U.S. patent number 8,314,107 [Application Number 12/428,334] was granted by the patent office on 2012-11-20 for carboxamide compounds and methods for using the same.
This patent grant is currently assigned to Rigel Pharmaceuticals, Inc.. Invention is credited to Ihab S. Darwish, Hui Hong, Rajinder Singh, Xiang Xu, Jiaxin Yu.
United States Patent |
8,314,107 |
Yu , et al. |
November 20, 2012 |
Carboxamide compounds and methods for using the same
Abstract
Disclosed are carboxamide compounds, as well as pharmaceutical
compositions and methods of use. One embodiment is a compound
having the structure ##STR00001## in which R.sup.1, R.sup.2,
R.sup.3, R.sup.4, D, J, Z, T, p, q, w and x are as described
herein. In certain embodiments, a compound disclosed herein
activates the AMPK pathway, and can be used to treat
metabolism-related disorders and conditions.
Inventors: |
Yu; Jiaxin (San Carlos, CA),
Hong; Hui (Palo Alto, CA), Darwish; Ihab S. (San Carlos,
CA), Xu; Xiang (Foster City, CA), Singh; Rajinder
(Belmont, CA) |
Assignee: |
Rigel Pharmaceuticals, Inc.
(South San Francisco, CA)
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Family
ID: |
40756385 |
Appl.
No.: |
12/428,334 |
Filed: |
April 22, 2009 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20090275609 A1 |
Nov 5, 2009 |
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Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
Issue Date |
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61047399 |
Apr 23, 2008 |
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61048997 |
Apr 30, 2008 |
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61054035 |
May 16, 2008 |
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61054934 |
May 21, 2008 |
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61058854 |
Jun 4, 2008 |
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61078166 |
Jul 3, 2008 |
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61078180 |
Jul 3, 2008 |
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61078209 |
Jul 3, 2008 |
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Current U.S.
Class: |
514/255.05;
546/194; 514/322; 514/307; 546/121; 546/149; 546/187; 514/316;
544/405; 514/318 |
Current CPC
Class: |
C07D
211/58 (20130101); C07D 413/14 (20130101); A61P
43/00 (20180101); A61K 31/4545 (20130101); A61K
31/4725 (20130101); C07D 471/04 (20130101); C07D
417/14 (20130101); A61P 3/00 (20180101); C07D
401/14 (20130101); C07D 413/12 (20130101); A61K
31/437 (20130101); A61K 31/454 (20130101); A61K
31/496 (20130101); A61P 9/00 (20180101); A61K
31/497 (20130101); C07D 401/12 (20130101); C07D
487/08 (20130101); A61P 9/10 (20180101); A61P
3/10 (20180101) |
Current International
Class: |
A61K
31/497 (20060101); C07D 401/12 (20060101); C07D
413/14 (20060101); C07D 487/04 (20060101); C07D
471/04 (20060101); A61K 31/4545 (20060101); C07D
401/14 (20060101); A61K 31/4725 (20060101); A61K
31/454 (20060101) |
Field of
Search: |
;514/307,253.01,255.05,316,318,322 ;544/364,405
;546/121,149,187,194 |
References Cited
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|
Primary Examiner: Bianchi; Kristin
Attorney, Agent or Firm: Young; Travis McDonnell Boehnen
Hulbert & Berghoff LLP
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing dates of
U.S. Provisional Patent Applications Ser. No. 61/047,399, filed
Apr. 23, 2008; Ser. No. 61/048,997, filed Apr. 30, 2008; Ser. No.
61/054,035, filed May 16, 2008; Ser. No. 61/054,934, filed May 21,
2008; Ser. No. 61/058,854, filed Jun. 4, 2008; Ser. No. 61/078,166,
filed Jul. 3, 2008; Ser. No. 61/078,180, filed Jul. 3, 2008; and
Ser. No. 61/078,209, filed Jul. 3, 2008, each of which is hereby
incorporated herein by reference in its entirety.
Claims
What is claimed is:
1. A compound having the structural formula ##STR00221## or a
pharmaceutically acceptable salt or N-oxide thereof, wherein ring
system "B" is ##STR00222## and is not fused to the ring system
denoted by "C", ##STR00223## in which Y is O or S, and is not fused
to the ring system denoted by "C", ##STR00224## and is not fused to
the ring system denoted by "C", ##STR00225## and is not fused to
the ring system denoted by "C", ##STR00226## and is not fused to
the ring system denoted by "C", in which w is 0 or 1, one of
E.sup.1 and E.sup.2 is N and the other is CH, C substituted with
R.sup.3, C substituted with the -J-(ring system "C"), or C
substituted with the --C(O)--NR.sup.1 R.sup.2, ##STR00227## and
together with the ring system denoted by "C" forms ##STR00228## J
is --O--, --N(R.sup.38)--C(O)--, or absent, provided that: (a) when
J is --O--or --N(R.sup.38)--C(O)--, J links ring systems "B" and
"C", the dotted line connecting ring system "B" to the carbon
denoted by "b" in ring system "C" is absent, and the bond in ring
system "C" between the carbon to which J is bound and the carbon
atom at the position denoted by "b" is a single bond, (b) when J is
--O--, the ring system denoted by "B" is other than phenyl; and (c)
when J is absent, the ring system denoted by "B" and the ring
system denoted by "C" are taken together to be ##STR00229## R.sup.1
is H, --(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.1-C.sub.4 alkyl) or
--C(O)O--(C.sub.1-C.sub.4 alkyl), and R.sup.2 is
optionally-substituted piperidin-4-yl each R.sup.3 is independently
selected from --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
haloalkyl), --(C.sub.0-C.sub.6 alkyl)-Ar, --(C.sub.0-C.sub.6
alkyl)-Het, --(C.sub.0-C.sub.6 alkyl)-Cak, --(C.sub.0-C.sub.6
alkyl)-Hca, --(C.sub.0-C.sub.6 alkyl)-L-R.sup.7, --(C.sub.0-C.sub.6
alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6 alkyl)-OR.sup.10,
--(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN; w is 0,
1, 2, 3 or 4; each R.sup.4 is independently selected from
--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alkyl)-Ar, --(C.sub.0-C.sub.6 alkyl)-Het,
--(C.sub.0-C.sub.6 alkyl)-Cak, --(C.sub.0-C.sub.6 alkyl)-Hca,
--(C.sub.0-C.sub.6 alkyl)-L-R.sup.7, --(C.sub.0-C.sub.6
alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6 alkyl)-OR.sup.10,
--(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN, and two
R.sup.4 on the same carbon optionally combine to form oxo; x is 0
or an integer .ltoreq.4 Q is --S(O).sub.2--, L, or (C.sub.0-C.sub.3
alkyl)-, in which each carbon of the --(C.sub.0-C.sub.3 alkyl)-is
optionally and independently substituted with one or two R.sup.16;
the ring denoted by "A" is heteroaryl, aryl, cycloalkyl or
heterocycloalkyl; each R.sup.5 is independently selected from
--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alkyl)-Ar, --(C.sub.0-C.sub.6 alkyl)-Het,
--(C.sub.0-C.sub.6 alkyl)-Cak, --(C.sub.0-C.sub.6 alkyl)-Hca,
--(C.sub.0-C.sub.6 alkyl)-L-R.sup.7, --(C.sub.0-C.sub.6
alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6 alkyl)-OR.sup.10,
--(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN; and y
is 0, 1, 2, 3 or 4; in which each L is independently selected from
--NR.sup.9C(O)O--, --OC(O)NR.sup.9--, --NR.sup.9C(O)--NR.sup.9--,
--NR.sup.9C(O)S--, --SC(O)NR.sup.9--, --NR.sup.9C(O)--,
--C(O)--NR.sup.9--, --NR.sup.9C(S)O--, --OC(S)NR.sup.9--,
--NR.sup.9C(S)--NR.sup.9--, --NR.sup.9C(S)S--, --SC(S)NR.sup.9--,
--NR.sup.9C(S)--, --C(S)NR.sup.9--, --SC(O)NR.sup.9--,
--NR.sup.9C(S)--, --S(O).sub.0-2--, --C(O)O, --OC(O)--, --C(S)O--,
--OC(S)--, --C(O)S--, --SC(O)--, --C(S)S--, --SC(S)--, --OC(O)O--,
--SC(O)O--, --OC(O)S--, --SC(S)O--, --OC(S)S--,
--NR.sup.9C(NR.sup.2)NR.sup.9--, --NR.sup.9SO.sub.2--,
--SO.sub.2NR.sup.9-- and --NR.sup.9SO.sub.2NR.sup.9--, each
R.sup.6, R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alkyl)-Ar, --(C.sub.0-C.sub.6 alkyl)-Het,
--(C.sub.0-C.sub.6 alkyl)-Cak, --(C.sub.0-C.sub.6 alkyl)-Hca,
--(C.sub.0-C.sub.6 alkyl)-L-(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-NR.sup.9--(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-O--(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl) and
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl),
each R.sup.9 is independently selected from --H, --(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.1-C.sub.4 alkyl) and
--C(O)O--(C.sub.1-C.sub.4 alkyl), each G is independently
--S(O).sub.2--, L, or --(C.sub.0-C.sub.3 alkyl)-, in which each
carbon of the --(C.sub.0-C.sub.3 alkyl)-is optionally and
independently substituted with one or two R.sup.16, each R.sup.16
is independently selected from --(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6 alkyl)-Ar,
--(C.sub.0-C.sub.6 alkyl)-Het, --(C.sub.0-C.sub.6 alkyl)-Cak,
--(C.sub.0-C.sub.6 alkyl)-Hca, --(C.sub.0-C.sub.6 alkyl)-L-R.sup.7,
--(C.sub.0-C.sub.6 alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6
alkyl)-OR.sup.10, --(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10,
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2R.sup.10, -halogen,
--NO.sub.2 and --CN, or two R.sup.16 on the same carbon combine to
form oxo, R.sup.38 is independently selected from --H,
--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.1-C.sub.4 alkyl) and
--C(O)O--(C.sub.1-C.sub.4 alkyl), each Ar is an optionally
substituted aryl, each Het is an optionally substituted heteroaryl,
each Cak is an optionally substituted cycloalkyl, each Hca is an
optionally substituted heterocycloalkyl, and each alkyl is
optionally substituted.
2. A compound according to claim 1, wherein ring system "B" is
##STR00230## and is not fused to the azacycloalkyl ring system
denoted by "C".
3. A compound according to claim 1, wherein ring system "B" is
##STR00231## and is not fused to the ring system denoted by
"C".
4. A compound according to claim 1, wherein ring system "B" is
##STR00232##
5. A compound according to claim 1, wherein ring system "B" is
##STR00233## and is not fused to the ring system denoted by
"C".
6. A compound according to claim 1, wherein ring system "B" is
##STR00234## and is not fused to the ring system denoted by
"C".
7. A compound according to claim 1, wherein ring system "B" is
##STR00235## and is not fused to ring system "C", in which w is 0
or 1, one of E.sup.1 and E.sup.2 is N and the other is CH, C
substituted with R.sup.3, C substituted with the -J-(ring system
"C"), or C substituted with the --C(O)--NR1R2.
8. A compound according to claim 1, wherein the compound has the
structural formula ##STR00236##
9. A compound according to claim 1, wherein each R.sup.16 is
independently selected from --(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6 alkyl)-L-R.sup.7,
--(C.sub.0-C.sub.6 alkyl)--NR.sup.8R.sup.9, --(C.sub.0-C.sub.6
alkyl)--OR.sup.10, --(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10,
--(C.sub.0-C.sub.6 alkyl)--S(O).sub.0-2R.sup.10, -halogen,
--NO.sub.2 and --CN, and two R.sup.16 on the same carbon optionally
combine to form an oxo, in which each R.sup.7, R.sup.8 and R.sup.10
is independently selected from H, --(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6
alkyl)-L-(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)--NR.sup.9(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)--O--(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)--C(O)--(C.sub.0-C.sub.6 alkyl), and --(C.sub.0-C.sub.6
alkyl)--S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl), and in which no
alkyl or haloalkyl is substituted with an aryl-, heteroaryl-,
cycloalkyl- or heterocycloalkyl-containing group.
10. A compound according to claim 1, wherein Q is an unsubstituted
--(C.sub.1-C.sub.3 alkyl)--.
11. A compound according to claim 1, wherein Q is --CH.sub.2--, a
single bond, --C(O)--, --S(O).sub.2--or --CH(CH.sub.3)--.
12. A compound according to claim 1, wherein y is 0.
13. A compound according to claim 1, wherein y is 1.
14. A compound according to claim 1, wherein each R.sup.5 is
independently selected from --(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6 alkyl)-L-R.sup.7,
--(C.sub.0-C.sub.6 alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6
alkyl)-OR.sup.10, --(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10,
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2R.sup.10, -halogen,
--NO.sub.2 and --CN, in which each R.sup.7, R.sup.8 and R.sup.10 is
independently selected from H, --(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6
alkyl)-L-(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-O--(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl) and --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl), and in which no alkyl
or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl-
or heterocycloalkyl-containing group.
15. A compound according to claim 1, wherein the ring system
denoted by "A" is an aryl or a heteroaryl.
16. A compound according to claim 1, wherein the ring system
denoted by "A" is a phenyl.
17. A compound according to claim 1, wherein the ring system
denoted by "A" is a heteroaryl.
18. A compound according to claim 1, wherein the compound has the
structural formula. ##STR00237##
19. A compound according to claim 1, wherein the compound has the
structural formula ##STR00238##
20. A compound according to claim 1, wherein the compound has the
structural formula ##STR00239##
21. A compound according to claim 20, wherein J is
--N(R.sup.38)--C(O)--.
22. A compound according to claim 1, wherein the compound has the
structural formula ##STR00240##
23. A compound according to claim 1, wherein the compound has the
structural formula ##STR00241##
24. A compound according to claim 1, wherein R.sup.1 is H.
25. A compound according to claim 1, wherein R.sup.2 is substituted
at its 1-position with --(C.sub.0-C.sub.3 alkyl)-Ar or
--(C.sub.0-C.sub.3 alkyl)-Het.
26. A compound according to claim 1, wherein R.sup.2 is substituted
at its 1-position with --C(O)--O(C.sub.0-C.sub.6 alkyl),
--C(O)-Het, --C(O)-Ar, --S(O).sub.2-Het, --S(O).sub.2-Ar or
--S(O).sub.2-0(C.sub.0-C.sub.6 alkyl).
27. A compound according to claim 1, wherein R.sup.2 is substituted
at its 1-position with --C(O)--NR.sup.9-Het or --C(O)--NR9-Ar.
28. A compound according to claim 1, wherein w is 0.
29. A compound according to claim 1, wherein each R.sup.3 is
independently selected from --(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6 alkyl)-L-R.sup.7,
--(C.sub.0-C.sub.6 alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6
alkyl)-OR.sup.10, --(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10,
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2R.sup.10, -halogen,
--NO.sub.2 and --CN, in which each R.sup.7, R.sup.8 and R.sup.10 is
independently selected from H, --(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6
alkyl)-L-(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-O--(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl), and --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl), and in which no alkyl
or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl-
or heterocycloalkyl-containing group.
30. A compound according to claim 1, wherein x is 0.
31. A compound according to claim 1, wherein each R.sup.4 is
independently selected from --(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6 alkyl)-L-R.sup.7,
--(C.sub.0-C.sub.6 alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6
alkyl)-OR.sup.10, --(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10,
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2R.sup.10, -halogen,
--NO.sub.2 and --CN, in which each R.sup.7, R.sup.8 and R.sup.10 is
independently selected from H, --(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6
alkyl)-L-(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-O--(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl) and --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl), and in which no alkyl
or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl-
or heterocycloalkyl -containing group.
32. A compound according to claim 1, having the structural formula
##STR00242## in which Q and G are each independently a bond,
--CH.sub.2--, --C(H)(R.sup.16)--, --C(R.sup.16).sub.2--, L or
--S(O).sub.2--; v is 0, 1, 2, 3 or 4; each R.sup.15 is
independently selected from --(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6 alkyl)-Ar,
--(C.sub.0-C.sub.6 alkyl)-Het, --(C.sub.0-C.sub.6 alkyl)-Cak,
--(C.sub.0-C.sub.6 alkyl)-Hca, --(C.sub.0-C.sub.6 alkyl)-L-R.sup.7,
--(C.sub.0-C.sub.6 alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6
alkyl)-OR.sup.10, --(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10,
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2R.sup.10, -halogen,
--NO.sub.2 and --CN, and two R.sup.15 on the same carbon optionally
combine to form oxo; R.sup.17 is Het or Ar.
33. A compound according to claim 32, wherein each R.sup.15 is
independently selected from --(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6 alkyl)-L-R.sup.7,
--(C.sub.0-C.sub.6 alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6
alkyl)-OR.sup.10, --(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10,
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2R.sup.10, -halogen,
--NO.sub.2 and --CN and two R.sup.15 on the same carbon optionally
combine to form oxo, in which each R.sup.7, R.sup.8 and R.sup.10 is
independently selected from H, --(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6
alkyl)-L-(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-O--(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl) and --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl), and in which no alkyl
or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl-
or heterocycloalkyl-containing group.
34. A compound according to claim 32, wherein G is --CH.sub.2--,
--CH(CH.sub.3)--, --C(O)--, --S(O).sub.2--or --C(O)--NH--.
35. A compound according to claim 32, having the structural formula
##STR00243##
36. A compound according to claim 32, having the structural formula
##STR00244## in which R.sup.25 is selected from halo, cyano,
--(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4 haloalkyl),
--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4 alkyl),
--C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl), NO.sub.2 and
--C(O)--Hca in which the Hca contains a ring nitrogen atom through
which it is bound to the --C(O)--, in which no alkyl or haloalkyl
is substituted by an aryl, heteroaryl, cycloalkyl or
heterocycloalkyl-containing group.
37. A compound according to claim 32, having the structural formula
##STR00245## in which Q is --C(O)--, --S(O).sub.2--or
--C(O)--NH--.
38. A compound according to claim 1, wherein the compound is
tert-butyl
4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-ca-
rboxamido)piperidine-1-carboxylate;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piper-
idin-4-yloxy)benzo[d]oxazole-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)-
piperidin-4-yloxy)benzo[d]oxazole-2-carboxamide;
N-(1-(4-fluorobenzoyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)pip-
eridin-4-yloxy)benzo[d]oxazole-2-carboxamide;
N-(piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benz-
o[d]oxazole-2-carboxamide;
N-(1-(4-cyanobenzoyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)pipe-
ridin-4-yloxy)benzo[d]oxazole-2-carboxamide; tert-butyl
4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]thiazole-2-c-
arboxamido)piperidine-1-carboxylate;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)-
piperidin-4-yloxy)benzo[d]thiazole-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piper-
idin-4-yloxy)benzo[d]thiazole-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-7-(1-(4-(trifluoromethyl)phenyl)-
piperidin-4-yloxy)imidazo[1,2-a]pyridine-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-7-(1-(4-(trifluoromethyl)phenyl)piper-
idin-4-yloxy)imidazo[1,2-a]pyridine-2-carboxamide; tert-butyl
4-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxami-
do)piperidine-1-carboxylate;
N-(piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyra-
zine-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)-
piperidin-4-yloxy)pyrazine-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piper-
idin-4-yloxy)pyrazine-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(1-(4-(trifluoromethyl)phenyl)piper-
idin-4-yloxy)thiazole-5-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(1-(4-cyanophenyl)piperidin-4-yloxy-
)thiazole-5-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(1-(4-(trifluoromethyl)benzyl)piper-
idin-4-yloxy)thiazole-5-carboxamide; tert-butyl
4-(5-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)thiazol-2-yloxy)piperidine-
-1-carboxylate;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(4-fluorobenzyl)-1,2,3,4-tetrahydro-
isoquinoline-7-carboxamide;
2-(4-fluorobenzyl)-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-1,2,3,4-tetra-
hydroisoquinoline-7-carboxamide;
2-(4-fluorobenzyl)-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-1,2,3,-
4-tetrahydroisoquinoline-7-carboxamide;
2-(4-cyanobenzyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-1,2,3,4-tetrahydroi-
soquinoline-7-carboxamide;
2-(4-cyanobenzyl)-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-1,2,3,4-tetrah-
ydroisoquinoline-7-carboxamide;
2-(4-cyanobenzyl)-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-1,2,3,4-
-tetrahydroisoquinoline-7-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(4-fluorobenzyl)-1,2,3,4-tetrahydro-
isoquinoline-7-carboxamide;
2-(4-fluorobenzyl)-N-(1-(pyridine-3-ylmethyl)piperidin-4-yl)-1,2,3,4-tetr-
ahydroisoquinoline-7-carboxamide; or
2-(4-fluorobenzyl)-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-1,2,3,-
4-tetrahydroisoquinoline-7-carboxamide.
39. A pharmaceutical composition comprising: at least one
pharmaceutically acceptable carrier, diluent or excipient; and a
compound according to claim 1 or a pharmaceutically acceptable salt
or N-oxide thereof.
40. A method for activating the AMPK pathway in a cell, the method
comprising contacting the cell with an effective amount of a
compound according to claim 1, or a pharmaceutically acceptable
salt or N-oxide thereof.
Description
BACKGROUND
1. Field
This disclosure relates generally to compounds, pharmaceutical
compositions and methods of use of the compounds and compositions
containing them. This disclosure relates more particularly to
certain carboxamide compounds and pharmaceutical compositions
thereof, and to methods of treating and preventing metabolic
disorders such as type II diabetes, atherosclerosis and
cardiovascular disease using certain carboxamide compounds.
2. Technical Background
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.
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
What is needed are compounds, pharmaceutical compositions and
methods of using them to treat disease states associated with
circulating adiponectin levels, such as type II diabetes,
atherosclerosis and cardiovascular disease.
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, D, J, Z, T, p, q, w and x are
as described herein.
Also disclosed herein are pharmaceutical compositions. Examples of
such compositions include those having at least one
pharmaceutically acceptable carrier, diluent or excipient; and a
compound, pharmaceutically acceptable salt, prodrug or N-oxide (or
solvate or hydrate) as described herein.
Another aspect of the present disclosure includes methods for
modulating metabolism in subjects. Accordingly, also disclosed are
methods for treating metabolic disorders using the presently
disclosed compounds and pharmaceutical compositions.
DETAILED DESCRIPTION
One aspect of the disclosure provides compounds having structural
formula (I):
##STR00003## and pharmaceutically acceptable salts, prodrugs and
N-oxides thereof (and solvates and hydrates thereof), wherein ring
system "B" is -(aryl or heteroaryl)-; ring system "C" is an
azacycloalkyl ring in which D is C, CH, CR.sup.4, or N, Z is CH,
CR.sup.4 or N, provided that at least one of D and Z is N, and the
bond between D and the carbon at the position denoted by "b" is a
single bond or a double bond; J is --O--, --N(R.sup.38)--C(O)--,
--C(O)-- or absent, provided that: (a) when J is --O-- or
--N(R.sup.38)--C(O)--, D is CH or CR.sup.4, Z is N, J links ring
systems "B" and "C", the dotted line connecting ring system "B" to
the carbon denoted by "b" in ring system "C" is absent, and the
bond between D and the carbon atom at the position denoted by "b"
is a single bond, (b) when J is --C(O)--, J links ring systems "B"
and "C", the dotted line connecting ring "B" to the carbon denoted
by "b" in ring system "C" is absent, and the bond between D and the
carbon atom at the position denoted by "b" is a single bond, (c)
when J is absent, the dotted line connecting ring system "B" to the
carbon denoted by "b" in ring system "C" signifies that ring
systems "B" and "C" are fused through the bond connecting D and the
carbon atom denoted by "b" in ring system "C", and (d) when J is
--O--, the ring system denoted by "B" is other than phenyl, that
is, the compound does not have the formula
##STR00004## R.sup.1 is H, --(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.4 alkyl) or --C(O)O--(C.sub.1-C.sub.4
alkyl), and R.sup.2 is -Hca, -Cak-N(R.sup.9)-G-R.sup.22 or
--(C.sub.2-C.sub.8 alkyl)-N(R.sup.9)--R.sup.24 in which one or two
(e.g., non-adjacent) carbons of the (C.sub.2-C.sub.8 alkyl) are
optionally replaced by --O--, --S-- or --N(R.sup.9)--, and R.sup.24
is --R.sup.23, -G-R.sup.23 or --C(O)O--(C.sub.1-C.sub.6 alkyl),
provided that two consecutive carbons of the (C.sub.2-C.sub.8
alkyl) are not replaced by --O--, or R.sup.1 and R.sup.2 together
with the nitrogen to which they are attached come together to form
-Hca; each R.sup.3 is independently selected from
--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alkyl)-Ar, --(C.sub.0-C.sub.6 alkyl)-Het,
--(C.sub.0-C.sub.6 alkyl)-Cak, --(C.sub.0-C.sub.6 alkyl)-Hca,
--(C.sub.0-C.sub.6 alkyl)-L-R.sup.7, --(C.sub.0-C.sub.6
alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6 alkyl)-OR.sup.10,
--(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN; w is 0,
1, 2, 3 or 4; each R.sup.4 is independently selected from
--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alkyl)-Ar, --(C.sub.0-C.sub.6 alkyl)-Het,
--(C.sub.0-C.sub.6 alkyl)-Cak, --(C.sub.0-C.sub.6 alkyl)-Hca,
--(C.sub.0-C.sub.6 alkyl)-L-R.sup.7, --(C.sub.0-C.sub.6
alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6 alkyl)-OR.sup.10,
--(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN, and two
R.sup.4 on the same carbon optionally combine to form oxo; p is 0,
1, 2, 3 or 4; q is 0, 1, 2, 3 or 4, provided that the sum of p and
q is 1, 2, 3 or 4; x is 0 or an integer .ltoreq.p+q, wherein when D
or Z is CR.sup.4, the R.sup.4 of D or Z is one of the x R.sup.4
groups on ring system "C"; T is --(C.sub.0-C.sub.6
alkyl)-L-R.sup.7, --(C.sub.0-C.sub.6 alkyl)-NR.sup.8R.sup.9,
--(C.sub.0-C.sub.6 alkyl)-OR.sup.10, --(C.sub.0-C.sub.6
alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2R.sup.10
or
##STR00005## in which Q is --S(O).sub.2--, L, or (C.sub.0-C.sub.3
alkyl)-, in which each carbon of the --(C.sub.0-C.sub.3 alkyl)-is
optionally and independently substituted with one or two R.sup.16;
the ring denoted by "A" is heteroaryl, aryl, cycloalkyl or
heterocycloalkyl; each R.sup.5 is independently selected from
--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alkyl)-Ar, --(C.sub.0-C.sub.6 alkyl)-Het,
--(C.sub.0-C.sub.6 alkyl)-Cak, --(C.sub.0-C.sub.6 alkyl)-Hca,
--(C.sub.0-C.sub.6 alkyl)-L-R.sup.7, --(C.sub.0-C.sub.6
alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6 alkyl)-OR.sup.10,
--(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN; and y
is 0, 1, 2, 3 or 4; in which each L is independently selected from
--NR.sup.9C(O)O--, --OC(O)NR.sup.9--, --NR.sup.9C(O)--NR.sup.9--,
--NR.sup.9C(O)S--, --SC(O)NR.sup.9--, --NR.sup.9C(O)--,
--C(O)--NR.sup.9--, --NR.sup.9C(S)O--, --OC(S)NR.sup.9--,
--NR.sup.9C(S)--NR.sup.9--, --NR.sup.9C(S)S--, --SC(S)NR.sup.9--,
--NR.sup.9C(S)--, --C(S)NR.sup.9--, --SC(O)NR.sup.9--,
--NR.sup.9C(S)--, --S(O).sub.0-2--, --C(O)O, --OC(O)--, --C(S)O--,
--OC(S)--, --C(O)S--, --SC(O)--, --C(S)S--, --SC(S)--, --OC(O)O--,
--SC(O)O--, --OC(O)S--, --SC(S)O--, --OC(S)S--,
--NR.sup.9C(NR.sup.2)NR.sup.9--, --NR.sup.9SO.sub.2--,
--SO.sub.2NR.sup.9-- and --NR.sup.9SO.sub.2NR.sup.9--, each
R.sup.6, R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alkyl)-Ar, --(C.sub.0-C.sub.6 alkyl)-Het,
--(C.sub.0-C.sub.6 alkyl)-Cak, --(C.sub.0-C.sub.6 alkyl)-Hca,
--(C.sub.0-C.sub.6 alkyl)-L-(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-NR.sup.9--(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-O--(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl) and
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl),
each R.sup.9 is independently selected from --H, --(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.1-C.sub.4 alkyl) and
--C(O)O--(C.sub.1-C.sub.4 alkyl), each G is independently
--S(O).sub.2--, L, or --(C.sub.0-C.sub.3 alkyl)-, in which each
carbon of the --(C.sub.0-C.sub.3 alkyl)- is optionally and
independently substituted with one or two R.sup.16, each R.sup.16
is independently selected from --(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6 alkyl)-Ar,
--(C.sub.0-C.sub.6 alkyl)-Het, --(C.sub.0-C.sub.6 alkyl)-Cak,
--(C.sub.0-C.sub.6 alkyl)-Hca, --(C.sub.0-C.sub.6 alkyl)-L-R.sup.7,
--(C.sub.0-C.sub.6 alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6
alkyl)-OR.sup.10, --(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10,
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2R.sup.10, -halogen,
--NO.sub.2 and --CN, or two R.sup.16 on the same carbon combine to
form oxo, R.sup.38 is independently selected from --H,
--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.1-C.sub.4 alkyl) and
--C(O)O--(C.sub.1-C.sub.4 alkyl), R.sup.22 and R.sup.23 are each
independently Ar or Het, each Ar is an optionally substituted aryl,
each Het is an optionally substituted heteroaryl, each Cak is an
optionally substituted cycloalkyl, each Hca is an optionally
substituted heterocycloalkyl, and each alkyl is optionally
substituted.
