U.S. patent application number 14/294717 was filed with the patent office on 2014-09-25 for triazole compounds that modulate hsp90 activity.
The applicant listed for this patent is Synta Pharmaceuticals Corp.. Invention is credited to Joseph A. Burlison, Dinesh U. Chimmanamada, Zachary Demko, David James, Teresa Kowalczyk-Przewloka, Stefan M. Schweizer, Lijun Sun, Weiwen Ying, Shijie Zhang.
Application Number | 20140288301 14/294717 |
Document ID | / |
Family ID | 39624217 |
Filed Date | 2014-09-25 |
United States Patent
Application |
20140288301 |
Kind Code |
A1 |
Chimmanamada; Dinesh U. ; et
al. |
September 25, 2014 |
TRIAZOLE COMPOUNDS THAT MODULATE HSP90 ACTIVITY
Abstract
The present invention relates to substituted triazole compounds
and compositions comprising substituted triazole compounds. The
invention further relates to methods of inhibiting the activity of
Hsp90 in a subject in need thereof and methods for preventing or
treating hyperproliferative disorders, such as cancer, in a subject
in need thereof comprising administering to the subject a
substituted triazole compound of the invention, or a composition
comprising such a compound.
Inventors: |
Chimmanamada; Dinesh U.;
(Arlington, MA) ; Burlison; Joseph A.;
(Louisville, KY) ; Ying; Weiwen; (Lexington,
MA) ; Sun; Lijun; (Harvard, MA) ; Schweizer;
Stefan M.; (Memphis, TN) ; Zhang; Shijie;
(Nashua, NH) ; Demko; Zachary; (Los Alto Hills,
CA) ; James; David; (Boston, MA) ;
Kowalczyk-Przewloka; Teresa; (Tewskbury, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Synta Pharmaceuticals Corp. |
Lexington |
MA |
US |
|
|
Family ID: |
39624217 |
Appl. No.: |
14/294717 |
Filed: |
June 3, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13662218 |
Oct 26, 2012 |
8748424 |
|
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14294717 |
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12526491 |
Jan 10, 2011 |
8299107 |
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PCT/US08/01693 |
Feb 8, 2008 |
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13662218 |
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60993709 |
Sep 13, 2007 |
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60900225 |
Feb 8, 2007 |
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Current U.S.
Class: |
544/132 ;
544/238; 544/364; 544/366; 546/15; 546/205; 546/256; 546/272.4;
548/193; 548/203; 548/264.2; 548/264.4; 548/266.4; 548/266.8;
548/269.4 |
Current CPC
Class: |
A61P 7/00 20180101; C07D
249/10 20130101; C07D 403/14 20130101; A61P 37/00 20180101; A61P
37/02 20180101; C07D 405/14 20130101; C07D 417/12 20130101; C07D
249/08 20130101; A61P 31/04 20180101; C07D 249/12 20130101; A61P
9/00 20180101; A61P 33/00 20180101; A61P 29/00 20180101; C07D
401/12 20130101; A61P 43/00 20180101; A61P 31/12 20180101; A61P
31/10 20180101; C07D 401/14 20130101; C07D 417/14 20130101; C07D
405/04 20130101; C07D 403/04 20130101; A61P 37/06 20180101; C07D
401/04 20130101; C07D 413/14 20130101; A61P 35/00 20180101 |
Class at
Publication: |
544/132 ;
548/264.2; 544/238; 548/203; 548/264.4; 546/272.4; 548/193;
548/269.4; 548/266.8; 548/266.4; 546/15; 544/366; 546/205; 544/364;
546/256 |
International
Class: |
C07D 417/14 20060101
C07D417/14; C07D 403/14 20060101 C07D403/14; C07D 401/14 20060101
C07D401/14; C07D 405/14 20060101 C07D405/14; C07D 249/10 20060101
C07D249/10; C07D 401/04 20060101 C07D401/04; C07D 249/08 20060101
C07D249/08; C07D 417/12 20060101 C07D417/12; C07D 249/12 20060101
C07D249/12; C07D 403/04 20060101 C07D403/04; C07D 401/12 20060101
C07D401/12 |
Claims
1. A compound represented by the following structural formula:
##STR00285## or a tautomer, pharmaceutically acceptable salt, or
prodrug thereof, wherein: X.sub.42 is CR.sub.44 or N; R.sub.41 is
--H, --OH, --SH, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a
heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy,
--NR.sub.10R.sub.11, --OR.sub.7, --C(O)R.sub.7, --C(O)OR.sub.7,
--C(S)R.sub.7, --C(O)SR.sub.7, --C(S)SR.sub.7, --C(S)OR.sub.7,
--C(S)NR.sub.10R.sub.11, --C(NR.sub.8)OR.sub.7,
--C(NR.sub.8)R.sub.7, --C(NR.sub.8)NR.sub.10R.sub.11,
--C(NR.sub.8)SR.sub.7, --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(S)OR.sub.7, --OC(NR.sub.8)OR.sub.7, --SC(O)R.sub.7,
--SC(O)OR.sub.7, --SC(NR.sub.8)OR.sub.7, --OC(S)R.sub.7,
--SC(S)R.sub.7, --SC(S)OR.sub.7, --OC(O)NR.sub.10R.sub.11,
--OC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)NR.sub.10R.sub.11,
--SC(O)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --NR.sub.7C(S)R.sub.7,
--NR.sub.7C(S)OR.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7,
--NR.sub.7C(O)OR.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(S)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --SR.sub.7,
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, --NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7, --S(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pR.sub.7, --SS(O).sub.pOR.sub.7,
--SS(O).sub.pNR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2; R.sub.42 is --H, an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, an optionally
substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a
heteroalkyl, --C(O)R.sub.7, --(CH.sub.2).sub.mC(O)OR.sub.7,
--C(O)OR.sub.7, --OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11,
--S(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7, or
--S(O).sub.pNR.sub.10R.sub.11; R.sub.43 and R.sub.44 are,
independently, --H, --OH, an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro,
guanadino, a haloalkyl, a heteroalkyl, --C(O)R.sub.7,
--C(O)OR.sub.7, --OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --SR.sub.7, --S(O).sub.pR.sub.7,
--OS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, --S(O).sub.pNR.sub.10R.sub.11, or
R.sub.43 and R.sub.44 taken together with the carbon atoms to which
they are attached form an optionally substituted cycloalkenyl, an
optionally substituted aryl, an optionally substituted
heterocyclyl, or an optionally substituted heteroaryl; R.sub.45 is
--H, --OH, --SH, --NR.sub.7H, --OR.sub.26, --SR.sub.26,
--NHR.sub.26, --O(CH.sub.2).sub.mOH, --O(CH.sub.2).sub.mSH,
--O(CH.sub.2).sub.mNR.sub.7H, --S(CH.sub.2).sub.mOH,
--S(CH.sub.2).sub.mSH, --S(CH.sub.2).sub.mNR.sub.7H,
--OC(O)NR.sub.10R.sub.11, --SC(O)NR.sub.10R.sub.11,
--NR.sub.7C(O)NR.sub.10R.sub.11, --OC(O)R.sub.7, --SC(O)R.sub.7,
--NR.sub.7C(O)R.sub.7, --OC(O)OR.sub.7, --SC(O)OR.sub.7,
--NR.sub.7C(O)OR.sub.7, --OCH.sub.2C(O)R.sub.7,
--SCH.sub.2C(O)R.sub.7, --NR.sub.7CH.sub.2C(O)R.sub.7,
--OCH.sub.2C(O)OR.sub.7, --SCH.sub.2C(O)OR.sub.7,
--NR.sub.7CH.sub.2C(O)OR.sub.7, --OCH.sub.2C(O)NR.sub.10R.sub.11,
--SCH.sub.2C(O)NR.sub.10R.sub.11,
--NR.sub.7CH.sub.2C(O)NR.sub.10R.sub.11, --OS(O).sub.pR.sub.7,
--SS(O).sub.pR.sub.7, --NR.sub.7S(O).sub.pR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11; --SS(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --OS(O).sub.pOR.sub.7,
--SS(O).sub.pOR.sub.7, --NR.sub.7S(O).sub.pOR.sub.7,
--OC(S)R.sub.7, --SC(S)R.sub.7, --NR.sub.7C(S)R.sub.7,
--OC(S)OR.sub.7, --SC(S)OR.sub.7, --NR.sub.7C(S)OR.sub.7,
--OC(S)NR.sub.10R.sub.11, --SC(S)NR.sub.10R.sub.11,
--NR.sub.7C(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7,
--OC(NR.sub.8)OR.sub.7, --SC(NR.sub.8)OR.sub.7,
--NR.sub.7C(NR.sub.8)OR.sub.7, --OC(NR.sub.8)NR.sub.10R.sub.11,
--SC(NR.sub.8)NR.sub.10R.sub.11, or
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11; and R.sub.7 and R.sub.8,
for each occurrence, is independently, --H, an optionally
substituted alkyl, an optionally substituted alkenyl, an optionally
substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted
heterocyclyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted aralkyl, or an
optionally substituted heteraralkyl; R.sub.10 and R.sub.11, for
each occurrence, is independently --H, an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; or R.sub.10 and R.sub.11, taken together
with the nitrogen to which they are attached, form an optionally
substituted heterocyclyl or an optionally substituted heteroaryl;
R.sub.26 is a lower alkyl; R.sub.35 and R.sub.36, for each
occurrence, is independently --H, an optionally substituted alkyl,
an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl, or R.sub.35 and R.sub.36, together with N
to which they are attached form a 5 to 7 membered heterocyclic
ring; m, for each occurrence, is independently, 1, 2, 3, or 4; p,
for each occurrence, is independently, 1 or 2.
2. The compound of claim 1, wherein X.sub.42 is CR.sub.44, R.sub.43
and R.sub.44 are, independently, selected from the group consisting
of --H, methyl, ethyl, propyl, isopropyl, and cyclopropyl, and one
of R.sub.35 or R.sub.36 is --H.
3. The compound of claim 1, wherein R.sub.43 and R.sub.44, taken
together with the carbon atoms to which they are attached, form a
C.sub.5-C.sub.8 cycloalkenyl or a C.sub.5-C.sub.8 aryl, and one of
R.sub.35 or R.sub.36 is --H.
4. The compound of claim 1, wherein the compound is represented by
the following structural formula: ##STR00286## or a tautomer,
pharmaceutically acceptable salt, or prodrug thereof, wherein:
X.sub.45 is CR.sub.54 or N; R.sub.56 is selected from the group
consisting of --H, methyl, ethyl, isopropyl, and cyclopropyl;
R.sub.52 is selected from the group consisting of --H, methyl,
ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl,
--(CH.sub.2).sub.2OCH.sub.3, --CH.sub.2C(O)OH, and
--C(O)N(CH.sub.3).sub.2; R.sub.53 and R.sub.54 are each,
independently, --H, methyl, ethyl, or isopropyl; or R.sub.53 and
R.sub.54 taken together with the carbon atoms to which they are
attached form a phenyl, cyclohexenyl, or cyclooctenyl ring; and
R.sub.55 is selected from the group consisting of --H, --OH,
--OCH.sub.3, and OCH.sub.2CH.sub.3.
5. The compound of claim 4, wherein one of R.sub.35 or R.sub.36 is
--H.
6. A compound represented by the following structural formula:
##STR00287## or a tautomer, pharmaceutically acceptable salt, or a
prodrug thereof, wherein: Y is --O-- or --S--; R.sub.1 is an
optionally substituted alkyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
alkenyl, an optionally substituted alkynyl, an optionally
substituted cycloalkyl, an optionally substituted cycloalkenyl, an
optionally substituted heterocyclyl, optionally substituted
aralkyl, an optionally substituted heteraralkyl, or
--C(O)N(R.sub.13).sub.2; R'.sub.3 is --OH, --SH, --OR.sub.26,
--SR.sub.26, --O(CH.sub.2).sub.mOH, --O(CH.sub.2).sub.mSH,
--O(CH.sub.2).sub.mNR.sub.7H, --S(CH.sub.2).sub.mOH,
--S(CH.sub.2).sub.mSH, --S(CH.sub.2).sub.mNR.sub.7H,
--OC(O)NR.sub.10R.sub.11, --SC(O)NR.sub.10R.sub.11, --OC(O)R.sub.7,
--SC(O)R.sub.7, --OC(O)OR.sub.7, --SC(O)OR.sub.7,
--OCH.sub.2C(O)R.sub.7, --SCH.sub.2C(O)R.sub.7,
--OCH.sub.2C(O)OR.sub.7, --SCH.sub.2C(O)OR.sub.7,
--OCH.sub.2C(O)NR.sub.10R.sub.11, --SCH.sub.2C(O)NR.sub.10R.sub.11,
--OS(O).sub.pR.sub.7, --SS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --SS(O).sub.pNR.sub.10R.sub.11,
--OS(O).sub.pOR.sub.7, --SS(O).sub.pOR.sub.7, --OC(S)R.sub.7,
--SC(S)R.sub.7, --OC(S)OR.sub.7, --SC(S)OR.sub.7,
--OC(S)NR.sub.10R.sub.11, --SC(S)NR.sub.10R.sub.11,
--OC(NR.sub.8)R.sub.7, --SC(NR.sub.8)R.sub.7,
--OC(NR.sub.8)OR.sub.7, --SC(NR.sub.8)OR.sub.7,
--OC(NR.sub.8)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--OP(O)(OR.sub.7).sub.2, or --SP(O)(OR.sub.7).sub.2; R'.sub.5 is
--X.sub.20R.sub.50, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; R.sub.6 is an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a
heteroalkyl, alkoxy, haloalkoxy, --NR.sub.10R.sub.11, --OR.sub.7,
--C(O)R.sub.7, --C(O)OR.sub.7, --C(S)R.sub.7, --C(O)SR.sub.7,
--C(S)SR.sub.7, --C(S)OR.sub.7, --C(S)NR.sub.10R.sub.11,
--C(NR.sub.8)OR.sub.7, --C(NR.sub.8)R.sub.7,
--C(NR.sub.8)NR.sub.10R.sub.11, --C(NR.sub.8)SR.sub.7,
--OC(O)R.sub.7, --OC(O)OR.sub.7, --OC(S)OR.sub.7,
--OC(NR.sub.8)OR.sub.7, --SC(O)R.sub.7, --SC(O)OR.sub.7,
--SC(NR.sub.8)OR.sub.7, --OC(S)R.sub.7, --SC(S)R.sub.7,
--SC(S)OR.sub.7, --OC(O)NR.sub.10R.sub.11,
--OC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)NR.sub.10R.sub.11,
--SC(O)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --NR.sub.7C(S)R.sub.7,
--NR.sub.7C(S)OR.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7,
--NR.sub.7C(O)OR.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(S)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --SR.sub.7,
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, --NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7, --S(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pR.sub.7, --SS(O).sub.pOR.sub.7,
--SS(O).sub.pNR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2; R.sub.7 and R.sub.8, for each occurrence,
is independently, --H, an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; R.sub.10 and R.sub.11, for each occurrence, is
independently --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; or R.sub.10 and R.sub.11, taken together with the
nitrogen to which they are attached, form an optionally substituted
heterocyclyl or an optionally substituted heteroaryl; each R.sub.13
is independently --H, an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; R.sub.26 is a lower alkyl; R.sub.50 is an optionally
substituted aryl or an optionally substituted heteroaryl; X.sub.20
is a C1-C4 alkyl, NR.sub.7, C(O), C(S), C(NR.sub.8), or S(O).sub.p;
Z, for each occurrence, is independently an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, an optionally
substituted heteroaralkyl, halo, cyano, nitro, guanadino, a
haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, --NR.sub.10R.sub.11,
--OR.sub.7, --C(O)R.sub.7, --C(O)OR.sub.7, --C(S)R.sub.7,
--C(O)SR.sub.7, --C(S)SR.sub.7, --C(S)OR.sub.7,
--C(S)NR.sub.10R.sub.11, --C(NR.sub.8)OR.sub.7,
--C(NR.sub.8)R.sub.7, --C(NR.sub.8)NR.sub.10R.sub.11,
--C(NR.sub.8)SR.sub.7, --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(S)OR.sub.7, --OC(NR.sub.8)OR.sub.7, --SC(O)R.sub.7,
--SC(O)OR.sub.7, --SC(NR.sub.8)OR.sub.7, --OC(S)R.sub.7,
--SC(S)R.sub.7, --SC(S)OR.sub.7, --OC(O)NR.sub.10R.sub.11,
--OC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)NR.sub.10R.sub.11,
--SC(O)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --NR.sub.7C(S)R.sub.7,
--NR.sub.7C(S)OR.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7,
--NR.sub.7C(O)OR.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(S)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --SR.sub.7,
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, --NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7, --S(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pR.sub.7, --SS(O).sub.pOR.sub.7,
--SS(O).sub.pNR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2; m for each occurrence is independently 1,
2, 3, or 4; p, for each occurrence, is independently, 1 or 2; n is
0, 1, 2, or 3; and provided that when Y is --S-- and R.sub.1 is an
optionally substituted C1-C3 alkyl, then R'.sub.3 is not
--OCH.sub.2OMe; provided that when Y is --S--, R.sub.1 is Me and
R'.sub.5 is lower alkyl, then R.sub.6 is not halo.
