U.S. patent application number 17/500681 was filed with the patent office on 2022-03-31 for direct ampk activators.
This patent application is currently assigned to Rigel Pharmaceuticals, Inc.. The applicant listed for this patent is Rigel Pharmaceuticals, Inc.. Invention is credited to Matthew Duncton, Yasumichi Hitoshi, Sarkiz Issakani, Nan Lin, Simon Shaw, Rajinder Singh, Xiang Xu.
Application Number | 20220098175 17/500681 |
Document ID | / |
Family ID | |
Filed Date | 2022-03-31 |
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United States Patent
Application |
20220098175 |
Kind Code |
A1 |
Shaw; Simon ; et
al. |
March 31, 2022 |
DIRECT AMPK ACTIVATORS
Abstract
Disclosed are benzimidazole compounds, as well as pharmaceutical
compositions and methods of use thereof. One embodiment is a
compound having the structure ##STR00001## and pharmaceutically
acceptable salts, prodrugs and N-oxides thereof (and solvates and
hydrates thereof), wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, Y
and X are as described herein. In certain embodiments, a compound
disclosed herein activates AMPK, and can be used to treat disease
by activating the AMPK pathway.
Inventors: |
Shaw; Simon; (Oakland,
CA) ; Xu; Xiang; (Foster City, CA) ; Issakani;
Sarkiz; (Redwood City, CA) ; Singh; Rajinder;
(Belmont, CA) ; Hitoshi; Yasumichi; (Brisbane,
CA) ; Duncton; Matthew; (San Bruno, CA) ; Lin;
Nan; (Foster City, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Rigel Pharmaceuticals, Inc. |
South San Francisco |
CA |
US |
|
|
Assignee: |
Rigel Pharmaceuticals, Inc.
South San Francisco
CA
|
Appl. No.: |
17/500681 |
Filed: |
October 13, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15677809 |
Aug 15, 2017 |
11174246 |
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17500681 |
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62376950 |
Aug 19, 2016 |
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International
Class: |
C07D 403/04 20060101
C07D403/04; C07D 235/26 20060101 C07D235/26; C07D 403/12 20060101
C07D403/12; C07D 403/14 20060101 C07D403/14 |
Claims
1. A compound having the structure of formula (I): ##STR00080##
wherein R.sup.1 and R.sup.2 together with the atoms to which they
are attached form ring A, wherein ring A is a 5- or 6-membered Het
optionally substituted with one or more R.sup.A groups that are
each independently C.sub.3-8Cak(C.sub.0-6alkyl),
Hca(C.sub.0-6alkyl), Ar(C.sub.0-6alkyl), Het(C.sub.0-6alkyl),
--O--C.sub.0-6alkyl-C.sub.3-8Cak, --O--C.sub.0-6alkyl-Hca,
--O--C.sub.0-6alkyl-Ar, --O--C.sub.0-6alkyl-Het, halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR)2 or --CH.sub.2--OP(O)(OR) wherein
each Ar, Het, Cak, Hca, alkyl, alkoxy and haloalkyl group is
optionally substituted by one or two --R.sup.Ax groups, wherein
each --R.sup.Ax is independently halogen, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR, --SR,
--NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR)2 or --CH.sub.2--OP(O)(OR); or one of
R.sup.1 and R.sup.2 is Ar or Het, wherein Ar and Het are optionally
substituted with one or more independently selected R.sup.A groups,
and the other is hydrogen, halogen, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR, --SR,
--NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR)2 or --CH.sub.2--OP(O)(OR); R.sup.3
and R.sup.4 are independently hydrogen, halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR); X is
--O--, --S--, --NR-- or --CF.sub.2--; ##STR00081## wherein R.sup.Y
is hydrogen or C.sub.1-6alkyl; and each R is independently
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
--(C.sub.0-C.sub.6alkyl)-Ar, --(C.sub.0-C.sub.6alkyl)-Het,
--(C.sub.0-C.sub.6alkyl)-Cak, or --(C.sub.0-C.sub.6alkyl)-Hca,
wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally
substituted with C.sub.1-C.sub.6alkyl, halogen,
C.sub.1-C.sub.6haloalkyl or cyano; or a pharmaceutically acceptable
salt thereof.
2. The compound of claim 1, wherein R.sup.1 and R.sup.2 together
with the atoms to which they are attached form ring A, wherein ring
A is 5- or 6-membered Het optionally substituted with one or more
R.sup.A groups that are each independently
C.sub.3-8Cak(C.sub.0-6alkyl), Hca(C.sub.0-6alkyl),
Ar(C.sub.0-6alkyl), Het(C.sub.0-6alkyl),
--O--C.sub.0-6alkyl-C.sub.3-8Cak, --O--C.sub.0-6alkyl-Hca,
--O--C.sub.0-6alkyl-Ar, --O--C.sub.0-6alkyl-Het, halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, -OP(O)(OR)2 or --CH.sub.2--OP(O)(OR), wherein
each Ar, Het, Cak, Hca, alkyl, alkoxy and haloalkyl group is
optionally substituted by one or two --R.sup.Ax groups, wherein
each --R.sup.Ax is independently halogen, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR, --SR,
--NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR); or
one of R.sup.1 and R.sup.2 is Ar or Het, wherein Ar and Het are
substituted with one or more R.sup.A groups, and the other is
hydrogen, halogen, cyano, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
--C.sub.1-C.sub.6alkoxy, --OR, --SR, --NR.sub.2, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R,
--N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or
--CH.sub.2--OP(O)(OR).
3. The compound of claim 1, wherein R.sup.1 and R.sup.2 together
with the atoms to which they are attached form a 5- or 6-membered
Het optionally substituted with one or more R.sup.A groups, or one
of R.sup.1 and R.sup.2 is Ar.
4. The compound of claim 1, wherein R.sup.1 and R.sup.2 together
with the atoms to which they are attached form a 5- or 6-membered
Het optionally substituted with one or more R.sup.A groups.
5. The compound of claim 1, wherein R.sup.1 is Ar optionally
substituted with one or more R.sup.A groups.
6. The compound of claim 1, wherein X is --O--.
7. The compound of claim 1, wherein each R.sup.A is independently
halogen, cyano, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
--C.sub.1-C.sub.6alkoxy, --OR, --SR, --NR.sub.2, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R,
--N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or
--CH.sub.2--OP(O)(OR), wherein each alkyl, alkoxy and haloalkyl
group is optionally substituted by one or two --R.sup.Ax groups,
wherein each --R.sup.Ax is independently halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR).
8. The compound of claim 1, wherein R.sup.Y is methyl.
9. The compound of claim 1, wherein the compound is in the form of
a pharmaceutically acceptable salt.
10. The compound of claim 1, wherein the compound is in the form of
a solvate.
11. A compound that is
1-(5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)--
2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one;
1-(5-((6-fluoro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)--
2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one;
1-(54(6-fluoro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2--
yl)oxy)-2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one;
5-((6-fluoro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-m-
ethylbenzoic acid;
1-(5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)--
2-methylphenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one;
1-(5-((6-fluoro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-
-yl)oxy)-2-methylphenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one; or
a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or
solvate or hydrate thereof.
12. The compound of claim 1, having the structure of formula (II):
##STR00082## wherein ring A is a 5- or 6-membered Het; and n is 1,
2, 3 or 4.
13. The compound of claim 12, wherein ring A is a 5-membered
Het.
14. The compound of claim 12, wherein ring A is a 6-membered
Het.
15. The compound of claim 12, wherein ring A is pyridyl,
pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, furanyl, thiophenyl,
pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl or
thiazolyl.
16. The compound of claim 13, wherein ring A is pyrrolyl.
17. The compound of claim 13, wherein ring A is
N-methylpyrrolyl.
18. The compound of claim 12, wherein each R.sup.A is independently
halogen, cyano, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
--C.sub.1-C.sub.6alkoxy, --OR, --SR, --NR.sub.2, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R,
--N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or
--CH.sub.2--OP(O)(OR), wherein each alkyl, alkoxy and haloalkyl
group is optionally substituted by one or two --R.sup.Ax groups,
wherein each --R.sup.Ax is independently halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR).
19. The compound of claim 12, wherein X is --O--.
20. A method for activating the AMPK pathway in a cell, the method
comprising contacting the cell with an effective amount of the
compound of claim 1.
21. The method of claim 20, wherein the cell is in a subject.
Description
BACKGROUND
Cross Reference to Related Applications
[0001] This is a continuation of application Ser. No. 15/677,809,
filed Aug. 15, 2017, which claims the benefit of U.S. 62/376,950,
filed Aug. 19, 2016, the entire contents of which are incorporated
by reference.
Field of Invention
[0002] This invention relates to the field of compounds,
pharmaceutical compositions, and methods of using the compounds and
compositions containing them. This invention relates more
particularly to the field of benzimidazole compounds and
pharmaceutical compositions thereof, methods of activating AMPK
with the compounds, and methods of treating and/or preventing
disease with the compounds.
Technical Background
[0003] Adiponectin is a protein hormone exclusively expressed in
and secreted from adipose tissue and is the most abundant
adipose-specific protein. Adiponectin has been implicated in the
modulation of glucose and lipid metabolism in insulin-sensitive
tissues. Decreased circulating adiponectin levels have been
demonstrated in some insulin-resistant states, such as obesity and
type 2 diabetes mellitus and also in patients with coronary artery
disease, atherosclerosis and hypertension. Adiponectin levels are
positively correlated with insulin sensitivity, HDL (high density
lipoprotein) levels and insulin stimulated glucose disposal and
inversely correlated with adiposity and glucose, insulin and
triglyceride levels. Thiazolidinedione drugs, which enhance insulin
sensitivity through activation of the peroxisome
proliferator-activated receptor-.gamma., increase endogenous
adiponectin production in humans.
[0004] Adiponectin binds its receptors in liver and skeletal muscle
and thereby activates the 5'-AMP-activated protein kinase (AMPK)
pathway. Adiponectin receptors 1 and 2 are membrane-bound proteins
found in skeletal muscle and liver tissue. Being a multi-substrate
enzyme, AMPK regulates a variety of metabolic processes, such as
glucose transport, glycolysis and lipid metabolism. It acts as a
sensor of cellular energy homeostasis and is activated in response
to certain hormones and muscle contraction as well as to
intracellular metabolic stress signals such as exercise ischemia,
hypoxia and nutrient deprivation. Once activated, AMPK switches on
catabolic pathways (such as fatty acid oxidation and Glycolysis)
and switches off ATP-consuming pathways (such as lipogenesis).
Adiponectin improves insulin sensitivity by directly stimulating
glucose uptake in adipocytes and muscle and by increasing fatty
acid oxidation in liver and muscle, resulting in reduced
circulating fatty acid levels and reduced intracellular
triglyceride contents. Moreover, adiponectin decreases glycogen
concentration by reducing the activity of glycogen synthase.
Adiponectin also plays a protective role against inflammation and
atherosclerosis. It suppresses the expression of adhesion molecules
in vascular endothelial cells and cytokine production from
macrophages, thus inhibiting the inflammatory processes that occur
during the early phases of atherosclerosis.
SUMMARY
[0005] In view of the foregoing, we recognized that new therapeutic
agents that activate the AMPK pathway may be useful and therefore
desirable for treating disease states associated with circulating
adiponectin levels, such as type II diabetes, atherosclerosis and
cardiovascular disease.
[0006] Accordingly, the present invention comprises compounds,
pharmaceutical compositions, and methods of using them to treat
and/or prevent disease by activating AMPK.
[0007] Disclosed herein are compounds having structural formula
(I)
##STR00002##
and pharmaceutically acceptable salts, prodrugs, and N-oxides
thereof (and solvates and hydrates thereof), wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, Y and X are as described herein.
[0008] Also disclosed herein are pharmaceutical compositions.
Examples of such compositions include those having at least one
pharmaceutically acceptable carer, diluent, or excipient; and a
compound, pharmaceutically acceptable salt, prodrug, or N-oxide (or
solvate or hydrate) as described herein.
[0009] Another aspect of the invention is a method for activating
the AMPK pathway in a cell, the method comprising contacting the
cell with an effective amount of a compound, pharmaceutically
acceptable salt, prodrug, solvate, hydrate or N-oxide or
composition described above. For the purposes of this disclosure,
"contacting the cell" with a compound of the disclosure includes
causing the cell to be contacted with the compound, e.g., by
administering the compound to an individual resulting in the
compound and a cell of the individual coming into contact in
vivo.
[0010] Another aspect of the invention is a method for increasing
fatty acid oxidation in a cell, the method comprising contacting
the cell with an effective amount of a compound, pharmaceutically
acceptable salt, prodrug, solvate, hydrate or N-oxide or
composition described above.
[0011] Another aspect of the invention is a method for decreasing
glycogen concentration in a cell, the method comprising contacting
the cell with an effective amount of a compound, pharmaceutically
acceptable salt, prodrug, solvate, hydrate or: T-oxide or
composition described above.
[0012] Another aspect of the invention is a method for reducing
triglyceride levels in a subject, the method comprising
administering to the subject an effective amount of a compound,
pharmaceutically acceptable salt, prodrug, solvate, hydrate or
N-oxide or composition described above.
[0013] Another aspect of the invention is a method for treating
type II diabetes in a subject with type diabetes, the method
comprising administering to the subject a therapeutically effective
amount of a compound, pharmaceutically acceptable salt, prodrug,
solvate, hydrate or N-oxide or composition described above to
ameleoriate the type II diabetes or at least one symptom thereof in
the subject.
[0014] Another aspect of the invention is a method for treating
atherosclerosis or cardiovascular disease in a subject with
atherosclerosis or cardiovascular disease, the method comprising
administering to the subject a therapeutically effective amount of
a compound, pharmaceutically acceptable salt, prodrug, solvate,
hydrate or N-oxide or composition described above to ameleoriate
atherosclerosis, cardiovascular disease, or at least one symptom
thereof in the subject.
[0015] Another aspect of the invention is a method for preventing
atherosclerosis or cardiovascular disease in a subject, the method
comprising administering to the subject an effective amount of a
compound, pharmaceutically acceptable salt, prodrug, solvate,
hydrate or N-oxide or composition described above to prevent
atherosclerosis or cardiovascular disease in the subject.
[0016] All publications referenced herein are incorporated by
reference in their entirety to the extent they are not inconsistent
with the teachings presented herein.
DETAILED DESCRIPTION
[0017] In one aspect, the invention comprises compounds that
activate AMPK.
[0018] In embodiment I.sub.1 of this first aspect, the compounds
have structural formula (i):
##STR00003##
or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof,
or a solvate or hydrate thereof, wherein
[0019] R.sup.1 and R.sup.2 together with the atoms to which they
are attached form ring A, wherein ring A is a 5- or 6-membered Het
optionally substituted with one or more R.sup.A groups that are
each independently C.sub.3-8Cak(C.sub.0-6alkyl),
Hca(C.sub.0-6alkyl), Ar(C.sub.0-6alkyl), Het(C.sub.0-6alkyl),
--O--C.sub.0-6alkyl-C.sub.3-8Cak, --O--C.sub.0-6alkyl-Hca,
--O--C.sub.0-6alkyl-Ar, --O--C.sub.0-6alkyl-Het, halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6alkoxy, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR)
wherein each Ar, Het, Cak, Hca, alkoxy and haloalkyl group is
optionally substituted by one or two --R.sup.Ax groups, [0020]
wherein each --R.sup.Ax is independently halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR);
[0021] or one of R.sup.1 and R.sup.2 is Ar or Het, wherein Ar and
Het are optionally substituted with one or more independently
selected R.sup.A groups, and the other is hydrogen, halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR);
[0022] R.sup.3 and R.sup.4 are independently hydrogen, halogen,
cyano, C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy,
--OR, --SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR);
[0023] X is --O--, --S--, --NR-- or --CF.sub.2--;
[0024] Y is, --NR.sub.2, --CN, --C(O)OR.sup.Y, --C(O)NHOH,
##STR00004## [0025] wherein R.sup.Y is hydrogen or C.sub.1-6alkyl;
and
[0026] each R is independently hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, --(C.sub.0-C.sub.6alkyl)-Ar,
--(C.sub.0-C.sub.6alkyl)-Het, --(C.sub.0-C.sub.6alkyl)-Cak, or
--(C.sub.0-C.sub.6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and
haloalkyl are optionally substituted with C.sub.1-C.sub.6alkyl,
halogen, C.sub.1-C.sub.6haloalkyl or cyano.
[0027] In embodiment I', the compounds are of embodiment I.sub.1,
provided that the compounds are not any of the compounds expressly
recited in U.S. Pat. No. 8,394,969 or International Publication No.
WO 2010/036613 A1.
[0028] In embodiment I.sub.2, the compounds are of embodiment
I.sub.1, or a pharmaceutically acceptable salt, prodrug, or N-oxide
thereof, or a solvate or hydrate thereof, provided that the
compound is not: [0029]
5-((6-([1,1'-biphenyl]-4-yl)-4H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoi-
c acid; [0030]
4-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)benzoi-
c acid; [0031]
4-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)benzam-
ide; [0032]
3-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)benzoi-
c acid; [0033]
3-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)benzoa-
te; [0034]
3-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)-
oxy)-5-methylbenzoic acid; [0035]
5-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-met-
hylbenzoic acid; [0036]
5-((5-([1,1'-biphenyl]-4-yl)-6-fluoro-1H-benzo[d]imidazol-2-yl)oxy)-1-met-
hylbenzoic acid; [0037]
5-((6-chloro-5-(2'-methyl-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)-
oxy)-2-methylbenzoic acid; [0038]
4-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-chl-
orobenzoic acid; [0039]
4-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-hyd-
roxybenzoic acid; [0040]
3-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-5-hyd-
roxybenzoic acid; [0041]
5-((6-chloro-5-(2-methyl-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)o-
xy)-2-methylbenzoic acid; [0042]
3-((6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl-
)oxy)-5-methylbenzoic acid; [0043]
5-((6-chloro-5-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl-
)oxy)-2-methylbenzoic acid; [0044]
5-((6-chloro-5-(2'-chloro-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)-
oxy)-2-methylbenzoic acid; [0045]
5-((6-chloro-5-(2'-fluoro-[1,1'-biphenyl]-4-yl)-benzo[d]imidazol-2-yl)oxy-
-2-methylbenzoic acid; [0046]
5-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-hyd-
roxybenzoic acid; [0047]
5-((6-chloro-5-(4'-fluoro-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)-
oxy)-2-methylbenzoic acid; [0048]
2-(3-(2H-tetrazol-5-yl)phenoxy)-5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benz-
o[d]imidazole; [0049]
5-((6-chloro-5-(4'-cyano-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)o-
xy)-2-methylbenzoic acid; [0050]
5-((6-chloro-5-(4'-methoxy-[1,1'-biphenyl]-4-y)-1H-benzo[d]imidazol-2-yl)-
oxy)-2-methylbenzoic acid; [0051]
5-((6-chloro-5-(3'-fluoro-[1,1'-biphenyl]-4-yl)-benzo[d]imidazol-2-yl)oxy-
-2-methylbenzoic acid; [0052]
5-((6-chloro-5-(3'-chloro-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)-
oxy)-2-methylbenzoic acid; [0053]
3-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-4-flu-
orobenzoic acid; [0054]
3-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-4-chl-
orobenzoic acid; [0055]
5-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-eth-
ylbenzoic acid; [0056]
5-((6-fluoro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl-
)oxy)-2-methylbenzoic acid; [0057]
4'-(2-(3-carboxy-4-methylphenoxy)-6-chloro-1H-benzo[d]imidazol-5-yl)-[1,1-
'-biphenyl]-4-carboxylic acid; [0058]
4'-(2-(3-carboxy-4-methylphenoxy)-6-fluoro-1H-benzo[d]imidazol-5-yl)-[1,1-
'-biphenyl]-4-carboxylic acid; [0059]
4-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)phthal-
ic acid; [0060]
5-((6-chloro-5-(3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl-
)oxy)-2-methylbenzoic acid; [0061]
5-((5-(2'-amino-[1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)o-
xy) 2-methylbenzoic acid; [0062]
3-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-4-met-
hoxybenzoic acid; [0063] methyl
5-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-met-
hylbenzoate; [0064] methyl
5-((5-([1,1'-biphenyl]-4-yl)-6-fluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-met-
hylbenzoate; [0065]
5-((6-chloro-5-(2'-methoxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl-
)oxy)-2-methylbenzoic acid; [0066]
5-((6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl-
)oxy)isophthalic acid; [0067] methyl
5-((6-chloro-5-(2'-methyl-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)-
oxy)-2-methylbenzoate; [0068] methyl
4-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-hyd-
roxybenzoate, [0069] methyl
5-((6-chloro-5-(2'-fluoro-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)-
oxy)-2-methylbenzoate; [0070] methyl
5-((6-chloro-5-(2'-chloro-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)-
oxy)-2-methylbenzoate; [0071] methyl
5-((5-chloro-6-(3'-fluoro-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)-
oxy)-2-methylbenzoate; [0072] methyl
5-((6-chloro-5-(2'-methoxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl-
)oxy)-2-methylbenzoate; [0073]
5-((5-(9H-carbazol-2-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylb-
enzoic acid; [0074] dimethyl
4-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)phthal-
ate; [0075] ethyl
4'-(6-fluoro-2-(3-(methoxycarbonyl)-4-methylphenoxy)-1H-benzo[d]imidazol--
5-yl)-[1,1'-biphenyl]-4-carboxylate; [0076] or a pharmaceutically
acceptable salt thereof
[0077] In embodiment I.sub.3, the compounds are of embodiment
I.sub.1, or a pharmaceutically acceptable salt, prodrug, or N-oxide
thereof, or a solvate or hydrate thereof, wherein
[0078] R.sup.1 and R.sup.2 together with the atoms to which they
are attached form ring A, wherein ring A is 5- or 6-membered Het
optionally substituted with one or more R.sup.A groups that are
each independently C.sub.3-8Cak(C.sub.0-6alkyl),
Hca(C.sub.0-6alkyl), Ar(C.sub.0-6alkyl), Het(C.sub.0-6alkyl),
--O--C.sub.0-6alkyl-C.sub.3-8Cak, --O--C.sub.0-6alkyl-Hca,
--O--C.sub.0-6alkyl-Ar, --O--C.sub.0-6alkyl-Het, halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR),
wherein each Ar, Het, Calc, Hca, alkyl, alkoxy and haloalkyl group
is optionally substituted by one or two --R.sup.Ax groups, [0079]
wherein each --R.sup.Ax is independently halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR);
[0080] or one of R.sup.1 and R.sup.2 is Ar or Het, wherein Ar and
Het are substituted with one or more R.sup.A groups, and the other
is hydrogen, halogen, cyano, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
--C.sub.1-C.sub.6alkoxy, --OR, --SR, --NR.sub.2, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R,
--N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or
--CH.sub.2--OP(O)(OR).
[0081] In embodiment I.sub.4, the compounds are of embodiment
I.sub.1, or a pharmaceutically acceptable salt, prodrug, or N-oxide
thereof, or a solvate or hydrate thereof, wherein
[0082] R.sup.1 and R.sup.2 together with the atoms to which they
are attached form a 5- or 6-membered Het optionally substituted
with one or more R.sup.A groups.
[0083] In embodiment I.sub.5, the compounds are of embodiment
I.sub.1, or a pharmaceutically acceptable salt, prodrug, or N-oxide
thereof, or a solvate or hydrate thereof, wherein
[0084] R.sup.1 is Ar optionally substituted with one or more
R.sup.A groups.
[0085] In embodiment I.sub.6, the compounds are of any of
embodiments I', I.sub.1-I.sub.5, or a pharmaceutically acceptable
salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
[0086] X is --O--.
[0087] In embodiment I.sub.7, the compounds are of any of
embodiments I', I.sub.1-I.sub.6, or a pharmaceutically acceptable
salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
[0088] each R.sup.A is independently halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR),
wherein each alkyl, alkoxy and haloalkyl group is optionally
substituted by one or two --R.sup.Ax groups, [0089] wherein each
--R.sup.Ax is independently halogen, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR, --SR,
--NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR).
[0090] In embodiment I.sub.8, the compounds are of any of
embodiments I', I.sub.1-I.sub.7 or a pharmaceutically acceptable
salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
[0091] each R is independently hydrogen, C.sub.1-C.sub.6alkyl or
C.sub.1-C.sub.6haloalkyl.
[0092] The invention further comprises subgenera of formula (I) in
which structural formula (1), R.sup.1, R.sup.2, R.sup.3, R.sup.4, Y
and X are any group or combinations of groups as defined
hereinbelow (e.g., wherein the compound is of structural formula
(I) as defined in any of the above embodiments and R.sup.1 is
phenyl optionally substituted with one R.sup.A group, wherein
R.sup.3 is halogen; or the compound is formula (Ib),
R.sup.1/R.sup.2 is group (1k), R.sup.3 is group (2g), R.sup.4 is
group (3d) and Y is group (4f)):
[0093] Structural Formula (I) is One of Formulae (Ia)-(Ik):
##STR00005## ##STR00006##
[0094] R.sup.1 and R.sup.2 are Selected From One of the Following
Groups (1a)-(1uuu): [0095] (1a) R.sup.1 and R.sup.2 together with
the atoms to which they are attached form ring A, wherein ring A is
a 5- or 6-membered Het optionally substituted with one or more
R.sup.A groups that are each independently
C.sub.3-8Cak(C.sub.0-6alkyl), Hca(C.sub.0-6alkyl),
Ar(C.sub.0-6alkyl), Het (C.sub.0-6alkyl),
--O--C.sub.0-6alkyl-C.sub.3-8Cak, --O--C.sub.0-6alkyl-Hca,
--O--C.sub.0-6alkyl-Ar, --O--C.sub.0-6alkyl-Het, halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR)
wherein each Ar, Het, Cak, Hca, alkyl alkoxy and haloalkyl group is
optionally substituted by one or two --R.sup.Ax groups,
[0096] wherein each --R.sup.Ax is independently halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR).
[0097] (1b) The group of (1a), wherein A is a 5-membered Het.
[0098] (1c) The group of (1a), wherein A is pyrrolyl, furanyl,
thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl,
isothiazolyl or thiazolyl. [0099] (1d) The group of (1a), wherein A
is pyrrolyl, pyrazolyl or imidazolyl. [0100] (1e) The group of
(1a), wherein A is furanyl, thiophenyl, isoxazolyl, oxazolyl,
isothiazolyl or thiazolyl. [0101] (1f) The group of (1a), wherein A
is furanyl, isoxazolyl or oxazolyl. [0102] (1g) The group of (1a),
wherein A is pyrrolyl. [0103] (1h) The group of (1a), wherein A is
N-methylpyrrolyl. [0104] (1i) The group of (1a), wherein A is a
6-membered Het [0105] (1j) The group of (1a), wherein A is pyridyl,
pyrimidinyl, pyrazinyl or pyridazinyl. [0106] (1k) The group of
(1a), wherein A is pyrimidinyl, pyrazinyl or pyridazinyl. [0107]
(1l) The group of (1a), wherein A is pyridyl. [0108] (1m) The group
of (1a), wherein A is pyrimidinyl or pyridazinyl. [0109] (1n) The
group of (1a), wherein A is pyrimidinyl. [0110] (1o) The group of
any one of (1a)-(1n), wherein each R.sup.A is independently
halogen, cyano, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
--C.sub.1-C.sub.6alkoxy, --OR, --SR, --NR.sub.2, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R,
--N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or
--CH.sub.2--OP(O)(OR) wherein each alkyl, alkoxy and haloalkyl
group is optionally substituted by one or two --R.sup.Ax
groups,
[0111] wherein each --R.sup.Ax is independently halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR).