In certain embodiments of the presently disclosed compounds of
structural formula (I), J is --O-- or --N(R.sup.38)--C(O)-- and D
is CH or C-- substituted with one of the x R.sup.4 groups. In other
embodiments of the presently disclosed compounds of structural
formula (I), J is --C(O)--. In certain such embodiments, D is
N.
In certain embodiments of the presently disclosed compounds of
structural formula (I), Z is N and D is C, CH or C-- substituted
with one of the x R.sup.4 groups. In other embodiments, D is N and
Z is CH or C-- substituted with one of the x R.sup.4 groups. In
further embodiments, D is N and Z is N.
In certain embodiments of the presently disclosed compounds of
structural formula (I), R.sup.38 is --H. In other embodiments,
R.sup.38 is --(C.sub.1-C.sub.4 alkyl), for example methyl, ethyl or
propyl. In other embodiments, R.sup.38 is --C(O)--(C.sub.1-C.sub.4
alkyl), for example acetyl. In other embodiments, R.sup.38 is
--C(O)--O--(C.sub.1-C.sub.4 alkyl)-, for example --C(O)--O-t-butyl.
In certain embodiments, no alkyl of R.sup.38 is substituted with an
aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing
group.
In certain embodiments of the presently disclosed compounds of
structural formula (I) as described above, ring system "B" is not
fused to ring system "C" at the position denoted by "b," so that
the compounds have structural formula (II):
##STR00006##
In other embodiments, ring system "B" is fused to ring system "C"
at the position denoted by "b"; for example, the compounds can have
structural formula (III):
##STR00007##
In certain embodiments of the presently disclosed compounds of
structural formula (I), "B" represents
##STR00008## in which the benzo ring is linked or fused to ring
system "C" and the dotted line is not a bond but merely indicates
that the benzo ring is fused to ring system "C" or not. Examples of
such compounds wherein ring system "B" is not fused to ring system
"C" are represented by the formula
##STR00009## In certain such embodiments, J is --O--, Z is N and D
is CH or C-- substituted by one of the x R.sup.4.
In other embodiments of the presently disclosed compounds of
structural formula (I), "B" represents
##STR00010## in which the benzo ring is linked or fused to ring
system "C" and the dotted line is not a bond but merely indicates
that the benzo ring is fused to ring system "C" or not. Examples of
such compounds wherein ring system "B" is not fused to ring system
"C" are represented by the formula
##STR00011## In certain such embodiments, J is --O--, Z is N and D
is CH or C-- substituted by one of the x R.sup.4.
In other embodiments of the presently disclosed compounds of
structural formula (I), "B" represents
##STR00012## in which the pyrido ring is linked or fused to ring
system "C" and the dotted line is not a bond but merely indicates
that the pyrido ring is fused to ring system "C" or not. Examples
of such compounds wherein ring system "B" is not fused to ring
system "C" are represented by the formula
##STR00013## In certain such embodiments, J is --O--, Z is N and D
is CH or C-- substituted by one of the x R.sup.4. Floating bonds
indicate attachment on any carbon of the imidazo[1,2-a]pyridine
ring system. In some embodiments, for example, the J moiety is on
the pyridine ring of the imidazo[1,2-a]pyridine ring system, and
the carboxamide (i.e., --C(O)--NR.sup.1R.sup.2) moiety is on the
imidazo ring of the imidazo[1,2-a]pyridine ring system, and any
R.sup.3 groups can be on either ring of the imidazo[1,2-a]pyridine
ring system.
In other embodiments of the presently disclosed compounds of
structural formula (I), "B" represents
##STR00014## in which the pyrazine ring is linked or fused to ring
system "C" and the dotted line is not a bond but merely indicates
that the pyrazine ring is fused to ring system "C" or not. Examples
of such compounds wherein ring system "B" is not fused to ring
system "C" are represented by the formula
##STR00015## In certain such embodiments, J is --O--, Z is N and D
is CH or C-- substituted by one of the x R.sup.4.
In other embodiments of the presently disclosed compounds of
structural formula (I), "B" represents
##STR00016## and is not fused to ring system "C", one of E.sup.1
and E.sup.2 is N and the other is CH, C substituted with the
R.sup.3, C substituted with the -J-(ring system "C"), or C
substituted with the --C(O)--NR.sup.1R.sup.2), w is 0 or 1. In
certain such embodiments, J is --O--, Z is N and D is CH or C--
substituted by one of the x R.sup.4.
In other embodiments of the presently disclosed compounds of
structural formula (I), ring system "B" is
##STR00017## and is not fused to ring system "C". In such
embodiments, J is other than O. In certain such embodiments, J is
--C(O)--, Z is N, CH or C-substituted by one of the x R.sup.4 and D
is N. In other such embodiments, J is --N(R.sup.38)--C(O)--, Z is N
and D is CH or C-- substituted by one of the x R.sup.4.
In certain embodiments according to structural formulae (I)-(III),
the sum of p and q is 2 or 3. For example, in one embodiment, the
sum of p and q is 2 (e.g., p is 1 and q is 1). In another
embodiment, the sum of p and q is 3 (e.g., p is 1 and q is 2).
In other embodiments of the presently disclosed compounds of
structural formula (I), ring system "B" is a phenyl and is fused to
ring system "C" (i.e., J is absent), Z is N, D is C, q is 2 and p
is 1, such that the compound has structural formula (IV):
##STR00018##
In certain embodiments of the presently disclosed compounds of
structural formulae (I)-(IV), T is
##STR00019## In such embodiments, Q is --S(O).sub.2--, L or
--(C.sub.0-C.sub.3 alkyl)-in which each carbon of the
(C.sub.0-C.sub.3 alkyl) is optionally and independently substituted
with one or two R.sup.16, in which each R.sup.16 is independently
selected from --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
haloalkyl), --(C.sub.0-C.sub.6 alkyl)-Ar, --(C.sub.0-C.sub.6
alkyl)-Het, --(C.sub.0-C.sub.6 alkyl)-Cak, --(C.sub.0-C.sub.6
alkyl)-Hca, --(C.sub.0-C.sub.6 alkyl)-L-R.sup.7, --(C.sub.0-C.sub.6
alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6 alkyl)-OR.sup.10,
--(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN, and
optionally two of R.sup.16 on the same carbon combine to form oxo.
In certain embodiments, each R.sup.16 is independently selected
from --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl)
(e.g., difluoromethyl, trifluoromethyl and the like),
--(C.sub.0-C.sub.6 alkyl)-L-R.sup.7, --(C.sub.0-C.sub.6
alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6 alkyl)-OR.sup.10,
--(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN, and two
R.sup.16 on the same carbon optionally combine to form an oxo, in
which each R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alkyl)-L-(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-O--(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl), and
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl),
and in which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For
example, in particular compounds, each R.sup.16 is
--(C.sub.1-C.sub.3 alkyl), --(C.sub.1-C.sub.3 haloalkyl),
--(C.sub.0-C.sub.3 alkyl)-L-R.sup.7, --(C.sub.0-C.sub.3
alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.3 alkyl)-OR.sup.10,
--(C.sub.0-C.sub.3 alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.3
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN, and two
R.sup.16 on the same carbon optionally combine to form an oxo, in
which each R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.2 alkyl), --(C.sub.1-C.sub.2 haloalkyl),
--(C.sub.0-C.sub.2 alkyl)-L-(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-NR.sup.9(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-O--(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-C(O)--(C.sub.0-C.sub.2 alkyl) and
--(C.sub.0-C.sub.2 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.2 alkyl),
and in which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In
certain embodiments, Q has at most one R.sup.16 or oxo substituted
thereon. Q can be, for example, an unsubstituted --(C.sub.0-C.sub.3
alkyl)-. In other embodiments, Q is a (C.sub.1-C.sub.3 alkyl)
having as its only substitution a single oxo group. For example, in
certain embodiments, Q is --CH.sub.2--; a single bond;
--S(O).sub.2--; --C(O)--; or --CH(CH.sub.3)--.
In certain embodiments of the compounds of structural formulae
(I)-(IV), the
##STR00020## moiety is
##STR00021## for example, p-(trifluoromethyl)phenyl. In other
embodiments, the
##STR00022## moiety is
##STR00023## in one such embodiment, Q is a single bond.
The number of substituents on the ring system denoted by "A", y, is
0, 1, 2, 3 or 4. For example, in some embodiments of the presently
disclosed compounds of structural formulae (I)-(IV), y is 0, 1, 2
or 3, such as 1. In one embodiment, y is not zero and at least one
R.sup.5 is halo, cyano, --(C.sub.1-C.sub.4 haloalkyl),
--O--(C.sub.1-C.sub.4 haloalkyl), --(C.sub.1-C.sub.4 alkyl),
--O--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl),
--C(O)O--(C.sub.0-C.sub.4 alkyl), --C(O)N(C.sub.0-C.sub.4
alkyl)(C.sub.0-C.sub.4 alkyl), NO.sub.2 or --C(O)--Hca wherein the
Hca contains a ring nitrogen atom through which it is bound to the
--C(O)--, and wherein no alkyl, haloalkyl or heterocycloalkyl is
substituted by an aryl, heteroaryl, cycloalkyl or
heterocycloalkyl-containing group.
In certain embodiments of the presently disclosed compounds of
structural formulae (I)-(IV), each R.sup.5 is independently
selected from --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like),
--(C.sub.0-C.sub.6 alkyl)-L-R.sup.7, --(C.sub.0-C.sub.6
alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6 alkyl)-OR.sup.10,
--(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN, in
which each R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl)
(e.g., difluoromethyl, trifluoromethyl and the like),
--(C.sub.0-C.sub.6 alkyl)-L-(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-O--(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl) and
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl),
and in which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For
example, in one embodiment, each R.sup.5 is --(C.sub.1-C.sub.3
alkyl), --(C.sub.1-C.sub.3 haloalkyl), --(C.sub.0-C.sub.3
alkyl)-L-R.sup.7, --(C.sub.0-C.sub.3 alkyl)-NR.sup.8R.sup.9,
--(C.sub.0-C.sub.3 alkyl)-OR.sup.10, --(C.sub.0-C.sub.3
alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.3
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN, in
which each R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.2 alkyl), --(C.sub.1-C.sub.2 haloalkyl),
--(C.sub.0-C.sub.2 alkyl)-L-(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-NR.sup.9(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-O--(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-C(O)--(C.sub.0-C.sub.2 alkyl) and
--(C.sub.0-C.sub.2 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.2 alkyl),
and in which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group.
In one embodiment of the compounds of structural formulae (I)-(IV),
y is 0.
In the presently disclosed compounds of structural formulae
(I)-(IV), the ring system denoted by "A" is heteroaryl, aryl,
cycloalkyl or heterocycloalkyl. For example, in one embodiment, the
ring system denoted by "A" is an aryl or a heteroaryl. The ring
system denoted by "A" can be, for example, a monocyclic aryl or
heteroaryl. In one embodiment, when the "A" ring system is aryl, Q
is a --(C.sub.0-C.sub.3 alkyl)- optionally substituted with oxo,
and optionally substituted with one or more R.sup.16. For example,
Q can be a --(C.sub.1-C.sub.3 alkyl)- having its only substitution
a single oxo, or an unsubstituted --(C.sub.0-C.sub.3 alkyl)-. For
example, in certain embodiments, Q is --CH.sub.2--; a single bond;
--S(O).sub.2--; --C(O)--; or --CH(CH.sub.3)--.
For example, in certain embodiments of the presently disclosed
compounds of structural formulae (I)-(IV), the ring system denoted
by "A" is a phenyl. In one embodiment, y is 1 and R.sup.5 is
attached to the phenyl in the para position relative to Q. In
another embodiment, y is 1 and R.sup.5 is selected from the group
consisting of halo, cyano, --(C.sub.1-C.sub.4 haloalkyl),
--O--(C.sub.1-C.sub.4 haloalkyl), --(C.sub.1-C.sub.4 alkyl),
--O--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl),
--C(O)O--(C.sub.0-C.sub.4 alkyl), --C(O)N(C.sub.0-C.sub.4
alkyl)(C.sub.0-C.sub.4 alkyl), NO.sub.2 and --C(O)--Hca in which
the Hca contains a ring nitrogen atom through which it is bound to
the --C(O)--, and in which no (C.sub.0-C.sub.4 alkyl) or
(C.sub.1-C.sub.4 alkyl) is substituted by an aryl, heteroaryl,
cycloalkyl or heterocycloalkyl-containing group. R.sup.5 can be,
for example, --Cl, --F, cyano, --C(O)CH.sub.3, --C(O)OH,
--C(O)NH.sub.2, trifluoromethyl, difluoromethyl, difluoromethoxy or
trifluoromethoxy. In another embodiment, the
##STR00024## moiety is a 3,4-dihalophenyl.
In another embodiment of the presently disclosed compounds of
structural formulae (I)-(IV), the ring system denoted by "A" is a
heteroaryl. For example, in certain embodiments, the ring system
denoted by "A" is a pyridyl, a thienyl, or a furanyl. In one
embodiment, when the "A" ring system is heteroaryl, Q is a
--(C.sub.0-C.sub.3 alkyl)- optionally substituted with oxo, and
optionally substituted with one or more R.sup.16. For example, Q
can be a --(C.sub.1-C.sub.3 alkyl)- having its only substitution a
single oxo, or an unsubstituted --(C.sub.0-C.sub.3 alkyl)-. In
certain embodiments, Q is --CH.sub.2--; a single bond;
--S(O).sub.2--; --C(O)--; or --CH(CH.sub.3)--.
In certain embodiments (e.g., when ring system "B" is a phenyl and
is fused to ring system "C", J is absent, Z is N, D is carbon, q is
2 and p is 1), T is not --C(O)O--(C.sub.0-C.sub.6 alkyl).
In certain embodiments (e.g., when ring system "B" is a phenyl and
is fused to ring system "C", J is absent, Z is N, D is carbon, q is
2 and p is 1), T is not is not --CH.sub.2C(O)OH;
--NH--CH.sub.2--C(O)OH; --O--CH.sub.2--C(O)OH;
--CH.sub.2--CH.sub.2--C(O)OH; --CH.dbd.CH--C(O)OH;
--N(C(O)CH.sub.3)--CH.sub.2--C(O)OH; .dbd.CH--C(O)OH or
.dbd.CH--CH.sub.2--CH.sub.2--C(O)OH.
In one embodiment of the presently disclosed compounds, the
compound has structural formula (V):
##STR00025## in which n is 1, 2, 3 or 4, and all other variables
are defined as described above with reference to structural
formulae (I)-(IV).
In one embodiment of the presently disclosed compounds, the
compound has structural formula (VI):
##STR00026## in which n is 1, 2, 3 or 4, and all other variables
are defined as described above with reference to structural
formulae (I)-(IV).
In one embodiment of the presently disclosed compounds, the
compound has structural formula (VII):
##STR00027## in which n is 1, 2, 3 or 4, and all other variables
are defined as described above with reference to structural
formulae (I)-(IV).
In one embodiment of the presently disclosed compounds, the
compound has structural formula (VIII):
##STR00028## in which n is 1, 2, 3 or 4, and all other variables
are defined as described above with reference to structural
formulae (I)-(IV).
In one embodiment of the presently disclosed compounds, the
compound has structural formula (IX):
##STR00029## in which n is 1, 2, 3 or 4, and all other variables
are defined as described above with reference to structural
formulae (I)-(IV).
In one embodiment of the presently disclosed compounds, the
compound has structural formula (X):
##STR00030## in which n is 1, 2, 3 or 4, and all other variables
are defined as described above with reference to structural
formulae (I)-(IV).
In one embodiment of the presently disclosed compounds, the
compound has structural formula (XI):
##STR00031## in which n is 1, 2, 3 or 4, and all other variables
are defined as described above with reference to structural
formulae (I)-(IV).
In one embodiment of the presently disclosed compounds, the
compound has structural formula (XII):
##STR00032## in which n is 1, 2, 3 or 4, and all other variables
are defined as described above with reference to structural
formulae (I)-(IV).
In one embodiment of the presently disclosed compounds, the
compound has structural formula (XIII):
##STR00033## in which n is 1, 2, 3 or 4, and all other variables
are defined as described above with reference to structural
formulae (I)-(IV).
In one embodiment of the presently disclosed compounds, the
compound has structural formula (XIV):
##STR00034## in which n is 1, 2, 3 or 4, and all other variables
are defined as described above with reference to structural
formulae (I)-(IV).
In one embodiment of the presently disclosed compounds, the
compound has structural formula (XV):
##STR00035## in which n is 1, 2, 3 or 4, w is 0 or 1, and all other
variables are defined as described above with reference to
structural formulae (I)-(IV). For example, in one embodiment,
E.sup.1 is N and E.sup.2 is --CH-- or --CR.sup.3--. In another
embodiment, E.sup.1 is --CH-- or --CR.sup.3-- and E.sup.2 is N.
In one embodiment of the presently disclosed compounds, the
compound has structural formula (XVI):
##STR00036## in which n is 1, 2, 3 or 4, w is 0 or 1, and all other
variables are defined as described above with reference to
structural formulae (I)-(IV). When w is 0, the ring position shown
occupied by R.sup.3 bears a hydrogen atom.
In one embodiment of the presently disclosed compounds, the
compound has structural formula (XVII):
##STR00037## in which n is 1, 2, 3 or 4, w is 0 or 1, and all other
variables are defined as described above with reference to
structural formulae (I)-(IV). When w is 0, the ring position shown
occupied by R.sup.3 bears a hydrogen atom.
In certain embodiments of the compounds disclosed with reference to
structural formulae (V) --(XVII), n is 1 or 2. For example, in one
embodiment, n is 2. In another embodiment, n is 1.
For example, in one embodiment of the presently disclosed
compounds, the compound has structural formula (XVIII):
##STR00038## in which all variables are defined as described above
with reference to structural formulae (I)-(IV).
In another embodiment of the presently disclosed compounds, the
compound has structural formula (XIX):
##STR00039## in which all variables are defined as described above
with reference to structural formulae (I)-(IV).
In another embodiment of the presently disclosed compounds, the
compound has structural formula (XX):
##STR00040## in which all variables are defined as described above
with reference to structural formulae (I)-(IV).
In another embodiment of the presently disclosed compounds, the
compound has structural formula (XXI):
##STR00041## in which all variables are defined as described above
with reference to structural formulae (I)-(IV).
In another embodiment of the presently disclosed compounds, the
compound has structural formula (XXII):
##STR00042## in which all variables are defined as described above
with reference to structural formulae (I)-(IV).
In another embodiment of the presently disclosed compounds, the
compound has structural formula (XXIII):
##STR00043## in which all variables are defined as described above
with reference to structural formulae (I)-(IV).
In another embodiment of the presently disclosed compounds, the
compound has structural formula (XXIV):
##STR00044## in which all variables are defined as described above
with reference to structural formulae (I)-(IV).
In another embodiment of the presently disclosed compounds, the
compound has structural formula (XXV):
##STR00045## in which all variables are defined as described above
with reference to structural formulae (I)-(IV).
In another embodiment of the presently disclosed compounds, the
compound has structural formula (XXVI):
##STR00046## in which all variables are defined as described above
with reference to structural formulae (I)-(IV).
In another embodiment of the presently disclosed compounds, the
compound has structural formula (XXVII):
##STR00047## in which all variables are defined as described above
with reference to structural formulae (I)-(IV).
In another embodiment of the presently disclosed compounds, the
compound has structural formula (XXVIII):
##STR00048## in which w is 0 or 1 and all other variables are
defined as described above with reference to structural formulae
(I)-(IV). When w is 0, the ring position shown occupied by R.sup.3
bears a hydrogen atom. In one embodiment, E.sup.1 is --CH-- or
--CR.sup.3-- and E.sup.2 is N. In another embodiment, E.sup.1 is N
and E.sup.2 is --CH-- or --CR.sup.3--.
In another embodiment of the presently disclosed compounds, the
compound has structural formula (XXIX):
##STR00049## in which w is 0 or 1 and all other variables are
defined as described above with reference to structural formulae
(I)-(IV). When w is 0, the ring position shown occupied by R.sup.3
bears a hydrogen atom.
In another embodiment of the presently disclosed compounds, the
compound has structural formula (XXX):
##STR00050## in which w is 0 or 1 and all other variables are
defined as described above with reference to structural formulae
(I)-(IV). When w is 0, the ring position shown occupied by R.sup.3
bears a hydrogen atom.
In one embodiment of the presently disclosed compounds, the
compound has structural formula (XXXI):
##STR00051## in which all variables are defined as described above
with reference to structural formulae (I)-(IV). In one such
embodiment, J is --C(O)--, Z is CH or C substituted with one of the
x R.sup.4 and D is N. In another such embodiment, J is --C(O)--, Z
is N and D is N. In a further such embodiment, J is
--N(R.sup.38)--C(O)-- (e.g., --NH--C(O)--), Z is N and D is CH or C
substituted with one of the x R.sup.4.
In another embodiment of the presently disclosed compounds, the
compound has structural formula (XXXII):
##STR00052## in which all variables are defined as described above
with reference to structural formulae (I)-(IV). In one such
embodiment, J is --C(O)--, Z is CH or C substituted with one of the
x R.sup.4 and D is N. In another such embodiment, J is --C(O)--, Z
is N and D is N. In a further such embodiment, J is
--N(R.sup.38)--C(O)-- (e.g., --NH--C(O)--), Z is N and D is CH or C
substituted with one of the x R.sup.4.
In another embodiment of the presently disclosed compounds, the
compound has structural formula (XXXIII):
##STR00053## in which all variables are defined as described above
with reference to structural formulae (I)-(IV). In one such
embodiment, J is --C(O)--, Z is CH or C substituted with one of the
x R.sup.4 and D is N. In another such embodiment, J is --C(O)--, Z
is N and D is N. In a further such embodiment, J is
--N(R.sup.38)--C(O)-- (e.g., --NH--C(O)--), Z is N and D is CH or C
substituted with one of the x R.sup.4.
In certain embodiments according to structural formulae
(XXXI)-(XXXIII), the sum of p and q is 2 or 3. For example, in one
embodiment, the sum of p and q is 2 (e.g., p is 1 and q is 1). In
another embodiment, the sum of p and q is 3 (e.g., p is 1 and q is
2).
For example, in one embodiment of the presently disclosed
compounds, the compound has structural formula (XXXIV):
##STR00054## in which all variables are defined as described above
with reference to structural formulae (I)-(IV). In one such
embodiment, Z is N. In another such embodiment, Z is CH or C
substituted with one of the x R.sup.4.
In another embodiment of the presently disclosed compounds, the
compound has structural formula (XXXV):
##STR00055## in which all variables are defined as described above
with reference to structural formulae (I)-(IV).
In another embodiment of the presently disclosed compounds, the
compound has structural formula (XXXVI):
##STR00056## in which all variables are defined as described above
with reference to structural formulae (I)-(IV). In one such
embodiment, Z is N. In another such embodiment, Z is CH or C
substituted with one of the x R.sup.4.
For example, in one embodiment of the presently disclosed
compounds, the compound has structural formula (XXXVII):
##STR00057## in which all variables are defined as described above
with reference to structural formulae (I)-(IV).
For example, in one embodiment of the presently disclosed
compounds, the compound has structural formula (XXXVIII):
##STR00058## in which all variables are defined as described above
with reference to structural formulae (I)-(IV). In one such
embodiment, Z is N. In another such embodiment, Z is CH or C
substituted with one of the x R.sup.4.
In another embodiment of the presently disclosed compounds, the
compound has structural formula (XXXIX):
##STR00059## in which all variables are defined as described above
with reference to structural formulae (I)-(IV).
In one embodiment of the presently disclosed compounds, the
compound has structural formula (XL):
##STR00060## in which all variables are defined as described above
with reference to structural formulae (I)-(IV).
In one embodiment of the presently disclosed compounds, the
compound has structural formula (XLI):
##STR00061## in which all variables are defined as described above
with reference to structural formulae (I)-(IV).
In one embodiment of the presently disclosed compounds, the
compound has structural formula (XLII):
##STR00062## in which all variables are defined as described above
with reference to structural formulae (I)-(IV).
In one embodiment of the presently disclosed compounds, the
compound has structural formula (XLIII):
##STR00063## in which all variables are defined as described above
with reference to structural formulae (I)-(IV).
In certain embodiments of the presently disclosed compounds of
structural formulae (I)-(XLIII), R.sup.1 is H, --(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.1-C.sub.4 alkyl) or
--C(O)O--(C.sub.1-C.sub.4 alkyl), and R.sup.2 is -Hca,
-Cak-N(R.sup.9)-G-R.sup.22 or --(C.sub.2-C.sub.8
alkyl)-N(R.sup.9)--R.sup.24 in which one or two (for example,
non-adjacent) carbons of the (C.sub.2-C.sub.8 alkyl) are optionally
replaced by --O--, --S-- or --N(R.sup.9)--, and R.sup.24 is
--R.sup.23, -G-R.sup.23 or --C(O)O--(C.sub.1-C.sub.6 alkyl),
provided that two consecutive carbons of the (C.sub.2-C.sub.8
alkyl) are not replaced by --O--. For example, in one embodiment,
R.sup.1 is H, --(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.1-C.sub.4
alkyl) or --C(O)O--(C.sub.1-C.sub.4 alkyl), and R.sup.2 is
-Hca.
In certain embodiments of the presently disclosed compounds of any
of structural formulae (I)-(XLIII), R.sup.1 is --H. In other
embodiments, R.sup.1 is (C.sub.1-C.sub.4 alkyl), for example
methyl, ethyl, n-propyl or isopropyl.
In certain embodiments of the presently disclosed compounds of any
structural formulae (I)-(XLIII), R.sup.2 is -Hca. In certain
embodiments, R.sup.2 is an optionally-substituted monocyclic
heterocycloalkyl.
In certain of the presently disclosed compounds of any structural
formulae (I)-(XLIII), R.sup.2 is -(optionally-substituted
azetidinyl), -(optionally-substituted pyrrolidinyl),
-(optionally-substituted piperidinyl) or -(optionally-substituted
azepanyl). For example, R.sup.2 can be -(optionally substituted
piperidinyl) or -(optionally substituted pyrrolidinyl). In one
embodiment, R.sup.2 is -(optionally substituted piperidinyl). In
another embodiment, R.sup.2 is -(optionally substituted
pyrrolidinyl).
In certain particular embodiments of the presently disclosed
compounds of any of structural formulae (I)-(XLIII), R.sup.2 is
-(optionally-substituted azetidin-3-yl), -(optionally substituted
piperidin-4-yl), -(optionally substituted pyrrolidin-3-yl) or
-(optionally-substituted azepan-4-yl). For example, in one
embodiment, R.sup.2 is -(optionally substituted piperidin-4-yl). In
another embodiment, R.sup.2 is -(optionally substituted
pyrrolidin-3-yl).
In certain embodiments of the presently disclosed compounds of any
of structural formulae (I)-(XLIII), the azetidinyl, pyrrolidinyl,
piperidinyl and azepanyl R.sup.2 moieties described above are
substituted at their 1-positions. For example, in one embodiment,
R.sup.2 is substituted at its 1-position with --(C.sub.0-C.sub.3
alkyl)-Ar or --(C.sub.0-C.sub.3 alkyl)-Het, for example
-(unsubstituted C.sub.0-C.sub.3 alkyl)-Ar or -(unsubstituted
C.sub.0-C.sub.3 alkyl)-Het. For example, in one particular
embodiment, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl
R.sup.2 moiety is substituted at its 1-position with an optionally
substituted benzyl or an optionally substituted phenyl. In another
embodiment, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl
R.sup.2 moiety is substituted at its 1-position with a benzyl
substituted with an electron withdrawing group; or with a
pyridinylmethyl optionally substituted with an electron withdrawing
group. For example, the benzyl or pyridinylmethyl can be
substituted with an electron withdrawing group selected from the
group consisting of halo, cyano, --(C.sub.1-C.sub.4 fluoroalkyl),
--O--(C.sub.1-C.sub.4 fluoroalkyl), --C(O)--(C.sub.0-C.sub.4
alkyl), --C(O)O--(C.sub.0-C.sub.4 alkyl), --C(O)N(C.sub.0-C.sub.4
alkyl)(C.sub.0-C.sub.4 alkyl), --S(O).sub.2O--(C.sub.0-C.sub.4
alkyl), 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. In
other embodiments, the azetidinyl, pyrrolidinyl, piperidinyl or
azepanyl R.sup.2 moiety is substituted at its 1-position with an
unsubstituted benzyl or an unsubstituted phenyl.
