atom of said alkyl, alkenyl, cycloalkyl,
cycloalkenyl, or Ar is optionally replaced with O, NH, NR1,
S, SO, or SO2;
Ar is independently selected from the group
consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl,
pyridazyl, quinolinyl, and isoquinolinyl; and
R1 and R3, independently, are hydrogen, C1-C4 straight
or branched chain alkyl, C3-C4 straight or branched chain
alkenyl or alkynyl, a bridged ring moiety, or Y-Z.
18. The compound of claim 1, wherein the compound is
formula XIV:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
V is CH, N, or S;
A and B, taken together with the atoms to which they
376
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety containing
one or more heteroatom(s) independently selected from the
group consisting of O, S, SO, SO2, N, NH, and NR7;
R7 is independently either C1-C9 straight or branched
chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar3, wherein R7 is either unsubstituted or substituted with
one or more substituent(s) independently selected from the
group consisting of halo, halo-C1-C6-alkyl, carbonyl,
carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched chain
alkenyl, a bridged ring moiety, C1-C4 alkoxy, C2-C4
alkenyloxy, phenoxy, benzyloxy, thio-C1-C6-alkyl, C1-C6-
alkylthio, sulfhydryl, amino, C1-C6-alkylamino, amino-C1-C6-
alkyl, aminocarboxyl, and Ar4;
Ar3 and Ar4 are independently an alicyclic or
aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic
ring; wherein the individual ring size is 5-8 members;
wherein said heterocyclic ring contains 1-6 heteroatom(s)
independently selected from the group consisting of O, N,
and S;
W is O, S, CH2, or H2;
R is independently C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar1, which is optionally substituted with one or more
substituent(s) independently selected from the group
consisting of C1-C4 alkyl, C2-C4 alkenyl, hydroxy, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, and
Ar2;
Ar1 and Ar2 are independently selected from the group
consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl,
2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-
377
pyridyl, 4-pyridyl and phenyl, having one or more
substituent(s) independently selected from the group
consisting of hydrogen, halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-
C6 straight or branched chain alkenyl, C2-C4 alkenyloxy,
phenoxy, benzyloxy, and amino;
X is O, NH, NR2, S, CH, CR1, or CR1R3;
Y is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl; wherein
said alkyl or alkenyl is optionally substituted with one
or more substituent(s) independently selected from the
group consisting of C1-C6 straight or branched chain alkyl,
C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl,
C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar;
wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or
Ar is optionally substituted with C1-C4 alkyl, C2-C4
alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon
atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or
Ar is optionally replaced with O, NH, NR2, S, SO, or SO2;
R2 is independently selected from the group consisting
of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar
group;
Z is an aromatic amine or a tertiary amine oxidized
to a corresponding N-oxide;
said aromatic amine is selected from the group
consisting of pyridyl, pyrimidyl, quinolinyl, or
isoquinolinyl, which is either unsubstituted or
substituted with one or more substituent(s) independently
selected from the group consisting of halo, hydroxy,
378
nitro, trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
said tertiary amine is NR4R5R6, wherein R4, R5, and R6
are independently selected from the group consisting of a
bridged ring moiety, or C1-C6 straight or branched chain
alkyl or C2-C6 straight or branched chain alkenyl
optionally substituted with one or more substituent(s)
independently selected from the group consisting of C1-C6
straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl, C3-C6 cycloalkyl, C5-C7
cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl
oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl,
cycloalkenyl, or Ar is optionally substituted with C1-C4
alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein
any carbon atom of said alkyl, alkenyl, cycloalkyl,
cycloalkenyl, or Ar is optionally replaced with O, NH, NR1,
S, SO, or SO2;
Ar is independently selected from the group
consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl,
pyridazyl, quinolinyl, and isoquinolinyl; and
R1 and R3 are independently hydrogen, C1-C4 straight or
branched chain alkyl, C3-C4 straight or branched chain
alkenyl or alkynyl, a bridged ring moiety, or Y-Z..
19. The compound of claim l, wherein the compound is
formula XV:
<IMG>
379
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
A and B, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety containing
one or more heteroatom(s) independently selected from the
group consisting of O, S, SO, SO2, N, NH, and NR3;
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino,
C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein
any carbon atom of said alkyl or alkenyl is optionally
replaced with O, NH, NR3, S, SO, or SO2;
R3 is independently selected from the group consisting
of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar
group;
Ar is independently an alicyclic or aromatic, mono-,
bi- or tricyclic, carbo- or heterocyclic ring, wherein the
ring is either unsubstituted or substituted with one or
more substituent(s) independently selected from the group
consisting of C1-C6-alkylamino, amido, amino, amino-C1-C6-
alkyl, azo, benzyloxy, C1-C9 straight or branched chain
alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or
branched chain alkenyl, C3-C8 cycloalkyl, C5-C7
380
cycloalkenyl, carbonyl, carboxy, cyano, diazo, C1-C6-ester,
formanilido, halo, halo-C1-C6-alkyl, hydroxy, imino,
isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy,
sulfhydryl, sulfonylsulfoxy, thio, thio-C1-C6-alkyl,
thiocarbonyl, thiocyano, thio-C1-C6-ester, thioformamido,
trifluoromethyl, and carboxylic and heterocyclic moieties;
wherein the individual ring size is 5-8 members; wherein
said heterocyclic ring contains 1-6 heteroatom(s)
independently selected from the group consisting of O, N,
and S; and wherein any aromatic or tertiary alkyl amine is
optionally oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino,
C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein
any carbon atom of said alkyl or alkenyl is optionally
replaced with O, NH, NR3, S, SO, or SO2;
C and D are independently hydrogen, Ar, C1-C6 straight
or branched chain alkyl, or C2-C6 straight or branched
chain alkenyl; wherein said alkyl or alkenyl is optionally
substituted with one or more substituent(s) independently
selected from the group consisting of C3-C8 cycloalkyl, C5-
C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein
said alkyl, alkenyl, cycloalkyl or cycloalkenyl is
optionally substituted with C1-C6-alkyl, C2-C6 alkenyl,
hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-
ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano,
nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl,
sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any
carbon atom of said alkyl or alkenyl is optionally
381
substituted in one or more position(s) with oxygen to form
a carbonyl; or wherein any carbon atom of said alkyl or
alkenyl is optionally replaced with O, NH, NR3, S, SO, or
SO2;
W is O or S; and
U is either O or N, provided that:
when U is O, then R1 is a lone pair of
electrons and R2 is selected from the group
consisting of Ar, C3-C8 cycloalkyl, a bridged
ring moiety, C1-C6 straight or branched chain
alkyl, and C2-C6 straight or branched chain
alkenyl, wherein said alkyl or alkenyl is
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of Ar and C3-C8 cycloalkyl; and
when U is N, then R1 and R2 are
independently selected from the group consisting
of hydrogen, Ar, C3-C10 cycloalkyl, a bridged
ring moiety, C7-C12 bi- or tri-cyclic carbocycle,
C1-C6 straight or branched chain alkyl, and C2-C6
straight or branched chain alkenyl, wherein said
alkyl or alkenyl is substituted with one or more
substituent(s) independently selected from the
group consisting of Ar, a bridged ring moiety,
and C3-C8 cycloalkyl; or R1 and R2 are taken
together to form a heterocyclic 5 or 6 membered
ring selected from the group consisting of
pyrrolidine, imidazolidine, pyrazolidine,
piperidine, and piperazine.
20. The compound of Claim 19 in which Ar is selected
from the group consisting of phenyl, benzyl, naphthyl,
indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl,
pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl,
382
fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl,
pyrazolyl, and thienyl.
21. The compound of claim 19, wherein the compound
is formula XVI:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
E, F, G and J are independently CH2, O, S, SO, SO2,
NH, or NR3;
Br is a heterocylic bridged ring moiety, wherein any
two or more of E, F, G and J are bonded to each other
through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino,
C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein
any carbon atom of said alkyl or alkenyl is optionally
replaced with O, NH, NR3, S, SO, or SO2;
383
R3 is independently selected from the group consisting
of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar
group;
Ar is independently an alicyclic or aromatic, mono-,
bi- or tricyclic, carbo- or heterocyclic ring, wherein the
ring is either unsubstituted or substituted with one or
more substituent(s) independently selected from the group
consisting of C1-C6-alkylamino, amido, amino, amino-C1-C6-
alkyl, azo, benzyloxy, C1-C9 straight or branched chain
alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or
branched chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, carbonyl, carboxy, cyano, diazo, C1-C6-ester,
formanilido, halo, halo-C1-C6-alkyl, hydroxy, imino,
isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy,
sulfhydryl, sulfonylsulfoxy, thio, thio-C1-C6-alkyl,
thiocarbonyl, thiocyano, thio-C1-C6-ester, thioformamido,
trifluoromethyl, and carboxylic and heterocyclic moieties,
including alicyclic and aromatic structures; wherein the
individual ring size is 5-8 members; wherein said
heterocyclic ring contains 1-6 heteroatom(s) independently
selected from the group consisting of O, N, and S; and
wherein any aromatic or tertiary alkyl amine is optionally
oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino,
384
C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein
any carbon atom of said alkyl or alkenyl is optionally
replaced with O, NH, NR3, S, SO, or SO2;
C and D are independently hydrogen, Ar, C1-C6 straight
or branched chain alkyl, or C2-C6 straight or branched
chain alkenyl; wherein said alkyl or alkenyl is optionally
substituted with one or more substituent(s) independently
selected from the group consisting of C3-C8 cycloalkyl, C5-
C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein
said alkyl, alkenyl, cycloalkyl or cycloalkenyl is
optionally substituted with C1-C6-alkyl, C2-C6 alkenyl,
hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-
ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano,
nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl,
sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any
carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with oxygen to form
a carbonyl; or wherein any carbon atom of said alkyl or
alkenyl is optionally replaced with O, NH, NR3, S, SO, or
SO2;
W is O or S; and
U is either O or N, provided that:
when U is O, then R1 is a lone pair of
electrons and R2 is selected from the group
consisting of Ar, C3-C8 cycloalkyl, a bridged
ring moiety, C1-C6 straight or branched chain
alkyl, and C2-C6 straight or branched chain
alkenyl, wherein said alkyl or alkenyl is
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of Ar and C3-C8 cycloalkyl; and
when U is N, then R1 and R2 are,
independently, selected from the group
385
consisting of hydrogen, Ar, a bridged ring
moiety, C3-C10 cycloalkyl, C7-C12 bi- or tri-
cyclic carbocycle, C1-C6 straight or branched
chain alkyl, and C2-C6 straight or branched chain
alkenyl, wherein said alkyl or alkenyl is
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of Ar and C3-C8 cycloalkyl; or
R1 and R2 are taken together to form a
heterocyclic 5 or 6 membered ring selected from
the group consisting of pyrrolidine,
imidazolidine, pyrazolidine, piperidine, and
piperazine.
22. The compound of Claim 21 in which Ar is selected
from the group consisting of phenyl, benzyl, naphthyl,
pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl,
quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl,
oxazolyl, thiazolyl, pyrazolyl, and thienyl.
23. The compound of claim 19, wherein the compound
is formula XVII:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
E, F, and G are independently CH2, O, S, SO, SO2, NH,
and NR3;
Br is a heterocylic bridged ring moiety, wherein any
386
two or more of E, F, and G are bonded to each other
through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino,
C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein
any carbon atom of said alkyl or alkenyl is optionally
replaced with O, NH, NR3, S, SO, or SO2;
R3 is independently selected from the group consisting
of hydrogen, C1-C9 straight or branched chain alkyl, C3-C4
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar
group;
Ar is independently an alicyclic or aromatic, mono-,
bi- or tricyclic, carbo- or heterocyclic ring, wherein the
ring is either unsubstituted or substituted with one or
more substituent(s) independently selected from the group
consisting of C1-C6-alkylamino, amido, amino, amino-C1-C6-
alkyl, azo, benzyloxy, C1-C9 straight or branched chain
alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or
branched chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, carbonyl, carboxy, cyano, diazo, C1-C6-ester,
387
formanilido, halo, halo-C1-C6-alkyl, hydroxy, imino,
isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy,
sulfhydryl, sulfonylsulfoxy, thio, thio-C1-C6-alkyl,
thiocarbonyl, thiocyano, thio-C1-C6-ester, thioformamido,
trifluoromethyl, and carboxylic and heterocyclic moieties,
including alicyclic and aromatic structures; wherein the
individual ring size is 5-8 members; wherein said
heterocyclic ring contains 1-6 heteroatom(s) independently
selected from the group consisting of O, N, and S; and
wherein any aromatic or tertiary alkyl amine is optionally
oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C1-C6-alkenoxy, cyano, nitro, imino,
C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein
any carbon atom of said alkyl or alkenyl is optionally
replaced with O, NH, NR3, S, SO, or SO2;
C and D are independently hydrogen, Ar, C1-C6 straight
or branched chain alkyl, or C2-C6 straight or branched
chain alkenyl; wherein said alkyl or alkenyl is optionally
substituted with one or more substituent(s) independently
selected from the group consisting of C3-C8 cycloalkyl, C5-
C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein
said alkyl, alkenyl, cycloalkyl or cycloalkenyl is
optionally substituted with C1-C6-alkyl, C2-C6 alkenyl,
hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-
ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano,
nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl,
sulfhydryl, thin-C1-C6-alkyl, or sulfonyl; wherein any
carbon atom of said alkyl or alkenyl is optionally
388
substituted in one or more position (s) with oxygen to form
a carbonyl; or wherein any carbon atom of said alkyl or
alkenyl is optionally replaced with O, NH, NR3, S, SO, or
SO2;
W is O or S; and
U is either O or N, provided that:
when U is O, then R1 is a lone pair of
electrons and R2 is selected from the group
consisting of Ar, a bridged ring moiety, C3-C8
cycloalkyl, C1-C6 straight or branched chain
alkyl, and C1-C6 straight or branched chain
alkenyl, wherein said alkyl or alkenyl is
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of Ar and C3-C8 cycloalkyl; and
when U is N, then R1 and R2 are,
independently, selected from the group
consisting of hydrogen, Ar, a bridged ring
moiety, C3-C8 cycloalkyl, C7-C12 bi- or tri-cyclic
carbocycle, C1-C6 straight or branched chain
alkyl, and C2-C6 straight or branched chain
alkenyl, wherein said alkyl or alkenyl is
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of Ar and C3-C8 cycloalkyl; or
R1 and R2 are taken together to form a
heterocyclic 5 or 6 membered ring selected from
the group consisting of pyrrolidine,
imidazolidine, pyrazolidine, piperidine, and
piperazine.
24. The compound of Claim 23 in which Ar is selected
from the group consisting of phenyl, benzyl, naphthyl,
pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl,
389
quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl,
oxazolyl, thiazolyl, pyrazolyl, and thienyl.