[0112] (1p) One of R.sup.1 and R.sup.2 is Ar or Het,
[0113] wherein Ar and Het are optionally substituted with one or
more independently selected R.sup.A groups; and
[0114] the other is hydrogen, halogen, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR --SR, --NR.sub.2,
--C(O)R, --C(O)OR, --C(O)NR.sub.2, --S(O).sub.2NR.sub.2,
--S(O).sub.2R, --OC(O)R, --N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2,
--N(R)C(O)OR, --N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R,
--OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR). [0115] (1q) The group
of (1p), wherein R.sup.1 is Ar or Het. [0116] (1r) The group of
(1p), wherein R.sup.1 is Ar. [0117] (1s) The group of (1p), wherein
R.sup.1 is phenyl. [0118] (1t) The group of (1p), wherein R.sup.1
is Het. [0119] (1u) The group of (1p), wherein R.sup.2 is Ar or
Het. [0120] (1v) The group of (1p), wherein R.sup.2 is Ar. [0121]
(1w) The group of (1p), wherein R.sup.2 is Het. [0122] (1x) The
group of (1s), wherein each R.sup.A is independently halogen,
cyano, C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy,
--OR, --SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR).
[0123] (1y) The group of (1s), wherein each R.sup.A is
independently halogen, cyano, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
--C.sub.1-C.sub.6alkoxy, --OR, --SR or --NR.sub.2. [0124] (1z) The
group of (1s), wherein each R.sup.A is independently halogen,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --OR, --SR or --NR.sub.2.
[0125] (1aa) The group of (1s), wherein each R.sup.A is
independently halogen, C.sub.1-6alkyl or --OR. [0126] (1bb) The
group of (1s), wherein each R.sup.A is independently halogen or
C.sub.1-6alkyl. [0127] (1cc) The group of (1s), wherein each
R.sup.A is independently halogen or --OR. [0128] (1dd) The group of
(1s), wherein each R.sup.A is independently C.sub.1-6alkyl or --OR.
[0129] (1ee) The group of (1s), wherein R.sup.A is halogen. [0130]
(1ff) The group of (1s), wherein each R.sup.A is independently
R.sup.A is chloro of fluoro. [0131] (1gg) The group of (1s),
wherein R.sup.A is C.sub.1-6alkyl. [0132] (1hh) The group of (1s),
wherein R.sup.A is methyl. [0133] (1ii) The group of (1s), wherein
R.sup.A is --OR. [0134] (1jj) The group of (1s), wherein R.sup.A is
--OH. [0135] (1kk) The group of (1s), wherein R.sup.A is --OMe.
[0136] (1ll) The group of (1s), wherein each R.sup.A is
independently cyano, C.sub.1-6alkyl, C.sub.1-6haloalkyl, or
--C.sub.1-C.sub.6alkoxy. [0137] (1mm) The group of (1s), wherein
each R.sup.A is independently C.sub.1-6alkyl, C.sub.1-6haloalkyl or
--C.sub.1-C.sub.6alkoxy. [0138] (1nn) The group of (1s), wherein
each R.sup.A is independently C.sub.1-6alkyl or C.sub.1-6haloalkyl.
[0139] (1oo) The group of (1s), wherein R.sup.A is
C.sub.1-6haloalkyl. [0140] (1pp) The group of (1s), wherein R.sup.A
is --C.sub.1-C.sub.6alkoxy. [0141] (1qq) The group of (1s), wherein
each R.sup.A is independently --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR).
[0142] (1rr) The group of (1s), wherein each R.sup.A is
independently --C(O)R, --C(O)OR, --C(O)NR.sub.2, --OC(O)R,
--N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or
--CH.sub.2--OP(O)(OR). [0143] (1ss) The group of (1s), wherein each
R.sup.A is independently --S(O).sub.2NR.sub.2, --S(O).sub.2R,
--OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR). [0144] (1tt) The group
of (1s), wherein each R.sup.A is independently --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2 or
--N(R)S(O).sub.2R. [0145] (1uu) The group of (1s), wherein R.sup.A
is --C(O)OR. [0146] (1vv) The group of (1s), wherein R.sup.A is
--C(O)OMe. [0147] (1ww) The group of (1s), wherein R.sup.A is
--C(O)OH. [0148] (1xx) The group of (1s), wherein each R.sup.A is
independently --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR). [0149]
(1yy) The group of (1s), wherein R.sup.A is --CH.sub.2--OP(O)(OR).
[0150] (1zz) Any of the groups of (1q)-(1t) or (1x)-(1yy), wherein
R.sup.2 is hydrogen, halogen, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR, --SR,
--NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR).
[0151] (1aaa) The group of (1zz), wherein R.sup.2 is hydrogen,
halogen, C.sub.1-6alkyl, C.sub.1-6haloalkyl or
--C.sub.1-C.sub.6alkoxy. [0152] (1bbb) The group of (1zz), wherein
R.sup.2 is hydrogen, halogen or C.sub.1-6alkyl. [0153] (1ccc) The
group of (1zz), wherein R.sup.2 is hydrogen or halogen. [0154]
(1ddd) The group of (1zz), wherein R.sup.2 is hydrogen or
C.sub.1-6alkyl. [0155] (1eee) The group of (1zz), wherein R.sup.2
is halogen or C.sub.1-6alkyl. [0156] (1fff) The group of (1zz),
wherein R.sup.2 is halogen. [0157] (1ggg) The group of (1 zz),
wherein R.sup.2 is C.sub.1-6alkyl. [0158] (1hhh) The group of
(1zz), wherein R.sup.2 is hydrogen, halogen, C.sub.1-6haloalkyl or
--C.sub.1-C.sub.6alkoxy. [0159] (1iii) The group of (1zz), wherein
R.sup.2 is halogen, C.sub.1-6haloalkyl or --C.sub.1-C.sub.6alkoxy.
[0160] (1jjj) The group of (1zz), wherein R.sup.2 is
--C.sub.1-C.sub.6alkoxy. [0161] (1kkk) The group of (1zz), wherein
R.sup.2 is hydrogen. [0162] (1lll) The group of (1zz), wherein
R.sup.2 is hydrogen, halogen, cyano, --OR, --SR or --NR.sub.2.
[0163] (1mmm) The group of (1zz), wherein R.sup.2 is hydrogen,
halogen, or --OR. [0164] (1nnn) The group of (1zz), wherein R.sup.2
is hydrogen or --OR. [0165] (1ooo) The group of (1zz), wherein
R.sup.2 is halogen, or --OR. [0166] (1ppp) The group of (1zz),
wherein R.sup.2 is --OR. [0167] (1qqq) The group of (1zz), wherein
R.sup.2 is hydrogen, halogen, cyano, C.sub.1-6haloalkyl,
--C.sub.1-C.sub.6alkoxy, --OR, --SR, --NR.sub.2, --C(O)OR,
--C(O)NR.sub.2, --S(O).sub.2NR.sub.2 or --S(O).sub.2R. [0168]
(1rrr) The group of (1zz), wherein R.sup.2 is hydrogen, --C(O)R,
--C(O)OR, --C(O)NR.sub.2, --S(O).sub.2NR.sub.2, --S(O).sub.2R,
--OC(O)R, --N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or
--CH.sub.2--OP(O)(OR). [0169] (1sss) The group of (1zz), wherein
R.sup.2 is hydrogen, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR or --OC(O)NR.sub.2. [0170] (1ttt) The group of (1zz),
wherein R.sup.2 is hydrogen or --C(O)OR. [0171] (1uuu) The group of
(1zz), wherein R.sup.2 is --C(O)OR.
[0172] R.sup.3 is Selected From One of the Following Groups
(2a)-(2oo): [0173] (2a) R.sup.3 is hydrogen, halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR).
[0174] (2b) R.sup.3 is halogen, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR, --SR,
--NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR).
[0175] (2c) R.sup.3 is hydrogen, halogen, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR, --SR,
--NR.sub.2. [0176] (2d) R.sup.3 is hydrogen, halogen,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy. [0177]
(2e) R.sup.5 is hydrogen, halogen, C.sub.1-6alkyl. [0178] (2f)
R.sup.3 is hydrogen or halogen. [0179] (2g) R.sup.3 is hydrogen or
C.sub.1-6alkyl. [0180] (2h) R.sup.3 is halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2. [0181] (2i) R.sup.3 is halogen, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy. [0182] (2j) R.sup.3 is
halogen or C.sub.1-6alkyl. [0183] (2k) R.sup.3 is halogen,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy. [0184]
(2l) R.sup.3 is hydrogen, C.sub.1-6haloalkyl,
--C.sub.1-C.sub.6alkoxy. [0185] (2m) R.sup.3 is halogen, [0186]
(2n) R.sup.3 is fluoro or chloro. [0187] (2o) R.sup.3 is fluoro.
[0188] (2p) R.sup.3 is chloro. [0189] (2q) R.sup.3 is
C.sub.1-6alkyl [0190] (2r) R.sup.3 is methyl, ethyl or isopropyl.
[0191] (2s) R.sup.3 is methyl or ethyl. [0192] (2t) R.sup.3 is
methyl. [0193] (2u) R.sup.3 is ethyl. [0194] (2v) R.sup.3 is
hydrogen. [0195] (2w) R.sup.3 is hydrogen, cyano, --OR, --SR,
--NR.sub.2. [0196] (2x) R.sup.3 is hydrogen, --OR, --SR,
--NR.sub.2. [0197] (2y) R.sup.3 is --OR, --SR, --NR.sub.2. [0198]
(2z) R.sup.3 is hydrogen or --OR. [0199] (2aa) R.sup.3 is --OR.
[0200] (2bb) R.sup.3 is hydrogen, --C(O)R, --C(O)OR or
--C(O)NR.sub.2. [0201] (2cc) R.sup.3 is hydrogen, --C(O)OR or
--C(O)NR.sub.2. [0202] (2dd) R.sup.3 is hydrogen or --C(O)OR.
[0203] (2ee) R.sup.3 is --C(O)OR. [0204] (2ff) R.sup.3 is hydrogen
or --C(O)NR.sub.2. [0205] (2gg) R.sup.3 is --C(O)NR.sub.2. [0206]
(2hh) R.sup.3 is hydrogen, --S(O).sub.2NR.sub.2, --S(O).sub.2R,
--OC(O)R, --N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or
--CH.sub.2--OP(O)(OR). [0207] (2ii) R.sup.3 is hydrogen, --OC(O)R,
--N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or
--CH.sub.2--OP(O)(OR), [0208] (2jj) R.sup.3 is hydrogen,
--S(O).sub.2NR.sub.2 or --S(O).sub.2R. [0209] (2kk) R.sup.3 is
hydrogen, --OC(O)R, --N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2,
--N(R)C(O)OR, --N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R,
--OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR). [0210] (2ll) R.sup.3 is
hydrogen, --OC(O)R, --OC(O)OR, --OC(O)NR.sub.2. [0211] (2mm)
R.sup.3 is hydrogen, --N(R)C(O)R, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R. [0212] (2nn) R.sup.3 is hydrogen, --OC(O)R,
--N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2 or --N(R)S(O).sub.2R. [0213] (2oo) R.sup.3 is
hydrogen, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR).
[0214] R.sup.4 is Selected From One of the Following Groups
(3a)-(3mm): [0215] (3a) R.sup.4 is hydrogen, halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR).
[0216] (3b) R.sup.4 is halogen, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR, --SR,
--NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR).
[0217] (3c) R.sup.4 is hydrogen, halogen, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR, --SR,
--NR.sub.2. [0218] (3d) R.sup.4 is hydrogen, halogen,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy. [0219]
(3e) R.sup.4 is hydrogen, halogen, C.sub.1-6alkyl. [0220] (3f)
R.sup.4 is hydrogen or halogen. [0221] (3g) R.sup.4 is hydrogen or
C.sub.1-6alkyl. [0222] (3h) R.sup.4 is halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2. [0223] (3i) R.sup.4 is halogen, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy. [0224] (3j) R.sup.4 is
halogen or C.sub.1-6alkyl. [0225] (3k) R.sup.4 is halogen,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy. [0226]
(3l) R.sup.4 is hydrogen, C.sub.1-6haloalkyl,
--C.sub.1-C.sub.6alkoxy. [0227] (3m) R.sup.4 is halogen,
C.sub.1-6alkyl. [0228] (3n) R.sup.4 is halogen. [0229] (3o) R.sup.4
is C.sub.1-6alkyl. [0230] (3p) R.sup.4 is methyl, ethyl or
isopropyl. [0231] (3q) R.sup.4 is methyl or ethyl. [0232] (3r)
R.sup.4 is methyl. [0233] (3s) R.sup.4 is ethyl. [0234] (3t)
R.sup.4 is hydrogen. [0235] (3u) R.sup.4 is hydrogen, cyano, --OR,
--SR, --NR.sub.2. [0236] (3v) R.sup.4 is hydrogen, --OR, --SR,
--NR.sub.2. [0237] (3w) R.sup.4 is --OR, --SR, --NR.sub.2. [0238]
(3x) R.sup.4 is hydrogen or --OR. [0239] (3y) R.sup.4 is --OR.
[0240] (3z) R.sup.4 is hydrogen, --C(O)R, --C(O)OR or
--C(O)NR.sub.2. [0241] (3aa) R.sup.4 is hydrogen, --C(O)OR or
--C(O)NR.sub.2. [0242] (3bb) R.sup.4 is hydrogen or --C(O)OR.
[0243] (3cc) R.sup.4 is --C(O)OR. [0244] (3dd) R.sup.4 is hydrogen
or --C(O)NR.sub.2. [0245] (3ee) R.sup.4 is --C(O)NR.sub.2. [0246]
(3ff) R.sup.4 is hydrogen, --S(O).sub.2NR.sub.2, --S(O).sub.2R,
--OC(O)R, --N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or
--CH.sub.2--OP(O)(OR). [0247] (3gg) R.sup.4 is hydrogen, --OC(O)R,
--N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or
--CH.sub.2--OP(O)(OR). [0248] (3hh) R.sup.4 is hydrogen,
--S(O).sub.2NR.sub.2 or --S(O).sub.2R. [0249] (3ii) R.sup.4 is
hydrogen, --OC(O)R, --N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2,
--N(R)C(O)OR, --N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R,
--OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR). [0250] (3jj) R.sup.4 is
hydrogen, --OC(O)R, --OC(O)OR, --OC(O)NR.sub.2. [0251] (3kk)
R.sup.4 is hydrogen, --N(R)C(O)R, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R. [0252] (3ll) R.sup.4 is hydrogen, --OC(O)R,
--N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2 or --N(R)S(O).sub.2R. [0253] (3mm) R.sup.4 is
hydrogen, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR).
[0254] Y is Selected From One of the Following Groups (4a)-(4cc):
[0255] (4a) Y is --NR.sub.2, --CN, --C(O)OR.sup.Y, --C(O)NHOH,
[0255] ##STR00007## [0256] (4b) Y is --C(O)NHOH,
[0256] ##STR00008## [0257] (4c) Y is --C(O)OR.sup.Y, --C(O)NHOH
or
[0257] ##STR00009## [0258] (4d) Y is --C(O)OH, --C(O)NHOH or
[0258] ##STR00010## [0259] (4e) Y is --C(O)NHOH or
[0259] ##STR00011## [0260] (4f) Y is --C(O)NHOH or
[0260] ##STR00012## [0261] (4g) Y is
[0261] ##STR00013## [0262] (4h) Y is --NR.sub.2, --CN,
--C(O)OR.sup.Y or --C(O)NHOH. [0263] (4i) Y is --C(O)OH or
--C(O)NHOH. [0264] (4j) Y is --NR.sub.2 or --CN. [0265] (4k) Y is
--NR.sub.2, or --C(O)NHOH. [0266] (4l) Y is --NR.sub.2, or
--C(O)OR.sup.Y. [0267] (4m) Y is --CN or --C(O)NHOH. [0268] (4n) Y
is --CN or --C(O)OR.sup.Y. [0269] (4o) Y is --NR.sub.2. [0270] (4p)
Y is NH.sub.2. [0271] (4q) Y is --CN. [0272] (4r) Y is
--C(O)OR.sup.Y. [0273] (4s) Y is --C(O)OH. [0274] (4t) Y is
--C(O)NHOH. [0275] (4u) Y is
[0275] ##STR00014## [0276] (4v) Y is
[0276] ##STR00015## [0277] (4w) Y is
[0277] ##STR00016## [0278] (4x) Y is
[0278] ##STR00017## [0279] (4y) Y is
[0279] ##STR00018## [0280] (4z) Y is
[0280] ##STR00019## [0281] (4aa) Y is
[0281] ##STR00020## [0282] (4bb) Y is
[0282] ##STR00021## [0283] (4cc) Y is
##STR00022##
[0284] Particular embodiments of this aspect of the invention
comprise compounds of any one of the formulae (I), and (Ia)-(Ig),
each as defined in each of the following rows (or a
pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a
solvate or hydrate thereof), wherein each entry is a group number
as defined above (e.g., (3y) refers to R.sup.3 is --OR) and a dash
"-" indicates that the variable is as defined in embodiment I.sub.1
or defined according to any one of the applicable variable
definitions (1a)-(4cc) [e.g., when R.sup.1 is a dash, it can be
either as defined in any of embodiments I.sub.1-I.sub.8 or any one
of definitions (3a)-(3mm)]:
TABLE-US-00001 (I) R.sup.1/R.sup.2 R.sup.3 R.sup.4 Y (1)-1 (Ia)
(1a) (2a) (3a) (4a) (1)-2 (Ia) (1b) (2c) (3c) (4c) (1)-3 (Ia) (1g)
(2d) (3g) (4i) (1)-4 (Ia) (1h) (2f) (3h) (4j) (1)-5 (Ia) (1i) (2h)
(3o) (4l) (1)-6 (Ia) (1p) (2k) (3p) (4u) (1)-7 (Ia) (1r) (2m) (3r)
(4x) (1)-8 (Ia) (1s) (2n) (3t) (4y) (1)-9 (Ia) (1x) (2o) (3u) (4z)
(1)-10 (Ia) (1ii) (2p) (3x) (4aa) (1)-11 (Ia) (1zz) (2t) (3g) (4bb)
(1)-12 (Ia) (Li) (2d) (3h) (4cc) (1)-13 (Ia) (1bbb) (2f) (3o) (4a)
(1)-14 (Ia) (1kkk) (2h) (3p) (4c) (1)-15 (Ia) (1a) (2k) (3c) (4i)
(1)-16 (Ia) (1b) (2m) (3g) (4j) (1)-77 (Ia) (1g) (2c) (3h) (4l)
(1)-18 (Ia) (1h) (2d) (3o) (4u) (1)-19 (Ia) (1i) (2f) (3p) (4x)
(1)-20 (Ia) (1p) (2h) (3r) (4y) (1)-21 (Ia) (1r) (2k) (3t) (4z)
(1)-22 (Ia) (1s) (2m) (3u) (4aa) (1)-23 (Ia) (1x) (2n) (3x) (4bb)
(1)-24 (Ia) (1ii) (2o) (3g) (4cc) (1)-25 (Ia) (1jj) (2p) (3h) (4j)
(1)-26 (Ia) (1zz) (2t) (3o) (4l) (1)-27 (Ia) (1bbb) (2d) (3p) (4u)
(1)-28 (Ia) (1kkk) (2f) (3c) (4x) (1)-29 (Ia) (1a) (2h) (3g) (4y)
(1)-30 (Ia) (1b) (2k) (3h) (4z) (1)-31 (Ia) (1g) (2m) (3o) (4aa)
(1)-32 (Ia) (1h) (2c) (3p) (4bb) (1)-33 (Ia) (1i) (2d) (3r) (4cc)
(1)-34 (Ia) (1p) (2f) (3t) (4a) (1)-35 (Ia) (1r) (2h) (3u) (4c)
(1)-36 (Ia) (1s) (2k) (3x) (4i) (1)-37 (Ia) (1x) (2m) (3g) (4j)
(1)-38 (Ia) (1ii) (2n) (3h) (4l) (1)-39 (Ia) (1jj) (2o) (3o) (4u)
(1)-40 (Ia) (1zz) (2p) (3p) (4x) (1)-41 (Ib) (1bbb) (2t) (3a) (4y)
(1)-42 (Ib) (1kkk) (2c) (3c) (4a) (1)-43 (Ib) (1g) (2d) (3g) (4c)
(1)-44 (Ib) (1h) (2f) (3h) (4i) (1)-45 (Ib) (1i) (2h) (3o) (4j)
(1)-46 (Ib) (1p) (2k) (3p) (4l) (1)-47 (Ib) (1r) (2m) (3r) (4a)
(1)-48 (Ib) (1s) (2f) (3t) (4c) (1)-49 (Ib) (1x) (2m) (3u) (4i)
(1)-50 (Ib) (1ii) (2n) (3x) (4j) (1)-51 (Ib) (1jj) (2n) (3c) (4l)
(1)-52 (Ib) (1zz) (2o) (3g) (4u) (1)-53 (Ib) (1bbb) (2p) (3h) (4x)
(1)-54 (Ib) (1kkk) (2t) (3o) (4y) (1)-55 (Ib) (1a) (2c) (3p) (4u)
(1)-56 (Ic) (1b) (2d) (3r) (4x) (1)-57 (Ic) (1g) (2c) (3t) (4y)
(1)-58 (Ic) (1h) (2d) (3g) (4z) (1)-59 (Ic) (1i) (2f) (3h) (4aa)
(1)-60 (Ic) (1p) (2h) (3o) (4y) (1)-61 (Ic) (1a) (2k) (3p) (4z)
(1)-62 (Ic) (1b) (2m) (3r) (4aa) (1)-63 (Ic) (1g) (2n) (3t) (4u)
(1)-64 (Ic) (1h) (2o) (3u) (4x) (1)-65 (Ic) (1i) (2p) (3x) (4y)
(1)-66 (Ic) (1p) (2t) (3c) (4z) (1)-67 (Ic) (1r) (2c) (3g) (4aa)
(1)-68 (Ic) (1a) (2d) (3h) (4y) (1)-69 (Ic) (1b) (2f) (3o) (4a)
(1)-70 (Ic) (1g) (2h) (3c) (4c) (1)-71 (Ic) (1h) (2k) (3g) (4i)
(1)-72 (Ic) (1i) (2m) (3h) (4c) (1)-73 (Ic) (1p) (2h) (3o) (4i)
(1)-74 (Ic) (1r) (2k) (3p) (4j) (1)-75 (Ic) (1s) (2m) (3r) (4l)
(1)-76 (Ic) (1x) (2c) (3t) (4u) (1)-77 (Ic) (1ii) (2d) (3h) (4x)
(1)-78 (Ic) (1a) (2a) (3o) (4y) (1)-79 (Ic) (1b) (2c) (3p) (4aa)
(1)-80 (Ic) (1g) (2d) (3r) (4l) (1)-81 (Ic) (1a) (2f) (3t) (4u)
(1)-82 (Ic) (1a) (2h) (3u) (4x) (1)-83 (Ic) (1b) (2k) (3x) (4y)
(1)-84 (Ic) (1g) (2m) (3p) (4z) (1)-85 (Ic) (1h) (2n) (3r) (4aa)
(1)-86 (Ic) (1i) (2o) (3t) (4bb) (1)-87 (Ic) (1p) (2p) (3u) (4cc)
(1)-88 (Ic) (1r) (2h) (3a) (4u) (1)-89 (Ic) (1s) (2k) (3c) (4x)
(1)-90 (Ic) (1x) (2m) (3g) (4z) (1)-91 (Ic) (1ii) (2a) (3h) (4aa)
(1)-92 (Ic) (1jj) (2c) (3p) (4l) (1)-93 (Ic) (1zz) (2d) (3r) (4u)
(1)-94 (Ic) (1bbb) (2f) (3t) (4x) (1)-95 (Ic) (1kkk) (2h) (3u) (4y)
(1)-96 (Id) (1a) (2k) (3a) (4z) (1)-97 (Id) (1b) (2m) (3c) (4aa)
(1)-98 (Id) (1g) (2n) (3g) (4bb) (1)-99 (Id) (1h) (2o) (3h) (4cc)
(1)-100 (Id) (1i) (2p) (3o) (4u) (1)-101 (Id) (1p) (2t) (3p) (4x)
(1)-102 (Id) (1a) (2d) (3r) (4y) (1)-103 (Id) (1b) (2f) (3t) (4z)
(1)-104 (Id) (1g) (2h) (3u) (4aa) (1)-105 (Id) (1h) (2k) (3x) (4a)
(1)-106 (Id) (1i) (2m) (3p) (4c) (1)-107 (Id) (1p) (2d) (3r) (4i)
(1)-108 (Id) (1r) (2f) (3t) (4j) (1)-109 (Id) (1s) (2h) (3u) (4l)
(1)-110 (Id) (1x) (2k) (3c) (4u) (1)-111 (Id) (1a) (2m) (3g) (4x)
(1)-112 (Id) (1b) (2n) (3h) (4y) (1)-113 (Id) (1g) (2o) (3o) (4z)
(1)-114 (Id) (1h) (2p) (3p) (4aa) (1)-115 (Id) (1i) (2t) (3r) (4bb)
(1)-116 (Id) (1p) (2m) (3t) (4cc) (1)-117 (Id) (1r) (2a) (3a) (4x)
(1)-118 (Id) (1s) (2d) (3c) (4z) (1)-119 (Id) (1x) (2f) (3g) (4aa)
(1)-120 (Id) (1ii) (2h) (3h) (4c) (1)-121 (Id) (1jj) (2k) (3o) (4i)
(1)-122 (Id) (1zz) (2m) (3p) (4j) (1)-123 (Id) (1bbb) (2c) (3r)
(4l) (1)-124 (Id) (1kkk) (2d) (3t) (4u) (1)-125 (Id) (1r) (2f) (3u)
(4x) (1)-126 (Id) (1s) (2h) (3x) (4y) (1)-127 (Id) (1x) (2k) (3a)
(4z) (1)-128 (Id) (1a) (2m) (3c) (4aa) (1)-129 (Id) (1b) (2n) (3g)
(4bb) (1)-130 (Id) (1g) (2o) (3h) (4cc) (1)-131 (Id) (1h) (2p) (3g)
(4l) (1)-132 (Id) (1r) (2t) (3h) (4u) (1)-133 (Id) (1s) (2h) (3o)
(4x) (1)-134 (Id) (1x) (2k) (3p) (4y) (1)-135 (Id) (1a) (2m) (3r)
(4z) (1)-136 (Ie) (1b) (2a) (3t) (4aa) (1)-137 (Ie) (1g) (2c) (3h)
(4bb) (1)-138 (Ie) (1h) (2d) (3o) (4cc) (1)-139 (Ie) (1i) (2f) (3p)
(4x) (1)-140 (Ie) (1h) (2h) (3r) (4z) (1)-141 (Ie) (1i) (2k) (3t)
(4aa) (1)-142 (Ie) (1p) (2m) (3u) (4a) (1)-143 (Ie) (1r) (2n) (3x)
(4c) (1)-144 (Ie) (1s) (2o) (3c) (4i) (1)-145 (Ie) (1x) (2p) (3g)
(4j) (1)-146 (Ie) (1ii) (2t) (3h) (4l) (1)-147 (Ie) (1jj) (2d) (3o)
(4u) (1)-148 (Ie) (1zz) (2f) (3p) (4x) (1)-149 (Ie) (1bbb) (2h)
(3r) (4y) (1)-150 (Ie) (1kkk) (2k) (3t) (4z) (1)-151 (If) (1a) (2m)
(3o) (4aa) (1)-152 (If) (1b) (2a) (3p) (4bb) (1)-153 (If) (1g) (2c)
(3r) (4cc) (1)-154 (If) (1h) (2d) (3t) (4x) (1)-155 (If) (1i) (2f)
(3u) (4z) (1)-156 (If) (1p) (2h) (3x) (4aa) (1)-157 (If) (1r) (2k)
(3a) (4a) (1)-158 (If) (1s) (2m) (3c) (4c) (1)-159 (If) (1x) (2n)
(3a) (4i) (1)-160 (If) (1ii) (2o) (3c) (4j) (1)-161 (If) (1jj) (2p)
(3g) (4l) (1)-162 (If) (1zz) (2t) (3h) (4u) (1)-163 (If) (1bbb)
(2h) (3c) (4x) (1)-164 (If) (1kkk) (2k) (3g) (4y) (1)-165 (If) (1r)
(2m) (3h) (4z) (1)-166 (If) (1s) (2c) (3o) (4aa) (1)-167 (If) (1x)
(2d) (3p) (4bb) (1)-168 (If) (1a) (2f) (3r) (4cc) (1)-169 (If) (1b)
(2h) (3t) (4c) (1)-170 (If) (1g) (2k) (3u) (4i) (1)-171 (If) (1h)
(2m) (3x) (4j) (1)-172 (If) (1i) (2n) (3c) (4l) (1)-173 (If) (1a)
(2o) (3g) (4u) (1)-174 (If) (1b) (2p) (3h) (4x) (1)-175 (If) (1g)
(2t) (3o) (4y) (1)-176 (If) (1h) (2d) (3p) (4z) (1)-177 (If) (1i)
(2f) (3r) (4aa) (1)-178 (If) (1p) (2h) (3t) (4bb) (1)-179 (If) (1r)
(2k) (3h) (4cc) (1)-180 (If) (1s) (2m) (3o) (4j) (1)-181 (If) (1x)