In other embodiments of the compounds disclosed herein having any
of structural formulae (I)-(XLIII), the azetidinyl, pyrrolidinyl,
piperidinyl or azepanyl R.sup.2 moiety is substituted at its
1-position with an optionally substituted pyridinylmethyl, an
optionally substituted furanylmethyl, an optionally substituted
thienylmethyl, an optionally substituted oxazolylmethyl, or an
optionally substituted imidazolylmethyl. For example, the
azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R.sup.2 moiety
can be substituted with an unsubstituted pyridinylmethyl, an
unsubstituted furanylmethyl, an unsubstituted thienylmethyl, an
unsubstituted oxazolylmethyl, or an unsubstituted imidazolylmethyl.
In other embodiments, the azetidinyl, pyrrolidinyl, piperidinyl or
azepanyl R.sup.2 moiety can be substituted with an pyridinylmethyl,
furanylmethyl, thienylmethyl, oxazolylmethyl or imidazolylmethyl
substituted with an electron withdrawing group as described
above.
In certain embodiments of the compounds disclosed herein having any
of structural formulae (I)-(XLIII), the azetidinyl, pyrrolidinyl,
piperidinyl or azepanyl R.sup.2 moiety is substituted at its
1-position with -L-Ar or -L-Het, in which Ar and Het can be, for
example, as described above with reference to --(C.sub.0-C.sub.3
alkyl)-Ar or --(C.sub.0-C.sub.3 alkyl)-Het. In one such embodiment,
L is --C(O)--NR.sup.9--, such as --C(O)--NH--.
In other embodiments of the presently disclosed compounds of any of
structural formulae (I)-(XLIII), the azetidinyl, pyrrolidinyl,
piperidinyl or azepanyl R.sup.2 moiety is substituted at its
1-position with --C(O)--O(C.sub.0-C.sub.6 alkyl), --C(O)-Het,
--C(O)--Ar, --S(O).sub.2-Het, --S(O).sub.2--Ar or
--S(O).sub.2--O(C.sub.0-C.sub.6 alkyl), in which Ar and Het can be,
for example, as described above with reference to
--(C.sub.0-C.sub.3 alkyl)-Ar or --(C.sub.0-C.sub.3 alkyl)-Het. In
one embodiment, the azetidinyl, pyrrolidinyl, piperidinyl or
azepanyl R.sup.2 moiety is substituted at its 1-position with
--C(O)-Het or --C(O)--Ar; in another embodiment, it is substituted
at its 1-position with --S(O).sub.2-Het or --S(O).sub.2--Ar. For
example, in certain embodiments, the azetidinyl, pyrrolidinyl,
piperidinyl or azepanyl R.sup.2 moiety is substituted at its
1-position with an optionally-substituted benzoyl (e.g.,
substituted with an electron withdrawing group as described above);
or with an optionally-substituted nicotinyl, isonicotinyl or
picolinyl (e.g., optionally substituted with an electron
withdrawing group as described above). In other embodiments, the
azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R.sup.2 moiety is
substituted at its 1-position with an unsubstituted benzoyl; or an
unsubstituted nicotinoyl, isonicotinoyl or picolinoyl.
In certain embodiments, R.sup.2 is an optionally-substituted
bridged azacycloalkyl or diazacycloalkyl, for example, a bridged
azabicyclohexyl, a bridged azabicycloheptyl, a bridged
azabicyclooctyl, a bridged diazabicyclohexyl, a bridged
diazabicycloheptyl or a bridged diazabicyclooctyl. Particular
examples of such R.sup.2 moieties include optionally substituted
azabicyclo[2.2.2]octyl, optionally substituted
azabicyclo[3.2.1]octyl, and optionally substituted
2,5-diazabicyclo[2.2.1]heptyl.
When R.sup.2 is a bridged azacycloalkyl or diazacycloalkyl, it can
be substituted as described above with reference to the azetidinyl,
pyrrolidinyl, piperidinyl and azepanyl R.sup.2 moieties. For
example, a bridged azacycloalkyl or diazacycloalkyl R.sup.2 moiety
can be substituted (e.g., at a nitrogen) with --(C.sub.0-C.sub.3
alkyl)-Ar, --(C.sub.0-C.sub.3 alkyl)-Het, -L-Ar, -L-Het,
--C(O)--O(C.sub.0-C.sub.6 alkyl), --C(O)-Het, --C(O)--Ar,
--S(O).sub.2-Het, --S(O).sub.2--Ar or
--S(O).sub.2--O(C.sub.0-C.sub.6 alkyl), as described above.
In certain embodiments of the compounds of any of structural
formulae (I)-(XLIII), R.sup.2 is -Cak-N(R.sup.9)-G-R.sup.22, as
described above. For example, in one embodiment of the disclosed
compounds, R.sup.2 has the structure
##STR00064## in which c is 0, 1, 2, 3 or 4, and each R.sup.21 is
independently selected from --(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6 alkyl)-Ar,
--(C.sub.0-C.sub.6 alkyl)-Het, --(C.sub.0-C.sub.6 alkyl)-Cak,
--(C.sub.0-C.sub.6 alkyl)-Hca, --(C.sub.0-C.sub.6 alkyl)-L-R.sup.7,
--(C.sub.0-C.sub.6 alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6
alkyl)-OR.sup.10, --(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10,
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2R.sup.10, -halogen,
--NO.sub.2 and --CN, and two R.sup.21 on the same carbon optionally
combine to form oxo. In certain embodiments of the presently
disclosed compounds, each R.sup.21 is independently selected from
--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl) (e.g.,
difluoromethyl, trifluoromethyl and the like), --(C.sub.0-C.sub.6
alkyl)-L-R.sup.7, --(C.sub.0-C.sub.6 alkyl)-NR.sup.8R.sup.9,
--(C.sub.0-C.sub.6 alkyl)-OR.sup.10, --(C.sub.0-C.sub.6
alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN and two
R.sup.21 on the same carbon optionally combine to form oxo, in
which each R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alkyl)-L-(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-O--(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl) and
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl),
and in which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For
example, in one embodiment, each R.sup.21 is --(C.sub.1-C.sub.3
alkyl), --(C.sub.1-C.sub.3 haloalkyl), --(C.sub.0-C.sub.3
alkyl)-L-R.sup.7, --(C.sub.0-C.sub.3 alkyl)-NR.sup.8R.sup.9,
--(C.sub.0-C.sub.3 alkyl)-OR.sup.10, --(C.sub.0-C.sub.3
alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.3
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN and two
R.sup.21 on the same carbon optionally combine to form oxo, in
which each R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.2 alkyl), --(C.sub.1-C.sub.2 haloalkyl),
--(C.sub.0-C.sub.2 alkyl)-L-(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-NR.sup.9(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-O--(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-C(O)--(C.sub.0-C.sub.2 alkyl) and
--(C.sub.0-C.sub.2 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.2 alkyl),
and in which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In
certain embodiments, c is 1 or 2. In other embodiments, c is 0. In
certain embodiments, R.sup.9 is H. In certain embodiments, G is a
single bond. In certain embodiments of the presently disclosed
compounds, R.sup.22 is not substituted with an aryl-, heteroaryl-,
cycloalkyl- or heterocycloalkyl-containing group. In certain
embodiments of the presently disclosed compounds, R.sup.23 is not
substituted with an aryl-, heteroaryl-, cycloalkyl- or
heterocycloalkyl-containing group.
In one embodiment of compounds of any of structural formulae
(I)-(XLIII), R.sup.2 has the structure
##STR00065##
In certain embodiments of the compounds of any of structural
formulae (I)-(XLIII), R.sup.2 is --(C.sub.2-C.sub.8
alkyl)-N(R.sup.9)--R.sup.24 in which one or two carbons of the
(C.sub.2-C.sub.8 alkyl) are optionally replaced by --O-- or
--N(R.sup.9)-- and R.sup.24 is --R.sup.23, -GR.sup.23 or
--C(O)O--(C.sub.1-C.sub.6 alkyl). In certain embodiments, the
(C.sub.2-C.sub.8 alkyl) is unsubstituted and no carbon is replaced
by --O-- or --N(R.sup.9)--. For example, in one embodiment, R.sup.2
is --CH.sub.2--CH.sub.2--CH.sub.2--N(R.sup.9)--R.sup.24 or
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--N(R.sup.9)--R.sup.24. In
other embodiments, the (C.sub.2-C.sub.8 alkyl) is substituted
and/or one or two carbons are replaced by --O-- or --N(R.sup.9)--.
For example, in one embodiment, R.sup.2 is
--CH.sub.2--CH.sub.2--O--CH.sub.2--CH.sub.2--N(R.sup.9)--R.sup.24;
--CH.sub.2--CH(CH.sub.3)--N(R.sup.9)--R.sup.24; or
--CH.sub.2--CH.sub.2--O--CH.sub.2--C(O)--N(R.sup.9)--R.sup.24. In
certain embodiments, R.sup.9 is H. In certain embodiments, R.sup.24
is Ar or Het. In certain embodiments, R.sup.24 is not substituted
with an aryl-, heteroaryl-, cycloalkyl- or
heterocycloalkyl-containing group. In certain embodiments, the
(C.sub.2-C.sub.8 alkyl) is a (C.sub.2-C.sub.5 alkyl).
In certain embodiments (e.g., when rings system "B" is
##STR00066## when R.sup.2 is an azabicycloalkyl moiety (e.g., a
1-azabicycloheptyl, a 1-azabicyclooctyl, a 1-azabicyclononyl or a
1-azabicyclodecyl), R.sup.2 is not vicinally substituted (i.e., at
the position next to the amide nitrogen) with
--(C.sub.0-C.sub.4)-Het.
In certain embodiments (e.g., when rings system "B" is
##STR00067## R.sup.2 is not a benzo-, pyrido-, pyrimido-, pyrazino-
or pyridazino-fused azacycloalkyl. In other embodiments, R.sup.2 is
not 7-azabicyclo[2.2.1]hept-2-yl. In other embodiments, R.sup.2 is
not a quinuclidin-3-yl moiety.
In certain embodiments (e.g., when "B" represents
##STR00068## R.sup.2 is not a 4,5-dihydroisoxazol-4-yl moiety or an
optionally substituted optionally ring-fused azetidin-2-on-3-yl
moiety. In one embodiment, R.sup.2 is not an oxo-substituted
heterocycloalkyl.
In certain embodiments of the presently disclosed compounds,
R.sup.1 and R.sup.2 together with the nitrogen to which they are
attached (i.e., the carboxamide nitrogen) come together to form
Hca. R.sup.1, R.sup.2 and the nitrogen can come together to form,
for example, an optionally-substituted monocyclic azacycloalkyl or
monocyclic diazacycloalkyl, such as a piperidine, a pyrrolidine, a
piperazine or an imidazolidine. In other embodiments, R.sup.1 and
R.sup.2 come together to form an optionally-substituted bridged
azacycloalkyl or diazacycloalkyl, for example, a bridged
azabicyclohexyl, a bridged azabicycloheptyl, a bridged
azabicyclooctyl, a bridged diazabicyclohexyl, a bridged
diazabicycloheptyl or a bridged diazabicyclooctyl. Particular
examples of such R.sup.2 moieties include azabicyclo[2.2.2]octyl,
azabicyclo[3.2.1]octyl, and 2,5-diazabicyclo[2.2.1]heptyl.
When R.sup.1, R.sup.2 and the nitrogen come together to form Hca,
the Hca can be substituted as described above with reference to the
azetidinyl, pyrrolidinyl, piperidinyl and azepanyl R.sup.2
moieties. For example, the heterocycloalkyl can be substituted with
--(C.sub.0-C.sub.3 alkyl)-Ar, --(C.sub.0-C.sub.3 alkyl)-Het, -L-Ar,
-L-Het, --C(O)--O(C.sub.0-C.sub.6 alkyl), --C(O)-Het, --C(O)--Ar,
--S(O).sub.2-Het, --S(O).sub.2--Ar or
--S(O).sub.2--O(C.sub.0-C.sub.6 alkyl), as described above. When
R.sup.1 and R.sup.2 come together to form a diazacycloalkyl, it can
be substituted at a nitrogen atom.
For example, in certain embodiments, the --C(O)--NR.sup.1R.sup.2
moiety is
##STR00069## in which f is 0 or 1; g is 0, 1 or 2; c is 0, 1, 2, 3
or 4; R.sup.28 is Ar or Het; E.sup.3 is NH, N substituted by one of
the c R.sup.21, N substituted by the -G-R.sup.28, CH.sub.2, CH
substituted by one of the c R.sup.21, CH substituted by the
-G-R.sup.28, or C substituted by one of the c R.sup.21 and the
-G-R.sup.28; and E.sup.4 is absent, NH, N substituted by one of the
c R.sup.21, N substituted by the -G-R.sup.28, CH.sub.2, CH
substituted by one of the c R.sup.21, CH substituted by the
-G-R.sup.28, or C substituted by one of the c R.sup.21 and the
-G-R.sup.28, provided that both of E.sup.3 and E.sup.4 are not N.
When g is 0, R.sup.1, R.sup.2 and the nitrogen come together to
form a monocyclic azacycloalkyl or diazacycloalkyl. In other
embodiments, when g is 1 or 2, R.sup.1, R.sup.2 and the nitrogen
come together to form a bridged bicyclic azacycloalkyl or
diazacycloalkyl. The c R.sup.21 moieties can be disposed anywhere
on the azacycloalkyl or diazacycloalkyl ring system. Each R.sup.21
is independently selected from --(C.sub.1-C.sub.6 alkyl),
--(C.sub.1-C.sub.6 haloalkyl), --(C.sub.0-C.sub.6 alkyl)-Ar,
--(C.sub.0-C.sub.6 alkyl)-Het, --(C.sub.0-C.sub.6 alkyl)-Cak,
--(C.sub.0-C.sub.6 alkyl)-Hca, --(C.sub.0-C.sub.6 alkyl)-L-R.sup.7,
--(C.sub.0-C.sub.6 alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6
alkyl)-OR.sup.10, --(C.sub.1-C.sub.6 alkyl)-C(O)R.sup.10,
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2R.sup.10, -halogen,
--NO.sub.2 and --CN, and two R.sup.21 on the same carbon optionally
combine to form oxo. In certain embodiments of the presently
disclosed compounds, each R.sup.21 is independently selected from
--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl) (e.g.,
difluoromethyl, trifluoromethyl and the like), --(C.sub.0-C.sub.6
alkyl)-L-R.sup.7, --(C.sub.0-C.sub.6 alkyl)-NR.sup.8R.sup.9,
--(C.sub.0-C.sub.6 alkyl)-OR.sup.10, --(C.sub.0-C.sub.6
alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN and two
R.sup.21 on the same carbon optionally combine to form oxo, in
which each R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alkyl)-L-(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-O--(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl) and
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl),
and in which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For
example, in one embodiment, each R.sup.21 is --(C.sub.1-C.sub.3
alkyl), --(C.sub.1-C.sub.3 haloalkyl), --(C.sub.0-C.sub.3
alkyl)-L-R.sup.7, --(C.sub.0-C.sub.3 alkyl)-NR.sup.8R.sup.9,
--(C.sub.0-C.sub.3 alkyl)-OR.sup.10, --(C.sub.0-C.sub.3
alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.3
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN and two
R.sup.21 on the same carbon optionally combine to form oxo, in
which each R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.2 alkyl), --(C.sub.1-C.sub.2 haloalkyl),
--(C.sub.0-C.sub.2 alkyl)-L-(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-NR.sup.9(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-O--(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-C(O)--(C.sub.0-C.sub.2 alkyl) and
--(C.sub.0-C.sub.2 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.2 alkyl),
and in which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In
certain embodiments, c is 1 or 2. In other embodiments, c is 0. In
certain embodiments, G is a single bond, CH.sub.2, or C(O). In
certain embodiments of the presently disclosed compounds, R.sup.28
is not substituted with an aryl-, heteroaryl-, cycloalkyl- or
heterocycloalkyl-containing group. In one embodiment, R.sup.28 is
monocyclic aryl or heteroaryl substituted with 0-3 substitutents
selected from halo, cyano, --(C.sub.1-C.sub.4 haloalkyl),
--O--(C.sub.1-C.sub.4 haloalkyl), --(C.sub.1-C.sub.4 alkyl),
--O--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl),
--C(O)O--(C.sub.0-C.sub.4 alkyl), --C(O)N(C.sub.0-C.sub.4
alkyl)(C.sub.0-C.sub.4 alkyl) and NO.sub.2, in which each alkyl is
not further substituted. The -G-R.sup.28 moiety, when present, can
in some embodiments be as described below for -G-R.sup.17.
For example, in certain embodiments, the --C(O)--NR.sup.1R.sup.2
moiety is
##STR00070##
In the compounds of any of structural formulae (I)-(XLIII), the
number of substituents on ring system "B", w, is 0, 1, 2 or 3. For
example, in one embodiment, w is 0, 1 or 2. In another embodiment,
w is 0. In other embodiments, w is at least 1, and at least one
R.sup.3 is selected from the group consisting of halo, cyano,
--(C.sub.1-C.sub.4 fluoroalkyl), --O--(C.sub.1-C.sub.4
fluoroalkyl), --C(O)--(C.sub.0-C.sub.4 alkyl),
--C(O)O--(C.sub.0-C.sub.4 alkyl), --C(O)N(C.sub.0-C.sub.4
alkyl)(C.sub.0-C.sub.4 alkyl), --S(O).sub.2O--(C.sub.0-C.sub.4
alkyl), 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. For
example, in certain embodiments, at least one R.sup.3 is halo
(e.g., chloro) or --(C.sub.1-C.sub.4 alkyl) (e.g., methyl, ethyl or
propyl). In certain embodiments, an R.sup.3 is substituted on the
"B" ring system at a 6-membered aromatic ring position in the meta
position relative to the J moiety.
In certain embodiments of the compounds of any of structural
formulae (I)-(XLIII), each R.sup.3 is independently selected from
--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl) (e.g.,
difluoromethyl, trifluoromethyl and the like), --(C.sub.0-C.sub.6
alkyl)-L-R.sup.7, --(C.sub.0-C.sub.6 alkyl)-NR.sup.8R.sup.9,
--(C.sub.0-C.sub.6 alkyl)-OR.sup.10, --(C.sub.0-C.sub.6
alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN, in
which each R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alkyl)-L-(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-O--(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl), and
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl),
and in which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For
example, in one embodiment, each R.sup.3 is --(C.sub.1-C.sub.3
alkyl), --(C.sub.1-C.sub.3 haloalkyl), --(C.sub.0-C.sub.3
alkyl)-L-R.sup.7, --(C.sub.0-C.sub.3 alkyl)-NR.sup.8R.sup.9,
--(C.sub.0-C.sub.3 alkyl)-OR.sup.10, --(C.sub.0-C.sub.3
alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.3
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN, in
which each R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.2 alkyl), --(C.sub.1-C.sub.2 haloalkyl),
--(C.sub.0-C.sub.2 alkyl)-L-(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-NR.sup.9(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-O--(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-C(O)--(C.sub.0-C.sub.2 alkyl) and
--(C.sub.0-C.sub.2 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.2 alkyl),
and in which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For
example, in certain embodiments, each R.sup.3 is halo (e.g.,
chloro) or --(C.sub.1-C.sub.4 alkyl) (e.g., methyl, ethyl or
propyl).
In certain embodiments of the compounds of any of structural
formulae (I)-(XLIII), w is at least one, and at least one R.sup.3
is --NR.sup.8R.sup.9. For example, in one embodiment, w is 1. In
certain such embodiments, R.sup.3 is substituted on the "B" ring
system at a 6-membered aromatic ring position in the meta position
relative to the J moiety.
In other embodiments of the compounds of any of structural formulae
(I)-(XLIII), w is at least one, and at least one R.sup.3 is
--(C.sub.0-C.sub.3 alkyl)-Y.sup.1--(C.sub.1-C.sub.3
alkyl)-Y.sup.2--(C.sub.0-C.sub.3 alkyl), in which each of Y.sup.1
and Y.sup.2 is independently L, --O--, --S-- or --NR.sup.9--. For
example, in one embodiment, w is 1. In certain such embodiments,
R.sup.3 is substituted on the "B" ring system at a 6-membered
aromatic ring position in the meta position relative to the J
moiety. In one particular embodiment, R.sup.3 is
--CH.sub.2--N(CH.sub.3)--CH.sub.2--C(O)--OCH.sub.3.
In certain embodiments in which ring system "B" is
##STR00071## the imidazo portion of the central
imidazo[1,2-a]pyridine ring system has no substitutions other than
the carboxamide substitution. In another embodiment, no R.sup.3 at
the 2-position of the imidazo[1,2-a]pyridine core is --(C.sub.1
alkyl)-N(R.sup.8)-(5,6,7,8-tetrahydroquinolin-8-yl); --(C.sub.1
alkyl)-N(R.sup.8)-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl);
--(C.sub.1
alkyl)-N(R.sup.8)-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl);
--(C.sub.1 alkyl)-N(R.sup.8)-(2,3-dihydrofuro[3,2-b]pyridin-3-yl);
--(C.sub.1
alkyl)-N(R.sup.8)-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl); or
--(C.sub.1
alkyl)-N(R.sup.8)-(6,7,8,9-tetrahydrooxepino[3,2-b]pyridin-9-yl).
In another embodiment, the compound does not have two R.sup.3
moieties that include Ar or Het as part of each of the moieties'
structure. In another embodiment, no R.sup.3 at the 3-position of
the imidazo[1,2-a]pyridine core is Het.
In certain embodiments in which ring system "B" is
##STR00072## the compound does not have two R.sup.3 moieties that
include Ar or Het in the moieties' structure. In another
embodiment, when an R.sup.3 is --NR.sup.9--(C.sub.0-C.sub.6
alkyl)-Ar, --NR.sup.9--(C.sub.0-C.sub.6 alkyl)-Het,
--NR.sup.9--Hca, --O--(C.sub.0-C.sub.6 alkyl)-Ar or
--O--(C.sub.0-C.sub.6 alkyl)-Het, it is not substituted on the
pyrazine core at a position ortho to (i.e., on the carbon adjacent
to) the amide. In another embodiment, when an R.sup.3 is --Ar or
-Het, it is substituted on the pyrazine core at a position para to
(i.e., directly across the ring from) the amide.
In certain embodiments in which ring system "B" is
##STR00073## when R.sup.3 is (C.sub.0-C.sub.4
alkyl)-O--(C.sub.0-C.sub.4 alkyl)-(optionally-substituted phenyl);
(C.sub.0-C.sub.4 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.4
alkyl)-(optionally-substituted phenyl) or (C.sub.0-C.sub.4
alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.4
alkyl)-O-(optionally-substituted phenyl), it is not at the 2
position of the thiazole core (i.e., not on the carbon between the
N and the S of the thiazole). In one embodiment, the compound does
not have two R.sup.3 moieties that include Ar or Het in the
moieties' structure.
In the presently disclosed compounds of any of structural formulae
(I)-(XLIII), the number of substituents on ring system "C", x, is 0
or an integer less than or equal to the sum of p and q. when D or Z
is CR.sup.4, the R.sup.4 of D or Z is one of the x R.sup.4 groups
on ring system "C". In one embodiment, x is 0, 1, 2 or 3. For
example, x can be 0, or can be 1 or 2.
In certain embodiments of the presently disclosed compounds of any
of structural formula (I)-(XLIII), two R.sup.4 groups combine to
form an oxo. The oxo can be bound, for example, at the position
alpha to a nitrogen of ring system "C". In other embodiments, no
two R.sup.4 groups combine to form an oxo.
In certain embodiments of the presently disclosed compounds of any
of structural formulae (I)-(XLIII), when x is 4, not all four
R.sup.4 groups are (C.sub.1-C.sub.6 alkyl).
In certain embodiments of the presently disclosed compounds of any
of structural formulae (I)-(XLIII), each R.sup.4 is independently
selected from --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like),
--(C.sub.0-C.sub.6 alkyl)-L-R.sup.7, --(C.sub.0-C.sub.6
alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6 alkyl)-OR.sup.10,
--(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN, in
which each R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alkyl)-L-(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-O--(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl) and
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl),
and in which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For
example, in one embodiment, each R.sup.4 is --(C.sub.1-C.sub.3
alkyl), --(C.sub.1-C.sub.3 haloalkyl), --(C.sub.0-C.sub.3
alkyl)-L-R.sup.7, --(C.sub.0-C.sub.3 alkyl)-NR.sup.8R.sup.9,
--(C.sub.0-C.sub.3 alkyl)-OR.sup.10, --(C.sub.0-C.sub.3
alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.3
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN, in
which each R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.2 alkyl), --(C.sub.1-C.sub.2 haloalkyl),
--(C.sub.0-C.sub.2 alkyl)-L-(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-NR.sup.9(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-O--(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-C(O)--(C.sub.0-C.sub.2 alkyl) and
--(C.sub.0-C.sub.2 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.2 alkyl),
and in which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group.
In certain embodiments, the presently disclosed compounds have the
structural formula (XLIV):
##STR00074## in which Q and G are each independently a bond,
--CH.sub.2--, --C(H)(R.sup.16)--, --C(R.sup.16).sub.2--, L (e.g.,
--C(O)--NR.sup.9-- or --NR.sup.9--C(O)--) or --S(O).sub.2--; V is
0, 1, 2, 3 or 4; each R.sup.15 is independently selected from
--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alkyl)-Ar, --(C.sub.0-C.sub.6 alkyl)-Het,
--(C.sub.0-C.sub.6 alkyl)-Cak, --(C.sub.0-C.sub.6 alkyl)-Hca,
--(C.sub.0-C.sub.6 alkyl)-L-R.sup.7, --(C.sub.0-C.sub.6
alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6 alkyl)-OR.sup.10,
--(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN, and two
R.sup.15 on the same carbon optionally combine to form oxo;
R.sup.17 is Het or Ar, and all other variables are defined as
described above with reference to any of structural formula
(I)-(XLIII). In one embodiment, Q is a single bond. In another
embodiment, Q is --CH.sub.2--. In other embodiments, Q is --C(O)--
or --S(O).sub.2--. In certain embodiments, G is --CH.sub.2--. In
other embodiments, G is --C(O)-- or --S(O).sub.2--. In other
embodiments, G is --CH(CH.sub.3)--. In other embodiments, G is
--C(O)--NH--. The above-recited Q and G moieties can be combined in
any possible combination. For example, in one embodiment, Q is a
single bond and G is --CH.sub.2-- or --C(O)--. As described above,
in certain embodiments, the ring system denoted by "A" is aryl or
heteroaryl. In one embodiment, the ring system denoted by "A" is
substituted with one or more electron-withdrawing groups as
described above. In another embodiment, R.sup.17 is substituted
with one or more electron-withdrawing groups as described above. In
certain embodiments, the ring system denoted by "A", R.sup.17 or
both are not substituted with an aryl, heteroaryl, cycloalkyl or
heterocycloalkyl-containing group. In certain embodiments, the
azacycloalkyl to which -G-R.sup.17 is bound is a piperidinyl; in
other embodiments, it is a pyrrolidinyl.
In the presently disclosed compounds of structural formula (XLIV),
v is 0, 1, 2, 3 or 4. In one embodiment, v is 0, 1, 2 or 3. For
example, v can be 0, or can be 1 or 2.
In certain embodiments of the presently disclosed compounds of
structural formula (XLIV), two R.sup.15 groups combine to form an
oxo. The oxo can be bound, for example, at the position alpha
relative to the nitrogen of the azacycloalkyl ring. In other
embodiments, no two R.sup.15 groups combine to form an oxo.
In certain embodiments of the presently disclosed compounds of
structural formula (XLIV), when v is 4, not all four R.sup.15
moieties are (C.sub.1-C.sub.6 alkyl).
In certain embodiments of the presently disclosed compounds of
structural formula (XLIV), each R.sup.15 is independently selected
from --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl)
(e.g., difluoromethyl, trifluoromethyl and the like),
--(C.sub.0-C.sub.6 alkyl)-L-R.sup.7, --(C.sub.0-C.sub.6
alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.6 alkyl)-OR.sup.10,
--(C.sub.0-C.sub.6 alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN and two
R.sup.15 on the same carbon optionally combine to form oxo, in
which each R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alkyl)-L-(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-O--(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl) and
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl),
and in which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For
example, in one embodiment, each R.sup.15 is --(C.sub.1-C.sub.3
alkyl), --(C.sub.1-C.sub.3 haloalkyl), --(C.sub.0-C.sub.3
alkyl)-L-R.sup.7, --(C.sub.0-C.sub.3 alkyl)-NR.sup.8R.sup.9,
--(C.sub.0-C.sub.3 alkyl)-OR.sup.10, --(C.sub.0-C.sub.3
alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.3
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN and two
R.sup.15 on the same carbon optionally combine to form oxo, in
which each R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.2 alkyl), --(C.sub.1-C.sub.2 haloalkyl),
--(C.sub.0-C.sub.2 alkyl)-L-(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-NR.sup.9(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-O--(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-C(O)--(C.sub.0-C.sub.2 alkyl) and
--(C.sub.0-C.sub.2 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.2 alkyl),
and in which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In
some embodiments, one R.sup.15 is --C(O)NR.sup.9R.sup.7, which can
be bound, for example, at a position alpha relative to the
piperidine nitrogen, or at the position linked to the
--N(R.sup.1)--.
