U.S. patent application number 12/498622 was filed with the patent office on 2009-12-17 for aromatic prodrugs of propofol, compositions and uses thereof.
This patent application is currently assigned to XenoPort, Inc.. Invention is credited to Mark A. Gallop, Feng Xu.
Application Number | 20090312424 12/498622 |
Document ID | / |
Family ID | 34273058 |
Filed Date | 2009-12-17 |
United States Patent
Application |
20090312424 |
Kind Code |
A1 |
Gallop; Mark A. ; et
al. |
December 17, 2009 |
AROMATIC PRODRUGS OF PROPOFOL, COMPOSITIONS AND USES THEREOF
Abstract
Prodrugs of propofol, methods of making prodrugs of propofol,
pharmaceutical compositions of prodrugs of propofol and methods of
using prodrugs of propofol and pharmaceutical compositions thereof
to treat or prevent diseases or disorders such as migraine headache
pain and post-chemotherapy or post-operative surgery nausea and
vomiting are disclosed herein.
Inventors: |
Gallop; Mark A.; (Santa
Clara, CA) ; Xu; Feng; (Palo Alto, CA) |
Correspondence
Address: |
DORSEY & WHITNEY, LLP;INTELLECTUAL PROPERTY DEPARTMENT
370 SEVENTEENTH STREET, SUITE 4700
DENVER
CO
80202-5647
US
|
Assignee: |
XenoPort, Inc.
Santa Clara
CA
|
Family ID: |
34273058 |
Appl. No.: |
12/498622 |
Filed: |
July 7, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11507968 |
Aug 21, 2006 |
7576127 |
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12498622 |
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10958089 |
Sep 9, 2004 |
7230003 |
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11507968 |
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60501609 |
Sep 9, 2003 |
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Current U.S.
Class: |
514/567 |
Current CPC
Class: |
C07C 271/28
20130101 |
Class at
Publication: |
514/567 |
International
Class: |
A61K 31/196 20060101
A61K031/196; A61P 43/00 20060101 A61P043/00 |
Claims
1. (canceled)
2. A method of treating nausea and vomiting in a patient comprising
administering to the patient in need of such treatment a
therapeutically effective amount of the compound of Formula (I):
##STR00011## or a pharmaceutically acceptable salt thereof, or a
pharmaceutically acceptable N-oxide of any of the foregoing,
wherein: n is 0 or 1; Y is selected from the group consisting of a
bond, CR.sup.1R.sup.2, NR.sup.3, O and S; A is CR.sup.4 or N; B is
CR.sup.5 or N; D is CR.sup.6 or N; E is CR.sup.7 or N; G is
CR.sup.8 or N; R.sup.18 is selected from the group consisting of
hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl,
substituted aryl, arylalkyl, carbamoyl, substituted carbamoyl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl,
substituted heteroaryl and heteroarylalkyl; R.sup.1 and R.sup.2 are
independently selected from the group consisting of hydrogen,
alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl,
substituted heteroaryl and heteroarylalkyl; R.sup.3 is selected
from the group consisting of hydrogen, alkyl, substituted alkyl,
aryl, arylalkyl, cycloalkyl and heteroaryl; R.sup.4 is selected
from the group consisting of hydrogen, alkyl, substituted alkyl,
alkoxy, substituted alkoxy, alkoxycarbonyl, aryl, substituted aryl,
arylalkyl, carboxy, cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl, halo, heteroaryl, substituted heteroaryl,
heteroarylalkyl, hydroxy and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; R.sup.5
is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl,
aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted
heteroaryl, heteroarylalkyl, hydroxy and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; R.sup.6
is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl,
aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted
heteroaryl, heteroarylalkyl, hydroxy and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; R.sup.7
is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl,
aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted
heteroaryl, heteroarylalkyl, hydroxy and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; R.sup.8
is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl,
aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted
heteroaryl, heteroarylalkyl, hydroxy and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; W is
selected from the group consisting of a bond, CR.sup.12R.sup.13,
NR.sup.14, O and S; Z is selected from the group consisting of
CR.sup.15R.sup.16, NR.sup.17, O and S; k is 0 or 1; r is 1, 2 or 3;
each of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.15
and R.sup.16 is independently selected from the group consisting of
hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
heteroaryl, substituted heteroaryl and heteroarylalkyl; and
R.sup.14 and R.sup.17 are independently selected from the group
consisting of hydrogen, alkyl, substituted alkyl, aryl, arylalkyl,
cycloalkyl and heteroaryl; with the provisos that: at least one of
A, B, D, E and G is not N; one and only one of R.sup.4, R.sup.5,
R.sup.6, R.sup.7 or R.sup.8 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; and if k
is 0 then W is a bond.
3. The method of claim 2, wherein: n is 0; Y is selected from the
group consisting of a bond and O; A is CR.sup.4; B is CR.sup.5; D
is CR.sup.6; E is CR.sup.7; G is CR.sup.5; R.sup.4 is selected from
the group consisting of hydrogen and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; R.sup.5
is selected from the group consisting of hydrogen and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; R.sup.6
is selected from the group consisting of hydrogen and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; R.sup.7
is selected from the group consisting of hydrogen and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; R.sup.8
is selected from the group consisting of hydrogen and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; W is a
bond; Z is NR.sup.7; k is 1; r is 1, 2 or 3; each of R.sup.9,
R.sup.10, and R.sup.11 is hydrogen; R.sup.17 is hydrogen; and
R.sup.18 is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkoxycarbonyl, aryl, substituted aryl,
arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted
heteroaryl and heteroarylalkyl; with the proviso that: one and only
one of R.sup.4, R.sup.5, R.sup.6, R.sup.7 or R.sup.8 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11.
4. The method of claim 3, wherein Y is a bond.
5. The method of claim 4, wherein the compound is
3-{[2-[2,6-bis(isopropyl)phenoxycarbonyl]-benzoyl]amino}-propanoic
acid or a pharmaceutically acceptable salt thereof.
6. The method of claim 3, wherein Y is O.
7. The method of claim 6, wherein the compound is
3-{[2-[2,6-bis(isopropyl)phenoxycarbonyloxy]-benzoyl]amino}-propanoic
acid or a pharmaceutically acceptable salt thereof.
8. A method of treating nausea and vomiting in a patient comprising
administering to the patient in need of such treatment a
pharmaceutical composition comprising a compound of Formula (I):
##STR00012## or a pharmaceutically acceptable salt thereof, or a
pharmaceutically acceptable N-oxide of any of the foregoing, and a
pharmaceutically acceptable vehicle, wherein: n is 0 or 1; Y is
selected from the group consisting of a bond, CR.sup.1R.sup.2,
NR.sup.3, O and S; A is CR.sup.4 or N; B is CR.sup.5 or N; D is
CR.sup.60r N; E is CR.sup.7 or N; G is CR.sup.8 or N; R.sup.18 is
selected from the group consisting of hydrogen, alkyl, substituted
alkyl, alkoxycarbonyl, aryl, substituted aryl, arylalkyl,
carbamoyl, substituted carbamoyl, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl
and heteroarylalkyl; R.sup.1 and R.sup.2 are independently selected
from the group consisting of hydrogen, alkyl, substituted alkyl,
aryl, substituted aryl, arylalkyl, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl
and heteroarylalkyl; R.sup.3 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl
and heteroaryl; R.sup.4 is selected from the group consisting of
hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxy,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo,
heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxy and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; R.sup.5
is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl,
aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted
heteroaryl, heteroarylalkyl, hydroxy and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; R.sup.6
is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl,
aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted
heteroaryl, heteroarylalkyl, hydroxy and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; R.sup.7
is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl,
aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted
heteroaryl, heteroarylalkyl, hydroxy and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; R.sup.8
is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl,
aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted
cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted
heteroaryl, heteroarylalkyl, hydroxy and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; W is
selected from the group consisting of a bond, CR.sup.12R.sup.13,
NR.sup.14, O and S; Z is selected from the group consisting of
CR.sup.15R.sup.16, NR.sup.17, 0 and S; k is 0 or 1; r is 1, 2 or 3;
each of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.15
and R.sup.16 is independently selected from the group consisting of
hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
heteroaryl, substituted heteroaryl and heteroarylalkyl; and
R.sup.14 and R.sup.17 are independently selected from the group
consisting of hydrogen, alkyl, substituted alkyl, aryl, arylalkyl,
cycloalkyl and heteroaryl; with the provisos that: at least one of
A, B, D, E and G is not N; one and only one of R.sup.4, R.sup.5,
R.sup.6, R.sup.7 or R.sup.8 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; and if k
is 0 then W is a bond.
9. The method of claim 8, wherein: n is 0; Y is selected from the
group consisting of a bond and O; A is CR.sup.4; B is CR.sup.5; D
is CR.sup.6; E is CR.sup.7; G is CR.sup.8; R.sup.4 is selected from
the group consisting of hydrogen and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; R.sup.5
is selected from the group consisting of hydrogen and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; R.sup.6
is selected from the group consisting of hydrogen and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; R.sup.7
is selected from the group consisting of hydrogen and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; R.sup.8
is selected from the group consisting of hydrogen and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11; W is a
bond; Z is NR.sup.17; k is 1; r is 1, 2 or 3; each of R.sup.9,
R.sup.10, and R.sup.11 is hydrogen; R.sup.17 is hydrogen; and
R.sup.18 is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkoxycarbonyl, aryl, substituted aryl,
arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted
heteroaryl and heteroarylalkyl; with the proviso that: one and only
one of R.sup.4, R.sup.5, R.sup.6, R.sup.7 or R.sup.8 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11.
10. The method of claim 9, wherein Y is a bond.
11. The method of claim 10, wherein the compound is
3-{[2-[2,6-bis(isopropyl)phenoxycarbonyl]-benzoyl]amino}-propanoic
acid or a pharmaceutically acceptable salt thereof.
12. The method of claim 9, wherein Y is O.
13. The method of claim 12, wherein the compound is
3-{[2-[2,6-bis(isopropyl)phenoxycarbonyloxy]-benzoyl]amino}-propanoic
acid or a pharmaceutically acceptable salt thereof.
14. The method of claim 9, wherein the pharmaceutical composition
is an oral formulation.
15. The method of claim 14, wherein the oral formulation is a
sustained release oral formulation.
16. The method of claim 8, wherein the pharmaceutical composition
is an oral formulation.
17. The method of claim 16, wherein the oral formulation is a
sustained release oral formulation.
Description
1. FIELD
[0001] Disclosed herein are prodrugs of propofol, methods of making
prodrugs of propofol, pharmaceutical compositions of prodrugs of
propofol and methods of using prodrugs of propofol and
pharmaceutical compositions thereof to treat or prevent diseases or
disorders such as migraine headache pain and post-chemotherapy or
post-operative surgery nausea and vomiting.
2. BACKGROUND
[0002] Propofol (2,6-diisopropylphenol), (1), is a low molecular
weight phenol that is widely used as an intravenous
sedative-hypnotic agent in the induction and maintenance of
anesthesia and/or sedation in mammals. The advantages of propofol
as an anesthetic include rapid onset of anesthesia, rapid
clearance, and minimal side effects (Langley et al., Drugs 1988,
35, 334-372). Propofol may mediate hypnotic effects through
interaction with the GABA.sub.A receptor complex, a
heterooligomeric ligand-gated chloride ion channel (Peduto et al.,
Anesthesiology 1991, 75, 1000-1009.).
##STR00001##
[0003] Propofol is rapidly metabolized in mammals with the drug
being eliminated predominantly as glucuronidated and sulfated
conjugates of propofol and 4-hydroxypropofol (Langley et al., Drugs
1988, 35, 334-372). Propofol clearance exceeds liver blood flow,
which indicates that extrahepatic tissues contribute to the overall
metabolism of the drug. Human intestinal mucosa glucuronidates
propofol in vitro and oral dosing studies in rats indicate that
approximately 90% of the administered drug undergoes first pass
metabolism, with extraction by the intestinal mucosa accounting for
the bulk of this presystemic elimination (Raoof et al., Pharm. Res.
1996, 13, 891-895). Accordingly, oral administration of propofol is
of little therapeutic utility because of extensive first-pass
metabolism.
[0004] Propofol has a broad range of biological and medical
applications, which are evident at sub-anesthetic doses and include
treatment and/or prevention of intractable migraine headache pain
(Krusz et al., Headache 2000, 40, 224-230; Krusz, International
Publication No. WO 00/54588). Propofol, when used to maintain
anesthesia, causes a lower incidence of post-operative nausea and
vomiting ("PONV") in comparison to common inhalational anesthetic
agents; numerous controlled clinical studies support the
anti-emetic activity of propofol (Tramer et al., Br. J. Anaesth.
1997, 78, 247-255; Brooker et al., Anaesth. Intensive Care 1998,
26, 625-629; Gan et al., Anesthesiology 1997, 87, 779-784).
Propofol also has anti-emetic activity when used in conjunction
with chemotherapeutic compounds (Phelps et al., Ann. Pharmacother.
1996, 30, 290-292; Borgeat et al., Oncology 1993, 50, 456-459;
Borgeat et al., Can. J. Anaesth. 1994, 41, 1117-1119; Tomioka et
al., Anesth. Analg. 1999, 89, 798-799). Nausea, retching and/or
vomiting induced by a variety of chemotherapeutic agents (e.g.,
cisplatin, cyclophosphamide, 5-fluorouracil, methotrexate,
anthracycline drugs, etc.) has been controlled by low-dose propofol
infusion in patients refractory to prophylaxis with conventional
anti-emetic drugs (e.g., serotonin antagonists and
corticosteroids).