25. The compound of claim 19, wherein the compound
is formula XVIII:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
n is 1, 2 or 3;
Br is a heterocylic bridged ring moiety, wherein any
two or more atoms of the primary ring (when n is 1, 2 or
3) are bonded to each other through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino,
C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein
any carbon atom of said alkyl or alkenyl is optionally
replaced with O, NH, NR3, S, SO, or SO2;
R3 is independently selected from the group consisting
390
of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar
group;
Ar is independently an alicyclic or aromatic, mono-,
bi- or tricyclic, carbo- or heterocyclic ring, wherein the
ring is either unsubstituted or substituted with one or
more substituent(s) independently selected from the group
consisting of C1-C6-alkylamino, amido, amino, amino-C1-C6-
alkyl, azo, benzyloxy, C1-C9 straight or branched chain
alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or
branched chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, carbonyl, carboxy, cyano, diazo, C1-C6-ester,
formanilido, halo, halo-C1-C6-alkyl, hydroxy, imino,
isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy,
sulfhydryl, sulfonylsulfoxy, thio, thio-C1-C6-alkyl,
thiocarbonyl, thiocyano, thio-C1-C6-ester, thioformamido,
trifluoromethyl, and carboxylic and heterocyclic moieties,
including alicyclic and aromatic structures; wherein the
individual ring size is 5-8 members; wherein said
heterocyclic ring contains 1-6 heteroatom(s) independently
selected from the group consisting of O, N, and S; and
wherein any aromatic or tertiary alkyl amine is optionally
oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-
C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
391
alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein
any carbon atom of said alkyl or alkenyl is optionally
replaced with O, NH, NR3, S, SO, or SO2;
C and D are independently hydrogen, Ar, C1-C6 straight
or branched chain alkyl, or C2-C6 straight or branched
chain alkenyl; wherein said alkyl or alkenyl is optionally
substituted with one or more substituent(s) independently
selected from the group consisting of C3-C8 cycloalkyl, C5-
C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein
said alkyl, alkenyl, cycloalkyl or cycloalkenyl is
optionally substituted with C1-C6-alkyl, C2-C6 alkenyl,
hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-
ester, thio-C1-C6-ester, alkoxy, C2-C6-alkenoxy, cyano,
nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl,
sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any
carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with oxygen to form
a carbonyl; or wherein any carbon atom of said alkyl or
alkenyl is optionally replaced with O, NH, NR3, S, SO, or
SO2;
W is O or S; and
U is either O or N, provided that:
when U is O, then R1 is a lone pair of
electrons and R2 is selected from the group
consisting of Ar, a bridged ring moiety, C3-C8
cycloalkyl, C1-C6 straight or branched chain
alkyl, and C2-C6 straight or branched chain or
alkenyl, wherein said alkyl or alkenyl is
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of Ar and C3-C8 cycloalkyl; and
when U is N, then R1 and R2 are,
independently, selected from the group
consisting of hydrogen, Ar, a bridged ring
392
moiety, C3-C10 cycloalkyl, C7-C12 bi- or tri-
cyclic carbocycle, C1-C6 straight or branched
chain alkyl, and C2-C6 straight or branched chain
alkenyl, wherein said alkyl or alkenyl is
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of Ar and C3-C8 cycloalkyl; or
R1 and R2 are taken together to form a
heterocyclic 5 or 6 membered ring selected from
the group consisting of pyrrolidine,
imidazolidine, pyrazolidine, piperidine, and
piperazine.
26. The compound of Claim 25 in which Ar is selected
from the group consisting of phenyl, benzyl, naphthyl,
pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl,
quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl,
oxazolyl, thiazolyl, pyrazolyl, and thienyl.
27. The compound of claim 1, wherein the compound is
formula XIX:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
V is CH, N, or S;
A and B, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
393
heterocylic or carbocyclic bridged ring moiety containing
one or more heteroatom(s) independently selected from the
group consisting of O, S, SO, SO2, N, NH, and NR3;
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino,
C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein
any carbon atom of said alkyl or alkenyl is optionally
replaced with O, NH, NR3, S, SO, or SO2;
R3 is independently selected from the group consisting
of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar
group;
Ar is independently an alicyclic or aromatic, mono-,
bi- or tricyclic, carbo- or heterocyclic ring, wherein the
ring is either unsubstituted or substituted with one or
more substituent(s) independently selected from the group
consisting of C1-C6-alkylamino, amido, amino, amino-C1-C6-
alkyl, azo, benzyloxy, C1-C9 straight or branched chain
alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or
branched chain alkenyl, C3-C6 cycloalkyl, C5-C7
cycloalkenyl, carbonyl, carboxy, cyano, diazo, C1-C6-ester,
formanilido, halo, halo-C1-C6-alkyl, hydroxy, imino,
isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy,
sulfhydryl, sulfonylsulfoxy, thin, thio-C1-C6-alkyl,
394
thiocarbonyl, thiocyano, thio-C1-C6-ester, thioformamido,
trifluoromethyl, and carboxylic and heterocyclic moieties;
wherein the individual ring size is 5-8 members; wherein
said heterocyclic ring contains 1-6 heteroatom(s)
independently selected from the group consisting of O, N,
and S; and wherein any aromatic or tertiary alkyl amine is
optionally oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C1-C6-alkenoxy, cyano, nitro, imino,
C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein
any carbon atom of said alkyl or alkenyl is optionally
replaced with O, NH, NR3, S, SO, or SO2;
C and D are independently hydrogen, Ar, C1-C6 straight
or branched chain alkyl, or C2-C6 straight or branched
chain alkenyl; wherein said alkyl or alkenyl is optionally
substituted with one or more substituent(s) independently
selected from the group consisting of C3-C8 cycloalkyl, C5-
C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein
said alkyl, alkenyl, cycloalkyl or cycloalkenyl is
optionally substituted with C1-C6-alkyl, C2-C6 alkenyl,
hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-
ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano,
nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl,
sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any
carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with oxygen to form
a carbonyl; or wherein any carbon atom of said alkyl or
alkenyl is optionally replaced with O, NH, NR3, S, SO, or
SO2;
395
W is O or S; and
U is either O or N, provided that:
when U is O, then R1 is a lone pair of
electrons and R2 is selected from the group
consisting of Ar, C3-C8 cycloalkyl, a bridged
ring moiety, C1-C6 straight or branched chain
alkyl, and C2-C6 straight or branched chain
alkenyl, wherein said alkyl or alkenyl is
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of Ar and C3-C8 cycloalkyl; and
when U is N, then R1 and R2 are
independently selected from the group consisting
of hydrogen, Ar, C3-C10 cycloalkyl, a bridged
ring moiety, C7-C12 bi- or tri-cyclic carbocycle,
C1-C6 straight or branched chain alkyl, and C2-C6
straight or branched chain alkenyl, wherein said
alkyl or alkenyl is substituted with one or more
substituent(s) independently selected from the
group consisting of Ar, a bridged ring moiety,
and C3-C8 cycloalkyl; or R1 and R2 are taken
together to form a heterocyclic 5 or 6 membered
ring selected from the group consisting of
pyrrolidine, imidazolidine, pyrazolidine,
piperidine, and piperazine.
Y is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino,
C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein
any carbon atom of said alkyl or alkenyl is optionally
396
replaced with O, NH, NR3, S, SO, or SO2.
28. The compound of claim 1, wherein the compound is
formula XX:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
A and B, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety containing
one or more heteroatom(s) independently selected from the
group consisting of O, S, SO, SO2, N, NH, and NR2;
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C2-C6-ester,
C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-
alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl,
sulfonyl, or oxygen to form a carbonyl, or wherein any
carbon atom of said alkyl or alkenyl is optionally
replaced with O, NH, NR3, S, SO, or SO2;
R2 is independently selected from the group consisting
of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
alkyl or alkenyl chain containing said heteroatom to form
397
a ring, wherein said ring is optionally fused to an Ar
group;
Ar is independently an alicyclic or aromatic, mono-,
bi- or tricyclic, carbo- or heterocyclic ring, wherein the
ring is either unsubstituted or substituted with one or
more substituent(s); wherein the individual ring size is
5-8 members; wherein the heterocyclic ring contains 1-6
heteroatom(s) independently selected from the group
consisting of O, N, and S; wherein any aromatic or
tertiary alkyl amine is optionally oxidized to a
corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino,
C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein
any atom of said alkyl or alkenyl is optionally replaced
with O, NH, NR2, S, SO, or SO2;
C and D are independently hydrogen, Ar, C1-C6 straight
or branched chain alkyl, or C2-C6 straight or branched
chain alkenyl; wherein said alkyl or alkenyl is optionally
substituted with one or more substituent(s) independently
selected from the group consisting of C3-C8 cycloalkyl, C5-
C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein
said alkyl, alkenyl, cycloalkyl or cycloalkenyl is
optionally substituted with C1-C6-alkyl, C2-C6 alkenyl,
hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-
ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano,
nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl,
sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any
carbon atom of said alkyl or alkenyl is optionally
398
substituted in one or more position(s) with oxygen to form
a carbonyl; or wherein any carbon atom of said alkyl or
alkenyl is optionally replaced with O, NH, NR2, S, SO, or
SO2; and
R1 is independently selected from the group consisting
of Ar, a bridged ring moiety, C3-C8 cycloalkyl, C1-C6
straight or branched chain alkyl, and C2-C6 straight or
branched chain alkenyl, wherein said alkyl or alkenyl is
optionally substituted with one or more substituent(s)
independently selected from the group consisting of Ar, a
bridged ring moiety, C3-C8 cycloalkyl, amino, halo, halo-C1-
C6-alkyl, hydroxy, trifluoromethyl, C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched chain
alkenyl, carbonyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino,
C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
alkyl, and sulfonyl, wherein any carbon atom of said alkyl
or alkenyl is optionally replaced with O, NH, NR3, S, SO,
or SO2.
29. The compound of claim 28 in which Ar is selected
from the group consisting of phenyl, benzyl, naphthyl,
indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl,
pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl,
fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl,
pyrazolyl, and thienyl.
30. The compound of Claim 29 in which A and B,
together with the nitrogen and carbon atoms to which they
are respectfully attached, form a 6 membered saturated or
unsaturated bridged heterocyclic ring; and R2 is C4-C7
branched chain alkyl, C4-C7 cycloalkyl, phenyl, or 3,4,5-
trimethoxyphenyl.
399
31. The compound of claim 28, wherein the compound
is formula XXI:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
E, F, G and J are independently CH2, O, S, SO, SO2, NH
or NR2;
Br is a heterocylic bridged ring moiety, wherein any
two or more of E, F, G and J are bonded to each other
through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure:
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino,
C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein
any carbon atom of said alkyl or alkenyl is optionally
replaced with O, NH, NR2, S, SO, or SO2;
R2 is independently selected from the group consisting
of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
400
formed between the nitrogen and a carbon atom of said
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar
group;
Z is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino,
C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein
any atom of said alkyl or alkenyl is optionally replaced
with O, NH, NR2, S, SO, or SO2;
Ar is independently an alicyclic or aromatic, mono-,
bi- or tricyclic, carbo- or heterocyclic ring, wherein the
ring is either unsubstituted or substituted with one or
more substituent(s); wherein the individual ring size is
5-8 members; wherein the heterocyclic ring contains 1-6
heteroatom(s) independently selected from the group
consisting of O, N, and S; wherein any aromatic or
tertiary alkyl amine is optionally oxidized to a
corresponding N-oxide;
C and D are independently hydrogen, Ar, C1-C6 straight
or branched chain alkyl, or C2-C6 straight or branched
chain alkenyl; wherein said alkyl or alkenyl is optionally
substituted with one or more substituent(s) independently
selected from the group consisting of C3-C8 cycloalkyl, C5-
C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein
said alkyl, alkenyl, cycloalkyl or cycloalkenyl is
optionally substituted with C1-C6-alkyl, C2-C6 alkenyl,
hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-
ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano,
vitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl,
401
sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any
carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with oxygen to form
a carbonyl; or wherein any carbon atom of said alkyl or
alkenyl is optionally replaced with O, NH, NR2, S, SO, or
SO2; and
R1 is independently selected from the group consisting
of Ar, a bridged ring moiety, C3-C8 cycloalkyl, C1-C6
straight or branched chain alkyl, and C2-C6 straight or
branched chain alkenyl, wherein said alkyl or alkenyl is
optionally substituted with one or more substituent(s)
independently selected from the group consisting of Ar, a
bridged ring moiety, C3-C8 cycloalkyl, amino, halo, halo-C1-
C6-alkyl, hydroxy, trifluoromethyl, C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched chain
alkenyl, carbonyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino,
C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
alkyl, and sulfonyl, wherein any carbon atom of said alkyl
or alkenyl is optionally replaced with O, NH, NR3, S, SO,
or SO2.
32. The compound of Claim 31 in which Ar is selected
from the group consisting of phenyl, benzyl, naphthyl,
indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl,
pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl,
fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl,
pyrazolyl, and thienyl.
33. The compound of claim 28, wherein the compound
is formula XXII:
402
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
E, F, and G are independently CH2, O, S, SO, SO2, NH
or NR2;
Br is a heterocylic bridged ring moiety, wherein any
two or more of E, F, and G are bonded to each other
through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo- (C1-C6) -alkyl, thiocarbonyl, (C1-C6) -ester, thio- (C1-
C6) -ester, (C1-C6) -alkoxy, (C2-C6) -alkenoxy, cyano, nitro,
imino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, sulfhydryl,
thio- (C1-C6) -alkyl, sulfonyl, or oxygen to form a carbonyl,
or wherein any carbon atom of said alkyl or alkenyl is
optionally replaced with O, NH, NR2, S, SO, or SO2;
R2 is independently selected from the group consisting
of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
403
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar
group;
Ar is independently an alicyclic or aromatic, mono-,
bi- or tricyclic, carbo- or heterocyclic ring, wherein the
ring is either unsubstituted or substituted with one or
more substituent(s); wherein the individual ring size is
5-8 members; wherein the heterocyclic ring contains 1-6
heteroatom(s) independently selected from the group
consisting of O, N, and S; wherein any aromatic or
tertiary alkyl amine is optionally oxidized to a
corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo- (C1-C6) -alkyl, thiocarbonyl, (C1-C6)-ester, thio- (C1-
C6) -ester, (C1-C6) -alkoxy, (C2-C6) -alkenoxy, cyano, nitro,
imino, (C1-C6) -alkyl amino, amino- (C1-C6) -alkyl, sulfhydryl,
thio- (C1-C6) -alkyl, sulfonyl, or oxygen to form a carbonyl,
or wherein any atom of said alkyl or alkenyl is optionally
replaced with O, NH, NR2, S, SO, or SO2;
C and D are independently hydrogen, Ar, C1-C6 straight
or branched chain alkyl, or C2-C6 straight or branched
chain alkenyl, wherein said alkyl or alkenyl is optionally
substituted with one or more substituent(s) independently
selected from the group consisting of C3-C8 cycloalkyl, C5-
C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein
said alkyl, alkenyl, cycloalkyl or cycloalkenyl is
optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, or
hydroxy; wherein any carbon atom of said alkyl or alkenyl
is optionally substituted in one or more position(s) with
oxygen to form a carbonyl, or wherein any carbon atom of
said alkyl or alkenyl is optionally replaced with O, NH,
404
NR2, S, SO, or SO2; and
R1 is independently selected from the group consisting
of Ar, a bridged ring moiety, C3-C8 cycloalkyl, C1-C6
straight or branched chain alkyl, and C2-C6 straight or
branched chain alkenyl, wherein said alkyl or alkenyl is
optionally substituted with one or more substituent(s)
independently selected from the group consisting of Ar, a
bridged ring moiety, C3-C8 cycloalkyl, amino, halo, halo-
(C1-C6) -alkyl, hydroxy, trifluoromethyl, C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched chain
alkenyl, carbonyl, thiocarbonyl, (C1-C6) -ester, thio- (C1-
C6) -ester, (C1-C6) -alkoxy, (C2-C6) -alkenoxy, cyano, nitro,
imino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, sulfhydryl,
thio-(C1-C6)-alkyl, and sulfonyl, wherein any carbon atom
of said alkyl or alkenyl is optionally replaced with O,
NH, NR3, S, SO, or SO2.
34. The compound of Claim 33 in which Ar is selected
from the group consisting of phenyl, benzyl, naphthyl,
indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl,
pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl,
fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl,
pyrazolyl, and thienyl.