In certain embodiments of the presently disclosed compounds of
structural formula (XLIV), R.sup.17 is an unsubstituted aryl or
heteroaryl. In other embodiments, the R.sup.17 Ar or Het is
substituted with 1, 2 or 3 substituents independently selected from
--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl) (e.g.,
difluoromethyl, trifluoromethyl and the like), --(C.sub.0-C.sub.6
alkyl)-L-R.sup.7, --(C.sub.0-C.sub.6 alkyl)-NR.sup.8R.sup.9,
--(C.sub.0-C.sub.6 alkyl)-OR.sup.10, --(C.sub.0-C.sub.6
alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN, in
which each R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl),
--(C.sub.0-C.sub.6 alkyl)-L-(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-O--(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl) and
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl),
and in which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For
example, in one embodiment, the R.sup.17 Ar or Het is substituted
with 1, 2 or 3 substituents independently selected from
--(C.sub.1-C.sub.3 alkyl), --(C.sub.1-C.sub.3 haloalkyl),
--(C.sub.0-C.sub.3 alkyl)-L-R.sup.7, --(C.sub.0-C.sub.3
alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.3 alkyl)-OR.sup.10,
--(C.sub.0-C.sub.3 alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.3
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN, in
which each R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.2 alkyl), --(C.sub.1-C.sub.2 haloalkyl),
--(C.sub.0-C.sub.2 alkyl)-L-(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-NR.sup.9(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-O--(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-C(O)--(C.sub.0-C.sub.2 alkyl) and
--(C.sub.0-C.sub.2 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.2 alkyl),
and in which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In
certain embodiments, R.sup.17 is substituted with 1, 2 or 3
substituents selected from halo, cyano, --(C.sub.1-C.sub.4
haloalkyl), --O--(C.sub.1-C.sub.4 haloalkyl), --(C.sub.1-C.sub.4
alkyl), --O--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.0-C.sub.4
alkyl), --C(O)O--(C.sub.0-C.sub.4 alkyl), --C(O)N(C.sub.0-C.sub.4
alkyl)(C.sub.0-C.sub.4 alkyl), NO.sub.2 and --C(O)--Hca. R.sup.17
can be substituted with, for example, one such substituent, or two
such substituents.
For example, in certain embodiments, the presently disclosed
compounds have the structural formula (XLV):
##STR00075## in which all variables are as defined above with
reference to any of structural formulae (I)-(XLIV).
In other embodiments, the presently disclosed compounds have
structural formula (XLVI):
##STR00076## in which all variables are as defined above with
reference to any of structural formulae (I)-(XLIV).
In certain embodiments, the presently disclosed compounds have the
structural formula (XLVII):
##STR00077## in which R.sup.27 is selected from H,
--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl) (e.g.,
difluoromethyl, trifluoromethyl and the like), --(C.sub.0-C.sub.6
alkyl)-L-(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-O--(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl)-(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl), in which no
heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and
R.sup.29 is --H, --(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.4 alkyl) or --C(O)--O--(C.sub.1-C.sub.4
alkyl) in which no (C.sub.1-C.sub.4 alkyl) is substituted by an
aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group,
or R.sup.27 and R.sup.29 together with the nitrogen to which they
are bound form Hca, and all other variables are as described above
with reference to any of structural formulae (I)-(XLVI). In one
embodiment, R.sup.27 and R.sup.29 are both H.
In certain embodiments, the presently disclosed compounds have the
structural formula (XLVIII):
##STR00078## in which R.sup.27 is selected from H,
--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl) (e.g.,
difluoromethyl, trifluoromethyl and the like), --(C.sub.0-C.sub.6
alkyl)-L-(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-O--(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl)-(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl), in which no
heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and
R.sup.29 is --H, --(C.sub.1-C.sub.4 alkyl), --C(O)--
(C.sub.1-C.sub.4 alkyl) or --C(O)--O--(C.sub.1-C.sub.4 alkyl) in
which no (C.sub.1-C.sub.4 alkyl) is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or
R.sup.27 and R.sup.29 together with the nitrogen to which they are
bound form Hca, and all other variables are as described above with
reference to any of structural formulae (I)-(XLVI). In one
embodiment, R.sup.27 and R.sup.29 are both H.
In certain embodiments, the presently disclosed compounds have the
structural formula (XLIX):
##STR00079## in which R.sup.27 is selected from H,
--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl) (e.g.,
difluoromethyl, trifluoromethyl and the like), --(C.sub.0-C.sub.6
alkyl)-L-(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-O--(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl)-(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl), in which no
heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and
R.sup.29 is --H, --(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.4 alkyl) or --C(O)--O--(C.sub.1-C.sub.4
alkyl) in which no (C.sub.1-C.sub.4 alkyl) is substituted by an
aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group,
or R.sup.27 and R.sup.29 together with the nitrogen to which they
are bound form Hca, and all other variables are as described above
with reference to any of structural formulae (I)-(XLVI). In one
embodiment, R.sup.27 and R.sup.29 are both H.
In certain embodiments, the presently disclosed compounds have the
structural formula (L):
##STR00080## in which R.sup.27 is selected from H,
--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl) (e.g.,
difluoromethyl, trifluoromethyl and the like), --(C.sub.0-C.sub.6
alkyl)-L-(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-O--(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl)-(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl), in which no
heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and
R.sup.29 is --H, --(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.4 alkyl) or --C(O)--O--(C.sub.1-C.sub.4
alkyl) in which no (C.sub.1-C.sub.4 alkyl) is substituted by an
aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group,
or R.sup.27 and R.sup.29 together with the nitrogen to which they
are bound form Hca, and all other variables are as described above
with reference to any of structural formulae (I)-(XLVI). In one
embodiment, R.sup.27 and R.sup.29 are both H.
In certain embodiments, the presently disclosed compounds have the
structural formula (LI):
##STR00081## in which all variables are as described above with
reference to any of structural formulae (I)-(XLVI).
In certain embodiments, the presently disclosed compounds have the
structural formula (LII):
##STR00082## in which R.sup.25 is selected from halo, cyano,
--(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4 haloalkyl),
--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4 alkyl),
--C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl), NO.sub.2 and
--C(O)--Hca in which the Hca contains a ring nitrogen atom through
which it is bound to the --C(O)--, in which no alkyl or haloalkyl
is substituted by an aryl, heteroaryl, cycloalkyl or
heterocycloalkyl-containing group; and all other variables are as
described above with reference to any of structural formulae
(I)-(XLVI). R.sup.25 can be, for example, --Cl, --F, cyano,
--C(O)CH.sub.3, --C(O)OH, --C(O)NH.sub.2, trifluoromethyl,
difluoromethyl, difluoromethoxy or trifluoromethoxy.
In certain embodiments, the presently disclosed compounds have the
structural formula (LIII):
##STR00083## in which G is --C(O)--, --S(O).sub.2-- or --C(O)--NH--
and all other variables are as described above with reference to
any of structural formulae (I)-(XLVI).
In certain embodiments, the presently disclosed compounds have the
structural formula (LIV):
##STR00084## in which R.sup.27 is selected from H,
--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl) (e.g.,
difluoromethyl, trifluoromethyl and the like), --(C.sub.0-C.sub.6
alkyl)-L-(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-O--(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl)-(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl), in which no
heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and
R.sup.29 is --H, --(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.4 alkyl) or --C(O)--O--(C.sub.1-C.sub.4
alkyl) in which no (C.sub.1-C.sub.4 alkyl) is substituted by an
aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group,
or R.sup.27 and R.sup.29 together with the nitrogen to which they
are bound form Hca, and all other variables are as described above
with reference to any of structural formulae (I)-(XLVI). In one
embodiment, R.sup.27 and R.sup.29 are both H. In some embodiments,
the compounds of structural formula (LIV) are present as racemic
mixtures or scalemic mixtures. In other embodiments, the compounds
of structural formula (LIV) are present in an
enantiomerically-enriched form, for example as a substantially pure
stereoisomer.
In certain embodiments, the presently disclosed compounds have the
structural formula (LV):
##STR00085## in which R.sup.27 is selected from H,
--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl) (e.g.,
difluoromethyl, trifluoromethyl and the like), --(C.sub.0-C.sub.6
alkyl)-L-(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-O--(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl)-(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl), in which no
heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and
R.sup.29 is --H, --(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.4 alkyl) or --C(O)--O--(C.sub.1-C.sub.4
alkyl) in which no (C.sub.1-C.sub.4 alkyl) is substituted by an
aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group,
or R.sup.27 and R.sup.29 together with the nitrogen to which they
are bound form Hca, and all other variables are as described above
with reference to any of structural formulae (I)-(XLVI). In one
embodiment, R.sup.27 and R.sup.29 are both H. In some embodiments,
the compounds of structural formula (LV) are present as racemic
mixtures or scalemic mixtures. In other embodiments, the compounds
of structural formula (LV) are present in an
enantiomerically-enriched form, for example as a substantially pure
stereoisomer.
In certain embodiments, the presently disclosed compounds have the
structural formula (LVI):
##STR00086## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XVIII). R.sup.5, y, v,
R.sup.15, R.sup.17, Q, G and the ring denoted by "A" can be
defined, for example, as described with reference to any of
structural formulae (XLVII)-(LV).
In certain embodiments, the presently disclosed compounds have the
structural formula (LVII):
##STR00087## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XIX). R.sup.5, y, v, R.sup.15,
R.sup.17, Q, G and the ring denoted by "A" can be defined, for
example, as described with reference to any of structural formulae
(XLVII)-(LV).
In certain embodiments, the presently disclosed compounds have the
structural formula (LVIII):
##STR00088## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XX). R.sup.5, y, v, R.sup.15,
R.sup.17, Q, G and the ring denoted by "A" can be defined, for
example, as described with reference to any of structural formulae
(XLVII)-(LV).
In certain embodiments, the presently disclosed compounds have the
structural formula (LIX):
##STR00089## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XXI). R.sup.5, y, v, R.sup.15,
R.sup.17, Q, G and the ring denoted by "A" can be defined, for
example, as described with reference to any of structural formulae
(XLVII)-(LV).
In certain embodiments, the presently disclosed compounds have the
structural formula (LX):
##STR00090## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLVII), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XXII). R.sup.5, y, v,
R.sup.15, R.sup.17, Q, G and the ring denoted by "A" can be
defined, for example, as described with reference to any of
structural formulae (XLVIII)-(LV).
In certain embodiments, the presently disclosed compounds have the
structural formula (LXI):
##STR00091## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XXIII). R.sup.5, y, v,
R.sup.15, R.sup.17, Q, G and the ring denoted by "A" can be
defined, for example, as described with reference to any of
structural formulae (XLVII)-(LV).
In certain embodiments, the presently disclosed compounds have the
structural formula (LXII):
##STR00092## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XXIV). R.sup.5, y, v,
R.sup.15, R.sup.17, Q, G and the ring denoted by "A" can be
defined, for example, as described with reference to any of
structural formulae (XLVII)-(LV).
In certain embodiments, the presently disclosed compounds have the
structural formula (LXIII):
##STR00093## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XXV). R.sup.5, y, v, R.sup.15,
R.sup.17, Q, G and the ring denoted by "A" can be defined, for
example, as described with reference to any of structural formulae
(XLVII)-(LV).
In certain embodiments, the presently disclosed compounds have the
structural formula (LXIV):
##STR00094## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XXVI). R.sup.5, y, v,
R.sup.15, R.sup.17, Q, G and the ring denoted by "A" can be
defined, for example, as described with reference to any of
structural formulae (XLVII)-(LV).
In certain embodiments, the presently disclosed compounds have the
structural formula (LXV):
##STR00095## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XXVII). R.sup.5, y, v,
R.sup.15, R.sup.17, Q, G and the ring denoted by "A" can be
defined, for example, as described with reference to any of
structural formulae (XLVII)-(LV).
In certain embodiments, the presently disclosed compounds have the
structural formula (LXVI):
##STR00096## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XXVIII). R.sup.5, y, v,
R.sup.15, R.sup.17, Q, G and the ring denoted by "A" can be
defined, for example, as described with reference to any of
structural formulae (XLVII)-(LV). In one embodiment, E.sup.1 is
carbon and E.sup.2 is N. In another embodiment, E.sup.1 is N and
E.sup.2 is carbon.
In certain embodiments, the presently disclosed compounds have the
structural formula (LXVII):
##STR00097## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) or (XXIX). R.sup.5, y, v, R.sup.15,
R.sup.17, Q, G and the ring denoted by "A" can be defined, for
example, as described with reference to any of structural formulae
(XLVII)-(LV). When w is 0, the ring position shown occupied by
R.sup.3 bears a hydrogen atom.
In certain embodiments, the presently disclosed compounds have the
structural formula (LXVIII):
##STR00098## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XXX). R.sup.5, y, v, R.sup.15,
R.sup.17, Q, G and the ring denoted by "A" can be defined, for
example, as described with reference to any of structural formulae
(XLVII)-(LV). When w is 0, the ring position shown occupied by
R.sup.3 bears a hydrogen atom.
In certain embodiments, the presently disclosed compounds have the
structural formula (LXIX):
##STR00099## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XXXIV). R.sup.5, y, v,
R.sup.15, R.sup.17, Q, G and the ring denoted by "A" can be
defined, for example, as described with reference to any of
structural formulae (XLVII)-(LV). In certain embodiments, Z is N.
In other embodiments, Z is CH or C substituted with one of the x
R.sup.4.
In certain embodiments, the presently disclosed compounds have the
structural formula (LXX):
##STR00100## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XXXV). R.sup.5, y, v,
R.sup.15, R.sup.17, Q, G and the ring denoted by "A" can be
defined, for example, as described with reference to any of
structural formulae (XLVII)-(LV).
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXI):
##STR00101## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XXXVI). R.sup.5, y, v,
R.sup.15, R.sup.17, Q, G and the ring denoted by "A" can be
defined, for example, as described with reference to any of
structural formulae (XLVII)-(LV). In certain embodiments, Z is N.
In other embodiments, Z is CH or C substituted with one of the x
R.sup.4.
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXII):
##STR00102## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XXXVII). R.sup.5, y, v,
R.sup.15, R.sup.17, Q, G and the ring denoted by "A" can be
defined, for example, as described with reference to any of
structural formulae (XLVII)-(LV).
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXIII):
##STR00103## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XXXVIII). R.sup.5, y, v,
R.sup.15, R.sup.17, Q, G and the ring denoted by "A" can be
defined, for example, as described with reference to any of
structural formulae (XLVII)-(LV). In certain embodiments, Z is N.
In other embodiments, Z is carbon (e.g., CH or C substituted with
one of the x R.sup.4).
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXIV):
##STR00104## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XXXIX). R.sup.5, y, v,
R.sup.15, R.sup.17, Q, G and the ring denoted by "A" can be
defined, for example, as described with reference to any of
structural formulae (XLVII)-(LV).
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXV):
##STR00105## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XL). R.sup.5, y, v, R.sup.15,
R.sup.17, Q, G and the ring denoted by "A" can be defined, for
example, as described with reference to any of structural formulae
(XLVII)-(LV).
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXVI):
##STR00106## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XLI). R.sup.5, y, v, R.sup.15,
R.sup.17, Q, G and the ring denoted by "A" can be defined, for
example, as described with reference to any of structural formulae
(XLVII)-(LV).
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXVII):
##STR00107## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XLII). R.sup.5, y, v,
R.sup.15, R.sup.17, Q, G and the ring denoted by "A" can be
defined, for example, as described with reference to any of
structural formulae (XLVII)-(LV).
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXVIII):
##STR00108## in which G, v, R.sup.15 and R.sup.17 are defined as
described above with reference to structural formula (XLIV), and
all other variables are defined as described above with reference
to structural formulae (I)-(IV) and (XLIII). R.sup.5, y, v,
R.sup.15, R.sup.17, Q, G and the ring denoted by "A" can be
defined, for example, as described with reference to any of
structural formulae (XLVII)-(LV).
In certain embodiments of compounds having structural formulae
(XLIV)-(XLVIII), (LIII) and (LVI)-(LXXVIII), the
##STR00109## moiety has the structure
##STR00110## in which G is --CH.sub.2--, --CH(CH.sub.3)--,
--C(O)--, --S(O).sub.2-- or --C(O)--NH--. For example, in one
embodiment, G is --CH.sub.2--. In another embodiment, G is --C(O)--
or --S(O).sub.2--. In another embodiment, G is --C(O)--NH--.
In other embodiments of compounds having structural formulae
(XLIV)-(XLVIII), (LIII) and (LVI)-(LXXVIII), the
##STR00111## moiety has the structure
##STR00112## in which G is --CH.sub.2--, --C(O)--, --S(O).sub.2--
or --C(O)--NH--, R.sup.27 is selected from H, --(C.sub.1-C.sub.6
alkyl), --(C.sub.1-C.sub.6 haloalkyl) (e.g., difluoromethyl,
trifluoromethyl and the like), --(C.sub.0-C.sub.6
alkyl)-L-(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-O--(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl)-(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl), in which no
heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and
R.sup.29 is --H, --(C.sub.1-C.sub.4 alkyl), --CO--(C.sub.1-C.sub.4
alkyl) or --CO--O--(C.sub.1-C.sub.4 alkyl) in which no
(C.sub.1-C.sub.4 alkyl) is substituted by an aryl, heteroaryl,
cycloalkyl or heterocycloalkyl-containing group, or R.sup.27 and
R.sup.29 together with the nitrogen to which they are bound form
Hca. In such embodiments, the compounds can be present as racemic
mixtures or scalemic mixtures, or in an enantiomerically-enriched
form, for example as a substantially pure stereoisomer.
In other embodiments of compounds having structural formulae
(XLIV)-(XLVIII), (LIII) and (LVI)-(LXXVIII), the
##STR00113## moiety has the structure
##STR00114## in which G is --CH.sub.2--, --C(O)--, --S(O).sub.2--
or --C(O)--NH--.
In certain embodiments of compounds having structural formulae
(XLIV)-(XLVIII), (LIII) and (LVI)-(LXXVIII), the R.sup.17 moiety
has the structure
##STR00115## in which R.sup.27 is selected from H,
--(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl) (e.g.,
difluoromethyl, trifluoromethyl and the like), --(C.sub.0-C.sub.6
alkyl)-L-(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-O--(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl) --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl), in which no
heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and
R.sup.29 is --H, --(C.sub.1-C.sub.4 alkyl), --CO--(C.sub.1-C.sub.4
alkyl) or --CO--O--(C.sub.1-C.sub.4 alkyl) in which no
(C.sub.1-C.sub.4 alkyl) is substituted by an aryl, heteroaryl,
cycloalkyl or heterocycloalkyl-containing group, or R.sup.27 and
R.sup.29 together with the nitrogen to which they are bound form
Hca.
In certain embodiments of compounds having structural formulae
(XLIV)-(LXXVIII), w is 1, and R.sup.3 is --NR.sup.8R.sup.9. In
certain such embodiments, R.sup.3 is substituted at a 6-membered
aromatic ring position in the meta position relative to the J
moiety.
In other embodiments of compounds having structural formulae
(XLIV)-(LXXVIII), w is 1, and R.sup.3 is --(C.sub.0-C.sub.3
alkyl)-Y.sup.1--(C.sub.1-C.sub.3 alkyl)-Y.sup.2--(C.sub.0-C.sub.3
alkyl), in which each of Y.sup.1 and Y.sup.2 is independently L,
--O--, --S-- or --NR.sup.9--. In certain such embodiments, R.sup.3
is substituted at a 6-membered aromatic ring position in the meta
position relative to the J moiety.
In certain embodiments described above, each R.sup.27 is selected
from --(C.sub.1-C.sub.3 alkyl), --(C.sub.1-C.sub.3 haloalkyl),
--(C.sub.0-C.sub.3 alkyl)-L-R.sup.7, --(C.sub.0-C.sub.3
alkyl)-NR.sup.8R.sup.9, --(C.sub.0-C.sub.3 alkyl)-OR.sup.10,
--(C.sub.0-C.sub.3 alkyl)-C(O)R.sup.10, --(C.sub.0-C.sub.3
alkyl)-S(O).sub.0-2R.sup.10, -halogen, --NO.sub.2 and --CN and two
R.sup.21 on the same carbon optionally combine to form oxo, in
which each R.sup.7, R.sup.8 and R.sup.10 is independently selected
from H, --(C.sub.1-C.sub.2 alkyl), --(C.sub.1-C.sub.2 haloalkyl),
--(C.sub.0-C.sub.2 alkyl)-L-(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-NR.sup.9(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-O--(C.sub.0-C.sub.2 alkyl),
--(C.sub.0-C.sub.2 alkyl)-C(O)--(C.sub.0-C.sub.2 alkyl) and
--(C.sub.0-C.sub.2 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.2 alkyl),
and in which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and
each R.sup.29 is H, methyl or ethyl, or R.sup.27 and R.sup.29
together with the nitrogen to which they are bound form Hca.
In certain embodiments of compounds having structural formulae
(XLIV)--(XLVI) and (XLIX)-(LXXVIII), at least one R.sup.5 moiety is
a haloalkyl group, and in exemplary embodiments of these formulae
the
##STR00116## moiety is p-(trifluoromethyl)phenyl.
In one embodiment, the presently disclosed compounds of any of
structural formulae (I)-(XLIII) have a T moiety having the
structural formula
##STR00117## and an R.sup.2 moiety having the structural
formula
##STR00118## in which G and R.sup.17 are as described above with
reference to any of structural formulae (I)-(LXXVIII), R.sup.18 is
H, --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6 haloalkyl) (e.g.,
difluoromethyl, trifluoromethyl and the like), --(C.sub.0-C.sub.6
alkyl)-L-(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-O--(C.sub.0-C.sub.6 alkyl), --(C.sub.0-C.sub.6
alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl) and --(C.sub.0-C.sub.6
alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl), in which no alkyl or
haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or
heterocycloalkyl-containing group and R.sup.19 is --H,
--(C.sub.1-C.sub.4 alkyl), --CO--(C.sub.1-C.sub.4 alkyl) or
--CO--O--(C.sub.1-C.sub.4 alkyl) in which no alkyl is substituted
by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing
group, or R.sup.18 and R.sup.19 together with the nitrogen to which
they are bound form Hca. In one embodiment, R.sup.18 and R.sup.19
are both H.
In another embodiment, the presently disclosed compounds of any of
structural formulae (I)-(XLIII) have a T moiety having the
structural formula
##STR00119## and an R.sup.2 moiety having the structural
formula
##STR00120## in which Q and R.sup.5 are defined as described above
with reference to any of structural formulae (I)-(LXXVIII),
R.sup.18 is H, --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like),
--(C.sub.0-C.sub.6 alkyl)-L-(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-O--(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl) and
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl), in
which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group and
R.sup.19 is --H, --(C.sub.1-C.sub.4 alkyl), --CO--(C.sub.1-C.sub.4
alkyl) or --CO--O--(C.sub.1-C.sub.4 alkyl) in which no alkyl is
substituted by an aryl, heteroaryl, cycloalkyl or
heterocycloalkyl-containing group, or R.sup.18 and R.sup.19
together with the nitrogen to which they are bound form Hca. In one
embodiment, R.sup.18 and R.sup.19 are both H.
In another embodiment, the presently disclosed compounds of any of
structural formulae (I)-(XLIII) have a T moiety having the
structural formula
##STR00121## and an R.sup.2 moiety having the structural
formula
##STR00122## in which Q and R.sup.5 are defined as described above
with reference to any of structural formulae (I)-(LXXVIII),
R.sup.18 is H, --(C.sub.1-C.sub.6 alkyl), --(C.sub.1-C.sub.6
haloalkyl) (e.g., difluoromethyl, trifluoromethyl and the like),
--(C.sub.0-C.sub.6 alkyl)-L-(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-NR.sup.9(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-O--(C.sub.0-C.sub.6 alkyl),
--(C.sub.0-C.sub.6 alkyl)-C(O)--(C.sub.0-C.sub.6 alkyl) and
--(C.sub.0-C.sub.6 alkyl)-S(O).sub.0-2--(C.sub.0-C.sub.6 alkyl), in
which no alkyl or haloalkyl is substituted with an aryl-,
heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group and
R.sup.19 is --H, --(C.sub.1-C.sub.4 alkyl), --CO--(C.sub.1-C.sub.4
alkyl) or --CO--O--(C.sub.1-C.sub.4 alkyl) in which no alkyl is
substituted by an aryl, heteroaryl, cycloalkyl or
heterocycloalkyl-containing group, or R.sup.18 and R.sup.19
together with the nitrogen to which they are bound form Hca. In one
embodiment, R.sup.18 and R.sup.19 are both H.
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXIX):
##STR00123## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LVI); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the benzo moiety of the central benzo[d]oxazole. In
another embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the benzo
moiety of the central benzo[d]oxazole.
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXX):
##STR00124## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LVII); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the benzo moiety of the central benzo[d]oxazole. In
another embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the benzo
moiety of the central benzo[d]oxazole.
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXXI):
##STR00125## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LVI); and
R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the benzo moiety of the
central benzo[d]oxazole. In another embodiment, one R.sup.3 (e.g.,
--Cl, --F, --CH.sub.3, --C.sub.2H.sub.5, --C.sub.3H.sub.7) is
substituted on the benzo moiety of the central benzo[d]oxazole.
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXXII):
##STR00126## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LVI); and
R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the benzo moiety of the
central benzo[d]oxazole. In another embodiment, one R.sup.3 (e.g.,
--Cl, --F, --CH.sub.3, --C.sub.2H.sub.5, --C.sub.3H.sub.7) is
substituted on the benzo moiety of the central benzo[d]oxazole.
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXXIII):
##STR00127## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LVIII); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the benzo moiety of the central benzo[d]thiazole. In
another embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the benzo
moiety of the central benzo[d]thiazole.
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXXIV):
##STR00128## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LIX); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the benzo moiety of the central benzo[d]thiazole. In
another embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the benzo
moiety of the central benzo[d]thiazole.
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXXV):
##STR00129## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LVIII); and
R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the benzo moiety of the
central benzo[d]thiazole. In another embodiment, one R.sup.3 (e.g.,
--Cl, --F, --CH.sub.3, --C.sub.2H.sub.5, --C.sub.3H.sub.7) is
substituted on the benzo moiety of the central
benzo[d]thiazole.
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXXVI):
##STR00130## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LIX); and
R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the benzo moiety of the
central benzo[d]thiazole. In another embodiment, one R.sup.3 (e.g.,
--Cl, --F, --CH.sub.3, --C.sub.2H.sub.5, --C.sub.3H.sub.7) is
substituted on the benzo moiety of the central
benzo[d]thiazole.
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXXVII):
##STR00131## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LX); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central imidazo[1,2-a]pyridine. In another
embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the central
imidazo[1,2-a]pyridine.
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXXVIII):
##STR00132## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXI); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central imidazo[1,2-a]pyridine. In another
embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the central
imidazo[1,2-a]pyridine.
In certain embodiments, the presently disclosed compounds have the
structural formula (LXXXIX):
##STR00133## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXII); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central imidazo[1,2-a]pyridine. In another
embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the central
imidazo[1,2-a]pyridine.
In certain embodiments, the presently disclosed compounds have the
structural formula (XC):
##STR00134## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXIII); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central imidazo[1,2-a]pyridine. In another
embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the central
imidazo[1,2-a]pyridine.
In certain embodiments, the presently disclosed compounds have the
structural formula (XCI):
##STR00135## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LX); and
R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central
imidazo[1,2-a]pyridine. In another embodiment, one R.sup.3 (e.g.,
--Cl, --F, --CH.sub.3, --C.sub.2H.sub.5, --C.sub.3H.sub.7) is
substituted on the central imidazo[1,2-a]pyridine.
In certain embodiments, the presently disclosed compounds have the
structural formula (XCII):
##STR00136## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXI); and
R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central
imidazo[1,2-a]pyridine. In another embodiment, one R.sup.3 (e.g.,
--Cl, --F, --CH.sub.3, --C.sub.2H.sub.5, --C.sub.3H.sub.7) is
substituted on the central imidazo[1,2-a]pyridine.
In certain embodiments, the presently disclosed compounds have the
structural formula (XCIII):
##STR00137## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXII); and
R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central
imidazo[1,2-a]pyridine. In another embodiment, one R.sup.3 (e.g.,
--Cl, --F, --CH.sub.3, --C.sub.2H.sub.5, --C.sub.3H.sub.7) is
substituted on the central imidazo[1,2-a]pyridine.
In certain embodiments, the presently disclosed compounds have the
structural formula (XCIV):
##STR00138## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXIII); and
R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central
imidazo[1,2-a]pyridine. In another embodiment, one R.sup.3 (e.g.,
--Cl, --F, --CH.sub.3, --C.sub.2H.sub.5, --C.sub.3H.sub.7) is
substituted on the central imidazo[1,2-a]pyridine.