[0005] Propofol may also be used to treat patients with refractory
status epilepticus (Brown et al., Pharmacother. 1998, 32,
1053-1059; Kuisma et al., Epilepsia 1995, 36, 1241-1243; Walder et
al., Neurology 2002, 58, 1327-1332; Sutherland et al., Anaesth.
Intensive Care 1994, 22, 733-737). Further, the anticonvulsant
effects of propofol have also been demonstrated in rat efficacy
models at sub-anesthetic doses (Holtkamp et al., Ann. Neurol. 2001,
49, 260-263; Hasan et al., Pharmacol. Toxicol. 1994, 74,
50-53).
[0006] Propofol may also be used as an antioxidant (Murphy et al.,
Br. J. Anaesth. 1992, 68, 613-618; Sagara et al., J. Neurochem.
1999, 73, 2524-2530; Young et al., Eur. J. Anaesthesiol. 1997, 14,
320-326; Wang et al. Eur. J. Pharmacol. 2002, 452, 303-308).
Propofol, at doses typically used for surgical anesthesia, has
observable antioxidant effects in humans (De la Cruz et al.,
Anesth. Analg. 1999, 89, 1050-1055). Pathogenesis or subsequent
damage pathways in various neurodegenerative diseases involve
reactive oxygen species and accordingly may be treated or prevented
with antioxidants (Simonian et al., Pharmacol. Toxicol. 1996, 36,
83-106). Examples of specific neurodegenerative diseases which may
be treated or prevented with anti-oxidants include, but are not
limited to, Friedrich's disease, Parkinson's disease, Alzheimer's
disease, Huntington's disease, amyotrophic lateral sclerosis
("ALS"), multiple sclerosis ("MS"), Pick disease, inflammatory
diseases and diseases caused by inflammatory mediators such as
tumor necrosis factor (TNF) and IL-1.
[0007] A significant problem with the therapeutic use of propofol
is its lack of appreciable solubility in water. Accordingly,
propofol must be specially formulated in aqueous media using
solubilizers or emulsifiers (Briggs et al., Anaesthesia 1982, 37,
1099-1101). For example, in a current commercial product
(Diprivan.RTM., Astra-Zeneca) an oil-in-water emulsion (the
emulsifier is the lecithin mixture Intralipid.RTM.), is used to
formulate propofol (Picard et al., Anesth. Analg. 2000, 90,
963-969).
[0008] One potential solution to the insolubility of propofol in
aqueous solution, which avoids the use of additives, solubilizers
or emulsifiers, is a water-soluble, stable propofol prodrug that is
converted to propofol in vivo. (Hendler et al., International
Publication No. WO 99/58555; Morimoto et al., International
Publication No. WO 00/48572; Hendler et al., U.S. Pat. No.
6,254,853; Stella et al., United States Patent Application No.
US2001/0025035; Hendler, U.S. Pat. No. 6,362,234; International
Publication No. WO 02/13810; Sagara et al., J. Neurochem. 1999, 73,
2524-2530; Banaszczyk et al., Anesth. Analg. 2002, 95, 1285-1292;
Trapani et al., Int. J. Pharm. 1998, 175, 195-204; Trapani et al.,
J. Med. Chem. 1998, 41, 1846-1854; Anderson et al., J. Med. Chem.
2001, 44, 3582-3591; Pop et al., Med. Chem. Res. 1992, 2, 16-21). A
significant problem with existing propofol prodrugs is their
stability under physiological conditions, which prevents release of
therapeutically significant concentrations of propofol,
particularly when the prodrug is orally administered. Thus, there
is a need for propofol prodrugs, which are sufficiently labile
under physiological conditions to provide therapeutically
significant concentrations of propofol, particularly, when the
prodrug is orally administered.
3. SUMMARY
[0009] These and other needs are met by providing prodrugs of
propofol, methods of making prodrugs of propofol, pharmaceutical
compositions of prodrugs of propofol and methods of using prodrugs
of propofol and pharmaceutical compositions thereof to treat or
prevent diseases or disorders such as migraine headache pain,
neurodegenerative disorders and post-chemotherapy or post-operative
surgery nausea and vomiting. In some embodiments, prodrugs of
propofol and pharmaceutical compositions thereof are orally
administered. In other embodiments, prodrugs of propofol are
translocated across the gastrointestinal mucosa via interaction
with transporter proteins expressed within enterocytes lining the
gastrointestinal tract.
[0010] In a first aspect, a compound of structural Formula (I) is
provided:
##STR00002##
or pharmaceutically acceptable salts, hydrates, solvates or
N-oxides thereof, wherein:
[0011] n is 0 or 1;
[0012] Y is selected from the group consisting of a bond,
CR.sup.1R.sup.2, NR.sup.3, O and S;
[0013] A is CR.sup.4 or N;
[0014] B is CR.sup.5 or N;
[0015] D is CR.sup.6 or N;
[0016] E is CR.sup.7 or N;
[0017] G is CR.sup.8 or N;
[0018] R.sup.18 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkoxycarbonyl, aryl, substituted aryl,
arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted
heteroaryl and heteroarylalkyl;
[0019] R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl, heteroaryl, substituted heteroaryl and
heteroarylalkyl;
[0020] R.sup.3 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl and
heteroaryl;
[0021] R.sup.4 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkoxy, substituted alkoxy,
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxyl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo,
heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxyl and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11;
[0022] R.sup.5 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkoxy, substituted alkoxy,
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxyl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo,
heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxyl and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11;
[0023] R.sup.6 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkoxy, substituted alkoxy,
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxyl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo,
heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxyl and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11;
[0024] R.sup.7 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkoxy, substituted alkoxy,
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxyl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo,
heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxyl and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11;
[0025] R.sup.8 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkoxy, substituted alkoxy,
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxyl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo,
heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxyl and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11;
[0026] W is selected from the group consisting of a bond,
CR.sup.12R.sup.13, NR.sup.14, O and S;
[0027] Z is selected from the group consisting of
CR.sup.15R.sup.16, NR.sup.17, O and S;
[0028] k is 0 or 1;
[0029] r is 1, 2 or 3;
[0030] each of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.15 and R.sup.16 is independently selected from the group
consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted
aryl, arylalkyl, cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl, heteroaryl, substituted heteroaryl and
heteroarylalkyl;
[0031] R.sup.14 and R.sup.17 are independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, aryl,
arylalkyl, cycloalkyl and heteroaryl;
[0032] with the provisos that:
[0033] at least one of A, B, D, E and G is not N;
[0034] one and only one of R.sup.4, R.sup.5, R.sup.6, R.sup.7 or
R.sup.8 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11;
[0035] and if k is 0 then W is a bond.
[0036] In a second aspect pharmaceutical compositions are provided,
which generally comprise one or more compounds disclosed herein,
and a pharmaceutically acceptable vehicle such as a diluent,
carrier, excipient or adjuvant. The choice of diluent, carrier,
excipient and adjuvant will depend upon, among other factors, the
desired mode of administration. In some embodiments, the mode of
administration is oral.
[0037] In a third aspect, methods for treating or preventing
various diseases or disorders including, but not limited to
migraine headache pain, post-chemotherapy or post-operative surgery
nausea and vomiting and neurodegenerative disorders (e.g.,
epilepsy, Friedrich's disease, Parkinson's disease, Alzheimer's
disease, Huntington's disease, amyotrophic lateral sclerosis (ALS),
multiple sclerosis (MS) and Pick disease) are provided. The methods
generally involve administering to a patient in need of such
treatment or prevention a therapeutically effective amount of a
compound disclosed herein and/or pharmaceutical compositions
thereof.
[0038] In a fourth aspect, methods for inducing and/or maintaining
anesthesia or sedation in a mammal are provided. The methods
generally involve administering to a patient in need of such
anesthesia sedation induction and/or maintenance a therapeutically
effective amount of a compound disclosed herein and/or
pharmaceutical compositions thereof.
4. DETAILED DESCRIPTION
4.1 Definitions
[0039] "Alkyl" by itself or as part of another substituent refers
to a saturated or unsaturated, branched, straight-chain or cyclic
monovalent hydrocarbon radical derived by the removal of one
hydrogen atom from a single carbon atom of a parent alkane, alkene
or alkyne. Typical alkyl groups include, but are not limited to,
methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as
propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl,
prop-1-en-2-yl, prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl;
cycloprop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls
such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl,
2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-1-yl,
but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,
but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,
cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,
but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the
like.
[0040] The term "alkyl" is specifically intended to include groups
having any degree or level of saturation, i.e., groups having
exclusively single carbon-carbon bonds, groups having one or more
double carbon-carbon bonds, groups having one or more triple
carbon-carbon bonds and groups having mixtures of single, double
and triple carbon-carbon bonds. Where a specific level of
saturation is intended, the expressions "alkanyl," "alkenyl," and
"alkynyl" are used. In some embodiments, an alkyl group comprises
from 1 to 20 carbon atoms. In other embodiments, an alkyl group
comprises from 1 to 10 carbon atoms. In still other embodiments, an
alkyl group comprises from 1 to 10 carbon atoms.
[0041] "Alkanyl" by itself or as part of another substituent refers
to a saturated branched, straight-chain or cyclic alkyl radical
derived by the removal of one hydrogen atom from a single carbon
atom of a parent alkane. Typical alkanyl groups include, but are
not limited to, methanyl; ethanyl; propanyls such as propan-1-yl,
propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such as
butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl
(isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.;
and the like.
[0042] "Alkenyl" by itself or as part of another substituent refers
to an unsaturated branched, straight-chain or cyclic alkyl radical
having at least one carbon-carbon double bond derived by the
removal of one hydrogen atom from a single carbon atom of a parent
alkene. The group may be in either the cis or trans conformation
about the double bond(s). Typical alkenyl groups include, but are
not limited to, ethenyl; propenyls such as prop-1-en-1-yl,
prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl,
cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as
but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,
but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,
buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,
cyclobuta-1,3-dien-1-yl, etc.; and the like.
[0043] "Alkynyl" by itself or as part of another substituent refers
to an unsaturated branched, straight-chain or cyclic alkyl radical
having at least one carbon-carbon triple bond derived by the
removal of one hydrogen atom from a single carbon atom of a parent
alkyne. Typical alkynyl groups include, but are not limited to,
ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.;
butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.;
and the like.
[0044] "Acyl" by itself or as part of another substituent refers to
a radical --C(O)R.sup.30, where R.sup.30 is hydrogen, alkyl,
cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,
heteroaryl, heteroarylalkyl as defined herein. Representative
examples include, but are not limited to formyl, acetyl,
cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl,
benzylcarbonyl and the like.
[0045] "Alkoxy" by itself or as part of another substituent refers
to a radical --OR.sup.31 where R.sup.31 represents an alkyl or
cycloalkyl group as defined herein. Representative examples
include, but are not limited to, methoxy, ethoxy, propoxy, butoxy,
cyclohexyloxy and the like.
[0046] "Alkoxycarbonyl" by itself or as part of another
substituent, refers to a radical --C(O)OR.sup.31 where R.sup.3 is
as defined above.
[0047] "Aryl" by itself or as part of another substituent refers to
a monovalent aromatic hydrocarbon radical derived by the removal of
one hydrogen atom from a single carbon atom of a parent aromatic
ring system. Typical aryl groups include, but are not limited to,
groups derived from aceanthrylene, acenaphthylene,
acephenanthrylene, anthracene, azulene, benzene, chrysene,
coronene, fluoranthene, fluorene, hexacene, hexaphene, hexylene,
as-indacene, s-indacene, indane, indene, naphthalene, octacene,
octaphene, octalene, ovalene, penta-2,4-diene, pentacene,
pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,
pleiadene, pyrene, pyranthrene, rubicene, triphenylene,
trinaphthalene and the like. In some embodiment, an aryl group
comprises from 6 to 20 carbon atoms. In other embodiments, and aryl
group comprises from 6 to 12 carbon atoms.
[0048] "Arylalkyl" by itself or as part of another substituent
refers to an acyclic alkyl radical in which one of the hydrogen
atoms bonded to a carbon atom, typically a terminal or sp.sup.3
carbon atom, is replaced with an aryl group. Typical arylalkyl
groups include, but are not limited to, benzyl, 2-phenylethan-1-yl,
2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,
2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and
the like. Where specific alkyl moieties are intended, the
nomenclature arylalkanyl, arylalkenyl and/or arylalkynyl is used.
In some embodiments, an arylalkyl group is (C.sub.6-C.sub.30)
arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the
arylalkyl group is (C.sub.1-C.sub.10) and the aryl moiety is
(C.sub.6-C.sub.20). In other embodiments, an arylalkyl group is
(C.sub.6-C.sub.20) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl
moiety of the arylalkyl group is (C.sub.1-C.sub.8) and the aryl
moiety is (C.sub.6-C.sub.12).
[0049] "Carbamoyl" by itself or as part of another substituent
refers to the radical --C(O)N(R.sup.32)R.sup.33 where R.sup.32 and
R.sup.33 are independently hydrogen, alkyl, substituted alkyl,
aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or
substituted heteroaryl, as defined herein.
[0050] "Compounds" refers to compounds encompassed by the generic
formulae disclosed herein and includes any specific compounds
within those formulae whose structure is disclosed herein.