35. The compound of claim 28, wherein the compound
is formula XXIII:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
405
n is 1, 2 or 3;
Br is a heterocylic bridged ring moiety, wherein any
two or more atoms of the primary ring (when n is 1, 2 or
3) are bonded to each other through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure:
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo- (C1-C6) -alkyl, thiocarbonyl, (C1-C6) -ester, thio- (C1-
C6) -ester, (C1-C6) -alkoxy, (C2-C6) -alkenoxy, cyano, nitro,
imino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, sulfhydryl,
thio- (C1-C6) -alkyl, sulfonyl, or oxygen to form a carbonyl,
or wherein any carbon atom of said alkyl or alkenyl is
optionally replaced with O, NH, NR2, S, SO, or SO2;
Z is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo- (C1-C6) -alkyl, thiocarbonyl, (C1-C6) -ester, thio- (C1-
C6) -ester, (C1-C6) -alkoxy, (C2-C6) -alkenoxy, cyano, nitro,
imino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, sulfhydryl,
thio- (C1-C6) -alkyl, sulfonyl, or oxygen to form a carbonyl,
or wherein any atom of said alkyl or alkenyl is optionally
replaced with O, NH, NR2, S, SO, or SO2;
R2 is independently selected from the group consisting
of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
406
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar
group;
Ar is independently an alicyclic or aromatic, mono-,
bi- or tricyclic, carbo- or heterocyclic ring, wherein the
ring is either unsubstituted or substituted with one or
more substituent(s); wherein the individual ring size is
5-8 members; wherein the heterocyclic ring contains 1-6
heteroatom(s) independently selected from the group
consisting of O, N, and S; wherein any aromatic or
tertiary alkyl amine is optionally oxidized to a
corresponding N-oxide;
C and D are independently hydrogen, Ar, C1-C6 straight
or branched chain alkyl, or C2-C6 straight or branched
chain alkenyl, wherein said alkyl or alkenyl is optionally
substituted with one or more substituent(s) independently
selected from the group consisting of C3-C8 cycloalkyl, C5-
C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein
said alkyl, alkenyl, cycloalkyl or cycloalkenyl is
optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, or
hydroxy; wherein any carbon atom of said alkyl or alkenyl
is optionally substituted in one or more position(s) with
oxygen to form a carbonyl, or wherein any carbon atom of
said alkyl or alkenyl is optionally replaced with O, NH,
NR2, S, SO, or SO2; and
R1 is independently selected from the group consisting
of Ar, a bridged ring moiety, C3-C6 cycloalkyl, C1-C6
straight or branched chain alkyl, and C2-C6 straight or
branched chain alkenyl, wherein said alkyl or alkenyl is
optionally substituted with one or more substituent(s)
independently selected from the group consisting of Ar, a
bridged ring moiety, C3-C8 cycloalkyl, amino, halo, halo-
(C1-C6)-alkyl, hydroxy, trifluoromethyl, C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched chain
407
alkenyl, carbonyl, thiocarbonyl, (C1-C6)-ester, thio-(C1-
C6)-ester, (C1-C6)-alkoxy, (C2-C6)-alkenoxy, cyano, nitro,
imino, (C1-C6)-alkylamino, amino-(C1-C6)-alkyl, sulfhydryl,
thio-(C1-C6)-alkyl, and sulfonyl, wherein any carbon atom
of said alkyl or alkenyl is optionally replaced with O,
NH, NR3, S, SO, or SO2.
36. The compound of Claim 35 in which Ar is selected
from the group consisting of phenyl, benzyl, naphthyl,
indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl,
pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl,
fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl,
pyrazolyl, and thienyl.
37. The compound of claim 1, wherein the compound is
formula XXIV:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
V is CH, N, or S;
A and B, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety containing
one or more heteroatom(s) independently selected from the
group consisting of O, S, SO, SO2, N, NH, and NR2;
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain
408
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester,
C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-
alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl,
sulfonyl, or oxygen to form a carbonyl, or wherein any
carbon atom of said alkyl or alkenyl is optionally
replaced with O, NH, NR3, S, SO, or SO2;
R2 is independently selected from the group consisting
of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar
group;
Ar is independently an alicyclic or aromatic, mono-,
bi- or tricyclic, carbo- or heterocyclic ring, wherein the
ring is either unsubstituted or substituted with one or
more substituent(s); wherein the individual ring size is
5-8 members; wherein the heterocyclic ring contains 1-6
heteroatom(s) independently selected from the group
consisting of O, N, and S; wherein any aromatic or
tertiary alkyl amine is optionally oxidized to a
corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain
alkyl, or C2-C6 straight or branched chain alkenyl, wherein
any carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with amino, halo,
halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino,
C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein
409
any atom of said alkyl or alkenyl is optionally replaced
with O, NH, NR2, S, SO, or SO2;
C and D are independently hydrogen, Ar, C1-C6 straight
or branched chain alkyl, or C2-C6 straight or branched
chain alkenyl; wherein said alkyl or alkenyl is optionally
substituted with one or more substituent(s) independently
selected from the group consisting of C3-C8 cycloalkyl, C5-
C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein
said alkyl, alkenyl, cycloalkyl or cycloalkenyl is
optionally substituted with C1-C6-alkyl, C2-C6 alkenyl,
hydroxy, amino, halo, halo-C1-C6-alkyl., thiocarbonyl, C1-C6-
ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano,
nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl,
sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any
carbon atom of said alkyl or alkenyl is optionally
substituted in one or more position(s) with oxygen to form
a carbonyl; or wherein any carbon atom of said alkyl or
alkenyl is optionally replaced with O, NH, NR2, S, SO, or
SO2; and
R1 is independently selected from the group consisting
of Ar, a bridged ring moiety, C3-C8 cycloalkyl, C1-C6
straight or branched chain alkyl, and C2-C6 straight or
branched chain alkenyl, wherein said alkyl or alkenyl is
optionally substituted with one or more substituent(s)
independently selected from the group consisting of Ar, a
bridged ring moiety, C3-C8 cycloalkyl, amino, halo, halo-C1-
C6-alkyl, hydroxy, trifluoromethyl, C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched chain
alkenyl, carbonyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-
ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino,
C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-
alkyl, and sulfonyl, wherein any carbon atom of said alkyl
or alkenyl is optionally replaced with O, NH, NR3, S, SO,
or SO2.
410
38. The compound of claim 1, wherein the compound is
formula XXV:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
Br is a heterocylic bridged ring moiety, wherein any
two or more atoms of the primary ring (when t is 1, 2 or
3) are bonded to each other through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
R1 is independently C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar1, wherein said R1 is unsubstituted or substituted with
one or more substituents independently selected from the
group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, hydroxy, a bridged ring
moiety, and Ar2;
Ar1 and Ar2 are independently selected from the group
consisting of 1-napthyl, 2-napthyl, 2-indolyl, 3-indolyl,
2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-
pyridyl, 4-pyridyl and phenyl, wherein said Ar1 is
unsubstituted or substituted with one or more
substituent(s) independently selected from the group
consisting of hydrogen, halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-
411
C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4
alkenyloxy, phenoxy, benzyloxy, and amino;
X is O, S, CH2 or H2;
Y is O or NR2, wherein R2 is a direct bond to a Z,
hydrogen or C1-C6 alkyl; and
each Z, independently, is C1-C6 straight or branched
chain alkyl, or C2-C6 straight or branched chain alkenyl,
wherein said Z is substituted with one or more
substituent(s) independently selected from the group
consisting of Ar1, C3-C8 cycloalkyl, and C1-C6 straight or
branched chain alkyl or C2-C6 straight or branched chain
alkenyl substituted with C3-C8 cycloalkyl; or Z is the
fragment
<IMG>
wherein:
R3 is independently C1-C9 straight or branched chain
alkyl which is unsubstituted or substituted with C3-C8
cycloalkyl,a bridged ring moiety, or Ar1;
X2 is O or NR5, wherein R5 is independently selected
from the group consisting of hydrogen, C1-C6 straight or
branched chain alkyl, and C2-C6 straight or branched chain
alkenyl;
R4 is independently selected from the group consisting
of phenyl, benzyl, C1-C5 straight or branched chain alkyl,
C2-C5 straight or branched chain alkenyl, a bridged ring
moiety, C1-C5 straight or branched chain alkyl substituted
with phenyl, and C2-C5 straight or branched chain alkenyl
substituted with phenyl;
n is 1 or 2, and;
t is 1, 2 or 3.
412
39. The compound of claim 38, wherein the compound
is formula XXVI:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
Br is a heterocylic bridged ring moiety, wherein any
two or more atoms of the pyrrolidine ring are bonded to
each other through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
R1 is independently C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar1, wherein said R1 is unsubstituted or substituted with
one or more substituents independently selected from the
group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, hydroxy, a bridged ring
moiety, and Ar2;
Ar1 and Ar2 are independently selected from the group
consisting of 1-napthyl, 2-napthyl, 2-indolyl, 3-indolyl,
2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-
pyridyl, 4-pyridyl and phenyl, wherein said Ar1 is
unsubstituted or substituted with one or more
substituent(s) independently selected from the group
consisting of hydrogen, halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-
413
C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4
alkenyloxy, phenoxy, benzyloxy, and amino;
Z is C1-C6 straight or branched chain alkyl, or C2-C6
straight or branched chain alkenyl, wherein said Z is
substituted with one or more substituent(s) independently
selected from the group consisting of Ar1, C3-C8 cycloalkyl,
and C1-C6 straight or branched chain alkyl or C2-C6 straight
or branched chain alkenyl substituted with C3-C8
cycloalkyl; or Z is the fragment
<IMG>
wherein:
R3 is independently C1-C9 straight or branched chain
alkyl which is unsubstituted or substituted with C3-C8
cycloalkyl, a bridged ring moiety, or Ar1;
X2 is 0 or NR5, wherein R5 is independently selected
from the group consisting of hydrogen, C1-C6 straight or
branched chain alkyl, and C2-C6 straight or branched chain
alkenyl; and
R4 is independently selected from the group consisting
of phenyl, benzyl, C1-C5 straight or branched chain alkyl,
C2-C5 straight or branched chain alkenyl, a bridged ring
moiety, C1-C5 straight or branched chain alkyl substituted
with phenyl, and C2-C5 straight or branched chain alkenyl
substituted with phenyl.
40. The compound of claim 38, wherein the compound
is formula XXVII:
414
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
Br is a heterocylic bridged ring moiety, wherein any
two or more atoms of the pyrrolidine ring are bonded to
each other through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
Z1 is the fragment
<IMG>
wherein:
R3 is independently C1-C9 straight or branched chain
alkyl or unsubstituted Ar1, wherein said alkyl is
unsubstituted or substituted with C3-C8 cycloalkyl, a
bridged ring moiety, or Ar1;
X2 is O or NR5, wherein R5 is independently selected
from the group consisting of hydrogen, C1-C6 straight or
branched chain alkyl, and C2-C6 straight or branched chain
alkenyl;
R4 is independently selected from the group consisting
of phenyl, benzyl, C1-C5 straight or branched chain alkyl,
C2-C5 straight or branched chain alkenyl, a bridged ring
moiety, C1-C5 straight or branched chain alkyl substituted
415
with phenyl, and C2-C5 straight or branched chain alkenyl
substituted with phenyl; and
Ar1 is selected from the group consisting of 1-
napthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-
furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-
pyridyl and phenyl, wherein said Ar1 is unsubstituted or
substituted with one or more substituent(s) independently
selected from the group consisting of hydrogen, halo,
hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched
chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino.
41. The compound of claim 38, wherein the compound
is formula XXVIII:
<IMG>
wherein:
Br is a heterocylic bridged ring moiety, wherein any
two or more atoms of the pyrrolidine ring are bonded to
each other through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
R1 is independently C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl, C3-C6
cycloalkyl, a bridged ring moiety, or Ar1, wherein said
alkyl or alkenyl is unsubstituted or substituted with C3-C6
cycloalkyl or Ar2;
416
Ar1 and Ar2 are independently selected from the group
consisting of 2-furyl, 2-thienyl, and phenyl;
X is selected from the group consisting of oxygen and
sulfur;
Y is oxygen or NR2, wherein R2 is independently a
direct bond to a Z, hydrogen or C1-C6 alkyl;
each Z, independently, is hydrogen, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or branched chain
alkenyl, wherein said Z is substituted with one or more
substituent(s) independently selected from the group
consisting of 2-furyl, 2-thienyl, C3-C6 cycloalkyl,
pyridyl, and phenyl, each having one or more
substituent(s) independently selected from the group
consisting of hydrogen and C1-C4 alkoxy; and
n is 1 or 2.
42. The compound of claim 1, wherein the compound is
formula XXIX:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
V is CH, N, or S;
A and B, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety containing
one or more heteroatom(s) independently selected from the
group consisting of O, S, SO, SO2, N, NH, and NR;
R is independently either C1-C9 straight or branched
417
chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar1, wherein R is independently either unsubstituted of
substituted with one or more substituent(s) independently
selected from the group consisting of halo, halo-(C1-C6)-
alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl,
C1-C6 straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl, C1-C9 alkoxy, C2-C4 alkenyloxy,
phenoxy, benzyloxy, thio- (C1-C6) -alkyl, alkylthio,
sulfhydryl, amino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl,
aminocarboxyl, a bridged ring moiety, and Ar2;
R1 is independently C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar1, wherein said R1 is unsubstituted or substituted with
one or more substituents independently selected from the
group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, hydroxy, a bridged ring
moiety, and Ar2;
Ar1 and Ar2 are independently an alicyclic or
aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic
ring, wherein the ring is either unsubstituted or
substituted with one or more substituent(s); wherein the
individual ring size is 5-8 members; wherein said
heterocyclic ring contains 1-6 heteroatom(s) independently
selected from the group consisting of O, N, and S;
X is O, S, CH2 or H2;
Y is O or NR2, wherein R2 is a direct bond to a Z,
hydrogen or C1-C6 alkyl; and
each Z, independently, is C1-C6 straight or branched
chain alkyl, or C2-C6 straight or branched chain alkenyl,
wherein said Z is substituted with one or more
substituent(s) independently selected from the group
consisting of Ar1, C3-C8 cycloalkyl, and C1-C6 straight or
418
branched chain alkyl or C2-C6 straight or branched chain
alkenyl substituted with C3-C8 cycloalkyl; or Z is the
fragment
<IMG>
wherein:
R3 is independently C1-C9 straight or branched chain
alkyl which is unsubstituted or substituted with C3-C8
cycloalkyl, a bridged ring moiety, or Ar1;
X2 is O or NR5, wherein R5 is independently selected
from the group consisting of hydrogen, C1-C6 straight or
branched chain alkyl, and C2-C6 straight or branched chain
alkenyl; and
R4 is independently selected from the group consisting
of phenyl, benzyl, C1-C5 straight or branched chain alkyl,
C2-C5 straight or branched chain alkenyl, a bridged ring
moiety, C1-C5 straight or branched chain alkyl substituted
with phenyl, and C2-C5 straight or branched chain alkenyl
substituted with phenyl; and,
n is 1 or 2.
43. The compound of claim 1, wherein the compound is
formula LV:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
m is 0-3;
419
A is CH2, O, NH, or N- (C1-C4 alkyl);
B and D are independently hydrogen, a bridged ring
moiety, Ar, C5-C7 cycloalkyl substituted C1-C6 straight or
branched chain alkyl or C2-C6 straight or branched chain
alkenyl, C5-C7 cycloalkenyl substituted C1-C6 straight or
branched chain alkyl or C2-C6 straight or branched chain
alkenyl, or Ar substituted C1-C6 straight or branched chain
alkyl or C2-C6 straight or branched chain alkenyl, wherein
in each case, one or two carbon atom(s) of said alkyl or
alkenyl may be substituted with one or two heteroatom(s)
independently selected from the group consisting of
oxygen, sulfur, SO, and SO2 in chemically reasonable
substitution patterns, or the fragment
<IMG>
wherein Q is hydrogen, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl; and
T is Ar or C5-C7 cycloalkyl substituted at
positions 3 and 4 with substituents
independently selected from the group consisting
o f hydrogen, hydroxy, O-(C1-C4 alkyl), 0-(C2-C4
alkenyl), and carbonyl;
Ar is independently selected from the group
consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-
thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and
phenyl, monocyclic and bicyclic heterocyclic ring systems
with individual ring sizes being 5 or 6 which contain in
either or both rings a total of 1-4 heteroatom(s)
independently selected from the group consisting of
oxygen, nitrogen and sulfur; wherein Ar contains 1-3
substituent(s) independently selected from the group
420
consisting of hydrogen, halo, hydroxy, hydroxymethyl,
nitro, CF3, trifluoromethoxy, C1-C6 straight or branched
chain alkyl, C2-C6 straight or branched chain alkenyl, O-
(C1-C4 straight or branched chain alkyl) , O-(C2-C4 straight
or branched chain alkenyl), O-benzyl, O-phenyl, amino,
1,2-methylenedioxy, carbonyl, and phenyl;
L is either hydrogen or U; M is either oxygen or CH-
U, provided that if L is hydrogen, then M is CH-U, or if
M is oxygen then L is U;
U is hydrogen, O-(C1-C4 straight or branched chain
alkyl), O-(C2-C4 straight or branched chain alkenyl), C1-C6
straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl
substituted with C1-C4 straight or branched chain alkyl or
C2-C4 straight or branched chain alkenyl, (C1-C4 alkyl or
C2-C4 alkenyl)-Ar, or Ar;
J is hydrogen, C1 or C2 alkyl, or benzyl;
K is C1-C4 straight or branched chain alkyl, benzyl or
cyclohexylmethyl; or
J and K, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety which is
substituted with oxygen, sulfur, SO, or SO2.