(2d) (3p) (4l) (1)-182 (If) (1ii) (2f) (3r) (4u) (1)-183 (If) (1jj)
(2h) (3t) (4x) (1)-184 (If) (1zz) (2k) (3u) (4y) (1)-185 (If)
(1bbb) (2m) (3x) (4i) (1)-186 (If) (1kkk) (2n) (3a) (4j) (1)-187
(If) (1r) (2o) (3c) (4l) (1)-188 (If) (1s) (2p) (3g) (4u) (1)-189
(If) (1x) (2t) (3h) (4x) (1)-190 (If) (1a) (2d) (3o) (4y) (1)-191
(Ig) (1b) (2f) (3p) (4z) (1)-192 (Ig) (1g) (2h) (3r) (4aa) (1)-193
(Ig) (1h) (2k) (3t) (4bb) (1)-194 (Ig) (1i) (2m) (3u) (4cc) (1)-195
(Ig) (1i) (2a) (3x) (4j) (1)-196 (Ig) (1p) (2c) (3o) (4l) (1)-197
(Ig) (1r) (2d) (3p) (4u) (1)-198 (Ig) (1s) (2f) (3r) (4x) (1)-199
(Ig) (ix) (2h) (3t) (4y) (1)-200 (Ig) (1ii) (2k) (3o) (4c) (1)-201
(Ig) (1jj) (2m) (3a) (4i) (1)-202 (Ig) (1zz) (2n) (3c) (4j) (1)-203
(Ig) (1bbb) (2o) (3g) (4l) (1)-204 (Ig) (1kkk) (2p) (3h) (4u)
(1)-205 (Ig) (1jj) (2t) (3o) (4x) (1)-206 (Ih) (1a) (2k) (3p) (4y)
(1)-207 (Ih) (1b) (2a) (3r) (4z) (1)-208 (Ih) (1g) (2c) (3t) (4aa)
(1)-209 (Ih) (1h) (2d) (3u) (4bb) (1)-210 (Ih) (1i) (2f) (3x) (4cc)
(1)-211 (Ih) (1p) (2h) (3o) (4u) (1)-212 (Ih) (1r) (2k) (3p) (4x)
(1)-213 (Ih) (1s) (2m) (3r) (4y) (1)-214 (Ih) (1x) (2n) (3t) (4z)
(1)-215 (Ih) (1ii) (2o) (3o) (4aa) (1)-216 (Ih) (1jj) (2p) (3h)
(4bb) (1)-217 (Ih) (1zz) (2t) (3o) (4cc) (1)-218 (Ih) (1bbb) (2m)
(3p) (4a) (1)-219 (Ih) (1kkk) (2a) (3r) (4c) (1)-220 (Ih) (1b) (2c)
(3t) (4i) (1)-221 (Ih) (1g) (2d) (3u) (4j) (1)-222 (Ih) (1h) (2f)
(3x) (4l) (1)-223 (Ih) (1i) (2a) (3o) (4u) (1)-224 (Ih) (1i) (2c)
(3p) (4x) (1)-225 (Ih) (1p) (2d) (3r) (4y) (1)-226 (Ih) (1r) (2f)
(3t) (4z) (1)-227 (Ih) (1s) (2h) (3o) (4aa) (1)-228 (Ih) (1a) (2k)
(3g) (4bb) (1)-229 (Ih) (1b) (2m) (3h) (4cc) (1)-230 (Ih) (1g) (2n)
(3o) (4a) (1)-231 (Ih) (1h) (2o) (3p) (4c) (1)-232 (Ih) (1i) (2p)
(3r) (4i) (1)-233 (Ih) (1a) (2t) (3t) (4j) (1)-234 (Ih) (1b) (2h)
(3u) (4l) (1)-235 (Ih) (1g) (2a) (3x) (4u) (1)-236 (Ih) (1h) (2c)
(3o) (4x) (1)-237 (Ih) (1i) (2d) (3p) (4y) (1)-238 (Ih) (1p) (2f)
(3r) (4z) (1)-239 (Ih) (1r) (2h) (3t) (4aa) (1)-240 (Ih) (1s) (2k)
(3o) (4bb) (1)-241 (Ih) (1x) (2m) (3a) (4cc) (1)-242 (Ih) (1ii)
(2n) (3c) (4u) (1)-243 (Ih) (1jj) (2o) (3g) (4x) (1)-244 (Ih) (1zz)
(2p) (3h) (4y) (1)-245 (Ih) (1bbb) (2t) (3o) (4z) (1)-246 (Ii)
(1kkk) (2h) (3p) (4aa) (1)-247 (Ii) (1b) (2a) (3r) (4bb)
(1)-248 (Ii) (1g) (2c) (3t) (4cc) (1)-249 (Ii) (1h) (2d) (3u) (4u)
(1)-250 (Ii) (1i) (2f) (3x) (4x) (1)-251 (Ii) (1p) (2h) (3o) (4y)
(1)-252 (Ii) (1r) (2k) (3p) (4z) (1)-253 (Ii) (1s) (2m) (3r) (4c)
(1)-254 (Ii) (1x) (2n) (3t) (4i) (1)-255 (Ii) (1ii) (2o) (3o) (4j)
(1)-256 (Ii) (1jj) (2p) (3a) (4l) (1)-257 (Ii) (1zz) (2t) (3c) (4u)
(1)-258 (Ii) (1bbb) (2m) (3g) (4x) (1)-259 (Ii) (1kkk) (2a) (3h)
(4y) (1)-260 (Ii) (1h) (2c) (3g) (4z) (1)-261 (Ii) (1i) (2d) (3h)
(4aa) (1)-262 (Ii) (1p) (2f) (3o) (4bb) (1)-263 (Ii) (1r) (2c) (3p)
(4cc) (1)-264 (Ij) (1s) (2d) (3r) (4u) (1)-265 (Ij) (1b) (2f) (3t)
(4u) (1)-266 (Ij) (1g) (2h) (3u) (4x) (1)-267 (Ij) (1h) (2k) (3x)
(4y) (1)-268 (Ij) (1i) (2m) (3a) (4z) (1)-269 (Ij) (1p) (2n) (3c)
(4a) (1)-270 (Ij) (1r) (2o) (3g) (4c) (1)-271 (Ij) (1s) (2p) (3h)
(4i) (1)-272 (Ij) (1x) (2t) (3a) (4j) (1)-273 (Ij) (1ii) (2m) (3c)
(4l) (1)-274 (Ij) (1jj) (2a) (3g) (4u) (1)-275 (Ij) (1zz) (2c) (3h)
(4x) (1)-276 (Ij) (1bbb) (2d) (3g) (4y) (1)-277 (Ij) (1kkk) (2f)
(3h) (4z) (1)-278 (Ij) (1h) (2d) (3o) (4aa) (1)-279 (Ij) (1i) (2f)
(3p) (4bb) (1)-280 (Ij) (1p) (2h) (3r) (4cc) (1)-281 (Ij) (1r) (2k)
(3t) (4a) (1)-282 (Ij) (1s) (2m) (3u) (4c) (1)-283 (Ik) (1a) (2n)
(3x) (4i) (1)-284 (Ik) (1b) (2o) (3a) (4j) (1)-285 (Ik) (1g) (2p)
(3c) (4l) (1)-286 (Ik) (1h) (2t) (3g) (4u) (1)-287 (Ik) (1i) (2a)
(3h) (4a) (1)-288 (Ik) (1p) (2c) (3o) (4c) (1)-289 (Ik) (1r) (2d)
(3p) (4a) (1)-290 (Ik) (1s) (2f) (3r) (4c) (1)-291 (Ik) (1x) (2h)
(3t) (4i) (1)-292 (Ik) (1ii) (2k) (3u) (4j) (1)-293 (Ik) (1jj) (2m)
(3x) (4l) (1)-294 (Ik) (1zz) (2n) (3g) (4u) (1)-295 (Ik) (1bbb)
(2o) (3h) (4x) (1)-296 (Ik) (1kkk) (2p) (3o) (4y) (1)-297 (Ik) (1a)
(2t) (3p) (4z) (1)-298 (Ik) (1b) (2m) (3r) (4aa) (1)-299 (Ik) (1g)
(2a) (3t) (4bb) (1)-300 (Ik) (1h) (2c) (3u) (4cc)
[0285] In some embodiments, the compound of formulae (I), (Ia)-(Ig)
is one of the following compounds (or a pharmaceutically acceptable
salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof)
in Table 1:
TABLE-US-00002 TABLE 1 No. Structure Name 1 ##STR00023##
5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-
benzo[d]imidazol-2-yl)oxy)-N-hydroxy-2- methylbenzamide; 2
##STR00024## 5-((6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-
1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 3 ##STR00025##
5-((6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-
1H-benzo[d]imidazol-2-yl)oxy)-N-hydroxy-2- methylbenzamide; 4
##STR00026## 1-(5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-
benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-
1,4-dihydro-5H-tetrazol-5-one; 5 ##STR00027##
1-(5-((6-fluoro-5-(1-methyl-1H-indol-5-yl)-1H-
benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-
1,4-dihydro-5H-tetrazol-5-one; 6 ##STR00028##
1-(5-((6-fluoro-5-(2'-hydroxy-[1,1'-biphenyl]-4-
yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-
methylphenyl)-1,4-dihydro-5H-tetrazol-5-one; 7 ##STR00029##
5-((6-fluoro-5-(1-methyl-1H-indol-5-yl)-1H-
benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid 8 ##STR00030##
1-(5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-
benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-4-
methyl-1,4-dihydro-5H-tetrazol-5-one 9 ##STR00031##
5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-
benzo[d]imidazol-2-yl)oxy)-2-methylaniline 10 ##STR00032##
4'-(6-fluoro-2-(4-methyl-3-(1H-tetrazol-1-
yl)phenoxy)-1H-benzo[d]imidazol-5-yl)-[1,1'- biphenyl]-2-ol 11
##STR00033## 5-((6-fluoro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-
1H-benzo[d]imidazol-2-yl)oxy)-2- methylbenzonitrile 12 ##STR00034##
4'-(6-fluoro-2-(4-methyl-3-(2H-tetrazol-5-
yl)phenoxy)-1H-benzo[d]imidazol-5-yl)-[1,1'- biphenyl]-2-ol 13
##STR00035## 1-(5-((6-fluoro-5-(2'-hydroxy-[1,1'-biphenyl]-4-
yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-
methylphenyl)-4-methyl-1,4-dihydro-5H- tetrazol-5-one
[0286] In embodiment II.sub.1 of this aspect, the invention
comprises compounds having the structure of formula (II):
##STR00036##
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof,
or solvate or hydrate thereof, wherein
[0287] ring A is a 5- or 6-membered Het;
[0288] each R.sup.A is independently C.sub.3-8Cak(C.sub.0-6alkyl),
Hca(C.sub.0-6alkyl), Ar(C.sub.0-6alkyl), Het (C.sub.0-6alkyl),
--O--C.sub.0-6alkyl-C.sub.3-8Cak, --O--C.sub.0-6alkyl-Hca,
--O--C.sub.0-6alkyl-Ar, --O--C.sub.0-6alkyl-Het, halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OR(O)(OR).sub.2, wherein each Ar, Het, Cak,
Hca, alkyl, alkoxy and haloalkyl group is optionally substituted by
one or two --R.sup.Ax groups, [0289] wherein each --R.sup.Ax is
independently halogen, cyano, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
--C.sub.1-C.sub.6alkoxy, --OR, --SR, --NR.sub.2, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R,
--N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or
--CH.sub.2--OP(O)(OR);
[0290] R.sup.3 and R.sup.4 are independently hydrogen, halogen,
cyano, C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy,
--OR, --SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2or --CH.sub.2--OP(O)(OR);
[0291] X is --O--, --S--, --NR-- or --CF.sub.2--;
[0292] Y is --NR.sub.2, --CN, --C(O)OR.sup.Y, --C(O)NHOH,
##STR00037## [0293] wherein R.sup.Y is hydrogen or C.sub.1-6alkyl;
and
[0294] each R is independently hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, --(C.sub.0-C.sub.6alkyl)-Ar,
--(C.sub.0-C.sub.6alkyl)-Het, --(C.sub.0-C.sub.6alkyl)-Cak, or
--(C.sub.0-C.sub.6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and
haloalkyl are optionally substituted with C.sub.1-C.sub.6alkyl,
halogen, C.sub.1-C.sub.6haloalkyl or cyano; and
[0295] n is 2, 3 or 4.
[0296] In embodiment II.sub.2 of this aspect, the invention
comprises compounds of embodiment II.sub.1, wherein
[0297] ring A is pyridyl, pyrimidinyl, pyrazinyl., pyridazinyl,
pyrrolyl, furanyl, thiophenyl, pyrazoyl, imidazolyl, isoxazolyl,
oxazolyl, isothiazolyl or thiazolyl.
[0298] In embodiment II.sub.3, the compounds are of any of
embodiments I.sub.1 or I.sub.2, or a pharmaceutically acceptable
salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
[0299] each R.sup.A is independently halogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR,
--SR, --NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2N.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR),
wherein each alkyl, alkoxy and haloalkyl group is optionally
substituted by one or two --R.sup.Ax groups, [0300] wherein each
--R.sup.Ax is independently halogen, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR, --SR,
--NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR).
[0301] In embodiment II.sub.4, the compounds are of any of
embodiments II.sub.1-I.sub.3, or a pharmaceutically acceptable
salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
[0302] X is --O--.
[0303] In embodiment II.sub.5, the compounds are of any of
embodiments II.sub.1-I.sub.4, or a pharmaceutically acceptable
salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
[0304] each R is independently hydrogen, C.sub.1-C.sub.6alkyl or
C.sub.1-C.sub.6haloalkyl.
[0305] In embodiment II.sub.6, the compounds of the invention are
one of formulae (IIa)-(IIg), wherein R.sup.3, R.sup.4, X, Y,
R.sup.a and n are as defined in any of embodiments
II.sub.1-II.sub.5 above:
[0306] Structural Formula (II) is One of Formulae (IIa)-(IIg):
##STR00038## ##STR00039##
[0307] Particular embodiments of this aspect of the invention
comprise compounds of any one of the formulae (II), and
(IIa)-(IIg), each as defined in each of the following rows (or a
pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a
solvate or hydrate thereof), wherein each entry is a group number
as defined above (e.g., (3y) refers to R.sup.1 is --OR, and a dash
"-" indicates that the variable is as defined in embodiment It or
defined according to any one of the applicable variable definitions
(1a)-(1uuu), (2a)-(2oo), (3a)-(3mm) and (4a)-(4cc) [e.g., when
R.sup.1 is a dash, it can be either as defined in any of
embodiments II.sub.1-II.sub.6 or any one of the applicable
definitions (1a)-(1uuu)]:
TABLE-US-00003 (II) A R.sup.3 R.sup.4 Y (2)-1 (IIa) (1a) (2a) (3a)
(4a) (2)-2 (IIa) (1b) (2c) (3c) (4c) (2)-3 (IIa) (1c) (2d) (3g)
(4i) (2)-4 (IIa) (1d) (2f) (3h) (4j) (2)-5 (IIa) (1l) (2h) (3o)
(4l) (2)-6 (IIa) (1m) (2k) (3p) (4u) (2)-7 (IIa) (1g) (2m) (3r)
(4x) (2)-8 (IIa) (1h) (2n) (3t) (4y) (2)-9 (IIa) (1e) (2o) (3u)
(4z) (2)-10 (IIa) (1f) (2p) (3x) (4aa) (2)-11 (IIa) (1g) (2t) (3g)
(4bb) (2)-12 (IIa) (1h) (2d) (3h) (4cc) (2)-13 (IIa) (1i) (2f) (3o)
(4a) (2)-14 (IIa) (1j) (2h) (3p) (4c) (2)-15 (IIa) (1a) (2p) (3t)
(4u) (2)-16 (IIa) (1b) (2t) (3x) (4x) (2)-17 (IIa) (1c) (2d) (3g)
(4y) (2)-18 (IIa) (1d) (2a) (3a) (4z) (2)-19 (IIa) (1l) (2c) (3c)
(4aa) (2)-20 (IIa) (1m) (2d) (3g) (4bb) (2)-21 (IIa) (1g) (2d) (3p)
(4a) (2)-22 (IIa) (1h) (2f) (3r) (4c) (2)-23 (IIa) (1a) (2h) (3c)
(4j) (2)-24 (IIa) (1b) (2a) (3g) (4l) (2)-25 (IIa) (1c) (2c) (3h)
(4a) (2)-26 (IIa) (1d) (2d) (30) (4c) (2)-27 (IIa) (1l) (2f) (3p)
(4i) (2)-28 (IIa) (1m) (2a) (3t) (4j) (2)-29 (IIa) (1g) (2c) (3r)
(4l) (2)-30 (IIb) (1h) (2d) (3a) (4a) (2)-31 (IIb) (1b) (2c) (3c)
(4c) (2)-32 (IIb) (1c) (2d) (3g) (4i) (2)-33 (IIb) (1d) (2f) (3h)
(4j) (2)-34 (IIb) (1l) (2h) (3o) (4l) (2)-35 (IIb) (1m) (2k) (3p)
(4u) (2)-36 (IIb) (1g) (2m) (3r) (4x) (2)-37 (IIb) (1h) (2n) (3t)
(4y) (2)-38 (IIb) (1e) (2o) (3u) (4z) (2)-39 (IIb) (1f) (2p) (3x)
(4aa) (2)-40 (IIb) (1g) (2t) (3g) (4bb) (2)-41 (IIb) (1h) (2d) (3h)
(4cc) (2)-42 (IIb) (1i) (2f) (3o) (4a) (2)-43 (IIb) (1j) (2h) (3p)
(4c) (2)-44 (IIb) (1a) (2p) (3x) (4i) (2)-45 (IIb) (1b) (2t) (3g)
(4j) (2)-46 (IIb) (1c) (2d) (3a) (4l) (2)-47 (IIb) (1d) (2d) (3c)
(4a) (2)-48 (IIb) (1l) (2f) (3g) (4c) (2)-49 (IIb) (1m) (2h) (3p)
(4u) (2)-50 (IIb) (1g) (2a) (3r) (4x) (2)-51 (IIb) (1h) (2c) (3c)
(4y) (2)-52 (IIb) (1a) (2d) (3g) (4z) (2)-53 (IIb) (1b) (2d) (3h)
(4aa) (2)-54 (IIb) (1c) (2a) (3o) (4bb) (2)-55 (IIb) (1d) (2c) (3p)
(4i) (2)-56 (IIb) (1l) (2d) (3t) (4j) (2)-57 (IIb) (1m) (2f) (3r)
(4l) (2)-58 (IIb) (1g) (2a) (3r) (4u) (2)-59 (IIc) (1h) (2c) (3a)
(4x) (2)-60 (IIc) (1b) (2d) (3c) (4y) (2)-61 (IIc) (1c) (2d) (3g)
(4z) (2)-62 (IIc) (1d) (2f) (3h) (4aa) (2)-63 (IIc) (1l) (2h) (3o)
(4bb) (2)-64 (IIc) (1m) (2k) (3p) (4u) (2)-65 (IIc) (1g) (2m) (3r)
(4x) (2)-66 (IIc) (1h) (2n) (3t) (4y) (2)-67 (IIc) (1e) (2o) (3u)
(4z) (2)-68 (IIc) (1f) (2p) (3x) (4aa) (2)-69 (IIc) (1g) (2t) (3g)
(4bb) (2)-70 (IIc) (1h) (2d) (3h) (4cc) (2)-71 (IIc) (1i) (2f) (3o)
(4a) (2)-72 (IIc) (1j) (2h) (3p) (4c) (2)-73 (IIc) (1a) (2a) (3p)
(4i) (2)-74 (IIc) (1b) (2c) (3r) (4j) (2)-75 (IIc) (1c) (2d) (3c)
(4l) (2)-76 (IIc) (1d) (2a) (3p) (4a) (2)-77 (IIc) (1l) (2c) (3r)
(4c) (2)-78 (IIc) (1m) (2d) (3c) (4c) (2)-79 (IIc) (1g) (2t) (3h)
(4u) (2)-80 (IIc) (1h) (2d) (3a) (4x) (2)-81 (IIc) (1a) (2f) (3c)
(4y) (2)-82 (IIc) (1b) (2p) (3g) (4z) (2)-83 (IIc) (1c) (2t) (3p)
(4aa) (2)-84 (IIc) (1d) (2d) (3r) (4bb) (2)-85 (IIc) (1l) (2a) (3c)
(4a) (2)-86 (IIc) (1m) (2c) (3h) (4c) (2)-87 (IIc) (1g) (2d) (3o)
(4j) (2)-88 (IIc) (1h) (2f) (3p) (4l) (2)-89 (IId) (1a) (2a) (3t)
(4a) (2)-90 (IId) (1b) (2c) (3c) (4c) (2)-91 (IId) (1c) (2d) (3g)
(4i) (2)-92 (IId) (1d) (2f) (3h) (4j) (2)-93 (IId) (1l) (2h) (3o)
(4l) (2)-94 (IId) (1m) (2k) (3p) (4u) (2)-95 (IId) (1g) (2m) (3r)
(4x) (2)-96 (IId) (1h) (2n) (3t) (4y) (2)-97 (IId) (1e) (20) (3u)
(4z) (2)-98 (IId) (1f) (2p) (3x) (4aa) (2)-99 (IId) (1g) (2t) (3g)
(4bb) (2)-100 (IId) (1h) (2d) (3h) (4cc) (2)-101 (IId) (1i) (2f)
(3o) (4a) (2)-102 (IId) (1j) (2h) (3p) (4c) (2)-103 (IId) (1a) (2a)
(3r) (4a) (2)-104 (IId) (1b) (2c) (3c) (4c) (2)-105 (IId) (1c) (2d)
(3h) (4y) (2)-106 (IId) (1d) (2d) (3g) (4z) (2)-107 (IId) (1l) (2f)
(3a) (4aa) (2)-108 (IId) (1m) (2a) (3c) (4c) (2)-109 (IId) (1g)
(2c) (3g) (4u) (2)-110 (IId) (1h) (2d) (3p) (4x) (2)-111 (IId) (1a)
(2f) (3r) (4u) (2)-112 (IId) (1b) (2h) (3c) (4x) (2)-113 (IId) (1c)
(2p) (3g) (4y) (2)-114 (IId) (1d) (2t) (3h) (4z) (2)-115 (IId) (1l)
(2d) (3o) (4aa) (2)-116 (IId) (1m) (2a) (3p) (4c) (2)-117 (IId)
(1g) (2c) (3t) (4u) (2)-118 (IIe) (1h) (2d) (3a) (4x) (2)-119 (IIe)
(1b) (2c) (3c) (4c) (2)-120 (IIe) (1c) (2d) (3g) (4i) (2)-121 (IIe)
(1d) (2f) (3h) (4j) (2)-122 (IIe) (1l) (2h) (3o) (4l) (2)-123 (IIe)
(1m) (2k) (3p) (4u) (2)-124 (IIe) (1g) (2m) (3r) (4x) (2)-125 (IIe)
(1h) (2n) (3t) (4y) (2)-126 (IIe) (1e) (2o) (3u) (4z) (2)-127 (IIe)
(1f) (2p) (3x) (4aa) (2)-128 (IIe) (1g) (2t) (3g) (4bb) (2)-129
(IIe) (1h) (2d) (3h) (4cc) (2)-130 (IIe) (1i) (2f) (3o) (4a)
(2)-131 (IIe) (1j) (2h) (3p) (4c) (2)-132 (IIe) (1a) (2p) (3p) (4a)
(2)-133 (IIe) (1b) (2t) (3r) (4c) (2)-134 (IIe) (1c) (2d) (3c) (4a)
(2)-135 (IIe) (1d) (2t) (3h) (4c) (2)-136 (IIe) (1l) (2d) (3p) (4u)
(2)-137 (IIe) (1m) (2f) (3t) (4x) (2)-138 (IIe) (1g) (2h) (3x) (4y)
(2)-139 (IIe) (1h) (2a) (3g) (4y) (2)-140 (IIe) (1a) (2c) (3a) (4z)
(2)-141 (IIe) (1b) (2d) (3c) (4aa) (2)-142 (IIe) (1c) (2c) (3g)
(4c) (2)-143 (IIe) (1d) (2d) (3p) (4u) (2)-144 (IIe) (1l) (2f) (3r)
(4x) (2)-145 (IIe) (1m) (2p) (3c) (4c) (2)-146 (IIe) (1g) (2t) (3g)
(4u) (2)-147 (IIf) (1h) (2d) (3a) (4x) (2)-148 (IIf) (1b) (2c) (3c)
(4c) (2)-149 (IIf) (1c) (2d) (3g) (4i) (2)-150 (IIf) (1d) (2f) (3h)
(4j) (2)-151 (IIf) (1l) (2h) (3o) (4l) (2)-152 (IIf) (1m) (2k) (3p)
(4u) (2)-153 (IIf) (1g) (2m) (3r) (4x) (2)-154 (IIf) (1h) (2n) (3t)
(4y) (2)-155 (IIf) (1e) (2o) (3u) (4z) (2)-156 (IIf) (1f) (2p) (3x)
(4aa) (2)-157 (IIf) (1g) (2t) (3g) (4bb) (2)-158 (IIf) (1h) (2d)
(3h) (4cc) (2)-159 (IIf) (1i) (2f) (3o) (4a) (2)-160 (IIf) (1j)
(2h) (3p) (4c) (2)-161 (IIf) (1a) (2a) (3h) (4x) (2)-162 (IIf) (1b)
(2c) (3o) (4y) (2)-163 (IIf) (1c) (2d) (3p) (4bb) (2)-164 (IIf)
(1d) (2a) (3t) (4c) (2)-165 (IIf) (1l) (2c) (3g) (4u) (2)-166 (IIf)
(1m) (2d) (3x) (4x) (2)-167 (IIf) (1g) (2d) (3g) (4a) (2)-168 (IIf)
(1h) (2p) (3a) (4c) (2)-169 (IIf) (1a) (2t) (3c) (4u) (2)-170 (IIf)
(1b) (2d) (3g) (4x) (2)-171 (IIf) (1c) (2a) (3p) (4y) (2)-172 (IIf)
(1d) (2c) (3r) (4z) (2)-173 (IIf) (1l) (2d) (3c) (4aa) (2)-174
(IIf) (1m) (2f) (3g) (4bb) (2)-175 (IIg) (1g) (2a) (3a) (4a)
(2)-176 (IIg) (1h) (2c) (3c) (4c) (2)-177 (IIg) (1c) (2d) (3g) (4i)
(2)-178 (IIg) (1d) (2f) (3h) (4j) (2)-179 (IIg) (1l) (2h) (3o) (4l)
(2)-180 (IIg) (1m) (2k) (3p) (4u) (2)-181 (IIg) (1g) (2m) (3r) (4x)
(2)-182 (IIg) (1h) (2n) (3t) (4y) (2)-183 (IIg) (1e) (2o) (3u) (4z)
(2)-184 (IIg) (1f) (2p) (3x) (4aa) (2)-185 (IIg) (1g) (2t) (3g)
(4bb) (2)-186 (IIg) (1h) (2d) (3h) (4cc) (2)-187 (IIg) (1i) (2f)
(3o) (4a) (2)-188 (IIg) (1j) (2h) (3p) (4c) (2)-189 (IIg) (1a) (2p)
(3h) (4bb) (2)-190 (IIg) (1b) (2t) (3o) (4x) (2)-191 (IIg) (1c)
(2d) (3p) (4y) (2)-192 (IIg) (1d) (2t) (3t) (4a) (2)-193 (IIg) (1l)
(2d) (3g) (4c) (2)-194 (IIg) (1m) (2a) (3a) (4u) (2)-195 (IIg) (1g)
(2c) (3c) (4x) (2)-196 (IIg) (1h) (2d) (3g) (4y) (2)-197 (IIg) (1a)
(2a) (3p) (4z) (2)-198 (IIg) (1b) (2c) (3r) (4c) (2)-199 (IIg) (1c)
(2d) (3c) (4u) (2)-200 (IIg) (1d) (2f) (3g) (4x)
[0308] In embodiment III.sub.1 of this aspect, the invention
comprises compounds having the structure of formula (III):
##STR00040##
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof,
or solvate or hydrate thereof, wherein
[0309] each R.sup.A1 is independently hydrogen,
C.sub.3-8Cak(C.sub.0-6alkyl), Hca(C.sub.0-6alkyl),
Ar(C.sub.0-6alkyl), Het(C.sub.0-6alkyl),
--O--C.sub.0-6alkyl-C.sub.3-8Cak, --O--C.sub.0-6alkyl-Hca,
--O--C.sub.0-6alkyl-Ar, --O--C.sub.0-6alkyl-Het, cyano,
--C.sub.1-C.sub.6alkoxy, --OR, --SR, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R,
--N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or
--CH.sub.2--OP(O)(OR);
[0310] each R.sup.A2 is independently hydrogen,
C.sub.3-8Cak(C.sub.0-6alkyl), Hca(C.sub.0-6alkyl),
Ar(C.sub.0-6alkyl), Het(C.sub.0-6alkyl),
--O--C.sub.0-6alkyl-C.sub.3-8Cak, --O--C.sub.0-6alkyl-Hca,
--O--C.sub.0-6alkyl-Ar, --O--C.sub.0-6alkyl-Het, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --SR,
--NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR);
[0311] R.sup.A3 is hydrogen, C.sub.3-8Cak(C.sub.0-6alkyl),
Hca(C.sub.0-6alkyl), Ar(C.sub.0-6alkyl), Het(C.sub.0-6alkyl),
--O--C.sub.0-6alkyl-C.sub.3-8Cak, --O--C.sub.0-6alkyl-Hca,
--O--C.sub.0-6alkyl-Ar, --O--C.sub.0-6alkyl-Het, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --SR, --NR.sub.2,
--C(O)R, --C(O)NR.sub.2, --S(O).sub.2NR.sub.2, --S(O).sub.2R,
--OC(O)R, --N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR)2 or
--CH.sub.2--OP(O)(OR);
[0312] wherein each Ar, Het, Cak, Hca, alkyl, alkoxy and haloalkyl
group in each R.sup.A1, R.sup.A2 and R.sup.A3 is optionally
substituted by one or two --R.sup.Ax groups, [0313] wherein each
--R.sup.Ax is independently halogen, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR, --SR,
--NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR);
[0314] R.sup.3 is hydrogen, halogen, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR, --SR,
--NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR);
[0315] R.sup.4 is halogen, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR, --SR,
--NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR);
[0316] X is --O--, --S--, --NR-- or --CF.sub.2--;
[0317] Y is --NR.sub.2, --CN, --C(O)OR.sup.Y, --C(O)NHOH,
##STR00041## [0318] wherein R.sup.Y is hydrogen or C.sub.1-6alkyl;
and
[0319] each R is independently hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, --(C.sub.0-C.sub.6alkyl)-Ar,
--(C.sub.0-C.sub.6alkyl)-Het, --(C.sub.0-C.sub.6alkyl)-Cak, or
--(C.sub.0-C.sub.6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and
haloallkyl are optionally substituted with C.sub.1-C.sub.6alkyl,
halogen, C.sub.1-C.sub.6haloalkyl or cyano; provided that
[0320] (a) at least one of R.sup.A1, R.sup.A2 or R.sup.A3 is not
hydrogen;
[0321] (b) when R.sup.A1 or R.sup.A3 is hydroxyl, R.sup.3 is not
fluoro; and
[0322] (c) when R.sup.A1 or R.sup.A5 is methoxy, R.sup.3 is not
chloro.