Compounds may be identified either by their chemical structure
and/or chemical name. When the chemical structure and chemical name
conflict, the chemical structure is determinative of the identity
of the compound. Compounds disclosed herein may contain one or more
chiral centers and/or double bonds and therefore, may exist as
stereoisomers, such as double-bond isomers (i.e., geometric
isomers), enantiomers or diastereomers. Accordingly, when
stereochemistry at chiral centers is not specified, the chemical
structures depicted herein encompass all possible configurations at
those chiral centers including the stereoisomerically pure form
(e.g., geometrically pure, enantiomerically pure or
diastereomerically pure) and enantiomeric and stereoisomeric
mixtures. Enantiomeric and stereoisomeric mixtures can be resolved
into their component enantiomers or stereoisomers using separation
techniques or chiral synthesis techniques well known to the skilled
artisan. Compounds disclosed herein may also exist in several
tautomeric forms including the enol form, the keto form and
mixtures thereof. Accordingly, the chemical structures depicted
herein encompass all possible tautomeric forms of the illustrated
compounds. Compounds disclosed herein also include isotopically
labeled compounds where one or more atoms have an atomic mass
different from the atomic mass conventionally found in nature.
Examples of isotopes that may be incorporated into the compounds
disclosed herein include, but are not limited to, .sup.2H, .sup.3H,
.sup.11C, .sup.13C, .sup.14C, .sup.15N, .sup.17O and .sup.18O.
Compounds disclosed herein may exist in unsolvated forms as well as
solvated forms, including hydrated forms and as N-oxides. In
general, the hydrated, solvated and N-oxide forms are within the
scope of the present disclosure. Certain compounds disclosed herein
may exist in multiple crystalline or amorphous forms. In general,
all physical forms are equivalent for the uses contemplated herein
and are intended to be within the scope of the present disclosure.
Further, it should be understood, when partial structures of
compounds are illustrated, that brackets indicate the point of
attachment of the partial structure to the rest of the
molecule.
[0051] "Cycloalkyl" by itself or as part of another substituent
refers to a saturated or unsaturated cyclic alkyl radical. Where a
specific level of saturation is intended, the nomenclature
"cycloalkanyl" or "cycloalkenyl" is used. Typical cycloalkyl groups
include, but are not limited to, groups derived from cyclopropane,
cyclobutane, cyclopentane, cyclohexane, and the like. Preferably,
the cycloalkyl group is (C.sub.3-C.sub.10) cycloalkyl, more
preferably (C.sub.3-C.sub.7) cycloalkyl.
[0052] "Cycloheteroalkyl" by itself or as part of another
substituent refers to a saturated or unsaturated cyclic alkyl
radical in which one or more carbon atoms (and any associated
hydrogen atoms) are independently replaced with the same or
different heteroatom. Typical heteroatoms to replace the carbon
atom(s) include, but are not limited to, N, P, O, S, Si, etc. Where
a specific level of saturation is intended, the nomenclature
"cycloheteroalkanyl" or "cycloheteroalkenyl" is used. Typical
cycloheteroalkyl groups include, but are not limited to, groups
derived from epoxides, azirines, thiiranes, imidazolidine,
morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine,
quinuclidine, and the like.
[0053] "Heteroalkyl, Heteroalkanyl, Heteroalkenyl and
Heteroalkynyl" by themselves or as part of another substituent
refer to alkyl, alkanyl, alkenyl and alkynyl groups, respectively,
in which one or more of the carbon atoms (and any associated
hydrogen atoms) are independently replaced with the same or
different heteroatomic groups. Typical heteroatomic groups which
can be included in these groups include, but are not limited to,
--O--, --S--, --O--O--, --S--S--, --O--S--, --NR.sup.34R.sup.35--,
.dbd.N--N.dbd., --N.dbd.N--, --N.dbd.N--NR.sup.36R.sup.37,
--PR.sup.38--, --P(O).sub.2--, --POR.sup.39--, --O--P(O).sub.2--,
--SO--, --SO.sub.2--, --SnR.sup.40R.sup.41-- and the like, where
R.sup.34, R.sup.35, R.sup.36, R.sup.37, R.sup.38, R.sup.39,
R.sup.40 and R.sup.41 are independently hydrogen, alkyl,
substituted alkyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,
substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,
heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl.
[0054] "Heteroaryl" by itself or as part of another substituent
refers to a monovalent heteroaromatic radical derived by the
removal of one hydrogen atom from a single atom of a parent
heteroaromatic ring system. Typical heteroaryl groups include, but
are not limited to, groups derived from acridine, arsindole,
carbazole, .beta.-carboline, chromane, chromene, cinnoline, furan,
imidazole, indazole, indole, indoline, indolizine, isobenzofuran,
isochromene, isoindole, isoindoline, isoquinoline, isothiazole,
isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,
phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,
purine, pyran, pyrazine, pyrazole, pyridazine, pyridine,
pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,
quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,
thiophene, triazole, xanthene, and the like. In some embodiments,
the heteroaryl group is from 5-20 membered heteroaryl. In other
embodiments, the heteroaryl group is from 5-10 membered heteroaryl.
Preferred heteroaryl groups are those derived from thiophene,
pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline,
imidazole, oxazole and pyrazine.
[0055] "Heteroarylalkyl" by itself or as part of another
substituent refers to an acyclic alkyl radical in which one of the
hydrogen atoms bonded to a carbon atom, typically a terminal or
sp.sup.3 carbon atom, is replaced with a heteroaryl group. Where
specific alkyl moieties are intended, the nomenclature
heteroarylalkanyl, heteroarylalkenyl and/or heteroarylalkynyl is
used. In some embodiments, the heteroarylalkyl group is a 6-30
membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl
moiety of the heteroarylalkyl is 1-10 membered and the heteroaryl
moiety is a 5-20-membered heteroaryl. In other embodiments, the
heteroarylalkyl group is 6-20 membered heteroarylalkyl, e.g., the
alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-8
membered and the heteroaryl moiety is a 5-12-membered
heteroaryl.
[0056] "Parent Aromatic Ring System" refers to an unsaturated
cyclic or polycyclic ring system having a conjugated .pi. electron
system. Specifically included within the definition of "parent
aromatic ring system" are fused ring systems in which one or more
of the rings are aromatic and one or more of the rings are
saturated or unsaturated, such as, for example, fluorene, indane,
indene, phenalene, etc. Typical parent aromatic ring systems
include, but are not limited to, aceanthrylene, acenaphthylene,
acephenanthrylene, anthracene, azulene, benzene, chrysene,
coronene, fluoranthene, fluorene, hexacene, hexaphene, hexylene,
as-indacene, s-indacene, indane, indene, naphthalene, octacene,
octaphene, octalene, ovalene, penta-2,4-diene, pentacene,
pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,
pleiadene, pyrene, pyranthrene, rubicene, triphenylene,
trinaphthalene and the like.
[0057] "Parent Heteroaromatic Ring System" refers to a parent
aromatic ring system in which one or more carbon atoms (and any
associated hydrogen atoms) are independently replaced with the same
or different heteroatom. Typical heteroatoms to replace the carbon
atoms include, but are not limited to, N, P, O, S, Si, etc.
Specifically included within the definition of "parent
heteroaromatic ring systems" are fused ring systems in which one or
more of the rings are aromatic and one or more of the rings are
saturated or unsaturated, such as, for example, arsindole,
benzodioxan, benzofuran, chromane, chromene, indole, indoline,
xanthene, etc. Typical parent heteroaromatic ring systems include,
but are not limited to, arsindole, carbazole, .beta.-carboline,
chromane, chromene, cinnoline, furan, imidazole, indazole, indole,
indoline, indolizine, isobenzofuran, isochromene, isoindole,
isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,
oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,
phenazine, phthalazine, pteridine, purine, pyran, pyrazine,
pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine,
quinazoline, quinoline, quinolizine, quinoxaline, tetrazole,
thiadiazole, thiazole, thiophene, triazole, xanthene, and the
like.
[0058] "Pharmaceutical composition" refers to at least one compound
disclosed herein and a pharmaceutically acceptable vehicle, with
which the compound is administered to a patient.
[0059] "Pharmaceutically acceptable salt" refers to a salt of a
compound disclosed herein, which possesses the desired
pharmacological activity of the parent compound. Such salts
include: (1) acid addition salts, formed with inorganic acids such
as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; or formed with organic acids such as
acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic
acid, glycolic acid, pyruvic acid, lactic acid, malonic acid,
succinic acid, malic acid, maleic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,
cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic
acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, 4-chlorobenzenesulfonic acid,
2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic
acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid,
glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid,
tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid,
glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid,
muconic acid, and the like; or (2) salts formed when an acidic
proton present in the parent compound is replaced by a metal ion,
e.g., an alkali metal ion, an alkaline earth ion, or an aluminum
ion; or coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, N-methylglucamine and the
like.
[0060] "Pharmaceutically acceptable vehicle" refers to a diluent,
adjuvant, excipient or carrier with which a compound is
administered.
[0061] "Patient" includes humans. The terms "human" and "patient"
are used interchangeably herein.
[0062] "Preventing" or "prevention" refers to a reduction in risk
of acquiring a disease or disorder (i.e., causing at least one of
the clinical symptoms of the disease not to develop in a patient
that may be exposed to or predisposed to the disease but does not
yet experience or display symptoms of the disease).
[0063] "Prodrug" refers to a derivative of a drug molecule that
requires a transformation within the body to release the active
drug. Prodrugs are frequently, although not necessarily,
pharmacologically inactive until converted to the parent drug. A
hydroxyl containing drug may be converted to, for example, to an
ester, carbonate, acyloxyalkyl or a sulfonate prodrug, which may be
hydrolyzed in vivo to provide the hydroxyl compound. Prodrugs for
drugs with functional groups different than those listed above are
well known to the skilled artisan.
[0064] "Promoiety" refers to a form of protecting group that when
used to mask a functional group within a drug molecule converts the
drug into a prodrug. Typically, the promoiety will be attached to
the drug via bond(s) that are cleaved by enzymatic or non-enzymatic
means in vivo.
[0065] "Protecting group" refers to a grouping of atoms that when
attached to a reactive functional group in a molecule masks,
reduces or prevents reactivity of the functional group. Examples of
protecting groups can be found in Green et al., "Protective Groups
in Organic Chemistry", (Wiley, 2.sup.nd ed. 1991) and Harrison et
al., "Compendium of Synthetic Organic Methods", Vols. 1-8 (John
Wiley and Sons, 1971-1996). Representative amino protecting groups
include, but are not limited to, formyl, acetyl, trifluoroacetyl,
benzyl, benzyloxycarbonyl ("CBz"), tert-butoxycarbonyl ("Boc"),
trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES"),
trityl and substituted trityl groups, allyloxycarbonyl,
9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl
("NVOC") and the like. Representative hydroxyl protecting groups
include, but are not limited to, those where the hydroxyl group is
either acylated or alkylated such as benzyl, and trityl ethers as
well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl
ethers and allyl ethers.
[0066] "SMVT" refers to the sodium-dependent multivitamin
transporter (SLC5A6). Genes encoding this transporter have been
cloned from rat, human and rabbit tissue (see Prasad et al., J.
Biol. Chem. 1998, 273, 7501-7506; Wang et al., J. Biol. Chem. 1999,
274, 14875-14883; Chatterjee et al., Am. J. Physiol. 1999, 277,
C605-C613; Prasad et al., Arch. Biochem. Biophys. 1999, 366,
95-106).
[0067] "Substituted" refers to a group in which one or more
hydrogen atoms are independently replaced with the same or
different substituent(s). Typical substituents include, but are not
limited to, -M, -R.sup.60, --O.sup.-, .dbd.O, --OR.sup.60,
--SR.sup.60, --S.sup.-, .dbd.S, --NR.sup.60R.sup.61,
.dbd.NR.sup.60, --CF.sub.3, --CN, --OCN, --SCN, --NO, --NO.sub.2,
.dbd.N.sub.2, --N.sub.3, --S(O).sub.2O.sup.-, --S(O).sub.2OH,
--S(O).sub.2R.sup.60, --OS(O.sub.2)O.sup.-, --OS(O).sub.2R.sup.60,
--P(O)(O.sup.-).sub.2, --P(O)(OR.sup.60)(O.sup.-),
--OP(O)(OR.sup.60)(OR.sup.61), --C(O)R.sup.60, --C(S)R.sup.60,
--C(O)OR.sup.60, --C(O)NR.sup.60R.sup.61--C(O)O.sup.-,
--C(S)OR.sup.60, --NR.sup.62C(O)NR.sup.60R.sup.61,
--NR.sup.62C(S)NR.sup.60R.sup.61,
--NR.sup.62C(NR.sup.63)R.sup.60R.sup.61 and
--C(NR.sup.62)NR.sup.60R.sup.61 where M is independently a halogen;
R.sup.60, R.sup.61, R.sup.62 and R.sup.63 are independently
hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted
heteroaryl, or optionally R.sup.60 and R.sup.61 together with the
nitrogen atom to which they are bonded form a cycloheteroalkyl or
substituted cycloheteroalkyl ring; and R.sup.64 and R.sup.65 are
independently hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, substituted
cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted
heteroaryl, or optionally R.sup.64 and R.sup.65 together with the
nitrogen atom to which they are bonded form a cycloheteroalkyl or
substituted cycloheteroalkyl ring. Preferably, substituents include
-M, -R.sup.60, .dbd.O, --OR.sup.60, --SR.sup.60, --S.sup.-, .dbd.S,
--NR.sup.60R.sup.61, .dbd.NR.sup.60, --CF.sub.3, --CN, --OCN,
--SCN, --NO, --NO.sub.2, .dbd.N.sub.2, --N.sub.3,
--S(O).sub.2R.sup.60, --OS(O.sub.2)O.sup.-, --OS(O).sub.2R.sup.60,
--P(O)(O.sup.-).sub.2, P(O)(OR.sup.60)(O.sup.-),
--OP(O)(OR.sup.60)(OR.sup.61), --C(O)R.sup.60, --C(S)R.sup.60,
--C(O)OR.sup.60, --C(O)NR.sup.60R.sup.61, --C(O)O.sup.-,
--NR.sup.62C(O)NR.sup.60R.sup.61, more preferably, -M, -R.sup.60,
.dbd.O, --OR.sup.60, --SR.sup.60, --NR.sup.60R.sup.61, --CF.sub.3,
--CN, --NO.sub.2, --S(O).sub.2R.sup.60, --P(O)(OR.sup.60)(O.sup.-),
--OP(O)(OR.sup.60)(OR.sup.61), --C(O)R.sup.60, --C(O)OR.sup.60,
--C(O)NR.sup.60R.sup.61, --C(O)O.sup.-, most preferably, -M,
-R.sup.60, .dbd.O, --OR.sup.60, --SR.sup.60, --NR.sup.60R.sup.61,
--CF.sub.3, --CN, --NO.sub.2, --S(O).sub.2R.sup.60,
--OP(O)(OR.sup.60)(OR.sup.61), --C(O)R.sup.60, --C(O)OR.sup.60,
--C(O)O.sup.-, where R.sup.60, R.sup.61 and R.sup.62 are as defined
above.