44. The compound of claim 43, wherein the compound
is formula LVI:
<IMG>
421
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
A is O, NH, or N- (C1-C4 alkyl);
B is hydrogen, CHL-Ar, C1-C6 straight or branched
chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7
cycloalkyl, C5-C7 cycloalkenyl, Ar substituted C1-C6 alkyl
or C2-C6 alkenyl, or
<IMG>
wherein L and Q are independently hydrogen, C1-C6
straight or branched chain alkyl, or C2-C6 straight or
branched chain alkenyl; and
T is Ar or C5-C7 cyclohexyl substituted at positions
3 and 4 with substituents independently selected from the
group consisting of hydrogen, hydroxy, O-(C1-C4 alkyl), O-
(C2-C4 alkenyl), and carbonyl;
Ar is independently selected from the group
consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-
thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having
1-3 substituent(s) independently selected from the group
consisting of hydrogen, halo, hydroxy, nitro, CF3, C1-C6
straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl, O- (C1-C4 straight or branched chain
alkyl), O-(C2-C4 straight or branched chain alkenyl), O-
benzyl, O-phenyl, amino, and phenyl.
D is hydrogen or U; E is oxygen or CH-U, provided
that if D is hydrogen, then E is CH-U, or if E is oxygen,
then D is U;
U is hydrogen, O-(C1-C4 straight or branched chain
alkyl), O-(C2-C4 straight or branched chain alkenyl), C1-C6
straight or branched chain alkyl, C2-C6 straight or
422
branched chain alkenyl, C5-C7-cycloalkyl, C5-C7 cycloalkenyl
substituted with C1-C4 straight or branched chain alkyl or
C2-C4 straight or branched chain alkenyl, 2-indolyl, 3-
indolyl, (C1-C4 alkyl or C2-C4 alkenyl) -Ar, or Ar;
J is hydrogen, C1 or C2 alkyl, or benzyl;
K is C1-C4 straight or branched chain alkyl, benzyl or
cyclohexylethyl; or
J and K, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety which is
substituted with oxygen, sulfur, SO, or SO2.
45. The compound of claim 93, wherein the compound
is Formula LVII:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
n is 2;
Br is a heterocylic bridged ring moiety, wherein any
two or more atoms of the piperidine ring (when n=2) are
bonded to each other through either
a chemical bond or
atoms) other than a bond
which do(es) not comprise a part of the primary ring
structure;
D is phenyl, methoxy, 2-furyl, or 3,4,5-
trimethoxyphenyl; and
B is benzyl, 3-phenylpropyl, 4-(4-
423
methoxyphenyl)butyl, 4-phenylbutyl, phenethyl, 3-
cyclohexylpropyl, 4-cyclohexylbutyl, 3-cyclopentylpropyl,
4-cyclohexylbutyl, 3-phenoxybenzyl, 3-(3-indolyl)propyl,
or 4-(4-methoxyphenyl)butyl.
46. The compound of claim 1, wherein the compound is
formula LVIII:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
V is CH, N, or S;
R is independently either C1-C9 straight or branched
chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar1, wherein R is independently either unsubstituted of
substituted with one or more substituent(s) independently
selected from the group consisting of halo, halo (C1-C6) -
alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl,
C1-C6 straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl, C1-C6 alkoxy, C2-C4 alkenyloxy,
phenoxy, benzyloxy, thio- (C1-C6) -alkyl, (C1-C6) -alkylthio,
sulfhydryl, amino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl,
aminocarboxyl, a bridged ring moiety, and Ar2;
Ar1 and Ar2 are independently an alicyclic or
aromatiC7 mono-, bi- or tricycliC7 carbo- or heterocyclic
ring; wherein the individual ring size is 5-8 members;
wherein said heterocyclic ring contains 1-6 heteroatom(s)
independently selected from the group consisting of O, N,
424
and S;
m is 0-3;
A is CH2, O, NH, or N- (C1-C4 alkyl);
B and D are independently hydrogen, a bridged ring
moiety, Ar, C5-C7 cycloalkyl substituted C1-C6 straight or
branched chain alkyl or C2-C6 straight or branched chain
alkenyl, C5-C7 cycloalkenyl substituted C1-C6 straight or
branched chain alkyl or C2-C6 straight or branched chain
alkenyl, or Ar substituted C1-C6 straight or branched chain
alkyl or C2-C6 straight or branched chain alkenyl, wherein
in each case, one or two carbon atom(s) of said alkyl or
alkenyl may be substituted with one or two heteroatom(s)
independently selected from the group consisting of
oxygen, sulfur, SO, and SO2 in chemically reasonable
substitution patterns, or the fragment
<IMG>
wherein Q is hydrogen, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl; and
T is Ar or C5-C7 cycloalkyl substituted at
positions 3 and 4 with substituents
independently selected from the group consisting
of hydrogen, hydroxy, O- (C1-C9 alkyl), O- (C2-C4
alkenyl), and carbonyl;
Ar is independently selected from the group
consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-
thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and
phenyl, monocyclic and bicyclic heterocyclic ring systems
with individual ring sizes being 5 or 6 which contain in
either or both rings a total of 1-4 heteroatom(s)
independently selected from the group consisting of
425
oxygen, nitrogen and sulfur; wherein Ar contains 1-3
substituent(s) independently selected from the group
consisting of hydrogen, halo, hydroxy, hydroxymethyl,
nitro, CF3, trifluoromethoxy, C1-C6 straight or branched
chain alkyl, C2-C6 straight or branched chain alkenyl, O-
(C1-C4 straight or branched chain alkyl), O- (C2-C4 straight
or branched chain alkenyl), O-benzyl, O-phenyl, amino,
1,2-methylenedioxy, carbonyl, and phenyl;
L is either hydrogen or U; M is either oxygen or CH-
U, provided that if L is hydrogen, then M is CH-U, or if
M is oxygen then L is U;
U is hydrogen, O-(C1-C4 straight or branched chain
alkyl), O-(C2-C4 straight or branched chain alkenyl), C1-C6
straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl
substituted with C1-C4 straight or branched chain alkyl or
C2-C4 straight or branched chain alkenyl, (C1-C4 alkyl or
C2-C4 alkenyl)-Ar, or Ar; and
J and K, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety which is
substituted with oxygen, sulfur, SO, or SO2.
47. The compound of claim 1, wherein the compound is
formula LIX:
<IMG>
or a pharmaceutically acceptable salt, ester or solvate
thereof, wherein:
426
A is CH2, O, NH, or N-(C1-C9 alkyl);
B and D are independently Ar, a bridged ring moiety,
hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6
straight or branched chain alkenyl, wherein said alkyl or
alkenyl is unsubstituted or substituted with C5-C7
cycloalkyl, C5-C7 cycloalkenyl or Ar, and wherein one or
two carbon atom(s) of said alkyl or alkenyl may be
substituted with one or two heteroatom(s) independently
selected from the group consisting of O, S, SO, and SO2 in
chemically reasonable substitution patterns, or
<IMG>
wherein Q is hydrogen, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl; and
T is Ar or C5-C7 cycloalkyl substituted at
positions 3 and 4 with one or more
substituent(s) independently selected from the
group consisting of hydrogen, hydroxy, O- (C1-C4
alkyl), O-(C2-C4 alkenyl), and carbonyl;
provided that both B and D are not hydrogen;
Ar is independently selected from the group
consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-
furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-
pyridyl, monocyclic and bicyclic heterocyclic ring systems
with individual ring sizes being 5 or 6 which contain in
either or both rings a total of 1-4 heteroatoms
independently selected from the group consisting of O, N,
and S; wherein Ar contains 1-3 substituent(s)
independently selected from the group consisting of
hydrogen., halo, hydroxy, nitro, trifluoromethyl,
427
trifluoromethoxy, C1-C6 straight or branched chain alkyl,
(C2-C6 straight or branched chain alkenyl, O- (C1-C4 straight
or branched chain alkyl), O-(C2-C4 straight or branched
chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy,
amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, (C2-C6
straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7
cycloalkenyl substituted with C1-C4 straight or branched
chain alkyl or (C2-C4 straight or branched chain alkenyl,
(C2-C4 alkyl or (C2-C4 alkenyl)-Ar, or Ar;
J and K, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety which is
substituted with O, S, SO, or SO2; and
n is 0 to 3.
48. The compound of claim 47, wherein the compound
is Formula LX:
<IMG>
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
Br is a heterocylic bridged ring moiety, wherein any
two or more atoms of the pyrrolidine ring (when n=1 ) or
the piperidine ring (when n=2) are bonded to each other
through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
428
structure;
B and D are independently Ar, a bridged ring moiety,
hydrogen, C1-C6 straight or branched chain alkyl, or (C2-C6
straight or branched chain alkenyl, wherein said alkyl or
alkenyl is unsubstituted or substituted with C5-C7
cycloalkyl, C5-C7 cycloalkenyl or Ar, and wherein one or
two carbon atom(s) of said alkyl or alkenyl may be
substituted with one or two heteroatom(s) independently
selected from the group consisting of O, S, SO, and SO2 in
chemically reasonable substitution patterns, or
<IMG>
wherein Q is hydrogen, C1-C6 straight or
branched chain alkyl, or (C2-C6 straight or
branched chain alkenyl; and
T is Ar or C5-C7 cycloalkyl substituted at
positions 3 and 4 with one or more
substituent(s) independently selected from the
group consisting of hydrogen, hydroxy, O- (C1-C4
alkyl), O-(C2-C4 alkenyl), and carbonyl;
provided that both B and D are not hydrogen; and
m is 0 or 1.
49. The compound of claim 47, wherein the compound
is formula LXI:
<IMG>
429
or a pharmaceutically acceptable salt, ester or solvate
thereof, wherein:
Br is a heterocylic bridged ring moiety, wherein any
two or more atoms of the primary piperidine ring are
bonded to each other through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
B and D are independently Ar, a bridged ring moiety,
hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6
straight or branched chain alkenyl, wherein said alkyl or
alkenyl is unsubstituted or substituted with C5-C7
cycloalkyl, C5-C7 cycloalkenyl or Ar, and wherein one or
two carbon atom(s) of said alkyl or alkenyl may be
substituted with one or two heteroatom((s) independently
selected from the group consisting of O, S, SO, and SO2 in
chemically reasonable substitution patterns, or
<IMG>
wherein Q is hydrogen, C1-C6 straight or branched
chain alkyl, or C2-C6 straight or branched chain alkenyl;
and
T is Ar or C5-C7 cycloalkyl substituted at positions
3 and 4 with one or more substituent(s) independently
selected from the group consisting of hydrogen, hydroxy,
O- (C1-C4 alkyl), O- C2-C4 alkenyl), and carbonyl;
provided that both B and D are not hydrogen;
Ar is independently selected from the group
430
consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-
furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-
pyridyl, monocyclic and bicyclic heterocyclic ring systems
with individual ring sizes being 5 or 6 which contain in
either or both rings a total of 1-4 heteroatoms
independently selected from the group consisting of O, N,
and S; wherein Ar contains 1-3 substituent(s)
independently selected from the group consisting of
hydrogen, halo, hydroxy, nitro, trifluoromethyl,
trifluoromethoxy, C1-C6 straight or branched chain alkyl,
C2-C6 straight or branched chain alkenyl, O- (C1-C4 straight
or branched chain alkyl), O-(C2-C4 straight or branched
chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy,
amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, C2-C6
straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7
cycloalkenyl substituted with C1-C4 straight or branched
chain alkyl or C2-C4 straight or branched chain alkenyl,
(C2-C4 alkyl or C2-C4 alkenyl)-Ar, or Ar; and
m is 0 to 3.
50. The compound of claim 49, wherein the compound
is Formula LXII:
<IMG>
or a pharmaceutically acceptable salt thereof, wherein:
Br is a heterocylic bridged ring moiety, wherein any
two or more atoms of the primary pyrrolidine ring are
bonded to each other through either
431
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
B and D are independently Ar, a bridged ring moiety,
hydrogen, C1-C6 straight or branched chain alkyl, or (C2-C6
straight or branched chain alkenyl, wherein said alkyl or
alkenyl is unsubstituted or substituted with C5-C7
cycloalkyl, C5-C7 cycloalkenyl, or Ar, and wherein one or
two carbon atom(s) of said alkyl or alkenyl may be
substituted with one or two heteroatom(s) independently
selected from the group consisting of O, S, SO, and SO2 in
chemically reasonable substitution patterns, or
<IMG>
wherein Q is hydrogen, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl; and
T is Ar or C5-C7 cycloalkyl substituted at
positions 3 and 4 with one or more
substituent(s) independently selected from the
group consisting of hydrogen, hydroxy, O- (C1-C4
alkyl), O-(C2-C4 alkenyl), and carbonyl;
provided that both B and D are not hydrogen;
Ar is independently selected from the group
consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-
furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-
pyridyl, monocyclic and bicyclic heterocyclic ring systems
with individual ring sizes being 5 or 6 which contain in
either or both rings a total of 1-4 heteroatoms
independently selected from the group consisting of O, N,
432
and S; wherein Ar contains 1-3 substituent(s)
independently selected from the group consisting of
hydrogen, halo, hydroxy, nitro, trifluoromethyl,
trifluoromethoxy, C1-C6 straight or branched chain alkyl,
C2-C6 straight or branched chain alkenyl, O-(C1-C4 straight
or branched chain alkyl), O-(C2-C4 straight or branched
chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy,
amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, C2-C6
straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7
cycloalkenyl substituted with C1-C4 straight or branched
chain alkyl or C2-C4 straight or branched chain alkenyl,
(C2-C4 alkyl or C2-C4 alkenyl) -Ar, or Ar; and
m is 0 to 3.