In certain embodiments, the presently disclosed compounds have the
structural formula (XCV):
##STR00139## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXIV); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central pyrazine. In another embodiment, one
R.sup.3 (e.g., --Cl, --F, --CH.sub.3, --C.sub.2H.sub.5,
--C.sub.3H.sub.7) is substituted on the central pyrazine.
In certain embodiments, the presently disclosed compounds have the
structural formula (XCVI):
##STR00140## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXV); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central pyrazine. In another embodiment, one
R.sup.3 (e.g., --Cl, --F, --CH.sub.3, --C.sub.2H.sub.5,
--C.sub.3H.sub.7) is substituted on the central pyrazine.
In certain embodiments, the presently disclosed compounds have the
structural formula (XCVII):
##STR00141## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I) and (LXIV); and
R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central pyrazine. In
another embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the central
pyrazine.
In certain embodiments, the presently disclosed compounds have the
structural formula (XCVIII):
##STR00142## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXV); and
R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central pyrazine. In
another embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the central
pyrazine.
In certain embodiments, the presently disclosed compounds have the
structural formula (XCIX):
##STR00143## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; E.sup.1, E.sup.2, R.sup.1 and R.sup.3 are as
described above with reference to any of structural formulae
(I)-(IV) and (LXVI); and R.sup.11, R.sup.12 and R.sup.13 are
independently selected from H, halo, cyano, --(C.sub.1-C.sub.4
haloalkyl), --O--(C.sub.1-C.sub.4 haloalkyl), --(C.sub.1-C.sub.4
alkyl), --O--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.0-C.sub.4
alkyl), --C(O)O--(C.sub.0-C.sub.4 alkyl), --C(O)N(C.sub.0-C.sub.4
alkyl)(C.sub.0-C.sub.4 alkyl), NO.sub.2 and --C(O)--Hca in which
the Hca contains a ring nitrogen atom through which it is bound to
the --C(O)--, in which no alkyl, haloalkyl or heterocycloalkyl is
substituted by an aryl, heteroaryl, cycloalkyl or
heterocycloalkyl-containing group. In one particular such
embodiment, at least one of R.sup.11, R.sup.12 and R.sup.13 is not
H. In one embodiment, R.sup.11 is attached in the para position
relative to the G moiety; in another embodiment, R.sup.11 is
attached in the meta position relative to the G moiety. In one
embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is methyl,
ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central thiazole. In another embodiment, one
R.sup.3 (e.g., --Cl, --F, --CH.sub.3, --C.sub.2H.sub.5,
--C.sub.3H.sub.7) is substituted on the central thiazole. In one
embodiment, E.sup.1 is carbon and E.sup.2 is N. In another
embodiment, E.sup.1 is N and E.sup.2 is carbon.
In certain embodiments, the presently disclosed compounds have the
structural formula (C):
##STR00144## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXVII); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central thiazole (i.e., the ring position shown
occupied by R.sup.3 bears a hydrogen atom). In another embodiment,
one R.sup.3 (e.g., --Cl, --F, --CH.sub.3, --C.sub.2H.sub.5,
--C.sub.3H.sub.7) is substituted on the central thiazole.
In certain embodiments, the presently disclosed compounds have the
structural formula (CI):
##STR00145## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXVIII); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central thiazole (i.e., the ring position shown
occupied by R.sup.3 bears a hydrogen atom). In another embodiment,
one R.sup.3 (e.g., --Cl, --F, --CH.sub.3, --C.sub.2H.sub.5,
--C.sub.3H.sub.7) is substituted on the central thiazole.
In certain embodiments, the presently disclosed compounds have the
structural formula (CII):
##STR00146## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; E.sup.1, E.sup.2, R.sup.1 and R.sup.3 are as
described above with reference to any of structural formulae
(I)-(IV) and (LXVI); and R.sup.11, R.sup.12 and R.sup.13 are
independently selected from H, halo, cyano, --(C.sub.1-C.sub.4
haloalkyl), --O--(C.sub.1-C.sub.4 haloalkyl), --(C.sub.1-C.sub.4
alkyl), --O--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.0-C.sub.4
alkyl), --C(O)O--(C.sub.0-C.sub.4 alkyl), --C(O)N(C.sub.0-C.sub.4
alkyl)(C.sub.0-C.sub.4 alkyl), NO.sub.2 and --C(O)--Hca in which
the Hca contains a ring nitrogen atom through which it is bound to
the --C(O)--, in which no alkyl, haloalkyl or heterocycloalkyl is
substituted by an aryl, heteroaryl, cycloalkyl or
heterocycloalkyl-containing group. In one embodiment, the pyridine
nitrogen is positioned in the para position relative to the G
moiety; in another embodiment, the pyridine nitrogen is positioned
in the meta position relative to the G moiety. In one embodiment,
R.sup.1 is H. In another embodiment, R.sup.1 is methyl, ethyl,
propyl or butyl. In one embodiment, no R.sup.3 is substituted on
the central thiazole. In another embodiment, one R.sup.3 (e.g.,
--Cl, --F, --CH.sub.3, --C.sub.2H.sub.5, --C.sub.3H.sub.7) is
substituted on the central thiazole. In one embodiment, E.sup.1 is
carbon and E.sup.2 is N. In another embodiment, E.sup.1 is N and
E.sup.2 is carbon.
In certain embodiments, the presently disclosed compounds have the
structural formula (CIII):
##STR00147## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXVII); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
embodiment, the pyridine nitrogen is positioned in the para
position relative to the G moiety; in another embodiment, the
pyridine nitrogen is positioned in the meta position relative to
the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central thiazole
(i.e., the ring position shown occupied by R.sup.3 bears a hydrogen
atom). In another embodiment, one R.sup.3 (e.g., --Cl, --F,
--CH.sub.3, --C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on
the central thiazole.
In certain embodiments, the presently disclosed compounds have the
structural formula (CIV):
##STR00148## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXVIII); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
embodiment, the pyridine nitrogen is positioned in the para
position relative to the G moiety; in another embodiment, the
pyridine nitrogen is positioned in the meta position relative to
the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central thiazole
(i.e., the ring position shown occupied by R.sup.3 bears a hydrogen
atom). In another embodiment, one R.sup.3 (e.g., --Cl, --F,
--CH.sub.3, --C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on
the central thiazole.
In certain embodiments, the presently disclosed compounds have the
structural formula (CV):
##STR00149## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; Z, R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXIX); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central phenyl ring. In another embodiment, one
R.sup.3 (e.g., --Cl, --F, --CH.sub.3, --C.sub.2H.sub.5,
--C.sub.3H.sub.7) is substituted on the central phenyl ring. In one
embodiment, Z is N. In another embodiment, Z is CH.
In certain embodiments, the presently disclosed compounds have the
structural formula (CVI):
##STR00150## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1, R.sup.3 and R.sup.38 are as described above
with reference to any of structural formulae (I)-(IV) and (LXX);
and R.sup.11, R.sup.12 and R.sup.13 are independently selected from
H, halo, cyano, --(C.sub.1-C.sub.4 haloalkyl),
--O--(C.sub.1-C.sub.4 haloalkyl), --(C.sub.1-C.sub.4 alkyl),
--O--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl),
--C(O)O--(C.sub.0-C.sub.4 alkyl), --C(O)N(C.sub.0-C.sub.4
alkyl)(C.sub.0-C.sub.4 alkyl), NO.sub.2 and --C(O)--Hca in which
the Hca contains a ring nitrogen atom through which it is bound to
the --C(O)--, in which no alkyl, haloalkyl or heterocycloalkyl is
substituted by an aryl, heteroaryl, cycloalkyl or
heterocycloalkyl-containing group. In one particular such
embodiment, at least one of R.sup.11, R.sup.12 and R.sup.13 is not
H. In one embodiment, R.sup.11 is attached in the para position
relative to the G moiety; in another embodiment, R.sup.11 is
attached in the meta position relative to the G moiety. In one
embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is methyl,
ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central phenyl ring. In another embodiment, one
R.sup.3 (e.g., --Cl, --F, --CH.sub.3, --C.sub.2H.sub.5,
--C.sub.3H.sub.7) is substituted on the central phenyl ring. In one
embodiment, R.sup.38 is H. In another embodiment, R.sup.38 is
methyl, ethyl, propyl or butyl.
In certain embodiments, the presently disclosed compounds have the
structural formula (CVII):
##STR00151## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; Z, R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXXI); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central phenyl ring. In another embodiment, one
R.sup.3 (e.g., --Cl, --F, --CH.sub.3, --C.sub.2H.sub.5,
--C.sub.3H.sub.7) is substituted on the central phenyl ring. In one
embodiment, Z is N. In another embodiment, Z is CH.
In certain embodiments, the presently disclosed compounds have the
structural formula (CVIII):
##STR00152## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1, R.sup.3 and R.sup.38 are as described above
with reference to any of structural formulae (I)-(IV) and (LXXII);
and R.sup.11, R.sup.12 and R.sup.13 are independently selected from
H, halo, cyano, --(C.sub.1-C.sub.4 haloalkyl),
--O--(C.sub.1-C.sub.4 haloalkyl), --(C.sub.1-C.sub.4 alkyl),
--O--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl),
--C(O)O--(C.sub.0-C.sub.4 alkyl), --C(O)N(C.sub.0-C.sub.4
alkyl)(C.sub.0-C.sub.4 alkyl), NO.sub.2 and --C(O)--Hca in which
the Hca contains a ring nitrogen atom through which it is bound to
the --C(O)--, in which no alkyl, haloalkyl or heterocycloalkyl is
substituted by an aryl, heteroaryl, cycloalkyl or
heterocycloalkyl-containing group. In one particular such
embodiment, at least one of R.sup.1, R.sup.12 and R.sup.13 is not
H. In one embodiment, R.sup.11 is attached in the para position
relative to the G moiety; in another embodiment, R.sup.11 is
attached in the meta position relative to the G moiety. In one
embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is methyl,
ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central phenyl ring. In another embodiment, one
R.sup.3 (e.g., --Cl, --F, --CH.sub.3, --C.sub.2H.sub.5,
--C.sub.3H.sub.7) is substituted on the central phenyl ring. In one
embodiment, R.sup.38 is H. In another embodiment, R.sup.38 is
methyl, ethyl, propyl or butyl.
In certain embodiments, the presently disclosed compounds have the
structural formula (CIX):
##STR00153## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; Z, R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXXIII); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central phenyl ring. In another embodiment, one
R.sup.3 (e.g., --Cl, --F, --CH.sub.3, --C.sub.2H.sub.5,
--C.sub.3H.sub.7) is substituted on the central phenyl ring. In one
embodiment, Z is N. In another embodiment, Z is CH.
In certain embodiments, the presently disclosed compounds have the
structural formula (CX):
##STR00154## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1, R.sup.3 and R.sup.38 are as described above
with reference to any of structural formulae (I)-(IV) and (LXXIV);
and R.sup.11, R.sup.12 and R.sup.13 are independently selected from
H, halo, cyano, --(C.sub.1-C.sub.4 haloalkyl),
--O--(C.sub.1-C.sub.4 haloalkyl), --(C.sub.1-C.sub.4 alkyl),
--O--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl),
--C(O)O--(C.sub.0-C.sub.4 alkyl), --C(O)N(C.sub.0-C.sub.4
alkyl)(C.sub.0-C.sub.4 alkyl), NO.sub.2 and --C(O)--Hca in which
the Hca contains a ring nitrogen atom through which it is bound to
the --C(O)--, in which no alkyl, haloalkyl or heterocycloalkyl is
substituted by an aryl, heteroaryl, cycloalkyl or
heterocycloalkyl-containing group. In one particular such
embodiment, at least one of R.sup.1, R.sup.12 and R.sup.13 is not
H. In one embodiment, R.sup.11 is attached in the para position
relative to the G moiety; in another embodiment, R.sup.11 is
attached in the meta position relative to the G moiety. In one
embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is methyl,
ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central phenyl ring. In another embodiment, one
R.sup.3 (e.g., --Cl, --F, --CH.sub.3, --C.sub.2H.sub.5,
--C.sub.3H.sub.7) is substituted on the central phenyl ring. In one
embodiment, R.sup.38 is H. In another embodiment, R.sup.38 is
methyl, ethyl, propyl or butyl.
In certain embodiments, the presently disclosed compounds have the
structural formula (CXI):
##STR00155## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; Z, R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXIX); and
R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central phenyl ring.
In another embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the central
phenyl ring. In one embodiment, Z is N. In another embodiment, Z is
CH.
In certain embodiments, the presently disclosed compounds have the
structural formula (CXII):
##STR00156## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1, R.sup.3 and R.sup.38 are as described above
with reference to any of structural formulae (I)-(IV) and (LXX);
and R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central phenyl ring.
In another embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the central
phenyl ring. In one embodiment, R.sup.38 is H. In another
embodiment, R.sup.38 is methyl, ethyl, propyl or butyl.
In certain embodiments, the presently disclosed compounds have the
structural formula (CXIII):
##STR00157## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; Z, R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXXI); and
R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central phenyl ring.
In another embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the central
phenyl ring. In one embodiment, Z is N. In another embodiment, Z is
CH.
In certain embodiments, the presently disclosed compounds have the
structural formula (CXIV):
##STR00158## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1, R.sup.3 and R.sup.38 are as described above
with reference to any of structural formulae (I)-(IV) and (LXXII);
and R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central phenyl ring.
In another embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the central
phenyl ring. In one embodiment, R.sup.38 is H. In another
embodiment, R.sup.38 is methyl, ethyl, propyl or butyl.
In certain embodiments, the presently disclosed compounds have the
structural formula (CXV):
##STR00159## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; Z, R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXXIII); and
R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central phenyl ring.
In another embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the central
phenyl ring. In one embodiment, Z is N. In another embodiment, Z is
CH.
In certain embodiments, the presently disclosed compounds have the
structural formula (CXVI):
##STR00160## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1, R.sup.3 and R.sup.38 are as described above
with reference to any of structural formulae (I)-(IV) and (LXXIV);
and R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central phenyl ring.
In another embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the central
phenyl ring. In one embodiment, R.sup.38 is H. In another
embodiment, R.sup.38 is methyl, ethyl, propyl or butyl.
In certain embodiments, the presently disclosed compounds have the
structural formula (CXVII):
##STR00161## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXXV); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central benzo moiety. In another embodiment, one
R.sup.3 (e.g., --Cl, --F, --CH.sub.3, --C.sub.2H.sub.5,
--C.sub.3H.sub.7) is substituted on the central benzo moiety.
In certain embodiments, the presently disclosed compounds have the
structural formula (CXVIII):
##STR00162## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXXVI); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central benzo moiety. In another embodiment, one
R.sup.3 (e.g., --Cl, --F, --CH.sub.3, --C.sub.2H.sub.5,
--C.sub.3H.sub.7) is substituted on the central benzo moiety.
In certain embodiments, the presently disclosed compounds have the
structural formula (CXIX):
##STR00163## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXXVII); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central benzo moiety. In another embodiment, one
R.sup.3 (e.g., --Cl, --F, --CH.sub.3, --C.sub.2H.sub.5,
--C.sub.3H.sub.7) is substituted on the central benzo moiety.
In certain embodiments, the presently disclosed compounds have the
structural formula (CXX):
##STR00164## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXXVIII); and
R.sup.11, R.sup.12 and R.sup.13 are independently selected from H,
halo, cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.11, R.sup.12 and
R.sup.13 is not H. In one embodiment, R.sup.11 is attached in the
para position relative to the G moiety; in another embodiment,
R.sup.11 is attached in the meta position relative to the G moiety.
In one embodiment, R.sup.1 is H. In another embodiment, R.sup.1 is
methyl, ethyl, propyl or butyl. In one embodiment, no R.sup.3 is
substituted on the central benzo moiety. In another embodiment, one
R.sup.3 (e.g., --Cl, --F, --CH.sub.3, --C.sub.2H.sub.5,
--C.sub.3H.sub.7) is substituted on the central benzo moiety.
In certain embodiments, the presently disclosed compounds have the
structural formula (CXXI):
##STR00165## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXXV); and
R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central benzo moiety.
In another embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the central
benzo moiety.
In certain embodiments, the presently disclosed compounds have the
structural formula (CXXII):
##STR00166## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXXVI); and
R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central benzo moiety.
In another embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the central
benzo moiety.
In certain embodiments, the presently disclosed compounds have the
structural formula (CXXIII):
##STR00167## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXXVII); and
R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central benzo moiety.
In another embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the central
benzo moiety.
In certain embodiments, the presently disclosed compounds have the
structural formula (CXXIV):
##STR00168## in which Q is --CH.sub.2--, --C(O)-- or a single bond;
G is a single bond, --CH.sub.2--, --C(O)--, --S(O).sub.2-- or
--C(O)--NH--; R.sup.1 and R.sup.3 are as described above with
reference to any of structural formulae (I)-(IV) and (LXXVIII); and
R.sup.12 and R.sup.13 are independently selected from H, halo,
cyano, --(C.sub.1-C.sub.4 haloalkyl), --O--(C.sub.1-C.sub.4
haloalkyl), --(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4
alkyl), --C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
NO.sub.2 and --C(O)--Hca in which the Hca contains a ring nitrogen
atom through which it is bound to the --C(O)--, in which no alkyl,
haloalkyl or heterocycloalkyl is substituted by an aryl,
heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In one
particular such embodiment, at least one of R.sup.12 and R.sup.13
is not H. In one embodiment, the pyridine nitrogen is positioned in
the para position relative to the G moiety; in another embodiment,
the pyridine nitrogen is positioned in the meta position relative
to the G moiety. In one embodiment, R.sup.1 is H. In another
embodiment, R.sup.1 is methyl, ethyl, propyl or butyl. In one
embodiment, no R.sup.3 is substituted on the central benzo moiety.
In another embodiment, one R.sup.3 (e.g., --Cl, --F, --CH.sub.3,
--C.sub.2H.sub.5, --C.sub.3H.sub.7) is substituted on the central
benzo moiety.
In one embodiment of the presently disclosed compounds, the
compound has the structural formula (XLIV), in which the "A" ring
system is an aryl or heteroaryl; and in which the compound has a
computed low energy three-dimensional conformer in which the oxygen
of the carboxamide --C(O)-- group is positioned at (0 .ANG., 0
.ANG., 0 .ANG.); the centerpoint of an aromatic ring of the aryl or
heteroaryl of the "B" ring system is positioned within 3.5 .ANG. of
(-3.1 .ANG., 0.4 .ANG., 1.2 .ANG.); the nitrogen of the right-hand
azacycloalkyl (i.e., the ring to which -G-R.sup.17 is bound) is
positioned within 3.5 .ANG. of (0.8 .ANG., 1.6 .ANG., -5.3 .ANG.);
the centerpoint of the left-hand azacycloalkyl (i.e., the ring to
which -Q-(A ring)-(R.sup.5).sub.y is bound) is positioned within
3.5 .ANG. of (-6.2 .ANG., 0.1 .ANG., 7.4 .ANG.); and the
centerpoint of an aromatic ring of the aryl or heteroaryl of the
"A" ring system is positioned within 3.5 .ANG. of (-7.4 .ANG., -1.9
.ANG., 10.7 .ANG.).
In certain embodiments of the presently disclosed compounds of
structural formula (XLIV), in a computed low energy
three-dimensional conformer: the oxygen of the carboxamide --C(O)--
group is positioned at (0 .ANG., 0 .ANG., 0 .ANG.); the centerpoint
of an aromatic ring of the aryl or heteroaryl of the "B" ring
system is positioned within 2.5 .ANG. of (-3.1 .ANG., 0.4 .ANG.,
1.2 .ANG.); the nitrogen of the right-hand azacycloalkyl is
positioned within 1.8 .ANG. of (0.8 .ANG., 1.6 .ANG., -5.3 .ANG.);
the centerpoint of the left-hand azacycloalkyl is positioned within
2.5 .ANG. of (-6.2 .ANG., 0.1 .ANG., 7.4 .ANG.); and the
centerpoint of an aromatic ring of the aryl or heteroaryl of the
"A" ring system is positioned within 2.5 .ANG. of (-7.4 .ANG., -1.9
.ANG., 10.7 .ANG.).
In one embodiment of the presently disclosed compounds of
structural formula (XLIV), the "A" ring system is an aryl or
heteroaryl substituted with a hydrophobic moiety; R.sup.17 is
substituted with an electron acceptor; and the compound has a
computed low energy three-dimensional conformer in which the oxygen
of the carboxamide --C(O)-- group is positioned at (0 .ANG., 0
.ANG., 0 .ANG.); the centerpoint of an aromatic ring of the aryl or
heteroaryl of the "B" ring system is positioned within 3.5 .ANG. of
(-3.1 .ANG., 0.4 .ANG., 1.2 .ANG.); the nitrogen of the right-hand
azacycloalkyl is positioned within 3.5 .ANG. of (0.8 .ANG., 1.6
.ANG., -5.3 .ANG.); the centerpoint of the left-hand azacycloalkyl
is positioned within 3.5 .ANG. of (-6.2 .ANG., 0.1 .ANG., 7.4
.ANG.); and the centerpoint of an aromatic ring of the aryl or
heteroaryl of the "A" ring system is positioned within 3.5 .ANG. of
(-7.4 .ANG., -1.9 .ANG., 10.7 .ANG.); the hydrophobic moiety
substituted on the "A" ring system is positioned within 3.5 .ANG.
of (-9.0 .ANG., -3.2 .ANG., 13.4 .ANG.); and the electron acceptor
substituted on R.sup.17 is positioned within 3.5 .ANG. of (7.0
.ANG., -2.7 .ANG., -7.0 .ANG.). The hydrophobic moiety can be, for
example, any of the following, as defined in SMARTS query format:
#INCLUDE [a]F group(2) [a]Cl group(2) [a]Br group(2) [a]I group(2)
[a]C(F)(F)(F) group(2,3,4,5) [a][CH2]C(F)(F)(F) group(2,3,4,5,6)
[a]O[CH3] group(2,3) [a]S[CH3] group(2,3) [a]OC(F)(F)(F)
group(2,3,4,5,6) C(F)(F)(F) group F group Cl group Br group I group
default_aromatic_surface group default_aliphatic_surface group
C[S;X2]C group [S;X2]CC group [S;X2]C group. The electron acceptor
can be, for example, any of the following, as defined in SMARTS
query format: #INCLUDE [N;X1]#[#6] vector(1) [N;X1]#CC vector(1)
[N;X2](.dbd.C.about.[C,c])C vector(1) [N;X2](O).dbd.N[a] vector(1)
[N;X2](.dbd.N--O)[a]vector(1) [n;X2]1ccccc1 vector(1)
[n;X2]([a])([a]) vector(1) [N;X2](.dbd.C.about.[C,c])(.about.[*])
vector(1) [N;X3](C)(C)[N;X3]C vector(1) [N;X2](.dbd.C)(.about.[*])
vector(1) [N;X2](.about.[C,c])=[N;X2] vector(1) [n;X2]1c[nH]cc1
vector(1) O.dbd.[S;X4](.dbd.O)([!#8])([!#8]) vector(1) [O;X2]C
vector(1) [O;X2]N vector(1) [O;X1]=[C,c] vector(1) o vector(1)
[O;X2](C)C vector(1) [O;X2]c1ncccc1 vector(1)
[O;X2].about.[a]vector(1) O.dbd.PO([!#1]) vector(1) [O;X2]
vector(1) [S;X2](C)C vector(1) [S;X2](.dbd.C)N vector(1) #EXCLUDE
O.dbd.C[O--,OH] point [O--,OH]C(.dbd.O) point [nH]([a])[a] point
[#7;X3][*]=[O,S] point [N;X3](C)(C)[C;X3] point [N;X3][a] point
N(.dbd.N.dbd.N)[#6] point [NH2](C(.dbd.O)[NH2]) point
[NH](C.dbd.O)(C.dbd.O) point [NH2](S(.dbd.O)(.dbd.O)[#6])[#6] point
[NH](S(.dbd.O)(.dbd.O)[#6])[#6] point n1c([NH2])ccnc1([NH2]) point
o1nccc1 point o1cncc1 point o1cccc1 point [O;X2]C.dbd.O point
[O;X2] point.
In one embodiment of the presently disclosed compounds of
structural formula (XLIV), the "A" ring system is an aryl or
heteroaryl substituted with a hydrophobic moiety; R.sup.17 is
substituted with an electron acceptor; and the compound has a
computed low energy three-dimensional conformer in which the oxygen
of the carboxamide --C(O)-- group is positioned at (0 .ANG., 0
.ANG., 0 .ANG.); the centerpoint of an aromatic ring of the aryl or
heteroaryl of the "B" ring system is positioned within 2.5 .ANG. of
(-3.1 .ANG., 0.4 .ANG., 1.2 .ANG.); the nitrogen of the right-hand
azacycloalkyl is positioned within 1.8 .ANG. of (0.8 .ANG., 1.6
.ANG., -5.3 .ANG.); the centerpoint of the left-hand azacycloalkyl
is positioned within 2.5 .ANG. of (-6.2 .ANG., 0.1 .ANG., 7.4
.ANG.); and the centerpoint of an aromatic ring of the aryl or
heteroaryl of the "A" ring system is positioned within 2.5 .ANG. of
(-7.4 .ANG., -1.9 .ANG., 10.7 .ANG.); the hydrophobic moiety
substituted on the "A" ring system is positioned within 2.5 .ANG.
of (-9.0 .ANG., -3.2 .ANG., 13.4 .ANG.); and the electron acceptor
substituted on R.sup.17 is positioned within 2 .ANG. of (7.0 .ANG.,
-2.7 .ANG., -7.0 .ANG.).
In certain embodiments of the presently disclosed compounds, the
computed low energy three-dimensional conformer has a root mean
square deviation from the given points of no greater than 3 .ANG.,
and a vector score greater than 0.2.
In certain embodiments of the presently disclosed compounds, the
computed low energy three-dimensional conformer has a root mean
square deviation from the given points of no greater than 1.5
.ANG., and a vector score greater than 0.4.
In certain embodiments of the presently disclosed compounds, the
computed lowenergy three-dimensional conformer has a root mean
square deviation from the given points of no greater than 1.2
.ANG., and a vector score greater than 0.5.
A centerpoint of a carbocyclic or heterocyclic ring is the average
position of the constituent atoms of the ring (i.e., excluding any
substituents) as positioned in the low energy three-dimensional
conformer. For example, the centerpoint of the left-hand
azacycloalkyl is the average position of its ring carbon and
nitrogen atom(s). Similarly, the centerpoint of a phenyl ring is
the average position of its six ring carbons. Centerpoints are
calculated only on single rings; multi-ring systems have multiple
centerpoints, one for each ring. For example, a benzofuran would
have two centerpoints, one calculated as the average position of
the six carbon rings making up the fused benzene subunit, and the
other calculated as the average position of the four carbon atoms
and one oxygen atom making up the fused furan subunit.
Low energy three-dimensional conformers can be calculated using the
Phase software package version 3.0, available from Schrodinger LLC.
Low energy three-dimensional conformers can be generated by a
torsion search procedure under OPLS.sub.--2005 force field with a
distance dependent dielectric constant. As the person of skill in
the art will appreciate, the low energy conformer should be
translated and rotated so that the oxygen of the E --C(O)-- group
is positioned at (0 .ANG., 0 .ANG., 0 .ANG.), or one of the oxygens
of the E --S(O).sub.2-- group is positioned at (0 .ANG., 0 .ANG., 0
.ANG.), and so that the root mean square deviation of the rest of
the listed features with respect to the given points is
minimized.
As the person of skill in the art will recognize, the various
embodiments described above can be combined to form other
embodiments of the presently disclosed compounds. For example, in
one embodiment, Q is --CH.sub.2--, as described above, and G is
--CH.sub.2--, as described above. In another embodiment, the ring
system denoted by "A" is a phenyl not fused to the azacycloalkyl,
the ring system denoted by "B" is a phenyl, J is --N(R.sup.38)--, D
is a carbon and Z is N.
Examples of compounds according to structural formula (I) include
those listed below in Table 1. These compounds can be made
according to the general schemes described below, for example using
procedures analogous to those described below in the Examples.