7. The compound of claim 6, wherein n is 0 or 1.
8. The compound of claim 6, wherein R.sub.1 is an optionally
substituted lower alkyl; R'.sub.3 is C1-C6 alkoxy or --OH; and
R.sub.6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a
C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
9. The compound of claim 6, wherein R'.sub.5 is represented by the
following formula: ##STR00288## wherein: R.sub.33 is a halo, lower
alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and
lower alkyl sulfanyl; R.sub.34 is H, a lower alkyl, or a lower
alkylcarbonyl; and Ring B and Ring C are optionally substituted
with one or more substituents.
10. The compound of claim 6, wherein R'.sub.5 is an optionally
substituted indolyl, an optionally substituted benzoimidazolyl, an
optionally substituted indazolyl, an optionally substituted
3H-indazolyl, an optionally substituted indolizinyl, an optionally
substituted quinolinyl, an optionally substituted isoquinolinyl, an
optionally substituted benzoxazolyl, an optionally substituted
benzo[1,3]dioxolyl, an optionally substituted benzofuryl, an
optionally substituted benzothiazolyl, an optionally substituted
benzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl,
an optionally substituted thiazolo[4,5-c]pyridinyl, an optionally
substituted thiazolo[5,4-c]pyridinyl, an optionally substituted
thiazolo[4,5-b]pyridinyl, an optionally substituted
thiazolo[5,4-b]pyridinyl, an optionally substituted
oxazolo[4,5-c]pyridinyl, an optionally substituted
oxazolo[5,4-c]pyridinyl, an optionally substituted
oxazolo[4,5-b]pyridinyl, an optionally substituted
oxazolo[5,4-b]pyridinyl, an optionally substituted
imidazopyridinyl, an optionally substituted benzothiadiazolyl,
benzoxadiazolyl, an optionally substituted benzotriazolyl, an
optionally substituted tetrahydroindolyl, an optionally substituted
azaindolyl, an optionally substituted quinazolinyl, an optionally
substituted purinyl, an optionally substituted
imidazo[4,5-a]pyridinyl, an optionally substituted
imidazo[1,2-a]pyridinyl, an optionally substituted
3H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-c]pyridinyl, an optionally substituted
3H-imidazo[4,5-c]pyridinyl, an optionally substituted
pyridopyrdazinyl, and optionally substituted pyridopyrimidinyl, an
optionally substituted pyrrolo[2,3]pyrimidyl, an optionally
substituted pyrazolo[3,4]pyrimidyl an optionally substituted
cyclopentaimidazolyl, an optionally substituted
cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an
optionally substituted pyrroloimidazolyl, an optionally substituted
pyrrolotriazolyl, or an optionally substituted benzo[b]thienyl.
11. The compound of claim 6, wherein R'.sub.5 is selected from the
group consisting of: ##STR00289## wherein: X.sub.11, for each
occurrence, is independently CH, CR.sub.9, N, N(O), or
N.sup.+(R.sub.17); X.sub.12, for each occurrence, is independently
CH, CR.sub.9, N, N(O), N.sup.+(R.sub.17), provided that at least
one X.sub.12 group is independently selected from CH and CR.sub.9;
X.sub.13, for each occurrence, is independently O, S, S(O)p,
NR.sub.7, or NR.sub.17; R.sub.9, for each occurrence, is
independently a substituent selected from the group consisting of
an optionally substituted alkyl, an optionally substituted alkenyl,
an optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, halo, cyano,
nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a
heteroalkyl, --NR.sub.10R.sub.11, --OR.sub.7, --C(O)R.sub.7,
--C(O)OR.sub.7, --OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --SR.sub.7, --S(O).sub.pR.sub.7,
--OS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, or --S(O).sub.pNR.sub.10R.sub.11,
--S(O).sub.pOR.sub.7, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2, --S(O).sub.pOR.sub.7,
--OP(O)(OR.sub.7).sub.2, or --SP(O)(OR.sub.7).sub.2; or two R.sub.9
groups taken together with the carbon atoms to which they are
attached form a fused ring; and R.sub.17, for each occurrence, is
independently an alkyl or an aralkyl.
12. The compound of claim 6, wherein R'.sub.5 is X.sub.20R.sub.50;
X.sub.20 is a C1-C4 alkyl and R.sub.50 is an optionally substituted
phenyl.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/662,218, filed Oct. 26, 2012 and now U.S. Pat. No.
8,748,424, which, in turn, is a continuation of U.S. application
Ser. No. 12/526,491 and now U.S. Pat. No. 8,299,107, which is a 35
U.S.C. .sctn.371 national stage filing of International Application
No. PCT/US2008/001693, filed Feb. 8, 2008, which, in turn, claims
the benefit of U.S. Provisional Application No. 60/993,709, filed
Sep. 13, 2007, and U.S. Provisional Application No. 60/900,225,
filed Feb. 8, 2007. The entire contents of each of the
aforementioned applications are incorporated herein by
reference.
BACKGROUND OF THE INVENTION
[0002] Although tremendous advances have been made in elucidating
the genomic abnormalities that cause malignant cancer cells,
currently available chemotherapy remains unsatisfactory, and the
prognosis for the majority of patients diagnosed with cancer
remains dismal. Most chemotherapeutic agents act on a specific
molecular target thought to be involved in the development of the
malignant phenotype. However, a complex network of signaling
pathways regulate cell proliferation, and the majority of malignant
cancers are facilitated by multiple genetic abnormalities in these
pathways. Therefore, it is unlikely that a therapeutic agent that
acts on one molecular target will be fully effective in curing a
patient who has cancer.
[0003] Heat shock proteins (HSPs) are a class of chaperone proteins
that are up-regulated in response to elevated temperature and other
environmental stresses, such as ultraviolet light, nutrient
deprivation, and oxygen deprivation. HSPs act as chaperones to
other cellular proteins (called client proteins) and facilitate
their proper folding and repair, and aid in the refolding of
misfolded client proteins. There are several known families of
HSPs, each having its own set of client proteins. The Hsp90 family
is one of the most abundant HSP families, accounting for about 1-2%
of proteins in a cell that is not under stress and increasing to
about 4-6% in a cell under stress Inhibition of Hsp90 results in
degradation of its client proteins via the ubiquitin proteasome
pathway. Unlike other chaperone proteins, the client proteins of
Hsp90 are mostly protein kinases or transcription factors involved
in signal transduction, and a number of its client proteins have
been shown to be involved in the progression of cancer. Examples of
Hsp90 client proteins that have been implicated in the progression
of cancer are described below.
[0004] Her-2 is a transmembrane tyrosine kinase cell surface growth
factor receptor that is expressed in normal epithelial cells. Her2
has an extracellular domain that interacts with extracellular
growth factors and an internal tyrosine kinase portion that
transmits the external growth signal to the nucleus of the cell.
Her2 is overexpressed in a significant proportion of malignancies,
such as breast cancer, ovarian cancer, prostate cancer, and gastric
cancers, and is typically associated with a poor prognosis.
[0005] Akt kinase is a serine/threonine kinase which is a
downstream effector molecule of phosphoinositide 3-kinase and is
involved in protecting the cell from apoptosis. Akt kinase is
thought to be involved in the progression of cancer because it
stimulates cell proliferation and suppresses apoptosis.
[0006] Cdk4/cyclin D complexes are involved in phosphorylation of
retinoblastoma protein which is an essential step in progression of
a cell through the G1 phase of the cell cycle. Disruption of Hsp90
activity has been shown to decrease the half life of newly
synthesized Cdk4.
[0007] Raf-1 is a MAP 3-kinase (MAP3K) which when activated can
phosphorylate and activate the serine/threonine specific protein
kinases ERK1 and ERK2. Activated ERKs play an important role in the
control of gene expression involved in the cell division cycle,
apoptosis, cell differentiation and cell migration.
[0008] The transforming protein of Rous sarcoma virus, v-src, is a
prototype of an oncogene family that induces cellular
transformation (i.e., tumorogenesis) by non-regulated kinase
activity. Hsp90 has been shown to complex with v-scr and inhibit
its degradation.
[0009] Hsp90 is required to maintain steroid hormone receptors in a
conformation capable of binding hormone with high affinity
Inhibition of the action of Hsp90 therefore is expected to be
useful in treating hormone-associated malignancies such as breast
cancer.
[0010] p53 is a tumor suppressor protein that causes cell cycle
arrest and apoptosis. Mutation of the p53 gene is found in about
half of all human cancers making it one of the most common genetic
alterations found in cancerous cells. In addition, p53 mutation is
associated with a poor prognosis. Wild-type p53 has been shown to
interact with Hsp90, but mutated p53 forms a more stable
association than wild-type p53 as a result of its misfolded
conformations. A stronger interaction with Hsp90 protects the
mutated protein form normal proteolytic degradation and prolongs
its half-life. In a cell that is heterozygous for mutated and
wild-type p53, inhibition of the stabilizing effect of Hsp90 causes
mutant p53 to be degraded and restores the normal transcriptional
activity of wild-type p53.
[0011] Hif-1.alpha. is a hypoxia-inducible transcription factor
that is up-regulated under low oxygen conditions. Under normal
oxygen conditions Hif-1.alpha. associates with Von Hippel-Lindau
(VHL) tumor suppressor protein and is degraded. Low oxygen
conditions inhibit this association and allows Hif-1.alpha. to
accumulate and complex with Hif-1.beta. to form an active
transcription complex that associates with hypoxia-response
elements to activate the transcription of vascular endothelial
growth factor (VEGF). Increased Hif-1.alpha. is associated with
increased metastasis and a poor prognosis.
[0012] There are two classes of PKs: protein tyrosine kinases
(PTKs), which catalyze the phosphorylation of tyrosine kinase
residues, and the serine-threonine kinases (STKs), which catalyze
the phosphorylation of serine or threonine residues. Growth factor
receptors with PTK activity are known as receptor tyrosine kinases.
Receptor tyrosine kinases are a family of tightly regulated
enzymes, and the aberrant activation of various members of the
family is one of the hallmarks of cancer. The receptor tyrosine
kinase family can be divided into subgroups that have similar
structural organization and sequence similarity within the kinase
domain.
[0013] Epidermal Growth Factor Receptor (EGFR) is a member of the
type 1 subgroup of receptor tyrosine kinase family of growth factor
receptors, which play critical roles in cellular growth,
differentiation, and survival. Activation of these receptors
typically occurs via specific ligand binding which results in
hetero- or homodimerization between receptor family members, with
subsequent autophosphorylation of the tyrosine kinase domain.
Specific ligands which bind to EGFR include epidermal growth factor
(EGF), transforming growth factor .alpha. (TGF.alpha., amphiregulin
and some viral growth factors. Activation of EGFR triggers a
cascade of intracellular signaling pathways involved in both
cellular proliferation (the ras/raf/MAP kinase pathway) and
survival (the PI3 kinase/Akt pathway). Members of this family,
including EGFR and HER2, have been directly implicated in cellular
transformation.
[0014] A number of human malignancies are associated with aberrant
or overexpression of EGFR and/or overexpression of its specific
ligands (Gullick, Br. Med. Bull. (1991), 47:87-98; Modijtahedi and
Dean, Int. J. Oncol. (1994), 4:277-96; Salomon, et al., Crit. Rev.
Oncol. Hematol. (1995);19:183-232, the entire teachings of each of
these references are incorporated herein by reference). Aberrant or
overexpression of EGFR has been associated with an adverse
prognosis in a number of human cancers, including head and neck,
breast, colon, prostate, lung (e.g., NSCLC, adenocarcinoma and
squamous lung cancer), ovaries, gastrointestinal cancers (gastric,
colon, pancreatic), renal cell cancer, bladder cancer, glioma,
gynecological carcinomas, and prostate cancer. In some instances,
overexpression of tumor EGFR has been correlated with both
chemoresistance and a poor prognosis (Lei, et al., Anticancer Res.
(1999), 19:221-8; Veale, et al., Br. J. Cancer (1993); 68:162-5,
the entire teachings of each of these references are incorporated
herein by reference).
[0015] Gefitinib, a chemotherapeutic agent that inhibits the
activity of EGFR, has been found to be highly efficacious in a
subset of lung cancer patients that have mutations in the tyrosine
kinase domain of EGFR. In the presence of EGF, these mutants
displayed two to three times higher activity than wild type EGFR.
In addition, wild type EGFR was internalized by the cells and
down-regulated after 15 minutes, where as mutant EGFR was
internalized more slowly and continued to be activated for up to
three hours (Lynch, et al., The New England Journal of Medicine
(2006), 350:2129-2139, the entire teachings of which are
incorporated herein by reference).
[0016] Gliomas are another type of cancer that is characterized by
amplification and/or mutation of the EGFR gene. One of the most
common mutations in the EGFR gene is a deletion of exons 2-7 which
results in a truncated form of EGFR in which amino acids 6-273 of
the extracellular domain are replaced with a single glycine
residue. This mutation is called EGFRvIII and is expressed in about
half of all glioblastomas. EGFRvIII is unable to bind EGF and TGF
and has constitutive, ligand-independent tyrosine kinase activity.
Hsp90 co-purifies with EGFRvIII indicating that Hsp90 complexes
with EGFRvIII. Moreover, Hsp90 inhibitor geldanamycin, a
benzoquinone ansamycin antibiotic, was able to decrease the
expression of EGFRvIII indicating that interaction with Hsp90 is
essential to maintain high expression levels of EGFRvIII
(Lavictoire, et al., Journal of Biological Chemistry (2003),
278(7):5292-5299, the entire teachings of which are incorporated
herein by reference). These results demonstrate that inhibiting the
activity of Hsp90 is an effective strategy for treating cancers
that are associated with inappropriate EGFR activity.
[0017] The members of the type III group of receptor tyrosine
kinases include platelet-derived growth factor (PDGF) receptors
(PDGF receptors alpha and beta), colony-stimulating factor (CSF-1)
receptor (CSF-1R, c-Fms), Fms-like tyrosine kinase (FLT3), and stem
cell factor receptor (c-kit). FlLT3 is primarily expressed on
immature hematopoietic progenitors and regulates their
proliferation and survival.
[0018] Hematologic cancers, also known as hematologic or
hematopoietic malignancies, are cancers of the blood or bone
marrow; including leukemia and lymphoma. Acute myelogenous leukemia
(AML) is a clonal hematopoietic stem cell leukemia that represents
about 90% of all acute leukemias in adults with an incidence of 3.9
per 100,000 (See e.g., Lowenberg et al., N. Eng. J. Med. 341:
1051-62 (1999) and Lopesde Menezes, et al, Clin. Cancer Res.
(2005), 11(14):5281-5291, the enter teachings of both references
are incorporated by reference). While chemotherapy can result in
complete remissions, the long term disease-free survival rate for
AML is about 14% with about 7,400 deaths from AML each year in the
United States. Approximately 70% of AML blasts express wild type
FLT3 and about 25% to about 35% express FLT3 kinase receptor
mutations which result in constitutively active FLT3. Two types of
activating mutations have been identified in AML patients: internal
tandem duplications (ITDs) and point mutation in the activating
loop of the kinase domain. FLT3-ITD mutations in AML patients is
indicative of a poor prognosis for survival, and in patients who
are in remission, FLT3-ITD mutations are the most significant
factor adversely affecting relapse rate with 64% of patients having
the mutation relapsing within 5 years (see Current Pharmaceutical
Design (2005), 11:3449-3457, the entire teachings of which are
incorporated herein by reference). The prognostic significance of
FLT3 mutations in clinical studies suggests that FLT3 plays a
driving role in AML and may be necessary for the development and
maintenance of the disease.
[0019] Mixed Lineage Leukemia (MLL) involve translocations of
chromosome 11 band q23 (11q23) and occur in approximately 80% of
infant hematological malignancies and 10% of adult acute leukemias.
Although certain 11q23 translocation have been shown to be
essential to immortalization of hematopoietic progenitors in vitro,
a secondary genotoxic event is required to develop leukemia. There
is a strong concordance between FLT3 and MLL fusion gene
expression, and the most consistently overexpressed gene in MLL is
FLT3. Moreover, it has been shown that activated FLT3 together with
MLL fusion gene expression induces acute leukemia with a short
latency period (see Ono, et al., J. of Clinical Investigation
(2005), 115:919-929, the entire teachings of which are incorporated
by reference). Therefore, it is believed that FLT3 signally is
involved in the development and maintenance of MLL (see Armstrong,
et al., Cancer Cell (2003), 3:173-183, the entire teachings of
which are incorporated herein by reference).