51. The compound of claim 1, wherein the compound is
formula LXIII:
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
V is CH, N, or S;
A is CH2, O, NH, or N- (C1-C4 alkyl);
B and D are independently Ar, a bridged ring moiety,
hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6
straight or branched chain alkenyl, wherein said alkyl or
alkenyl is unsubstituted or substituted with C5-C7
cycloalkyl, C5-C7 cycloalkenyl or Ar, and wherein one or
two carbon atom(s) of said alkyl or alkenyl may be
substituted with one or two heteroatom(s) independently
433
selected from the group consisting of O, S, SO, and SO2 in
chemically reasonable substitution patterns, or
<IMG>
wherein Q is hydrogen, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl; and
T is Ar or C5-C7 cycloalkyl substituted at
positions 3 and 4 with one or more
substituent(s) independently selected from the
group consisting of hydrogen, hydroxy, O-(C1-C4
alkyl), O-(C2-C4 alkenyl), and carbonyl;
provided that both B and D are not hydrogen;
R is independently either C1-C9 straight or branched
chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or
Ar1, wherein R is independently either unsubstituted of
substituted with one or more substituent(s) independently
selected from the group consisting of halo, halo (C1-C6) -
alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl,
C1-C6 straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy,
phenoxy, benzyloxy, thio- (C1-C6) -alkyl, (C1-C6) -alkylthio,
sulfhydryl, amino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl,
aminocarboxyl, a bridged ring moiety, and Ar2;
Ar, and Ar2 are independently an alicyclic or
aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic
ring; wherein the individual ring size is 5-8 members;
wherein said heterocyclic ring contains 1-6 heteroatom(s)
independently selected from the group consisting of O, N,
and S; E is C1-C6 straight or branched chain alkyl, C2-C6
434
straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7
cycloalkenyl substituted with C1-C4 straight or branched
chain alkyl or C2-C4 straight or branched chain alkenyl,
(C2-C9 alkyl or C2-C4 alkenyl)-Ar, or Ar;
J and K, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety containing
one or more heteroatom(s) selected from the group
consisting of O, S, SO, SO2, N, NH, and NR; and
n is 0 to 3.
52. The compound of claim 1, wherein the compound is
formula LXIV:
<IMG>
in which:
n is 1-3;
Br is a heterocylic bridged ring moiety, wherein any
two or more atoms of the primary ring (when n is 1-3) are
bonded to each other through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
X is either O or S;
R1 is independently selected from the group consisting
of C1-C9 straight or branched chain alkyl, C2-C9 straight or
branched chain alkenyl, a bridged ring moiety, aryl,
heteroaryl, carbocycle, or heterocycle;
435
D is a bond, or a C1-C10 straight or branched chain
alkyl, C2-C10 alkenyl or C2-C10 alkynyl; and
R2 is independently a carboxylic acid or a carboxylic
acid isostere;
or a pharmaceutically acceptable salt, ester, or solvate
thereof.
53. The compound of Claim 52 in which R2 is selected
from the group consisting of:
<IMGS>
436
-COOH, -SO3H, -SO2HNR3, -PO2(R3)2, -CN, -PO3(R3)2. -OR3, -SR3.
-NHCOR3, -N(R3)2, -CON(R3)2, -CONH(O)R3, -CONHNHSO2R3, -
COHNSO2R3, and -CONR3CN wherein R3 is hydrogen, hydroxy,
halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-alkoxy, C2-C6-
alkenoxy, C1-C6-alkylaryloxy, aryloxy, aryl- C1-C6-alkyloxy,
cyano, nitro, imino, C1-C6-alkylamino, amino- C1-C6-alkyl,
sulfhydryl, thio- C1-C6-alkyl, C1-C6-alkylthio, sulfonyl,
C1-C6 straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl or alkynyl, a bridged ring moiety,
aryl, heteroaryl, carbocycle, heterocycle, and CO2R4 where
R4 is hydrogen or C1-C9 straight or branched chain alkyl or
alkenyl.
54. The compound of claim 1, wherein the compound is
formula LXV:
<IMG>
in which
X, Y, and Z are independently selected from the group
consisting of C, O, S, or N, provided that X, Y, and Z are
not all C:
n is 1-3;
Br is a heterocylic bridged ring moiety, wherein any
two or more atoms of the primary ring (when n is 1-3) are
bonded to each other through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
A is selected from the group consisting of L1, L2, L3,
437
or L4, in which
<IMGS>
and R1 and E, independently, are selected from the group
consisting of hydrogen, C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, a bridged
ring moiety, aryl, heteroaryl, carbocycle, and
heterocycle;
R2 is carboxylic acid or a carboxylic acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl,
heteroaryl, carbocycle, heterocycle, or carboxylic acid
isostere is optionally substituted with one or more
substituents selected from R3, where
R3 is hydrogen, hydroxy, halo, halo (C1-C6) -alkyl,
thiocarbonyl, (C1-C6)-alkoxy, (C2-C6)-alkenoxy,
(C1-C6)-alkylaryloxy, aryloxy, aryl-(C1-C6)-
alkyloxy, cyano, nitro, imino, (C1-C6)-
alkylamino, amino-(C1-C6)-alkyl, sulfhydryl,
thio-(C1-C6)-alkyl, (C1-C6)-alkylthio, sulfonyl,
C1-C6 straight or branched chain alkyl, C2-C6
straight or branched chain alkenyl or alkynyl,
a bridged ring moiety, aryl, heteroaryl,
carbocycle, heterocycle, or CO2R4 where R4 is
hydrogen or C1-C9 straight or branched chain
alkyl or alkenyl;
438
or a pharmaceutically acceptable salt, ester, or solvate
thereof.
55. The compound of claim 54, wherein the compound
is formula LXVI:
<IMG>
in which:
n is 1-3;
Br is a heterocylic bridged ring moiety, wherein any
two or more atoms of the primary ring (when n is 1-3) are
bonded to each other through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
R1 and A are independently selected from the group
consisting of hydrogen, C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, a bridged
ring moiety, aryl, heteroaryl, carbocycle, and
heterocycle;
D is a bond, or a C1-C10 straight or branched chain
alkyl, C2-C10 alkenyl or C2-C10 alkynyl;
R2 is independently carboxylic acid or a carboxylic
acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl,
heteroaryl, carbocycle, heterocycle, or carboxylic acid
isostere is optionally substituted with one or more
substituents selected from R3, where
439
R3 is hydrogen, hydroxy, halo, halo(C1-C6)-alkyl,
thiocarbonyl, (C1-C6)-alkoxy, (C2-C6)-alkenoxy,
(C1-C6)-alkylaryloxy, aryloxy, aryl-(C1-C6)-
alkyloxy, cyano, nitro, imino, (C1-C6)-
alkylamino, amino-(C1-C6)-alkyl, sulfhydryl,
thio-(C1-C6)-alkyl, (C1-C6)-alkylthio, sulfonyl,
C1-C6 straight or branched chain alkyl, C2-C6
straight or branched chain alkenyl or alkynyl,
a bridged ring moiety, aryl, heteroaryl,
carbocycle, heterocycle, and CO2R4 where R4 is
hydrogen or C1-C9 straight or branched chain
alkyl or alkenyl;
or a pharmaceutically acceptable salt, ester, or solvate
thereof.
56. The compound of claim 54, wherein the compound
is formula LXVII:
<IMG>
in which:
n is 1-3;
Br is a heterocylic bridged ring moiety, wherein any
two or more atoms of the primary ring (when n is 1-3) are
bonded to each other through either
a chemical bond or
atom(s) other than a bond
which do(es) not comprise a part of the primary ring
structure;
R1 is independently selected from the group consisting
440
of hydrogen, C1-C9 straight or branched chain alkyl, C2-C9
straight or branched chain alkenyl, a bridged ring moiety,
aryl, heteroaryl, carbocycle, or heterocycle;
D is a bond, or a C1-C10 straight or branched chain
alkyl, C2-C10 alkenyl or C2-C10 alkynyl;
R2 is independently a carboxylic acid or a carboxylic
acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,
carbocycle, heterocycle, or carboxylic acid isostere is
optionally substituted with one or more substituents
selected from R3, where
R3 is independently hydrogen, hydroxy,
halo, , halo-(C1-C6)-alkoxy, thiocarbonyl, (C1-
C6)-alkoxy, (C2-C6)-alkenyloxy, (C1-C6) -
alkylaryloxy, aryloxy, aryl-(C1-C6)-alkyloxy,
cyano, nitro, imino, (C1-C6)-alkyl amino, amino-
(C1-C6)-alkyl, sulfhydryl, thio-(C1-C6)alkyl, (C1-
C6)-alkylthio, sulfonyl, C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched
chain alkenyl or alkynyl, a bridged ring moiety,
aryl, heteroaryl, carbocycle, heterocycle, or
CO2R4 where R4 is hydrogen or C1-C9 straight or
branched chain alkyl or alkenyl;
or a pharmaceutically acceptable salt, ester or solvate
thereof.
57. A pharmaceutical composition, comprising:
a. an effective amount of a bridged heterocyclic
derivative; and
b. a pharmaceutically acceptable carrier.
58. The pharmaceutical composition of claim 57,
wherein the bridged heterocyclic derivative is a compound
of formula I':
441
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
A and B, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety which
contains one or more O, C (R1)2, S (O)p, N, NR1, or NR5 atoms;
V is CH, S, or N;
X is O, CH2 or S;
m is 0 or 1;
G is
<IMGS>
R1 is independently hydrogen, C1-C9 straight or
branched chain alkyl, or C2-C9 straight or branched chain
alkenyl or alkynyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, a
carboxylic acid or carboxylic acid isostere, N (R4)n, Ar1,
Ar4, a bridged ring moiety, or K-L, wherein said alkyl,
cycloalkyl, cycloalkenyl, alkynyl, alkenyl, Ar1, Ar4, or
bridged ring moiety, is optionally substituted with one or
more substituent(s) independently selected from the group
consisting of:
2-furyl, 2-thienyl, pyridyl, phenyl, C3-C6
cycloalkyl wherein said furyl, thienyl, pyridyl,
phenyl or cycloalkyl group optionally is
substituted with C1-C4 alkoxy, (Ar1)n, halo, halo-
C1-C6-alkyl, carbonyl, thiocarbonyl, C1-C6
442
thioester, cyano, imino, COOR6 in which R6 is
independently C1-C9 straight or branched chain
alkyl or alkenyl, hydroxy, nitro,
trifluoromethyl, C1-C6 alkoxy, C2-C4 alkenyloxy,
C1-C6 alkylaryloxy C1-C6 aryloxy, aryl- (C1-C6)-
alkyloxy, phenoxy, benzyloxy, thio- (C1-C6) -alkyl,
C1-C6-alkylthio, sulfhydryl, sulfonyl, amino,
(C1-C6)-mono- or di-alkylamino, amino- (C1-C6)-
alkyl, aminocarboxy, C3-C8 cycloalkyl, C1-C6
straight or branched chain alkyl, C2-C6 straight
or branched chain alkenyl optionally substituted
with (Ar1)n, C3-C8 cycloalkyl, C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched
chain alkenyl substituted with C3-C8 cycloalkyl,
C3-C8 cycloalkyl, and Ar2, and, wherein any
carbon atom of an alkyl or alkenyl group may
optionally replaced with O, NR5, or S(O)p;
Ar1 or Ar2, independently, is an alicyclic
or aromatic, mono-, bi- or tricyclic, carbo- or
heterocyclic ring, wherein the ring is
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl,
C3-C8 cycloalkyl, C5-C7 cycloalkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and
amino; wherein the individual ring contains 5-8
members; and wherein the heterocyclic ring
contains 1-6 heteroatom(s) independently
selected from the group consisting of O, N, and
S, and, wherein any aromatic or tertiary
alkylamine is optionally oxidized to a
corresponding N-oxide;
443
or, R1 is independently a moiety of the formula:
<IMG>
wherein:
R3 is independently C1-C9 straight
or branched chain alkyl which is
optionally substituted with C3-C8
cycloalkyl, a bridged ring moiety, or
Ar1;
X2 is O or NR6, wherein R6 is
independently selected from the group
consisting of hydrogen, C1-C6 straight
or branched chain alkyl, and C2-C6
straight or branched chain alkenyl;
R4 is independently selected from
the group consisting of phenyl,
benzyl, C1-C5 straight or branched
chain alkyl, C2-C5 straight or
branched chain alkenyl, C1-C5 straight
or branched chain alkyl substituted
with phenyl, C2-C5 straight or
branched chain alkenyl substituted
with phenyl, and a bridged ring
moiety;
R2 is independently C1-C9 straight or
branched chain alkyl, C2-C9 straight or branched
chain alkenyl, C3-C9 cycloalkyl, C5-C7
cycloalkenyl, a bridged ring moiety, or Ar1,
wherein said alkyl, alkenyl, cycloalkyl,
cycloalkenyl, or bridged ring moiety, is
444
optionally substituted with one or more
substituents selected from the group consisting
of C1-C6 straight or branched chain alkyl,C2-C6
straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, (Ar1)n and
hydroxy; or,
R2 is independently either hydrogen or P;
Y is either oxygen or CH-P, provided that
if R2 is hydrogen, then Y is CH-P, or if Y is
oxygen then R2 is P;
P is hydrogen, O-(C1-C4 straight
or branched chain alkyl) , O- (C2-C4
straight or branched chain alkenyl),
C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched
chain alkenyl, C5-C7 cycloalkyl, C5-C7
cycloalkenyl substituted with C1-C4
straight or branched chain alkyl or
C2-C4 straight or branched chain
alkenyl, (C1-C4 alkyl or C2-C4
alkenyl) -Ar5, or Ar5;
U is either O or N, provided that:
when U is O, then R' is a lone
pair of electrons and R" is selected
from the group consisting of Ar4, a
bridged ring moiety, C3-C8 cycloalkyl,
C1-C9 straight or branched chain
alkyl, and C2-C9 straight or branched
chain alkenyl, wherein said alkyl or
alkenyl is optionally substituted with
one or more substituent (s)
independently selected from the group
consisting of Ar4 and C3-C8 cycloalkyl;
and
445
when U is N, then R' and R" are,
independently, selected from the group
consisting of hydrogen, Ar4, a
bridged ring moiety, G3-C10 cycloalkyl,
a C7-C12 bi- or tri-cyclic carbocycle,
C1-C9 straight or branched chain
alkyl, and C2-C9 straight or branched
chain alkenyl, wherein said alkyl or
alkenyl is optionally substituted with
one or more substituent(s)
independently selected from the group
consisting of Ar4 and C3-C8 cycloalkyl;
or R' and R'' are taken together to
form a heterocyclic 5- or 6-membered
ring selected from the group
consisting of pyrrolidine,
imidazolidine, pyrazolidine,
piperidine, and piperazine.