TABLE-US-00001 TABLE 1 No. Name Structure 1 tert-butyl 4-(6-(1-(4-
(trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazole-2-
carboxamido)piperidine-1- carboxylate ##STR00169## 2
N-(1-(4-cyanobenzyl)piperidin-4- yl)-6-(1-(4-
(trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazole-2-
carboxamide ##STR00170## 3 N-(1-(pyridin-4-ylmethyl)piperidin-
4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin-
4-yloxy)benzo[d]oxazole-2- carboxamide ##STR00171## 4
N-(1-(4-fluorobenzoyl)piperidin-4- yl)-6-(1-(4-
(trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazole-2-
carboxamide ##STR00172## 5 N-(piperidin-4-yl)-6-(1-(4-
(trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazole-2-
carboxamide ##STR00173## 6 N-(1-(4-cyanobenzyl)piperidin-4-
yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin-
4-yloxy)benzo[d]oxazole-2- carboxamide ##STR00174## 7
N-(4-isonicotinoylcyclohexyl)-6-(1- (4-
(trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazole-2-
carboxamide ##STR00175## 8 (5-(pyridin-4-ylmethyl)-2,5-
diazabicyclo[2.2.1]heptan-2-yl)(6- (1-(4-
(trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazol-2-
yl)methanone ##STR00176## 9 4-((5-(6-(1-(4-
(trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazole-2-
carbonyl)-2,5- diazabicyclo[2.2.1]heptan-2- yl)methyl)benzamide
##STR00177## 10 4-((5-(6-(1-(4- (trifluoromethyl)phenyl)piperidin-
4-yloxy)benzo[d]oxazole-2- carbonyl)-2,5-
diazabicyclo[2.2.1]heptan-2- yl)methyl)benzonitrile ##STR00178## 11
(5-isonicotinoyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)(6- (1-(4-
(trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazol-2-
yl)methanone ##STR00179## 12 4-(5-(6-(1-(4-
(trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazole-2-
carbonyl)-2,5- diazabicyclo[2.2.1]heptane-2- carbonyl)benzonitrile
##STR00180## 13 (5-(4-fluorobenzoyl)-2,5-
diazabicyclo[2.2.1]heptan-2-yl)(6- (1-(4-
(trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]oxazol-2-
yl)methanone ##STR00181## 14 tert-butyl 4-(6-(1-(4-
(trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]thiazole-2-
carboxamido)piperidine-1- carboxylate ##STR00182## 15
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-6-(1-(4-
(trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[d]thiazole-2-
carboxamide ##STR00183## 16 N-(1-(4-cyanobenzyl)piperidin-4-
yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin-
4-yloxy)benzo[d]thiazole-2- carboxamide ##STR00184## 17
N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-7-(1-(4-
(trifluoromethyl)phenyl)piperidin-
4-yloxy)imidazo[1,2-a]pyridine-2- carboxamide ##STR00185## 18
N-(1-(4-cyanobenzyl)piperidin-4- yl)-7-(1-(4-
(trifluoromethyl)phenyl)piperidin-
4-yloxy)imidazo[1,2-a]pyridine-2- carboxamide ##STR00186## 19
tert-butyl 4-(5-(1-(4- (trifluoromethyl)phenyl)piperidin-
4-yloxy)pyrazine-2- carboxamido)piperidine-1- carboxylate
##STR00187## 20 N-(piperidin-4-yl)-5-(1-(4-
(trifluoromethyl)phenyl)piperidin- 4-yloxy)pyrazine-2-carboxamide
##STR00188## 21 N-(1-(pyridin-4-ylmethyl)piperidin- 4-yl)-5-(1-(4-
(trifluoromethyl)phenyl)piperidin- 4-yloxy)pyrazine-2-carboxamide
##STR00189## 22 N-(1-(4-cyanobenzyl)piperidin-4- yl)-5-(1-(4-
(trifluoromethyl)phenyl)piperidin- 4-yloxy)pyrazine-2-carboxamide
##STR00190## 23 N-(1-(4-cyanobenzyl)piperidin-4- yl)-2-(1-(4-
(trifluoromethyl)phenyl)piperidin- 4-yloxy)thiazole-5-carboxamide
##STR00191## 24 N-(1-(4-cyanobenzyl)piperidin-4-
yl)-2-(1-(4-cyanophenyl)piperidin- 4-yloxy)thiazole-5-carboxamide
##STR00192## 25 N-(1-(4-cyanobenzyl)piperidin-4- yl)-2-(1-(4-
(trifluoromethyl)benzyl)piperidin-4- yloxy)thiazole-5-carboxamide
##STR00193## 26 tert-butyl 4-(5-(1-(4- cyanobenzyl)piperidin-4-
ylcarbamoyl)thiazol-2- yloxy)piperidine-1-carboxylate ##STR00194##
27 N-(1-(4-cyanobenzyl)piperidin-4- yl)-4-(1-(4-
ethoxybenzyl)piperidine-4- carbonyl)benzamide ##STR00195## 28
4-(4-(4-chlorobenzyl)piperazine-1- carbonyl)-N-(1-(4-
cyanobenzyl)piperidin-4- yl)benzamide ##STR00196## 29
4-(4-(4-chlorophenyl)piperazine-1- carbonyl)-N-(1-(4-
cyanobenzyl)piperidin-4- yl)benzamide ##STR00197## 30
N-(1-(4-cyanobenzyl)piperidin-4- yl)-4-(4-(5-
(trifluoromethyl)pyridin-2- yl)piperazine-1- carbonyl)benzamide
##STR00198## 31 N.sup.1-(1-(4-cyanobenzyl)piperidin-4-
yl)-N.sup.4-(1-(4- (trifluoromethyl)benzyl)piperidin-4-
yl)terephthalamide ##STR00199## 32
N.sup.1-(1-(4-cyanobenzyl)piperidin-4-
yl)-N.sup.4-(1-phenylpiperidin-4- yl)terephthalamide ##STR00200##
33 N.sup.1-(1-benzylpiperidin-4-yl)-N.sup.4-(1-
(4-cyanobenzyl)piperidin-4- yl)terephthalamide ##STR00201## 34
N-(1-(4-cyanobenzyl)piperidin-4- yl)-2-(4-fluorobenzyl)-1,2,3,4-
tetrahydroisoquinoline-7- carboxamide ##STR00202## 35
2-(4-fluorobenzyl)-N-(1-(pyridin-3-
ylmethyl)piperidin-4-yl)-1,2,3,4- tetrahydroisoquinoline-7-
carboxamide ##STR00203## 36 2-(4-fluorobenzyl)-N-(1-(4-
(trifluoromethyl)benzyl)piperidin-4-
yl)-1,2,3,4-tetrahydroisoquinoline- 7-carboxamide ##STR00204## 37
2-(4-cyanobenzyl)-N-(1-(4- cyanobenzyl)piperidin-4-yl)-
1,2,3,4-tetrahydroisoquinoline-7- carboxamide ##STR00205## 38
2-(4-cyanobenzyl)-N-(1-pyridin-3- ylmethyl)piperidin-4-yl)-1,2,3,4-
tetrahydroisoquinoline-7- carboxamide ##STR00206## 39
2-(4-cyanobenzyl)-N-(1-(4- (trifluoromethyl)benzyl)piperidin-4-
yl)-1,2,3,4-tetrahydroisoquinoline- 7-carboxamide ##STR00207## 40
N-(1-(4-cyanobenzyl)piperidin-4- yl)-2-(4-fluorobenzyl)-1,2,3,4-
tetrahydroisoquinoline-7- carboxamide ##STR00208## 41
2-(4-fluorobenzyl)-N-(1-(pyridine-
3-ylmethyl)piperidin-4-yl)-1,2,3,4- tetrahydroisoquinoline-7-
carboxamide ##STR00209## 42 2-(4-fluorobenzyl)-N-(1-(4-
(trifluoromethyl)benzyl)piperidin-4-
yl)-1,2,3,4-tetrahydroisoquinoline- 7-carboxamide ##STR00210##
The present disclosure contemplates combinations of particularly
described embodiments. For example, paragraph [0020] discloses
certain embodiments of ring system "B" and paragraph [0023]
discloses certain embodiments of T; also contemplated are
embodiments in which ring system "B" is as described as in
paragraph [0020], and T is as described in paragraph [0023]. This
disclosure contemplates all such combinations, to the extent the
definitions of the various structural features do not conflict with
one another.
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--CH.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--.
As used herein, the term "alkyl" includes alkyl, alkenyl and
alkynyl groups of a designed number of carbon atoms, desirably from
1 to about 12 carbons (i.e., inclusive of 1 and 12). The term
"C.sub.m--C.sub.n alkyl" 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.n alkyl" means an alkyl group having from m to n
carbon atoms. For example, "C.sub.1-C.sub.6 alkyl" 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.0 alkyl"), 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.6
alkyl)-Ar" signifies connection of an optionally substituted aryl
through a single bond or an alkylene bridge having from 1 to 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 12 carbons.
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.
The term "aryl" 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.
The term "heteroaryl" refers to an aromatic ring system containing
at least one heteroatom selected from nitrogen, oxygen and sulfur
in an aromatic ring. The heteroaryl may be fused to one or more
cycloalkyl or heterocycloalkyl rings. Examples of heteroaryl groups
include, for example, pyridyl, pyrimidinyl, quinolinyl,
benzothienyl, indolyl, indolinyl, pyridazinyl, pyrazinyl,
isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl,
imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,
indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl,
benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,
thiadiazolyl, benzo[1,4]oxazinyl, triazolyl, tetrazolyl,
isothiazolyl, naphthyridinyl, isochromanyl, chromanyl,
tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl,
isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl,
pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,
purinyl, benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl,
imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl,
benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl,
benzopyranyl, benzothiopyranyl, chromonyl, chromanonyl,
pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl,
dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl,
dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl,
benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl 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, oxazolyl N-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.
The term "heterocycloalkyl" 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 be saturated
(i.e., a heterocycloalkyl) or partially unsaturated (i.e., a
heterocycloalkenyl). Heterocycloalkyl includes monocyclic groups as
well as bicyclic and polycyclic ring systems, including bridged and
fused systems. 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. 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, homopiperidinyl,
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.
The term "cycloalkyl" 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.
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.
The term "ring system" encompasses monocycles, as well as fused
and/or bridged polycycles.
The term "oxa" means a divalent oxygen radical in a chain,
sometimes designated as --O--.
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.
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, cyano, --(C.sub.1-C.sub.4 fluoroalkyl), --O--(C.sub.1-C.sub.4
fluoroalkyl), --C(O)--(C.sub.0-C.sub.4 alkyl),
--C(O)O--(C.sub.0-C.sub.4 alkyl), --C(O)N(C.sub.0-C.sub.4
alkyl)(C.sub.0-C.sub.4 alkyl), --S(O).sub.2O--(C.sub.0-C.sub.4
alkyl), 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.
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.
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, --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.+, --P(O)(OR.sup.71).sub.2,
--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.3 alkyl 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.6 alkyl) or (C.sub.1-C.sub.6
fluoroalkyl); 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.3 alkyl 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 be 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.
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.80C(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.
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, --OC(S)R.sup.70,
--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.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.30 and M.sup.+ are as previously defined.
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.
In certain preferred embodiments, substituent groups on
"substituted" alkyl, cycloalkyl, heterocycloalkyl, aryl and
heteroaryl groups are -halo, --OH, --O--(C.sub.1-C.sub.4 alkyl),
--O--(C.sub.1-C.sub.4 haloalkyl), --N(C.sub.0-C.sub.4
alkyl)(C.sub.0-C.sub.4 alkyl), --SH,
--S(O).sub.0-2--(C.sub.1-C.sub.4 alkyl), --(C.sub.1-C.sub.4 alkyl),
--(C.sub.1-C.sub.4 haloalkyl), --C(O)--(C.sub.0-C.sub.4 alkyl),
--C(O)N(C.sub.0-C.sub.4 alkyl)(C.sub.0-C.sub.4 alkyl),
--N(C.sub.0-C.sub.4 alkyl)C(O)(C.sub.0-C.sub.4
alkyl)(C.sub.0-C.sub.4 alkyl), --C(O)O--(C.sub.0-C.sub.4 alkyl),
--OC(O)--(C.sub.0-C.sub.4 alkyl), S(O).sub.2--O(C.sub.0-C.sub.4
alkyl), and --NO.sub.2, in which no alkyl is further
substituted.
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-gluconic acid, glycolic acid, lactic
acid, malic acid, malonic acid, mandelic acid, phosphoric acid,
propanoic acid, succinic acid, sulfuric acid, tartaric acid (d, 1,
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-glutaric 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.
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.
The compounds disclosed herein can also be provided as
N-oxides.
The presently disclosed compounds, salts, prodrugs and N-oxides can
be provided, for example, in solvate or hydrate form.
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 will be apparent to those of
skill in the art upon consideration of the present compounds,
certain atoms can be enriched an isotope of that atom. 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 can be enriched in a radioactive isotope
of carbon, such as .sup.13C. Such compounds can be useful, for
example, in studying the AMPK pathway and its role in
metabolism.
Compounds can be assayed for binding to a membrane-bound
adiponectin receptor by performing a competitive binding assay with
adiponectin. In one such procedure, HEK 293 cellular membrane is
coated onto a COSTAR 384 plate, which is then blocked with 1%
casein. Polyhistidine-tagged globular adiponectin and a candidate
compound is incubated with the membrane in HEPES buffer. Unbound
ligands are washed away and the degree of binding of the
adiponectin is determined using horseradish peroxidase-conjugated
anti-polyhistidine. Compounds that compete with adiponectin binding
to the membrane (i.e., give a reduced signal compared to a control
performed without a candidate compound) can be chosen as hits and
further screened using the below-described functional assays to
identify adiponectin receptor agonists.
An in-cell western assay can be performed to demonstrate the
activation of AMPK in human liver cells by globular adiponectin
using glutathione S-transferase (GST). AMPK activity can be
measured by the relative concentration of phosphorylated acetyl
Co-A carboxylase, which is one of the products of AMPK. An increase
in pACC correlates with an increase in the rate of fatty acid
oxidation.
The compounds of structural formulae (I)-(CXXIV) 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.
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)-(CXXIV).
In the pharmaceutical compositions disclosed herein, one or more
compounds of structural formulae (I)-(CXXIV) 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)-(CXXIV) 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.
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 be 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 be 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.
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.
Formulations for oral use can also be presented as lozenges.
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.
Oily suspensions can be formulated by suspending the active
ingredients in a vegetable oil, for example arachis 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.
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.
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.
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.
Compounds of structural formulae (I)-(CXXIV) 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.
Compounds of structural formula (I)-(CXXIV) 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.
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 formulae
(V)-(VI) can be prepared according to Scheme 1, below, or analogous
synthetic schemes:
##STR00211##
Referring to Scheme 1, a 4-aminoresorcinol i, for example, is
reacted with methyl trimethoxyacetate to form a methyl
hydroxybenzo[d]oxazolecarboxylate ii, which in turn is saponified
then condensed with a heterocycloalkylamine (e.g., a protected
4-aminopiperidine) to form an N-heterocycloalkyl
hydroxybenzo[d]oxazolecarboxamide iv.
Hydroxybenzo[d]oxazolecarboxamide iv is coupled with, for example,
a 1-substituted piperidin-4-ol (e.g.,
1-(4-(trifluoromethyl)phenyl)piperidin-4-ol) to form an
N-substituted-heterocycloalkyloxybenzo[d]oxazolecarboxamide v. The
heterocycloalkyl moiety of the carboxamide can then be further
substituted. For example, as shown in Scheme 1, in which the
N-substituent of the amide is a 1-protected piperidin-4-yl, the
protecting group can be removed and the piperidine nitrogen can be
coupled with an aroyl halide or an arylmethyl halide to form
compound vii. Of course, in certain situations one of ordinary
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. Synthetic examples are provided below in Example
1.
Compounds of structural formulae (VII)-(VIII) can be prepared
according to Scheme 2, below, or analogous synthetic schemes:
##STR00212##
Referring to Scheme 2, a 6-methoxybenzo[d]thiazole-2-carbonitrile
i, for example, is reacted with pyridinium hydrochloride, then
acidic methanol to form methyl hydroxybenzo[d]thiazolecarboxylate
iii, which in turn is saponified and acidified to form acid iv.
Acid iv is then condensed with a heterocycloalkylamine (e.g., a
protected 4-aminopiperidine) to form an N-heterocycloalkyl
hydroxybenzo[d]thiazolecarboxamide v. Hydroxybenzo[d]thiazole
carboxamide v is coupled with, for example, a 1-substituted
piperidin-4-ol (e.g., 1-(4-trifluoromethylphenyl)piperidin-4-ol)
then deprotected to form an
N-substituted-heterocycloalkyloxybenzo[d]thiazolecarboxamide vi.
The heterocycloalkyl moiety of the carboxamide can then be further
substituted. For example, as shown in Scheme 2, in which the
N-substituent of the amide is a 1-protected piperidin-4-yl, the
protecting group can be removed and the piperidine nitrogen can be
coupled with an arylmethyl halide (or e.g. an aroyl halide) to form
compound viii. One of ordinary skill in the art would recognize
that different reagents can be used to affect one or more of the
individual steps or to protect intermediates where appropriate.
Specific synthetic examples are provided below in Example 2.
Compounds of structural formulae (IX)--(XII) can be prepared
according to Scheme 3, below, or analogous synthetic schemes:
##STR00213##
Referring to Scheme 3, a 2-amino-4-methoxypyridine is reacted with
ethyl 3-bromo-2-oxopropanoate to form an ethyl
7-methoxyimidazo[1,2-a]pyridine-2-carboxylate ii, which is
hydrolyzed, for example, with hydrobromic acid to provide
7-hydroxyimidazo[1,2-a]pyridine-2-carboxylic acid as its
hydrobromide salt iii. The
7-hydroxyimidazo[1,2-a]pyridine-2-carboxylic acid iii is then
condensed with a heterocycloalkylamine (e.g., a protected
4-aminopiperidine) to form an N-heterocycloalkyl
7-hydroxyimidazo[1,2-a]pyridine-2-carboxamide iv.
7-Hydroxyimidazo[1,2-a]pyridine-2-carboxamide iv is coupled with,
for example, a 1-substituted piperidin-4-ol (e.g.,
1-(4-trifluoromethylphenyl)piperidin-4-ol) to form an
N-substituted-heterocycloalkyloxyimidazo[1,2-a]pyridinecarboxamide
v. The heterocycloalkyl moiety of the carboxamide can then be
further substituted. For example, as shown in Scheme 3, in which
the N-substituent of the amide is a 1-protected piperidin-4-yl, the
protecting group can be removed and the piperidine nitrogen can be
coupled with an arylmethyl halide (or alternatively an aroyl
halide) to form compound vii. Of course, in certain situations one
of ordinary 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. Specific synthetic examples are
provided below in Example 3.
Compounds of structural formulae (XIII)-(XIV) can be prepared
according to Scheme 4, below, or analogous synthetic schemes:
##STR00214##
Referring to Scheme 4, a methyl chloropyrazine-2-carboxylate i, for
example, is reacted with a 1-substituted piperidin-4-ol (e.g.,
1-(4-trifluoromethylphenyl)piperidin-4-ol) to form a methyl
(piperidin-4-yloxy)pyrazine-2-carboxylate ii, which in turn is
saponified and then acidified to form the corresponding carboxylic
acid iii. The (piperidin-4-yloxy)pyrazine-2-carboxylic acid iii is
condensed with a heterocycloalkylamine (e.g., a protected
4-aminopiperidine) to form an
N-substituted-heterocycloalkyloxypyrazinecarboxamide iv. The
heterocycloalkyl moiety of the carboxamide can then be further
substituted. For example, as shown in Scheme 4, in which the
N-substituent of the amide is a 1-protected piperidin-4-yl, the
protecting group can be removed and the piperidine nitrogen can be
coupled with an arylmethyl halide (or alternatively an aroyl
halide) to form compound vi. Of course, in certain situations one
of ordinary 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. Specific synthetic examples are
provided below in Example 4.
Compounds of structural formulae (XV) --(XVII) can be prepared
according to Scheme 5, below, or analogous synthetic schemes:
##STR00215##
Referring to Scheme 5, a bromothiazolecarboxylic acid i can be
condensed with an appropriately substituted heterocycloalkylamine
(e.g., 4-((4-aminopiperidin-1-yl)methyl)benzonitrile in the example
of Scheme 1) to form the N-heterocycloalkyl
bromothiazolecarboxamide ii. Bromothiazolecarboxamide ii can then
be coupled with, for example, a 1-substituted piperidin-4-ol (e.g.,
1-(4-trifluoromethylphenyl)piperidin-4-ol) to form an N-substituted
heterocycloalkyloxybromothiazolecarboxamide iii. Of course, in
certain situations one of ordinary skill in the art will use
different reagents to affect one or more of the individual steps,
use protected versions of certain of the substituents or use
alternative synthetic strategies to synthesize the presently
disclosed compounds. Specific synthetic examples are provided below
in Example 5.
Compounds of structural formulae (XXXI)-(XXXIII) can be prepared
according to Scheme 6, below, or analogous synthetic schemes:
##STR00216##
Referring to Scheme 6, carboxylic acid ester i can be condensed
with an appropriately substituted heterocycloalkylamine (e.g.,
4-((4-aminopiperidin-1-yl)methyl)benzonitrile in the example of
Scheme 6) to form the methyl (heterocycloalkylcarbamoyl)benzoate
ii. Benzoate ii can then be saponified to form the corresponding
benzoic acid iii, which is then coupled with an appropriate amine
(e.g., a substituted piperidine as shown in Scheme 6, or
alternatively a substituted piperazine, or a substituted
piperidinylamine) to form an N-substituted terephthalamide ii. Of
course, in certain situations one of ordinary 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.
Specific synthetic examples provided below in Example 6.
Compounds of structural formulae (XL)-(XLIII) can be prepared
according to Scheme 7, below, or analogous synthetic schemes:
##STR00217##
Referring to Scheme 7, a cyano-1,2,3,4-tetrahydroisoquinoline i can
be converted to the corresponding methyl ester ii, then reductively
coupled with an aryl aldehyde to form a methyl
2-benzyl-1,2,3,4-tetrahydroisoquinoline carboxylate iii.
Saponification of iii to its corresponding carboxylic acid iv
followed by condensation with a heterocycloalkylamine (in this
case, a 1-benzylpiperidin-4-ylamine) can provide carboxamide v. Of
course, the person of skill in the art can modify this scheme to
provide the desired substitution and regiochemistry of the final
compound. Moreover, in certain situations one of ordinary 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. Specific synthetic examples are provided below in
Example 7.
One of skill in the art can adapt the reaction sequences of Schemes
1-7 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)-(CXXIV) can be synthesized using different routes
altogether.
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.
While not intending to be bound by theory, the inventors surmise
that compounds of structural formulae (I)-(CXXIV) are mimics of
adiponectin which act as adiponectin receptor agonists, thereby
activating the AMPK pathway. 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 AMPK
pathway, compounds of structural formulae (I)-(CXXIV) should also
inhibit the inflammatory processes which occur during the early
phases of atherosclerosis. Accordingly, compounds of structural
formulae (I)-(CXXIV) 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.
Accordingly, another aspect of the present disclosure relates to a
method of activating the AMPK pathway. According to this aspect, 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, N-oxide (or solvate or
hydrate thereof) or composition described above.
In one embodiment, 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, N-oxide (or
solvate or hydrate thereof) 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 the presently disclosed compounds can increase
the rate of phosphorylation of ACC, they can reduce the inhibition
of fatty acid oxidation and therefore increase its overall
rate.
In another embodiment, a method of decreasing glycogen
concentration in a cell 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.
In another embodiment, a method of increasing glucose uptake in a
cell 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.
In another embodiment, a method of reducing triglyceride levels in
a subject includes administering to the subject an effective amount
of a compound, pharmaceutically acceptable salt, prodrug, N-oxide
(or solvate or hydrate thereof) or composition described above.
In another embodiment, a method of increasing insulin sensitivity
of a subject includes administering to the subject an effective
amount of a compound, pharmaceutically acceptable salt prodrug,
N-oxide (or solvate or hydrate thereof) or composition described
above.
Accordingly, the compounds and compositions disclosed herein can be
used to treat a variety of metabolic disorders. For example, in one
embodiment, 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.
In another embodiment, 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 prodrug, N-oxide (or
solvate or hydrate thereof) or composition described above.
As described above, the compounds disclosed herein can act as
activators of the AMPK pathway. Accordingly, in another embodiment,
a method comprises modulating the AMPK pathway (either in vitro or
in vivo) by contacting a cell with a compound, pharmaceutically
acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof)
or composition described above, or administering a compound,
pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or
hydrate thereof) 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.
Another embodiment is the use of a compound, pharmaceutically
acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof)
or composition as described above in the manufacture of a
medicament for any of the therapeutic purposes described above. For
example, the medicament can be for the reduction of triglyceride
levels in a subject, the treatment of type II diabetes in a
subject, or the treatment or prevention of atherosclerosis or
cardiovascular disease in a subject.
The compounds disclosed herein can be linked to labeling agents,
for example for use in variety of experiments exploring their
receptor binding, efficacy and metabolism. Accordingly, another
embodiment is a labeled conjugate comprising a compound as
disclosed herein covalently linked to a labeling agent, optionally
through a linker. Suitable linker and labeling agents will be
readily apparent to those of skill in the art upon consideration of
the present disclosure. The labeling agent can be, for example, an
affinity label such as biotin or strepavidin, a hapten such as
digoxigenin, an enzyme such as a peroxidase, or a fluorophoric or
chromophoric tag. Any suitable linker can be used. For example, in
some embodiments, an ethylene glycol, oligo(ethylene glycol) or
poly(ethylene glycol) linker is used. Other examples of linkers
include amino acids, which can be used alone or in combination with
other linker groups, such as ethylene glycol, oligoethylene glycol
or polyethylene glycol. Suitable linkers include, without
limitation, single amino acids, as well as di- and tripeptides. In
one embodiment, the linker includes a glycine residue. The person
of skill in the art will realize, of course, that other linkers and
labeling agents can be used. In other embodiments, an alkylene
chain is the linker. In other embodiments, the linker has the
structure --[(C.sub.0-C.sub.3 alkyl)-Y.sup.m--].sub.m--, in which
each Y.sup.m is --O--, --N(R.sup.9)--, or L, and m is in the range
of 1-40. For example, in certain embodiments, a labeled conjugate
has structural formula (CXXV):
##STR00218## in which the "LINK" moiety is a linker and is
optional, and the "LABEL" moiety is a labeling agent, and all other
variables are as described above, for example with reference to
structural formula (I). Any of the compounds disclosed with
reference to structural formulae (I)-(CXXIV) can be used in the
labeled conjugate of structural formula (CXXV).
In certain embodiments, the -(LINK).sub.0-1-(LABEL) moiety is
attached the "B" ring system at a benzo, pyrido, pyrazino or thieno
ring position in the meta position relative to the J moiety. For
example, in one embodiment, a labeled conjugate has structural
formula (CXXVI):
##STR00219## in which the "LINK" moiety is a linker and is
optional, and the "LABEL" moiety is a labeling agent, and all other
variables are as described above, for example with reference to
structural formula (I).
For example, in one particular embodiment, a labeled conjugate has
structural formula (CXXVII):
##STR00220## in which all variables are as described above, for
example with reference to structural formula (I).
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
(a) Synthetic Example: tert-butyl
4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-ca-
rboxamido)piperidine-1-carboxylate (compound 1)
Step 1
A mixture of 4-aminobenzene-1,3-diol hydrochloride (i in Scheme 1)
(0.50 g, 3.1 mmol) and sodium hydrogen carbonate (2.5 mg) in methyl
trimethoxyacetate (2 mL) was stirred at 100.degree. C. overnight
and then concentrated under reduced pressure. The residue obtained
was purified by flash chromatography (silica gel, methylene
chloride/ethyl acetate=9/1) to afford methyl
6-hydroxybenzo[d]oxazole-2-carboxylate as a white solid (0.49 g,
82%). .sup.1H-NMR (DMSO-d.sub.6, 300 MHz): .delta. 10.26 (s, 1H),
7.70 (m, 1H), 7.12 (m, 1H), 6.95 (m, 1H), 3.92 (s, 3H) ppm; MS
(ESI): 194.3 (M+1).
Step 2
A mixture of methyl 6-hydroxybenzo[d]oxazole-2-carboxylate (0.19 g,
1 mmol) and 1N aqueous sodium hydroxide (2 mL) was stirred at room
temperature overnight. The reaction mixture was then acidified with
concentrated hydrochloric acid. The precipitate was filtered,
washed with water, and dried under reduced pressure to afford
6-hydroxybenzo[d]oxazole-2-carboxylic acid as a white solid (0.16
g, 88%). .sup.1H-NMR (DMSO-d.sub.6, 300 MHz): .delta. 10.17 (s,
1H), 7.66 (m, 1H), 7.08 (m, 1H), 6.92 (m, 1H) ppm; MS (ESI): 180.1
(M+1).
Step 3
To a stirred mixture of 6-hydroxybenzo[d]oxazole-2-carboxylic acid
(0.15 g, 0.86 mmol) in anhydrous N,N-dimethylformamide (2 mL) was
added triethylamine (0.10 g, 0.99 mmol), 1-hydroxybenzotriazole
hydrate (0.14 g, 0.99 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.20
g, 0.99 mmol), and tert-butyl 4-aminopiperidine-1-carboxylate (0.20
g, 0.99 mmol). The mixture was stirred at room temperature
overnight and then concentrated under reduced pressure. The residue
obtained was purified by flash chromatography (silica gel, ethyl
acetate/hexanes=1/1) to afford tert-butyl
4-(6-hydroxybenzo[d]oxazole-2-carboxamido)piperidine-1-carboxylate
as a off-white solid (0.16 g, 52%). .sup.1H-NMR (DMSO-d.sub.6, 300
MHz): .delta. 10.10 (s, 1H), 9.04 (m, 1H), 7.63 (m, 1H), 7.10 (m,
1H), 7.27 (m, 5H), 6.91 (m, 1H), 3.92 (m, 3H), 2.78 (m, 2H), 1.72
(m, 2H), 1.49 (m, 2H), 1.38 (s, 9H); MS (ESI): 362.1 (M+1).