[0020] The FLT3-ITD mutation is also present in about 3% of cases
of adult myelodysplastic syndrome and some cases of acute
lymphocytic leukemia (ALL) (Current Pharmaceutical Design (2005),
11:3449-3457).
[0021] FLT3 has been shown to be a client protein of Hsp90, and
17AAG, a benzoquinone ansamycin antibiotic that inhibits Hsp90
activity, has been shown to disrupts the association of Flt3 with
Hsp90. The growth of leukemia cell that express either wild type
FLT3 or FLT3-ITD mutations was found to be inhibited by treatment
with 17'' AAG (Yao, et al., Clinical Cancer Research (2003),
9:4483-4493, the entire teachings of which are incorporated herein
by reference).
[0022] c-Kit is a membrane type III receptor protein tyrosine
kinase which binds Stem Cell Factor (SCF) to its extraellular
domain. c-Kit has tyrosine kinase activity and is required for
normal hematopoiesis. However, mutations in c-kit can result in
ligand-independent tyrosine kinase activity, autophosphorylation,
and uncontrolled cell proliferation. Aberrant expression and/or
activation of c-Kit has been implicated in a variety of pathologic
states. For example, evidence for a contribution of c-Kit to
neoplastic pathology includes its association with leukemias and
mast cell tumors, small cell lung cancer, testicular cancer, and
some cancers of the gastrointestinal tract and central nervous
system. In addition, c-Kit has been implicated in playing a role in
carcinogenesis of the female genital tract sarcomas of
neuroectodermal origin, and Schwann cell neoplasia associated with
neurofibromatosis. (Yang et al., J Clin Invest. (2003),
112:1851-1861; Viskochil, J Clin Invest. (2003), 112:1791-1793, the
entire teachings of each of these reference are incorporated herein
by reference). c-Kit has been shown to be a client protein of
Hsp90, and Hsp90 inhibitor 17AAG, a benzoquinon ansamycin, has been
shown to induce apoptosis in Kasumi-1 cells, an acute myeloid
leukemia cell line that harbors a mutation in c-kit.
[0023] c-Met is a receptor tyrosine kinase that is encoded by the
Met protooncogene and transduces the biological effects of
hepatocyte growth factor (HGF), which is also referred to as
scatter factor (SF). Jiang et al., Crit. Rev. Oncol. Hemtol. 29:
209-248 (1999), the entire teachings of which are incorporated
herein by reference. c-Met and HGF are expressed in numerous
tissues, although their expression is normally confined
predominantly to cells of epithelial and mesenchymal origin,
respectively. c-Met and HGF are required for normal mammalian
development and have been shown to be important in cell migration,
cell proliferation and survival, morphogenic differentiation, and
organization of 3-dimensional tubular structures (e.g., renal
tubular cells, gland formation, etc.). The c-Met receptor has been
shown to be expressed in a number of human cancers. c-Met and its
ligand, HGF, have also been shown to be co-expressed at elevated
levels in a variety of human cancers (particularly sarcomas).
However, because the receptor and ligand are usually expressed by
different cell types, c-Met signaling is most commonly regulated by
tumor-stroma (tumor-host) interactions. Furthermore, c-Met gene
amplification, mutation, and rearrangement have been observed in a
subset of human cancers Families with germine mutations that
activate c-Met kinase are prone to multiple kidney tumors as well
as tumors in other tissues. Numerous studies have correlated the
expression of c-Met and/or HGF/SF with the state of disease
progression of different types of cancer (including lung, colon,
breast, prostate, liver, pancreas, brain, kidney, ovarian, stomach,
skin, and bone cancers). Furthermore, the overexpression of c-Met
or HGF have been shown to correlate with poor prognosis and disease
outcome in a number of major human cancers including lung, liver,
gastric, and breast.
[0024] BCR-ABL is an ocoprotein with tyrosine kinase activity and
has been associated with chronic myelogenous leukemia (CML), with a
subset of patients with acute lymphocytic leukemia (ALL) and with a
subset of patients with acute myelogenous leukemia (AML). In fact,
the BCR-ABL oncogene has been found in at least 90-95% of patients
with CML, 20% of adults with ALL, 5% of children with ALL, and in
about 2% of adults with AML. The BCR-ABL oncoprotein is generated
by the transloction of gene sequences from the c-ABL protein
tyrosine kinase on chromosome 9 into the BCR sequences on
chromosome 22, producing the Philadelphia chromosome. The BCR-ABL
gene has been shown to produce at least three alternative chimeric
proteins, p230 Bcr-Abl, p210 Bcr-Abl, and p190 Bcr-Abl which have
unregulated tyrosine kinase activity. The p210 Bcr-Abl fusion
protein is most often associated with CML, while the p190 Bcr-Abl
fusion protein is most often associated with ALL. Bcr-Abl has also
been associated with a variety of additional hematological
malignancies including granulocytic hyperplasia, myelomonocytic
leukemia, lymphomas and erythroid leukemia.
[0025] Studies have shown that lowering the expression or activity
of Bcr-Abl is effective in treating Bcr-Abl-positive leukemias. For
example, agents such as As.sub.2O.sub.3 which lower Bcr-Abl
expression have been shown to be highly effective against Bcr-Abl
leukemias. In addition, inhibition of Bcr-Abl tyrosine kinase
activity by Imatinib (also known as STI571 and Gleevic) induces
differentiation and apoptosis and causes eradication of Bcr-Abl
positive leukemia cells both in vivo and in vitro. In patients with
CML in the chronic phase, as well as in a blast crisis, treatment
with Imatinib typically will induce remission. However, in many
cases, particularly in those patients who were in a blast crisis
before remission, the remission is not durable because the Bcr-Abl
fusion protein develops mutations that cause it to be resistance to
Imatinib. (See Nimmanapalli, et al., Cancer Research (2001),
61:1799-1804; and Gorre, et al., Blood (2002), 100:3041-3044, the
entire teachings of each of these references are incorporated
herein by reference).
[0026] Bcr-Abl fusion proteins exist as complexes with Hsp90 and
are rapidly degraded when the action of Hsp90 is inhibited. It has
been shown that geldanamycin, a benzoquinone ansamycin antibiotic
that disrupts the association of Bcr-Abl with Hsp90, results in
proteasomal degradation of Bcr-Abl and induces apoptosis in Bcr-Abl
leukemia cells.
[0027] Hsp90 has been shown by mutational analysis to be necessary
for the survival of normal eukaryotic cells. However, Hsp90 is over
expressed in many tumor types indicating that it may play a
significant role in the survival of cancer cells and that cancer
cells may be more sensitive to inhibition of Hsp90 than normal
cells. For example, cancer cells typically have a large number of
mutated and overexpressed oncoproteins that are dependent on Hsp90
for folding. In addition, because the environment of a tumor is
typically hostile due to hypoxia, nutrient deprivation, acidosis,
etc., tumor cells may be especially dependent on Hsp90 for
survival. Moreover, inhibition of Hsp90 causes simultaneous
inhibition of a number of oncoproteins, as well as hormone
receptors and transcription factors making it an attractive target
for an anti-cancer agent. In fact, benzoquinone ansamycins, a
family of natural products that inhibit Hsp90, has shown evidence
of therapeutic activity in clinical trials.
[0028] Although promising, benzoquinone ansamycins, and their
derivatives, suffer from a number of limitations. For example, they
have low oral bioavailability, and their limited solubility makes
them difficult to formula. In addition, they are metabolized by
polymorphic cytochrome P450 CYP3A4 and are a substrate for
P-glycoprotein export pump involved in the development of multidrug
resistance. Therefore, a need exist for new therapeutics that
improve the prognosis of cancer patients and that reduces or
overcomes the limitations of currently used anti-cancer agents.
[0029] HSPs are highly conserved from microorganisms to mammals.
When a pathogen invades a host, both the pathogen and the host
increase HSP production. HSPs appear to play various roles in the
infection process. For instance, Hsp90 has been shown to play a
role in the pathways involved in the uptake and/or killing of
bacteria in phagocytic cells. Yan, L. et al., Eukaryotic Cell,
567-578, 3(3), 2004. Hsp90 has also been shown to be essential for
the uptake of binary actin ADP-ribosylating toxins into eukaryotic
cells. Haug, G., Infection and Immunity, 12, 3066-3068, 2004.
Additionally, Hsp90 has been identified as playing a role in viral
proliferation in a number of viruses including influenza virus,
vaccinia virus, herpes simplex virus type I, and HIV-1 virus.
Momose, F, et al., J. Biol. Chem., 45306-45314, 277(47), 2002;
Hung, J., et al., J. Virology, 1379-1390, 76(3), 2002; Li, Y., et
al., Antimicrobial Agents and Chemotherapy, 867-872, 48(3), 2004;
O'Keefe, B., et al., J. Biol. Chem., 279-287, 275(1), 2000.
[0030] Opportunistic fungal infections that are resistant to
antifungal drugs have become an increasing problem, particularly in
immunocompromised patients. Hsp90 has been shown to play a role in
the evolution of drug resistance in fungi. Cowen, L. et al.,
Eukaryotic Cell, 2184-2188, 5(12), 2006; Cowen, L. et al., Science,
309:2185-2189, 2005.
SUMMARY OF THE INVENTION
[0031] The present invention provides compounds which inhibit the
activity of Hsp90 and are useful in the treatment of proliferative
disorders, such as cancer.
[0032] The present invention also relates to compounds which
inhibit the activity of Hsp90 and are useful in the treatment of or
prevention of infections.
[0033] The present invention also relates to compounds which
inhibit the activity of topoisomerase II.
[0034] The present invention also relates to the discovery that
treatment of cells, such as peripheral blood mononuclear cells
(PMBCs) that have been stimulated with an inflammatory stimulus,
such as INF.gamma./LPS or SAC, with an Hsp90 inhibitor reduces the
expression of GR in the PMBCs and reduces the production of
inflammatory cytokines.
[0035] In one embodiment, the present invention provides compounds
represented by structural formula (I):
##STR00001## [0036] wherein: [0037] L is null, --S--CR.sub.12--,
--O--CR.sub.12--, --NR.sub.14--CR.sub.12--, --CR.sub.12--S--,
--CR.sub.12--O--, --CR.sub.12--NR.sub.13--,
--CR.sub.12--CR.sub.12--, --CR.sub.12--, --O--, --S--,
--NR.sub.14--, --O--O--, --S--S--, --NR.sub.13--NR.sub.13--,
--O--S--, --S--O--, --S--NR.sub.13--, --O--NR.sub.13--,
--NR.sub.13--O--, or --NR.sub.13--S--; [0038] R.sub.1 is an
optionally substituted alkyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
alkenyl, an optionally substituted alkynyl, an optionally
substituted cycloalkyl, an optionally substituted cycloalkenyl, an
optionally substituted heterocyclyl, optionally substituted
aralkyl, an optionally substituted heteraralkyl, or
[0039] --C(O)N(R.sub.13).sub.2; [0040] R.sub.2 and R.sub.3 are
independently --OH, --SH, --NR.sub.7H, --OR.sub.26, --SR.sub.26,
--O(CH.sub.2).sub.mOH, --O(CH.sub.2).sub.mSH,
--O(CH.sub.2).sub.mNR.sub.7H, --S(CH.sub.2).sub.mOH,
--S(CH.sub.2).sub.mSH, --S(CH.sub.2).sub.mNR.sub.7H,
--OC(O)NR.sub.10R.sub.11, --SC(O)NR.sub.10R.sub.11,
--NR.sub.7C(O)NR.sub.10R.sub.11, --OC(O)R.sub.7, --SC(O)R.sub.7,
--NR.sub.7C(O)R.sub.7, --OC(O)OR.sub.7, --SC(O)OR.sub.7,
--NR.sub.7C(O)OR.sub.7, --OCH.sub.2C(O)R.sub.7,
--SCH.sub.2C(O)R.sub.7, --NR.sub.7CH.sub.2C(O)R.sub.7,
--OCH.sub.2C(O)OR.sub.7, --SCH.sub.2C(O)OR.sub.7,
--NR.sub.7CH.sub.2C(O)OR.sub.7, --OCH.sub.2C(O)NR.sub.10R.sub.11,
--SCH.sub.2C(O)NR.sub.10R.sub.11,
--NR.sub.7CH.sub.2C(O)NR.sub.10R.sub.11, --OS(O).sub.pR.sub.7,
--SS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pR.sub.7, --OS(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --OS(O).sub.pOR.sub.7,
--SS(O).sub.pOR.sub.7, --NR.sub.7S(O).sub.pOR.sub.7,
--OC(S)R.sub.7, --SC(S)R.sub.7, --NR.sub.7C(S)R.sub.7,
--OC(S)OR.sub.7, --SC(S)OR.sub.7, --NR.sub.7C(S)OR.sub.7,
--OC(S)NR.sub.10R.sub.11, --SC(S)NR.sub.10R.sub.11,
--NR.sub.7C(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7,
--OC(NR.sub.8)OR.sub.7, --SC(NR.sub.8)OR.sub.7,
--NR.sub.7C(NR.sub.8)OR.sub.7, --OC(NR.sub.8)NR.sub.10R.sub.11,
--SC(NR.sub.8)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2; [0041] R.sub.5 is --H, --X.sub.20R.sub.50,
an optionally substituted alkyl, an optionally substituted alkenyl,
an optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, or an optionally substituted heteraralkyl; [0042] R.sub.7
and R.sub.8, for each occurrence, is independently, --H, an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, or an optionally substituted heteraralkyl; [0043] R.sub.10
and R.sub.11, for each occurrence, is independently --H, an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, or an optionally substituted heteraralkyl; or R.sub.10 and
R.sub.11, taken together with the nitrogen to which they are
attached, form an optionally substituted heterocyclyl or an
optionally substituted heteroaryl; [0044] each R.sub.12 is
independently --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; [0045] each R.sub.13 is independently --H, an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, or an optionally substituted heteraralkyl; [0046] each
R.sub.14 is independently an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl; [0047] R.sub.26 is a lower alkyl; [0048] R.sub.50 is
an optionally substituted aryl or an optionally substituted hetero
aryl; [0049] X.sub.20 is a C1-C4 alkyl, NR.sub.7, C(O), C(S),
C(NR.sub.8), or S(O).sub.p; [0050] Z is a substituent; [0051] p,
for each occurrence, is independently, 1 or 2; [0052] m for each
occurrence, is independently 1, 2, 3, or 4; [0053] n is 0, 1, 2, or
3;
[0054] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate or a prodrug thereof.
[0055] In one embodiment of compounds of formula (I) one or more of
the following provisos apply: [0056] when L is --S--CH.sub.2--,
--CH.sub.2--O--, or --O--CH.sub.2--, R.sub.1 is not optionally
substituted lower alkyl; [0057] when L is --S--CH.sub.2-- and
R.sub.5 is a methoxy phenyl, R.sub.1 is not
tetrahydro-2H-pyran-2-yl; [0058] when L is --S--CH.sub.2-- and
R.sub.5 is --H, R.sub.1 is not optionally substituted pyridyl;
[0059] when L is --O-- or --S--, R.sub.1 is not
--C(O)N(R.sub.13).sub.2 or optionally substituted lower alkyl;
[0060] when L is --N(CH.sub.3)-- or --O--, R.sub.1 is not
optionally substituted fluorophenyl; when L is --CH.sub.2--,
R.sub.1 is not a 1,2,3-triazolyl; [0061] when L is --CH.sub.2-- or
--CH.sub.2--CH.sub.2--, R.sub.1 is not an optionally substituted
C1-C7 alkyl; and [0062] when L is --CH.sub.2--S--, R.sub.1 is not a
chlorophenyl.
[0063] In one embodiment of compounds of formula (I) one or more of
the following provisos apply: [0064] when L is --S--CH.sub.2--,
--CH.sub.2--O--, or --O--CH.sub.2--, R.sub.1 is not optionally
substituted lower alkyl; [0065] when L is --S--CH.sub.2-- and
R.sub.5 is a methoxy phenyl, R.sub.1 is not
tetrahydro-2H-pyran-2-yl; [0066] when L is --S--CH.sub.2-- and
R.sub.5 is --H, R.sub.1 is not optionally substituted pyridyl;
[0067] when L is --O-- or --S--, R.sub.1 is not
--C(O)N(R.sub.13).sub.2 or optionally substituted lower alkyl;
[0068] when L is --N(CH.sub.3)-- or --O--, R.sub.1 is not
optionally substituted fluorophenyl; when L is --CH.sub.2--,
R.sub.1 is not a 1,2,3-triazolyl; [0069] when L is --S--CH.sub.2--
and R.sub.5 is --H, R.sub.1 is not optionally substituted pyridyl
or a fluorophenyl; [0070] when L is --CH.sub.2-- or
--CH.sub.2--CH.sub.2--, R.sub.1 is not an optionally substituted
C1-C7 alkyl; and [0071] when L is --CH.sub.2--S--, R.sub.1 is not a
chlorophenyl.