[0068] "Transported by the SMVT transporter" refers to the
translocation of a molecule across a membrane of a cell expressing
the SMVT transporter. The translocation occurs through interaction
with the transporter and is energized by cotransport of Na.sup.+
ions across the membrane.
[0069] "Treating" or "treatment" of any disease or disorder refers.
In some embodiments, to ameliorating the disease or disorder (i.e.,
arresting or reducing the development of the disease or at least
one of the clinical symptoms thereof). In other embodiments
"treating" or "treatment" refers to ameliorating at least one
physical parameter, which may not be discernible by the patient. In
yet another embodiment, "treating" or "treatment" refers to
inhibiting the disease or disorder, either physically, (e.g.,
stabilization of a discernible symptom), physiologically, (e.g.,
stabilization of a physical parameter), or both. In yet another
embodiment, "treating" or "treatment" refers to delaying the onset
of the disease or disorder.
[0070] "Therapeutically effective amount" means the amount of a
compound that, when administered to a patient for treating a
disease, is sufficient to effect such treatment for the disease.
The "therapeutically effective amount" will vary depending on the
compound, the disease and its severity and the age, weight, etc.,
of the patient to be treated.
[0071] Reference will now be made in detail to various embodiments
of the invention. While the invention will be described in
conjunction with these embodiments, it will be understood that it
is not intended to limit the invention to those embodiments. To the
contrary, it is intended to cover alternatives, modifications, and
equivalents as may be included within the spirit and scope of the
invention as defined by the appended claims.
5.2 Compounds
[0072] The compounds disclosed herein are prodrugs of propofol. In
some embodiments, the compounds are orally administered. In some
embodiments, the compounds are able to pass across the
gastrointestinal tract. In other embodiments, prodrugs of propofol
are translocated across the gastrointestinal mucosa via interaction
with transporter proteins expressed within enterocytes lining the
gastrointestinal tract.
[0073] In some embodiments, compounds of structural Formula (I) are
provided:
##STR00003##
[0074] or pharmaceutically acceptable salts, hydrates, solvates or
N-oxides thereof, wherein:
[0075] n is 0 or 1;
[0076] Y is selected from the group consisting of a bond,
CR.sup.1R.sup.2, NR.sup.3, O and S;
[0077] A is CR.sup.4 or N;
[0078] B is CR.sup.5 or N;
[0079] D is CR.sup.6 or N;
[0080] E is CR.sup.7 or N;
[0081] G is CR.sup.8 or N;
[0082] R.sup.18 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkoxycarbonyl, aryl, substituted aryl,
arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl,
substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted
heteroaryl and heteroarylalkyl;
[0083] R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, aryl,
substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl, heteroaryl, substituted heteroaryl and
heteroarylalkyl;
[0084] R.sup.3 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl and
heteroaryl;
[0085] R.sup.4 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkoxy, substituted alkoxy,
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxyl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo,
heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxyl and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11;
[0086] R.sup.5 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkoxy, substituted alkoxy,
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxyl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo,
heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxyl and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11;
[0087] R.sup.6 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkoxy, substituted alkoxy,
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxyl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo,
heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxyl and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11;
[0088] R.sup.7 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkoxy, substituted alkoxy,
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxyl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo,
heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxyl and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11;
[0089] R.sup.8 is selected from the group consisting of hydrogen,
alkyl, substituted alkyl, alkoxy, substituted alkoxy,
alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxyl,
cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo,
heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxyl and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11;
[0090] W is selected from the group consisting of a bond,
CR.sup.12R.sup.13, NR.sup.14, O and S;
[0091] Z is selected from the group consisting of
CR.sup.15R.sup.16, NR.sup.17, O and S;
[0092] k is 0 or 1;
[0093] r is 1, 2 or 3;
[0094] each of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.15 and R.sup.16 is independently selected from the group
consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted
aryl, arylalkyl, cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl, heteroaryl, substituted heteroaryl and
heteroarylalkyl;
[0095] R.sup.14 and R.sup.17 are independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, aryl,
arylalkyl, cycloalkyl and heteroaryl;
[0096] with the provisos that:
[0097] at least one of A, B, D, E and G is not N;
[0098] one and only one of R.sup.4, R.sup.5, R.sup.6, R.sup.7 or
R.sup.8 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11;
[0099] and if k is 0 then W is a bond.
[0100] In some embodiments of a compound of Formula (I), n is 0. In
other embodiments of a compound of Formula (I), n is 1.
[0101] In still other embodiments of a compound of Formula (I), n
is 1 and R.sup.18 is selected from the group consisting of
hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl and heteroaryl.
[0102] In the above embodiment, R.sup.18 is selected from the group
consisting of hydrogen, alkyl and substituted alkyl. Preferably,
R.sup.18 is selected from the group consisting of hydrogen and
C.sub.1-4 alkyl. More preferably, R.sup.18 is hydrogen or
methyl.
[0103] In the above embodiment, R.sup.18 is selected from the group
consisting of hydrogen, aryl and substituted aryl. Preferably,
R.sup.18 is selected from the group consisting of hydrogen, phenyl
and substituted phenyl.
[0104] In the above embodiment, R.sup.18 is selected from the group
consisting of hydrogen, arylalkyl and substituted arylalkyl.
Preferably, R.sup.18 is selected from the group consisting of
hydrogen, benzyl and substituted benzyl.
[0105] In still other embodiments of a compound of Formula (I), Y
is a bond.
[0106] In still other embodiments of a compound of Formula (I), Y
is CR.sup.1R.sup.2 and R.sup.1 and R.sup.2 are independently
selected from the group consisting of hydrogen, alkyl, substituted
alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl. Preferably,
R.sup.1 and R.sup.2 are independently hydrogen or alkanyl. More
preferably, R.sup.1 and R.sup.2 are independently hydrogen or
methyl.
[0107] In still other embodiments of a compound of Formula (I), Y
is NR.sup.3 and R.sup.3 is hydrogen or alkanyl. More preferably,
R.sup.3 is hydrogen or methyl.
[0108] In still other embodiments of a compound of Formula (I), Y
is O.
[0109] In still other embodiments of a compound of Formula (I), Y
is S.
[0110] In still other embodiments of a compound of Formula (I), A
is CR.sup.4. Preferably, R.sup.4 is selected from the group
consisting of hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
C.sub.1-4 alkoxycarbonyl, carboxyl, halo, hydroxyl and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11. More
preferably, R.sup.4 is hydrogen, C.sub.1-4 alkyl or
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11.
Preferably, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11 and each
of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, aryl,
arylalkyl, cycloalkyl and heteroaryl. Preferably, R.sup.9,
R.sup.10, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and
R.sup.17 are independently hydrogen or alkyl, and R.sup.11 is
selected from the group consisting of hydrogen, C.sub.1-4 alkyl,
phenyl, substituted phenyl, benzyl and substituted benzyl. More
preferably, R.sup.9, R.sup.10, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 are independently hydrogen or
C.sub.1-4 alkyl, and R.sup.11 is hydrogen.
[0111] In still other embodiments of a compound of Formula (I), A
is N.
[0112] In still embodiment of a compound of Formula (I), B is
CR.sup.5. Preferably, R.sup.5 is selected from the group consisting
of hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
alkoxycarbonyl, carboxyl, halo, hydroxyl and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11. More
preferably, R.sup.5 is hydrogen, C.sub.1-4 alkyl or
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11.
Preferably, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11 and each
of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, aryl,
arylalkyl, cycloalkyl and heteroaryl. Preferably, R.sup.9,
R.sup.10, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and
R.sup.17 are independently hydrogen or alkyl, and R.sup.11 is
selected from the group consisting of hydrogen, C.sub.1-4 alkyl,
phenyl, substituted phenyl, benzyl and substituted benzyl. More
preferably, R.sup.9, R.sup.10, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 are independently hydrogen or
C.sub.1-4 alkyl, and R.sup.11 is hydrogen.
[0113] In still other embodiments of a compound of Formula (I), B
is N.
[0114] In still other embodiments of a compound of Formula (I), D
is CR.sup.6. Preferably, R.sup.6 is selected from the group
consisting of hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
C.sub.1-4 alkoxycarbonyl, carboxyl, halo, hydroxyl and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11. More
preferably, R.sup.6 is hydrogen, C.sub.1-4 alkyl or
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11.
Preferably, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11 and each
of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, aryl,
arylalkyl, cycloalkyl and heteroaryl. Preferably, R.sup.9,
R.sup.10, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and
R.sup.17 are independently hydrogen or alkyl, and R.sup.11 is
selected from the group consisting of hydrogen, C.sub.1-4 alkyl,
phenyl, substituted phenyl, benzyl and substituted benzyl. More
preferably, R.sup.9, R.sup.10, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 are independently hydrogen or
C.sub.1-4 alkyl, and R.sup.11 is hydrogen.
[0115] In still other embodiments of a compound of Formula (I), D
is N.
[0116] In still other embodiments of a compound of Formula (I), E
is CR.sup.7. Preferably, R.sup.7 is selected from the group
consisting of hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
C.sub.1-4 alkoxycarbonyl, carboxyl, halo, hydroxyl and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11. More
preferably, R.sup.7 is hydrogen, C.sub.1-4 alkyl or
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11.
Preferably, R.sup.7 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11 and each
of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, aryl,
arylalkyl, cycloalkyl and heteroaryl. Preferably, R.sup.9,
R.sup.10, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and
R.sup.17 are independently hydrogen or alkyl, and R.sup.11 is
selected from the group consisting of hydrogen, C.sub.1-4 alkyl,
phenyl, substituted phenyl, benzyl and substituted benzyl. More
preferably, R.sup.9, R.sup.10, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 are independently hydrogen or
C.sub.1-4 alkyl, and R.sup.11 is hydrogen.
[0117] In still other embodiments of a compound of Formula (I), E
is N.
[0118] In still other embodiments of a compound of Formula (I), G
is CR.sup.8. Preferably, R.sup.8 is selected from the group
consisting of hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
C.sub.1-4 alkoxycarbonyl, carboxyl, halo, hydroxyl and
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11. More
preferably, R.sup.8 is hydrogen, C.sub.1-4 alkyl or
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11.
Preferably, R.sup.8 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11 and each
of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, aryl,
arylalkyl, cycloalkyl and heteroaryl. Preferably, R.sup.9,
R.sup.10, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and
R.sup.17 are independently hydrogen or alkyl, and R.sup.11 is
selected from the group consisting of hydrogen, C.sub.1-4 alkyl,
phenyl, substituted phenyl, benzyl and substituted benzyl. More
preferably, R.sup.9, R.sup.10, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 are independently hydrogen or
C.sub.1-4 alkyl, and R.sup.11 is hydrogen.
[0119] In still other embodiments of a compound of Formula (I), G
is N.
[0120] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.5,
R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4
alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0121] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 1, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0122] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.4 is
W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 2, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0123] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0124] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0125] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0126] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0127] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 1, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11 is hydrogen.
[0128] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11 each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 2, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11 is hydrogen.
[0129] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 1, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0130] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 2, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0131] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 1 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0132] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 2 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0133] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0134] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0135] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 1, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15, and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0136] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 2, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0137] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is N, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0138] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is N, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4-alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.5,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0139] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is N, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6 and R.sup.8 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.5,
R.sup.6 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.5, R.sup.6 and R.sup.8 are hydrogen.
Preferably, each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0140] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is N, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6 and R.sup.7 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.5,
R.sup.6 and R.sup.7 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.5, R.sup.6 and R.sup.7 are hydrogen.
Preferably, each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0141] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is N, D is CR.sup.6, E is
CR.sup.7, G is N, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.6 and R.sup.8 is independently hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo or
hydroxyl, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.6 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.6 and R.sup.8 are hydrogen. Preferably, each of
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0142] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.4,
R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4
alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0143] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 1, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0144] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 2, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0145] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is
hydrogen. Preferably, R.sup.11 is hydrogen.
[0146] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0147] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.5 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0148] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0149] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 1, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is
hydrogen. Preferably, R.sup.11 is hydrogen.
[0150] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 2, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is
hydrogen. Preferably, R.sup.11 is hydrogen.
[0151] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 1, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0152] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 2, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0153] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 1 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0154] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 2 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0155] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0156] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is --NR.sup.4, k is 1, Z is O, r is
2, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0157] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is. NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 1, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0158] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 2, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6, R.sup.7 and
R.sup.5 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0159] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is N, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0160] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is N, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.7 and R.sup.8 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.4,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.7 and R.sup.8 are hydrogen.
Preferably, each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0161] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is N, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6 and R.sup.8 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.4,
R.sup.6 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.6 and R.sup.8 are hydrogen.