Step 4
To a stirred solution of tert-butyl
4-(6-hydroxybenzo[d]oxazole-2-carboxamido)piperidine-1-carboxylate
(0.15 g, 0.41 mmol) in toluene (4 mL) at room temperature was added
diisopropyl azodicarboxylate (0.1 g, 0.49 mmol),
1-(4-(trifluoromethyl)phenyl)piperidin-4-ol (0.1 g, 0.41 mmol), and
triphenylphosphine (0.13 g, 0.49 mmol). The mixture was stirred at
room temperature overnight and then concentrated under reduced
pressure. The residue obtained was purified by flash chromatography
(silica gel, ethyl acetate/hexanes=2/3) to afford tert-butyl
4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-ca-
rboxamido)piperidine-1-carboxylate (compound 1) as a off-white
solid (0.16 g, 66%). .sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta.
7.65 (m, 1H), 7.48 (m, 2H), 7.15 (m, 1H), 7.05 (m, 2H), 6.96 (m,
2H), 4.56 (m, 1H), 4.12 (m, 3H), 3.60 (m, 2H), 3.28 (m, 2H), 2.93
(m, 2H), 2.04 (m, 8H), 1.47 (s, 9H) ppm; MS (ESI): 589.6 (M+1).
(b) Synthetic Example: Compounds 2-7
Step 1
A mixture of tert-butyl
4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-ca-
rboxamido)piperidine-1-carboxylate (compound 1) (0.16 g, 0.27 mmol)
and 4N hydrochloric acid in dioxane (2 mL) was stirred at room
temperature for 1 h. The reaction mixture was concentrated and
washed with diethyl ether (2.times.3 mL) and then dried under
reduced pressure to afford
N-(piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benz-
o[d]oxazole-2-carboxamide dihydrochloride salt as a off-white solid
(0.15 g, 99%). .sup.1H NMR (CD.sub.3OD, 300 MHz) 7.83 (m, 5H), 7.48
(s, 1H), 7.23 (m, 1H), 4.93 (m, 1H), 4.22 (m, 1H), 3.90 (m, 3H),
3.35 (m, 2H), 3.17 (m, 2H), 2.23 (m, 8H), 1.98 (m, 2H) ppm; MS (ES)
489.1 (M+1).
Step 2
To a stirred mixture of
N-(piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benz-
o[d]oxazole-2-carboxamide dihydrochloride salt (0.03 g, 0.05 mmol)
in anhydrous N,N-dimethylformamide (0.5 mL) or methylene chloride
(1 mL) at room temperature was added the appropriately-substituted
benzyl halide (0.06 mmol) or benzoyl halide (0.06 mmol) and
N,N-diisopropylethylamine (0.03 g, 0.22 mmol). The resulting
mixture was stirred at room temperature overnight. After this time
the mixture was concentrated under reduced pressure and the
resulting residue was purified by flash chromatography (silica gel,
methylene chloride/methanol/30% ammonium hydroxide) to afford
compounds 2-7 in solid form.
N-(1-(4-Cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piper-
idin-4-yloxy)benzo[d]oxazole-2-carboxamide (compound 2):
.sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 7.63 (m, 2H), 7.46 (m,
4H), 7.18-6.94 (m, 6H), 4.58 (m, 1H), 4.03 (m, 1H), 3.58 (m, 4H),
3.29 (m, 2H), 2.82 (m, 2H), 2.11 (m, 8H), 1.61 (m, 2H) ppm; MS
(ESI): 604.7 (M+1).
N-(1-(Pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)-
piperidin-4-yloxy)benzo[d]oxazole-2-carboxamide (compound 3):
.sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 8.55 (m, 2H), 7.65 (m,
1H), 7.48 (m, 2H), 7.28 (m, 2H), 7.08 (m, 3H), 6.94 (m, 2H), 4.56
(m, 1H), 4.04 (m, 1H), 3.62 (m, 2H), 3.56 (s, 2H), 3.28 (m, 2H),
2.89-1.91 (m, 8H), 1.67 (m, 2H) ppm; MS (ESI): 578.5 (M-1).
N-(1-(4-Fluorobenzoyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)pip-
eridin-4-yloxy)benzo[d]oxazole-2-carboxamide (compound 4):
.sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 7.66 (m, 1H), 7.44 (m,
4H), 7.10 (m, 5H), 6.96 (m, 2H), 4.58 (m, 1H), 4.27 (m, 1H), 3.28
(m, 2H), 3.13 (m, 2H), 2.12 (m, 4H), 2.01 (m, 2H), 1.58 (m, 4H)
ppm; MS (ESI): 611.6 (M+1).
N-(Piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benz-
o[d]oxazole-2-carboxamide (compound 5): .sup.1H NMR (CD.sub.3OD,
300 MHz) 7.83 (m, 5H), 7.48 (s, 1H), 7.23 (m, 1H), 4.93 (m, 1H),
4.22 (m, 1H), 3.90 (m, 3H), 3.35 (m, 2H), 3.17 (m, 2H), 2.23 (m,
8H), 1.98 (m, 2H) ppm; MS (ES) 489.1 (M+1).
N-(1-(4-Cyanobenzoyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)pipe-
ridin-4-yloxy)benzo[d]oxazole-2-carboxamide (compound 6):
.sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 7.74 (m, 2H), 7.66 (m,
1H), 7.50 (m, 4H), 7.14 (m, 2H), 7.06 (m, 1H), 6.96 (m, 2H), 4.71
(m, 1H), 4.58 (m, 1H), 4.28 (m, 1H), 3.60 (m, 3H), 3.16 (m, 4H),
2.04 (m, 6H), 1.63 (m, 2H) ppm; MS (ESI): 618.5 (M+1).
N-(4-Isonicotinoylcyclohexyl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-
-yloxy)benzo[d]oxazole-2-carboxamide (compound 7): .sup.1H-NMR
(CDCl.sub.3, 300 MHz): .delta. 8.71 (m, 2H), 7.65 (m, 1H), 7.48 (m,
2H), 7.29 (m, 2H), 7.16 (m, 2H), 7.06 (m, 1H), 6.96 (m, 2H), 4.72
(m, 1H), 4.58 (m, 1H), 4.28 (m, 1H), 3.62 (m, 3H), 3.16 (m, 4H),
2.04 (m, 6H), 1.65 (m, 2H) ppm; MS (ESI): 594.5 (M+1).
(c) Synthetic Example: Compounds 9-11
Compounds 9-11 were prepared using procedures analogous to those
described in Example 1(a).
4-((5-(6-(1-(4-(Trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole--
2-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)benzamide
(compound 9): .sup.1H NMR (CDCl.sub.3, 300 MHz) 8.542 (m, 2H), 7.67
(m, 1H), 7.43 (m, 4H), 7.48 (m, 2H), 7.31 (m, 2H), 7.17 (m, 1H),
7.01 (m, 3H), 4.58 (m, 1H), 3.95 (m, 1H), 3.82 (m, 2H), 3.59 (m,
4H), 3.28 (m, 2H), 2.96 (m, 1H). 2.80 (m, 1H), 2.02 (m. 6H) ppm; MS
(ES) 578.6 (M+H).
4-((5-(6-(1-(4-(Trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole--
2-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)benzonitrile
(compound 10): .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 7.90 (m, 1H),
7.79 (m, 3H), 7.56 (m, 1H), 7.42 (m, 4H), 7.28 (m, 1H), 7.08 (m,
3H), 4.75 (m, 1H), 3.79 (m, 2H), 3.60 (m, 4H), 3.36 (m, 2H), 2.93
(m, 1H), 2.70 (m, 1H), 2.59 (m, 2H), 1.91 (m, 6H) ppm; MS (ES)
620.6 (M+H).
(5-Isonicotinoyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)(6-(1-(4-(trifluorome-
thyl)phenyl)piperidin-4-yloxy)benzo[d]oxazol-2-yl)methanone
(compound 11): .sup.1H NMR (CDCl.sub.3, 300 MHz) 8.73 (m, 2H),
7.710 (m, 1H), 7.47 (m, 2H), 7.40 (m, 2H), 7.16 (m, 1H), 7.04 (m,
1H), 6.96 (m, 2H), 4.57 (m, 1H), 4.19 (m, 1H), 3.83 (m, 3H), 3.60
(m, 4H), 3.28 (m, 2H), 2.04 (m, 6H) ppm; MS (ES) 592.5 (M+H).
(d) Increase in AMPK Activity
Compounds 1-13 were assayed for their ability to activate AMPK
using an enzyme-linked immunosorbent assay. The EC.sub.50 values
for AMPK activation for compounds 1-13 are presented in Table 2
below, in which "A" is less than 0.1 .mu.M; "B" is 0.1-1 .mu.M; "C"
is 1-10 .mu.M; and "D" is 10-100 .mu.M:
TABLE-US-00002 TABLE 2 Cpd No. AMPK EC.sub.50 1 A 2 A 3 A 4 A 5 D 6
A 7 A 8 B 9 B 10 B 11 B 12 A 13 A
Example 2
(a) Synthetic Example: tert-butyl
4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]thiazole-2-c-
arboxamido)piperidine-1-carboxylate (compound 14)
Step 1
A mixture of 6-methoxybenzo[d]thiazole-2-carbonitrile (1.0 g, 5.3
mmol) and dry pyridinium hydrochloride (11.3 g, 98.1 mmol) was
stirred at 190.degree. C. for 3 h. After the completion of
reaction, it was cooled to room temperature to obtain a yellow
solid. This solid was purified by flash chromatography (silica gel,
methylene chloride/ethyl acetate=25/1) to afford
6-hydroxybenzo[d]thiazole-2-carbonitrile as a yellow solid (0.42 g,
45%). .sup.1H-NMR (DMSO-d.sub.6, 300 MHz): .delta. 10.20 (s, 1H),
8.70 (m, 1H), 8.45 (m, 1H), 8.10 (m, 1H) ppm; MS (ESI): 177.1
(M+1).
Step 2
Dry methanol (30 mL) was bubbled with dry HCl gas for 10 min. To
this solution was added 6-hydroxybenzo[d]thiazole-2-carbonitrile
(0.42 g, 2.38 mmol) and the resulting mixture was stirred at room
temperature for 4 days. The resulting solids were collected by
filtration, washed with water and dried under reduced pressure to
afford methyl 6-hydroxybenzo[d]thiazole-2-carboxylate as a yellow
solid (0.43 g, 86%). .sup.1H-NMR (DMSO-d.sub.6, 300 MHz): .delta.
10.28 (s, 1H), 7.99 (m, 1H), 7.46 (m, 1H), 7.08 (m, 1H), 3.93 (s,
3H) ppm; MS (ESI): 210.1 (M+1).
Step 3
A mixture of methyl 6-hydroxybenzo[d]thiazole-2-carboxylate (0.21
g, 1 mmol) and 1N aqueous sodium hydroxide (2 mL) was stirred at
room temperature overnight. The reaction mixture was then carefully
acidified with concentrated hydrochloric acid. The precipitate
formed was filtered, washed with water, and dried under reduced
pressure to afford 6-hydroxybenzo[d]thiazole-2-carboxylic acid as a
white solid (0.20 g, 99%). .sup.1H-NMR (DMSO-d.sub.6, 300 MHz):
.delta. 10.20 (s, 1H), 7.96 (m, 1H), 7.44 (m, 1H), 7.06 (m, 1H)
ppm; MS (ESI): 196.1 (M+1).
Step 4
To a stirred mixture of 6-hydroxybenzo[d]thiazole-2-carboxylic acid
(0.20 g, 1 mmol) in anhydrous N,N-dimethylformamide (2 mL) was
added triethylamine (0.12 g, 1.2 mmol), 1-hydroxybenzotriazole
hydrate (0.16 g, 1.2 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23
g, 1.2 mmol), and tert-butyl 4-aminopiperidine-1-carboxylate (0.24
g, 1.2 mmol). The mixture was stirred at room temperature overnight
and then concentrated under reduced pressure. The residue obtained
was purified by flash chromatography (silica gel, ethyl
acetate/hexanes=1/1) to afford tert-butyl
4-(6-hydroxybenzo[d]thiazole-2-carboxamido)piperidine-1-carboxylate
as a white solid (0.23 g, 62%). .sup.1H-NMR (CDCl.sub.3, 300 MHz):
.delta. 7.90 (m, 1H), 7.38 (m, 1H), 7.28 (m, 2H), 7.11 (m, 1H),
4.12 (m, 3H), 2.95 (m, 2H), 2.04 (m, 2H), 1.58 (m, 2H), 1.48 (s,
9H) ppm; MS (ESI): 379.1 (M+1).
Step 5
To a stirred solution of tert-butyl
4-(6-hydroxybenzo[d]thiazole-2-carboxamido)piperidine-1-carboxylate
(0.20 g, 0.54 mmol) in toluene (4 mL) at room temperature was added
diisopropyl azodicarboxylate (0.13 g, 0.64 mmol),
1-(4-(trifluoromethyl)phenyl)-piperidin-4-ol (0.13 g, 0.54 mmol),
and triphenylphosphine (0.17 g, 0.64 mmol). The mixture was stirred
at room temperature overnight and then concentrated under reduced
pressure. The residue obtained was purified by flash chromatography
(silica gel, ethyl acetate/hexanes=3/7) to afford tert-butyl
4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]thiazole-2-c-
arboxamido)piperidine-1-carboxylate (compound 14) as a white solid
(0.28 g, 86%). .sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 7.95 (m,
1H), 7.48 (m, 3H), 7.27 (m, 1H), 7.17 (m, 1H), 6.97 (m, 2H), 4.62
(m, 1H), 4.12 (m, 3H), 3.61 (m, 2H), 3.29 (m, 2H), 2.95 (m, 2H),
2.06 (m, 6H), 1.56 (m, 2H), 1.41 (s, 9H) ppm; MS (ESI): 605.5
(M+1).
(b) Synthetic Example: Compounds 15-16
Step 1
A mixture of tert-butyl
4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]thiazole-2-c-
arboxamido)piperidine-1-carboxylate (compound 8) (0.16 g, 0.27
mmol) and 4N hydrochloric acid in dioxane (2 mL) was stirred at
room temperature for 1 h. The reaction mixture was concentrated and
washed with diethyl ether (2.times.3 mL) and then dried under
reduced pressure to afford
N-(piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benz-
o[d]thiazole-2-carboxamide as a off-white solid (0.15 g, 99%).
.sup.1H NMR (CD.sub.3OD, 300 MHz) 7.83 (m, 5H), 7.48 (s, 1H), 7.23
(m, 1H), 4.93 (m, 1H), 4.22 (m, 1H), 3.90 (m, 3H), 3.35 (m, 2H),
3.17 (m, 2H), 2.23 (m, 8H), 1.98 (m, 2H) ppm; MS (ES) 489.1
(M+1).
Step 2
To a stirred mixture of
N-(piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benz-
o[d]thiazole-2-carboxamide (0.03 g, 0.05 mmol) in anhydrous
N,N-dimethylformamide (0.5 mL) at room temperature was added the
appropriately-substituted benzyl bromide (0.06 mmol) and
N,N-diisopropylethylamine (0.03 g, 0.22 mmol). The resulting
mixture was stirred at room temperature overnight. After this time
the mixture was concentrated under reduced pressure and the
resulting residue was purified by flash chromatography (silica gel,
methylene chloride/methanol/30% ammonium hydroxide) to afford
compounds 15-16 in solid form.
N-(1-(Pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)-
piperidin-4-yloxy)benzo[d]thiazole-2-carboxamide (compound 15):
.sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 8.56 (m, 2H), 7.95 (m,
1H), 7.46 (m, 3H), 7.27 (m, 3H), 7.17 (m, 1H), 6.97 (m, 2H), 4.62
(m, 1H), 4.01 (m, 1H), 3.62 (m, 2H), 3.53 (s, 2H), 3.29 (m, 2H),
2.84 (m, 2H), 2.13 (m, 8H), 1.68 (m, 2H) ppm; MS (ESI): 596.5
(M+1).
N-(1-(4-Cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piper-
idin-4-yloxy)benzo[d]thiazole-2-carboxamide (compound 16):
.sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 7.95 (m, 1H), 7.62 (m,
2H), 7.45 (m, 5H), 7.27 (m, 1H), 7.17 (m, 1H), 6.96 (m, 2H), 4.62
(m, 1H), 4.02 (m, 1H), 3.61 (m, 4H), 3.29 (m, 2H), 2.84 (m, 2H),
2.11 (m, 8H), 1.69 (m, 2H) ppm; MS (ESI): 620.5 (M+1).
(c) Increase in AMPK Activity
Compounds 14-16 were assayed for their ability to activate AMPK
using an enzyme-linked immunosorbent assay. The EC.sub.50 values
for AMPK activation for compounds 14-16 are presented in Table 3
below, in which "A" is less than 0.1 .mu.M; "B" is 0.1-1 .mu.M; "C"
is 1-10 .mu.M; and "D" is 10-100 .mu.M:
TABLE-US-00003 TABLE 3 Cpd No. AMPK EC.sub.50 14 C 15 B 16 B
Example 3
(a) Synthetic Example: tert-butyl
4-(7-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)imidazo[1,2-a]pyridi-
ne-2-carboxamido)piperidine-1-carboxylate
Step 1
A mixture of 2-amino-4-methoxypyridine (1.0 g, 8.1 mmol) and ethyl
3-bromo-2-oxopropanoate (1.77 g, 9.1 mmol) in ethanol (10 mL) was
refluxed for 6 h. After the reaction was concentrated, ethyl
acetate (20 mL) was added to the residue. The mixture was basified
by saturated aqueous sodium bicarbonate. The separated organic
layer was washed with brine and dried over sodium sulfate. The
solvent was evaporated and the residue obtained was purified by
flash chromatography (silica gel, methylene chloride/ethyl
acetate=1/1) to afford ethyl
7-methoxyimidazo[1,2-a]pyridine-2-carboxylate as a solid (1.04 g,
58%). .sup.1H-NMR (DMSO-d.sub.6, 300 MHz): .delta. 8.37 (m, 2H),
6.91 (s, 1H), 6.70 (m, 1H), 4.25 (m, 2H), 3.81 (s, 3H), 1.28 (m,
3H) ppm; MS (ESI): 221.1 (M+1).
Step 2
A mixture of ethyl 7-methoxyimidazo[1,2-a]pyridine-2-carboxylate
(0.22 g, 1.0 mmol) and 48% hydrobromic acid (20 mL) was heated at
reflux for 3 days. After the completion of reaction, the reaction
mixture was concentrated and the residue obtained was washed with
diethyl ether and dried under reduced pressure to afford
7-hydroxyimidazo[1,2-a]pyridine-2-carboxylic acid hydrobromide salt
as a brown solid (0.24 g, 93%). .sup.1H-NMR (CD.sub.3OD, 300 MHz):
.delta. 8.57 (m, 1H), 8.44 (s, 1H), 7.07 (m, 1H), 6.95 (m, 1H) ppm;
MS (ESI): 178.1 (M+1).
Step 3
To a stirred mixture of
7-hydroxyimidazo[1,2-a]pyridine-2-carboxylic acid hydrobromide salt
(0.24 g, 0.93 mmol) in anhydrous N,N-dimethylformamide (2 mL) was
added triethylamine (0.22 g, 2.2 mmol), 1-hydroxybenzotriazole
hydrate (0.16 g, 1.2 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23
g, 1.2 mmol), and tert-butyl 4-aminopiperidine-1-carboxylate (0.24
g, 1.2 mmol). The mixture was stirred at room temperature overnight
and then concentrated under reduced pressure. The residue obtained
was purified by flash chromatography (silica gel, ethyl
acetate/hexanes=1/1) to afford tert-butyl
4-(7-hydroxyimidazo[1,2-a]pyridine-2-carboxamido)piperidine-1-carboxylate
as an off-white solid (0.27 g, 81%). .sup.1H-NMR (CDCl.sub.3, 300
MHz): .delta. 7.93 (m, 2H), 7.31 (m, 1H), 7.25 (m, 1H), 6.85 (m,
1H), 6.65 (m, 1H), 4.08 (m, 3H), 3.13 (m, 2H), 2.93 (m, 2H), 1.97
(m, 2H), 1.44 (s, 9H) ppm; MS (ESI): 361.1 (M+1).
Step 4
To a stirred solution of tert-butyl
4-(7-hydroxyimidazo[1,2-a]pyridine-2-carboxamido)piperidine-1-carboxylate
(0.18 g, 0.50 mmol) in toluene (4 mL) at room temperature was added
diisopropyl azodicarboxylate (0.12 g, 0.6 mmol),
1-(4-(trifluoromethyl)phenyl)-piperidin-4-ol (0.12 g, 0.5 mmol),
and triphenylphosphine (0.16 g, 0.6 mmol). The mixture was stirred
at room temperature overnight and then concentrated under reduced
pressure. The residue obtained was purified by flash chromatography
(silica gel, methylene chloride/methanol/30% ammonium
hydroxide=20/1/0.01) to afford tert-butyl
4-(7-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)imidazo[1,2-a]pyridi-
ne-2-carboxamido)piperidine-1-carboxylate as a off-white solid
(0.13 g, 44%). .sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 7.97 (m,
2H), 7.47 (m, 2H), 7.18 (m, 1H), 6.95 (m, 2H), 6.81 (s, 1H), 6.58
(m, 1H), 4.56 (m, 1H), 4.11 (m, 3H), 3.61 (m, 2H), 3.26 (m, 2H),
2.92 (m, 2H), 2.15 (m, 2H), 2.03 (m, 4H), 1.66 (m, 2H), 1.47 (s,
9H) ppm; MS (ESI): 588.4 (M+1).
(b) Synthetic Example: Compounds 17-18
Step 1
A mixture of tert-butyl
4-(7-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)imidazo[1,2-a]pyridi-
ne-2-carboxamido)piperidine-1-carboxylate (0.13 g, 0.22 mmol) and
4N hydrochloric acid in dioxane (2 mL) was stirred at room
temperature for 1 h. The reaction mixture was concentrated and
washed with diethyl ether (2.times.3 mL) and then dried under
reduced pressure to afford
N-(piperidin-4-yl)-7-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)imid-
azo[1,2-a]pyridine-2-carboxamide dihydrochloride salt as a brown
solid (0.13 g, 98%). .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta. 8.72
(m, 1H), 8.56 (m, 1H), 7.64 (m, 2H), 7.45 (m, 2H), 7.31 (m, 1H),
7.26 (m, 1H), 4.97 (m, 1H), 3.64 (m, 5H), 3.01 (m, 2H), 2.14 (m,
10H) ppm; MS (ES) 488.1 (M+1).
Step 2
To a stirred mixture of
N-(piperidin-4-yl)-7-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)imid-
azo[1,2-a]pyridine-2-carboxamide dihydrochloride salt (0.03 g, 0.05
mmol) in anhydrous N,N-dimethylformamide (0.5 mL) at room
temperature was added the appropriately-substituted benzyl bromide
(0.06 mmol) and N,N-diisopropylethylamine (0.03 g, 0.22 mmol). The
resulting mixture was stirred at room temperature overnight. After
this time the mixture was concentrated under reduced pressure and
the resulting residue was purified by flash chromatography (silica
gel, methylene chloride/methanol/30% ammonium hydroxide) to afford
compounds 17-18 in solid form.
N-(1-(Pyridin-4-ylmethyl)piperidin-4-yl)-7-(1-(4-(trifluoromethyl)phenyl)-
piperidin-4-yloxy)imidazo[1,2-a]pyridine-2-carboxamide (compound
17): .sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 8.55 (m, 2H), 7.97
(m, 2H), 7.48 (m, 2H), 7.30 (m, 2H), 7.20 (m, 1H), 6.96 (m, 2H),
6.82 (m, 1H), 6.57 (m, 1H), 4.56 (m, 1H), 4.02 (m, 1H), 3.60 (m,
4H), 3.26 (m, 2H), 2.88 (m, 2H), 2.20 (m, 4H), 2.02 (m, 4H), 1.68
(m, 2H) ppm; MS (ESI): 579.6 (M+1).
N-(1-(4-Cyanobenzyl)piperidin-4-yl)-7-(1-(4-(trifluoromethyl)phenyl)piper-
idin-4-yloxy)imidazo[1,2-a]pyridine-2-carboxamide (compound 18):
.sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 7.96 (m, 2H), 7.61 (m,
2H), 7.47 (m, 4H), 7.17 (m, 1H), 6.95 (m, 2H), 6.81 (m, 1H), 6.58
(m, 1H), 4.56 (m, 1H), 4.02 (m, 1H), 3.59 (m, 4H), 3.26 (m, 2H),
2.82 (m, 2H), 2.17 (m, 4H), 2.01 (m, 4H), 1.65 (m, 2H) ppm; MS
(ESI): 603.6 (M+1).
(c) Increase in AMPK Activity
Compounds 17-18 were assayed for their ability to activate AMPK
using an enzyme-linked immunosorbent assay. The EC.sub.50 values
for AMPK activation for compounds 17-18 are presented in Table 4
below, in which "A" is less than 0.1 .mu.M; "B" is 0.1-1 .mu.M; "C"
is 1-10 .mu.M; and "D" is 10-100 .mu.M:
TABLE-US-00004 TABLE 4 Cpd No. AMPK EC.sub.50 17 A 18 A
Example 4
(a) Synthetic Example: tert-butyl
4-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxami-
do)piperidine-1-carboxylate (compound 19)
Step 1
1-(4-(Trifluoromethyl)phenyl)piperidin-4-ol (0.59 g, 2.41 mmol) was
dissolved in anhydrous N,N-dimethylformamide (10 mL), cooled in an
ice bath and treated with 60% sodium hydride (0.1 g, 2.55 mmol).
The mixture was allowed to warm to room temperature over 1 h. A
solution of methyl 5-chloropyrazine-2-carboxylate (0.5 g, 2.9 mmol)
in anhydrous N,N-dimethylformamide (1 mL) was added and the mixture
was stirred at room temperature overnight. The mixture was quenched
by water and extracted with ethyl acetate. The organic layer was
dried over sodium sulfate and evaporated. The residue obtained was
purified by flash chromatography (silica gel, ethyl
acetate/hexanes=1/4) to afford methyl
5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxylate
as a white solid (0.23 g, 25%). .sup.1H-NMR (CD.sub.3Cl, 300 MHz):
.delta. 8.86 (m, 1H), 8.28 (m, 1H), 7.48 (m, 2H), 6.96 (m, 2H),
5.36 (m, 1H), 4.00 (s, 3H), 3.64 (m, 2H), 3.26 (m, 2H), 2.16 (m,
2H), 1.99 (m, 2H) ppm; MS (ESI): 382.6 (M+1).
Step 2
A mixture of methyl
5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxylate
(0.10 g, 0.26 mmol) and 2N aqueous sodium hydroxide (0.4 mL) in
acetone (2 mL) was stirred at room temperature for 0.5 h. The
reaction mixture was acidified by concentrated hydrochloric acid
and concentrated under reduced pressure to afford
5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxylic
acid hydrochloric acid salt as an off-white solid (0.10 g, 96%)
which was used next step without further purifications. MS (ESI):
368.4 (M+1).
Step 3
To a stirred mixture of
5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxylic
acid hydrochloric acid salt (0.10 g, 0.25 mmol) in anhydrous
N,N-dimethylformamide (3 mL) was added triethylamine (0.56 g, 0.55
mmol), 1-hydroxybenzotriazole hydrate (0.04 g, 0.3 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.06
g, 0.3 mmol), and tert-butyl 4-aminopiperidine-1-carboxylate (0.06
g, 0.3 mmol). The mixture was stirred at room temperature overnight
and then concentrated under reduced pressure. The residue obtained
was purified by flash chromatography (silica gel, ethyl
acetate/hexanes=1/1) to afford tert-butyl
4-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxami-
do)piperidine-1-carboxylate (compound 19) as a white solid (0.06 g,
44%). .sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 8.89 (m, 1H), 8.06
(m, 1H), 7.50 (m, 3H), 6.96 (m, 2H), 5.33 (m, 1H), 4.10 (m, 3H),
3.64 (m, 2H), 3.25 (m, 2H), 2.95 (m, 2H), 2.15 (m, 2H), 1.97 (m,
4H), 1.56 (m, 2H), 1.47 (s, 9H) ppm; MS (ESI): 550.7 (M+1).
(b) Synthetic Example: Compounds 20-22
Step 1
A mixture of tert-butyl
4-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxami-
do)piperidine-1-carboxylate (0.06 g, 0.11 mmol) and 4N hydrochloric
acid in dioxane (1 mL) was stirred at room temperature for 0.5 h.