[0323] In embodiment III.sub.2, the compounds are of embodiment
III.sub.1, or a pharmaceutically acceptable salt, prodrug, or
N-oxide thereof, or a solvate or hydrate thereof, wherein
[0324] each R.sup.A1 is independently hydrogen, cyano,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR, --SR, --C(O)R,
--C(O)OR, --C(O)NR.sub.2, --S(O).sub.2NR.sub.2, --S(O).sub.2R,
--OC(O)R, --N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or
--CH.sub.2--OP(O)(OR);
[0325] each R.sup.A2 is independently hydrogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --SR,
--NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR);
[0326] R.sup.A3 is hydrogen, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
--C.sub.1-C.sub.6alkoxy, --SR, --NR.sub.2, --C(O)R, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR);
[0327] wherein each alkyl, alkoxy and haloalkyl group in each
R.sup.A1, R.sup.A2 and R.sup.A3 is optionally substituted by one or
two --R.sup.Ax groups.
[0328] In embodiment III.sub.3 of this aspect, the invention
comprises compounds having the structure of formula (IIIa):
##STR00042##
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof,
or solvate or hydrate thereof, wherein
[0329] R.sup.A1 is C.sub.3-8Cak(C.sub.0-6alkyl),
Hca(C.sub.0-6alkyl), Ar(C.sub.0-6alkyl), Het(C.sub.0-6alkyl),
--O--C.sub.0-6alkyl-C.sub.3-8Cak, --O--C.sub.0-6alkyl-Hca,
--O--C.sub.0-6alkyl-Ar, --O--C.sub.0-6alkyl-Het, cyano,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OH, --SR, --C(O)R,
--C(O)OR, --C(O)NR.sub.2, --S(O).sub.2NR.sub.2, --S(O).sub.2R,
--OC(P)R, --N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or
--CH.sub.2--OP(O)(OR);
[0330] each R.sup.A2 group is independently hydrogen,
C.sub.3-8Cak(C.sub.0-6alkyl), Hca(C.sub.0-6alkyl), Ar
(C.sub.0-6alkyl), Het(C.sub.0-6alkyl),
--O--C.sub.0-6alkyl-C.sub.3-8Cak, --O--C.sub.0-6alkyl-Hca,
--O--C.sub.0-6alkyl-Ar, --O--C.sub.0-6alkyl-Het, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --SR,
--NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR);
[0331] R.sup.A3 is hydrogen, C.sub.3-8Cak(C.sub.0-6alkyl),
Hca(C.sub.0-6alkyl), Ar(C.sub.0-6alkyl), Het(C.sub.0-6alkyl),
--O--C.sub.0-6alkyl-C.sub.3-8Cak, --O--C.sub.0-6alkyl-Hca,
--O--C.sub.0-6alkyl-Ar, --O--C.sub.0-6alkyl-Het, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --SR, --NR.sub.2,
--C(O)R, --C(O)NR.sub.2, --S(O).sub.2NR.sub.2, --S(O).sub.2R,
--OC(O)R, --N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(P)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or
--CH.sub.2--OP(O)(OR);
[0332] wherein each Ar, Het, Cak, Hca, alkyl, alkoxy and haloalkyl
group in each R.sup.A1, R.sup.A2 and R.sup.A3 is optionally
substituted by one or two --R.sup.Ax groups, [0333] wherein each
--R.sup.Ax is independently halogen, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR, --SR,
--NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR);
[0334] R.sup.3 is hydrogen, chloro, bromo, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR, --SR,
--NR.sub.2, --COR, --C(O)OR, --C(O)NR.sub.2, --S(O).sub.2NR.sub.2,
--S(O).sub.2R, --OC(O)R, --N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2,
--N(R)C(O)OR, --N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R,
--OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR);
[0335] R.sup.4 is halogen, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --OR, --SR,
--NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR);
[0336] X is --O--, --S--, --NR-- or --CF.sub.2--;
[0337] Y is, --NR.sub.2, --CN, --C(O)OR, --C(O)NHOH,
##STR00043## [0338] wherein R.sup.Y is hydrogen or C.sub.1-6alkyl;
and
[0339] each R is independently hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, --(C.sub.0-C.sub.6alkyl)-Ar,
--(C.sub.0-C.sub.6alkyl)-Het, --(C.sub.0-C.sub.6alkyl)-Cak, or
--(C.sub.0-C.sub.6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and
haloalkyl are optionally substituted with C.sub.1-C.sub.6alkyl,
halogen, C.sub.1-C.sub.6haloalkyl or cyano.
[0340] In embodiment III.sub.4, the compounds are of embodiment
III.sub.3, or a pharmaceutically acceptable salt, prodrug, or
N-oxide thereof, or a solvate or hydrate thereof,
wherein
[0341] R.sup.A1 is cyano, C.sub.1-6haloalkyl,
--C.sub.1-C.sub.6alkoxy, --OH, --SR, --C(O)R, --C(O)OR,
--C(O)NR.sub.2, --S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R,
--N(R)C(O)R, --OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR,
--N(R)C(O)NR.sub.2, --N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or
--CH.sub.2--OP(O)(OR);
[0342] each R.sup.A2 group is independently hydrogen, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-C.sub.6alkoxy, --SR,
--NR.sub.2, --C(O)R, --C(O)OR, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR);
[0343] R.sup.A3 is hydrogen, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
--C.sub.1-C.sub.6alkoxy, --SR, --NR.sub.2, --C(O)R, --C(O)NR.sub.2,
--S(O).sub.2NR.sub.2, --S(O).sub.2R, --OC(O)R, --N(R)C(O)R,
--OC(O)OR, --OC(O)NR.sub.2, --N(R)C(O)OR, --N(R)C(O)NR.sub.2,
--N(R)S(O).sub.2R, --OP(O)(OR).sub.2 or --CH.sub.2--OP(O)(OR);
[0344] wherein each alkyl, alkoxy and haloalkyl group in each
R.sup.A1, R.sup.A2 and R.sup.A3 is optionally substituted by one or
two --R.sup.Ax groups.
[0345] In embodiment III.sub.5, the compounds are of any of
embodiments III.sub.1-I.sub.4, or a pharmaceutically acceptable
salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
[0346] X is --O--.
[0347] In embodiment III.sub.6, the compounds are of any of
embodiments III.sub.1-I.sub.5, or a pharmaceutically acceptable
salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
[0348] each R is independently hydrogen, C.sub.1-C.sub.6alkyl or
C.sub.1-C.sub.6haloalkyl.
[0349] In embodiment III.sub.7, the compounds of the invention are
of one of formulae (IIIa)-(IIIk), wherein R.sup.A1, R.sup.A2,
R.sup.A3, R.sup.3, R.sup.4, X and Y are as defined in embodiment
III.sub.1 above:
##STR00044## ##STR00045##
[0350] Particular embodiments of this aspect of the invention
comprise compounds of any one of the formulae (III), and
(IIIa)-(IIk), each as defined in each of the following rows (or a
pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a
solvate or hydrate thereof), wherein each entry is a group number
as defined above (e.g., (3y) refers to R.sup.1 is --OR), an "X"
indicates that the variable is covered by another group number
(e.g., formula (IIIa) includes a Z group) and a dash "-" indicates
that the variable is as defined in embodiment I.sub.1 or defined
according to any one of the applicable variable definitions
(2a)-(oo), (3a)-(3mm) and (4a)-(4cc) [e.g. , when R.sup.4 is a
dash, it can be either as defined in embodiment III.sub.1 or any
one of the applicable definitions (3a)-(3mm)]:
TABLE-US-00004 (III) R.sup.3 R.sup.4 Y (3)-1 (IIIa) (2a) (3b) (4a)
(3)-2 (IIIa) (2c) (3c) (4c) (3)-3 (IIIa) (2d) (3g) (4i) (3)-1
(IIIa) (2f) (3h) (4j) (3)-5 (IIIa) (2h) (3o) (4l) (3)-6 (IIIa) (2k)
(3p) (4u) (3)-7 (IIIa) (2m) (3r) (4x) (3)-8 (IIIa) (2n) (3t) (4y)
(3)-9 (IIIa) (2o) (3u) (4z) (3)-10 (IIIa) (2p) (3x) (4aa) (3)-11
(IIIa) (2t) (3g) (4bb) (3)-12 (IIIa) (2d) (3h) (4cc) (3)-13 (IIIa)
(2a) (3o) (4u) (3)-14 (IIIa) (2c) (3p) (4x) (3)-15 (IIIa) (2d) (3r)
(4z) (3)-16 (IIIa) (2m) (3t) (4bb) (3)-17 (IIIa) (2n) (3g) (4cc)
(3)-18 (IIIa) (2f) (3h) (4j) (3)-19 (IIIb) (2a) (3b) (4a) (3)-20
(IIIb) (2c) (3c) (4c) (3)-21 (IIIb) (2d) (3g) (4i) (3)-22 (IIIb)
(2f) (3h) (4j) (3)-23 (IIIb) (2h) (3o) (4l) (3)-24 (IIIb) (2k) (3p)
(4u) (3)-25 (IIIb) (2m) (3r) (4x) (3)-26 (IIIb) (2n) (3t) (4y)
(3)-27 (IIIb) (2o) (3u) (4z) (3)-28 (IIIb) (2p) (3x) (4aa) (3)-29
(IIIb) (2t) (3g) (4bb) (3)-30 (IIIb) (2d) (3h) (4cc) (3)-31 (IIIb)
(2c) (3g) (4i) (3)-32 (IIIb) (2d) (3h) (4j) (3)-33 (IIIb) (2m) (3p)
(4u) (3)-34 (IIIb) (2m) (3r) (4x) (3)-35 (IIIb) (2n) (3t) (4z)
(3)-36 (IIIb) (2t) (3g) (4i) (3)-37 (IIIc) (2a) (3h) (4j) (3)-38
(IIIc) (2c) (3c) (4c) (3)-39 (IIIc) (2d) (3g) (4i) (3)-40 (IIIc)
(2f) (3h) (4j) (3)-41 (IIIc) (2h) (3o) (4l) (3)-42 (IIIc) (2k) (3p)
(4u) (3)-43 (IIIc) (2m) (3r) (4x) (3)-44 (IIIc) (2n) (3t) (4y)
(3)-45 (IIIc) (2o) (3u) (4z) (3)-46 (IIIc) (2p) (3x) (4aa) (3)-47
(IIIc) (2t) (3g) (4bb) (3)-48 (IIIc) (2d) (3h) (4cc) (3)-49 (IIIc)
(2m) (3g) (4i) (3)-50 (IIIc) (2n) (3h) (4j) (3)-51 (IIIc) (2t) (3o)
(4bb) (3)-52 (IIIc) (2c) (3p) (4cc) (3)-53 (IIIc) (2d) (3r) (4x)
(3)-54 (IIIc) (2m) (3t) (4z) (3)-55 (IIId) (2a) (3b) (4a) (3)-56
(IIId) (2c) (3c) (4c) (3)-57 (IIId) (2d) (3g) (4i) (3)-58 (IIId)
(2f) (3h) (4j) (3)-59 (IIId) (2h) (3o) (4l) (3)-60 (IIId) (2k) (3p)
(4u) (3)-61 (IIId) (2m) (3r) (4x) (3)-62 (IIId) (2n) (3t) (4y)
(3)-63 (IIId) (2o) (3u) (4z) (3)-64 (IIId) (2p) (3x) (4aa) (3)-65
(IIId) (2t) (3g) (4bb) (3)-66 (IIId) (2d) (3h) (4cc) (3)-67 (IIId)
(2m) (3g) (4i) (3)-68 (IIId) (2n) (3h) (4j) (3)-69 (IIId) (2t) (3o)
(4u) (3)-70 (IIId) (2d) (3p) (4x) (3)-71 (IIId) (2m) (3r) (4z)
(3)-72 (IIId) (2n) (3t) (4i) (3)-73 (IIIe) (2t) (3b) (4j) (3)-74
(IIIe) (2c) (3c) (4c) (3)-75 (IIIe) (2d) (3g) (4i) (3)-76 (IIIe)
(2f) (3h) (4j) (3)-77 (IIIe) (2h) (3o) (4l) (3)-78 (IIIe) (2k) (3p)
(4u) (3)-79 (IIIe) (2m) (3r) (4x) (3)-80 (IIIe) (2n) (3t) (4y)
(3)-81 (IIIe) (2o) (3u) (4z) (3)-82 (IIIe) (2p) (3x) (4aa) (3)-83
(IIIe) (2t) (3g) (4bb) (3)-84 (IIIe) (2d) (3h) (4cc) (3)-85 (IIIe)
(2c) (3g) (4i) (3)-86 (IIIe) (2d) (3h) (4j) (3)-87 (IIIe) (2m) (3o)
(4x) (3)-88 (IIIe) (2m) (3p) (4z) (3)-89 (IIIe) (2n) (3r) (4i)
(3)-90 (IIIe) (2t) (3t) (4j) (3)-91 (IIIf) (2a) (3b) (4a) (3)-92
(IIIf) (2c) (3c) (4c) (3)-93 (IIIf) (2d) (3g) (4i) (3)-94 (IIIf)
(2f) (3h) (4j) (3)-95 (IIIf) (2h) (3o) (4l) (3)-96 (IIIf) (2k) (3p)
(4u) (3)-97 (IIIf) (2m) (3r) (4x) (3)-98 (IIIf) (2n) (3t) (4y)
(3)-99 (IIIf) (2o) (3u) (4z) (3)-100 (IIIf) (2p) (3x) (4aa) (3)-101
(IIIf) (2t) (3g) (4bb) (3)-102 (IIIf) (2d) (3h) (4cc) (3)-103
(IIIf) (2m) (3o) (4bb) (3)-104 (IIIf) (2n) (3p) (4cc) (3)-105
(IIIf) (2t) (3r) (4u) (3)-106 (IIIf) (2d) (3t) (4x) (3)-107 (IIIf)
(2m) (3h) (4z) (3)-108 (IIIf) (2m) (3o) (4i) (3)-109 (IIIg) (2n)
(3b) (4j) (3)-110 (IIIg) (2t) (3c) (4c) (3)-111 (IIIg) (2d) (3g)
(4i) (3)-112 (IIIg) (2f) (3h) (4j) (3)-113 (IIIg) (2h) (3o) (4l)
(3)-114 (IIIg) (2k) (3p) (4u) (3)-115 (IIIg) (2m) (3r) (4x) (3)-116
(IIIg) (2n) (3t) (4y) (3)-117 (IIIg) (2o) (3u) (4z) (3)-118 (IIIg)
(2p) (3x) (4aa) (3)-119 (IIIg) (2t) (3g) (4bb) (3)-120 (IIIg) (2d)
(3h) (4cc) (3)-121 (IIIg) (2m) (3b) (4bb) (3)-122 (IIIg) (2n) (3b)
(4cc) (3)-123 (IIIg) (2t) (3o) (4j) (3)-124 (IIIg) (2d) (3p) (4u)
(3)-125 (IIIg) (2m) (3r) (4x) (3)-126 (IIIg) (2n) (3t) (4z) (3)-127
(IIIh) (2t) (3b) (4a) (3)-128 (IIIh) (2c) (3c) (4c) (3)-129 (IIIh)
(2d) (3g) (4i) (3)-130 (IIIh) (2f) (3h) (4j) (3)-131 (IIIh) (2h)
(3o) (4l) (3)-132 (IIIh) (2k) (3p) (4u) (3)-133 (IIIh) (2m) (3r)
(4x) (3)-134 (IIIh) (2n) (3t) (4y) (3)-135 (IIIh) (2o) (3u) (4z)
(3)-136 (IIIh) (2p) (3x) (4aa) (3)-137 (IIIh) (2t) (3g) (4bb)
(3)-138 (IIIh) (2d) (3h) (4cc) (3)-139 (IIIh) (2m) (3b) (4bb)
(3)-140 (IIIh) (2n) (3o) (4cc) (3)-141 (IIIh) (2t) (3p) (4x)
(3)-142 (IIIh) (2d) (3r) (4z) (3)-143 (IIIh) (2m) (3t) (4i) (3)-144
(IIIh) (2m) (3b) (4j) (3)-145 (IIIi) (2n) (3b) (4a) (3)-146 (IIIi)
(2t) (3c) (4c) (3)-147 (IIIi) (2d) (3g) (4i) (3)-148 (IIIi) (2f)
(3h) (4j) (3)-149 (IIIi) (2h) (3o) (4l) (3)-150 (IIIi) (2k) (3p)
(4u) (3)-151 (IIIi) (2m) (3r) (4x) (3)-152 (IIIi) (2n) (3t) (4y)
(3)-153 (IIIi) (2o) (3u) (4z) (3)-154 (IIIi) (2p) (3x) (4aa)
(3)-155 (IIIi) (2t) (3g) (4bb) (3)-156 (IIIi) (2m) (3h) (4cc)
(3)-157 (IIIi) (2n) (3b) (4bb) (3)-158 (IIIi) (2t) (3o) (4cc)
(3)-159 (IIIi) (2d) (3p) (4j) (3)-160 (IIIi) (2m) (3r) (4u) (3)-161
(IIIi) (2m) (3t) (4x) (3)-162 (IIIi) (2n) (3b) (4z) (3)-163 (IIIj)
(2t) (3b) (4a) (3)-164 (IIIj) (2c) (3c) (4c) (3)-165 (IIIj) (2d)
(3g) (4i) (3)-166 (IIIj) (2f) (3h) (4j) (3)-167 (IIIj) (2h) (3o)
(4l) (3)-168 (IIIj) (2k) (3p) (4u) (3)-169 (IIIj) (2m) (3r) (4x)
(3)-170 (IIIj) (2n) (3t) (4y) (3)-171 (IIIj) (2o) (3u) (4z) (3)-172
(IIIj) (2p) (3x) (4aa) (3)-173 (IIIj) (2t) (3g) (4bb) (3)-174
(IIIj) (2d) (3h) (4cc) (3)-175 (IIIj) (2m) (3o) (4bb) (3)-176
(IIIj) (2n) (3p) (4cc) (3)-177 (IIIj) (2t) (3r) (4i) (3)-178 (IIIj)
(2c) (3t) (4j) (3)-179 (IIIj) (2d) (3p) (4u) (3)-180 (IIIj) (2m)
(3r) (4x) (3)-181 (IIIk) (2a) (3t) (4z) (3)-182 (IIIk) (2c) (3c)
(4c) (3)-183 (IIIk) (2d) (3g) (4i) (3)-184 (IIIk) (2f) (3h) (4j)
(3)-185 (IIIk) (2h) (3o) (4l) (3)-186 (IIIk) (2k) (3p) (4u) (3)-187
(IIIk) (2m) (3r) (4x) (3)-188 (IIIk) (2n) (3t) (4y) (3)-189 (IIIk)
(2o) (3u) (4z) (3)-190 (IIIk) (2p) (3x) (4aa) (3)-191 (IIIk) (2t)
(3g) (4bb) (3)-192 (IIIk) (2d) (3h) (4cc) (3)-193 (IIIk) (2c) (3b)
(4bb) (3)-194 (IIIk) (2m) (3o) (4cc) (3)-195 (IIIk) (2n) (3p) (4j)
(3)-196 (IIIk) (2t) (3r) (4bb) (3)-197 (IIIk) (2f) (3o) (4cc)
(3)-198 (IIIk) (2h) (3p) (4x) (3)-199 (IIIk) (2k) (3r) (4z) (3)-200
(IIIk) (2m) (3t) (4bb)
[0351] In another aspect, the present invention comprises
pharmaceutical compositions comprising a compound according to any
one of the preceding aspects of the invention or any embodiment
thereof, together with a pharmaceutically acceptable excipient,
diluent, or carrier.
[0352] While not intending to he bound by theory, the inventors
surmise that compounds of structural formulae (I)-(IIIk) are direct
activators of AMPK, thereby activating the AMPK pathway. In one
embodiment, the present compounds selectively activate one isoform
of AMPK. For example, certain compounds selectively activate the
.alpha..sub.2.beta..sub.2.gamma..sub.3 isoform, such as with an
EC.sub.50 of two-fold, three-fold or even twenty-fold less than an
EC.sub.50 for another isoform. Such selectivity can confer tissue
selectivity since different AMPK isoforms are expressed in
different tissues. In particular the .alpha..sub.2, .beta..sub.2
and .gamma..sub.3 subunit isoforms are found in skeletal muscle.
Thus, in certain embodiments the present compounds are selective
activators of AMPK in skeletal muscle.
[0353] Activation of the AMPK pathway has the effect of increasing
glucose uptake, decreasing glycogen synthesis and increasing fatty
acid oxidation, thereby reducing glycogen, intracellular
triglyceride and fatty acid concentration and causing an increase
in insulin sensitivity. Because they activate the AMIPK pathway,
compounds of structural formulae (I)-(IIIk) should also inhibit the
inflammatory processes which occur during the early phases of
atherosclerosis, Accordingly, compounds of structural formulae
(I)-(IIIk) can be useful in the treatment of type II diabetes and
in the treatment and prevention of atherosclerosis, cardiovascular
disease, obesity and non-alcoholic fatty liver disease.
[0354] Accordingly, another aspect of the invention is a method of
activating the AMPK pathway. According to this aspect of the
invention, a method for activating the AMPK pathway in a cell
includes contacting the cell with an effective amount of a
compound, pharmaceutically acceptable salt, prodrug, solvate,
hydrate, N-oxide or composition described above.
[0355] Another aspect of the invention is a method of increasing
fatty acid oxidation in a cell. According to this aspect of the
invention, a method of increasing fatty acid oxidation in a cell
includes contacting the cell with an effective amount of a
compound, pharmaceutically acceptable salt, prodrug, solvate,
hydrate, N-oxide or composition described above. Acetyl Co-A
carboxylase (ACC) catalyzes the formation of malonyl Co-A, a potent
inhibitor of fatty acid oxidation; phosphorylation of ACC greatly
reduces its catalytic activity, thereby reducing the concentration
of malonyl Co-A and increasing the rate of fatty acid oxidation.
Because compounds of the invention can increase the rate of
phosphorylation of ACC, they can reduce the inhibition of fatty
acid oxidation and therefore increase its overall rate.
[0356] Another aspect of the invention is a method of decreasing
glycogen concentration in a cell. According to this aspect of the
invention, a method of decreasing glycogen concentration in a cell
includes contacting the cell with an effective amount of a
compound, pharmaceutically acceptable salt, prodrug, solvate,
hydrate, N-oxide or composition described above.
[0357] Another aspect of the invention is a method of increasing
glucose uptake in a cell. According to this aspect of the
invention, a method of increasing glucose uptake in a cell includes
contacting the cell with an effective amount of a compound,
pharmaceutically acceptable salt, prodrug, solvate, hydrate,
N-oxide or composition described above.