Preferably, each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0162] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is N, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6 and R.sup.7 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.4,
R.sup.6 and R.sup.7 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.6 and R.sup.7 are hydrogen.
Preferably, each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0163] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is N, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is N, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.6 and R.sup.7 is independently hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo or
hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.6 and
R.sup.7 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.6 and R.sup.7 are hydrogen. Preferably, each of
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0164] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is N, B is CR.sup.5, D is N, E is CR.sup.7, G
is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.7 and R.sup.8 is independently hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo or
hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.7 and R.sup.8 are hydrogen. Preferably, each of
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0165] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is N, B is CR.sup.5, D is CR.sup.6, E is N, G
is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.7 and R.sup.8 is independently hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo or
hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.7 and R.sup.8 are hydrogen. Preferably, each of
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0166] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is N, E is
CR.sup.7, G is N, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4 and R.sup.8 is independently hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo or
hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.4 and
R.sup.5 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4 and R.sup.8 are hydrogen. Preferably, each of
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0167] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.4,
R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4
alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are
hydrogen. Preferably, each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0168] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 1, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0169] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 2, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0170] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0171] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0172] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0173] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.16 and R.sup.17 are
hydrogen.
[0174] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11,
[0175] each of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is
independently hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
C.sub.1-4 alkoxycarbonyl, carboxyl, halo or hydroxyl, W is O, k is
1, Z is O, r is 1, and each of R.sup.9, R.sup.10 and R.sup.11 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 is hydrogen.
[0176] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 2, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11 is hydrogen.
[0177] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 1, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0178] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 2, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0179] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 1 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.5, R.sup.7 and R.sup.5 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0180] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 2 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-7 alkyl. Preferably,
each of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0181] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.11 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0182] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0183] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 1, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0184] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E
is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 2, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0185] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is N, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.7 and R.sup.5 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.5,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0186] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is N, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.7 and R.sup.8 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.4,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0187] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is N, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is N, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5 and R.sup.7 is independently hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo or
hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.5 and
R.sup.7 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5 and R.sup.7 are hydrogen. Preferably, each of
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0188] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is N, B is CR.sup.5, D is CR.sup.6, E is N, G
is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5 and R.sup.8 is independently hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo or
hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.5 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5 and R.sup.8 are hydrogen. Preferably, each of
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0189] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is CR.sup.4, B is N, D is CR.sup.6, E is N, G
is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4 and R.sup.8 is independently hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo or
hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.4 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4 and R.sup.8 are hydrogen. Preferably, each of
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0190] In still other embodiments of a compound of Formula (I), n
is 0, Y is a bond, A is N, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is N, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5 and R.sup.7 is independently hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo or
hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.5 and
R.sup.7 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5 and R.sup.7 are hydrogen. Preferably, each of
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0191] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.5,
R.sup.6, R.sup.7 and R.sup.5 is independently hydrogen or C.sub.1-4
alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0192] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 1, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0193] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 2, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0194] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0195] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0196] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0197] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.7, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0198] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 1, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11 is hydrogen.
[0199] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 2, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11 is hydrogen.
[0200] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 1, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0201] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 2, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0202] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 1 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0203] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 2 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0204] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0205] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0206] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 1, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0207] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14; k is 1, Z is
CR.sup.15R.sup.16, r is 2, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0208] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.4,
R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4
alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0209] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 1, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.9 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0210] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 2, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0211] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is
hydrogen. Preferably, R.sup.11 is hydrogen.
[0212] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.5 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0213] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0214] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0215] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 1, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6, R.sup.7 and
R.sup.5 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is
hydrogen. Preferably, R.sup.11 is hydrogen.
[0216] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 2, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is
hydrogen. Preferably, R.sup.11 is hydrogen.
[0217] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 1, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0218] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 2, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0219] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.9 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 1 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.6, R.sup.7 and R.sup.9 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0220] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 2 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0221] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10), R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0222] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0223] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 1, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0224] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 2, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0225] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.4,
R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4
alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are
hydrogen. Preferably, each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0226] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 1, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0227] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 2, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0228] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0229] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0230] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0231] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.7, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0232] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 1, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11 is hydrogen.
[0233] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 2, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5, R.sup.7 and
R.sup.9 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11 is hydrogen.
[0234] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 1, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0235] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 2, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0236] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 1 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0237] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G, is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 2 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0238] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0239] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0240] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 1, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0241] In still other embodiments of a compound of Formula (I), n
is 0, Y is O, A is CR.sup.4, B is CR.sup.5, D is CR.sup.6, E is
CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 2, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5, R.sup.7 and
R.sup.5 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.5 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0242] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7; G is CR.sup.8, R.sup.4
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.5,
R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4
alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0243] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 1, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.5 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.5 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0244] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 2, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0245] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, -R.sup.8 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0246] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0247] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0248] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.5 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0249] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 1, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11 is hydrogen.
[0250] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 2, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11 is hydrogen.
[0251] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 1, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0252] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 2, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0253] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 1 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0254] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 2 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0255] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0256] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.4, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0257] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 1, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0258] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 2, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.9 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0259] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is CR.sup.4, B is N, D is
CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, R.sup.18 is selected
from the group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
substituted phenyl, benzyl and substituted benzyl. More preferably,
R.sup.18 is hydrogen or methyl. Preferably, each of R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0260] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is CR.sup.4, B is
CR.sup.5, D is N, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.5, R.sup.16 and R.sup.17 is independently
hydrogen or alkyl. Preferably, R.sup.18 is selected from the group
consisting of hydrogen, C.sub.1-4 alkyl, phenyl, substituted
phenyl, benzyl and substituted benzyl. More preferably, R.sup.18 is
hydrogen or methyl. Preferably, each of R.sup.5, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.7 and R.sup.8 are hydrogen. Preferably,
each of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0261] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is N, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6 and R.sup.8 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, R.sup.18 is selected
from the group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
substituted phenyl, benzyl and substituted benzyl. More preferably,
R.sup.18 is hydrogen or methyl. Preferably, each of R.sup.5,
R.sup.6 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.5, R.sup.6 and R.sup.8 are hydrogen.
Preferably, each of PR.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0262] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is N, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6 and R.sup.7 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14R.sup.15, R.sup.16 and R.sup.17 is independently
hydrogen or alkyl. Preferably, R.sup.18 is selected from the group
consisting of hydrogen, C.sub.1-4 alkyl, phenyl, substituted
phenyl, benzyl and substituted benzyl. More preferably, R.sup.18 is
hydrogen or methyl. Preferably, each of R.sup.5, R.sup.6 and
R.sup.7 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.6 and R.sup.7 are hydrogen. Preferably,
each of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0263] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is CR.sup.4, B is N, D is
CR.sup.6, E is CR.sup.7, G is N, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4 and R.sup.6 is independently hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo or
hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, R.sup.18 is selected
from the group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
substituted phenyl, benzyl and substituted benzyl. More preferably,
R.sup.11 is hydrogen or methyl. Preferably, each of R.sup.4 and
R.sup.6 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4 and R.sup.6 are hydrogen. Preferably, each of
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0264] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl and heteroaryl, A is CR.sup.4, B is CR.sup.5,
D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.4,
R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4
alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0265] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.7, r
is 1, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0266] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 2, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0267] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is
hydrogen. Preferably, R.sup.11 is hydrogen.
[0268] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0269] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5
is -0W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0270] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R's is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0271] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 1, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is
hydrogen. Preferably, R.sup.11 is hydrogen.
[0272] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 2, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is
hydrogen. Preferably, R.sup.11 is hydrogen.
[0273] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 1, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0274] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 2, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0275] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 1 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0276] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 2 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0277] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0278] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0279] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 1, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0280] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 2, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0281] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R's is selected from the group consisting of
hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is N, B is CR.sup.5, D is
CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably R.sup.18 is selected
from the group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
substituted phenyl, benzyl and substituted benzyl. More preferably
R.sup.18 is hydrogen or methyl. Preferably, each of R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.6, R.sup.7 and R.sup.8 is hydrogen.
Preferably, each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0282] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is CR.sup.4, B is
CR.sup.5, D is N, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.7 and R.sup.8 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably R.sup.18 is selected
from the group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
substituted phenyl, benzyl and substituted benzyl. More preferably
R.sup.18 is hydrogen or methyl. Preferably, each of R.sup.4,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.7 and R.sup.8 are hydrogen.
Preferably, each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0283] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is N, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6 and R.sup.8 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably R.sup.18 is selected
from the group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
substituted phenyl, benzyl and substituted benzyl. More preferably
R.sup.18 is hydrogen or methyl. Preferably, each of R.sup.4,
R.sup.6 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.6 and R.sup.8 are hydrogen.
Preferably, each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0284] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is N, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5 and R.sup.7 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.5, R.sup.16 and R.sup.17 is independently
hydrogen or alkyl. Preferably R.sup.18 is selected from the group
consisting of hydrogen, C.sub.1-4 alkyl, phenyl, substituted
phenyl, benzyl and substituted benzyl. More preferably R.sup.18 is
hydrogen or methyl. Preferably, each of R.sup.4, R.sup.5 and
R.sup.7 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.5 and R.sup.7 are hydrogen. Preferably,
each of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0285] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is N, B is CR.sup.5, D is
CR.sup.6, E is CR.sup.7, G is N, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.6 and R.sup.7 is independently hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo or
hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably R.sup.18 is selected
from the group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
substituted phenyl, benzyl and substituted benzyl. More preferably
R.sup.18 is hydrogen or methyl. Preferably, each of R.sup.6 and
R.sup.7 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.6 and R.sup.7 are hydrogen. Preferably, each of
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0286] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is N, B is CR.sup.5, D is
N, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.7 and R.sup.8 is independently hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo or
hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably R.sup.18 is selected
from the group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
substituted phenyl, benzyl and substituted benzyl. More preferably
R.sup.18 is hydrogen or methyl. Preferably, each of R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.7 and R.sup.8 are hydrogen. Preferably, each of
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0287] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is N, B is CR.sup.5, D is
CR.sup.6, E is N, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.6 and R.sup.8 is independently hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo or
hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably R.sup.18 is selected
from the group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
substituted phenyl, benzyl and substituted benzyl. More preferably
R.sup.18 is hydrogen or methyl. Preferably, each of R.sup.6 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.6 and R.sup.8 are hydrogen. Preferably, each of
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0288] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is CR.sup.4, B is
CR.sup.5, D is N, E is CR.sup.7, G is N, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4 and R.sup.8 is independently hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo or
hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably R.sup.18 is selected
from the group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
substituted phenyl, benzyl and substituted benzyl. More preferably
R.sup.18 is hydrogen or methyl. Preferably, each of R.sup.4 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4 and R.sup.8 are hydrogen. Preferably, each of
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0289] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably R.sup.18 is selected
from the group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
substituted phenyl, benzyl and substituted benzyl. More preferably,
R.sup.18 is hydrogen or methyl. Preferably, each of R.sup.4,
R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4
alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are
hydrogen. Preferably, each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0290] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 1, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0291] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 2, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0292] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0293] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R's is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0294] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0295] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0296] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 1, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11 is hydrogen.
[0297] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 2, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11 is hydrogen.
[0298] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 1, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0299] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 2, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0300] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 1 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0301] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 2 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0302] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0303] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0304] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 1, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5, R.sup.7 and
R.sup.5 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0305] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B
is CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6
is --W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each
of R.sup.5, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 2, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0306] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is N, B is CR.sup.5, D is
CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably R.sup.18 is selected
from the group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
substituted phenyl, benzyl and substituted benzyl. More preferably
R.sup.18 is hydrogen or methyl. Preferably, each of R.sup.5,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0307] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is CR.sup.4, B is N, D is
CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.7 and R.sup.8 is independently hydrogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo
or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.17, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably R.sup.18 is selected
from the group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
substituted phenyl, benzyl and substituted benzyl. More preferably
R.sup.18 is hydrogen or methyl. Preferably, each of R.sup.4,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0308] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is N, B is CR.sup.5, D is
CR.sup.6, E is CR.sup.7, G is N, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5 and R.sup.7 is independently hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo or
hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably R.sup.18 is selected
from the group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
substituted phenyl, benzyl and substituted benzyl. More preferably
R.sup.18 is hydrogen or methyl. Preferably, each of R.sup.5 and
R.sup.7 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5 and R.sup.7 are hydrogen. Preferably, each of
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0309] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is N, B is CR.sup.5, D is
CR.sup.6, E is N, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5 and R.sup.8 is independently hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo or
hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably R.sup.18 is selected
from the group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
substituted phenyl, benzyl and substituted benzyl. More preferably
R.sup.18 is hydrogen or methyl. Preferably, each of R.sup.5 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5 and R.sup.8 are hydrogen. Preferably, each of
R.sup.9, R.sup.10, R.sup.11, R.sup.12R.sup.13, R.sup.14, R.sup.15,
R.sup.16 and R.sup.17 is independently hydrogen or C.sub.1-4
alkyl.
[0310] In still other embodiments of a compound of Formula (I), n
is 1, Y is a bond, R.sup.18 is selected from the group consisting
of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is CR.sup.4, B is N, D is
CR.sup.6, E is N, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4 and R.sup.8 is independently hydrogen, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, carboxyl, halo or
hydroxyl and each of R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably R.sup.18 is selected
from the group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
substituted phenyl, benzyl and substituted benzyl. More preferably
R.sup.18 is hydrogen or methyl. Preferably, each of R.sup.4 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4 and R.sup.8 are hydrogen. Preferably, each of
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16 and R.sup.17 is independently hydrogen or
C.sub.1-4 alkyl.