W and Y, independently, are O, S, CH2 or H2;
Z is C (R1)2, O, S, a direct bond or NR1; or,
Z-R1 is independently
<IMGS>
wherein:
C and D are, independently, hydrogen, a
bridged ring moiety, Ar4, Ar1, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl; wherein said alkyl or
alkenyl is optionally substituted with one or
more substituent(s) independently selected from
446
the group consisting of C3-C8 cycloalkyl, C5-C7
cycloalkenyl, hydroxy, carbonyl oxygen, Ar1 and
Ar4; wherein said alkyl, alkenyl, cycloalkyl or
cycloalkenyl is optionally substituted with C1-C6
alkyl, C2-C6 alkenyl, hydroxy, amino, halo,
haloalkyl, thiocarbonyl, C1-C6 ester, C1-C6
thioester, C1-C6 alkoxy, C1-C6 alkenoxy, cyano,
nitro, imino, C1-C6 alkylamino, amino- (C1-
C6) alkyl, sulfhydryl, thio- (C1-C6) alkyl, or
sulfonyl; wherein any carbon atom of said alkyl
or alkenyl is optionally substituted in one or
more position (s) with oxygen to form a carbonyl;
or wherein any carbon atom of said alkyl or
alkenyl is optionally replaced with O, NR5, or
(SO) p;
C' and D' are independently hydrogen, a
bridged ring moiety, Ar5, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl, wherein said alkyl or
alkenyl is optionally substituted with C5-C7
cycloalkyl, C5-C7 cycloalkenyl, or Ar5, wherein,
one or two carbon atom(s) of said alkyl or
alkenyl may be substituted with one or two
heteroatom(s) independently selected from the
group consisting of oxygen, sulfur, SO, and SO2
in chemically reasonable substitution patterns,
or
<IMG>
wherein
Q is hydrogen, C1-C6 straight or
branched chain alkyl, or C2-C6
447
straight or branched chain alkenyl;
and
T is Ar5 or C5-C7 cycloalkyl
substituted at positions 3 and 4 with
substituents independently selected
from the group consisting of hydrogen,
hydroxy, O- (C1-C4 alkyl), O-(C2-C4
alkenyl), and carbonyl,
J is O, NR1, S, or (CR1)2;
K is a direct bond, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl; wherein said alkyl or
alkenyl is optionally substituted with one or
more substituent(s) independently selected from
the group consisting of C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched
chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, a bridged ring moiety, hydroxy,
carbonyl oxygen, and Ar3; wherein said alkyl,
alkenyl, cycloalkyl, cycloalkenyl or Ar3, is
optionally substituted with C1-C4 alkyl, C2-C9
alkenyl, hydroxy, or carbonyl oxygen; wherein
any carbon atom of said alkyl, alkenyl,
cycloalkyl, cycloalkenyl or Ar3, is optionally
replaced with O, NR"' , or S(O) p,
wherein R" ' is selected from the
group consisting of hydrogen, C1-C4
straight or branched chain alkyl, C3-
C4 straight or branched chain alkenyl
or alkynyl, a bridged ring moiety,
and C1-C4 bridging alkyl wherein a
bridge is formed between the nitrogen
and a carbon atom of said alkyl or
alkenyl chain containing said
448
heteroatom to form a ring, wherein
said ring is optionally fused to an
Ar3 group;
K' is a direct bond, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl, wherein any carbon atom
of said alkyl or alkenyl is optionally
substituted in one or more position(s) with
amino, halo, haloalkyl, thiocarbonyl, ester,
thioester, alkoxy, alkenoxy, cyano, nitro,
imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, sulfonyl, or oxygen to form a
carbonyl, or wherein any carbon atom of said
alkyl or alkenyl is optionally replaced with O,
NR5, S(O) p;
K'' is C(R1)2, O, S, a direct bond or NR1;
L is an aromatic amine or a tertiary amine
oxidized to a corresponding N-oxide; said
aromatic amine being selected from the group
consisting of pyridyl, pyrimidyl, quinolinyl,
and isoquinolinyl, said aromatic amine being
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl,
C1-C4 alkoxy, C2-C6 alkenyloxy, phenoxy,
benzyloxy, and amino; and wherein said tertiary
amine is NRxRyRz, wherein Rx, Ry, and Rz are
independently selected from the group consisting
of C1-C6 straight or branched chain alkyl and C2-
C6 straight or branched chain alkenyl; wherein
said alkyl or alkenyl is optionally substituted
with one or more substituent(s) independently
449
selected from the group consisting of C1-C6
straight or branched chain alkyl, C2-C6 straight
or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, hydroxy, carbonyl oxygen, a
bridged ring moiety, and Ar3; wherein said
alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar3
is optionally substituted with C1-C4 alkyl, C2-C4
alkenyl, hydroxy, or carbonyl oxygen; wherein
any carbon atom of said alkyl, alkenyl,
cycloalkyl, cycloalkenyl, or Ar3 is optionally
replaced with O, NR', S(O)p;
L' is a direct bond, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl, wherein any carbon atom
of said alkyl or alkenyl is optionally
substituted in one or more position(s) with
amino, halo, haloalkyl, thiocarbonyl, ester,
thioester, alkoxy, alkenoxy, cyano, nitro,
imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, sulfonyl, or oxygen to form a
carbonyl, or wherein any carbon atom of said
alkyl or alkenyl is optionally replaced with O,
NR5, S(O)p;
n is 1 or 2;
p is 0, l, or 2;
t is 0, l, 2, 3, or 4;
Ar3 is independently selected from the group
consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl,
pyridazyl, quinolinyl, and isoquinolinyl;
Ar4 is independently an alicyclic or aromatic, mono-,
bi- or tricyclic, carbo- or heterocyclic ring, wherein the
ring is optionally substituted with one or more
substituent(s) independently selected from the group
consisting of alkylamino, amido, amino, aminoalkyl, azo,
450
benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9
alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain
alkenyl, C3-C8 cycloalkyl, C3-C7 cycloalkenyl, carbonyl,
carboxy, cyano, diazo, ester, formanilido, halo,
haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo,
nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy,
thio, thioalkyl, thiocarbonyl, thiocyano, thioester,
thioformamido, trifluoromethyl, and carboxylic and
heterocyclic moieties; wherein the individual alicyclic or
aromatic ring contains 5-8 members and wherein said
heterocyclic ring contains 1-6 heteroatom(s) independently
selected from the group consisting of O, N, and S; and
wherein any aromatic or tertiary alkyl amine is optionally
oxidized to a corresponding N-oxide;
Ar5 is independently selected from the group
consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-
thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and
phenyl, monocyclic and bicyclic heterocyclic ring systems
with individual ring sizes being 5 or 6 which contain in
either or both rings a total of 1-4 heteroatom(s)
independently selected from the group consisting of
oxygen, nitrogen and sulfur; wherein Ar5 optionally
contains 1-3 substituent(s) independently selected from
the group consisting of hydrogen, halo, hydroxy,
hydroxymethyl, nitro, CF3, trifluoromethoxy, C1-C6 straight
or branched chain alkyl, C2-C6 straight or branched chain
alkenyl, O-(C1-C4 straight or branched chain alkyl), 0-(C2-
C4 straight or branched chain alkenyl), O-benzyl, O-phenyl,
amino, 1,2-methylenedioxy, carbonyl, and phenyl; and
R5 is independently selected from the group consisting
of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
451
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar4 or
Ar1 group.
59. A method of treating a neurological disorder in
an animal, comprising:
administering to the animal an effective amount of a
bridged heterocyclic derivative.
60. The method of claim 59, wherein the bridged
heterocyclic derivative is a compound of formula I':
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
A is hydrogen, C1 or C2 alkyl, or benzyl and B is C1-
C4 straight or branched chain alkyl, benzyl, or
cyclohexylmethyl; or,
A and B, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety which
contains one or more O, C(R1)2, S(O)p, N, NR1, or NR5 atoms;
V is CH, S, or N;
X is O, CH2 or S;
m is 0 or 1;
G is
<IMG>
452
R1 is independently hydrogen, C1-C9 straight or
branched chain alkyl, or C2-C9 straight or branched chain
alkenyl or alkynyl, C3-C9 cycloalkyl, C5-C7, cycloalkenyl, a
carboxylic acid or carboxylic acid isostere, N(R4)n, Ar1,
Ar4, a bridged ring moiety, or K-L, wherein said alkyl,
cycloalkyl, cycloalkenyl, alkynyl, alkenyl, Ar1, Ar4, or
bridged ring moiety, is optionally substituted with one or
more substituent(s) independently selected from the group
consisting of:
2-furyl, 2-thienyl, pyridyl, phenyl, C3-C6
cycloalkyl wherein said furyl, thienyl, pyridyl,
phenyl or cycloalkyl group optionally is
substituted with C1-C4 alkoxy, (Ar1)n, halo, halo-
C1-C6-alkyl, carbonyl, thiocarbonyl, C1-C6
thioester, cyano, imino, COOR6 in which R6 is
independently C1-C9 straight or branched chain
alkyl or alkenyl, hydroxy, nitro,
trifluoromethyl, C1-C6 alkoxy, C2-C4 alkenyloxy,
C1-C6 alkylaryloxy C1-C6 aryloxy, aryl-(C1-C6)-
alkyloxy, phenoxy, benzyloxy, thio-(C1-C6)-alkyl,
C1-C6-alkylthio, sulfhydryl, sulfonyl, amino,
(C1-C6)-mono- or di-alkylamino, amino-(C1-C6)-
alkyl, aminocarboxy, C3-C8 cycloalkyl, C1-C6
straight or branched chain alkyl, C2-C6 straight
or branched chain alkenyl optionally substituted
with (Ar1)n, C3-C8 cycloalkyl, C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched
chain alkenyl substituted with C3-C8 cycloalkyl,
C3-C8 cycloalkyl, and Ar2, and, wherein any
carbon atom of an alkyl or alkenyl group may
optionally replaced with O, NR5, or S(O)p;
Ar1 or Ar2, independently, is an alicyclic
or aromatic, mono-, bi- or tricyclic, carbo- or
heterocyclic ring, wherein the ring is
453
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl,
C3-C8 cycloalkyl, C5-C7 cycloalkenyl, C1-C4
alkoxy, C2-C9 alkenyloxy, phenoxy, benzyloxy, and
amino; wherein the individual ring contains 5-8
members; and wherein the heterocyclic ring
contains 1-6 heteroatom(s) independently
selected from the group consisting of O, N, and
S, and, wherein any aromatic or tertiary
alkylamine is optionally oxidized to a
corresponding N-oxide;
or, R1 is independently a moiety of the formula:
<IMG>
wherein:
R3 is independently C1-C9 straight
or branched chain alkyl which is
optionally substituted with C3-C8
cycloalkyl, a bridged ring moiety, or
Ar1;
X2 is O or NR6, wherein R6 is
independently selected from the group
consisting of hydrogen, C1-C6 straight
or branched chain alkyl, and C2-C6
straight or branched chain alkenyl;
R4 is independently selected from
the group consisting of phenyl,
454
benzyl, C1-C5 straight or branched
chain alkyl, C2-C5 straight or
branched chain alkenyl, C1-C5 straight
or branched chain alkyl substituted
with phenyl, C2-C5 straight or
branched chain alkenyl substituted
with phenyl, and a bridged ring
moiety;
R2 is independently C1-C9 straight or
branched chain alkyl, C2-C9 straight or branched
chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, a bridged ring moiety, or Ar1,
wherein said alkyl, alkenyl, cycloalkyl,
cycloalkenyl, or bridged ring moiety, is
optionally substituted with one or more
substituents selected from the group consisting
of C1-C6 straight or branched chain alkyl, C2-C6
straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, (Ar1)n and
hydroxy; or,
R2 is independently either hydrogen or P;
Y is either oxygen or CH-P, provided that
if R2 is hydrogen, then Y is CH-P, or if Y is
oxygen then R2 is P;
P is hydrogen, O-(C1-C4 straight
or branched chain alkyl), O-(C2-C4
straight or branched chain alkenyl),
C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched
chain alkenyl, C5-C7 cycloalkyl, C5-C7
cycloalkenyl substituted with C1-C4
straight or branched chain alkyl or
C2-C4 straight or branched chain
alkenyl, (C1-C4 alkyl or C2-C4
455
alkenyl )-Ar5, or Ar5;
U is either O or N, provided that:
when U is O, then R' is a lone
pair of electrons and R'' is selected
from the group consisting of Ar4, a
bridged ring moiety, C3-C8 cycloalkyl,
C1-C9 straight or branched chain
alkyl, and C2-C9 straight or branched
chain alkenyl, wherein said alkyl or
alkenyl is optionally substituted with
one or more substituent(s)
independently selected from the group
consisting of Ar4 and C3-C8 cycloalkyl;
and
when U is N, then R' and R'' are,
independently, selected from the group
consisting of hydrogen, Ar4, a
bridged ring moiety, C3-C10 cycloalkyl,
a C7-C12 bi- or tri-cyclic carbocycle,
C1-C9 straight or branched chain
alkyl, and C2-C9 straight or branched
chain alkenyl, wherein said alkyl or
alkenyl is optionally substituted with
one or more substituent(s)
independently selected from the group
consisting of Ar4 and C3-C8 cycloalkyl;
or R' and R'' are taken together to
form a heterocyclic 5- or 6-membered
ring selected from the group
consisting of pyrrolidine,
imidazolidine, pyrazolidine,
piperidine, and piperazine.
W and Y, independently, are O, S, CH2 or H2;
Z is C (R1)2, O, S, a direct bond or NR1; or,
456
Z-R1 is independently
J-K-L, <IMG>
wherein:
C and D are, independently, hydrogen, a
bridged ring moiety, Ar4, Ar1, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl; wherein said alkyl or
alkenyl is optionally substituted with one or
more substituent(s) independently selected from
the group consisting of C3-C8 cycloalkyl, C5-C7
cycloalkenyl, hydroxy, carbonyl oxygen, Ar1 and
Ar4; wherein said alkyl, alkenyl, cycloalkyl or
cycloalkenyl is optionally substituted with C1-C6
alkyl, C2-C6 alkenyl, hydroxy, amino, halo,
haloalkyl, thiocarbonyl, C1-C6 ester, C1-C6
thioester, C1-C6 alkoxy, C1-C6 alkenoxy, cyano,
nitro, imino, C1-C6 alkylamino, amino-(C1-
C6)alkyl, sulfhydryl, thio-(C1-C6)alkyl, or
sulfonyl; wherein any carbon atom of said alkyl
or alkenyl is optionally substituted in one or
more position(s) with oxygen to form a carbonyl;
or wherein any carbon atom of said alkyl or
alkenyl is optionally replaced with O, NR5, or
(SO)p;
C' and D' are independently hydrogen, a
bridged ring moiety, Ar5, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl, wherein said alkyl or
alkenyl is optionally substituted with C5-C7
457
cycloalkyl, C5-C7 cycloalkenyl, or Ar5, wherein,
one or two carbon atom(s) of said alkyl or
alkenyl may be substituted with one or two
heteroatom(s) independently selected from the
group consisting of oxygen, sulfur, SO, and SO2
in chemically reasonable substitution patterns,
or
<IMG>
wherein
Q is hydrogen, C1-C6 straight or
branched chain alkyl, or C2-C6
straight or branched chain alkenyl;
and
T is Ar5 or C5-C7 cycloalkyl
substituted at positions 3 and 4 with
substituents independently selected
from the group consisting of hydrogen,
hydroxy, O-(C1-C4 alkyl), O-(C2-C4
alkenyl), and carbonyl,
J is O, NR1, S, or (CR1)2;
K is a direct bond, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl; wherein said alkyl or
alkenyl is optionally substituted with one or
more substituent(s) independently selected from
the group consisting of C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched
chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, a bridged ring moiety, hydroxy,
carbonyl oxygen, and Ar3; wherein said alkyl,
alkenyl, cycloalkyl, cycloalkenyl or Ar3, is
458
optionally substituted with C1-C4 alkyl, C2-C4
alkenyl, hydroxy, or carbonyl oxygen; wherein
any carbon atom of said alkyl, alkenyl,
cycloalkyl, cycloalkenyl or Ar3, is optionally
replaced with O, NR"' , or S (O)p,
wherein R"' is selected from the
group consisting of hydrogen, C1-C4
straight or branched chain alkyl, C3-
C4 straight or branched chain alkenyl
or alkynyl, a bridged ring moiety,
and C1-C9 bridging alkyl wherein a
bridge is formed between the nitrogen
and a carbon atom of said alkyl or
alkenyl chain containing said
heteroatom to form a ring, wherein
said ring is optionally fused to an
Ar3 group;
K' is a direct bond, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl, wherein any carbon atom
of said alkyl or alkenyl is optionally
substituted in one or more position(s) with
amino, halo, haloalkyl, thiocarbonyl, ester,
thioester, alkoxy, alkenoxy, cyano, nitro,
imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, sulfonyl, or oxygen to form a
carbonyl, or wherein any carbon atom of said
alkyl or alkenyl is optionally replaced with O,
NR5, S(O)p;
K" is C(R1)2, O, S, a direct bond or NR1;
L is an aromatic amine or a tertiary amine
oxidized to a corresponding N-oxide; said
aromatic amine being selected from the group
consisting of pyridyl, pyrimidyl, quinolinyl,
459
and isoquinolinyl, said aromatic amine being
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight ar branched chain
alkyl, C2-C6 straight or branched chain alkenyl,
C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy,
benzyloxy, and amino; and wherein said tertiary
amine is NR x R y R z, wherein R x, R y, and R z are
independently selected from the group consisting
of C1-C6 straight or branched chain alkyl and C2-
C6 straight or branched chain alkenyl; wherein
said alkyl or alkenyl is optionally substituted
with one or more substituent(s) independently
selected from the group consisting of C1-C6
straight or branched chain alkyl, C2-C6 straight
or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, hydroxy, carbonyl oxygen, a
bridged ring moiety, and Ar3; wherein said
alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar3
is optionally substituted with C1-C4 alkyl, C2-C4
alkenyl, hydroxy, or carbonyl oxygen; wherein
any carbon atom of said alkyl, alkenyl,
cycloalkyl, cycloalkenyl, or Ar3 is optionally
replaced with O, NR', S(O)p;
L' is a direct bond, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl, wherein any carbon atom
of said alkyl or alkenyl is optionally
substituted in one or more position(s) with
amino, halo, haloalkyl, thiocarbonyl, ester,
thioester, alkoxy, alkenoxy, cyano, nitro,
imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, sulfonyl, or oxygen to form a
460
carbonyl, or wherein any carbon atom of said
alkyl or alkenyl is optionally replaced with O,
NR5, S(O)p;
n is 1 or 2;
p is 0, 1, or 2;
t is 0, 1, 2, 3, or 4;
Ar3 is independently selected from the group
consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl,
pyridazyl, quinolinyl, and isoquinolinyl;
Ar4 is independently an alicyclic or aromatic, mono-,
bi- or tricyclic, carbo- or heterocyclic ring, wherein the
ring is optionally substituted with one or more
substituent(s) independently selected from the group
consisting of alkylamino, amido, amino, aminoalkyl, azo,
benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9
alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain
alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl,
carboxy, cyano, diazo, ester, formanilido, halo,
haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo,
nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy,
thio, thioalkyl, thiocarbonyl, thiocyano, thioester,
thioformamido, trifluoromethyl, and carboxylic and
heterocyclic moieties wherein the individual alicyclic or
aromatic ring contains 5-8 members and wherein said
heterocyclic ring contains 1-6 heteroatom(s) independently
selected from the group consisting of O, N, and S; and
wherein any aromatic or tertiary alkyl amine is optionally
oxidized to a corresponding N-oxide;
Ar5 is independently selected from the group
consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-
thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and
phenyl, monocyclic and bicyclic heterocyclic ring systems
with individual ring sizes being 5 or 6 which contain in
either or both rings a total of 1-4 heteroatom(s)
461
independently selected from the group consisting of
oxygen, nitrogen and sulfur; wherein Ar5 optionally
contains 1-3 substituent(s) independently selected from
the group consisting of hydrogen, halo, hydroxy,
hydroxymethyl, nitro, CF3, trifluoromethoxy, C1-C6 straight
or branched chain alkyl, C2-C6 straight or branched chain
alkenyl, O-(C1-C4 straight or branched chain alkyl) , O-(C2-
C4 straight or branched chain alkenyl), O-benzyl, O-phenyl,
amino, 1,2-methylenedioxy, carbonyl, and phenyl; and
R5 is independently selected from the group consisting
of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar4 or
Ar1 group.