[0072] In one embodiment, the present invention provides compounds
represented by structural formula (II):
##STR00002## [0073] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.5, Z
and L are defined as for formula (I); [0074] or a tautomer,
pharmaceutically acceptable salt, solvate, clathrate or a prodrug
thereof.
[0075] In one embodiment, the present invention provides compounds
represented by structural formula (III):
##STR00003## [0076] wherein: [0077] L' is --S--CR.sub.12--,
--O--CR.sub.12--, --O--, or --S--; [0078] R'.sub.1 is an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, optionally
substituted aralkyl, an optionally substituted heteraralkyl, or
--C(O)N(R.sub.13).sub.2; [0079] R'.sub.5 is --X.sub.20R.sub.50, an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, or an optionally substituted heteraralkyl; and [0080]
R.sub.1, R.sub.2, R.sub.3, and Z are defined as for formula (I);
[0081] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate or a prodrug thereof.
[0082] In one embodiment of compounds of formula (III) one or more
of the following provisos apply: [0083] when L' is --S--CH.sub.2--
and R'.sub.5 is a methoxy phenyl, R'.sub.1 is not
tetrahydro-2H-pyran-2-yl; [0084] when L' is --O-- or --S--,
R'.sub.1 is not --C(O)N(R.sub.13).sub.2.
[0085] In one embodiment, the present invention provides compounds
represented by formula (IV):
##STR00004## [0086] wherein: [0087] X.sub.41 is O, S, or NR.sub.42;
[0088] X.sub.42 is CR.sub.44 or N; [0089] Y.sub.40 is N or
CR.sub.43; [0090] Y.sub.41 is N or CR.sub.45; [0091] Y.sub.42, for
each occurrence, is independently N, C or CR.sub.46; [0092]
R.sub.41 is --H, --OH, --SH, an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a
heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy,
--NR.sub.10R.sub.11, --OR.sub.7, --C(O)R.sub.7, --C(O)OR.sub.7,
--C(S)R.sub.7, --C(O)SR.sub.7, --C(S)SR.sub.7, --C(S)OR.sub.7,
--C(S)NR.sub.10R.sub.11, --C(NR.sub.8)OR.sub.7,
--C(NR.sub.8)R.sub.7, --C(NR.sub.8)NR.sub.10R.sub.11,
--C(NR.sub.8)SR.sub.7, --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(S)OR.sub.7, --OC(NR.sub.8)OR.sub.7, --SC(O)R.sub.7,
--SC(O)OR.sub.7, --SC(NR.sub.8)OR.sub.7, --OC(S)R.sub.7,
--SC(S)R.sub.7, --SC(S)OR.sub.7, --OC(O)NR.sub.10R.sub.11,
--OC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)NR.sub.10R.sub.11,
--SC(O)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --NR.sub.7C(S)R.sub.7,
--NR.sub.7C(S)OR.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7,
--NR.sub.7C(O)OR.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(S)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --SR.sub.7,
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, --NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7, --S(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pR.sub.7, --SS(O).sub.pOR.sub.7,
--SS(O).sub.pNR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2; [0093] R.sub.42 is --H, an optionally
substituted alkyl, an optionally substituted alkenyl, an optionally
substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted
heterocyclyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted aralkyl, an
optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a
haloalkyl, a heteroalkyl, --C(O)R.sub.7,
--(CH.sub.2).sub.mC(O)OR.sub.7, --C(O)OR.sub.7, --OC(O)R.sub.7,
--C(O)NR.sub.10R.sub.11, --S(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
or --S(O).sub.pNR.sub.10R.sub.11; [0094] R.sub.43 and R.sub.44 are,
independently, --H, --OH, an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro,
guanadino, a haloalkyl, a heteroalkyl, --C(O)R.sub.7,
--C(O)OR.sub.7, --OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --SR.sub.7, --S(O).sub.pR.sub.7,
--OS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, --S(O).sub.pNR.sub.10R.sub.11, or
R.sub.43 and R.sub.44 taken together with the carbon atoms to which
they are attached form an optionally substituted cycloalkenyl, an
optionally substituted aryl, an optionally substituted
heterocyclyl, or an optionally substituted heteroaryl; [0095]
R.sub.45 is --H, --OH, --SH, --NR.sub.7H, --OR.sub.26, --SR.sub.26,
--NHR.sub.26, --O(CH.sub.2).sub.mOH, --O(CH.sub.2).sub.mSH,
--O(CH.sub.2).sub.mNR.sub.7H, --S(CH.sub.2).sub.mOH,
--S(CH.sub.2).sub.mSH, --S(CH.sub.2).sub.mNR.sub.7H,
--OC(O)NR.sub.10R.sub.11, --SC(O)NR.sub.10R.sub.11,
--NR.sub.7C(O)NR.sub.10R.sub.11, --OC(O)R.sub.7, --SC(O)R.sub.7,
--NR.sub.7C(O)R.sub.7, --OC(O)OR.sub.7, --SC(O)OR.sub.7,
--NR.sub.7C(O)OR.sub.7, --OCH.sub.2C(O)R.sub.7,
--SCH.sub.2C(O)R.sub.7, --NR.sub.7CH.sub.2C(O)R.sub.7,
--OCH.sub.2C(O)OR.sub.7, --SCH.sub.2C(O)OR.sub.7,
--NR.sub.7CH.sub.2C(O)OR.sub.7, --OCH.sub.2C(O)NR.sub.10R.sub.11,
--SCH.sub.2C(O)NR.sub.10R.sub.11,
--NR.sub.7CH.sub.2C(O)NR.sub.10R.sub.11, --OS(O).sub.pR.sub.7,
--SS(O).sub.pR.sub.7, --NR.sub.7S(O).sub.pR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --SS(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --OS(O).sub.pOR.sub.7,
--SS(O).sub.pOR.sub.7, --NR.sub.7S(O).sub.pOR.sub.7,
--OC(S)R.sub.7, --SC(S)R.sub.7, --NR.sub.7C(S)R.sub.7,
--OC(S)OR.sub.7, --SC(S)OR.sub.7, --NR.sub.7C(S)OR.sub.7,
--OC(S)NR.sub.10R.sub.11, --SC(S)NR.sub.10R.sub.11,
--NR.sub.7C(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7,
--OC(NR.sub.8)OR.sub.7, --SC(NR.sub.8)OR.sub.7,
--NR.sub.7C(NR.sub.8)OR.sub.7, --OC(NR.sub.8)NR.sub.10R.sub.11,
--SC(NR.sub.8)NR.sub.10R.sub.11, or
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11; and [0096] R.sub.46, for
each occurrence, is independently, selected from the group
consisting of H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a
heteroalkyl, --NR.sub.10R.sub.11, --OR.sub.7, --C(O)R.sub.7,
--C(O)OR.sub.7, --OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --SR.sub.7, --S(O).sub.pR.sub.7,
--OS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, or --S(O).sub.pNR.sub.10R.sub.11; and
[0097] L'.sub.1 and R'.sub.1 are defined as for formula (III);
[0098] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate or a prodrug thereof.
[0099] In one embodiment, the present invention provides compounds
represented by formula (V):
##STR00005## [0100] wherein R'.sub.1, R.sub.41, R.sub.42, R.sub.43,
R.sub.45, X.sub.42, and L' are defined as for formula (IV); [0101]
or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof.
[0102] In one embodiment, the present invention provides compounds
represented by formula (VI):
##STR00006## [0103] wherein: [0104] X.sub.45 is CR.sub.54 or N;
[0105] R.sub.56 is selected from the group consisting of --H,
methyl, ethyl, isopropyl, and cyclopropyl; [0106] R.sub.52 is
selected from the group consisting of --H, methyl, ethyl, n-propyl,
isopropyl, n-butyl, n-pentyl, n-hexyl, --(CH.sub.2).sub.2OCH.sub.3,
--CH.sub.2C(O)OH, and --C(O)N(CH.sub.3).sub.2; [0107] R.sub.53 and
R.sub.54 are each, independently, --H, methyl, ethyl, or isopropyl;
or [0108] R.sub.53 and R.sub.54 taken together with the carbon
atoms to which they are attached form a phenyl, cyclohexenyl, or
cyclooctenyl ring; [0109] R.sub.55 is selected from the group
consisting of --H, --OH, --OCH.sub.3, and OCH.sub.2CH.sub.3; and
[0110] L'.sub.1 and R'.sub.1 are defined as for formula (III);
[0111] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof.
[0112] In one embodiment, the present invention provides compounds
represented by formula (VII):
##STR00007## [0113] wherein L'.sub.1 and R'.sub.1 are defined as
for formula (III); and R.sub.41 and R.sub.42 are defined as for
formula (IV); [0114] or a tautomer, pharmaceutically acceptable
salt, solvate, clathrate, or prodrug thereof.
[0115] In one embodiment, the present invention provides compounds
represented by formula (VIII):
##STR00008## [0116] wherein: [0117] Y is O or S; [0118] R.sub.3 is
--OH, --SH, --NR.sub.7H, --OR.sub.26, --SR.sub.26,
--O(CH.sub.2).sub.mOH, --O(CH.sub.2).sub.mSH,
--O(CH.sub.2).sub.mNR.sub.7H, --S(CH.sub.2).sub.mOH,
--S(CH.sub.2).sub.mSH, --S(CH.sub.2).sub.mNR.sub.7H,
--OC(O)NR.sub.10R.sub.11, --SC(O)NR.sub.10R.sub.11,
--NR.sub.7C(O)NR.sub.10R.sub.11, --OC(O)R.sub.7, --SC(O)R.sub.7,
--NR.sub.7C(O)R.sub.7, --OC(O)OR.sub.7, --SC(O)OR.sub.7,
--NR.sub.7C(O)OR.sub.7, --OCH.sub.2C(O)R.sub.7,
--SCH.sub.2C(O)R.sub.7, --NR.sub.7CH.sub.2C(O)R.sub.7,
--OCH.sub.2C(O)OR.sub.7, --SCH.sub.2C(O)OR.sub.7,
--NR.sub.7CH.sub.2C(O)OR.sub.7, --OCH.sub.2C(O)NR.sub.10R.sub.11,
--SCH.sub.2C(O)NR.sub.10R.sub.11,
--NR.sub.7CH.sub.2C(O)NR.sub.10R.sub.11, --OS(O).sub.pR.sub.7,
--SS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pR.sub.7, --OS(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --OS(O).sub.pOR.sub.7,
--SS(O).sub.pOR.sub.7, --NR.sub.7S(O).sub.pOR.sub.7,
--OC(S)R.sub.7, --SC(S)R.sub.7, --NR.sub.7C(S)R.sub.7,
--OC(S)OR.sub.7, --SC(S)OR.sub.7, --NR.sub.7C(S)OR.sub.7,
--OC(S)NR.sub.10R.sub.11, --SC(S)NR.sub.10R.sub.11,
--NR.sub.7C(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7,
--OC(NR.sub.8)OR.sub.7, --SC(NR.sub.8)OR.sub.7,
--NR.sub.7C(NR.sub.8)OR.sub.7, --OC(NR.sub.8)NR.sub.10R.sub.11,
--SC(NR.sub.8)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2; [0119] R.sub.5 is --H, --X.sub.20R.sub.50,
an optionally substituted alkyl, an optionally substituted alkenyl,
an optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, or an optionally substituted heteraralkyl; [0120] R.sub.7
and R.sub.8, for each occurrence, is independently, --H, an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, or an optionally substituted heteraralkyl; [0121] R.sub.10
and R.sub.11, for each occurrence, is independently --H, an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, or an optionally substituted heteraralkyl; or R.sub.10 and
R.sub.11, taken together with the nitrogen to which they are
attached, form an optionally substituted heterocyclyl or an
optionally substituted heteroaryl; [0122] R.sub.26 is a lower
alkyl; [0123] R.sub.35 and R.sub.36, for each occurrence, is
independently --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl, or R.sub.35 and R.sub.36, together with N to which
they are attached form a 5 to 7 membered heterocyclic ring; [0124]
R.sub.50 is an optionally substituted aryl or an optionally
substituted heteroaryl; [0125] X.sub.20 is a C1-C4 alkyl, NR.sub.7,
C(O), C(S), C(NR.sub.8), or S(O).sub.p; [0126] Z is a substituent;
[0127] t is 0, 1, 2, 3, or 4; [0128] p, for each occurrence, is
independently, 1 or 2; or a tautomer, pharmaceutically acceptable
salt, solvate, clathrate or a prodrug thereof.
[0129] In one embodiment, the present invention provides compounds
represented by formula (IX):
##STR00009##
wherein: R.sub.2 is --OH, --SH, --NR.sub.7H, --OR.sub.26,
--SR.sub.26, --O(CH.sub.2).sub.mOH, --O(CH.sub.2).sub.mSH,
--O(CH.sub.2).sub.mNR.sub.7H, --S(CH.sub.2).sub.mOH,
--S(CH.sub.2).sub.mSH, --S(CH.sub.2).sub.mNR.sub.7H,
--OC(O)NR.sub.10R.sub.11, --SC(O)NR.sub.10R.sub.11,
--NR.sub.7C(O)NR.sub.10R.sub.11, --OC(O)R.sub.7, --SC(O)R.sub.7,
--NR.sub.7C(O)R.sub.7, --OC(O)OR.sub.7, --SC(O)OR.sub.7,
NR.sub.7C(O)OR.sub.7, --OCH.sub.2C(O)R.sub.7,
--SCH.sub.2C(O)R.sub.7, --NR.sub.7CH.sub.2C(O)R.sub.7,
--OCH.sub.2C(O)OR.sub.7, --SCH.sub.2C(O)OR.sub.7,
--NR.sub.7CH.sub.2C(O)OR.sub.7, --OCH.sub.2C(O)NR.sub.10R.sub.11,
--SCH.sub.2C(O)NR.sub.10R.sub.11,
--NR.sub.7CH.sub.2C(O)NR.sub.10R.sub.11, --OS(O).sub.pR.sub.7,
--SS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.7S(O).sub.pR.sub.7, --OS(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --OS(O).sub.pOR.sub.7,
--SS(O).sub.pOR.sub.7, --NR.sub.7S(O).sub.pOR.sub.7,
--OC(S)R.sub.7, --SC(S)R.sub.7, --NR.sub.7C(S)R.sub.7,
--OC(S)OR.sub.7, --SC(S)OR.sub.7, --NR.sub.7C(S)OR.sub.7,
--OC(S)NR.sub.10R.sub.11, --SC(S)NR.sub.10R.sub.11,
--NR.sub.7C(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7,
--OC(NR.sub.8)OR.sub.7, --SC(NR.sub.8)OR.sub.7,
--NR.sub.7C(NR.sub.8)OR.sub.7, --OC(NR.sub.8)NR.sub.10R.sub.11,
--SC(NR.sub.8)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2; and [0130] n is 0, 1, 2, or 3; or a
tautomer, pharmaceutically acceptable salt, solvate, clathrate or a
prodrug thereof.
[0131] In one embodiment, the present invention provides compounds
represented by formula (X):
##STR00010##
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate
or a prodrug thereof.