[0311] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is selected from the group consisting of
hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl and heteroaryl, A is CR.sup.4, B is CR.sup.5,
D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.5,
R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4
alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0312] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 1, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0313] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 2, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0314] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0315] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0316] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0317] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0318] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 1, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11 is hydrogen.
[0319] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 2, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11 is hydrogen.
[0320] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 1, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0321] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 2, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0322] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 1 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0323] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 2 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0324] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0325] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0326] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 1, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0327] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.4 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 2, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0328] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is selected from the group consisting of
hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl and heteroaryl, A is CR.sup.4, B is CR.sup.5,
D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably, each of R.sup.4,
R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4
alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0329] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 1, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0330] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 2, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0331] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, each of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is
hydrogen. Preferably, R.sup.11 is hydrogen.
[0332] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0333] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0334] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0335] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 1, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is
hydrogen. Preferably, R.sup.11 is hydrogen.
[0336] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 2, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is
hydrogen. Preferably, R.sup.11 is hydrogen.
[0337] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 1, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0338] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 2, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0339] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 1 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0340] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 2 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0341] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.4, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.9 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0342] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0343] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 1, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0344] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.5 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.6, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 2, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.6, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0345] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is selected from the group consisting of
hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
arylalkyl, cycloalkyl, and heteroaryl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or alkyl. Preferably R.sup.18 is selected
from the group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
substituted phenyl, benzyl and substituted benzyl. More preferably,
R.sup.18 is hydrogen or methyl. Preferably, each of R.sup.4,
R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4
alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are
hydrogen. Preferably, each of R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl.
[0346] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 1, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0347] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R's is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is NR.sup.17, r
is 2, and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0348] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G; is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0349] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is a bond, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10 and R.sup.11 is independently
hydrogen or C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 is independently hydrogen or C.sub.1-4 alkyl.
More preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are
hydrogen. Preferably, R.sup.11 is hydrogen.
[0350] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0351] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, (3 is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is NR.sup.17, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, R.sup.11 and R.sup.17 are
hydrogen.
[0352] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 1, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11 is hydrogen.
[0353] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is O, r is 2, and
each of R.sup.9, R.sup.10 and R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11 is hydrogen.
[0354] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G; is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 1, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0355] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is O, k is 1, Z is CR.sup.15R.sup.16,
r is 2, and each of R.sup.9, R.sup.10, R.sup.11, R.sup.15 and
R.sup.16 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.15
and R.sup.16 are hydrogen.
[0356] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 1 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0357] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is NR.sup.17,
r is 2 and each of R.sup.9, R.sup.10, R.sup.11, R.sup.14 and
R.sup.17 is independently hydrogen or C.sub.1-4 alkyl. Preferably,
each of R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently
hydrogen or C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5,
R.sup.7 and R.sup.8 are hydrogen. Preferably, R.sup.11, R.sup.14
and R.sup.17 are hydrogen.
[0358] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 1,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0359] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is O, r is 2,
and each of R.sup.9, R.sup.10, R.sup.11 and R.sup.14 is
independently hydrogen or C.sub.1-4 alkyl. Preferably, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen or
C.sub.1-4 alkyl. More preferably, R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 are hydrogen. Preferably, each of R.sup.11 and R.sup.14 are
hydrogen.
[0360] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.4, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 1, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0361] In still other embodiments of a compound of Formula (I), n
is 1, Y is O, R.sup.18 is hydrogen or methyl, A is CR.sup.4, B is
CR.sup.5, D is CR.sup.6, E is CR.sup.7, G is CR.sup.8, R.sup.6 is
--W[C(O)].sub.kZ(CR.sup.9R.sup.10).sub.rCO.sub.2R.sup.11, each of
R.sup.5, R.sup.5, R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl,
carboxyl, halo or hydroxyl, W is NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, r is 2, and each of R.sup.9, R.sup.10, R.sup.11,
R.sup.14, R.sup.15 and R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl. Preferably, each of R.sup.4, R.sup.5, R.sup.7 and
R.sup.8 is independently hydrogen or C.sub.1-4 alkyl. More
preferably, R.sup.4, R.sup.5, R.sup.7 and R.sup.8 are hydrogen.
Preferably, R.sup.11, R.sup.14, R.sup.15 and R.sup.16 are
hydrogen.
[0362] Compounds of structural Formula (I) may be substrates for
intestinal anion transporters such as the sodium-dependent
multivitamin transporter ("SMVT") and members of the
proton-dependent monocarboxylate transporter ("MCT") family. The
SMVT transporter typically mediates the intestinal absorption of
the water-soluble vitamins pantothenate and biotin whereas natural
substrates for intestinally expressed monocarboxylate transporters
include lactate and pyruvate (Wang et al., J. Biol. Chem. 1999,
274, 14875-14883; Halestrap et al., Biochem. J. 1999, 343,
281-299). The intestinal permeability of certain monocarboxylate
drugs (e.g., carindacillin, atorvastatin, etc.) may be mediated via
interaction with MCTs. Monocarboxylate transporter 1 ("MCT1")
expression extends from the upper regions of the mammalian
gastrointestinal tract through the large intestine, where it plays
a role in absorption of short-chain fatty acids (e.g., butyrate)
produced by colonic bacteria. Molecules transported by such
colonically expressed proteins are candidates for formulation in
sustained oral delivery systems, where controlled release of the
drug during its prolonged residence in the colon leads to sustained
systemic drug levels relative to conventional immediate release
formulations. Similarly, compounds that passively diffuse across
the colonic mucosa may be administered via oral sustained release
formulations.
[0363] Methods for determining whether compounds may serve as
substrates for the SMVT transporter are disclosed in Example 3
herein (see Section 5).
4.3 Synthesis
[0364] Compounds disclosed herein may be obtained via the synthetic
methods illustrated in Schemes 1-7. Compounds of Formula (I) where
n is 0, Y is a bond or CR.sup.1R.sup.2, W is a bond, k is 1, Z is O
or NR.sup.17 and R.sup.11 is hydrogen, i.e., compound (7), are
prepared according to methods illustrated in Scheme 1. The aromatic
or heteroaromatic carboxylic acid compound (2) is first converted
into a reactive acylating agent (3), by treatment with a phosgene
equivalent, thionyl halide or related activating agent. Reaction
with propofol in the presence of base, and optionally a catalyst
such as DMAP, affords bis-ester (4). Removal of the carboxylate
protecting group, conversion to a reactive acylating-agent by
treatment with an appropriate coupling reagent, followed by
addition of protected amino acid or hydroxyl acid (5) generates
compound (6). Finally, removal of the carboxylate protecting group
affords the desired compound (7).
##STR00004##
[0365] Alternatively, ortho-disubstituted aromatic or
heteroaromatic derivatives related to compound (7), i.e., compound
(10), can be expediently prepared starting with anhydride compound
(8), as illustrated in Scheme 2.
##STR00005##
[0366] Compounds of Formula (I) where n is 0, Y is a bond or
CR.sup.1R.sup.2, W is O or NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, O or NR.sup.17 and R.sup.11 is hydrogen, i.e.,
compound (16), are prepared according to methods illustrated in
Scheme 3. The aromatic or heteroaromatic carboxylic acid compound
(11) is first converted into a reactive acylating agent (12), by
treatment with a phosgene equivalent, thionyl halide or related
activating agent. Reaction with propofol in the presence of base,
and optionally a catalyst such as DMAP, affords ester (13). Removal
of the protecting group from either the oxygen or nitrogen atom in
(13), followed by treatment with acylating agent (14) or (15)
affords, after deprotection of the carboxylate moiety, compound
(16).
##STR00006##
[0367] Compounds of Formula (I) where n is 0, Y is O or NR.sup.3, W
is a bond, k is 1, Z is O or NR.sup.17 and R.sup.11 is hydrogen,
i.e., compound (20), are prepared according to methods illustrated
in Scheme 4. The phenolic or anilino compound (17) is reacted with
a phosgene equivalent to give respectively the chloroformate or
amidoyl chloride species (18). Displacement of the chloro group by
treatment with propofol in the presence of base, and optionally a
catalyst like DMAP, affords carbonate or carbamate (19).
Alternatively, compound (19) can be elaborated directly from
compound (17) by reaction with the propofol chloroformate
derivative (31). Coupling of the carboxyalkyl moiety (5) proceeds
as previously described to afford compound (20).
##STR00007##
[0368] Compounds of Formula (I) where n is 0, Y is O or NR.sup.3, W
is O or NR.sup.14, k is 1, Z is CR.sup.5R.sup.6, O or NR.sup.17 and
R.sup.11 is hydrogen, i.e., compound (24), are prepared in an
analogous fashion from compound (21), as illustrated in Scheme
5.
##STR00008##
[0369] Compounds of Formula (I) where n is 1, Y is a bond or
CR.sup.1R.sup.2, W is a bond, k is 1, Z is O or NR.sup.17 and
R.sup.11 is hydrogen, i.e., compound (27), are prepared according
to methods illustrated in Scheme 6. The acyloxyalkyl ether (26) is
prepared from aromatic or heteroaromatic carboxylic acid compound
(2), either by sequential halide displacements of compound (32) in
the presence of a base or metal promoter agent (typically a soluble
Ag.sup.+ or Hg.sup.2+ salt), or by reaction with the haloalkyl (or
thioalkyl) propofol ether (33). If X.sub.2 in (25) is --SR (e.g.,
thiomethyl), activation by treatment with sulfuryl chloride or
similar halogenating agents precedes displacement by propofol to
generate compound (26). Coupling of the carboxyalkyl moiety (5)
proceeds as previously described to afford compound (27).
##STR00009##
[0370] Compounds of Formula (I) where n is 1, Y is a bond or
CR.sup.1R.sup.2, W is O or NR.sup.14, k is 1, Z is
CR.sup.15R.sup.16, O or NR.sup.17 and R.sup.11 is hydrogen, i.e.,
compound (30), are prepared according to methods illustrated in
Scheme 7. The acyloxyalkyl ether (29) is prepared from (11), either
by sequential halide displacements of compound (32) under
conditions previously described (i.e., in the presence of base or
with a metal salt promoter), or by reaction with the haloalkyl (or
thioalkyl) propofol ether (33). Removal of the protecting group
from either the oxygen or nitrogen atom in (29), followed by
treatment with acylating agent (14) or (15) affords, after
deprotection of the carboxylate moiety, compound (30).
##STR00010##
5.4 Therapeutic/Prophylactic Uses of the Compounds and Modes of
Administration
[0371] The compounds described herein, may be used to treat and/or
prevent migraine in patients. The methods comprise administering to
a patient a therapeutically effective amount of a compound to treat
or prevent migraine. In the therapeutic methods disclosed herein, a
therapeutically effective amount of the compound is administered to
a patient suffering from a migraine headache. In the prophylactic
methods disclosed herein a therapeutically effective amount of the
compound is administered to a patient at risk of developing a
migraine.
[0372] In some embodiments, compounds disclosed herein are
administered orally to treat or prevent migraine. However, in other
embodiments, compounds disclosed herein are administered
parenterally (e.g., via inhalation or injection). In some
embodiments, compounds are administered in amounts of between about
10 mg to about 2 g to treat or prevent migraine.
[0373] Compounds disclosed herein may also be used as anti-emetics
and can be administered to patients at risk of vomiting or who are
nauseous. For example, compounds disclosed herein may be
administered to patients that are being concurrently treated with
various chemotherapy agents and/or surgical procedures, which
induce nausea. Accordingly, methods for treating and preventing
nausea and vomiting are provided. Typically, a therapeutically
effective amount of a compound disclosed herein is administered to
a patient to treat or prevent nausea and vomiting.
[0374] In some embodiments, compounds are administered orally to
treat or prevent nausea or vomiting. However, in other embodiments,
compounds are administered parenterally (e.g., via inhalation or
injection to treat or prevent nausea or vomiting. In some
embodiments, compounds are administered in amounts of between about
10 mg to about 2 g to treat or prevent nausea or vomiting.
[0375] Compounds may also be used as hypnotic agents to induce
and/or maintain general anesthesia and/or as a sedative. Typically,
a therapeutically effective amount of compound is administered to a
patient to induce hypnosis.
[0376] In some embodiments, compounds are administered
intravenously when used as a general anesthetic. In other
embodiments, compounds are administered by inhalation. Compounds
may be formulated by the same methods used to formulate propofol,
which are well known in the art. In some embodiments, compounds are
formulated as an aqueous solution, which contains significantly
less emulsifiers or solubilizers than used in aqueous formulations
of propofol.
[0377] In some embodiments, compounds are administered orally in
amounts of about 10 mg to 2 g daily when used as a sedative (e.g.,
for the treatment of anxiety conditions). However, in other
embodiments, compound may also be administered by inhalation,
intravenously or intramuscularly when used as a sedative.
[0378] Compounds disclosed herein may be administered in similar
amounts and in the same schedule as described in the art for
propofol. In some embodiments, dosage levels of compounds for
producing general anesthesia, maintaining anesthesia and producing
a sedative effect are as described in the art for propofol.
[0379] Compounds may also be used to inhibit oxidation in
biological materials. The methods involve contacting the biological
material with an effective amount of the compound. In therapeutic
methods disclosed herein, a therapeutically effective amount of the
compound is administered to a patient suffering from a pathological
condition treated by inhibition of oxidation. In prophylactic
methods disclosed herein a therapeutically effective amount of the
compound is administered to a patient at risk of developing a
disease as a result of exposure to oxidative stress. Compounds
disclosed herein may find particular use in preventing or treating
oxidation in disorders of the central nervous system that involve
an inflammatory component.