61. The method of claim 60, wherein the neurological
disorder is selected from the group consisting of
peripheral neuropathies cause by physical injury or
disease state, physical damage to the brain, physical
damage to the spinal cord, stroke associated with brain
damage, and neurological disorders relating to
neurodegeneration.
62. The method of claim 60, wherein the neurological
disorder is selected from the group consisting of
Alzheimer's Disease, Parkinson's Disease, and amyotrophic
lateral sclerosis.
63. The method of claim 60, wherein the neurological
disorder is Alzheimer's disease.
462
69. The method of claim 60, wherein the neurological
disorder is Parkinson's disease.
65. The method of claim 60, wherein the neurological
disorder is amyotrophic lateral sclerosis.
66. The method of claim 59, wherein the bridged
heterocyclic derivative is non-immunosuppressive.
67. The method of claim 59, wherein the bridged
heterocyclic derivative has an affinity for an FKBP-type
immunophilin.
68. The method of claim 67, wherein the FKBP-type
immunophilin is FKBP-12.
69. A method for treating alopecia or promoting hair
growth in an animal, which comprises administering to said
animal an effective amount of a bridged heterocyclic
derivative.
70. The method of claim 69, wherein the bridged
heterocyclic derivative is non-immunosuppressive.
71. The method of claim 69, wherein the bridged
heterocyclic derivative has an affinity for an FKBP-type
immunophilin.
72. The method of claim 71, wherein the FKBP-type
immunophilin is FKBP-12.
73. The method of claim 69, wherein the bridged
heterocyclic derivative is a compound of formula formula
I':
463
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
A is hydrogen, C1 or C2 alkyl, or benzyl and B is C1-
C4 straight or branched chain alkyl, benzyl, or
cyclohexylmethyl; or,
A and B, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety which
contains one or more O, C (R1)2, S(O)p, N, NR1, or NR5 atoms;
V is CH, S, or N;
X is O, CH2 or S;
m is 0 or 1;
G is
<IMGS>
R1 is independently hydrogen, C1-C9 straight or
branched chain alkyl, or C2-C9 straight or branched chain
alkenyl or alkynyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, a
carboxylic acid or carboxylic acid isostere, N(R4)n, Ar1,
Ar4, a bridged ring moiety, or K-L, wherein said alkyl,
cycloalkyl, cycloalkenyl, alkynyl, alkenyl, Ar1, Ar4, or
bridged ring moiety, is optionally substituted with one or
more substituent(s) independently selected from the group
consisting of:
2-furyl, 2-thienyl, pyridyl, phenyl, C3-C6
cycloalkyl wherein said furyl, thienyl, pyridyl,
464
phenyl or cycloalkyl group optionally is
substituted with C1-C9 alkoxy, (Ar1)n, halo, halo-
C1-C6-alkyl, carbonyl, thiocarbonyl, C1-C6
thioester, cyano, imino, COOR6 in which R6 is
independently C1-C9 straight or branched chain
alkyl or alkenyl, hydroxy, nitro,
trifluoromethyl, C1-C6 alkoxy, C2-C4 alkenyloxy,
C1-C6 alkylaryloxy C1-C6 aryloxy, aryl-(C1-C6)-
alkyloxy, phenoxy, benzyloxy, thio-(C1-C6)-alkyl,
C1-C6-alkylthio, sulfhydryl, sulfonyl, amino,
(C1-C6)-mono- or di-alkylamino, amino-(C1-C6)-
alkyl, aminocarboxy, C3-C8 cycloalkyl, C1-C6
straight or branched chain alkyl, C2-C6 straight
or branched chain alkenyl optionally substituted
with (Ar1)n, C3-C8 cycloalkyl, C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched
chain alkenyl substituted with C3-C8 cycloalkyl,
C3-C8 cycloalkyl, and Ar2, and, wherein any
carbon atom of an alkyl or alkenyl group may
optionally replaced with O, NR5, or S(O)p;
Ar1 or Ar2, independently, is an alicyclic
or aromatic, mono-, bi- or tricyclic, carbo- or
heterocyclic ring, wherein the ring is
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl,
C3-C8 cycloalkyl, C5-C7 cycloalkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and
amino: wherein the individual ring contains 5-8
members; and wherein the heterocyclic ring
contains 1-6 heteroatom(s) independently
selected from the group consisting of O, N, and
465
S, and, wherein any aromatic or tertiary
alkylamine is optionally oxidized to a
corresponding N-oxide;
or, R1 is independently a moiety of the formula:
<IMG>
wherein:
R3 is independently C1-C9 straight
or branched chain alkyl. which is
optionally substituted with C3-C8
cycloalkyl, a bridged ring moiety, or
Ar1;
X2 is O or NR6, wherein R6 is
independently selected from the group
consisting of hydrogen, C1-C6 straight
or branched chain alkyl, and C2-C6
straight or branched chain alkenyl;
R4 is independently selected from
the group consisting of phenyl,
benzyl, C1-C5 straight or branched
chain alkyl, C2-C5 straight or
branched chain alkenyl, C1-C5 straight
or branched chain alkyl substituted
with phenyl, C2-C5 straight or
branched chain alkenyl substituted
with phenyl, and a bridged ring
moiety;
R2 is independently C1-C9 straight or
branched chain alkyl, C2-C9 straight or branched
chain alkenyl, C3-C8 cycloalkyl, C5-C7
466
cycloalkenyl, a bridged ring moiety, or Ar1,
wherein said alkyl, alkenyl, cycloalkyl,
cycloalkenyl, or bridged ring moiety, is
optionally substituted with one or more
substituents selected from the group consisting
of C1-C6 straight or branched chain alkyl, C2-C6
straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, (Ar1)n and
hydroxy; or,
R2 is independently either hydrogen or P;
Y is either oxygen or CH-P, provided that
if R2 is hydrogen, then Y is CH-P, or if Y is
oxygen then R2 is P;
P is hydrogen, O-(C1-C4 straight
or branched chain alkyl), O-(C2-C4
straight or branched chain alkenyl),
C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched
chain alkenyl, C5-C7 cycloalkyl, C5-C7
cycloalkenyl substituted with C1-C4
straight or branched chain alkyl or
C2-C4 straight or branched chain
alkenyl, (C1-C4 alkyl or C2-C4
alkenyl)-Ar5, or Ar5;
U is either O or N, provided that:
when U is O, then R' is a lone
pair of electrons and R'' is selected
from the group consisting of Ar4, a
bridged ring moiety, C3-C8 cycloalkyl,
C1-C9 straight or branched chain
alkyl, and C2-C9 straight or branched
chain alkenyl, wherein said alkyl or
alkenyl is optionally substituted with
one or more substituent(s)
467
independently selected from the group
consisting of Ar4 and C3-C8 cycloalkyl;
and
when U is N, then R' and R'' are,
independently, selected from the group
consisting of hydrogen, Ar4, a
bridged ring moiety, C3-C10 cycloalkyl,
a C7-C12 bi- or tri-cyclic carbocycle,
C1-C9 straight or branched chain
alkyl, and C2-C9 straight or branched
chain alkenyl, wherein said alkyl or
alkenyl is optionally substituted with
one or more substituent(s)
independently selected from the group
consisting of Ar9 and C3-C8 cycloalkyl;
or R' and R'' are taken together to
form a heterocyclic 5- or 6-membered
ring selected from the group
consisting of pyrrolidine,
imidazolidine, pyrazolidine,
piperidine, and piperazine.
W and Y, independently, are O, S, CH2 or H2;
Z is C(R1)2, O, S, a direct bond or NR1; or,
Z-R1 is independently
J-K-L , <IMGS>
wherein:
C and D are, independently, hydrogen, a
bridged ring moiety, Ar4, Ar1, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl; wherein said alkyl or
468
alkenyl is optionally substituted with one or
more substituent(s) independently selected from
the group consisting of C3-C8 cycloalkyl, C5-C7
cycloalkenyl, hydroxy, carbonyl oxygen, Ar1 and
Ar4; wherein said alkyl, alkenyl, cycloalkyl or
cycloalkenyl is optionally substituted with C1-C6
alkyl, C2-C6 alkenyl, hydroxy, amino, halo,
haloalkyl, thiocarbonyl, C1-C6 ester, C1-C6
thioester, C1-C6 alkoxy, C1-C6 alkenoxy, cyano,
nitro, imino, C1-C6 alkylamino, amino- (C1-
C6)alkyl, sulfhydryl, thio- (C1-C6) alkyl, or
sulfonyl; wherein any carbon atom of said alkyl
or alkenyl is optionally substituted in one or
more position(s) with oxygen to form a carbonyl;
or wherein any carbon atom of said alkyl or
alkenyl is optionally replaced with O, NR5, or
(SO)p;
C' and D' are independently hydrogen, a
bridged ring moiety, Ar5, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl, wherein said alkyl or
alkenyl is optionally substituted with C5-C7
cycloalkyl, C5-C7 cycloalkenyl, or Ar5, wherein,
one or two carbon atom(s) of said alkyl or
alkenyl may be substituted with one or two
heteroatom(s) independently selected from the
group consisting of oxygen, sulfur, SO, and SO2
in chemically reasonable substitution patterns,
or
<IMG>
wherein
469
Q is hydrogen, C1-C6 straight or
branched chain alkyl, or C2-C6
straight or branched chain alkenyl;
and
T is Ar5 or C5-C7 cycloalkyl
substituted at positions 3 and 4 with
substituents independently selected
from the group consisting of hydrogen,
hydroxy, O-(C1-C4 alkyl), O-(C2-C4
alkenyl), and carbonyl,
J is O, NR1, S, or (CR1)2;
K is a direct bond, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl; wherein said alkyl or
alkenyl is optionally substituted with one or
more substituent(s) independently selected from
the group consisting of C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched
chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, a bridged ring moiety, hydroxy,
carbonyl oxygen, and Ar3; wherein said alkyl,
alkenyl, cycloalkyl, cycloalkenyl or Ar3, is
optionally substituted with C1-C4 alkyl, C2-C4
alkenyl, hydroxy, or carbonyl oxygen; wherein
any carbon atom of said alkyl, alkenyl,
cycloalkyl, cycloalkenyl or Ar3, is optionally
replaced with 0, NR''', or S(O) p,
wherein R''' is selected from the
group consisting of hydrogen, C1-C4
straight or branched chain alkyl, C3-
C4 straight or branched chain alkenyl
or alkynyl, a bridged ring moiety,
and C1-C4 bridging alkyl wherein a
bridge is formed between the nitrogen
470
and a carbon atom of said alkyl or.
alkenyl chain containing said
heteroatom to form a ring, wherein
said ring is optionally fused to an
Ar3 group;
K' is a direct bond, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl, wherein any carbon atom
of said alkyl or alkenyl is optionally
substituted in one or more position(s) with
amino, halo, haloalkyl, thiocarbonyl, ester,
thioester, alkoxy, alkenoxy, cyano, nitro,
imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, sulfonyl, or oxygen to form a
carbonyl, or wherein any carbon atom of said
alkyl or alkenyl is optionally replaced with 0,
NR5, S(O) p;
K'' is C(R1)2, O, S, a direct bond or NR1;
L is an aromatic amine or a tertiary amine
oxidized to a corresponding N-oxide; said
aromatic amine being selected from the group
consisting of pyridyl, pyrimidyl, quinolinyl,
and isoquinolinyl, said aromatic amine being
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl,
C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy,
benzyloxy, and amino; and wherein said tertiary
amine is NR xR yR z, wherein R x, R y, and R z, are
independently selected from the group consisting
of C1-C6 straight or branched chain alkyl and C2
C6 straight or branched chain alkenyl; wherein
471
said alkyl or alkenyl is optionally substituted
with one or more substituent(s) independently
selected from the group consisting of C1-C6
straight or branched chain alkyl, C2-C6 straight
or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, hydroxy, carbonyl oxygen, a
bridged ring moiety, and Ar3; wherein said
alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar3
is optionally substituted with C1-C4 alkyl, C2-C4
alkenyl, hydroxy, or carbonyl oxygen; wherein
any carbon atom of said alkyl, alkenyl,
cycloalkyl, cycloalkenyl, or Ar3 is optionally
replaced with O, NR', S(O)P;
L' is a direct bond, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl, wherein any carbon atom
of said alkyl or alkenyl is optionally
substituted in one or more position(s) with
amino, halo, haloalkyl, thiocarbonyl, ester,
thioester, alkoxy, alkenoxy, cyano, nitro,
imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, sulfonyl, or oxygen to form a
carbonyl, or wherein any carbon atom of said
alkyl or alkenyl is optionally replaced with O,
NR5, S(O)p;
n is 1 or 2;
p is 0, 1, or 2;
t is 0, 1, 2, 3, or 4;
Ar3 is independently selected from the group
consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl,
pyridazyl, quinolinyl, and isoquinolinyl;
Ar4 is independently an alicyclic or aromatic, mono-,
bi- or tricyclic, carbo- or heterocyclic ring, wherein the
ring is optionally substituted with one or more
472
substituent(s) independently selected from the group
consisting of alkylamino, amido, amino, aminoalkyl, azo,
benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9
alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain
alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl,
carboxy, cyano, diazo, ester, formanilido, halo,
haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo,
nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy,
thio, thioalkyl, thiocarbonyl, thiocyano, thioester,
thioformamido, trifluoromethyl, and carboxylic and
heterocyclic moieties; wherein the individual alicyclic or
aromatic ring contains 5-8 members and wherein said
heterocyclic ring contains 1-6 heteratom(s) independently
selected from the group consisting of O, N, and S; and
wherein any aromatic or tertiary alkyl amine is optionally
oxidized to a corresponding N-oxide;
Ar5 is independently selected from the group
consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-
thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and
phenyl, monocyclic and bicyclic heterocyclic ring systems
with individual ring sizes being 5 or 6 which contain in
either or both rings a total of 1-4 heteroatom(s)
independently selected from the group consisting of
oxygen, nitrogen and sulfur; wherein Ar5 optionally
contains 1-3 substituent(s) independently selected from
the group consisting of hydrogen, halo, hydroxy,
hydroxymethyl, nitro, CF3, trifluoromethoxy, C1-C6 straight
or branched chain alkyl, C2-C6 straight or branched chain
alkenyl, O-(C1-C4 straight or branched chain alkyl), O-(C2-
C4 straight or branched chain alkenyl) , O-benzyl, O-phenyl,
amino, 1,2-methylenedioxy, carbonyl, and phenyl; and
R5 is independently selected from the group consisting
of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6
straight or branched chain alkenyl or alkynyl, a bridged
473
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar4 or
Ar1 group.