[0358] Another aspect of the invention is a method of reducing
triglyceride levels in a subject. According to this aspect of the
invention, a method of reducing triglyceride levels in a subject
includes administering to the subject an effective amount of a
compound, pharmaceutically acceptable salt, prodrug, solvate,
hydrate, N-oxide or composition described above.
[0359] Another aspect of the invention is a method of increasing
the insulin sensitivity of a subject. According to this aspect of
the invention, a method of increasing insulin sensitivity of a
subject includes administering to the subject an effective amount
of a compound, pharmaceutically acceptable salt, prodrug, solvate,
hydrate, N-oxide or composition described above.
[0360] Another aspect of the invention is a method of treating type
II diabetes. According to this aspect of the invention, a method of
treating type II diabetes in a subject, in need of such treatment
includes administering to the subject an effective amount of a
compound, pharmaceutically acceptable salt, prodrug, solvate,
hydrate, N-oxide or composition described above.
[0361] Another aspect of the invention is a method of treating or
preventing atherosclerosis or cardiovascular disease. According to
this aspect of the invention, a method of treating or preventing
atherosclerosis or cardiovascular disease in a subject includes
administering to the subject an effective amount of a compound,
pharmaceutically acceptable salt, prodrug, solvate, hydrate,
N-oxide or composition described above.
[0362] In another aspect, the compounds of the invention, as
activators of the AMPK pathway, the invention comprises modulating
the AMPK pathway (either in vitro or in vivo) by contacting a cell
with a compound, pharmaceutically acceptable salt, prodrug,
solvate, hydrate, N-oxide or composition described above, or
administering a compound, pharmaceutically acceptable salt,
prodrug, solvate, hydrate, N-oxide or composition described above
to a mammal (e.g., a human) in an amount sufficient to modulate the
AMPK activity and study the effects thereby induced. Such methods
are useful for studying the AMPK pathway and its role in biological
mechanisms and disease states both in vitro and in vivo.
[0363] In certain embodiments, the compounds disclosed herein
affect lipid signaling pathways. For example, in some embodiments,
the compounds up-regulate ceramidase activity. Ceramide is a
central player in sphingolipid metabolism, and is the immediate
precursor of sphingomyelins and glycosphingolipids as well as the
bioactive products sphingosine and sphingosine-1-phosphate.
Moreover, endogenous ceramide itself mediates, at least in part,
the actions of a variety of stimuli on cell differentiation,
apoptosis, and growth suppression. Ceramide is deacylated by
ceramidase to form sphingosine, which is in turn phosphorylated to
sphingosine-1-phosphate by sphingosine kinase.
[0364] Elevated ceramide levels have been shown to induce cell
apoptosis, differentiation and senescence. Moreover, elevated
ceramide levels are linked to a variety of diseases and disorders,
including, for example, Batten's disease, inflammatory bowel
diseases, diffuse intravascular coagulation, fever, protein
catabolism and/or lipid depletion, hepatosplenomegaly associated
with inflammatory or metabolic liver diseases, endomyocarditis,
endolithial cell and leucocyte activation, capillary thrombosis,
meningo-encephalitis due to infectious agents, complications in
organ transplantation, rheumatoid arthritis and connective tissue
diseases, autoimmune diseases, hyperthyroidism, damage by
radiation/chemotherapy agents and chronic fatigue syndrome.
[0365] Up-regulating, ceramidase function (and therefore reducing
the concentration of ceramide) can be used to treat disorders
involving deficient cell proliferation (growth) or in which cell
proliferation is otherwise desired, for example, degenerative
disorders, growth deficiencies, lesions, physical trauma, and
diseases in which ceramide accumulates within cells, such as Fabry
disease. Other disorders that may benefit from the activation of
ceramidase include neurodegenerative disorders such as Alzheimer's
disease and amyotrophic lateral sclerosis and disorders of aging
such as immune dysfunction, as well as disorders, such as those
listed above, linked to elevated ceramide levels.
[0366] The compounds, salts, prodrugs, V-oxides, solvates and
hydrates described herein can be administered, for example, to a
mammalian host to retard cellular responses associated with the
activation of the ceramide-mediated signal transduction pathway.
The compounds can be useful, for example, in providing protection
against cell senescence or apoptosis, such as occurs as a result of
trauma (for example, radiation dermatitis) and aging (for example,
of the skin or other organs).
[0367] Another embodiment is a method for up-regulating ceramidase
function in a cell (either in vivo or in vitro), the method
including contacting the cell with an effective amount of a
compound, pharmaceutically acceptable salt, prodrug, N-oxide (or
solvate or hydrate thereof) or composition of a compound described
above.
[0368] In another embodiment, a method for decreasing ceramide
concentration in a cell. (either in vivo or in vitro) includes
contacting the cell with an effective amount of a compound,
pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or
hydrate thereof) or composition of a compound described above.
[0369] In another embodiment, a method for inhibiting
ceramide-activated responses to stimuli in a cell (either in vivo
or in vitro) includes contacting the cell with an effective amount
of a compound, pharmaceutically acceptable salt, prodrug, N-oxide
(or solvate or hydrate thereof) or composition described above. The
stimuli can be, for example, stimuli for cell senescence and/or
apoptosis.
[0370] Another embodiment is a method for treating or preventing a
disease or disorder in which cell proliferation is deficient or
desired in a subject, the method including administering to the
subject an effective amount of a compound, pharmaceutically
acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof)
or composition of a compound described above. Various applicable
diseases and disorders are described above.
[0371] Another embodiment is a method for treating a disease or
disorder linked to elevated ceramide levels in a subject, the
method including administering to the subject an effective amount
of a compound, pharmaceutically acceptable salt, prodrug, N-oxide
(or solvate or hydrate thereof) or composition as described herein.
Various applicable diseases and disorders are described above. In
certain embodiments, the subject has a ceramide level higher than
about 50 pmol/10.sup.6 cells.
[0372] Moreover, since some drugs can induce high levels of
ceramide, the compounds, salts, prodrugs, N-oxides, solvates and
hydrates described herein can be usefully co-administered with such
drugs in order to at least partially ameliorate this effect. For
example, in certain embodiments, an effective amount of a compound,
pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or
hydrate thereof) or composition as described herein is
co-administered with a corticosteroid (for example, dexamethasone),
an anti-inflammatory (for example, indomethacin), an antiviral (for
example, interfereon), immunosuppressant (for example,
cyclosporin), a chemotherapy agent (for example, adriamicin), and
immunopotentiant (for example, an immunoglobulin or a vaccine), or
an andocrinological agent (for example, metimazole). As the person
of skill in the art will appreciate, co-administration contemplates
not only administration at the same time, but also administration
at different times, but with tinge-overlapping pharmacological
effects.
[0373] Another embodiment is a method for reducing the effect of
aging in the skin of a subject, the method including contacting the
skin with a compound, pharmaceutically acceptable salt, prodrug,
N-oxide (or solvate or hydrate thereof) or composition as described
herein.
[0374] Another embodiment is a method for treating or preventing
radiation dermatitis in the skin of a subject, the method including
contacting the skin with a compound, pharmaceutically acceptable
salt, prodrug, N-oxide (or solvate or hydrate thereof) or
composition as described herein.
[0375] The presently disclosed AMPK activating compounds are useful
for increasing metabolic efficiency, for example by increasing
fiber oxidative capacity, endurance and aerobic workload. In
particular, the present compounds are useful for treating and
regulating disorders of mitochondrial function, including, without
limitation, exercise intolerance, chronic fatigue syndrome, muscle
weakness, myoclonus, myoclonus epilepsy, such as associated with
ragged-red fibers syndrome, Kearns-Sayre syndrome, Leigh's
syndrome, mitochondrial myopathy encephalopathy lactacidosis stroke
(MELAS) syndrome and stroke like episodes. The disclosed compounds
also are useful for treating muscular dystrophic states, such as
Duchenne's and Becker's muscular dystrophies and Friedreich's
ataxia.
[0376] The presently disclosed AMPK activating compounds also
function to reduce oxidative stress and secondary effects of such
stress. Many diseases, including several of those listed above,
have secondary effects caused by damage due to excessive oxidative
stress which can be treated using the compounds disclosed herein.
For example, free radical damage has been implicated in
neurological disorders, such as Parkinson's disease, amyotrophic
lateral sclerosis (Lou Gehrig's disease) and Alzheimers disease.
Additional diseases in which excessive free radical damage occurs
generally include hypoxic conditions and a variety of other
disorders. More specifically, such disorders include ischemia,
ischemic reperfusion injury (such as coronary or cerebral
reperfusion injury), myocardial ischemia or infarction,
cerebrovascular accidents (such as a thromboembolic or hemorrhagic
stroke) that can lead to ischemia in the brain, operative ischemia,
traumatic hemorrhage (for example, a hypovolemic stroke that can
lead to CNS hypoxia or anoxia), resuscitation injury, spinal cord
trauma, inflammatory diseases, autoimmune disorders (such as
rheumatoid arthritis or systemic lupus erythematosis), Down's
syndrome, Hallervorden-Spatz disease, Huntingtons chorea, Wilson's
disease, diabetic angiopathy (such as peripheral vascular disease
or retinal degeneration), uveitis, chronic obstructive pulmonary
disease (COPD), including chronic bronchitis and emphysema, asthma,
neoplasia, Crohn's disease, inflammatory bowel disease and
pancreatitis. Free radical damage is also implicated in a variety
of age-related disorders, particularly ophthalmic conditions such
as cataracts and age-related macular degeneration.
[0377] In particular the present compounds are useful for treating
neurological disorders associated with reduced mitochondrial
function, oxidative stress, or both. For example, Alzheimer's
disease, dementia and Parkinson's disease can be treated using the
present AMPK activating compounds.
[0378] Metabolic efficiency is enhanced by the disclosed AMPK
activating compounds. Thus the compounds can be administered to a
subject to improve exercise efficiency and athletic performance.
Moreover, conditions including, without limitation, hypoxic states,
angina pectoris, coronary ischemia and organ damage secondary to
coronary vessel occlusion, intermittent claudication, multi-infarct
dementia, myocardial infarction, stroke, high altitude sickness and
heart failure, including congestive heart failure can be treated
using the disclosed compounds.
[0379] Inflammatory disorders and effects can be treated using the
present compounds. For example, in one aspect, the present
compounds are particularly useful for treating lung inflammation,
such as is involved in asthma, COPD and transplant rejection.
Similarly, the present compounds are useful in reducing organ
inflammation, particularly macrophage-associated inflammation, such
as inflammation of the kidney, liver and other organs. The
anti-inflammatory activity of the presently disclosed compounds can
be assessed as is known to those of skill in the art, for example,
by using the mixed lymphocyte response in vitro.
[0380] Accordingly, one aspect of the disclosure relates to a
method for treating or ameliorating a disorder or condition related
to oxidative stress, mitochondrial dysfunction, free radical damage
and/or metabolic inefficiency in a subject in need thereof, the
method including administering to the subject an effective amount
of a compound, pharmaceutically acceptable salt, prodrug, N-oxide
(or solvate or hydrate thereof) or pharmaceutical composition
described. above.
[0381] Another aspect of the present disclosure relates to a method
for the treatment or amelioration of a disorder of mitochondrial
dysfunction in a subject in need thereof, the method including
administering to the subject an effective amount of a compound,
pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or
hydrate thereof) or pharmaceutical composition described above. in
certain embodiments, the disorder is selected from the group
consisting of exercise intolerance, chronic fatigue syndrome,
muscle weakness, myoclonus, myoclonus epilepsy (such as associated
with ragged-red fibers syndrome), Kearns-Sayre syndrome, Leigh's
syndrome, mitochondrial myopathy encephalopathy lactacidosis stroke
(MELAS) syndrome and stroke like episodes.
[0382] Another aspect of the disclosure relates to a method of
increasing metabolic efficiency in a subject in need thereof, the
method including administering to the subject an effective amount
of a compound, pharmaceutically acceptable salt, prodrug, N-oxide
(or solvate or hydrate thereof) or pharmaceutical composition
described above. Such methods can be used to increase fiber
oxidative capacity, endurance, aerobic workload, or any combination
thereof. These methods can be used, for example, to improve
exercise efficiency, exercise endurance and/or athletic performance
in a subject.
[0383] Another aspect of the present disclosure relates to methods
for mimicking the effects of exercise in a subject in need thereof,
the method including administering to the subject an effective
amount of a compound, pharmaceutically acceptable salt, prodrug,
N-oxide (or solvate or hydrate thereof) or pharmaceutical
composition described above.
[0384] Another aspect of the disclosure relates to a method for
treating or ameliorating a disorder in a subject in need thereof,
the disorder being selected from the group consisting of hypoxic
states, angina pectoris, coronary ischemic and organ damage
secondary to coronary vessel occlusion, intermittent claudication,
multi-infarct dementia, myocardial infarction, stroke, high
altitude sickness and heart failure, including congestive heart
failure, the method including administering to the subject an
effective amount of a compound, pharmaceutically acceptable salt,
prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical
composition described above.
[0385] Another aspect of the disclosure relates to a method for the
treatment of amelioration of a muscular dystrophic state in a
subject in need thereof, the method including administering to the
subject an effective amount of a compound, pharmaceutically
acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof)
or pharmaceutical composition described above. In certain
embodiments, the muscular dystrophic state is Duchenne's muscular
dystrophy, Becker's muscular dystrophy, or reidreich's ataxia.
[0386] Another aspect of the disclosure relates to a method for
increasing oxidative capacity of a muscle fiber, the method
including contacting the muscle fiber with a compound,
pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or
hydrate thereof) or pharmaceutical composition described above. The
contacting may be performed in vitro or in vivo.
[0387] Another aspect of the disclosure relates to a method for
reducing oxidative stress in a subject in need thereof, the method
including administering to the subject an effective amount of a
compound, pharmaceutically acceptable salt, prodrug, N-oxide (or
solvate or hydrate thereof) or pharmaceutical composition described
above.
[0388] Another aspect of the disclosure relates to a method for
reducing free radical damage in a subject in need thereof, the
method including administering to the subject an effective amount
of a compound, pharmaceutically acceptable salt, prodrug, oxide (or
solvate or hydrate thereof) or pharmaceutical composition described
above.
[0389] Another aspect of the disclosure relates to a method for
treating or ameliorating a disorder or condition in a subject in
need thereof, the disorder or condition selected from the group
consisting of neurological disorders, hypoxic conditions, ischemia,
ischemic reperfusion injury, myocardial ischemia or infarction,
cerebrovascular accidents, operative ischemia, traumatic
hemorrhage, resuscitation injury, spinal cord trauma, inflammatory
diseases, autoimmune disorders, Down's syndrome, Hallervorden-Spatz
disease, Huntingtons chorea, Wilson's disease, diabetic angiopathy,
uveitis, chronic obstructive pulmonary disease (COPD), asthma,
neoplasia, Crohn's disease, inflammatory bowel disease,
pancreatitis and age-related disorders, the method including
administering to the subject an effective amount of a compound,
pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or
hydrate thereof) or pharmaceutical composition described above.
Particular examples of such disorders and conditions are discussed
above.
[0390] Another aspect of the disclosure is a method for treating or
ameliorating a neurological disorder in a subject in need thereof,
the neurological disorder being associated with reduced
mitochondrial function, oxidative stress, or both, the method
including administering to the subject an effective amount of a
compound, pharmaceutically acceptable salt, prodrug, N-oxide (or
solvate or hydrate thereof) or pharmaceutical composition described
above. Particular examples of such neurological disorders are
discussed above.
[0391] Another aspect of the disclosure relates to a method for
reducing oxidative stress in a cell, the method including
contacting the cell with a compound, pharmaceutically acceptable
salt, prodrug, N-oxide (or solvate or hydrate thereof) or
pharmaceutical composition described above. The contacting may be
performed in vitro or in vivo.
[0392] Another aspect of the disclosure relates to a method for
reducing free radical damage in a cell, the method including
contacting the cell with a compound, pharmaceutically acceptable
salt, prodrug, N-oxide (or solvate or hydrate thereof) or
pharmaceutical composition described above. The contacting may be
performed in vitro or in vivo.
[0393] Another aspect of the disclosure is a method for treating an
inflammatory disorder or effect in a subject in need thereof, the
method including including administering to the subject an
effective amount of a compound, pharmaceutically acceptable salt,
prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical
composition described above. For example, in one embodiment, the
inflammatory disorder or effect is lung inflammation, such as is
involved in asthma, COPD and transplant rejection. In another
embodiment, the inflammatory disorder or effect is organ
inflammation, particularly macrophage-associated inflammation, such
as inflammation of the kidney, liver and other organs.
[0394] The presently disclosed AMPK-activating compounds act on
particular aspects of metabolism; for example, the present
compounds negatively regulate glycogen synthase and positively
regulate glycogen phosphorylase. Thus, the present compounds are
useful in treating disorders of glycogen storage, such as Pompe
disease. The present compounds also increase autophagy, which is
decreased in Pompe disease. The present compounds can be used to
treat Pompe disease either alone or in adjunctively with enzyme
replacement therapy, such as alglucosidase alfa (sold under the
trade name MYOZYME) or the targeted enzyme therapy BMN-701
(IFG2-GAA). The compounds are useful in treating other rare
metabolic disorders, including Fabry disease.
[0395] Another aspect of the disclosure is a method of increasing
vascular flow in a subject in need thereof the method including
administering to the subject a therapeutically-effective amount of
an AMPK-activating compound or a pharmaceutically acceptable salt,
prodrug or N-oxide thereof (or a solvate or hydrate thereof).
Accordingly, one embodiment of the disclosure is a method of
treating a disorder of vascular flow in a subject in need thereof,
the method including administering to the subject a
therapeutically-effective amount of an AMPK-activating compound or
a pharmaceutically acceptable stilt, prodrug or N-oxide thereof (or
a solvate or hydrate thereof). In certain embodiments, the disorder
of vascular flow is selected from erectile dysfunction, primary or
secondary Reynaud's disease, peripheral vascular disease, diabetic
angiopathy and peripheral artery disease. In other embodiments, the
disorder of vascular flow is selected from arteriosclerosis
obliterans and Buerger's disease, and progressive systemic
sclerosis, systemic erythematosus, vibration syndrome, aneurysm,
and vasculitis. The person of ordinary skill in the art will
determine a therapeutically-effective amount for a particular
patient and a particular cancer using standard methods in the
art.
[0396] Another aspect of the disclosure is a method of treating
pulmonary arterial hypertension in a subject in need thereof, the
method including administering to the subject a
therapeutically-effective amount of an AMPK-activating compound or
a pharmaceutically acceptable salt, prodrug or N-oxide thereof (or
a solvate or hydrate thereof). Pulmonary arterial hypertension is a
life-threatening disease involving endothelial dysfunction,
vasoconstriction in small pulmonary arteries, dysregulated
proliferation of certain vascular cells, and dysregulated
inflammatory signaling leading to vascular remodeling, pulmonary
fibrosis, and right ventricular hypertrophy. The presently
disclosed compounds have antioxidative and anti-inflammatory
properties, and exert beneficial effects on endothelial
dysfunction, as well as inhibiting excessive proliferation of
certain cells. Pulmonary arterial hypertension is described in S.
L. Archer et al., Circulation, vol. 121, 2045-66 (2010), which is
hereby incorporated herein by reference in its entirety. The person
of ordinary skill in the art will determine a
therapeutically-effective amount for a particular patient and a
particular pulmonary arterial hypertensive state using standard
methods in the art,
[0397] Another aspect of the disclosure is a method of treating
vasculitis or venous ulcers in a subject in need thereof, the
method including administering to the subject a
therapeutically-effective amount of an AMPK-activating compound or
a pharmaceutically acceptable salt, prodrug or N-oxide thereof (or
a solvate or hydrate thereof). Accordingly, one embodiment of the
disclosure is a method of treating a vasculitis in a subject in
need thereof, the method including administering to the subject a
therapeutically-effective amount of an AMPK-activating compound or
a pharmaceutically acceptable salt, prodrug or N-oxide thereof (or
a solvate or hydrate thereof. Another embodiment of the disclosure
is a method of treating a venous ulcers in a subject in need
thereof, the method including administering to the subject a
therapeutically-effective amount of an AMMP-activating compound or
a pharmaceutically acceptable salt, prodrug or N-oxide thereof (or
a solvate or hydrate thereof). The person of ordinary skill in the
art will determine a therapeutically-effective amount for a
particular patient and a particular disorder to be treated using
standard methods in the art.
[0398] The methods described herein can be useful with a wide
variety of subjects. For example, in certain embodiments, the
subject suffers from oxidative stress. In other embodiments, the
subject does not suffer from oxidative stress. Similarly, in
certain embodiments, the subject suffers from diabetes or
hyperglycemia. In other embodiments, the subject does not suffer
from diabetes or hyperglycemia.
Definitions
[0399] Terms used herein may be preceded and/or followed by a
single dash, "-", or a double dash, "=", to indicate the bond order
of the bond between the named substituent and its parent moiety; a
single dash indicates a single bond and a double dash indicates a
double bond or a pair of single bonds in the case of a
Spiro-substituent. in the absence of a single or double dash it is
understood that a single bond is formed between the substituent and
its parent moiety; further, substituents are intended to be read
"left to right" unless a dash indicates otherwise. For example,
arylalkyl, arylalkyl-, and -alkylaryl indicate the same
functionality.
[0400] For simplicity, chemical moieties are defined and referred
to throughout primarily as univalent chemical moieties (e.g.,
alkyl, aryl, etc.). Nevertheless, such terms are also used to
convey corresponding multivalent moieties under the appropriate
structural circumstances clear to those skilled in the art. For
example, while an "alkyl" moiety can refer to a monovalent radical
(e.g. CH.sub.3--CH.sub.2--), in some circumstances a bivalent
linking moiety can be "alkyl," in which case those skilled in the
art will understand the alkyl to be a divalent radical (e.g,
--CH.sub.2--H.sub.2--), which is equivalent to the term "alkylene."
(Similarly, in circumstances in which a divalent moiety is required
and is stated as being "aryl," those skilled in the art will
understand that the term "aryl" refers to the corresponding
divalent moiety, arylene). All atoms are understood to have their
normal number of valences for bond formation (i.e., 4 for carbon, 3
for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation
state of the S). Nitrogens in the presently disclosed compounds can
be hypervalent, e.g., an N-oxide or tetrasubstituted ammonium salt.
On occasion a moiety may be defined, for example, as (A).sub.a-B--,
wherein a is 0 or 1. In such instances, when a is 0 the moiety is
B-- and when a is 1 the moiety is A-B--.
[0401] As used herein, the term "alkyl" includes alkyl, alkenyl and
alkynyl groups of a designed number of carbon atoms, such as 1 to 6
carbons (i.e., inclusive of 1 and 6), 1 to 6 carbons, 1 to 3
carbons, or 1, 2, 3, 4, 5 or 6. The term "C.sub.m-C.sub.nalkyl"
means an alkyl group having from m to n carbon atoms (i.e.,
inclusive of m and n). The term "C.sub.m-C.sub.nalkyl" means an
alkyl group having from m to n carbon atoms. For example,
"C.sub.1-C.sub.6alkyl" is an alkyl group having from one to six
carbon atoms. Alkyl and alkyl groups may be straight or branched
and depending on context, may be a monovalent radical or a divalent
radical (i.e., an alkylene group). In the case of an alkyl or alkyl
group having zero carbon atoms (i.e., "C.sub.0alkyl"), the group is
simply a single covalent bond if it is a divalent radical or is a
hydrogen atom if it is a monovalent radical. For example, the
moiety "--(C.sub.0-C.sub.6alkyl)-Ar" signifies connection of an
optionally substituted aryl through a single bond or an alkylene
bridge having from Ito 6 carbons. Examples of "alkyl" include, for
example, methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and
tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, 3-hexenyl and
propargyl. If the number of carbon atoms is not specified, the
subject "alkyl" or "alkyl" moiety has from 1 to 6 carbons.
[0402] The term "haloalkyl" is an alkyl group substituted with one
or more halogen atoms, e.g. F, Cl, Br and I. A more specific term,
e.g., "fluoroalkyl" is an alkyl group substituted with one or more
fluorine atoms. Examples of "fluoroalkyl" include fluoromethyl,
difluoromethyl, trifluoromethyl, pentafluoroethyl,
hexafluoroisopropyl and the like. In certain embodiments of the
compounds disclosed herein, each haloalkyl is a fluoroalkyl.
[0403] The term "aryl" or "Ar" represents an aromatic ring system
having a single ring (e.g., phenyl) which is optionally fused to
other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings.
"Aryl" includes ring systems having multiple condensed rings and in
which at least one is carbocyclic and aromatic, (e.g.,
1,2,3,4-tetrahydronaphthyl, naphthyl). Examples of aryl groups
include phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl,
dihydronaphthyl, fluorenyl, tetralinyl, and
6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. In certain examples,
aryl groups include those having a first carbocyclic, aromatic ring
fused to an aromatic or aliphatic heterocycle, for example,
2,3-dihydrobenzofuranyl. The aryl groups herein are unsubstituted
or, when specified as "optionally substituted", can unless stated
otherwise be substituted in one or more substitutable positions
with various groups, as described below.
[0404] The term "heteroaryl" or "Het" refers to an aromatic ring
system containing at least one heteroatom selected from nitrogen,
oxygen and sulfur in an aromatic ring. Most commonly, the
heteroaryl groups will have 1, 2, 3, or 4 heteroatoms. The
heteroaryl may be fused to one or more non-aromatic ring, for
example, cycloalkyl or heterocycloalkyl rings, wherein the
cycloalkyl (Cak) and heterocycloalkyl (Hca) rings are described
herein. In one embodiment of the present compounds the heteroaryl
group is bonded to the remainder of the structure through an atom
in a heteroaryl group aromatic ring. In another embodiment, the
heteroaryl group is bonded to the remainder of the structure
through a non-aromatic ring atom. Examples of heteroaryl groups
include, for example, pyridyl, pyrimidinyl, quinolinyl,
benzothienyl, indolyl, indolinyl, pyridazinyl, pyrazirayl
isoindolyl isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl,
imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,
indolizinyl, indazolyl, benzothiazolyl, benzitnidazolyl,
benzofuranyl, furanyl, thienyl, pyrrolyl oxadiazolyl, thiadiazolyl
benzo[1,4]oxazinyl, triazolyl, tetrazolyl, isothiazolyl,
naphthyridinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,
isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,
isobenzothienyl, benzoxazoly , pyridopyridinyl,
benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl,
benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl,
imidazopyrinyl, imidazothiazolyl, dihydrobenzisoxazinyl,
benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl,
benzopyranyl, benzothiopyranyl, chromonyl, thromanonyl,
pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl,
dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl,
dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl,
benzoxazolitionyl, pyrrolyl N-oxide, pyrinlidinyl N-oxide,
pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl
N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl
N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl
N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide,
indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,
benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,
thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,
benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. Preferred
heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl,
pyrrolyl, furanyl, thienyl and imidazolyl, pyrazolyl, indazolyl,
thiazolyl and benzothiazolyl. In certain embodiments, each
heteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl,
pyrazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,
furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, isothiazolyl, pyridinyl-N-oxide, pyrrolyl N-oxide,
pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide,
imidazolyl N-oxide, isoxazolyl N-oxide, oxazolylN-oxide, thiazolyl
N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl
N-oxide, triazolyl N-oxide, and tetrazolyl N-oxide. Preferred
heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl,
pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, indazolyl,
thiazolyl and benzothiazolyl. The heteroaryl groups herein are
unsubstituted or, when specified as "optionally substituted", can
unless stated otherwise be substituted in one or more substitutable
positions with various groups, as described below.