[0380] Compounds disclosed herein may be used to treat or prevent
neurodegenerative conditions of the nervous system, which include,
but are not limited to, Friedrich's disease, Parkinson's disease,
Alzheimer's disease, Huntington's disease, amyotrophic lateral
sclerosis (ALS), multiple sclerosis (MS) and Pick disease. In some
embodiments, a therapeutically effective amount of a compound
(e.g., between about 10 mg to about 2 g daily) is orally
administered to treat or prevent chronic neurodegenerative
diseases.
[0381] Compounds disclosed herein may also be used to treat trauma
to the central nervous system such as, for example, skull fracture
and its resulting edema, concussion, contusion, brain hemorrhages,
shearing lesions, subdural and epidural hematoma, and spinal cord
injury (e.g., mechanical injury due to compression or flexion of
the spinal cord). In some embodiments, a compound is parenterally
administered by intravenous injection or injection directly into
the central nervous system (i.e., intrathecally ("IT") or into the
brain) to treat or prevent traumatic conditions of the central
nervous system. In other embodiments, a therapeutically effective
amount of a compound (e.g., between about 25 mg to about 500 mg IV
or IM and between about 5 mg to about 100 mg IT) are administered
to treat or prevent traumatic conditions of the central nervous
system.
[0382] Compounds may also be used as anti-convulsives to treat or
prevent seizures (e.g., epileptic seizures). Methods for treating
or preventing convulsions, which comprise administering a
therapeutically effective amount of a compound disclosed herein to
a patient in need of such treatment are provided. In some
embodiments, compounds are administered orally to treat or prevent
convulsions. In other embodiments, compounds are parenterally
administered to treat or prevent convulsions. In other embodiments,
compounds are administered in amounts of between about 10 mg to
about 2 g daily to treat or prevent convulsions.
[0383] When used to treat or prevent the above disease or disorders
compounds and/or pharmaceutical compositions thereof may be
administered or applied singly, in combination with other agents.
Compounds and/or pharmaceutical compositions thereof may also be
administered or applied singly, in combination with other
pharmaceutically active agents, including other compounds disclosed
herein.
[0384] Methods of treatment and prophylaxis by administration to a
patient of a therapeutically effective amount of a compound or
pharmaceutical composition thereof are provided herein. The patient
may be an animal, is more preferably a mammal, and most preferably,
a human.
[0385] The present compounds and/or pharmaceutical compositions
thereof, are preferably administered orally. Compounds and/or
pharmaceutical compositions thereof may also be administered by any
other convenient route, for example, by infusion or bolus
injection, by absorption through epithelial or mucocutaneous
linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.).
Administration can be systemic or local. Various delivery systems
are known, (e.g., encapsulation in liposomes, microparticles,
microcapsules, capsules, etc.) that can be used to administer
compounds and/or pharmaceutical composition thereof. Methods of
administration include, but are not limited to, intradermal,
intramuscular, intraperitoneal, intravenous, subcutaneous,
intranasal, epidural, oral, sublingual, intranasal, intracerebral,
intravaginal, transdermal, rectally, by inhalation, or topically,
particularly to the ears, nose, eyes, or skin.
[0386] In specific embodiments, it may be desirable to administer
one or more compounds and/or pharmaceutical composition thereof
locally to the area in need of treatment. This may be achieved, for
example, and not by way of limitation, by local infusion during
surgery, topical application, e.g., in conjunction with a wound
dressing after surgery, by injection, by means of a catheter, by
means of a suppository, or by means of an implant, said implant
being of a porous, non-porous, or gelatinous material, including
membranes, such as sialastic membranes, or fibers.
[0387] In certain embodiments, it may be desirable to introduce one
or more compounds and/or pharmaceutical compositions thereof into
the central nervous system by any suitable route, including
intraventricular, intrathecal and epidural injection.
Intraventricular injection may be facilitated by an
intraventricular catheter, for example, attached to a reservoir,
such as an Ommaya reservoir.
[0388] In some embodiments, compounds and/or pharmaceutical
compositions thereof can be delivered via sustained release
systems, preferably, oral sustained release systems. In some
embodiments, a pump may be used (see Langer, supra; Sefton, 1987,
CRC Crit. Ref Biomed Eng. 14:201; Saudek et al., 1989, N. Engl. J.
Med. 321:574).
[0389] In other embodiments, polymeric materials can be used (see
"Medical Applications of Controlled Release," Langer and Wise
(eds.), CRC Pres., Boca Raton, Fla. (1974); "Controlled Drug
Bioavailability," Drug Product Design and Performance, Smolen and
Ball (eds.), Wiley, New York (1984); Langer et al., 1983, J
Macromol. Sci. Rev. Macromol Chem. 23:61; see also Levy et al.,
1985, Science 228: 190; During et al., 1989, Ann. Neurol. 25:351;
Howard et al., 1989, J. Neurosurg. 71:105). In still other
embodiments, polymeric materials are used for oral sustained
release delivery. Such polymers include, for example, sodium
carboxymethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose and hydroxyethylcellulose. Other
cellulose ethers have been described (Alderman, Int. J. Pharm.
Tech. & Prod. Mfr. 1984, 5(3) 1-9). Factors affecting drug
release are well known to the skilled artisan and have been
described in the art (Bamba et al., Int. J. Pharm. 1979, 2,
307).
[0390] In other embodiments, enteric-coated preparations are used
for oral sustained release administration. Coating materials
include, for example, polymers with pH-dependent solubility (i.e.,
pH-controlled release), polymers with slow or pH-dependent rate of
swelling, dissolution or erosion (i.e., time-controlled release),
polymers that are degraded by enzymes (i.e., enzyme-controlled
release) and polymers that form firm layers that are destroyed by
an increase in pressure (i.e., pressure-controlled release).
[0391] In still other embodiments, osmotic delivery systems are
used for oral sustained release administration (Verma et al., Drug
Dev. Ind. Pharm. 2000, 26:695-708). In some embodiments, OROS.TM.
osmotic devices are used for oral sustained release delivery
devices (Theeuwes et al., U.S. Pat. No. 3,845,770; Theeuwes et al.,
U.S. Pat. No. 3,916,899).
[0392] For administration by inhalation, compounds may be
conveniently delivered to the lung by a number of different
devices. For example, a Metered Dose Inhaler ("MDI") which utilizes
canisters that contain a suitable low boiling propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas may
be used to deliver compounds disclosed herein directly to the
lung.
[0393] Alternatively, a Dry Powder Inhaler ("DPI)" device may be
used to administer compounds to the lung (See, e.g. Raleigh et al.,
Proc. Amer. Assoc. Cancer Research Annual Meeting, 1999, 40, 397).
DPI devices typically use a mechanism such as a burst of gas to
create a cloud of dry powder inside a container, which may then be
inhaled by the patient. A popular variation is the multiple dose
DPI ("MDDPI") system, which allows for the delivery of more than
one therapeutic dose. For example, capsules and cartridges of
gelatin for use in an inhaler or insufflator may be formulated
containing a powder mix of a compound and a suitable powder base
such as lactose or starch for these systems.
[0394] Another type of device that may be used to deliver compounds
to the lung is a liquid spray device supplied, for example, by
Aradigm Corporation, Hayward, Calif. Liquid spray systems use
extremely small nozzle holes to aerosolize liquid drug formulations
that may then be directly inhaled into the lung.
[0395] In some embodiments, a nebulizer device is used to deliver a
compound disclosed herein to the lung. Nebulizers create aerosols
from liquid drug formulations by using, for example, ultrasonic
energy to form fine particles that may be readily inhaled (see
e.g., Verschoyle et al., British J. Cancer, 1999, 80, Suppl. 2,
96). Examples of nebulizers include devices supplied by Batelle
Pulmonary Therapeutics (Columbus, Ohio) (See, Armer et al., U.S.
Pat. No. 5,954,047; van der Linden et al., U.S. Pat. No. 5,950,619;
van der Linden et al., U.S. Pat. No. 5,970,974).
[0396] In still other embodiments, an electrohydrodynamic ("EHD")
aerosol device is used to deliver a compound to the lung. EHD
aerosol devices use electrical energy to aerosolize liquid drug
solutions or suspensions (see e.g., Noakes et al., U.S. Pat. No.
4,765,539; Coffee, U.S. Pat. No. 4,962,885; Coffee, International
Publication No. WO 94/12285; Coffee, International Publication No.
WO 94/14543; Coffee, International Publication No. WO 95/26234,
Coffee, International Publication No. WO 95/26235, Coffee,
International Publication No. WO 95/32807). Electrochemical
properties of a compound may be important parameters to optimize
when delivering this compound to the lung with an EHD aerosol
device; such optimization is routinely performed by one of skill in
the art. EHD aerosol devices may more efficiently deliver compounds
to the lung than existing pulmonary delivery technologies. Other
methods of intra-pulmonary delivery of compounds are known to the
skilled artisan and are within the scope of the present
disclosure.
[0397] The compounds and/or pharmaceutical compositions thereof
preferably, provide therapeutic or prophylactic levels of propofol
upon in vivo administration to a patient. While not wishing to
bound by theory, the promoiety or promoieties of the compounds may
be cleaved either chemically and/or enzymatically. One or more
enzymes present in the stomach, intestinal lumen, intestinal
tissue, blood, liver, brain or any other suitable tissue of a
mammal may enzymatically cleave the promoiety or promoieties of the
compounds disclosed herein. The mechanism of cleavage is not
important.
[0398] While not wishing to bound by theory, the promoiety or
promoieties of the compounds disclosed herein may be cleaved prior
to absorption by the gastrointestinal tract (e.g., within the
stomach or intestinal lumen) and/or after absorption by the
gastrointestinal tract (e.g., in intestinal tissue, blood, liver or
other suitable tissue of a mammal). Propofol may remain conjugated
to a promoiety during transit across the intestinal mucosal barrier
to provide protection from presystemic metabolism. In some
embodiments, compounds are essentially not metabolized to propofol
within enterocytes, but are metabolized to the parent drug within
the systemic circulation. Cleavage of the promoiety or promoieties
of the compounds after absorption by the gastrointestinal tract,
may allow these prodrugs to be absorbed into the systemic
circulation either by active transport, passive diffusion or by a
mixture of both active and passive processes. In some embodiments,
compounds are actively absorbed through interaction with anion
transporters like SMVT or MCT's.
[0399] Cleavage of the promoiety or promoieties of compounds after
absorption by the gastrointestinal tract, may allow these prodrugs
to be absorbed into the systemic circulation from the large
intestine. In some embodiments, the compounds and/or pharmaceutical
compositions thereof are administered as sustained release systems.
In other embodiments, the compounds and/or pharmaceutical
compositions thereof are delivered by oral sustained release
administration. Preferably, in this embodiment, the compounds
and/or pharmaceutical compositions are administered twice per day
(more preferably, once per day).
5.5 Pharmaceutical Compositions
[0400] The present pharmaceutical compositions contain a
therapeutically effective amount of one or more compounds,
preferably in purified form, together with a suitable amount of a
pharmaceutically acceptable vehicle, to provide the form for proper
administration to a patient. When administered to a patient, the
compounds and pharmaceutically acceptable vehicles are preferably
sterile. Water is a preferred vehicle when a compound is
administered intravenously. Saline solutions and aqueous dextrose
and glycerol solutions can also be employed as liquid vehicles,
particularly for injectable solutions. Suitable pharmaceutical
vehicles also include excipients such as starch, glucose, lactose,
sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium
stearate, glycerol monostearate, talc, sodium chloride, dried skim
milk, glycerol, propylene, glycol, water, ethanol and the like. The
present pharmaceutical compositions, if desired, can also contain
minor amounts of wetting or emulsifying agents, or pH buffering
agents. In addition, auxiliary, stabilizing, thickening,
lubricating and coloring agents may be used.
[0401] Pharmaceutical compositions comprising a compound disclosed
herein may be manufactured by means of conventional mixing,
dissolving, granulating, dragee-making, levigating, emulsifying,
encapsulating, entrapping or lyophilizing processes. Pharmaceutical
compositions may be formulated in conventional manner using one or
more physiologically acceptable carriers, diluents, excipients or
auxiliaries, which facilitate processing of compounds into
preparations which can be used pharmaceutically. Proper formulation
is dependent upon the route of administration chosen.
[0402] The present compositions can take the form of solutions,
suspensions, emulsion, tablets, pills, pellets, capsules, capsules
containing liquids, powders, sustained-release formulations,
suppositories, emulsions, aerosols, sprays, suspensions, or any
other form suitable for use. In some embodiments, the
pharmaceutically acceptable vehicle is a capsule (see e.g.,
Grosswald et al., U.S. Pat. No. 5,698,155). Other examples of
suitable pharmaceutical vehicles have been described in the art
(see Remington's Pharmaceutical Sciences, Philadelphia College of
Pharmacy and Science, 19th Edition, 1995). In other embodiment,
pharmaceutical compositions are formulated for oral delivery.
[0403] Pharmaceutical compositions for oral delivery may be in the
form of tablets, lozenges, aqueous or oily suspensions, granules,
powders, emulsions, capsules, syrups, or elixirs, for example.
Orally administered pharmaceutical compositions may contain one or
more optional agents, for example, sweetening agents such as
fructose, aspartame or saccharin, flavoring agents such as
peppermint, oil of wintergreen, or cherry coloring agents and
preserving agents, to provide a pharmaceutically palatable
preparation. Moreover, where in tablet or pill form, the
pharmaceutical compositions may be coated to delay disintegration
and absorption in the gastrointestinal tract, thereby providing a
sustained action over an extended period of time. Selectively
permeable membranes surrounding an osmotically active driving
compound are also suitable for orally administered compounds and
pharmaceutical compositions. In these later platforms, fluid from
the environment surrounding the capsule is imbibed by the driving
compound, which swells to displace the agent or agent composition
through an aperture. These delivery platforms can provide an
essentially zero order delivery profile as opposed to the spiked
profiles of immediate release formulations. A time delay material
such as glycerol monostearate or glycerol stearate may also be
used. Oral compositions can include standard vehicles such as
mannitol, lactose, starch, magnesium stearate, sodium saccharine,
cellulose, magnesium carbonate, etc. Such vehicles are preferably
of pharmaceutical grade.