[0132] In one embodiment, the present invention provides compounds
represented by formula (XI):
##STR00011##
wherein: [0133] X.sub.41 is O, S, or NR.sub.42; [0134] X.sub.42 is
CR.sub.44 or N; [0135] Y.sub.40 is N or CR.sub.43; [0136] Y.sub.41
is N or CR.sub.45; [0137] Y.sub.42, for each occurrence, is
independently N, C or CR.sub.46; [0138] R.sub.41 is --H, --OH,
--SH, an optionally substituted alkyl, an optionally substituted
alkenyl, an optionally substituted alkynyl, an optionally
substituted cycloalkyl, an optionally substituted cycloalkenyl, an
optionally substituted heterocyclyl, an optionally substituted
aryl, an optionally substituted heteroaryl, an optionally
substituted aralkyl, an optionally substituted heteraralkyl, halo,
cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or
cycloalkoxy, a haloalkoxy, --NR.sub.10R.sub.11, --OR.sub.7,
--C(O)R.sub.7, --C(O)OR.sub.7, --C(S)R.sub.7, --C(O)SR.sub.7,
--C(S)SR.sub.7, --C(S)OR.sub.7, --C(S)NR.sub.10R.sub.11,
--C(NR.sub.8)OR.sub.7, --C(NR.sub.8)R.sub.7,
--C(NR.sub.8)NR.sub.10R.sub.11; --C(NR.sub.8)SR.sub.7,
--OC(O)R.sub.7, --OC(O)OR.sub.7, --OC(S)OR.sub.7,
--OC(NR.sub.8)OR.sub.7, --SC(O)OR.sub.7, --SC(O)OR.sub.7,
--SC(NR.sub.8)OR.sub.7, --OC(S)R.sub.7, --SC(S)R.sub.7,
--SC(S)OR.sub.7, --OC(O)NR.sub.10R.sub.11,
--OC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)NR.sub.10R.sub.11,
--SC(O)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.SC(O)R.sub.7, --NR.sub.7C(S)R.sub.7,
--NR.sub.7C(S)OR.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7,
--NR.sub.7C(O)OR.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(S)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --SR.sub.7,
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, --NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7, --S(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pR.sub.7, --SS(O).sub.pOR.sub.7,
--SS(O).sub.pNR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2; [0139] R.sub.42 is --H, an optionally
substituted alkyl, an optionally substituted alkenyl, an optionally
substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted
heterocyclyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted aralkyl, an
optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a
haloalkyl, a heteroalkyl, --C(O)R.sub.7,
--(CH.sub.2).sub.mC(O)OR.sub.7, --C(O)OR.sub.7, --OC(O)R.sub.7,
--C(O)NR.sub.10R.sub.11, --S(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
or --S(O).sub.pNR.sub.10R.sub.11; [0140] R.sub.43 and R.sub.44 are,
independently, --H, --OH, an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro,
guanadino, a haloalkyl, a heteroalkyl, --C(O)R.sub.7,
--C(O)OR.sub.7, --OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --SR.sub.7, --S(O).sub.pR.sub.7,
--OS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, --S(O).sub.pNR.sub.10R.sub.11, or
R.sub.43 and R.sub.44 taken together with the carbon atoms to which
they are attached form an optionally substituted cycloalkenyl, an
optionally substituted aryl, an optionally substituted
heterocyclyl, or an optionally substituted heteroaryl; [0141]
R.sub.45 is --H, --OH, --SH, --NR.sub.7H, --OR.sub.26, --SR.sub.26,
--NHR.sub.26, --O(CH.sub.2).sub.mOH, --O(CH.sub.2).sub.mSH,
--O(CH.sub.2).sub.mNR.sub.7H, --S(CH.sub.2).sub.mOH,
--S(CH.sub.2).sub.mSH, --S(CH.sub.2).sub.mNR.sub.7H,
--OC(O)NR.sub.10R.sub.11, --SC(O)NR.sub.10R.sub.11,
--NR.sub.7C(O)NR.sub.10R.sub.11, --OC(O)R.sub.7, --SC(O)R.sub.7,
--NR.sub.7C(O)R.sub.7, --OC(O)OR.sub.7, --SC(O)OR.sub.7,
--NR.sub.7C(O)OR.sub.7, --OCH.sub.2C(O)R.sub.7,
--SCH.sub.2C(O)R.sub.7, --NR.sub.7CH.sub.2C(O)R.sub.7,
--OCH.sub.2C(O)OR.sub.7, --SCH.sub.2C(O)OR.sub.7,
--NR.sub.7CH.sub.2C(O)OR.sub.7, --OCH.sub.2C(O)NR.sub.10R.sub.11,
--SCH.sub.2C(O)NR.sub.10R.sub.11,
--NR.sub.7CH.sub.2C(O)NR.sub.10R.sub.11, --OS(O).sub.pR.sub.7,
--SS(O).sub.pR.sub.7, --NR.sub.7S(O).sub.pR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --SS(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pNR.sub.10R.sub.11, --OS(O).sub.pOR.sub.7,
--SS(O).sub.pOR.sub.7, --NR.sub.7S(O).sub.pOR.sub.7,
--OC(S)R.sub.7, --SC(S)R.sub.7, --NR.sub.7C(S)R.sub.7,
--OC(S)OR.sub.7, --SC(S)OR.sub.7, --NR.sub.7C(S)OR.sub.7,
--OC(S)NR.sub.10R.sub.11, --SC(S)NR.sub.10R.sub.11,
--NR.sub.7C(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7,
--OC(NR.sub.8)OR.sub.7, --SC(NR.sub.8)OR.sub.7,
--NR.sub.7C(NR.sub.8)OR.sub.7, --OC(NR.sub.8)NR.sub.10R.sub.11,
--SC(NR.sub.8)NR.sub.10R.sub.11, or
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11; and [0142] R.sub.46, for
each occurrence, is independently, selected from the group
consisting of H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a
heteroalkyl, --NR.sub.10R.sub.11, --OR.sub.7, --C(O)R.sub.7,
--C(O)OR.sub.7, --OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --SR.sub.7, --S(O).sub.pR.sub.7,
--OS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, or --S(O).sub.pNR.sub.10R.sub.11; or a
tautomer, pharmaceutically acceptable salt, solvate, clathrate or a
prodrug thereof.
[0143] In one embodiment, the present invention provides compounds
represented by formula (XII):
##STR00012## [0144] or a tautomer, pharmaceutically acceptable
salt, solvate, clathrate, or prodrug thereof.
[0145] In one embodiment, the present invention provides compounds
represented by formula (XIII):
##STR00013## [0146] wherein: [0147] X.sub.45 is CR.sub.54 or N;
[0148] R.sub.56 is selected from the group consisting of --H,
methyl, ethyl, isopropyl, and cyclopropyl; [0149] R.sub.52 is
selected from the group consisting of --H, methyl, ethyl, n-propyl,
isopropyl, n-butyl, n-pentyl, n-hexyl, --(CH.sub.2).sub.2OCH.sub.3,
--CH.sub.2C(O)OH, and --C(O)N(CH.sub.3).sub.2; [0150] R.sub.53 and
R.sub.54 are each, independently, --H, methyl, ethyl, or isopropyl;
or [0151] R.sub.53 and R.sub.54 taken together with the carbon
atoms to which they are attached form a phenyl, cyclohexenyl, or
cyclooctenyl ring; and [0152] R.sub.55 is selected from the group
consisting of --H, --OH, --OCH.sub.3, and OCH.sub.2CH.sub.3; [0153]
or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate, or prodrug thereof.
[0154] In one embodiment, the present invention provides compounds
represented by formula (XIV):
##STR00014## [0155] or a tautomer, pharmaceutically acceptable
salt, solvate, clathrate, or prodrug thereof.
[0156] In one embodiment, the present invention provides compounds
represented by formula (XV):
##STR00015##
wherein: [0157] Y is --O-- or --S--; [0158] R.sub.1 is an
optionally substituted alkyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
alkenyl, an optionally substituted alkynyl, an optionally
substituted cycloalkyl, an optionally substituted cycloalkenyl, an
optionally substituted heterocyclyl, optionally substituted
aralkyl, an optionally substituted heteraralkyl, or
--C(O)N(R.sub.13).sub.2;
[0158] [0159] R'.sub.3 is --OH, --SH, --OR.sub.26, --SR.sub.26,
--O(CH.sub.2).sub.mOH, --O(CH.sub.2).sub.mSH,
--O(CH.sub.2).sub.mNR.sub.7H, --S(CH.sub.2).sub.mOH,
--S(CH.sub.2).sub.mSH, --S(CH.sub.2).sub.mNR.sub.7H,
--OC(O)NR.sub.10R.sub.11, --SC(O)NR.sub.10R.sub.11, --OC(O)R.sub.7,
--SC(O)R.sub.7, --OC(O)OR.sub.7, --SC(O)OR.sub.7,
--OCH.sub.2C(O)R.sub.7, --SCH.sub.2C(O)R.sub.7,
--OCH.sub.2C(O)OR.sub.7, --SCH.sub.2C(O)OR.sub.7,
--OCH.sub.2C(O)NR.sub.10R.sub.11, --SCH.sub.2C(O)NR.sub.10R.sub.11,
--OS(O).sub.pR.sub.7, --SS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --SS(O).sub.pNR.sub.10R.sub.11,
--OS(O).sub.pOR.sub.7, --SS(O).sub.pOR.sub.7, --OC(S)R.sub.7,
--SC(S)R.sub.7, --OC(S)OR.sub.7, --SC(S)OR.sub.7,
--OC(S)NR.sub.10R.sub.11, --SC(S)NR.sub.10R.sub.11,
--OC(NR.sub.8)R.sub.7, --SC(NR.sub.8)R.sub.7,
--OC(NR.sub.8)OR.sub.7, --SC(NR.sub.8)OR.sub.7,
--OC(NR.sub.8)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--OP(O)(OR.sub.7).sub.2, or --SP(O)(OR.sub.7).sub.2;
[0160] R'.sub.5 is --X.sub.20R.sub.50, an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; [0161] R.sub.6 is an optionally
substituted alkyl, an optionally substituted alkenyl, an optionally
substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted
heterocyclyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted aralkyl, an
optionally substituted heteroaralkyl, halo, cyano, nitro,
guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,
--NR.sub.10R.sub.11, --OR.sub.7, --C(O)R.sub.7, --C(O)OR.sub.7,
--C(S)R.sub.7, --C(O)SR.sub.7, --C(S)SR.sub.7, --C(S)OR.sub.7,
--C(S)NR.sub.10R.sub.11, --C(NR.sub.8)OR.sub.7,
--C(NR.sub.8)R.sub.7, --C(NR.sub.8)NR.sub.10R.sub.11,
--C(NR.sub.8)SR.sub.7, --OC(O)R.sub.7, --OC(O)OR.sub.7,
--OC(S)OR.sub.7, --OC(NR.sub.8)OR.sub.7, --SC(O)R.sub.7,
--SC(O)OR.sub.7, --SC(NR.sub.8)OR.sub.7, --OC(S)R.sub.7,
--SC(S)R.sub.7, --SC(S)OR.sub.7, --OC(O)NR.sub.10R.sub.11,
--OC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)NR.sub.10R.sub.11,
--SC(O)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --NR.sub.7C(S)R.sub.7,
--NR.sub.7C(S)OR.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7,
--NR.sub.7C(O)OR.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(S)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --SR.sub.7,
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7, --S(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pR.sub.7, --SS(O).sub.pOR.sub.7,
--SS(O).sub.pNR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2; [0162] R.sub.7 and R.sub.8, for each
occurrence, is independently, --H, an optionally substituted alkyl,
an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; [0163] R.sub.10 and R.sub.11, for each
occurrence, is independently --H, an optionally substituted alkyl,
an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl; or R.sub.10 and R.sub.11, taken together
with the nitrogen to which they are attached, form an optionally
substituted heterocyclyl or an optionally substituted heteroaryl;
[0164] R.sub.26 is a lower alkyl; [0165] R.sub.50 is an optionally
substituted aryl or an optionally substituted heteroaryl; [0166]
X.sub.20 is a C1-C4 alkyl, NR.sub.7, C(O), C(S), C(NR.sub.8), or
S(O).sub.p; [0167] Z is a substituent; [0168] m for each occurrence
is independently 1, 2, 3, or 4; [0169] p, for each occurrence, is
independently, 1 or 2; [0170] n is 0, 1, 2, or 3; or a tautomer,
pharmaceutically acceptable salt, solvate, clathrate or a prodrug
thereof.
[0171] In one embodiment of compounds of formula (XV) one or more
of the following provisos apply: [0172] provided that when Y is
--S-- and R.sub.1 is an optionally substituted C1-C3 alkyl, then
R'.sub.3 is not --OCH.sub.2OMe;
[0173] provided that when Y is --S--, R.sub.1 is Me and R'.sub.5 is
lower alkyl, then R.sub.6 is not halo.
[0174] The compounds shown in Table 1 or compounds of any formula
herein, or tautomers, pharmaceutically acceptable salts, solvates,
clathrates, hydrates, polymorphs or prodrugs thereof, inhibit the
activity of Hsp90 and, thereby facilitates the degradation of Hsp90
client proteins. Hsp90 is necessary for the survival of normal
eukaryotic cells. However, Hsp90 is over expressed in many tumor
types indicating that it may play a significant role in the
survival of cancer cells and that cancer cells may be more
sensitive to inhibition of Hsp90 than normal cells. Thus, the
compounds shown in Table 1 or compounds of any formula herein, or
tautomers, pharmaceutically acceptable salts, solvates, clathrates,
hydrates, polymorphs or prodrugs thereof, are useful treating
proliferative disorders such as cancer.
[0175] Although chemotherapeutic agents initially cause tumor
regression, most agents that are currently used to treat cancer
target only one pathway to tumor progression. Therefore, in many
instances, after treatment with one or more chemotherapeutic
agents, a tumor develops multidrug resistance and no longer
responses positively to treatment. One of the advantages of
inhibiting Hsp90 activity is that several of its client proteins,
which are mostly protein kinases or transcription factors involved
in signal transduction, have been shown to be involved in the
progression of cancer. Thus, inhibition of Hsp90 provides a method
of short circuiting several pathways for tumor progression
simultaneously.
[0176] Therefore, treatment of tumors with an Hsp90 inhibitor of
the invention either alone, or in combination with other
chemotherapeutic agents, is more likely to result in regression or
elimination of the tumor, and less likely to result in the
development of more aggressive multidrug resistant tumors than
other currently available therapies.
DETAILED DESCRIPTION OF THE INVENTION
[0177] A description of preferred embodiments of the invention
follows.
[0178] When a disclosed compound is named or depicted by structure,
it is to be understood that solvates (e.g., hydrates) of the
compound or its pharmaceutically acceptable salts are also
included. "Solvates" refer to crystalline forms wherein solvent
molecules are incorporated into the crystal lattice during
crystallization. Solvate may include water or nonaqueous solvents
such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and
EtOAc. Solvates, wherein water is the solvent molecule incorporated
into the crystal lattice, are typically referred to as "hydrates".
Hydrates include stoichiometric hydrates as well as compositions
containing variable amounts of water.
[0179] When a disclosed compound is named or depicted by structure,
it is to be understood that the compound, including solvates
thereof, may exist in crystalline forms, non-crystalline forms or a
mixture thereof. The compounds or solvates may also exhibit
polymorphism (i.e. the capacity to occur in different crystalline
forms). These different crystalline forms are typically known as
"polymorphs." It is to be understood that when named or depicted by
structure, the disclosed compounds and solvates (e.g., hydrates)
also include all polymorphs thereof. Polymorphs have the same
chemical composition but differ in packing, geometrical
arrangement, and other descriptive properties of the crystalline
solid state. Polymorphs, therefore, may have different physical
properties such as shape, density, hardness, deformability,
stability, and dissolution properties. Polymorphs typically exhibit
different melting points, IR spectra, and X-ray powder diffraction
patterns, which may be used for identification. One of ordinary
skill in the art will appreciate that different polymorphs may be
produced, for example, by changing or adjusting the conditions used
in solidfying the compound. For example, changes in temperature,
pressure, or solvent may result in different polymorphs. In
addition, one polymorph may spontaneously convert to another
polymorph under certain conditions.
[0180] When a disclosed compound is named or depicted by structure,
it is to be understood that clathrates ("inclusion compounds") of
the compound or its pharmaceutically acceptable salts, solvates or
polymorphs are also included. "Clathrate" refers to a chemical
substance consisting of a lattice of one type of molecule trapping
and containing a second type of molecule.
[0181] The present invention provides compounds disclosed herein
and uses of said compounds to inhibit Hsp90 activity and for the
treatment of a proliferative disorder, such as cancer. In
particular, the present invention encompasses the use of compounds
of the invention to slow or stop the growth of cancerous cells or
to reduce or eliminate cancerous cells in a subject, preferably the
subject is a mammal.
[0182] In certain embodiments, the compounds of the invention can
be used in combination with other chemotherapeutic agents and may
help to prevent or reduce the development of multidrug resistant
cancerous cells in a mammal. In this embodiment, the compounds of
the invention may allow a reduced efficacious amount of a second
chemotherapeutic agent given to a mammal, because compounds of the
invention should inhibit the development of multidrug resistant
cancerous cells.
[0183] In certain embodiments, compounds of the invention can be
used in the treatment of or prevention of infections.
[0184] In another embodiment, the present invention relates to a
method of treating or preventing fungal drug resistance in a mammal
in need of such treatment. The method comprises administering to
the mammal an effective amount of an Hsp90 inhibitor disclosed
herein.
[0185] In certain embodiments, compounds of the invention can be
used to inhibit the activity of topoisomerase II.
[0186] In certain embodiments, compounds of the invention can be
used for modulating the activity of glucocorticoid receptors in a
cell.
A. TERMINOLOGY
[0187] Unless otherwise specified, the below terms used herein are
defined as follows:
[0188] As used herein, the term "alkyl" means a saturated straight
chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon
atoms. Representative saturated straight chain alkyls include
methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl,
n-octyl, n-nonyl and n-decyl; while saturated branched alkyls
include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl,
2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl,
4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl,
5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl,
2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl,
2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl,
3,3-dimtheylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl,
2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl,
4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl,
2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl,
2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl,
3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like.