[0405] The term "heterocycloalkyl" or "Hca" refers to a
non-aromatic ring or ring system containing at least one heteroatom
that is preferably selected from nitrogen, oxygen and sulfur,
wherein said heteroatom is in a non-aromatic ring. The
heterocycloalkyl may have 1, 2, 3 or 4 heteroatoms. The
heterocycloalkyl may be saturated (i.e., a heterocycloalkyl) or
partially unsaturated (i.e., a heterocycloalkenyl).
Heterocycloalkyl includes monocyclic groups of three to eight
annular atoms as well as bicyclic and polycyclic ring systems,
including bridged and fused systems, wherein each ring includes
three to eight annular atoms. The heterocycloalkyl ring is
optionally fused to other heterocycloalkyl rings and/or
non-aromatic hydrocarbon rings and/or phenyl rings. In certain
embodiments, the heterocycloalkyl groups have from 3 to 7 members
in a single ring. in other embodiments, heterocycloalkyl groups
have 5 or 6 members in a single ring. In some embodiments, the
heterocycloalkyl groups have 3, 4, 5, 6 or 7 members in a single
ring. Examples of heterocycloalkyl groups include, for example,
azabicyclo[2.2.2]octyl (in each case also "quinuclidinyl" or a
quinuclidine derivative), azabicyclo[3.2.1]octyl,
2,5-diazabicyclo[2.2.1]heptyl , morpholinyl, thiomorpholinyl,
thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide,
2-oxazolidonyl, piperazinyl, homopiperazinyl, piperazinonyl,
pyrrolidinyl, azepanyl, azetidinyl, pyrrolinyl, tetrahydropyranyl,
piperidinyl, tetrahydrofuranyl, tetrahydrothienyl,
3,4-dihydroisoquinolin-2(1H)-yl, isoindolindionyl, homopipenidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,
dihydrofuryl, dihydropyranyl, imidazolidonyl, tetrahydrothienyl
S-oxide, tetrahydrothienyl S,S-dioxide and homothiomorpholinyl
S-oxide. Especially desirable heterocycloalkyl groups include
morpholinyl, 3,4-dihydroisoquinolin-2(1H)-yl, tetrahydropyranyl,
piperidinyl, aza-bicyclo[2.2.2]octyl, .gamma.-butyrolactonyl (i.e.,
an oxo-substituted tetrahydrofuranyl), .gamma.-butryolactamyl
(i.e., an oxo-substituted pyrrolidine), pyrrolidinyl, piperazinyl,
azepanyl, azetidinyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide,
2-oxazolidonyl, imidazolidonyl, isoindolindionyl piperazinonyl. The
heterocycloalkyl groups herein are unsubstituted or, when specified
as "optionally substituted," can unless stated otherwise be
substituted in one or more substitutable positions with various
groups, as described below.
[0406] The term "cycloalkyl" or "Cak" refers to a non-aromatic
carbocyclic ring or ring system, which may be saturated (i.e., a
cycloalkyl) or partially unsaturated (i.e., a cycloalkenyl). The
cycloalkyl ring optionally fused to or otherwise attached (e.g.,
bridged systems) to other cycloalkyl rings. Certain examples of
cycloalkyl groups present in the disclosed compounds have from 3 to
7 members in a single ring, such as having 5 or 6 members in a
single ring. In some embodiments, the cycloalkyl groups have 3, 4,
5, 6 or 7 members in a single ring. Examples of cycloalkyl groups
include, for example, cyclohexyl, cyclopentyl, cyclobutyl,
cyclopropyl, tetrahydronaphthyl and bicyclo[2.2.1]heptane. The
cycloalkyl groups herein are unsubstituted or, when specified as
"optionally substituted", may be substituted in one or more
substitutable positions with various groups.
[0407] The term "ring system" encompasses monocycles, as well as
fused and/or bridged polycycles.
[0408] The term "oxa" means a divalent oxygen radical in a chain,
sometimes designated as --O--.
[0409] The term "oxo" means a doubly bonded oxygen, sometimes
designated as .dbd.O or for example in describing a carbonyl "C(O)"
may be used to show an oxo substituted carbon.
[0410] The term "electron withdrawing group" means a group that
withdraws electron density from the structure to which it is
attached than would a similarly-attached hydrogen atom. For
example, electron withdrawing groups can be selected from the group
consisting of halo fluoro, chloro, bronco, and iodo), cyano,
--(C.sub.1-C.sub.4 fluoroalkyl), --O--(C.sub.1-C.sub.4
fluoroalkyl), --C(O)--(C.sub.0-C.sub.4alkyl),
--C(O)O--(C.sub.0-C.sub.4alkyl),
--C(O)N(C.sub.0-C.sub.4alkyl)(C.sub.0-C.sub.4alkyl),
--S(O).sub.2O--(C.sub.0-C.sub.4alkyl), NO.sub.2 and --C(O)-Hca in
which the Hca includes a nitrogen atom to which the --C(O)-- is
bound, in which no alkyl, fluoroalkyl or heterocycloalkyl is
substituted with an aryl, heteroaryl, cycloalkyl or
heterocycloalkyl-containing group.
[0411] The term "substituted," when used to modify a specified
group or radical, means that one or more hydrogen atoms of the
specified group or radical are each, independently of one another,
replaced with the same or different substituent groups as defined
below, unless specified otherwise.
[0412] Substituent groups for substituting for hydrogens on
saturated carbon atoms in the specified group or radical are,
unless otherwise specified, --R.sup.60, halo, --O.sup.-M.sup.+,
.dbd.O, --OR.sup.70, --SR.sup.70, --S.sup.-M.sup.+, .dbd.S,
--NR.sup.80R.sup.80 , .dbd.NR.sup.70, .dbd.N--OR.sup.70,
trihalomethyl, --CF.sub.3, --CN, --OCN, --SCN, --NO, --NO.sub.2,
.dbd.N.sub.2, --N.sub.3, --SO.sub.2R.sup.70,
--SO.sub.2O.sup.-M.sup.+, --SO.sub.2OR.sup.70, --OSO.sub.2R.sup.70,
--OSO.sub.2O.sup.-M.sup.+, --OSO.sub.2OR.sup.70,
--P(O)(O.sup.-).sub.2(M.sup.+).sub.2,
--P(O)(OR.sup.70)O.sup.-M.sup.+, --P(O)(OR.sup.70).sub.2,
--C(O)R.sup.70, --C(S)R.sup.70, --C(NR.sup.70)R.sup.70,
--C(O)O.sup.-M.sup.+, --C(O)OR.sup.70, --C(S)OR.sup.70,
--C(O)NR.sup.80R.sup.80, --C(NR.sup.70)NR.sup.80R.sup.80,
--OC(O)R.sup.70, --OC(S)R.sup.70, --OC(O)O.sup.-M.sup.+,
--OC(O)OR.sup.70, --OC(S)OR.sup.70, --NR.sup.70C(O)R.sup.70,
--NR.sup.70C(S)R.sup.70, --NR.sup.70CO.sub.2.sup.-M.sup.+,
--NR.sup.70CO.sub.2R.sup.70, --NR.sup.70C(S)OR.sup.70,
--NR.sup.70C(O)NR.sup.80R.sup.80, --NR.sup.70C(NR.sup.70)R.sup.70
and --NR.sup.70C(NR.sup.70)NR.sup.80R.sup.80. Each R.sup.60 is
independently selected from the group consisting of alkyl,
heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl,
each of which is optionally substituted with 1, 2, 3, 4 or 5 groups
selected from the group consisting of halo, --O.sup.-M.sup.+,
.dbd.O, --OR.sup.71, --SR.sup.71, --S.sup.-M.sup.+.dbd.S,
--NR.sup.81R.sup.81, .dbd.NR.sup.71, .dbd.N--OR.sup.71,
trihalomethyl, --CF.sub.3, --CN, --OCN, --SCN, --NO, --NO.sub.2,
.dbd.N.sub.2, --N.sub.3, --SO.sub.2R.sup.71,
--SO.sub.2O.sup.-M.sup.+, --SO.sub.2OR.sup.71, --OSO.sub.2R.sup.71,
--OSO.sub.2O.sup.-M.sup.+, --OSO.sub.2OR.sup.71,
--P(O)(O.sup.-).sub.2(M.sup.+).sub.2,
--P(O)(OR.sup.71)O.sup.-M.sup.+, --SO.sub.2OR.sup.71, 13
C(O)R.sup.71, --C(S)R.sup.71, --C(NR.sup.71)R.sup.71,
--C(O)O.sup.-M.sup.+, --C(O)OR.sup.71, --C(S)OR.sup.71,
--C(O)NR.sup.81R.sup.81, --C(NR.sup.71)NR.sup.81R.sup.81,
--OC(O)R.sup.71, --OC(S)R.sup.71, --OC(O)O.sup.-M.sup.+,
--OC(O)OR.sup.71, --OC(S)OR.sup.71, --NR.sup.71C(O)R.sup.71,
--NR.sup.71C(S)R.sup.71, --NR.sup.71CO.sub.2.sup.-M.sup.+,
--NR.sup.71CO.sub.2R.sup.71, --NR.sup.71C(S)OR.sup.71,
--NR.sup.71C(O)NR.sup.81R.sup.81, --NR.sup.71C(NR.sup.71)R.sup.71
and --NR.sup.71C(NR.sup.71)NR.sup.81R.sup.81. Each R.sup.70 is
independently hydrogen or R.sup.60; each R.sup.80 is independently
R.sup.70 or alternatively, two R.sup.80's, taken together with the
nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered
heterocycloalkyl which may optionally include from 1 to 4 of the
same or different additional heteroatoms selected from the group
consisting of O, N and S, of which N may have --H or
C.sub.1-C.sub.3alkyl substitution; and each M.sup.+ is a counter
ion with a net single positive charge. Each R.sup.71 is
independently hydrogen or R.sup.61, in which R.sup.61 is alkyl,
heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl,
cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl,
each of which is optionally substituted with 1, 2, 3, 4 or 5 groups
selected from the group consisting of halo, --O.sup.-M.sup.+,
.dbd.O, --OR.sup.72, --SR.sup.72, --S.sup.-M.sup.+, .dbd.S,
--NR.sup.82R.sup.82, .dbd.NR.sup.72, .dbd.N--OR.sup.72,
trihalomethyl, --CF.sub.3, --CN, --OCN, --SCN, --NO, --NO.sub.2,
.dbd.N.sub.2, --N.sub.3, --SO.sub.2R.sup.71,
--SO.sub.2O.sup.-M.sup.+, --SO.sub.2OR.sup.72, --OSO.sub.2R.sup.72,
--OSO.sub.2O.sup.-M.sup.+, --OSO.sub.2OR.sup.72,
--P(O)(O.sup.-).sub.2(M.sup.+).sub.2,
--P(O)(OR.sup.72)O.sup.-M.sup.+, --P(O)(OR.sup.72).sub.2,
--C(O)R.sup.72, --C(S)R.sup.72, --C(NR.sup.72)R.sup.72,
--C(O)O.sup.-M.sup.+, --C(O)OR.sup.72, --C(S)OR.sup.72,
--C(O)NR.sup.82R.sup.82, --C(NR.sup.72)NR.sup.82R.sup.82,
--OC(O)R.sup.72, --OC(S)R.sup.72, --OC(O)O.sup.-M.sup.+,
--OC(O)OR.sup.72, --OC(S)OR.sup.72, --NR.sup.72C(O)R.sup.72,
--NR.sup.72C(S)R.sup.72, --NR.sup.72CO.sub.2.sup.-M.sup.+,
--NR.sup.72CO.sub.2R.sup.72, --NR.sup.72C(S)OR.sup.72,
--NR.sup.72C(O)NR.sup.82R.sup.82, --NR.sup.72C(NR.sup.72)R.sup.72
and --NR.sup.72C(NR.sup.72)NR.sup.82R.sup.82; and each R.sup.81 is
independently R.sup.71 or alternatively, two R.sup.81s, taken
together with the nitrogen atom to which they are bonded, form a
5-, 6- or 7-membered. heterocycloalkyl which may optionally include
from 1 to 4 of the same or different additional heteroatoms
selected from the group consisting of O, N and S, of which N may
have --H or C.sub.1-C.sub.3 alkyl substitution. Each R.sup.72 is
independently hydrogen, (C.sub.1-C.sub.6alkyl) or
(C.sub.1-C.sub.6fluoroalkyl); each R.sup.82 is independently
R.sup.72 or alternatively, two R.sup.82s, taken together with the
nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered
heterocycloalkyl which may optionally include 1, 2, 3 or 4 of the
same or different additional heteroatoms selected from the group
consisting of O, N and S, of which N may have --H or
C.sub.1-C.sub.3alkyl substitution. Each M.sup.+ may independently
be, for example, an alkali ion, such as K.sup.+, Na.sup.+,
Li.sup.+; an ammonium ion, such as .sup.+N(R.sup.60).sub.4; or an
alkaline earth ion, such as [Ca.sup.2+].sub.0.5,
[Mg.sup.2+].sub.0.5, or [Ba.sup.2+].sub.0.5 ("subscript 0.5 means
e.g. that one of the counter ions for such divalent alkali earth
ions can he an ionized form of a presently disclosed compound and
the other a typical counter ion such as chloride, or two ionized
presently disclosed molecules can serve as counter ions for such
divalent alkali earth ions, or a doubly ionized compound can serve
as the counter ion for such divalent alkali earth ions). As
specific examples, --NR.sup.80R.sup.80 is meant to include
--NH.sub.2, --NH-alkyl, N-pyrrolidinyl, N-piperazinyl,
4-methyl-piperazin-1-yl and N-morpholinyl.
[0413] Substituent groups for hydrogens on unsaturated carbon atoms
in "substituted" alkene, alkyne, aryl and heteroaryl groups are,
unless otherwise specified, --R.sup.60, halo, --O.sup.-M.sup.+,
--OR.sup.70, --SR.sup.70, --S.sup.-M.sup.+, --NR.sup.80R.sup.80,
trihalomethyl, --CF.sub.3, --CN, --OCN, --SCN, --NO, --NO.sub.2,
--N.sub.3, --SO.sub.2R.sup.70, --SO.sub.3.sup.-M.sup.+,
--SO.sub.3R.sup.70, --OSO.sub.2R.sup.70, --OSO.sub.3.sup.-M.sup.+,
--OSO.sub.3R.sup.70, --PO.sub.3.sup.-2(M.sup.+).sub.2,
--P(O)(OR.sup.70)O.sup.-M.sup.+, --P(O)(OR.sup.70).sub.2,
--C(O)R.sup.70, --C(S)R.sup.70, --C(NR.sup.70)R.sup.70,
--CO.sub.2.sup.-M.sup.+, --CO.sub.2R.sup.70, --C(S)OR.sup.70,
--C(O)NR.sup.80R.sup.80, --C(NR.sup.70)NR.sup.80R.sup.80,
--OC(O)R.sup.70, --OC(S)R.sup.70, --OCO.sub.2.sup.-M.sup.+,
--OCO.sub.2R.sup.70, --OC(S)OR.sup.70, --NR.sup.70C(O)R.sup.70,
--NR.sup.70C(S)R.sup.70, --NR.sup.70CO.sub.2.sup.-M.sup.+,
--NR.sup.70CO.sub.2R.sup.70, --NR.sup.70C(S)OR.sup.70,
--NR.sup.70C(O)NR.sup.80R.sup.80, --NR.sup.70C(NR.sup.70)R.sup.70
and --NR.sup.70C(NR.sup.70)NR.sup.80R.sup.80, where R.sup.60,
R.sup.70, R.sup.80 and M.sup.+ are as previously defined.
[0414] Substituent groups for hydrogens on nitrogen atoms in
"substituted" heteroalkyl and heterocycloalkyl groups are, unless
otherwise specified, --R.sup.60, --O.sup.-M.sup.+, --OR.sup.70,
--SR.sup.70, --S.sup.-M.sup.+, --NR.sup.80R.sup.80, trihalomethyl,
--CF.sub.3, --CN, --NO, --NO.sub.2, --S(O).sub.2R.sup.70,
--S(O).sub.2O.sup.-M.sup.+, --S(O).sub.2OR.sup.70,
--OS(O).sub.2R.sup.70, --OS(O).sub.2O.sup.-M.sup.+,
--OS(O).sub.2OR.sup.70, --P(O)(O.sup.-).sub.2(M.sup.+).sub.2,
--P(O)(OR.sup.70)O.sup.-M.sup.+, --P(O)(OR.sup.70)(OR.sup.70),
--C(O)R.sup.70, --C(S)R.sup.70, --C(NR.sup.70)R.sup.70,
--C(O)OR.sup.70, --C(S)OR.sup.70, --C(O)NR.sup.80R.sup.80,
--C(NR.sup.70)NR.sup.80R.sup.80, --OC(O)--R.sup.70, --C(S)R.sup.70,
--C(O)OR.sup.70, --OC(S)OR.sup.70, --NR.sup.70C(O)R.sup.70,
--NR.sup.70C(S)R.sup.70, --NR.sup.70C(O)OR.sup.70,
--NR.sup.70C(S)OR.sup.70, --NR.sup.70C(O)NR.sup.80R.sup.80,
--NR.sup.70C(NR.sup.70)R.sup.70 and
--NR.sup.70C(NR.sup.70)NR.sup.80R.sup.80, where R.sup.60, R.sup.70,
R.sup.80 and M.sup.+ are as previously defined.
[0415] In certain embodiments of the compounds disclosed herein, a
group that is substituted has 1, 2, 3, or 4 substituents, 1. 2, or
3 substituents, 1 or 2 substituents, or 1 substituent.
[0416] In certain embodiments, substituent groups on "substituted"
alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are
-halo, --OH, --O--(C.sub.1-C.sub.4alkyl),
--O--(C.sub.1-C.sub.4haloalkyl), --N(C.sub.0-C.sub.4
alkyl)(C.sub.0-C.sub.4alkyl), --SH,
--S(O).sub.0-2--(C.sub.1-C.sub.4alkyl), --(C.sub.1-C.sub.4alkyl),
--(C.sub.1-C.sub.4haloalkyl), --C(O)--(C.sub.0-C.sub.4alkyl),
--C(O)N(C.sub.0-C.sub.4alkyl)(C.sub.0-C.sub.4alkyl),
--N(C.sub.0-C.sub.4alkyl)C(O)(C.sub.0-C.sub.4alkyl)(C.sub.0-C.sub.4alkyl)-
, --C(O)O--(C.sub.0-C.sub.4alkyl), --OC(O)--(C.sub.0-C.sub.4alkyl),
S(O).sub.2--O(C.sub.0-C.sub.4alkyl), and --NO.sub.2, in which no
alkyl is further substituted.
[0417] The compounds disclosed herein can also be provided as
pharmaceutically acceptable salts. The term "pharmaceutically
acceptable salts" or "a pharmaceutically acceptable salt thereof"
refer to salts prepared from pharmaceutically acceptable non-toxic
acids or bases including inorganic acids and bases and organic
acids and bases. If the compound is basic, salts may be prepared
from pharmaceutically acceptable non-toxic acids. Such salts may
be, for example, acid addition salts of at least one of the
following acids: benzenesulfonic acid, citric acid,
.alpha.-glucoheptonic acid, D-glitconic acid, glycolic acid, lactic
acid, inane acid, malonic acid, mandelic acid, phosphoric acid,
propanoic acid, succinic acid, sulfuric acid, tartaric acid (d, l,
or dl), tosic acid (toluenesulfonic acid), valeric acid, palmitic
acid, pamoic acid, sebacic acid, stearic acid, lauric acid, acetic
acid, adipic acid, carbonic acid, 4-chlorobenzenesulfonic acid,
ethanedisulfonic acid, ethylsuccinic acid, fumaric acid, galactaric
acid (mucic acid), D-glucuronic acid, 2-oxo-giutaric acid,
glycerophosphoric acid, hippuric acid, isethionic acid
(ethanolsulfonic acid), lactobionic acid, maleic acid,
1,5-naphthalene-disulfonic acid, 2-naphthalene-sulfonic acid,
pivalic acid, terephthalic acid, thiocyanic acid, cholic acid,
n-dodecyl sulfate, 3-hydroxy-2-naphthoic acid,
1-hydroxy-2-naphthoic acid, oleic acid, undecylenic acid, ascorbic
acid, (+)-camphoric acid, d-camphorsulfonic acid, dichloroacetic
acid, ethanesulfonic acid, formic acid, hydriodic acid, hydrobromic
acid, hydrochloric acid, methanesulfonic acid, nicotinic acid,
nitric acid, orotic acid, oxalic acid, picric acid, L-pyroglutamic
acid, saccharine, salicylic acid, gentisic acid, and/or
4-acetamidobenzoic acid.
[0418] The compounds described herein can also be provided in
prodrug form. "Prodrug" refers to a derivative of an active
compound (drug) that undergoes a transformation under the
conditions of use, such as within the body, to release the active
drug. Prodrugs are frequently, but not necessarily,
pharmacologically inactive until converted into the active drug.
Prodrugs are typically obtained by masking a functional group in
the drug believed to be in part required for activity with a
progroup (defined below) to form a promoiety which undergoes a
transformation, such as cleavage, under the specified conditions of
use to release the functional group, and hence the active drug. The
cleavage of the promoiety can proceed spontaneously, such as by way
of a hydrolysis reaction, or it can be catalyzed or induced by
another agent, such as by an enzyme, by light, by acid, or by a
change of or exposure to a physical or environmental parameter,
such as a change of temperature. The agent can be endogenous to the
conditions of use, such as an enzyme present in the cells to which
the prodrug is administered or the acidic conditions of the
stomach, or it can be supplied exogenously. A wide variety of
progroups, as well as the resultant promoieties, suitable for
masking functional groups in the active drugs to yield prodrugs are
well-known in the art. For example, a hydroxyl functional group can
be masked as a sulfonate, ester or carbonate promoiety, which can
be hydrolyzed in vivo to provide the hydroxyl group. An amino
functional group can be masked as an amide, carbamate, imine, urea,
phosphenyl, phosphoryl or sulfenyl promoiety, which can be
hydrolyzed in vivo to provide the amino group. A carboxyl group can
be masked as an ester (including silyl esters and thioesters),
amide or hydrazide promoiety, which can be hydrolyzed in vivo to
provide the carboxyl group. Specific examples of suitable progroups
and their respective promoieties will be apparent to those of skill
in the art
[0419] The compounds disclosed herein can also be provided as
N-oxides.
[0420] The presently disclosed compounds, salts, prodrugs and
N-oxides can be provided, for example, in solvate or hydrate
form.
[0421] One of ordinary skill in the art of medicinal chemistry also
will appreciate that the disclosed structures are intended to
include isotopically enriched forms of the present compounds. As
used herein "isotopes" includes those atoms having the same atomic
number but different mass numbers. As is known to those of skill in
the art, certain atoms, such as hydrogen occur in different
isotopic forms. For example, hydrogen includes three isotopic
forms, protium, deuterium and tritium. As will he apparent to those
of skill in the art upon consideration of the present compounds,
certain compounds can be enriched at a given position with a
particular isotope of the atom at that position. For example,
compounds having a fluorine atom, may be synthesized in a form
enriched in the radioactive fluorine isotope .sup.18F. Similarly,
compounds may be enriched in the heavy isotopes of hydrogen:
deuterium and tritium; and similarly can be enriched in a
radioactive isotope of carbon, such as .sup.13C. Such isotopic
variant compounds undergo different metabolic pathways and can be
useful, for example, in studying the ubiquitination pathway and its
role in disease.
[0422] As used herein, the term "cell" is meant to refer to a cell
that is in vitro, ex vivo or in vivo. In some embodiments, an ex
vivo cell can be part of a tissue sample excised from an organism
such as a mammal. in some embodiments, an in vitro cell can be a
cell in a cell culture. In some embodiments, an in vivo cell is a
cell living in an organism such as a mammal.
[0423] As used herein, the term "contacting" refers to the bringing
together of indicated moieties in an in vitro system or an in vivo
system. For example, "contacting" an enzyme with a compound
includes the administration of a compound described herein to an
individual or patient, such as a human, as well as, for example,
introducing a compound into a sample containing a cellular or
purified preparation containing the enzyme.
[0424] As used herein, the terms "individual," "patient," or
"subject" are used interchangeably, refers to any animal, including
mammals, preferably mice, rats, other rodents, rabbits, dogs, cats,
swine, cattle, sheep, horses, or primates, and most preferably
humans.
[0425] As used herein, the phrase "therapeutically effective
amount" refers to the amount of active compound or pharmaceutical
agent that elicits the biological or medicinal response that is
being sought in a tissue, system, animal, individual or human by a
researcher, veterinarian, medical doctor or other clinician.
[0426] In certain embodiments, a therapeutically effective amount
can be an amount suitable for
[0427] (1) preventing the disease; for example, preventing a
disease, condition or disorder in an individual who may be
predisposed or otherwise susceptible to the disease, condition or
disorder but does not yet experience or display the pathology or
symptomatology of the disease;
[0428] (2) inhibiting the disease; for example, inhibiting a
disease, condition, or disorder in an individual who is
experiencing or displaying the pathology or symptomatology of the
disease, condition or disorder; or
[0429] (3) ameliorating the disease (including a symptom thereof);
for example, ameliorating a disease, condition, or disorder in an
individual who is experiencing or displaying the pathology or
symptomatology of the disease, condition or disorder (Le reversing
the pathology and/or symptomatology) such as decreasing the
severity of disease.
[0430] As used here, the terms "treatment" and "treating" mean (i)
ameliorating the referenced disease state, condition, or disorder
(or a symptom thereof), such as, for example, ameliorating a
disease, condition or disorder in an individual who is experiencing
or displaying the pathology or symptomatology of the disease,
condition or disorder (e.g., reversing or improving the pathology
and/or symptomatology) such as decreasing the severity of disease
or symptom thereof.
[0431] As used here, the terms "activating" and "activation" are
meant to represent the biological effect of increasing the activity
(i.e., phosphorylation of downstream substrates) of fully
phosphorylated AMPK or increasing the phosphorylation of AMPK. An
"activator" is a compound capable of achieving this biological
effect.
[0432] As used herein, the phrase "pharmaceutically acceptable
salt" refers to both pharmaceutically acceptable acid and base
addition salts and solvates. Such pharmaceutically acceptable salts
include salts of acids such as hydrochloric, phosphoric,
hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic,
methanesulfonic, nitric, benzoic, citric, tartaric, maleic,
hydroiodic, alkanoic such as acetic, HOOC--(CH.sub.2).sub.n--COOH
where n is 0-4, and the like. Non-toxic pharmaceutical base
addition salts include salts of bases such as sodium, potassium,
calcium, ammonium, and the like. Those skilled in the art will
recognize a wide variety of non-toxic pharmaceutically acceptable
addition salts.
Pharmaceutical Formulations and Dosage Forms
[0433] The compounds of structural formulae (I)-(III) can be
administered, for example, orally, topically, parenterally, by
inhalation or spray or rectally in dosage unit formulations
containing one or more pharmaceutically acceptable carriers,
diluents or excipients. The term parenteral as used herein includes
percutaneous, subcutaneous, intravascular (e.g., intravenous),
intramuscular, or intrathecal injection or infusion techniques and
the like.
[0434] Pharmaceutical compositions can be made using the presently
disclosed compounds. For example, in one embodiment, a
pharmaceutical composition includes a pharmaceutically acceptable
carrier, diluent or excipient, and compound as described above with
reference to structural formulae (I)-(III).
[0435] In the pharmaceutical compositions disclosed herein, one or
more compounds of structural formulae (I)-(III) may be present in
association with one or more pharmaceutically acceptable carriers,
diluents or excipients, and, if desired, other active ingredients.
The pharmaceutical compositions containing compounds of structural
formulae (I)-(III) may be in a form suitable for oral use, for
example, as tablets, troches, lozenges, aqueous or oily
suspensions, dispersible powders or granules, emulsion, hard or
soft capsules, or syrups or elixirs.