74. A method for treating a vision disorder,
improving vision in an animal, treating age related memory
impairment, enhancing memory performance, which comprises
administering to said animal an effective amount of a
bridged heterocyclic derivative.
75. The method of claim 74, wherein the bridged
heterocyclic derivative is immunosuppressive or non-
immunosuppressive.
76. The method of claim 74, wherein the bridged
heterocyclic derivative has an affinity for an FKBP-type
immunophilin.
77. The method of claim 76, wherein the FKBP-type
immunophilin is FKBP-12.
78. The method of claim 74, wherein the vision
disorder is selected from the group consisting of visual
impairments; orbital disorders; disorders of the lacrimal
apparatus; disorders of the eyelids; disorders of the
conjunctiva; disorders of the cornea; cataracts; disorders
of the uveal tract; disorders of the retina; disorders of
the optic nerve or visual pathways; tree radical induced
eye disorders and diseases; immunologically-mediated eye
disorders and diseases; eye injuries; and symptoms and
complications of eye disease, eye disorder, or eye injury.
474
79. The method of claim 79, which is improving
naturally-occurring vision in an animal, in the absence of
any ophthalmologic disorder, disease, or injury.
80. The method of claim 74, wherein the bridged
heterocyclic derivative is a compound of formula I':
<IMG>
or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
A and B, taken together with the atoms to which they
are attached, form a saturated, unsaturated, or aromatic
heterocylic or carbocyclic bridged ring moiety which
contains one or more O, C(R1)2, S(O) p, N, NR1, or NR5 atoms;
V is CH, S, or N;
X is 0, CH2 or S;
m is 0 or 1;
G is
<IMGS>
R1 is independently hydrogen, C1-C9 straight or
branched chain alkyl, or C2-C9 straight or branched chain
alkenyl or alkynyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, a
carboxylic acid or carboxylic acid isostere, N(R4)n, Ar1,
Ar4, a bridged ring moiety, or K-L, wherein said alkyl,
cycloalkyl, cycloalkenyl, alkynyl, alkenyl, Ar1, Ar4, or
bridged ring moiety, is optionally substituted with one or
more substituent(s) independently selected from the group
475
consisting of:
2-furyl, 2-thienyl, pyridyl, phenyl, C3-C6
cycloalkyl wherein said furyl, thienyl, pyridyl,
phenyl or cycloalkyl group optionally is
substituted with C1-C4 alkoxy, (Ar1)n, halo, halo-
C1-C6-alkyl, carbonyl, thiocarbonyl, C1-C6
thioester, cyano, imino, COOR6 in which R6 is
independently C1-C9 straight or branched chain
alkyl or alkenyl, hydroxy, nitro,
trifluoromethyl, C1-C6 alkoxy, C2-C4 alkenyloxy,
C1-C6 alkylaryloxy C1-C6 aryloxy, aryl- (C1-C6) -
alkyloxy, phenoxy, benzyloxy, thio- (C1-C6) -alkyl,
C1-C6-alkylthio, sulfhydryl, sulfonyl, amino,
(C1-C6)-mono- or di-alkylamino, amino- (C1-C6) -
alkyl, aminocarboxy, C3-C8 cycloalkyl, C1-C6
straight or branched chain alkyl, C2-C6 straight
or branched chain alkenyl optionally substituted
with (Ar1)n, C3-C8 cycloalkyl, C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched
chain alkenyl substituted with C3-C8 cycloalkyl,
C3-C8 cycloalkyl, and Ar2, and, wherein any
carbon atom of an alkyl or alkenyl group may
optionally replaced with O, NRS, or S(O)P;
Ar1 or Ar2, independently, is an alicyclic
or aromatic, mono-, bi- or tricyclic, carbo- or
heterocyclic ring, wherein the ring is
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl,
C3-C8 cycloalkyl, C5-C7 cycloalkenyl, C1-C4
alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and
amino; wherein the individual ring contains 5-8
476
members; and wherein the heterocyclic ring
contains 1-6 heteroatom(s) independently
selected from the group consisting of O, N, and
S, and, wherein any aromatic or tertiary
alkylamine is optionally oxidized to a
corresponding N-oxide;
or, R1 is independently a moiety of the formula:
<IMG>
wherein:
R3 is independently C1-C9 straight
or branched chain alkyl which is
optionally substituted with C3-C8
cycloalkyl, a bridged ring moiety, or
Ar1;
X2 is O or NR6, wherein R6 is
independently selected from the group
consisting of hydrogen, C1-C6 straight
or branched chain alkyl, and C2-C6
straight or branched chain alkenyl;
R4 is independently selected from
the group consisting of phenyl,
benzyl, C1-C5 straight or branched
chain alkyl, C2-C5 straight or
branched chain alkenyl, C1-C5 straight
or branched chain alkyl substituted
with phenyl, C2-C5 straight or
branched chain alkenyl substituted
with phenyl, and a bridged ring
moiety;
477
R2 is independently C1-C9 straight or
branched chain alkyl, C2-C9 straight or branched
chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, a bridged ring moiety, or Ar1,
wherein said alkyl, alkenyl, cycloalkyl,
cycloalkenyl, or bridged ring moiety, is
optionally substituted with one or more
substituents selected from the group consisting
of C1-C6 straight or branched chain alkyl, C2-C6
straight or branched chain alkenyl, C3-C8
cycloalkyl, C5-C7 cycloalkenyl, (Ar1)n and
hydroxy; or,
R2 is independently either hydrogen or P;
Y is either oxygen or CH-P, provided that
if R2 is hydrogen, then Y is CH-P, or if Y is
oxygen then R2 is P;
P is hydrogen, O- (C1-C4 straight
or branched chain alkyl), O-(C2-C4
straight or branched chain alkenyl),
C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched
chain alkenyl, C5-C7 cycloalkyl, C5-C7
cycloalkenyl substituted with C1-C4
straight or branched chain alkyl or
C2-C4 straight or branched chain
alkenyl, (C1-C4 alkyl or C2-C4
alkenyl) -Ar5, or Ar5;
U is either O or N, provided that:
when U is O, then R' is a lone
pair of electrons and R'' is selected
from the group consisting of Ar4, a
bridged ring moiety, C3-C8 cycloalkyl,
C1-C9 straight or branched chain
alkyl, and C2-C9 straight or branched
478
chain alkenyl, wherein said alkyl or
alkenyl is optionally substituted with
one or more substituent(s)
independently selected from the group
consisting of Ar4 and C3-C8 cycloalkyl;
and
when U is N, then R' and R'' are,
independently, selected from the group
consisting of hydrogen, Ar4, a
bridged ring moiety, C3-C10 cycloalkyl,
a C7-C12 bi- or tri-cyclic carbocycle,
C1-C9 straight or branched chain
alkyl, and C2-C9 straight or branched
chain alkenyl, wherein said alkyl or
alkenyl is optionally substituted with
one or more substituent(s)
independently selected from the group
consisting of Ar4 and C3-C8 cycloalkyl;
or R' and R'' are taken together to
form a heterocyclic 5- or 6-membered
ring selected from the group
consisting of pyrrolidine,
imidazolidine, pyrazolidine,
piperidine, and piperazine.
W and Y, independently, are O, S, CH2 or H2;
Z is C(R1)2, O, S, a direct bond or NR1; or,
Z-R1 is independently
<IMGS>
wherein:
C and D are, independently, hydrogen, a
bridged ring moiety, Ar4, Ar1, C1-C6 straight or
479
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl; wherein said alkyl or
alkenyl is optionally substituted with one or
more substituent(s) independently selected from
the group consisting of C3-C8 cycloalkyl, C5-C7
cycloalkenyl, hydroxy, carbonyl oxygen, Ar1 and
Ar4; wherein said alkyl, alkenyl, cycloalkyl or
cycloalkenyl is optionally substituted with C1-C6
alkyl, C2-C6 alkenyl, hydroxy, amino, halo,
haloalkyl, thiocarbonyl, C1-C6 ester, C1-C6
thioester, C1-C6 alkoxy, C1-C6 alkenoxy, cyano,
nitro, imino, C1-C6 alkylamino, amino- (C1-
C6) alkyl, sulfhydryl, thio-(C1-C6)alkyl, or
sulfonyl; wherein any carbon atom of said alkyl
or alkenyl is optionally substituted in one or
more position (s) with oxygen to form a carbonyl;
or wherein any carbon atom of said alkyl or
alkenyl is optionally replaced with O, NR5, or
(SO) p;
C' and D' are independently hydrogen, a
bridged ring moiety, Ar5, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl, wherein said alkyl or
alkenyl is optionally substituted with C5-C7
cycloalkyl, C5-C7 cycloalkenyl, or Ar5, wherein,
one or two carbon atom(s) of said alkyl or
alkenyl may be substituted with one or two
heteroatom(s) independently selected from the
group consisting of oxygen, sulfur, SO, and SO2
in chemically reasonable substitution patterns,
or
<IMG>
480
wherein
Q is hydrogen, C1-C6 straight or
branched chain alkyl, or C2-C6
straight or branched chain alkenyl;
and
T is Ar5 or C5-C7 cycloalkyl
substituted at positions 3 and 4 with
substituents independently selected
from the group consisting of hydrogen,
hydroxy, O- (C1-C4 alkyl) , O- (C2-C4
alkenyl), and carbonyl,
J is O, NR1, S, or (CR1)2;
K is a direct bond, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl; wherein said alkyl or
alkenyl is optionally substituted with one or
more substituent(s) independently selected from
the group consisting of C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched
chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, a bridged ring moiety, hydroxy,
carbonyl oxygen, and Ar3; wherein said alkyl,
alkenyl, cycloalkyl, cycloalkenyl or Ar3, is
optionally substituted with C1-C4 alkyl, C2-C4
alkenyl, hydroxy, or carbonyl oxygen; wherein
any carbon atom of said alkyl, alkenyl,
cycloalkyl, cycloalkenyl or Ar3, is optionally
replaced with O, NR''' , or S(O) p,
wherein R''' is selected from the
group consisting of hydrogen, C1-C4
straight or branched chain alkyl, C3-
C4 straight or branched chain alkenyl
or alkynyl, a bridged ring moiety,
and C1-C4 bridging alkyl wherein a
481
bridge is formed between the nitrogen
and a carbon atom of said alkyl or
alkenyl chain containing said
heteroatom to form a ring, wherein
said ring is optionally fused to an
Ar3 group;
K' is a direct bond, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl, wherein any carbon atom
of said alkyl or alkenyl is optionally
substituted in one or more position(s) with
amino, halo, haloalkyl, thiocarbonyl, ester,
thioester, alkoxy, alkenoxy, cyano, nitro,
imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, sulfonyl, or oxygen to form a
carbonyl, or wherein any carbon atom of said
alkyl or alkenyl is optionally replaced with O,
NR5, S(O) p;
K'' is C(R1)2, O, S, a direct bond or NR1,
L is an aromatic amine or a tertiary amine
oxidized to a corresponding N-oxide; said
aromatic amine being selected from the group
consisting of pyridyl, pyrimidyl, quinolinyl,
and isoquinolinyl, said aromatic amine being
optionally substituted with one or more
substituent(s) independently selected from the
group consisting of halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight or branched chain
alkyl, C2-C6 straight or branched chain alkenyl,
C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy,
benzyloxy, and amino; and wherein said tertiary
amine is NR xR yR z, wherein R x, R y, and R z are
independently selected from the group consisting
of C1-C6 straight or branched chain alkyl and C2
482
C6 straight or branched chain alkenyl; wherein
said alkyl or alkenyl is optionally substituted
with one or more substituent(s) independently
selected from the group consisting of C1-C6
straight or branched chain alkyl, C2-C6 straight
or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7
cycloalkenyl, hydroxy, carbonyl oxygen, a
bridged ring moiety, and Ar3; wherein said
alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar3
is optionally substituted with C1-C4 alkyl, C2-C4
alkenyl, hydroxy, or carbonyl oxygen; wherein
any carbon atom of said alkyl, alkenyl,
cycloalkyl, cycloalkenyl, or Ar3 is optionally
replaced with O, NR', S(O) p;
L' is a direct bond, C1-C6 straight or
branched chain alkyl, or C2-C6 straight or
branched chain alkenyl, wherein any carbon atom
of said alkyl or alkenyl is optionally
substituted in one or more position(s) with
amino, halo, haloalkyl, thiocarbonyl, ester,
thioester, alkoxy, alkenoxy, cyano, nitro,
imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, sulfonyl, or oxygen to form a
carbonyl, or wherein any carbon atom of said
alkyl or alkenyl is optionally replaced with O,
NR5, S (O) p;
n is 1 or 2;
p is 0, 1, or 2;
t is 0, 1, 2, 3, or 4;
Ar3 is independently selected from the group
consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl,
pyridazyl, quinolinyl, and isoquinolinyl;
Ar4 is independently an alicyclic or aromatic, mono-,
bi- or tricyclic, carbo- or heterocyclic ring, wherein the
483
ring is optionally substituted with one or more
substituent(s) independently selected from the group
consisting of alkylamino, amido, amino, aminoalkyl, azo,
benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9
alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain
alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl,
carboxy, cyano, diazo, ester, formanilido, halo,
haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo,
nitro, nitroso, phenoxy; sulfhydryl, sulfonylsulfoxy,
thio, thioalkyl, thiocarbonyl, thiocyano, thioester,
thioformamido, trifluoromethyl, and carboxylic and
heterocyclic moieties; wherein the individual alicyclic or
aromatic ring contains 5-8 members and wherein said
heterocyclic ring contains 1-6 heteroatom(s) independently
selected from the group consisting of O, N, and S; and
wherein any aromatic or tertiary alkyl amine is optionally
oxidized to a corresponding N-oxide;
Ar5 is independently selected from the group
consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-
thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and
phenyl, monocyclic and bicyclic heterocyclic ring systems
with individual ring sizes being 5 or 6 which contain in
either or both rings a total of 1-4 heteroatom(s)
independently selected from the group consisting of
oxygen, nitrogen and sulfur; wherein Ar5 optionally
contains 1-3 substituent(s) independently selected from
the group consisting of hydrogen, halo, hydroxy,
hydroxymethyl, nitro, CF3, trifluoromethoxy, C1-C6 straight
or branched chain alkyl, C2-C6 straight or branched chain
alkenyl, O-(C1-C4 straight or branched chain alkyl ), O-(C2-
C4 straight or branched chain alkenyl), O-benzyl, O-phenyl,
amino, 1,2-methylenedioxy, carbonyl, and phenyl; and
R5 is independently selected from the group consisting
of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6
484
straight or branched chain alkenyl or alkynyl, a bridged
ring moiety, and C1-C4 bridging alkyl wherein a bridge is
formed between the nitrogen and a carbon atom of said
alkyl or alkenyl chain containing said heteroatom to form
a ring, wherein said ring is optionally fused to an Ar9 or
Ar1 group.