The term "(C.sub.1-C.sub.6)alkyl" means a saturated straight chain
or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms.
Representative (C.sub.1-C.sub.6)alkyl groups are those shown above
having from 1 to 6 carbon atoms. Alkyl groups included in compounds
of this invention may be optionally substituted with one or more
substituents.
[0189] As used herein, the term "alkenyl" means a saturated
straight chain or branched non-cyclic hydrocarbon having from 2 to
10 carbon atoms and having at least one carbon-carbon double bond.
Representative straight chain and branched
(C.sub.2-C.sub.10)alkenyls include vinyl, allyl, 1-butenyl,
2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl,
3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl,
1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl,
3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl,
3-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl and the like. Alkenyl
groups may be optionally substituted with one or more
substituents.
[0190] As used herein, the term "alkynyl" means a saturated
straight chain or branched non-cyclic hydrocarbon having from 2 to
10 carbon atoms and having at least one carbon-carbon triple bond.
Representative straight chain and branched alkynyls include
acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl,
3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl,
1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl,
7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl,
9-decynyl, and the like. Alkynyl groups may be optionally
substituted with one or more substituents.
[0191] As used herein, the term "cycloalkyl" means a saturated,
mono- or polycyclic alkyl radical having from 3 to 20 carbon atoms.
Representative cycloalkyls include cyclopropyl,
1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclononyl, -cyclodecyl,
octahydro-pentalenyl, and the like. Cycloalkyl groups may be
optionally substituted with one or more substituents.
[0192] As used herein, the term "cycloalkenyl" means a mono- or
poly-cyclic non-aromatic alkyl radical having at least one
carbon-carbon double bond in the cyclic system and from 3 to 20
carbon atoms. Representative cycloalkenyls include cyclopentenyl,
cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,
cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl,
cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl,
cyclononadienyl, cyclodecenyl, cyclodecadienyl,
1,2,3,4,5,8-hexahydronaphthalenyl and the like. Cycloalkenyl groups
may be optionally substituted with one or more substituents.
[0193] As used herein, the term "haloalkyl" means an alkyl group,
in which one or more (including all) the hydrogen radicals are
replaced by a halo group, wherein each halo group is independently
selected from --F, --Cl, --Br, and --I. The term "halomethyl" means
a methyl in which one to three hydrogen radical(s) have been
replaced by a halo group. Representative haloalkyl groups include
trifluoromethyl, bromomethyl, 1,2-dichloroethyl, 4-iodobutyl,
2-fluoropentyl, and the like.
[0194] As used herein, an "alkoxy" is an alkyl group which is
attached to another moiety via an oxygen linker
[0195] As used herein, an "haloalkoxy" is an haloalkyl group which
is attached to another moiety via an oxygen linker
[0196] As used herein, the term an "aromatic ring" or "aryl" means
a hydrocarbon monocyclic or polycyclic radical in which at least
one ring is aromatic. Examples of suitable aryl groups include, but
are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl,
azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties
such as 5,6,7,8-tetrahydronaphthyl.
[0197] Aryl groups may be optionally substituted with one or more
substituents. In one embodiment, the aryl group is a monocyclic
ring, wherein the ring comprises 6 carbon atoms, referred to herein
as "(C.sub.6)aryl."
[0198] As used herein, the term "aralkyl" means an aryl group that
is attached to another group by a (C.sub.1-C.sub.6)alkylene group.
Representative aralkyl groups include benzyl, 2-phenyl-ethyl,
naphth-3-yl-methyl and the like. Aralkyl groups may be optionally
substituted with one or more substituents.
[0199] As used herein, the term "alkylene" refers to an alkyl group
that has two points of attachment. The term
"(C.sub.1-C.sub.6)alkylene" refers to an alkylene group that has
from one to six carbon atoms. Straight chain
(C.sub.1-C.sub.6)alkylene groups are preferred. Non-limiting
examples of alkylene groups include methylene (--CH.sub.2--),
ethylene (--CH.sub.2CH.sub.2--), n-propylene
(--CH.sub.2CH.sub.2CH.sub.2--), isopropylene
(--CH.sub.2CH(CH.sub.3)--), and the like. Alkylene groups may be
optionally substituted with one or more substituents.
[0200] As used herein, the term "heterocyclyl" means a monocyclic
(typically having 3- to 10-members) or a polycyclic (typically
having 7- to 20-members) heterocyclic ring system which is either a
saturated ring or a unsaturated non-aromatic ring. A 3- to
10-membered heterocycle can contain up to 5 heteroatoms; and a 7-
to 20-membered heterocycle can contain up to 7 heteroatoms.
Typically, a heterocycle has at least one carbon atom ring member.
Each heteroatom is independently selected from nitrogen, which can
be oxidized (e.g., N(O)) or quaternized; oxygen; and sulfur,
including sulfoxide and sulfone. The heterocycle may be attached
via any heteroatom or carbon atom. Representative heterocycles
include morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl,
piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl,
oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,
tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,
tetrahydrothiopyranyl, and the like. A heteroatom may be
substituted with a protecting group known to those of ordinary
skill in the art, for example, the hydrogen on a nitrogen may be
substituted with a tert-butoxycarbonyl group. Furthermore, the
heterocyclyl may be optionally substituted with one or more
substituents. Only stable isomers of such substituted heterocyclic
groups are contemplated in this definition.
[0201] As used herein, the term "heteroaromatic", "heteroaryl" or
like terms means a monocyclic or polycyclic heteroaromatic ring
comprising carbon atom ring members and one or more heteroatom ring
members. Each heteroatom is independently selected from nitrogen,
which can be oxidized (e.g., N(O)) or quaternized; oxygen; and
sulfur, including sulfoxide and sulfone. Representative heteroaryl
groups include pyridyl, 1-oxo-pyridyl, furanyl, benzo[1,3]dioxolyl,
benzo[1,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, imidazolyl,
thiazolyl, a isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl,
pyridazinyl, pyrimidinyl, pyrazinyl, a triazinyl, triazolyl,
thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl,
indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl,
benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl,
tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl,
purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl,
imidazo[1,2-a]pyridyl, and benzothienyl. In one embodiment, the
heteroaromatic ring is selected from 5-8 membered monocyclic
heteroaryl rings. The point of attachment of a heteroaromatic or
heteroaryl ring may be at either a carbon atom or a heteroatom of
the heteroaromatic or heteroaryl rings. Heteroaryl groups may be
optionally substituted with one or more substituents.
[0202] As used herein, the term "(C.sub.5)heteroaryl" means an
aromatic heterocyclic ring of 5 members, wherein at least one
carbon atom of the ring is replaced with a heteroatom such as, for
example, oxygen, sulfur or nitrogen. Representative
(C.sub.5)heteroaryls include furanyl, thienyl, pyrrolyl, oxazolyl,
imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,
pyrazinyl, triazolyl, thiadiazolyl, and the like.
[0203] As used herein, the term "(C.sub.6)heteroaryl" means an
aromatic heterocyclic ring of 6 members, wherein at least one
carbon atom of the ring is replaced with a heteroatom such as, for
example, oxygen, nitrogen or sulfur. Representative
(C.sub.6)heteroaryls include pyridyl, pyridazinyl, pyrazinyl,
triazinyl, tetrazinyl and the like.
[0204] As used herein, the term "heteroaralkyl" means a heteroaryl
group that is attached to another group by a
(C.sub.1-C.sub.6)alkylene. Representative heteroaralkyls include
2-(pyridin-4-yl)-propyl, 2-(thien-3-yl)-ethyl, imidazol-4-yl-methyl
and the like. Heteroaralkyl groups may be optionally substituted
with one or more substituents.
[0205] As used herein, the term "halogen" or "halo" means --F,
--Cl, --Br or --I.
[0206] As used herein the term "heteroalkyl" means a linear
straight or branched chain alkyl group, wherein one or more of the
internal carbon atoms in the chain is replaced by a heteroatom,
such as, O, N or S, e.g.,
--[CH.sub.2].sub.x--O--[CH.sub.2].sub.y[CH.sub.3] wherein x is a
positive integer and y is 0 or a positive integer, and wherein
replacement of the carbon atom does not result in a unstable
compound.
[0207] Suitable substituents for an alkyl, alkylene, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl,
heteroaryl, and heteroaralkyl groups include are those substituents
which form a stable compound of the invention without significantly
adversely affecting the reactivity or biological activity of the
compound of the invention. Examples of substituents for an alkyl,
alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl,
aryl, aralkyl, heteroaryl, and heteroarylalkyl include an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, an optionally
substituted haloalkyl, an optionally substituted heteroalkyl,
optionally substituted alkoxy, --C(O)NR.sub.28R.sub.29,
--C(S)NR.sub.28R.sub.29, --C(NR.sub.32)NR.sub.28R.sub.29,
--NR.sub.33C(O)R.sub.31, --NR.sub.33C(S)R.sub.31,
--NR.sub.33C(NR.sub.32)R.sub.31, halo, --OR.sub.33, cyano, nitro,
haloalkoxy, --C(O)R.sub.33, --C(S)R.sub.33, --C(NR.sub.32)R.sub.33,
--NR.sub.28R.sub.29, --C(O)OR.sub.33, --C(S)OR.sub.33,
--C(NR.sub.32)OR.sub.33, --OC(O)R.sub.33, --OC(S)R.sub.33,
--OC(NR.sub.32)R.sub.33, --NR.sub.30C(O)NR.sub.28R.sub.29,
--NR.sub.33C(S)NR.sub.28R.sub.29,
--NR.sub.33C(NR.sub.32)NR.sub.28R.sub.29, --OC(O)NR.sub.28R.sub.29,
--OC(S)NR.sub.28R.sub.29, --OC(NR.sub.32)NR.sub.28R.sub.29,
--NR.sub.33C(O)OR.sub.31, --NR.sub.33C(S)OR.sub.31,
--NR.sub.33C(NR.sub.32)OR.sub.31, --S(O).sub.hR.sub.33,
--OS(O).sub.pR.sub.33, --NR.sub.33S(O).sub.pR.sub.33,
--S(O).sub.pNR.sub.28R.sub.29, --OS(O).sub.pNR.sub.28R.sub.29, or
--NR.sub.33S(O).sub.pNR.sub.28R.sub.29 guanadino, --C(O)SR.sub.31,
--C(S)SR.sub.31, --C(NR.sub.32)SR.sub.31, --OC(O)OR.sub.31,
--OC(S)OR.sub.31, --OC(NR.sub.32)OR.sub.31, --SC(O)R.sub.33,
--SC(O)OR.sub.31, --SC(NR.sub.32)OR.sub.31, --SC(S)R.sub.33,
--SC(S)OR.sub.31, --SC(O)NR.sub.28R.sub.29,
--SC(NR.sub.32)NR.sub.28R.sub.28, --SC(S)NR.sub.28R.sub.29,
--SC(NR.sub.32)R.sub.33, --OS(O).sub.pOR.sub.31,
--S(O).sub.pOR.sub.31, --NR.sub.3OS(O).sub.pOR.sub.31,
--SS(O).sub.pR.sub.33, --SS(O).sub.pOR.sub.31,
--SS(O).sub.pNR.sub.28R.sub.29, --OP(O)(OR.sub.31).sub.2, or
--SP(O)(OR.sub.31).sub.2, (preferably the alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl,
heteroalkyl, alkoxy, heteroaralkyl and haloalkyl are
unsubstituted); wherein R.sub.28 and R.sub.29, for each occurrence
is independently, H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, or an optionally substituted
heteraralkyl (preferably the alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl and
heteraralkyl are unsubstituted); [0208] R.sub.33 and R.sub.31 for
each occurrence is independently, H, an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, or an optionally
substituted heteraralkyl (preferably the alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl,
and heteraralkyl are unsubstituted); and [0209] R.sub.32, for each
occurrence is independently, H, an optionally substituted alkyl, an
optionally substituted alkenyl, an optionally substituted alkynyl,
an optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, --C(O)R.sub.33, --C(O)NR.sub.28R.sub.29,
--S(O).sub.pR.sub.33, or --S(O).sub.pNR.sub.28R.sub.29 (preferably
the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
heterocyclyl, aryl, heteroaryl, aralkyl and heteraralkyl are
unsubstituted); [0210] p is 0, 1 or 2; and [0211] h is 0, 1 or
2.
[0212] In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl,
and any saturated portion of a alkenyl, cycloalkenyl, alkynyl,
aralkyl, and heteroaralkyl groups, may also be substituted with
.dbd.O, .dbd.S, .dbd.N--R.sub.32.
[0213] When a heterocyclyl, heteroaryl, or heteroaralkyl group
contains a nitrogen atom, it may be substituted or unsubstituted.
When a nitrogen atom in the aromatic ring of a heteroaryl group has
a substituent the nitrogen may be a quaternary nitrogen.
[0214] As used herein, the terms "subject", "patient" and "mammal"
are used interchangeably. The terms "subject" and "patient" refer
to an animal (e.g., a bird such as a chicken, quail or turkey, or a
mammal), preferably a mammal including a non-primate (e.g., a cow,
pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse)
and a primate (e.g., a monkey, chimpanzee and a human), and more
preferably a human. In one embodiment, the subject is a non-human
animal such as a farm animal (e.g., a horse, cow, pig or sheep), or
a pet (e.g., a dog, cat, guinea pig or rabbit). In a preferred
embodiment, the subject is a human.
[0215] As used herein, the term "lower" refers to a group having up
to four atoms. For example, a "lower alkyl" refers to an alkyl
radical having from 1 to 4 carbon atoms, "lower alkoxy" refers to
"--O--(C.sub.1-C.sub.4)alkyl and a "lower alkenyl" or "lower
alkynyl" refers to an alkenyl or alkynyl radical having from 2 to 4
carbon atoms, respectively.
[0216] Unless indicated otherwise, the compounds of the invention
containing reactive functional groups (such as (without limitation)
carboxy, hydroxy, thiol, and amino moieties) also include protected
derivatives thereof. "Protected derivatives" are those compounds in
which a reactive site or sites are blocked with one or more
protecting groups. Examples of suitable protecting groups for
hydroxyl groups include benzyl, methoxymethyl, allyl,
trimethylsilyl, tert-butyldimethylsilyl, acetate, and the like.
Examples of suitable amine protecting groups include
benzyloxycarbonyl, tert-butoxycarbonyl, tert-butyl, benzyl and
fluorenylmethyloxy-carbonyl (Fmoc). Examples of suitable thiol
protecting groups include benzyl, tert-butyl, acetyl, methoxymethyl
and the like. Other suitable protecting groups are well known to
those of ordinary skill in the art and include those found in T. W.
Greene, Protecting Groups in Organic Synthesis, John Wiley &
Sons, Inc. 1981.
[0217] As used herein, the term "compound(s) of this invention" and
similar terms refers to a compound of formula (I)-(XV), or Table 1,
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate,
polymorph or prodrug thereof, and also include protected
derivatives thereof.
[0218] The compounds of the invention may contain one or more
chiral centers and/or double bonds and, therefore, exist as
stereoisomers, such as double-bond isomers (i.e., geometric
isomers), enantiomers, or diastereomers. According to this
invention, the chemical structures depicted herein, including the
compounds of this invention, encompass all of the corresponding
compounds' enantiomers, diastereomers and geometric isomers, that
is, both the stereochemically pure form (e.g., geometrically pure,
enantiomerically pure, or diastereomerically pure) and isomeric
mixtures (e.g., enantiomeric, diastereomeric and geometric isomeric
mixtures). In some cases, one enantiomer, diastereomer or geometric
isomer will possess superior activity or an improved toxicity or
kinetic profile compared to other isomers. In those cases, such
enantiomers, diastereomers and geometric isomers of compounds of
this invention are preferred.
[0219] As used herein, the term "polymorph" means solid crystalline
forms of a compound of the present invention or complex thereof.
Different polymorphs of the same compound can exhibit different
physical, chemical and/or spectroscopic properties. Different
physical properties include, but are not limited to stability
(e.g., to heat or light), compressibility and density (important in
formulation and product manufacturing), and dissolution rates
(which can affect bioavailability). Differences in stability can
result from changes in chemical reactivity (e.g., differential
oxidation, such that a dosage form discolors more rapidly when
comprised of one polymorph than when comprised of another
polymorph) or mechanical characteristics (e.g., tablets crumble on
storage as a kinetically favored polymorph converts to
thermodynamically more stable polymorph) or both (e.g., tablets of
one polymorph are more susceptible to breakdown at high humidity).
Different physical properties of polymorphs can affect their
processing. For example, one polymorph might be more likely to form
solvates or might be more difficult to filter or wash free of
impurities than another due to, for example, the shape or size
distribution of particles of it.