[0436] Compositions intended for oral use can be prepared according
to any suitable method for the manufacture of pharmaceutical
compositions and such compositions may contain one or more agents
selected from the group consisting of sweetening agents, flavoring
agents, coloring agents and preservative agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets
contain the active ingredient in admixture with non-toxic
pharmaceutically acceptable excipients that are suitable for the
manufacture of tablets. These excipients can he for example, inert
diluents, such as calcium carbonate, sodium carbonate, lactose,
calcium phosphate or sodium phosphate; granulating and
disintegrating agents, for example, corn starch, or alginic acid;
binding agents, for example starch, gelatin or acacia, and
lubricating agents, for example magnesium stearate, stearic acid or
talc. The tablets can be uncoated or they can be coated by known
techniques. In some cases such coatings can he prepared by suitable
techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action over
a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate can be employed.
[0437] Formulations for oral use can also be presented as hard
gelatin capsules, wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin or olive oil.
[0438] Formulations for oral use can also be presented as
lozenges.
[0439] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients can be suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone,
gum tragacanth and gum acacia; dispersing or wetting agents such as
a naturally-occurring phosphatide, for example, lecithin, or
condensation products of an alkylene oxide with fatty acids, for
example polyoxyethylene stearate, or condensation products of
ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene
oxide with partial esters derived from fatty acids and a hexitol
such as polyoxyethylene sorbitol monooleate, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and hexitol anhydrides, for example polyethylene sorbitan
monooleate. The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or n-propyl p-hydroxybenzoate,
one or more coloring agents, one or more flavoring agents, and one
or more sweetening agents, such as sucrose or saccharin.
[0440] Oily suspensions can be formulated by suspending the active
ingredients in a vegetable oil, for example araehis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
and flavoring agents may be added to provide palatable oral
preparations. These compositions may be preserved by the addition
of an anti-oxidant such as ascorbic acid.
[0441] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents or suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, can also be present.
[0442] Pharmaceutical compositions can also be in the form of
oil-in-water emulsions. The oily phase can be a vegetable oil or a
mineral oil or mixtures of these. Suitable emulsifying agents can
be naturally-occurring gums, for example gum acacia or gum
tragacanth, naturally-occurring phosphatides, for example soy bean,
lecithin, and esters or partial esters derived from fatty acids and
hexitol, anhydrides, for example sorbitan monooleate, and
condensation products of the said partial esters with ethylene
oxide, for example polyoxyethylene sorbitan monooleate. The
emulsions can also contain sweetening and flavoring agents.
[0443] In some embodiments, the pharmaceutically acceptable
carrier, diluent, or excipient is not water. In other embodiments,
the water comprises less than 50% of the composition. In some
embodiments, compositions comprising less than 50% water have at
least 1%, 2%, 3%, 4% or 5% water. In other embodiments, the water
content is present in the composition in a trace amount.
[0444] In some embodiments, the pharmaceutically acceptable
earlier, diluent, or excipient is not alcohol. In other
embodiments, the alcohol comprises less than 50% of the
composition. in some embodiments, compositions comprising less than
50% alcohol have at least 1%, 2%, 3%, 4% or 5% alcohol. In other
embodiments, the alcohol content is present in the composition in a
trace amount.
[0445] Syrups and elixirs can be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol, glucose or
sucrose. Such formulations can also contain a demulcent, a
preservative, flavoring, and coloring agents. The pharmaceutical
compositions can be in the form of a sterile injectable aqueous or
oleaginous suspension. This suspension can be formulated according
to the known art using those suitable dispersing or wetting agents
and suspending agents that have been mentioned above. The sterile
injectable preparation can also be a sterile injectable solution or
suspension in a non-toxic parentally acceptable diluent or solvent,
for example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that can be employed are water, Ringer's
solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils can be employed as a solvent or suspending
medium. For this purpose any bland fixed oil can be employed
including synthetic mono- or diglycerides. In addition, fatty acids
such as oleic acid find use in the preparation of injectables.
[0446] Compounds of structural formulae (I)-(III) can also be
administered in the form of suppositories, e.g., for rectal
administration of the drug. These compositions can be prepared by
mixing the compound with a suitable non-irritating excipient that
is solid at ordinary temperatures but liquid at the rectal
temperature and will therefore melt in the rectum to release the
drug. Such materials include cocoa butter and polyethylene
glycols.
[0447] Compounds of structural formula (I)-(III) can also be
administered parenterally in a sterile medium. The drug, depending
on the vehicle and concentration used, can either be suspended or
dissolved in the vehicle. Advantageously, adjuvants such as local
anesthetics, preservatives and buffering agents can be dissolved in
the vehicle.
[0448] The compositions can be formulated in a unit dosage form,
each dosage containing from about 5 to about 100 mg, more usually
about 10 to about 30 mg, of the active ingredient. The term "unit
dosage forms" refers to physically discrete units suitable as
unitary dosages for human subjects and other mammals, each unit
containing a predetermined quantity of active material calculated
to produce the desired therapeutic effect, in association with a
suitable pharmaceutical excipient.
[0449] The active compound can be effective over a wide dosage
range and is generally administered in a pharmaceutically effective
amount. It will be understood, however, that the amount of the
compound actually administered will usually be determined by a
physician, according to the relevant circumstances, including the
condition to be treated, the chosen route of administration, the
actual compound administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms, and the
like.
[0450] For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical
excipient to form a solid preformulation composition containing a
homogeneous mixture of a compound described herein. When referring
to these preformulation compositions as homogeneous, the active
ingredient is typically dispersed evenly throughout the composition
so that the composition can be readily subdivided into equally
effective unit dosage forms such as tablets, pills and capsules.
This solid preformulation is then subdivided into unit dosage forms
of the type described above containing from, for example, 0.1 to
about 500 mg of the active ingredient of a compound described
herein.
[0451] The tablets or pills can be coated or otherwise compounded
to provide a dosage form affording the advantage of prolonged
action. For example, the tablet or pill can comprise an inner
dosage and an outer dosage component, the latter being in the form
of an envelope over the former. The two components can be separated
by an enteric layer which serves to resist disintegration in the
stomach and permit the inner component to pass intact into the
duodenum or to be delayed in release. A variety of materials can be
used for such enteric layers or coatings, such materials including
a number of polymeric acids and mixtures of polymeric acids with
such materials as shellac, cetyl alcohol, and cellulose
acetate.
[0452] The amount of compound or composition administered to a
patient will vary depending upon what is being administered, the
purpose of the administration, such as prophylaxis or therapy, the
state of the patient, the manner of administration, and the like.
In therapeutic applications, compositions can be administered to a
patient already suffering from a disease in an amount sufficient to
cure or at least partially arrest the symptoms of the disease and
its complications. Effective doses will depend on the disease
condition being treated as well as by the judgment of the attending
clinician depending upon factors such as the severity of the
disease, the age, weight and general condition of the patient, and
the like.
[0453] The compositions administered to a patient can be in the
form of pharmaceutical compositions described above. These
compositions can be sterilized by conventional sterilization
techniques, or may be sterile filtered. Aqueous solutions can be
packaged for use as is, or lyophilized, the lyophilized preparation
being combined with a sterile aqueous carrier prior to
administration. The pH of the compound preparations typically will
be between 3 and 11, more preferably from 5 to 9 and most
preferably from 7 to 8. it will be understood that use of certain
of the foregoing excipients, carriers, or stabilizers will result
in the formation of pharmaceutical salts.
[0454] The therapeutic dosage of the compounds can vary according
to, for example, the particular use for which the treatment is
made, the manner of administration of the compound, the health and
condition of the patient, and the judgment of the prescribing
physician. The proportion or concentration of a compound described
herein in a pharmaceutical composition can vary depending upon a
number of factors including dosage, chemical characteristics (e.g.,
hydrophobicity), and the route of administration. For example, the
compounds described herein can be provided in an aqueous
physiological buffer solution containing about 0.1 to about 10% w/v
of the compound for parenteral administration. Some typical dose
ranges are from about 1 .mu.g/kg to about 1 g/kg of body weight per
day. In some embodiments, the dose range is from about 0.01 mg/kg
to about 100 mg/kg of body weight per day. The dosage is likely to
depend on such variables as the type and extent of progression of
the disease or disorder, the overall health status of the
particular patient, the relative biological efficacy of the
compound selected, formulation of the excipient, and its route of
administration. Effective doses can be extrapolated from
dose-response curves derived from in vitro or animal model test
systems.
[0455] The compounds described herein can also be formulated in
combination with one or more additional active ingredients which
can include any pharmaceutical agent such as anti-viral agents,
vaccines, antibodies, immune enhancers, immune suppressants,
anti-inflammatory agents and the like.
EXAMPLES
General Synthetic Methodologies
[0456] Many general references providing commonly known chemical
synthetic schemes and conditions useful for synthesizing the
disclosed compounds are available (see, e.g., Smith and March,
March's Advanced Organic Chemistry: Reactions, Mechanisms, and
Structure, Fifth Edition, Wiley-Interscience, 2001; or Vogel, A
Textbook of Practical Organic Chemistry, Including Qualitative
Organic Analysis, Fourth Edition, New York: Longman, 1978).
[0457] Compounds as described herein can be purified by any of the
means known in the art, including chromatographic means, such as
HPLC, preparative thin layer chromatography, flash column
chromatography and ion exchange chromatography. Any suitable
stationary phase can be used, including normal and reversed phases
as well as ionic resins. Most typically the disclosed compounds are
purified via silica gel and/or alumina chromatography. See, e.g.,
Introduction to Modern Liquid Chromatography, 2nd Edition, ed. L.
R, Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin
Layer Chromatography, ed E. Stahl, Springer-Verlag, New York,
1969,
[0458] During any of the processes for preparation of the subject
compounds, it may be necessary and/or desirable to protect
sensitive or reactive groups on any of the molecules concerned.
This may be achieved by means of conventional protecting groups as
described in standard works, such as J. F. W. McOmie, "Protective
Groups in Organic Chemistry," Plenum Press, London and New York
1973, in T. W. Greene and P. G. M. Wats, "Protective Groups in
Organic Synthesis," Third edition, Wiley, New York 1999, in "The
Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic
Press, London and New York 1981, in "Methoden der organischen
Chemie," Houben-Weyl, 4.sup.th edition, Vol. 15/1, Georg Thieme
Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit,
"Aminosauren, Peptide, Proteine," Verlag Chemie, Weinheim,
Deerfield Beach, and Basel 1982, and/or in Jochen Lehmann, "Chemie
der Kohlenhydrate: Monosaccharide and Derivate," Georg Thieme
Verlag, Stuttgart 1974. The protecting groups may be removed at a
convenient subsequent stage using methods known from the art.
[0459] The compounds disclosed herein can be made using procedures
familiar to the person of ordinary skill in the art and as
described herein. For example, compounds of structural formula (I)
can be prepared according to Schemes 1-3, or analogous synthetic
schemes.
[0460] One of skill in the art can adapt the reaction sequences of
Schemes 1-3 to fit the desired target molecule. Of course, in
certain situations one of skill in the art will use different
reagents to affect one or more of the individual steps or to use
protected versions of certain of the substituents. Additionally,
one skilled in the art would recognize that compounds of structural
formulae (I)-(III) can be synthesized using different routes
altogether.
[0461] Compounds suitable for use in the presently disclosed
pharmaceutical compositions include compounds of Table 1, above.
These compounds can be made according to the general schemes
described above, for example using a procedure similar to that
described below in the Examples.
[0462] The following examples are intended to further illustrate
certain embodiments and are not intended to limit the scope of the
presently disclosed compounds.
EXAMPLES
Example 1
Synthesis and Characterization
##STR00046##
[0464] To a solution of the benzoic acid (0.013 g, 0.028 mmol, 1.0
eq) in dimethylformamide (0.5 mL) was added
tetrahydropyranylhydroxylamine (0.005 g, 0041 mmol, 1.5 eq).
Triethylamine (0.008 mL, 0.055 mmol, 2.0 eq) was added followed by
HATU (0.016 g, 0.041 mmol, 1.5 eq) and the reaction stirred at room
temperature for 14 hours. The reaction was partitioned between
EtOAc (40 mL) and water (35 mL). The organics were washed with
brine (35 mL), water (35 mL) and brine (35 mL), dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure. The
crude material was dissolved in methanol (0.5 mL) and
toluenesulfonic acid monohydrate (0.008 g, 0.041 mmol, 1.5 eq)
added. The reaction was stirred at room temperature for 2 hours
before adding brine (15 mL). The organics were extracted with EtOAc
(3.times.20 mL), combined, dried (Na.sub.2SO.sub.4) and
concentrated under reduced pressure. Column chromatography (silica,
0.fwdarw.10% MeOH--CH.sub.2Cl.sub.2) yielded the hydroxamic acid as
a white solid.
Compound 1:
5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-N-h-
ydroxy-2-methylbenzamide
##STR00047##
[0466] .sup.1H NMR (CD.sub.3OD) .delta. 7.55 (1H, d, J 1.5 Hz,
1.times.ArH), 7.47 (1H, s, 1.times.ArH), 7.41-7.33 (5H, m,
5.times.ArH), 7.21 (1H, dd, J 8.5, 2.0 Hz, 1.times.ArH), 7.18 (1H,
d, J 3.0 Hz, indoleH-2 or H-3), 6.45 (1H, dd, J 3.0, 1.0 Hz,
indoleH-2 or H-3), 3.84 (3H, s, NCH.sub.3), 2.44 (3H, s,
ArCH.sub.3); m/z: 450, 448 [M+H].sup.+ (found [M+H].sup.+,
448.1229, C.sub.24H.sub.19ClN.sub.4O.sub.3 requires [M+H].sup.+
448.1218).
Compound 3:
5-((6-chloro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl-
)oxy)-N-hydroxy-2-methylbenzamide
##STR00048##
[0468] .sup.1H NMR (CD.sub.3OD) .delta. 7.63 (2H, d, J 8.5 Hz, 2H
of C.sub.6R.sub.4phenol), 7.50 (1H, s, BzimidazoleH-4 or H-7), 7.45
(2H, d, J 8.5 Hz, 2H of C.sub.6H.sub.4phenol), 7.41-7.30 (5H, m,
BzimidazoleH-4 or H-7, 4.times.ArH), 7.16 (1H, td, J 7.5, 1.5 Hz,
PhOH H-4 or H-5), 6.91 (2H, m, 2.times.ArH), 2.45 (3H, s,
C.sub.6H.sub.3CH.sub.3); m/z: 489, 487 [M+H.sup.+].
Compound 9:
5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-m-
ethylaniline
##STR00049##
[0470] .sup.1H NMR (CD.sub.3OD+CDCl.sub.3) .delta. 7.56 (1H, d, J
2.0 Hz, indoleH-7), 7.44 (1H, s, benzimidazoleH-4 or H-7), 7.36
(1H, d, J 8.5 Hz, indoleH-4), 7.33 (1H, s, benzimidazoleH-4 or
H-7), 7.22 (1H, dd, J 8.5, 2.0 Hz, indoleH-5), 7.14 (1H, d, J 3.5
Hz, indoleH-2 or H-3), 7.03 (1H, d, J 8.5 Hz, C.sub.6H.sub.3H-5),
6.64 (1H, d, J 2.5 Hz, C.sub.6H.sub.3H-2), 6.52 (1H, dd, J 8.0, 2.5
Hz, C.sub.6H.sub.3H-6), 6.45 (1H, d, J 3.0 Hz, indoleH-2 or H-3),
3.82 (3H, s, NCH.sub.3), 2.15 (3H, s, ArCH.sub.3); m/z: 406, 404
[M+H].sup.+ (found [M+H].sup.+, 403.1298,
C.sub.23H.sub.19ClN.sub.4O requires [M+H].sup.+ 403.1320).
Compound 11:
5-((6-fluoro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl-
)oxy)-2-methylbenzonitrile
##STR00050##
[0472] .sup.1H NMR (CD.sub.3OD) .delta. 7.78 (1H, d, J 2.0 Hz,
C.sub.6H.sub.3H-2), 7.70 (2H, d, J 8.5 Hz, 2H of
C.sub.6H.sub.4phenol), 7.64-7.55 (4H, in, 2H of
C.sub.6H.sub.4phenol, BzimidazoleH-4, 1H of C.sub.6H.sub.4OH H-4 or
H-5), 7.52 (1H, d, 7.0 Hz, C.sub.6H.sub.4OH H-3 or H-6), 7.37 (1H,
dd, J 8.0, 1.5 Hz, C.sub.6H.sub.4OH H-3 or H-6), 7.27 (1H, d, J
11.0 Hz, BzimidazoleH-7), 7.23 (1H, td, J 7.5, 2.0 Hz,
C.sub.6H.sub.4OH H-4 or H-5), 7.01-6.96 (2H, m, (C.sub.6H.sub.3H-5,
H-6), 2.63 (3H, s, C.sub.6H.sub.3CH.sub.3); .sup.19F NMR
(CD.sub.3OD) .delta. -125.8; m/z: 437 [M+H].sup.+ (found
[M+H].sup.+, 436.1456, C.sub.27H.sub.18FN.sub.3O.sub.2 requires
[M+H].sup.+ 436.1456).
##STR00051##
Formation of 5-(N-Methylindol-5-yl)-6-chlorobenzimidazole
##STR00052##
[0474] To a solution of the methyl ester (0.52 g, 0.908 mmol, 1.0
eq) in methanol-tetrahydrofuran (5:3, 8 mL) was added aqueous
sodium hydroxide (2 mL of a 2.5M solution, 5.0 mmol), The reaction
was stirred at room temperature for 14 hours and concentrated to
remove methanol. The concentrate was partitioned between EtOAc (60
mL) and HCl (1M, 50 mL). The aqueous phase was extracted with EtOAc
(2.times.50 ml.), The combined organics were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure. Column
chromatography (silica, 20.fwdarw.80% EtOAc-hexane) yielded the
carboxylic acid (0.28 g, 55%); m/z: 562, 560 [M+H].sup.+.
##STR00053##
[0475] A solution of the benzoic acid (0.277 g, 0.496 mmol, 1.0 eq)
in dichloromethane (5 mL) was cooled to 0.degree. C. and oxalyl
chloride (0.056 g, 0.645 mmol, 1.3 eq) added followed by
dimethylformamide (1 drop). The reaction was stirred at 0.degree.
C. for 10 minutes and room temperature for 2 hours. The reaction
was concentrated under reduced pressure, concentrating from ethyl
acetate (2.times.10 mL). The residue was suspended in
azidotrimethylsilane (5 mL). The reaction was allowed to warm
slowly to 90.degree. C. and stirred at 90.degree. C. for 14 hours.
The reaction was cooled and concentrated to dryness. Column
chromatography (silica, 20.fwdarw.100% EtOAc-hexane) yielded the
tetrazalone; .sup.1H NMR (CDCl.sub.3) .delta. 8.03 (0.5H, s, 1
isomer of Bzimidazole H-4 or H-7), 7.87 (0.5H, s, 1 isomer of
Bzimidazole H-4 or H-7), 7.68 (0.5H, 1 isomer of Bzimidazole H-4 or
H-7), 7.54 (1.5H, m, 1H of C.sub.6H.sub.3, 1 isomer of Bzimidazole
H-4 or H-7), 7.42 (2H, m, 2H of C.sub.6H.sub.3), 5.49 (2H, s,
NCH.sub.2O), 3.64 (2H, m, OCH.sub.2CH.sub.2TMS), 2.33 (3H, s,
C.sub.6H.sub.3CH.sub.3), 0.96 (2H, m, OCH.sub.2CH.sub.2TMS), -0.02
(4.5H, s 1 isomer of Si(CH.sub.3).sub.3), -0.02 (4.5H, s 1 isomer
of Si(CH.sub.3).sub.3); m/z: 601, 599 [M+H].sup.+.
##STR00054##
[0476] To a solution of the tetrazalone (0.050 g, 0.084 mmol, 1.0
eq) dimethylformamide (1.0 mL) was added
(trimethylsilyl)ethoxymethyl chloride (0.030 mL, 0.167 mmol, 2.0
eq) followed by ground potassium carbonate (0.029 g, 0.209 mmol,
2.5 eq). The reaction was stirred at room temperature for 18 hours
and partitioned between EtOAc (40 mL) and water (40 mL). The
organics were washed with brine (40 mL), water (40 mL) and brine
(40 mL), dried (Na.sub.2SO.sub.4), and concentrated under reduced
pressure. Column chromatography (silica, 10.fwdarw.40%
EtOAc-hexane) yielded the SEM protected tetrazalone (0.031 g, 51%)
as a white solid; .sup.1H NMR (CDCl.sub.3) .delta. 8.02 (0.5H, s, 1
isomer of Bzimidazole H-4 or H-7), 7.87 (0.5H, s, 1 isomer of
Bzimidazole H-4 or H-7), 7.67 (0.5H, 5, 1 isomer of Bzimidazole H-4
or H-7),7.54 (0.5H, s, 1 isomer of Bzimidazole H-4 or H-7), 7.50
(1H, m, 1H of C.sub.6H.sub.3), 7.46 (2H, m, 2H of C.sub.6H.sub.3),
5.47 (2H, s, 1.times.NCH.sub.2O), 5.39 (2H, s, 1.times.NCH.sub.2O),
3.76 (2H, m, 1.times.OCH.sub.2CH.sub.2TMS), 3.63 (2H, m,
1.times.OCH.sub.2CH.sub.2TMS), 2.34 (3H, s,
C.sub.6H.sub.3CH.sub.3), 1.02-0.92 (4H, m,
2.times.OCH.sub.2CH.sub.2TMS), 0.02 (9H, s,
1.times.Si(CH.sub.3).sub.3), -0.02 (4.5H, s, 1 isomer of
Si(CH.sub.3).sub.3), -0.03 (4.5H, s, 1 isomer of
Si(CH.sub.3).sub.3); m/z: 732, 730 [M+H].sup.+.
##STR00055##
[0477] To a mixture of N-methyl-5-indoleboronic acid (0,009 g,
0.051 mmol, 1.2 eq), X-Phos (0.002, 0.004 mmol, 0.1 eq) was added
aqueous sodium carbonate (0.043 mL, 2.0M, 0.085 mmol, 2.0 eq). A
solution of iodoberizimidazole (0.031 g, 0.043 mmol, 1.0 eq) in
dioxane (1.0 mL) was added and the reaction mixture degassed by
bubbling argon through for five minutes. X-Phos precatalyst (0.003
g, 0.04 mmol, 0.1 eq) was added and the reaction further degassed.
before heating to 100.degree. C. for 22 hours. The reaction was
cooled and partitioned between EtOAc (40 mL) and water (40 mL). The
aqueous phase was extracted with EtOAc (40 mL). The combined
organics were washed with brine (40 mL), dried (Na.sub.2SO.sub.4)
and concentrated under reduced pressure. Column chromatography
(silica, 5.fwdarw.50% EtOAc-hexane) yielded the coupled product;
mtz: 735, 733 [M+H].sup.+.
##STR00056##
[0478] A similar procedure was used to that described above on a
0.035 mmol scale, with heating to 110.degree. C. carried out for 24
hours before adding additional X-Phos (0.1 eq) and X-Phos
precatalyst (0.1 eq) and stirring at 110.degree. C. for a further
24 hours. Column chromatography (silica, 5.fwdarw.50% EtOAc-hexane)
yielded starting material and coupled product (0.011 g) as a
colourless oil.
Compound 4:
1-(5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)--
2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one
##STR00057##
[0480] To a solution of the bis-(SEM) protected benzimidazole
(0.012 g, 0.016 mmol, 1.0 eq) in tetrahydrofuran (0.5 mL) was added
tetrabutylammonium fluoride (0.066 mL of a 1.0M solution in
tetrahydrofuran, 0.066 mmol, 4.0 eq). The reaction was heated to
80.degree. C. for 2 hours. Further tetrabutylammonium fluoride
(0.066 mL of a 1.0M solution in tetrahydrofuran, 0.066 mmol, 4.0
eq) was added and the reaction stirred at 80.degree. C. for 4
hours. The reaction was cooled and partitioned between EtOAc (50
mL) and KHSO.sub.4 (40 mL). The aqueous phase was extracted with
EtOAc (2.times.20 mL). The combined organics were washed with water
(30 mL) and brine (30 mL), dried (Na.sub.2SO.sub.4) and
concentrated under reduced pressure. Column chromatography (silica,
0.fwdarw.10% MeOH--CH.sub.2Cl.sub.2) yielded Compound 4: .sup.1H
NMR (CD.sub.3OD) .delta. 7.55-7.48 (3H, m, 3.times.ArH), 7.46-7.43
(2H, m, 2.times.ArH), 7.39 (1H, d, J 9.0 Hz, C.sub.6H.sub.3H-6 or
indoleH-7), 7.36 (1H, s, BzimidazoleH-4 or H-7), 7.21 (1H, dd, J
8.5, 2.0 Hz, C.sub.6H.sub.3H-5 or indoleH-6), 7.18 (1H, d, J 3.5
Hz, indoleH-2 or H-3), 6.45 (1H, dd, J 3.0, 1.0 Hz, indoleH-2 or
H-3), 3.83 (3H, s, NCH.sub.3), 2.29 (3H, s,
C.sub.6H.sub.3CH.sub.3); m/z: 475, 473 [M+H].sup.+ (found
[M+H].sup.+, 472.1253, C.sub.24H.sub.18ClN.sub.7O.sub.2 requires
[M+H].sup.+ 472.1283).
Mono-Deprotected Analog of Compound 4
##STR00058##
[0482] In the deprotection reaction a sample of the monodeprotected
product was isolated as a mixture of benzimidazole regioisomers;
m/z: 605, 603 [M+H].sup.+.
Compound 6:
1-(5-((6-fluoro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-
-yl)oxy)-2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one
##STR00059##
[0484] A similar deprotection procedure was used to that described
above on a 0.015 mmol scale with the reaction stirred at 80.degree.
C. for 3 hours. Compound 6 was obtained as a white solid: .sup.1H
NMR (CD.sub.3OD) .delta. 7.70 (2H, d, J 8.5 Hz,
C.sub.6H.sub.4phenol), 7.62 (2H, dd, J 8.5, 1.5 Hz, 2H of
C.sub.6H.sub.4phenol), 7.59 (1H, d, J 9.0 Hz, 1.times.ArH), 7.51
(3H, m, 3.times.ArH), 7.37 (1H, dd, J 8.0, 2.0 Hz, 1.times.ArH),
7.27 (1H, d, J 11.0 Hz, BzimidazoleH-3), 7.22 (1H, td, J 7.5, 2.0
Hz, PhOH H-4 or H-5), 6.97 (2H, m, 2.times.ArH), 2.36 (3H, s,
C.sub.6H.sub.3CH.sub.3); .sup.19F NMR (CDCl.sub.3) .delta. -125.8;
m/z: 495 [M+H].sup.+ (found [M+H].sup.+, 495.1555,
C.sub.27H.sub.19FN.sub.6O.sub.3 requires [M+H].sup.+ 495.1575).
Compound 8:
1-(5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)--
2-methylphenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one
##STR00060##
[0486] A similar series of procedures was used to that described
above except that the N-methyl tetrazalone was generated instead of
the N-SEM tetrazalone by reaction with iodomethane. A similar
deptroection procedure was used to that described above to obtain
Compound 8 as a white solid; .sup.1H NMR (CD.sub.3OD+CDCl.sub.3)
.delta. 7.56 (1H, d, J 1.0 Hz, indoleH-4 or C.sub.6H.sub.3H-2),
7.51-7.45 (4H, m, BzimidazoleH-4 or H-7, indoleH-4, H-6, H-7 or
C.sub.6H.sub.3H-2, H-5, H-6), 7.36 (1H, d, J 8.5 Hz, indolH-7 or
C.sub.6H.sub.3H-5), 7.35 (1H, s, BzimidazoleH-4 or H-7), 7.22 (1H,
dd, 8.5, 1.5 Hz, indoleH-6 or C.sub.6H.sub.3H-6), 7.13 (1H, d, J
3.0 Hz, indoleH-2 or H-3), 6.45 (1H, d, J 3.0 Hz, indoleH-2 or
H-3), 3.82 (3H, s, 1.times.NCH.sub.3), 3.68 (3H, s,
1.times.NCH.sub.3), 2.30 (3H, s, C.sub.6H.sub.3CH.sub.3); m/z: 489,
487 [M+H].sup.+.