The reaction mixture was concentrated and washed with diethyl ether
(2.times.1 mL) and then dried under reduced pressure to afford
N-(piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyra-
zine-2-carboxamide dihydrochloride salt (compound 20) as a brown
solid (0.56 g, 99%). .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta. 8.80
(s, 1H), 8.25 (s, 5H), 7.59 (m, 2H), 7.28 (m, 2H), 5.44 (m, 1H),
4.18 (m, 1H), 3.55 (m, 4H), 3.77 (m, 2H), 3.42 (m, 4H), 3.15 (m,
2H), 2.07 (m, 8H) ppm; MS (ES) 450.5 (M+1).
Step 2
To a stirred mixture of
N-(piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyra-
zine-2-carboxamide dihydrochloride salt (0.03 g, 0.05 mmol) in
anhydrous N,N-dimethylformamide (0.5 mL) at room temperature was
added the appropriately-substituted benzyl bromide (0.06 mmol)
(0.06 mmol) and N,N-diisopropylethylamine (0.03 g, 0.22 mmol). The
resulting mixture was stirred at room temperature overnight. After
this time the mixture was concentrated under reduced pressure and
the resulting residue was purified by flash chromatography (silica
gel, methylene chloride/methanol/30% ammonium hydroxide) to afford
compounds 21-22 in solid form.
N-(1-(Pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)-
piperidin-4-yloxy)pyrazine-2-carboxamide (compound 21): .sup.1H-NMR
(CDCl.sub.3, 300 MHz): .delta. 8.87 (m, 1H), 8.56 (m, 1H), 8.06 (m,
1H), 7.49 (m, 3H), 7.31 (m, 2H), 6.95 (m, 2H), 5.33 (m, 1H), 4.03
(m, 3H), 3.58 (m, 4H), 3.25 (m, 2H), 2.87 (m, 2H), 2.35-1.69 (m,
10H) ppm; MS (ESI): 541.8 (M+1).
N-(1-(4-Cyanobenzyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piper-
idin-4-yloxy)pyrazine-2-carboxamide (compound 22): .sup.1H-NMR
(CDCl.sub.3, 300 MHz): .delta. 8.89 (m, 1H), 8.06 (m, 1H), 7.61 (m,
2H), 7.48 (m, 5H), 6.96 (m, 2H), 5.34 (m, 1H), 4.00 (m, 1H), 3.62
(m, 4H), 3.24 (m, 2H), 2.80 (m, 2H), 2.19 (m, 4H), 1.99 (m, 4H),
1.63 (m, 2H) ppm; MS (ESI): 565.9 (M+1).
(c) Increase in AMPK Activity
Compounds 19-22 were assayed for their ability to activate AMPK
using an enzyme-linked immunosorbent assay. The EC.sub.50 values
for AMPK activation for compounds 19-22 are presented in Table 5
below, in which "A" is less than 0.1 .mu.M; "B" is 0.1-1 .mu.M; "C"
is 1-10 .mu.M; "D" is 10-100 .mu.M and "F" is >100 .mu.M:
TABLE-US-00005 TABLE 5 Cpd No. AMPK EC.sub.50 19 C 20 F 21 A 22
A
Example 5
(a) Synthetic Example:
N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(1-(4-(trifluoromethyl)phenyl)piper-
idin-4-yloxy)thiazole-5-carboxamide (compound 23)
Step 1
To a stirred mixture of 2-bromothiazole-5-carboxylic acid (500 mg,
2.4 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added
triethylamine (1.1 mL, 7.92 mmol), HATU (1 g, 2.64 mmol), and
4-((4-aminopiperidin-1-yl)methyl)benzonitrile (762 mg, 2.64 mmol).
The mixture was stirred at room temperature overnight and then
poured into water. The resulting solids were collected by
filtration and purified by column chromatography to yield 972 mg
(100%) of
2-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)thiazole-5-carboxamide
as a yellow solid. LCMS (m/z): 406 (MH.sup.+).
Step 2
To a stirred solution of
1-(4-(trifluoromethyl)benzyl)piperidin-4-ol (121 mg, 0.493 mmol) in
N,N-dimethylormamide (5 mL) at room temperature was slowly added
sodium hydride (30 mg, 0.741 mmol).
2-Bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)thiazole-5-carboxamide
(100 mg, 0.247 mmol) was added to the reaction mixture, which was
stirred at 80.degree. C. overnight and then poured into ice-water.
The residue was purified by flash chromatography (silica gel, 2%
methanol in methylene chloride) to afford
N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(1-(4-(trifluoromethyl)phenyl)piper-
idin-4-yloxy)thiazole-5-carboxamide (compound 23) as a yellow solid
(30 mg, 21%). .sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 7.61 (m,
2H), 7.499-7.425 (m, 5H), 6.93 (d, 2H), 6.98 (d, 2H), 5.64 (d, 1H),
5.207 (m, 1H), 3.935 (m, 1H), 3.589 (m, 2H), 3.561 (s, 2H), 3.249
(m, 2H), 2.821 (m, 2H), 2.196 (m, 4H), 2.028 (m, 4H), 1.587 (m,
2H); LCMS: MS (m/z): 570 (MH.sup.+).
(b) Synthetic Example: Compounds 24-25
Compounds 24 and 25 were prepared using procedures analogous to
those described in Example 5(a).
N-(1-(4-Cyanobenzyl)piperidin-4-yl)-2-(1-(4-cyanophenyl)piperidin-4-yloxy-
)thiazole-5-carboxamide (compound 24): .sup.1H-NMR (CDCl.sub.3, 300
MHz): .delta. 7.61 (m, 2H), 7.499-7.425 (m, 5H), 6.880 (d, 2H),
5.66 (d, 1H), 5.2031 (m, 1H), 3.935 (m, 1H), 3.589 (m, 2H), 3.555
(s, 2H), 3.321 (m, 2H), 2.821 (m, 2H), 2.187 (m, 4H), 2.015 (m,
4H), 1.566 (m, 2H); LCMS: MS (m/z): 527 (MH.sup.+).
N-(1-(4-Cyanobenzyl)piperidin-4-yl)-2-(1-(4-(trifluoromethyl)benzyl)piper-
idin-4-yloxy)thiazole-5-carboxamide (compound 25): .sup.1H-NMR
(CDCl.sub.3, 300 MHz): .delta. 7.570 (m, 4H), 7.419-7.471 (m, 5H),
5.66 (d, 1H), 5.103 (m, 1H), 3.935 (m, 1H), 3.71 (m, 1H), 3.565 (m,
4H), 2.76 (m, 4H), 2.29 (m, 2H), 2.18 (m, 2H), 2.015 (m, 4H), 1.566
(m, 4H); LCMS: MS (m/z): 584 (MH.sup.+).
tert-Butyl
4-(5-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)thiazol-2-yloxy)piperidine-
-1-carboxylate (compound 26): .sup.1H NMR (DMSO-d.sub.6) .delta.
8.26 (d, J=7.4 Hz, 1H), 7.82 (s, 1H), 7.78 (d, J=7.4 Hz, 2H), 7.71
(d, J=7.7 Hz, 2H), 5.15-5.05 (m, 1H), 3.68-3.58 (m, 2H), 3.56 (s,
2H), 3.24-3.12 (m, 2H), 2.82-2.72 (m, 3H), 2.10-1.94 (m, 4H),
1.82-1.72 (m, 2H), 1.69-1.46 (m, 4H), 1.40 (s, 9H). MS
(M+H)=526.
(c) Increase in AMPK Activity
Compounds 23-26 were assayed for their ability to activate AMPK
using an enzyme-linked immunosorbent assay. The EC.sub.50 values
for AMPK activation for compounds 23-26 are presented in Table 6
below, in which "A" is less than 0.1 .mu.M; "B" is 0.1-1 .mu.M; "C"
is 1-10 .mu.M; "D" is 10-100 .mu.M and "F" is >100 .mu.M:
TABLE-US-00006 TABLE 6 Cpd No. AMPK EC.sub.50 23 A 24 A 25 A 26
C
Example 6
(a) Synthetic Example:
N-(1-(4-cyanobenzyl)piperidin-4-yl)-4-(1-(4-ethoxybenzyl)piperidine-4-car-
bonyl)benzamide (compound 27)
Step 1
To a stirred mixture of 4-(methoxycarbonyl)benzoic acid (1 g, 5.55
mmol) in anhydrous N,N-dimethylormamide (5 mL) was added
triethylamine (2.6 ml, 18.32 mmol), HATU (2.32 g, 6.11 mmol), and
4-((4-aminopiperidin-1-yl)methyl)benzonitrile as its HCl salt (1.6
g, 5.55 mmol). The mixture was stirred at room temperature
overnight and then poured into water. The resulting solids were
collected by filtration, purified by column chromatography to yield
0.91 g (44%) of methyl
4-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)benzoate as a white
solid. LCMS (m/z): 379 (MH.sup.+).
Step 2
Methyl 4-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)benzoate (900
mg, 2.38 mmol) and lithium hydroxide (600 mg, 14.28 mmol) was added
to MeOH/THF/H.sub.2O(2/1/1, 20 mL), and the mixture was stirred
overnight, then acidified with 2M hydrochloric acid (10 mL) to pH
5. A white solid separated, and was collected by filtration and
washed with water. The combined filtrate and washings were
acidified by adding further 2M hydrochloric acid to pH 1 and the
solution was extracted three times with ethyl acetate. The combined
organic extracts were washed with brine, dried with magnesium
sulphate and evaporated to give
4-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)benzoic acid (0.718 g,
83%). LCMS (m/z): 364 (MH.sup.+).
Step 3
To a stirred mixture of
4-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)benzoic acid (100 mg,
0.275 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added
triethylamine (84 .mu.l, 0.825 mmol), HATU (115 mg, 0.3 mmol), and
4-(4-ethoxybenzyl)piperidine (61 mg, 0.275 mmol). The mixture was
stirred at room temperature overnight and then poured into water.
The resulting solids were collected by filtration, purified by
column chromatography to yield 0.7 g (55%) of
N-(1-(4-cyanobenzyl)piperidin-4-yl)-4-(1-(4-ethoxybenzyl)piperidine-4-car-
bonyl)benzamide (compound 27) as an offwhite solid. .sup.1H-NMR
(CDCl.sub.3, 300 MHz): .delta. 7.761 (d, 2H), 7.600 (m, 2H), 7.434
(m, 4H), 7.022 (d, 2H), 6.812 (d, 2H), 6.022 (d, 1H), 4.658 (m,
1H), 3.994 (dd, 2H), 3.569 (m, 3H), 2.885 (m, 4H), 2.505 (m, 2H),
2.227 (m, 2H), 2.049 (m, 2H), 1.639 (m, 6H), 1.405 (m, 3H); LCMS
(m/z): 565 (MH.sup.+).
(b) Synthetic Example: Compounds 28-33
Compounds 28-31 were prepared using procedures analogous to those
described in Example 6(a).
4-(4-(4-Chlorobenzyl)piperazine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-
-4-yl)benzamide (compound 28): .sup.1H-NMR (CDCl.sub.3, 300 MHz):
.delta. 7.8 (d, 2H), 7.6 (d, 2H), 7.43 (m, 4H), 7.22 (m, 4H), 6.0
(d, 1H), 4.01 (m, 1H), 3.89 (m, 2H), 3.563 (s, 2H), 3.496 (s, 2H),
3.39 (m, 2H), 2.82 (m, 2H), 2.5 (m, 2H), 2.36 (m, 2H), 2.21 (m,
4H), 2.01 (m, 2H); LCMS (m/z): 565 (MH.sup.+).
4-(4-(4-Chlorophenyl)piperazine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-
-4-yl)benzamide (compound 29): .sup.1H-NMR (CDCl.sub.3, 300 MHz):
.delta. 7.79 (d, 2H), 7.600 (d, 2H), 7.434 (m, 4H), 7.21 (d, 2H),
6.83 (d, 2H), 5.98 (d, 1H), 4.05 (m, 1H), 3.9 (m, 2H), 3.565 (s,
2H), 3.12 (m, 4H), 2.81 (m, 2H), 2.21 (m, 4H), 2.04 (m, 4H); LCMS
(m/z): 542 (MH.sup.+).
N-(1-(4-Cyanobenzyl)piperidin-4-yl)-4-(4-(5-(trifluoromethyl)pyridin-2-yl-
)piperazine-1-carbonyl)benzamide (compound 30): .sup.1H-NMR
(CDCl.sub.3, 300 MHz): .delta. 8.396 (s, 1H), 7.8 (d, 2H), 7.65 (m,
2H), 7.621 (d, 2H), 7.47 (dd, 4H), 6.57 (d, 1H), 4.05 (m, 1H), 3.90
(m, 2H), 3.69 (m, 4H), 2.85 (m, 2H), 2.24 (m, 4H), 2.06 (m, 4H);
LCMS (m/z): 577 (MH.sup.+).
N.sup.1-(1-(4-Cyanobenzyl)piperidin-4-yl)-N.sup.4-(1-(4-(trifluoromethyl)-
benzyl)piperidin-4-yl)terephthalamide (compound 31): .sup.1H-NMR
(CDCl.sub.3, 300 MHz): .delta. 7.783 (m, 4H), 7.585 (m, 4H), 7.434
(m, 4H), 7.44 (d, 4H), 6.0 (m, 2H), 4.1 (m, 2H), 3.6 (m, 4H), 2.854
(m, 4H), 2.23 (m, 8H), 2.05 (m, 4H); LCMS (m/z): 604
(MH.sup.+).
N.sup.1-(1-(4-Cyanobenzyl)piperidin-4-yl)-N.sup.4-(1-phenylpiperidin-4-yl-
)terephthalamide (compound 32): MS (m/z): 522 (MH.sup.+).
N.sup.1-(1-Benzylpiperidin-4-yl)-N.sup.4-(1-(4-cyanobenzyl)piperidin-4-yl-
)terephthalamide (compound 33): MS (m/z): 536 (MH.sup.+).
(c) Increase in AMPK Activity
Compounds 27-33 were assayed for their ability to activate AMPK
using an enzyme-linked immunosorbent assay. The EC.sub.50 values
for AMPK activation for compounds 27-33 are presented in Table 7
below, in which "A" is less than 0.1 .mu.M; "B" is 0.1-1 .mu.M; "C"
is 1-10 .mu.M; and "D" is 10-100 .mu.M:
TABLE-US-00007 TABLE 7 Cpd No. AMPK EC.sub.50 27 A 28 A 29 D 30 A
31 A 32 D 33 D
Example 7
(a) Synthetic Example:
2-(4-cyanobenzyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-1,2,3,4-tetrahydroi-
soquinoline-7-carboxamide (compound 37)
Step 1
A solution of 7-cyano-1,2,3,4-tetrahydroisoquinoline (5 g, 31.6
mmol) in methanol (150 mL) was saturated with HCl gas (bubbled HCl
gas into solution for 15 min at room temperature) and placed in a
sealed tube. The resulting reaction mixture was heated at
65.degree. C. for 17 h, concentrated to dryness and partitioned
between 5% sodium bicarbonate solution (200 mL) and dichloromethane
(50 mL). The layers were separated and the aqueous layer was
extracted with dichloromethane (3.times.25 mL). The combined
organic layer was dried (MgSO.sub.4), filtered and concentrated to
provide methyl 1,2,3,4-tetrahydroisoquinoline-7-carboxylate
hydrochloride as a pale brown oily residue (4.5 g, 63%). .sup.1H
NMR (CDCl.sub.3) .delta. 7.82 (1H, dd, J=8.0, 1.7 Hz); 7.74 (1H, d,
J=1.4 Hz); 7.18 (1H, d, J=8.0 Hz); 4.16 (2H, br s); 3.92 (3H, s);
3.27 (2H, br s); 2.97 (2H, br s). MS (M+H).sup.+=192.
Step 2
Sodium triacetoxyborohydride (2.2 g, 10.4 mmol) was added to a
solution of methyl 1,2,3,4-tetrahydroisoquinoline-7-carboxylate
hydrochloride (1.0 g, 4.4 mmol) and 4-cyanobenzaldehyde (0.83 g,
6.3 mmol) in dichloromethane (10 mL). The resulting reaction
mixture was allowed to stir at room temperature overnight, poured
over saturated sodium bicarbonate solution (75 mL) and extracted
with dichloromethane (3.times.30 mL). The combined organic layer
was washed with water (2.times.30 mL), dried (MgSO.sub.4), filtered
and concentrated to give a foamy residue. Column chromatography
(30% ethyl acetate/hexanes) provided methyl
2-(4-cyanobenzyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate as a
white crystalline solid upon trituration with ethyl ether (1.30 g,
97%). .sup.1H NMR (CDCl.sub.3) .delta. 7.85 (1H, d, J=7.7 Hz);
7.72-7.58 (5H, m); 7.23 (1H, d, J=8.0 Hz); 4.00-3.98 (2H, m); 3.92
(3H, s); 3.83 (2H, br s); 3.08 (2H, br s); 2.97 (2H, br s). MS
(M+H).sup.+=307.
Step 3
A solution of methyl
2-(4-cyanobenzyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate
(1.26 g, 4.1 mmol) and lithium hydroxide hydrate (1.04 g, 24.8
mmol) in THF/MeOH/H.sub.2O (2:1:1, 48 mL) was allowed to stir at
room temperature until all the starting material disappeared
(overnight). The resulting cloudy reaction mixture was then
concentrated to give a yellow foamy residue. Trituration with 10%
HCl solution provided
2-(4-cyanobenzyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid
hydrochloride as a white crystalline solid upon filtration and
drying under vacuum (1.06 g, 78%). .sup.1H NMR (DMSO-d.sub.6)
.delta. 11.52 (1H, br s); 7.97 (2H, d, J=8.3 Hz); 7.87 (2H, d,
J=8.0 Hz); 7.79 (2H, d, J=9.4 Hz); 7.35 (1H, d, J=8.0 Hz); 4.55
(2H, br s); 4.36 (2H, br s); 3.65 (1H, br s); 3.31 (2H, d, J=9.9
Hz); 3.12 (1H, t, J=13.5 Hz). MS (M+H).sup.+=293.
Step 4
To a solution of
2-(4-cyanobenzyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid
hydrochloride (50 mg, 0.17 mmol) in DMF (2 mL), HATU (78 mg, 0.21
mmol), 4-amino-1-(4-cyanobenzyl)piperidine dihydrochloride (52 mg,
0.18 mmol) and triethylamine (125 uL, 91 mg, 0.9 mmol) were added.
The resulting reaction mixture was allowed to stir at room
temperature overnight and poured into saturated sodium bicarbonate
solution (30 mL) to give a white precipitate which was filtered and
dried under vacuum. The resulting solid was triturated with ethyl
ether to provide
2-(4-cyanobenzyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-1,2,3,4-tetrahydroi-
soquinoline-7-carboxamide (compound 37) as a white crystalline
solid (69 mg, 82%). .sup.1H NMR (DMSO-d.sub.6): .delta. 8.08 (1H,
d, J=7.7 Hz); 7.79 (4H, dd, J=8.5, 6.9 Hz); 7.60-7.54 (3H, m); 7.49
(3H, d, J=8.8 Hz); 7.16 (1H, d, J=8.3 Hz); 3.78-3.66 (3H, m); 3.55
(4H, br s); 2.86 (2H, t, J=5.2 Hz); 2.82-2.66 (4H, m); 2.04 (2H, t,
J=11.3 Hz); 1.75 (2H, d, J=11.3 Hz); 1.55 (2H, q, J=11.8 Hz). MS
(M+H).sup.+=490.
(b) Synthetic Example: Compounds 34-36 and 38-39
Compounds 34-36 and 38-39 were prepared using procedures analogous
to those described in Example 7(a).
N-(1-(4-Cyanobenzyl)piperidin-4-yl)-2-(4-fluorobenzyl)-1,2,3,4-tetrahydro-
isoquinoline-7-carboxamide (compound 34): .sup.1H NMR
(DMSO-d.sub.6): .delta. 8.08 (d, J=7.7 Hz, 1H), 7.78 (d, J=8.3 Hz,
2H), 7.57 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.3 Hz, 3H), 7.41-7.36 (m,
2H), 7.18-7.12 (m, 3H), 3.78-3.68 (m, 1H), 3.64 (s, 2H), 3.53 (d,
J=7.7 Hz, 4H), 2.89-2.65 (m, 6H), 2.04 (t, J=10.6 Hz, 2H), 1.74 (d,
J=12.1 Hz, 2H), 1.54 (q, J=11.6 Hz, 2H). MS (M+H).sup.+=483.
2-(4-Fluorobenzyl)-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-1,2,3,4-tetra-
hydroisoquinoline-7-carboxamide (compound 35): .sup.1H NMR
(DMSO-d.sub.6): .delta. 8.47-8.44 (m, 2H), 8.08 (d, J=7.7 Hz, 1H),
7.68 (d, J=7.7 Hz, 1H), 7.57 (d, J=7.7 Hz, 1H), 7.47 (s, 1H),
7.40-7.32 (m, 3H), 7.18-7.12 (m, 3H), 3.78-3.68 (m, 1H), 3.64 (s,
2H), 3.50 (d, J=9.9 Hz, 4H), 2.89-2.64 (m, 6H), 2.02 (t, J=11.1 Hz,
2H), 1.74 (d, J=11.8 Hz, 2H), 1.55 (q, J=12.0 Hz, 2H). MS
(M+H).sup.+=459.
2-(4-Fluorobenzyl)-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-1,2,3,-
4-tetrahydroisoquinoline-7-carboxamide (compound 36): .sup.1H NMR
(DMSO-d.sub.6): .delta. 8.09 (d, J=7.7 Hz, 1H), 7.67 (d, J=8.3 Hz,
2H), 7.57 (d, J=8.0 Hz, 1H), 7.52 (d, J=7.7 Hz, 2H), 7.47 (s, 1H),
7.41-7.36 (m, 2H), 7.18-7.12 (m, 3H), 3.78-3.68 (m, 1H), 3.64 (s,
2H), 3.54 (d, J=8.5 Hz, 4H), 2.89-2.74 (m, 4H), 2.73-2.64 (m, 2H),
2.04 (t, J=11.1 Hz, 2H), 1.75 (d, J=12.4 Hz, 2H), 1.55 (q, J=10.6
Hz, 2H). MS (M+H).sup.+=526.
2-(4-Cyanobenzyl)-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-1,2,3,4-tetrah-
ydroisoquinoline-7-carboxamide (compound 38): White crystalline
solid (58 mg, 73%). .sup.1H NMR (DMSO-d.sub.6): .delta. 8.68-8.65
(2H, m); 8.45 (1H, d, J=7.2 Hz); 7.99-7.93 (3H, m); 7.74 (3H, d,
J=8.0 Hz); 7.64 (1H, s); 7.55-7.51 (1H, dd, J=7.7, 4.7 Hz); 7.32
(1H, d, J=8.0 Hz); 4.54 (3H, br s); 4.35 (2H, br s); 4.31 (2H, br
s); 4.06-3.9 (1H, m); 3.43 (3H, d, J=11.3 Hz); 3.13 (4H, br s);
2.01 (2H, d, J=12.4 Hz); 1.75 (2H, q, J=11.7 Hz). MS
(M+H).sup.+=466.
2-(4-Cyanobenzyl)-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-1,2,3,4-
-tetrahydroisoquinoline-7-carboxamide (compound 39): White
crystalline solid (47 mg, 52%). .sup.1H NMR (DMSO-d.sub.6): .delta.
8.09 (1H, d, J=8.0 Hz); 7.81 (2H, d, J=8.3 Hz); 7.68 (2H, d, J=8.0
Hz); 7.60-7.44 (6H, m); 7.16 (1H, d, J=8.0 Hz); 3.78-3.66 (3H, m);
3.56 (4H, br s); 2.91-2.66 (6H, m); 2.07 (2H, m); 1.75 (2H, d,
J=11.0 Hz); 1.57 (2H, q, J=11.7 Hz). MS (M+H).sup.+=533.
(c) Synthetic Example:
N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(4-fluorobenzyl)-1,2,3,4-tetrahydro-
isoquinoline-7-carboxamide (compound 40)
Step 1
Methyl
2-(4-fluorobenzyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate was
prepared as described in step 2 of Example 7(a), above, using
4-fluorobenzaldehyde in place of 4-cyanobenzaldehyde. Column
chromatography (20.fwdarw.30% ethyl acetate/hexanes) provided the
compound as an off-white crystalline solid (1.26 g, 81%). .sup.1H
NMR (CDCl.sub.3) .delta. 7.84 (1H, d, J=7.7 Hz); 7.71 (1H, s); 7.47
(2H, br s); 7.22 (1H, d, J=8.0 Hz); 7.08 (2H, t, J=8.5 Hz);
4.00-3.94 (2H, m); 3.91 (3H, s); 3.86 (2H, br s); 3.09 (2H, br s);
2.98 (2H, br s). MS (M+H).sup.+=300.
Step 2
2-(4-Fluorobenzyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid
hydrochloride was prepared from methyl
2-(4-fluorobenzyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate as
described in step 3 of Example 7(a), above. The compound was
obtained as a white crystalline solid was upon filtration and
drying under vacuum (1.20 g, 90%). .sup.1H NMR (DMSO-d.sub.6)
.delta. 11.06 (1H, br s); 7.81-7.79 (2H, m); 7.68 (2H, dd, J=8.3,
5.5 Hz); 7.36-7.29 (3H, m); 4.45 (2H, br s); 4.38-4.34 (2H, m);
3.64 (2H, br s); 3.14 (2H, app t, J=14.9, 9.6 Hz). MS
(M+H).sup.+=286.
Step 3
N-(1-(4-Cyanobenzyl)piperidin-4-yl)-2-(4-fluorobenzyl)-1,2,3,4-tetrahydro-
isoquinoline-7-carboxamide (compound 40) was prepared from methyl
2-(4-fluorobenzyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate as
described in step 4 of Example 7(a) above to yield the compound as
a tan crystalline solid (70 mg, 83%). .sup.1H NMR (DMSO-d.sub.6):
.delta. 8.08 (1H, d, J=7.7 Hz); 7.78 (2H, d, J=8.3 Hz); 7.57 (1H,
d, J=8.0 Hz); 7.49 (3H, d, J=8.3 Hz); 7.41-7.36 (2H, m); 7.18-7.12
(3H, m); 3.78-3.68 (1H, m); 3.64 (2H, s); 3.53 (4H, d, J=7.7 Hz);
2.89-2.65 (6H, m); 2.04 (2H, t, J=10.6 Hz); 1.74 (2H, d, J=12.1
Hz); 1.54 (2H, q, J=11.6 Hz). MS (M+H).sup.+=483.
(d) Synthetic Example: Compounds 41-42
Compounds 41-42 were prepared using procedures analogous to those
described in Example 7(c).
2-(4-Fluorobenzyl)-N-(1-(pyridine-3-ylmethyl)piperidin-4-yl)-1,2,3,4-tetr-
ahydroisoquinoline-7-carboxamide (compound 41): Tan crystalline
solid (40 mg, 50%). .sup.1H NMR (DMSO-d.sub.6): .delta. 8.47-8.44
(2H, m); 8.08 (1H, d, J=7.7 Hz); 7.68 (1H, d, J=7.7 Hz); 7.57 (1H,
d, J=7.7 Hz); 7.47 (1H, s); 7.40-7.32 (3H, m); 7.18-7.12 (3H, m);
3.78-3.68 (1H, m); 3.64 (2H, s); 3.50 (4H, d, J=9.9 Hz); 2.89-2.64
(6H, m); 2.02 (2H, t, J=11.1 Hz); 1.74 (2H, d, J=11.8 Hz); 1.55
(2H, q, J=12.0 Hz). MS (M+H).sup.+=459.
2-(4-Fluorobenzyl)-N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-1,2,3,-
4-tetrahydroisoquinoline-7-carboxamide (compound 42): White
crystalline solid (55 mg, 60%). .sup.1H NMR (DMSO-d.sub.6): .delta.
8.09 (1H, d, J=7.7 Hz); 7.67 (2H, d, J=8.3 Hz); 7.57 (1H, d, J=8.0
Hz); 7.52 (2H, d, J=7.7 Hz); 7.47 (1H, s); 7.41-7.36 (2H, m);
7.18-7.12 (3H, m); 3.78-3.68 (1H, m); 3.64 (2H, s); 3.54 (4H, d,
J=8.5 Hz); 2.89-2.74 (4H, m); 2.73-2.64 (2H, m); 2.04 (2H, t,
J=11.1 Hz); 1.75 (2H, d, J=12.4 Hz); 1.55 (2H, q, J=10.6 Hz). MS
(M+H).sup.+=526.
(e) Increase in AMPK Activity
Compounds 34-42 were assayed for their ability to activate AMPK
using an enzyme-linked immunosorbent assay. The EC.sub.50 values
for AMPK activation for compounds 34-42 are presented in Table 8
below, in which "A" is less than 0.1 .mu.M; "B" is 0.1-1 .mu.M; "C"
is 1-10 .mu.M; and "D" is 10-100 .mu.M:
TABLE-US-00008 TABLE 8 Cpd No. AMPK EC.sub.50 34 A 35 C 36 B 37 A
38 A 39 C 40 A 41 C 42 B
* * * * *