[0220] As used herein, the term "hydrate" means a compound of the
present invention or a salt thereof, that further includes a
stoichiometric or non-stoichiometric amount of water bound by
non-covalent intermolecular forces.
[0221] As used herein, he term "clathrate" means a compound of the
present invention or a salt thereof in the form of a crystal
lattice that contains spaces (e.g., channels) that have a guest
molecule (e.g., a solvent or water) trapped within.
[0222] As used herein and unless otherwise indicated, the term
"prodrug" means a derivative of a compound that can hydrolyze,
oxidize, or otherwise react under biological conditions (in vitro
or in vivo) to provide a compound of this invention. Prodrugs may
become active upon such reaction under biological conditions, or
they may have activity in their unreacted forms. Examples of
prodrugs contemplated in this invention include, but are not
limited to, analogs or derivatives of compounds of formula (I)-(XV)
or Table 1 that comprise biohydrolyzable moieties such as
biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable
carbamates, biohydrolyzable carbonates, biohydrolyzable ureides,
and biohydrolyzable phosphate analogues. Other examples of prodrugs
include derivatives of compounds of formula (I)-(XV) or Table 1
that comprise --NO, --NO.sub.2, --ONO, or --ONO.sub.2 moieties.
Prodrugs can typically be prepared using well-known methods, such
as those described by 1 BURGER'S MEDICINAL CHEMISTRY AND DRUG
DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5.sup.th
ed).
[0223] As used herein and unless otherwise indicated, the terms
"biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable
carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide"
and "biohydrolyzable phosphate analogue" mean an amide, ester,
carbamate, carbonate, ureide, or phosphate analogue, respectively,
that either: 1) does not destroy the biological activity of the
compound and confers upon that compound advantageous properties in
vivo, such as improved water solubility, improved circulating
half-life in the blood (e.g., because of reduced metabolism of the
prodrug), improved uptake, improved duration of action, or improved
onset of action; or 2) is itself biologically inactive but is
converted in vivo to a biologically active compound. Examples of
biohydrolyzable amides include, but are not limited to, lower alkyl
amides, .alpha.-amino acid amides, alkoxyacyl amides, and
alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable esters
include, but are not limited to, lower alkyl esters, alkoxyacyloxy
esters, alkyl acylamino alkyl esters, and choline esters. Examples
of biohydrolyzable carbamates include, but are not limited to,
lower alkylamines, substituted ethylenediamines, aminoacids,
hydroxyalkylamines, heterocyclic and heteroaromatic amines, and
polyether amines.
[0224] As used herein, "Hsp90" includes each member of the family
of heat shock proteins having a mass of about 90-kiloDaltons. For
example, in humans the highly conserved Hsp90 family includes
cytosolic Hsp90.alpha. and Hsp90.beta. isoforms, as well as GRP94,
which is found in the endoplasmic reticulum, and HSP75/TRAP1, which
is found in the mitochondrial matrix.
[0225] The term "c-kit" or "c-kit kinase" refers to a membrane
receptor protein tyrosine kinase which is preferably activated upon
binding Stem Cell Factor (SCF) to its extracellular domain (Yarden
et al., 1987; Qiu et al., 1988). The full length amino acid
sequence of a c-kit kinase preferably is as set forth in Yarden, et
al., 1987, EMBO J., 11:3341-3351; and Qiu, et al., 1988, EMBO J.,
7:1003-1011, which are incorporated by reference herein in their
entirety, including any drawings. Mutant versions of c-kit kinase
are encompassed by the term "c-kit" or "c-kit kinase" and include
those that fall into two classes: (1) having a single amino acid
substitution at codon 816 of the human c-kit kinase, or its
equivalent position in other species (Ma et al., 1999, J. Invest
Dermatol., 112:165-170), and (2) those which have mutations
involving the putative juxtamembrane z-helix of the protein (Ma, et
al., 1999, J. Biol. Chem., 274:13399-13402). Both of these
publications are incorporated by reference herein in their
entirety, including any drawings.
[0226] As used herein, "Bcr-Abl" is a fusion protein that results
from the translocation of gene sequences from c-ABL protein
tyrosine kinase on chromosome 9 into BCR sequences on chromosome 22
producing the Philadelphia chromosome. A schematic representation
of human Bcr, Abl, and Bcr-Abl can be seen in FIG. 1 of U.S. patent
application Ser. No. 10/193,651, filed on Jul. 9, 2002, the entire
teachings of which are incorporated herein by reference. Depending
on the breaking point in the Bcr gene, Bcr-Abl fusion proteins can
vary in size from 185-230 kDa but they must contain at least the
OLI domain from Bcr and the TK domain from Abl for transforming
activity. The most common Bcr-Abl gene products found in humans are
P230 Bcr-Abl, P210 Bcr-Abl, and P190 Bcr-Abl. P210 Bcr-Abl is
characteristic of CML and P190 Bcr-Abl is characteristic of
ALL.
[0227] FLT3 kinase is a tyrosine kinase receptor involved in the
regulation and stimulation of cellular proliferation (see Gilliland
et al., Blood (2002), 100:1532-42, the entire teachings of which
are incorporated herein by reference). The FLT3 kinase has five
immunoglobulin-like domains in its extracellular region as well as
an insert region of 75-100 amino acids in the middle of its
cytoplasmic domain. FLT3 kinase is activated upon the binding of
the FLT3 ligand, which causes receptor dimerization. Dimerization
of the FLT3 kinase by FLT3 ligand activates the intracellular
kinase activity as well as a cascade of downstream substrates
including Stat5, Ras, phosphatidylinositol-3-kinase (PI3K), PLC,
Erk2, Akt, MAPK, SHC, SHP2, and SHIP (see Rosnet et al., Acta
Haematol. (1996), 95:218; Hayakawa et al., Oncogene (2000), 19:624;
Mizuki et al., Blood (2000), 96:3907; and Gilliand et al., Curr.
Opin. Hematol. (2002), 9: 274-81, the entire teachings of each of
these references are incorporated herein by reference). Both
membrane-bound and soluble FLT3 ligand bind, dimerize, and
subsequently activate the FLT3 kinase.
[0228] Normal cells that express FLT3 kinase include immature
hematopoietic cells, typically CD34+ cells, placenta, gonads, and
brain (see Rosnet, et al., Blood (1993), 82:1110-19; Small et al.,
Proc. Natl. Acad. Sci. U.S.A. (1994), 91:459-63; and Rosnet et al.,
Leukemia (1996), 10:238-48, the entire teachings of each of these
references are incorporated herein by reference). However,
efficient stimulation of proliferation via FLT3 kinase typically
requires other hematopoietic growth factors or interleukins FLT3
kinase also plays a critical role in immune function through its
regulation of dendritic cell proliferation and differentiation (see
McKenna et al., Blood (2000), 95:3489-97, the entire teachings of
which are incorporated herein by reference).
[0229] Numerous hematologic malignancies express FLT3 kinase, the
most prominent of which is AML (see Yokota et al., Leukemia (1997),
11:1605-09, the entire teachings of which are incorporated herein
by reference). Other FLT3 expressing malignancies include
B-precursor cell acute lymphoblastic leukemias, myelodysplastic
leukemias, T-cell acute lymphoblastic leukemias, and chronic
myelogenous leukemias (see Rasko et al., Leukemia (1995),
9:2058-66, the entire teachings of which are incorporated herein by
reference).
[0230] FLT3 kinase mutations associated with hematologic
malignancies are activating mutations. In other words, the FLT3
kinase is constitutively activated without the need for binding and
dimerization by FLT3 ligand, and therefore stimulates the cell to
grow continuously. Two types of activating mutations have been
identified: internal tandem duplications (ITDs) and point mutation
in the activating loop of the kinase domain. As used herein, the
term "FLT3 kinase" refers to both wild type FLT3 kinase and mutant
FLT3 kinases, such as FLT3 kinases that have activating
mutations.
[0231] Compounds provided herein are useful in treating conditions
characterized by inappropriate FLT3 activity such as proliferative
disorders. Inappropriate FLT3 activity includes, but is not limited
to, enhanced FLT3 activity resulting from increased or de novo
expression of FLT3 in cells, increased FLT3 expression or activity,
and FLT3 mutations resulting in constitutive activation. The
existence of inappropriate or abnormal FLT3 ligand and FLT3 levels
or activity can be determined using well known methods in the art.
For example, abnormally high FLT3 levels can be determined using
commercially available ELISA kits. FLT3 levels can be determined
using flow cytometric analysis, immunohistochemical analysis, and
in situ hybridization techniques.
[0232] By "epidermal growth factor receptor" or "EGFR" as used
herein is meant, any epidermal growth factor receptor (EGFR)
protein, peptide, or polypeptide having EGFR or EGFR family (e.g.,
HER1, HER2, HER3, and/or HER4) activity (such as encoded by EGFR
Genbank Accession Nos. shown in Table I of U.S. patent application
Ser. No. 10/923,354, filed on Aug. 20, 2004, the entire teachings
of which are incorporated herein by reference), or any other EGFR
transcript derived from a EGFR gene and/or generated by EGFR
translocation. The term "EGFR" is also meant to include other EGFR
protein, peptide, or polypeptide derived from EGFR isoforms (e.g.,
HER1, HER2, HER3, and/or HER4), mutant EGFR genes, splice variants
of EGFR genes, and EGFR gene polymorphisms.
[0233] As used herein, a "proliferative disorder" or a
"hyperproliferative disorder," and other equivalent terms, means a
disease or medical condition involving pathological growth of
cells. Proliferative disorders include cancer, smooth muscle cell
proliferation, systemic sclerosis, cirrhosis of the liver, adult
respiratory distress syndrome, idiopathic cardiomyopathy, lupus
erythematosus, retinopathy, e.g., diabetic retinopathy or other
retinopathies, cardiac hyperplasia, reproductive system associated
disorders such as benign prostatic hyperplasia and ovarian cysts,
pulmonary fibrosis, endometriosis, fibromatosis, harmatomas,
lymphangiomatosis, sarcoidosis, desmoid tumors.
[0234] Smooth muscle cell proliferation includes hyperproliferation
of cells in the vasculature, for example, intimal smooth muscle
cell hyperplasia, restenosis and vascular occlusion, particularly
stenosis following biologically- or mechanically-mediated vascular
injury, e.g., vascular injury associated with angioplasty.
Moreover, intimal smooth muscle cell hyperplasia can include
hyperplasia in smooth muscle other than the vasculature, e.g., bile
duct blockage, bronchial airways of the lung in patients with
asthma, in the kidneys of patients with renal interstitial
fibrosis, and the like.
[0235] Non-cancerous proliferative disorders also include
hyperproliferation of cells in the skin such as psoriasis and its
varied clinical forms, Reiter's syndrome, pityriasis rubra pilaris,
and hyperproliferative variants of disorders of keratinization
(e.g., actinic keratosis, senile keratosis), scleroderma, and the
like.
[0236] In a preferred embodiment, the proliferative disorder is
cancer. Cancers that can be treated or prevented by the methods of
the present invention include, but are not limited to human
sarcomas and carcinomas, e.g., fibrosarcoma, myxosarcoma,
liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,
angiosarcoma, endotheliosarcoma, lymphangiosarcoma,
lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's
tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma,
pancreatic cancer, breast cancer, ovarian cancer, prostate cancer,
squamous cell carcinoma, basal cell carcinoma, adenocarcinoma,
sweat gland carcinoma, sebaceous gland carcinoma, papillary
carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary
carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma,
bile duct carcinoma, choriocarcinoma, seminoma, embryonal
carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung
carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial
carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma,
ependymoma, pinealoma, hemangioblastoma, acoustic neuroma,
oligodendroglioma, meningioma, melanoma, neuroblastoma,
retinoblastoma; leukemias, e.g., acute lymphocytic leukemia and
acute myelocytic leukemia (myeloblastic, promyelocytic,
myelomonocytic, monocytic and erythroleukemia); chronic leukemia
(chronic myelocytic (granulocytic) leukemia and chronic lymphocytic
leukemia); and polycythemia vera, lymphoma (Hodgkin's disease and
non-Hodgkin's disease), multiple myeloma, Waldenstrobm's
macroglobulinemia, and heavy chain disease.
[0237] Other examples of leukemias include acute and/or chronic
leukemias, e.g., lymphocytic leukemia (e.g., as exemplified by the
p388 (murine) cell line), large granular lymphocytic leukemia, and
lymphoblastic leukemia; T-cell leukemias, e.g., T-cell leukemia
(e.g., as exemplified by the CEM, Jurkat, and HSB-2 (acute), YAC-1
(murine) cell lines), T-lymphocytic leukemia, and T-lymphoblastic
leukemia; B cell leukemia (e.g., as exemplified by the SB (acute)
cell line), and B-lymphocytic leukemia; mixed cell leukemias, e.g.,
B and T cell leukemia and B and T lymphocytic leukemia; myeloid
leukemias, e.g., granulocytic leukemia, myelocytic leukemia (e.g.,
as exemplified by the HL-60 (promyelocyte) cell line), and
myelogenous leukemia (e.g., as exemplified by the K562
(chronic)cell line); neutrophilic leukemia; eosinophilic leukemia;
monocytic leukemia (e.g., as exemplified by the THP-1 (acute) cell
line); myelomonocytic leukemia; Naegeli-type myeloid leukemia; and
nonlymphocytic leukemia. Other examples of leukemias are described
in Chapter 60 of The Chemotherapy Sourcebook, Michael C. Perry Ed.,
Williams & Williams (1992) and Section 36 of Holland Frie
Cancer Medicine 5th Ed., Bast et al. Eds., B.C. Decker Inc. (2000).
The entire teachings of the preceding references are incorporated
herein by reference.
[0238] In one embodiment, the disclosed method is believed to be
particularly effective in treating subject with non-solid tumors
such as multiple myeloma. In another embodiment, the disclosed
method is believed to be particularly effective against T-leukemia
(e.g., as exemplified by Jurkat and CEM cell lines); B-leukemia
(e.g., as exemplified by the SB cell line); promyelocytes (e.g., as
exemplified by the HL-60 cell line); uterine sarcoma (e.g., as
exemplified by the MES-SA cell line); monocytic leukemia (e.g., as
exemplified by the THP-1 (acute) cell line); and lymphoma (e.g., as
exemplified by the U937 cell line).
[0239] In one embodiment, the disclosed method is believed to be
particularly effective in treating subject with non-Hodgkin's
lymphoma (NHL). Lymphomas are generally classified as either
Hodgkin's disease (HD) or non-Hodgkin's lymphomas (NHL). NHL
differs from HD by the absence of Reed-Sternberg cells. The course
of NHL is less predictable than HD and is more likely to spread to
areas beyond the lymph nodes. NHL can be further divided into
B-cell NHL and T-cell NHL each of which can be further categorized
into a variety of different subtypes. For example, B-cell NHL
includes Burkitt's lymphoma, follicular lymphoma, diffuse large
B-cell lymphoma, nodal marginal zone B-cell lymphoma, plasma cell
neoplasms, small lymphocytic lymphoma/chronic lymphocytic leukemia,
mantle cell lymphoma, extranodal marginal zone B-cell lymphoma, and
lymphoplamacytic lymphoma/Waldenstrom macroglobulinemia. T-cell NHL
include anaplastic large-cell lymphoma, precursor-T-cell
lymphoblastic leukemia/lymphoma, unspecified peripheral T-cell
lymphoma, acute lymphoblastic leukemia/lymphoma, angioimmunoblastic
T-cell lymphoma, and mycosis fungoides.
[0240] Without wishing to be bound by any theory, it is believed
that the compounds of the invention are useful for treating NHLs,
including B-cell and T-cell NHLs, since Hsp90 is upregulated in
many NHLs. In particular, in a survey of 412 cases of NHL in B-cell
NHL, Hsp90 was found to be moderately to strongly over expressed in
all cases of Burkitt's lymphoma (5/5, 100%), and in a subset of
follicular lymphoma (17/28, 61%), diffuse large B-cell lymphoma
(27/46, 59%), nodal marginal zone B-cell lymphoma (6/16, 38%),
plasma cell neoplasms (14/39, 36%), small lymphocytic
lymphoma/chronic lymphocytic leukemia (3/9, 33%), mantle cell
lymphoma (12/38, 32%), and lymphoplamacytic lymphoma/Waldenstrom
macroglobulinemia (3/10, 30%). In addition, in T-cell NHL, Hsp90
was found to be moderately to strongly over expressed in a subset
of anaplastic large-cell lymphoma (14/24, 58%), precursor-T-cell
lymphoblastic leukemia/lymphoma (20/65, 31%), unspecified
peripheral T-cell lymphoma (8/43, 23%), and angioimmunoblastic
T-cell lymphoma (2/17, 12%). (See Valbuena, et al., Modern
Pathology (2005), 18:1343-1349, the entire teachings of which are
incorporated herein by reference.)