##STR00061## ##STR00062##
Formation of
3-(N-trimethylethoxymethyl)tetrazol-1-yl)-4-methylphenol
##STR00063##
[0488] To a solution of hydroxymethylaniline (0.180 g, 1.46 mmol,
1.0 eq) and triethylamine (0.31 mL, 1.61 mmol, 1.1 eq) in
dichloromethane (14 mL) at -78.degree. C. was added
t-butyldimethylsilyl trifluoromethanesuifonate (0.37 mL, 1.61 mmol,
1.1 eq). The reaction was stirred at -78.degree. C. for 2 hours
before warming to 0.degree. C. and stirring for 1 hour. Further
t-butyldimethylsilyl trifluoromethanesulfonate (0.37 mL, 1.61 mmol,
1.1 eq) was added and the reaction stirred at 0.degree. C. for 30
minutes. The reaction was added to NaHCO.sub.3 (50 mL) and the
organics extracted with CH.sub.2Cl.sub.2 (3.times.50 mL). The
combined organics were dried (Na.sub.2SO.sub.4) and concentrated
under reduced pressure. Column chromatography (silica,
10.fwdarw.30% EtOAc-hexane) yielded the silyl-protected aniline
(0.27 g, 78%) as a white solid; .sup.1H NMR (CDCl.sub.3) .delta.
6.87 (1H, d, J 9.0 Hz, C.sub.6H.sub.3H-5), 6.21 (2H, m,
C.sub.6H.sub.3H-2, H-6), 2.09 (3H, C.sub.6H.sub.3CH.sub.3), 0.97
(9H, s, SiC(CH.sub.3).sub.3), 0.17 (6H, s,
Si(CH.sub.3).sub.2C(CH.sub.3).sub.3).
##STR00064##
[0489] A solution of the aniline (0.271 g, 1.14 mmol, 1.0 eq) in
toluene (2.0 mL) was added. to a phosgene (1.63 mL, of a 15% wt/wt
solution in toluene, 2.29 mmol, 2.0 eq) at -15.degree. C. dropwise,
maintaining the internal temperature below 0.degree. C. After
complete addition, the reaction was heated to 90.degree. C. for 3
hours. The reaction was cooled and concentrated to dryness,
concentrating from EtOAc (2.times.15 mL) (to remove traces of
hydrogen chloride). The residue was dried under vacuum for 1 hour
and dissolved in azidotrimethylsilane (3 mL) at room temperature.
The reaction was placed in a room temperature heating bath and the
reaction slowly warmed to 90.degree. C. Heating at 90.degree. C.
was maintained for 12 hours. The reaction was cooled and
concentrated under reduced pressure. Column chromatography (silica,
10.fwdarw.50% EtOAc-hexane) yielded the tetrazalone (0.201 g, 57%)
as a colourless oil; .sup.1H NMR (CDCl.sub.3) .delta. 7.22 (1H, d,
J 8.5 Hz, C.sub.6H.sub.3H-5), 6.92 (1H, dd, J 8.5, 2.5 Hz,
C.sub.6H.sub.3H-6), 6.86 (1H, d, J 2.0 Hz, C.sub.6H.sub.3H-2), 2.23
(3H, C.sub.6H.sub.3CH.sub.3), 0.99 (9H, s, SiC(CH.sub.3).sub.3),
0.22 (6H, s, Si(CH.sub.3).sub.2C(CH.sub.3).sub.3).
##STR00065##
[0490] To a solution of the tetrazalone (0.201 g, 0.657 mmol, 1.0
eq) in dimethylformamide (6.5 mL) was added
(trimethylsilyl)ethoxymethyl chloride (0.128 mL, 0.723 mmol, 1.1
eq) followed by ground potassium carbonate (0.109 g, 0.788 mmol,
1.2 eq). The reaction was stirred at room temperature for 14 hours
and partitioned between EtOAc (80 mL) and water (80 mL). The
organics were washed with brine (60 mL), water (80 mL) and brine
(60 mL), dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure. Column chromatography (silica, 5.fwdarw.40% EtOAc-hexane)
yielded the (trimethylsilylethoxymethyl protected product (0.157 g,
55%) as a colourless oil; .sup.1H NMR (CDCl.sub.3) .delta. 7.19
(1H, d, J 8.5 Hz, C.sub.6H.sub.3H-5), 6.87 (1H, dd, J 8.0, 2.5 Hz,
C.sub.6H.sub.3H-6), 6.84 (1H, d, J 2.5 Hz, C.sub.6H.sub.3H-2), 5.38
(2H, s, NCH.sub.2O), 3.76 (2H, m, OCH.sub.2CH.sub.2TMS), 2.20 (3H,
C.sub.6H.sub.3CH.sub.3), 0.98 (2H, m, OCH.sub.2CH.sub.2TMS), 0.97
(9H, s, SiC(CH.sub.3).sub.3), 0.20 (6H, s,
Si(CH.sub.3).sub.2C(CH.sub.3).sub.3), 0.02 (9H, s,
Si(CH.sub.3).sub.3).
##STR00066##
[0491] To a solution of the t-butyldimethylsilylether (0.157 g,
0.360 mmol, 1.0 eq) in tetrahydrofuran (3.5 mL) at 0.degree. C. was
added a solution of tetrabutylammonium fluoride (0.36 of a 1.0M
solution in tetrahydrofuran, 0.360 mmol, 1.0 eq). The reaction was
stirred at 0.degree. C. for 15 minutes and NH.sub.4Cl (25 mL) was
added to quench the reaction. The organics were extracted with
EtOAc (3.times.25 mL). The combined organics were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure. Column
chromatography (silica, 5.fwdarw.40% EtOAc-hexane) yielded
3-(N-trimethylethoxymethyl)tetrazalon-1-yl)-4-methylphenol as a
white waxy solid; .sup.1H NMR (CDCl.sub.3) .delta. 7.11 (1H, d, J
8.5 Hz, C.sub.6H.sub.3H-5), 6.76 (1H, dd, J 8.5, 2.5 Hz,
C.sub.6H.sub.3H-6), 6.73 (1H, d, J 2.0 Hz, C.sub.6H.sub.3H-2), 5.41
(2H, s, NCH.sub.2O), 3.77 (2H, m, OCH.sub.2CH.sub.2TMS), 2.14 (3H,
C.sub.6H.sub.3CH.sub.3), 0.99 (2H, m, OCH.sub.2CH.sub.2TMS), 0.01
(9H, s, Si(CH.sub.3).sub.3).
Formation of 5-(N-Methylindol-5-yl)-6-fluorobenzimidazole and
5-(2'-Hydroxyphenyl-4-phenyl)-6-fluorobenzimidazole
##STR00067##
[0493] To a solution of the fluoronitroaniline (2.00 g, 12.82 mmol,
1.0 eq) in acetic acid (30 mL) was added N-iodosuccinimide (3.17 g,
14.10 mmol, 1.1 eq). The reaction was heated to 70.degree. C. for
4.5 hours. The reaction was cooled and poured into water (300 mL)
forming a yellow precipitate, which was isolated by filtration to
obtain the iodinated aniline (3.58 g, quantitative) as a yellow
solid; .sup.1H NMR (D.sub.6-DMSO) .delta. 8.33 (1H, d, J 7.0 Hz,
H-3), 7.65 (2H, br s, NH.sub.2), 6.83 (1H, d, J 10.5 Hz, H-6); m/z:
283 [M+H].sup.+.
##STR00068##
[0494] A suspension of the nitrobenzene (3.58 g, 12.70 mmol, 1.0
eq) in ethanol (30 mL) was heated to 80.degree. C. forming a
solution. A suspension of iron (3.55 g, 63.48 mmol, 5.0 eq) in
aqueous ammonium chloride (3.40 g, 63.48 mmol, 5.0 eq in 20 mL of
water) was added and the reaction stirred vigorously at 80.degree.
C. for 40 minutes before filtering hot through celite, eluting with
EtOAc-EtOH (1:1, 60 mL). The filtrate was concentrated and
partitioned between EtOAc (100 mL) and brine (80 mL). The aqueous
phase was extracted with EtOAc (3.times.60 mL). The combined
organics were dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure to obtain a brown-black solid, which was used
without further purification; .sup.1H NMR (D.sub.6-DMSO) .delta.
6.78 (1H, d, J 6.5 Hz, H-3), 6.37 (1H, d, J 10.5 Hz, H-6), 4.79
(2H, br s, NH.sub.2); .sup.19F NMR (D.sub.6-DMSO) .delta. -111.3;
m/z: 253 [M+H].sup.+.
##STR00069##
[0495] To a solution of the crude fluoroiodobenzeriediamine (1270
mmol, 1.0 eq) in ethanol (20 mL) was added aqueous potassium
hydroxide (0.71 g, 12.70 mmol, 1.0 eq in 4 mL of water) and carbon
disulfide (0.76 mL, 12.70 mmol, 1.0 eq). The reaction was heated to
reflux for 3.5 hours. After cooling the reaction was filtered and
water (20 mL) added to the filtrate--a precipitate forms. Acetic
acid (2 mL) in water (4 mL) was added forming more precipitate,
which was isolated by filtration to obtain a brown solid (2.11 g,
57%); .sup.1H NMR (D.sub.6-DMSO) .delta. 7.42 (1H, d, J 5.5 Hz,
H-3), 7.04 (1H, d, J 8.0 Hz, H-6); .sup.19F NMR (D.sub.6-DMSO)
.delta. -101.8.
##STR00070##
[0496] To a solution of the dihydrobenzathiazolethione (2.11 g,
7.18 mmol, 1.0 eq) in acetone (45 mL) at 0.degree. C. was added
ground potassium carbonate (0.50 g, 3.59 mmol, 0.5 eq) followed by
iodomethane (0.22 mL, 3.59 mmol, 0.5 eq). The reaction was stirred
at room temperature for 1 hour before coaling to 0.degree. C. and
adding ground potassium carbonate (0.50 g, 3.59 mmol, 0.5 eq) and
iodomethane (0.22 mL, 3.59 mmol, 0.5 eq). The reaction was warmed
to room temperature and stirred for 20 hours. The reaction was
concentrated to remove the volatiles and the residue partitioned
between. EtOAc (100 mL) and water (75 mL). The aqueous phase was
extracted with EtOAc (50 mL). The combined organics were washed
with brine (100 mL), dried (Na.sub.2SO.sub.4) and concentrated
under reduced pressure to yield a brown oil, which was used without
purification; .sup.1H NMR (D.sub.6-DMSO) .delta. 7.90 (0.5H, d, J
6.0 Hz, 1 isomer of H-3), 7.72 (0.5H, d, 6.0 Hz, 1 isomer of H-3),
7.41 (0.5H, d, j 8.0 Hz, 1 isomer of H-6), 7.30 (0.5H, d, j 8.0 Hz,
1 isomer of H-6), 2.66 (1.5H, s, 1 isomer of SCH.sub.3), 2.65
(1.5H, s, 1 isomer of SCH.sub.3); .sup.19F NMR (D.sub.6-DMSO)
.delta. -102.8, -104.1; m/z: 309 [M+H].sup.+.
##STR00071##
[0497] To a solution/suspension of the benzimidazole thiomethyl
ether (2.16 g, 7.00 mmol, 1.0 eq) in dichloromethane (100 mL) was
added m-chloroperoxybenzoic acid (3.23 g of a 75% solid, 14.03
mmol, 2.0 eq). A solution resulted, which was stirred at room
temperature for 15 minutes. The reaction was added to NaHCO.sub.3
(100 mL) and the organics extracted with CH.sub.2Cl.sub.2
(3.times.50 mL). The combined organics were washed with brine (100
mL), dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure to obtain an orange foam (2.34 g), which was used without
purification; m/z: 341 [M+H].sup.+.
##STR00072##
[0498] To a solution of the benzimidazole (2.34 g, 6.88 mmol, 1.0
eq) in tetrahydrofuran (20 mL) was added triethylamine (1.91 mL,
13.76 mmol, 2.0 eq) followed by 2-(trimethylsilyl)ethoxymethyl
chloride (1.58mL, 8.95 mmol, 1.3 eq). The reaction was stirred at
room temperature for 90 minutes and concentrated to remove
volatiles. The residue was partitioned between EtOAc (10 mL) and
water (80 mL). The organics were washed with HCl (1M, 60 mL) and
brine (60 mL), dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure. The crude material was used without purification;
.sup.1H NMR (D.sub.6-DMSO) .delta. 8.24 (0.5H, d, J 5.5 Hz, 1
isomer of H-3), 8.07 (0.5H, d, J 5.5 Hz, 1 isomer of H-3), 7.52
(0.5H, d, J 8.0 Hz, 1 isomer of H-6), 7.41 (0.5H, d, J 7.5 Hz, 1
isomer of H-6), 5.89 (1H, s, 1 isomer of NCH.sub.2O), 5.87 (1H, s,
1 isomer of NCH.sub.2O), 3.81 (2H, m, OCH.sub.2CH.sub.2TMS), 3.53
(1.5H, s, 1 isomer of SO.sub.2CH.sub.3), 3.52 (1.5H, s, 1 isomer of
SO.sub.2CH.sub.3), 1.03-0.89 (2H, m, OCH.sub.2CH.sub.2TMS), 0.03
(4.5H, s, 1 isomer of Si(CH.sub.3).sub.3), -0.03 (4.5H, s, 1 isomer
of Si(CH.sub.3).sub.3); .sup.19F NMR (D.sub.6-DMSO) .delta. -93.2,
-97.4; m/z: 471 [M+H].sup.+.
##STR00073##
[0499] To a mixture of the iodohenzimidazole (0.132 g, 0.281 mmol,
1.0 eq) and N-methylindole-5-boronic acid (0.059 g, 0.337 mmol, 1.2
eq) was added dioxane (2.0 mL) followed by aqueous sodium carbonate
(0.28 mL of a 2.0M solution, 0.562 mmol, 2.0 eq). The reaction was
degassed by bubbling argon through the reaction mixture for five
minutes. Tetrakis(triphenylphosphine)palladium (0.032 g, 0.028
mmol, 0.1 eq) was added and the reaction further degassed before
heating in the microwave to 100.degree. C. for 1 hour. The reaction
was partitioned between EtOAc (50 mL) and water (50 mL). The
organics were washed with brine (40 mL), dried (Na.sub.2SO.sub.4)
and concentrated under reduced pressure. Column chromatography
(silica, 5.fwdarw.50% EtOAc-hexane) yielded the coupled material;
m/z: 475 [M+H].sup.+.
##STR00074##
[0500] Dimethylformamide (1.0 mL) was added to a mixture of the
benzimidazole methyl sulfone (0.030 g, 0.063 mmol, 1.0 eq), the
phenol (0.031 g, 0.095 mmol, 1.5 eq) and ground potassium carbonate
(0.034 g, 0.247 mmol, 3.9 eq). The reaction was stirred at room
temperature for 20 hours and at 60.degree. C. for 2 hours before
cooling and partitioning between EtOAc (60 mL) and water (50 mL).
The organics were washed with brine (50 mL), water (50 mL) and
brine (50 mL), dried (Na.sub.2SO.sub.4) oncentrated under reduced
pressure. Column chromatography (silica, 10.fwdarw.50%
EtOAc-hexane) yielded benzimidazole-'2-phenyl ether (0.041 g, 90%)
as a colourless oil; m/z: 717 [M+H].sup.+.
Compound 5:
1-(5-((6-fluoro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)--
2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one
##STR00075##
[0502] To a solution of the bis-((trimethylsilyl)ethoxymethyl)
protected compound (0.041 g, 0.057 mmol, 1.0 eq) in tetrahydrofuran
(0.5 mL) was added tetrabutylammonium fluoride (0.46 mL of a 1M
solution in tetrahydrofuran, 0.459 mmol, 8.0 eq). The reaction was
heated to 80.degree. C. and stirred for 4 hours. Further
tetrabutylammonium fluoride (0.23 mL, 0.230 mmol, 4.0 eq) was added
and the reaction stirred for 2 hours. After cooling the reaction
was partitioned between EtOAc (40 mL) and KHSO.sub.4 (40 mL). The
aqueous phase was extracted with EtOAc (2.times.30 mL). The
combined organics were washed with water (40 mL) and brine (40 mL),
dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure.
Column chromatography (silica, 0.fwdarw.10 MeOH--CH.sub.2Cl.sub.2)
yielded Compound 5 as a white solid; .sup.1H NMR (CD.sub.3OD)
.delta. 7.55-7.48 (3H, m, 3.times.ArH), 7.46-7.43 (2H, m,
2.times.ArH), 7.39 (1H, d, 9.0 Hz, C.sub.6H.sub.3H-6 or indoleH-7),
7.36 (1H, s, BzimidazoleH-4 or H-7), 7.21 (1H, dd, J 8.5, 2.0 Hz,
C.sub.6H.sub.3H-5 or indoleH-6), 7.18 (1H, d, J 3.5 Hz, indoleH-2
or H-3), 6.45 (1H, dd, J 3.0, 1.0 Hz, indoleH-2 or H-3), 3.83 (3H,
s, NCH.sub.3), 2.29 (3H, s, C.sub.6H.sub.3CH.sub.3); m/z: 475, 473
[M+H].sup.+ (found [M+H].sup.+, 472.1253,
C.sub.24H.sub.18ClN.sub.7O.sub.2 requires [M+H].sup.+
472.1283).
Compound 2:
5-((6-chloro-5-(2'-hydroxy[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)-
oxy)-2-methylbenzoic acid
##STR00076##
[0504] .sup.1H NMR (D.sub.6-DMSO) .delta. 9.60 (1H, br s,
1.times.NH), 7.60 (2H, d, J 8.5 Hz, 2H of C.sub.6H.sub.4phenol),
7.53 (1H, s, BzimidazoleH-4 or H-7), 7.44 (2H, d, J 8.0 Hz, 2H of
C.sub.6H.sub.4phenol), 7.36 (1H, s, BzimidazoleH-4 or HH-7), 7.32
(1H, m, PhOH H-3 or H-6), 7.20 (1H, d, j 3.0 Hz,
C.sub.6H.sub.3H-2), 7.16 (1H, m, PhOH H-4 or H-5), 7.04 (1H, d, J
8.5 Hz, C.sub.6H.sub.3H-5), 695 (1H, d. J 7.5 Hz, PhOH H-3 or H-6),
6.88 (1H, t, J 7.0 Hz, PhOH H-4 or H-5), 6.80 (1H, dd, J 8.5, 2.5
Hz, C.sub.6H.sub.3H-6), 2.36 (3H, s, C.sub.6H.sub.3CH.sub.3); m/z:
474, 472 [M+H].sup.+ (found 471.1117,
C.sub.27H.sub.18ClN.sub.2O.sub.4 requries [M+H].sup.+
471.1106).
Compound 7:
5-((6-fluoro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-m-
ethylbenzoic acid
##STR00077##
[0506] .sup.1H NMS (CD.sub.3OD) .delta. 7.81 (1H, d, J 2.0 Hz,
indoleH-4 or C.sub.6H.sub.3H-2), 7.69 (1H, br s, indoleH-4 or
C.sub.6H.sub.3H-2), 7.42-7.35 (5H, m, indoleH-6 and H-7,
C.sub.6H.sub.3H-5 and H-6, BzimidazoleH-4), 7.16 (1H, d, J 11.0 Hz,
BzimidazoleH-7), 7.14 (1H, d, J 3.0 Hz, indoleH-2 or H-3), 6.46
(1H, dd, 3 3.0, 1.0 Hz, indoleH-2 or H-3), 3.82 (3H, s, NCH.sub.3),
2.60 (3H, s, C.sub.6H.sub.3CH.sub.3); .sup.19F NMR (CD.sub.3OD)
.delta. -125.5; m/z: 417 [M+H].sup.+.
Compound 10:
4'-(6-fluoro-2-(4-methyl-3-(1H-tetrazol-1-yl)phenoxy)-1H-benzo[d]imidazol-
-5-yl)-[1,1'-biphenyl]-2-ol
##STR00078##
[0508] .sup.1H NMR (CD.sub.3OD) .delta. 9.95 (1H, s, tetrazoleH-5),
7.69-7.58 (7H, m, C.sub.6H.sub.4phenol, BzimidazoleH-4,
2.times.ArH), 7.50 (1H, d, J 7.0 Hz, 1.times.ArH), 7.34 (1H, dd, J
8.0, 2.0 Hz, C.sub.6H.sub.4OH H-3 or H-6), 7.25 (1H, d, J 11.0 Hz,
BzimidazoleH-7), 7.20 (1H, td, J 7.5, 2.0 Hz, C.sub.6H.sub.4OH H-4
or H-5), 6.95 (2H, m, 2.times.ArH), 2.28 (3H, s,
C.sub.6H.sub.3CH.sub.3); .sup.19F NMR (CD.sub.3OD) .delta. -125.7;
m/z: 479 [M+H].sup.+ (found [M+H].sup.+, 479.1631,
C.sub.27H.sub.18FN.sub.6O.sub.2 requires [M+H].sup.+ 479.1626).
Compound 12.
4'-(6-fluoro-2-(4-methyl-3-(2H-tetrazol-5-yl)phenoxy)-1H-benzo[d]imidazol-
-5-yl)-[1,1'-biphenyl]-2-ol
##STR00079##
[0510] .sup.1H NMR (CD.sub.3OD) .delta. 7.71 (1H, d, J 2.5 Hz,
C.sub.6H.sub.3H-2), 7.64 (2H, d, J 9.0 Hz, 2H of
C.sub.6H.sub.4phenol), 7.57-7.53 (3H, in, 2H of
C.sub.6H.sub.4phenol, C.sub.6H.sub.3H-6), 7.46-7.43 (2H, m,
BzimidazoleH-4, C.sub.6H.sub.3H-6), 7.31 (1H, dd, J 8.0, 1.5 Hz,
C.sub.6H.sub.4OH H-3 or H-6), 7.20 (1H, d, J 11.0 Hz,
BzimidazoleH-7), 7.15 (1H, in, C.sub.6H.sub.4OH H-4 or H-5),
6.94-6.88 (2H, m, 2H of C.sub.6H.sub.4OH), 2.56 (3H, s,
C.sub.6H.sub.3CH.sub.3); .sup.19F nmr (CD.sub.3OD) .delta. -125.8;
m/z: 480 [M+H].sup.+ (found [M+H].sup.+, 479.1619,
C.sub.27H.sub.19FN.sub.6O.sub.2 requires [M+H].sup.+ 479.1626).
Compound 13:
1-(5-((6-fluoro-5-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-
-yl)oxy)-2-methylphenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one
[0511] .sup.1H nmr (CD.sub.3OD) .delta. 7.82 (2H, d, J 8.5 Hz, 2H
of C.sub.6H.sub.4phenol), 7.75-7.71 (311, m, 3.times.ArH),
7.67-7.63 (3H, m, 3.times.ArH), 7.49 (1H, dd, 8.0, 1.5 Hz,
C.sub.6H.sub.4OH H-3 or H-6), 7.39 (1H, d, J 11.0 Hz,
BzimidazoleH-7), 7.34 (1H, m, C.sub.6H.sub.4OH H-4 or H-5), 7.10
(1H, dd, J 6.0, 1.5 Hz, 1.times.ArH), 7.08 (1H, d, J 8.0 Hz,
C.sub.6H.sub.3H-5), 3.87 (3H, s, NCH.sub.3), 2.49 (3H, s,
C.sub.6H.sub.3CH.sub.3); .sup.19F nmr (CD.sub.3OD) .delta. -125.7;
m/z: 510 [M+H].sup.+ (found [M+H].sup.+, 509.1737,
C.sub.28H.sub.21FN.sub.6O.sub.3 requires [M+H].sup.+ 509.1732).
Example 2
AMPK In Vitro Kinase Assay
[0512] Materials: [0513] Gutathione coated 384well white plate
(Fisher, Cat #NC:18702X) [0514] Anti-Rabbit-HRP conjugate (Cell
Signaling Tech. Cath 70745) [0515] Phospho-Acetyl-CoA Carboxvlase
(Ser79) Antibody (Cell Signaling Tech. Cat #36615)
TABLE-US-00005 [0515] GST-ACC2 (0.8 mg/ml stock) 40 .mu.l (final
200 ng/well) Low AMP (10 mM stock) Mixed with the GST-ACC (final
0.1 .mu.M) GST-AMPK (0.5 mg/ml stock) 5 .mu.l (final 200 ng/ml)
High AMP (10 mM stock) 5 .mu.l (final 100 .mu.M) 75 .mu.M ATP (10
mM stock) 5 .mu.l (final 7.5 .mu.M)
[0516] All diluted in ix Kinase Buffer. [0517] NaPy has to be added
to AMPK when a new tube of AMPK is used. [0518] NaPy Stock: 0.25M.
Final concentration: 2 nM. *warm up in warm water for it to go into
solution.
[0519] Procedures: [0520] 1. Add 500 nL/well of compound using
Echo. [0521] 2. Add 40 .mu.l/well of GST-ACC with low AMP to all
wells. [0522] 3. Add 5 .mu.l/well of 1 mM AMP to the last two
columns, columns 23 & 24. [0523] 4. Add 5 of GST-AMPK to all
well. [0524] 5. Add 5 of ATP to all well. [0525] 6. Shake for 1 min
and incubate the kinase reaction at RT for 1 hr. [0526] 7. Wash
plate twice with 50 .mu.l TBST. [0527] 8. Add 1.sup.st antibody and
2.sup.nd antibody in 50 .mu.l/well TBST with 1% BSA (1.sup.st
antibody Anti-phospho ACC 1:4000 and 2.sup.nd antibody 1:6000
anti-rabbit-HRP). Incubate at RT for 1 hr. [0528] 9. Wash plate
twice with 50 .mu.l TBST. [0529] 10. Add 50 .mu.l substrate
(Millipore HRP substrate WBKLS0500) and read (gain 1800)
TABLE-US-00006 [0529] Kinase Buffer 100 ml Stock 50 mM Hepes pH 7.5
10 ml 0.5 M 1 mM MgCl.sub.2 1 ml 1.0 M 1 mM EGTA pH8.0 0.4 ml 0.25
M 0.01% Brij-35 0.333 ml 3% 0.4 mM TCEP 80 .mu.l 0.5 M TBST 1000 ml
Stock 150 mM NaCl 30 ml 5 M 20 mM Tris pH7.5 20 ml 1 M 0.05% Tween
20 0.5 ml 100%
[0530] ELISA substrate (per 100 .mu.l) [0531] 25 .mu.l solution A
[0532] 25 .mu.l solution B [0533] 50 .mu.l ddH.sub.2O [0534]
(Millipore-WBKLS0500)
[0535] Note: [0536] 10 mM ATP, add 6 mg/mL [0537] 10 mM AMP, 3.47
mg/mL [0538] Syringe A: ACC with low AMP to all wells. [0539] NX:
High AMP to last two columns (23 & 24) [0540] Combi 1: AMPK to
all wells. [0541] Combi 2: ATP to all wells. [0542] Peri:
Antibodies to all wells. [0543] Syringe B: Substrate to all
wells.
[0544] The representative compounds activate AMPK with an EC.sub.50
of less than 20 micromolar, such as less than 10 micromolar or less
than 1 micromolar.
* * * * *