[0404] For oral liquid preparations such as, for example,
suspensions, elixirs and solutions, suitable carriers, excipients
or diluents include water, saline, alkyleneglycols (e.g., propylene
glycol), polyalkylene glycols (e.g., polyethylene glycol) oils,
alcohols, slightly acidic buffers between pH 4 and pH 6 (e.g.,
acetate, citrate, ascorbate at between about 5 mM to about 50 mM),
etc. Additionally, flavoring agents, preservatives, coloring
agents, bile salts, acylcamitines and the like may be added.
[0405] Compounds may also be formulated in rectal or vaginal
pharmaceutical compositions such as suppositories or retention
enemas, e.g., containing conventional suppository bases such as
cocoa butter or other glycerides.
[0406] In addition to the formulations described previously,
compounds may also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation (for
example, subcutaneously or intramuscularly) or by intramuscular
injection. Thus, for example, compounds may be formulated with
suitable polymeric or hydrophobic materials (for example, as an
emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble
salt.
[0407] When a compound is acidic, it may be included in any of the
above-described formulations as the free acid, a pharmaceutically
acceptable salt, a solvate or hydrate. Pharmaceutically acceptable
salts substantially retain the activity of the free acid, may be
prepared by reaction with bases and tend to be more soluble in
aqueous and other protic solvents than the corresponding free acid
form.
[0408] Liquid drug formulations suitable for use with nebulizers
and liquid spray devices and EHD aerosol devices will typically
include a compound with a pharmaceutically acceptable carrier. The
pharmaceutically acceptable carrier may be a liquid such as
alcohol, water, polyethylene glycol or perfluorocarbon. Optionally,
another material may be added to alter the aerosol properties of
the solution or suspension of compounds disclosed herein.
Preferably, this material is liquid such as an alcohol, glycol,
polyglycol or fatty acid. Other methods of formulating liquid drug
solutions or suspension suitable for use in aerosol devices are
known to those of skill in the art (see, e.g., Biesalski, U.S. Pat.
No. 5,112,598; Biesalski, U.S. Pat. No. 5,556,611).
5.6 Combination Therapy
[0409] In certain embodiments, the compounds disclosed herein can
be used in combination therapy with at least one other therapeutic
agent. The compound and the therapeutic agent can act additively
or, more preferably, synergistically. In some embodiments, a
pharmaceutical composition comprising a compound disclosed herein
is administered concurrently with the administration of another
therapeutic agent, which can be part of the same pharmaceutical
composition a or a different pharmaceutical composition. In other
embodiments, a pharmaceutical composition comprising a compound
disclosed herein is administered prior or subsequent to
administration of another therapeutic agent.
6. EXAMPLES
[0410] The following examples, further define the disclosure and
describe in detail preparation of compounds, pharmaceutical
compositions thereof and assays for using compounds and
pharmaceutical compositions. It will be apparent to those skilled
in the art that many modifications, both to materials and methods,
may be practiced without departing from the scope of the
invention.
[0411] In the examples below, the following abbreviations have the
following meanings. If an abbreviation is not defined, it has its
generally accepted meaning. [0412] Atm=atmosphere [0413]
Boc=tert-butyloxycarbonyl [0414] Bzl=benzyl [0415]
Cbz=carbobenzyloxy [0416] DCC=dicyclohexylcarbodiimide [0417]
DMAP=4-N,N-dimethylaminopyridine [0418] DMEM=Dulbecco's minimun
eagle medium [0419] DMF=N,N-dimethylformamide [0420]
DMSO=dimethylsulfoxide [0421] Fmoc=9-fluorenylmethyloxycarbonyl
[0422] g=gram [0423] h=hour [0424] HBSS=Hank's buffered saline
solution [0425] L=liter [0426] LC/MS=liquid chromatography/mass
spectroscopy [0427] M=molar [0428] min=minute [0429] mL=milliliter
[0430] mmol=millimoles [0431] NHS=N-hydroxysuccinimide [0432]
PBS=phosphate buffered saline [0433] THF=tetrahydrofuran [0434]
TFA=trifluoroacetic acid [0435] TMS=trimethylsilyl [0436]
.mu.L=microliter [0437] .mu.M=micromolar [0438] v/v=volume to
volume
Example 1
3-{[2-[2,6-Bis(isopropyl)phenoxycarbonyl]-benzoyl]amino}-propanoic
acid (101)
Step A: 2-[2,6-Bis(isopropyl)phenoxycarbonyl]-benzoic acid
(102)
[0439] To a mixture of phthalic anhydride (0.84 g, 5.6 mmol) and
propofol (1 g, 5.6 mmol) was added triethylamine (0.65 g, 6.4 mmol)
and a catalytic amount of DMAP. The reaction mixture was brought to
90.degree. C., stirred for 14 h, cooled to room temperature and
diluted with ethyl ether (100 mL). The organic layer was washed
with 10% aqueous citric acid solution (2.times.50 mL). The phases
were separated and the organic phase was dried over MgSO.sub.4 and
concentrated in vacuo. The crude product was sufficiently pure to
be carried to the subsequent step.
Step B
3-{[2-[2,6-Bis(isopropyl)phenoxycarbonyl]-benzoyl]amino}-propanoic
acid (101)
[0440] To a solution containing (102) (2.1 g, 6.4 mmol) and
beta-alanine tert-butyl ester hydrochloride (1.16 g, 6.4 mmol) in
DMF (20 mL) was added diisopropylethylamine (2.4 mL, 13.7 mmol)
followed by O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (2.5 g, 6.5 mmol). The resulting reaction
mixture was stirred at room temperature for 14 h, diluted with
ethyl acetate (100 mL), washed with 10% aqueous citric acid
solution (50 mL), followed by saturated aqueous NaHCO.sub.3
solution (50 mL) and brine (2.times.50 mL). The organic phase was
dried over MgSO.sub.4 and concentrated in vacuo. The crude residue
was dissolved in anhydrous dichloromethane (30 mL) and cooled to
0.degree. C. before a solution of hydrochloric acid (10 mL, 4 N in
dioxane) was added. The reaction was stirred for 1 h at 0.degree.
C. and 1 h at room temperature. The solvent was removed in vacuo
and the crude residue was purified by preparative LC/MS to afford
0.85 g (38% yield over three steps) of the title compound (101).
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 8.20 (dd, J=7.6, 0.8 Hz,
1H), 7.70-7.68 (m, 1H), 7.63-7.59 (m, 1H), 7.49 (dd, J=7.6, 0.8 Hz,
1H), 7.22-7.17 (m, 3H), 3.54 (t, J=7.2 Hz, 2H), 3.06-3.00 (m, 2H),
2.57 (t, J=6.8 Hz, 2H), 1.19 (d, J=6.8 Hz, 12H). MS (ESI) m/z 398.3
(M+H.sup.+).
Example 2
3-{[2-[2,6-Bis(isopropyl)phenoxycarbonyloxy]-benzoyl]amino}-propanoic
acid (103)
Step A: 2,6-Bis(isopropyl)phenoxycarbonyl chloride (104)
[0441] Phosgene (13 mL, 20% in toluene) was added to propofol (3.6
g, 20 mmol) under a nitrogen atmosphere. The mixture was cooled to
0.degree. C. and N,N-dimethylaniline (3.3 mL, 26 mmol) was added
dropwise. The reaction mixture was allowed to warm to room
temperature slowly and stirred for 14 h. The solvent was removed in
vacuo. The crude product was carried to next step without further
purification.
Step B: Benzyl 2-[2,6-Bis(isopropyl)phenoxycarbonyloxy]-benzoate
(105)
[0442] To a cooled (0.degree. C.) solution of benzyl salicylate
(0.77 g, 3.3 mmol) in dichloromethane (6 mL) was added
triethylamine (0.52 mL, 3.7 mmol) and a catalytic amount of DMAP.
To this mixture a suspension of compound (104) (0.9 g, 3.7 mmol,
crude product from last step) in dichloromethane (4 mL) was further
added. The reaction was allowed to warm to room temperature slowly
and stirred for 14 h. The reaction mixture was then diluted with
10% aqueous citric acid solution (10 mL) and extracted with ethyl
ether (2.times.40 mL). The organic phase was dried over MgSO.sub.4
and concentrated in vacuo. The residue was purified by radial
chromatography on silica gel (eluting with ethyl acetate/hexane) to
afford 0.8 g (57% yield over two steps) of the title compound
(105).
Step C: 2-[2,6-Bis(isopropyl)phenoxycarbonyloxy]-benzoic acid
(106)
[0443] To a suspension of 10% Pd--C (100 mg) in ethyl acetate (15
mL) under nitrogen was added a solution of compound (105) (0.7 g,
1.6 mmol) in ethyl acetate (5 mL). The resulting suspension was
degassed three times and then hydrogen gas was introduced. The
reaction mixture was stirred under 1 atm hydrogen atmosphere for 14
h, then filtered through a small plug of celite. The filtrate was
concentrated in vacuo. The crude product (106) was carried to next
step without further purification.
Step D
3-{[2-[2,6-Bis(isopropyl)phenoxycarbonyloxy]-benzoyl]amino}-propanoic
acid (103)
[0444] To a solution of crude compound (106) (0.4 g, 1.1 mmol) from
above and beta-alanine tert-butyl ester hydrochloride (0.2 g, 1.1
mmol) in DMF (5 mL) was added diisopropylethylamine (0.41 mL, 2.3
mmol) followed by O-(benotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (0.44 g, 1.1 mmol). The resulting reaction
mixture was stirred at room temperature for 14 h, diluted with
ethyl acetate (50 mL), washed with 10% aqueous citric acid solution
(30 mL), followed by saturated aqueous NaHCO.sub.3 solution (30 mL)
and brine (2.times.20 mL). The organic phase was dried over
MgSO.sub.4 and concentrated in vacuo. The crude residue was then
dissolved in anhydrous dichloromethane (5 mL) and cooled to
0.degree. C. before a solution of hydrochloric acid (1 mL, 4 N in
dioxane) was added. The reaction was stirred for 2 h at 0.degree.
C. and the solvent was removed in vacuo. The crude residue was
purified by preparative LC/MS to afford 50 mg (8% yield over three
steps) of the title compound (103). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.85 (dd, J=7.6, 1.6 Hz, 1H), 7.51-7.48 (m,
1H), 7.34-7.13 (m, 5H), 3.72 (q, J=6.0 Hz, 2H), 3.13-3.10 (m, 2H),
2.67 (t, J=6.4 Hz, 2H), 1.25 (d, J=6.8 Hz, 12H). MS (ESI) m/z 414.3
(M+H.sup.+).
Example 3
Analysis of Electrogenic Transport in SMVT-Expressing Xenopus
Oocytes
[0445] Transporter Cloning The complete open reading frame of human
SMVT (SLC5A6) was amplified from human cDNA prepared from
intestinal mRNA. Gene-specific oligonucleotide primers were
designed against Genbank sequences (NM-021095). Amplified PCR
products were cloned into a modified version of the mammalian
expression vector pcDNA3 (termed pMO) that was engineered to
contain the 5' and 3' untranslated regions from the Xenopus
beta-globin gene. All clones were completely sequenced and tested
for function by transient transfection in HEK293 cells.
Radiolabeled .sup.3H biotin was used to assess SMVT function (see
method below).
[0446] Xenopus Oocyte Expression and Electrophysiology: cRNA for
oocyte expression was prepared by linearization of plasmid cDNA and
in vitro transcription using T7 polymerase (Epicentre Ampliscribe
kit). Xenopus oocytes were prepared and maintained as previously
described (Collins et al., Proc. Natl. Acad. Sci. 1997,
13:5456-5460) and injected with 10-30 ng RNA. Transport currents
were measured 2-6 days later using two-electrode voltage-clamp
(Axon Instruments). All experiments were performed using a modified
oocyte ringers solution (90 mM NaCl, 2 mM KCl, 1.8 mM CaCl.sub.2, 1
mM MgCl.sub.2, and 10 mM NaHEPES, pH 7.4; in Na.sup.+-free
solutions 90 mM choline chloride was substituted for NaCl). The
membrane potential of oocytes was held at -60 mV and current traces
acquired using PowerLab software (ADInstruments). Full
7-concentration dose-responses were performed for each compound.
Current responses at the highest concentration were normalized to
the maximal biotin elicited currents (i.e., at 0.5 mM).
Half-maximal concentrations were calculated using non-linear
regression curve fitting software (Prism) with the Hill
co-efficient fixed to 1. To ensure that currents were specific for
the over-expressed transporter, all compounds were tested against
uninjected oocytes. Since SMVT requires Na.sup.+ for transport,
transport specificity was confirmed by application of the compounds
in a Na.sup.+-free solution.
[0447] Compound (101) elicited SMVT-specific currents significantly
above background (at least 10% of I.sub.max for biotin) when tested
at 0.5 mM on oocytes expressing SMVT, confirming that this compound
serves as a substrate for the transporter.
[0448] Finally, it should be noted that there are alternative ways
of implementing the present invention. Accordingly, the disclosed
embodiments are to be considered as illustrative and not
restrictive, and the invention is not to be limited to the details
given herein, but may be modified within the scope and equivalents
of the appended claims. All publications and patents cited herein
are incorporated by reference.
* * * * *