[0241] Some of the disclosed methods can be particularly effective
at treating subjects whose cancer has become "multi-drug
resistant". A cancer which initially responded to an anti-cancer
drug becomes resistant to the anti-cancer drug when the anti-cancer
drug is no longer effective in treating the subject with the
cancer. For example, many tumors will initially respond to
treatment with an anti-cancer drug by decreasing in size or even
going into remission, only to develop resistance to the drug. Drug
resistant tumors are characterized by a resumption of their growth
and/or reappearance after having seemingly gone into remission,
despite the administration of increased dosages of the anti-cancer
drug. Cancers that have developed resistance to two or more
anti-cancer drugs are said to be "multi-drug resistant". For
example, it is common for cancers to become resistant to three or
more anti-cancer agents, often five or more anti-cancer agents and
at times ten or more anti-cancer agents.
[0242] As used herein, the term "c-kit associated cancer" refers to
a cancer which has aberrant expression and/or activation of c-kit.
c-Kit associated cancers include leukemias, mast cell tumors, small
cell lung cancer, testicular cancer, some cancers of the
gastrointestinal tract and some central nervous system. In
addition, c-kit has been implicated in playing a role in
carcinogenesis of the female genital tract (Inoue, et al., 1994,
Cancer Res., 54-(11):3049-3053), sarcomas of neuroectodermal origin
(Ricotti, et al., 1998, Blood, 91:2397-2405), and Schwann cell
neoplasia associated with neurofibromatosis (Ryan, et al., 1994, J.
Neuro. Res., 37:415-432).
[0243] Other anti-proliferative or anticancer therapies may be
combined with the compounds of this invention to treat
proliferative diseases and cancer. Other therapies or anticancer
agents that may be used in combination with the inventive
anticancer agents of the present invention include surgery,
radiotherapy (including, but not limited to, gamma-radiation,
neutron beam radiotherapy, electron beam radiotherapy, proton
therapy, brachytherapy, and systemic radioactive isotopes),
endocrine therapy, biologic response modifiers (including, but not
limited to, interferons, interleukins, and tumor necrosis factor
(TNF)), hyperthermia and cryotherapy, agents to attenuate any
adverse effects (e.g., antiemetics), and other approved
chemotherapeutic drugs.
[0244] In one embodiment, compounds of the invention are vascular
targeting agents. In one aspect, compounds of the invention are
effective for blocking, occluding, or otherwise disrupting blood
flow in "neovasculature." In one aspect, the invention provides a
novel treatment for diseases involving the growth of new blood
vessels ("neovasculature"), including, but not limited to: cancer;
infectious diseases; autoimmune disorders; benign tumors, e.g.
hemangiomas, acoustic neuromas, neurofibromas, trachomas, and
pyogenic granulomas; artheroscleric plaques; ocular angiogenic
diseases, e.g., diabetic retinopathy, retinopathy of prematurity,
macular degeneration, corneal graft rejection, neovascular
glaucoma, retrolental fibroplasia, rubeosis, retinoblastoma,
persistent hyperplastic vitreous syndrome, choroidal
neovascularization, uvietis and Pterygia (abnormal blood vessel
growth) of the eye; rheumatoid arthritis; psoriasis; warts;
allergic dermatitis; blistering disease; Karposi sarcoma; delayed
wound healing; endometriosis; uterine bleeding; ovarian cysts;
ovarian hyperstimulation; vasculogenesis; granulations;
hypertrophic scars (keloids); nonunion fractures; scleroderma;
trachoma; vascular adhesions; vascular malformations; DiGeorge
syndrome; HHT; transplant arteriopathy; restinosis; obesity;
myocardial angiogenesis; coronary collaterals; cerebral
collaterals; arteriovenous malformations; ischemic limb
angiogenesis; primary pulmonary hypertension; asthma; nasal polyps;
inflammatory bowel disease; periodontal disease; ascites;
peritoneal adhesions; Osler-Webber Syndrome; plaque
neovascularization; telangiectasia; hemophiliac joints; synovitis;
osteomyelitis; osteophyte formation; angiofibroma; fibromuscular
dysplasia; wound granulation; Crohn's disease; and
atherosclerosis.
[0245] Vascular targeting can be demonstrated by any method known
to those skilled in the art, such as the method described herein in
Examples 8 and 9.
[0246] As used herein, the term "angiogenesis" refers to a
fundamental process of generating new blood vessels in tissues or
organs. Angiogenesis is involved with or associated with many
diseases or conditions, including, but not limited to: cancer;
ocular neovascular disease; age-related macular degeneration;
diabetic retinopathy, retinopathy of prematurity; corneal graft
rejection; neovascular glaucoma; retrolental fibroplasias; epidemic
keratoconjunctivitis; Vitamin A deficiency; contact lens overwear;
atopic keratitis; superior limbic keratitis; pterygium keratitis
sicca; sjogrens; acne rosacea; warts; eczema; phylectenulosis;
syphilis; Mycobacteria infections; lipid degeneration; chemical
burns; bacterial ulcers; fungal ulcers; Herpes simplex infections;
Herpes zoster infections; protozoan infections; Kaposi's sarcoma;
Mooren's ulcer; Terrien's marginal degeneration; mariginal
keratolysis; rheumatoid arthritis; systemic lupus; polyarteritis;
trauma; Wegener's sarcoidosis; scleritis; Stevens-Johnson disease;
pemphigoid; radial keratotomy; corneal graph rejection; diabetic
retinopathy; macular degeneration; sickle cell anemia; sarcoid;
syphilis; pseudoxanthoma elasticum; Paget's disease; vein
occlusion; artery occlusion; carotid obstructive disease; chronic
uveitis/vitritis; mycobacterial infections; Lyme's disease;
systemic lupus erythematosis; retinopathy of prematurity; Eales'
disease; Behcet's disease; infections causing a retinitis or
choroiditis; presumed ocular histoplasmosis; Best's disease;
myopia; optic pits; Stargardt's disease; pars planitis; chronic
retinal detachment; hyperviscosity syndromes; toxoplasmosis; trauma
and post-laser complications; diseases associated with rubeosis
(neovasculariation of the angle); diseases caused by the abnormal
proliferation of fibrovascular or fibrous tissue including all
forms of proliferative vitreoretinopathy; rheumatoid arthritis;
osteoarthritis; ulcerative colitis; Crohn's disease; Bartonellosis;
atherosclerosis; Osler-Weber-Rendu disease; hereditary hemorrhagic
telangiectasia; pulmonary hemangiomatosis; pre-eclampsia;
endometriosis; fibrosis of the liver and of the kidney;
developmental abnormalities (organogenesis); skin disclolorations
(e.g., hemangioma, nevus flammeus, or nevus simplex); wound
healing; hypertrophic scars, i.e., keloids; wound granulation;
vascular adhesions; cat scratch disease (Rochele ninalia quintosa);
ulcers (Helicobacter pylori); keratoconjunctivitis; gingivitis;
periodontal disease; epulis; hepatitis; tonsillitis; obesity;
rhinitis; laryngitis; tracheitis; bronchitis; bronchiolitis;
pneumonia; interstitial pulmonary fibrosis; neurodermitis;
thyroiditis; thyroid enlargement; endometriosis;
glomerulonephritis; gastritis; inflammatory bone and cartilage
destruction; thromboembolic disease; and Buerger's disease.
[0247] The term "infection" is used herein in its broadest sense
and refers to any infection e.g. a viral infection or one caused by
a microorganism: bacterial infection, fungal infection, or
parasitic infection (e.g. protozoal, amoebic, or helminth).
Examples of such infections may be found in a number of well known
texts such as "Medical Microbiology" (Greenwood, D., Slack, R.,
Peutherer, J., Churchill Livingstone Press, 2002); "Mims'
Pathogenesis of Infectious Disease" (Mims, C., Nash, A., Stephen,
J., Academic Press, 2000); "Fields" Virology. (Fields, B. N.,
Knipe, D. M., Howley, P. M., Lippincott Williams and Wilkins,
2001); and "The Sanford Guide To Antimicrobial Therapy," 26th
Edition, J. P. Sanford et al. (Antimicrobial Therapy, Inc., 1996),
all of which are incorporated by reference herein in their
entirety.
[0248] "Bacterial infections" include, but are not limited to,
infections caused by Gram Positive Bacteria including Bacillus
cereus, Bacillus anthracis, Clostridium botulinum, Clostridium
difficile, Clostridium tetani, Clostridium perfringens,
Corynebacteria diphtheriae, Enterococcus (Streptococcus D),
Listeria monocytogenes, Pneumoccoccal infections (Streptococcus
pneumoniae), Staphylococcal infections and Streptococcal
infections; Gram Negative Bacteria including Bacteroides,
Bordetella pertussis, Brucella, Campylobacter infections,
enterohaemorrhagic Escherichia coli (EHEC/E. coli 0157: H7)
enteroinvasive Escherichia coli (EIEC), enterotoxigenic Escherichia
coli (ETEC), Haemophilus influenzae, Helicobacter pylori,
Klebsiella pneumoniae, Legionella spp., Moraxella catarrhalis,
Neisseria gonnorrhoeae, Neisseria meningitidis, Proteus spp.,
Pseudomonas aeruginosa, Salmonella spp., Shigella spp., Vibrio
cholera and Yersinia; acid fast bacteria including Mycobacterium
tuberculosis, Mycobacterium avium-intracellulare, Myobacterium
johnei, Mycobacterium leprae, atypical bacteria, Chlamydia,
Mycoplasma, Rickettsia, Spirochetes, Treponema pallidum, Borrelia
recurrentis, Borrelia burgdorfii and Leptospira icterohemorrhagiae;
or other miscellaneous bacteria, including Actinomyces and
Nocardia.
[0249] The term "fungus" or "fungal" refers to a distinct group of
eukaryotic, spore-forming organisms with absorptive nutrition and
lacking chlorophyll. It includes mushrooms, molds, and yeasts.
[0250] "Fungal infections" include, but are not limited to,
infections caused by Alternaria alternata, Aspergillus flavus,
Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger,
Aspergillus versicolor, Blastomyces dermatiditis, Candida albicans,
Candida dubliensis, Candida krusei, Candida parapsilosis, Candida
tropicalis, Candida glabrata, Coccidioides immitis, Cryptococcus
neoformans, Epidermophyton floccosum, Histoplasma capsulatum,
Malassezia furfur, Microsporum canis, Mucor spp., Paracoccidioides
brasiliensis, Penicillium marneffei, Pityrosporum ovale,
Pneumocystis carinii, Sporothrix schenkii, Trichophyton rubrum,
Trichophyton interdigitale, Trichosporon beigelii, Rhodotorula
spp., Brettanomyces clausenii, Brettanomyces custerii,
Brettanomyces anomalous, Brettanomyces naardenensis, Candida
himilis, Candida intermedia, Candida saki, Candida solani, Candida
tropicalis, Candida versatilis, Candida bechii, Candida famata,
Candida lipolytica, Candida stellata, Candida vini, Debaromyces
hansenii, Dekkera intermedia, Dekkera bruxellensis, Geotrichium
sandidum, Hansenula fabiani, Hanseniaspora uvarum, Hansenula
anomala, Hanseniaspora guillermondii Hanseniaspora vinae,
Kluyveromyces lactis, Kloekera apiculata, Kluveromyces marxianus,
Kluyveromyces fragilis, Metschikowia pulcherrima, Pichia
guilliermodii, Pichia orientalis, Pichia fermentans, Pichia
memranefaciens, Rhodotorula Saccharomyces bayanus, Saccharomyces
cerevisiae, Saccharomyces dairiensis Saccharomyces exigus,
Saccharomyces uinsporus, Saccharomyces uvarum, Saccharomyces
oleaginosus, Saccharomyces boulardii, Saccharomycodies ludwigii,
Schizosaccharomyces pombe, Torulaspora delbruekii, Torulopsis
stellata, Zygoaccharomyces bailli and Zygosaccharomyces rouxii.
[0251] Drug resistance in fungi is characterized by the failure of
an antifungal therapy to control a fungal infection. "Antifungal
resistance" as used herein refers to both intrinsic or primary
(present before exposure to antifungal agents) and secondary or
acquired (develops after exposure to antifungals). Hsp90 has been
shown to play a role in the evolution of drug resistance in fungi.
Cowen, L. et al., Eukaryotic Cell, 2184-2188, 5(12), 2006; Cowen,
L. et al., Science, 309:2185-2189, 2005. It has been shown that the
key mediator of Hsp90 dependent azole resistance is calcineurin (a
client protein of Hsp90). Calcineurin is required for tolerating
the membrane stress exerted by azole drugs. Hsp90 keeps calcineurin
stable and poised for activation. In addition, it has been shown
that Hsp90 is required for the emergence of drug resistance and
continued drug resistance to azoles and echinocandins.
[0252] "Parasitic infections" include, but are not limited to,
infections caused by Leishmania, Toxoplasma, Plasmodia, Theileria,
Acanthamoeba, Anaplasma, Giardia, Trichomonas, Trypanosoma,
Coccidia, and Babesia.
[0253] For example, parasitic infections include those caused by
Trypanosoma cruzi, Eimeria tenella, Plasmodium falciparum,
Plasmodium vivax, Plasmodium ovale, Cryptosporidium parvum,
Naegleria fowleri, Entamoeba histolytica, Balamuthia mandrillaris,
Entameoba histolytica, Schistostoma mansoni, Plasmodium falciparum,
P. vivax, P. ovale P. malariae, P. berghei, Leishmania donovani, L.
infantum, L. chagasi, L. mexicana, L. amazonensis, L.
venezuelensis, L. tropics, L. major, L. minor, L. aethiopica, L.
Biana braziliensis, L. (V.) guyanensis, L. (V.) panamensis, L. (V.)
peruviana, Trypanosoma brucei rhodesiense, T. brucei gambiense,
Giardia intestinalis, G. lambda, Toxoplasma gondii, Trichomonas
vaginalis, Pneumocystis carinii, Acanthamoeba castellani A.
culbertsoni, A. polyphaga, A. healyi, (A. astronyxis), A.
hatchetti, A. rhysodes, and Trichinella spiralis.
[0254] As used herein, the term "viral infection" refers to any
stage of a viral infection, including incubation phase, latent or
dormant phase, acute phase, and development and maintenance of
immunity towards a virus. Consequently, the term "treatment" is
meant to include aspects of generating or restoring immunity of the
patient's immune system, as well as aspects of suppressing or
inhibiting viral replication.
[0255] Viral infections include, but are not limited to those
caused by Adenovirus, Lassa fever virus (Arenavirus), Astrovirus,
Hantavirus, Rift Valley Fever virus (Phlebovirus), Calicivirus,
Ebola virus, Marburg Virus, Japanese encephalitis virus, Dengue
virus, Yellow fever virus, Hepatitis C virus, Hepatitis G virus,
Hepatitis B virus, Hepatitis D virus, Herpes simplex virus 1,
Herpes simplex virus 2), Cytomegalovirus, Epstein Barr virus,
Varicella Zoster Virus, Human Herpesvirus 7, Human Herpesvirus 8,
Influenza virus, Parainfluenza virus, Rubella virus, Mumps virus,
Morbillivirus, Measles virus, Respiratory Syncytial virus,
Papillomaviruses, JC virus (Polyomavirus), BK virus (Polyomavirus),
Parvovirus, Coxsackie virus (A and B), Hepatitis A virus,
Polioviruses, Rhinoviruses, Reovirus, Rabies Virus (Lyssavirus),
Human Immunodeficiency virus 1 and 2, Human T-cell Leukemia
virus.
[0256] Examples of viral infections include Adenovirus acute
respiratory disease, Lassa fever, Astrovirus enteritis, Hantavirus
pulmonary syndrome, Rift valley fever, Hepatitis E, diarrhoea,
Ebola hemorrhagic fever, Marburg hemorrhagic fever, Japanese
encephalitis, Dengue fever, Yellow fever, Hepatitis C, Hepatitis G,
Hepatitis B, Hepatitis D, Cold sores, Genital sores,
Cytomegalovirus infection, Mononucleosis, Chicken Pox, Shingles,
Human Herpesvirus infection 7, Kaposi Sarcoma, Influenza,
Brochiolitis, German measles, Mumps, Measles (rubeola), Measles,
Brochiolitis, Papillomas (Warts), cervical cancer, Progressive
multifocal leukoencephalopathy, Kidney disease, Erythema
infectiosum, Viral myocarditis, meninigitis, entertitis, Hepatitis,
Poliomyelitis, Cold, Diarrhoea, Rabies, AIDS and Leukemia.
[0257] DNA topoisomerases are enzymes present in all cells that
catalyze topological changes in DNA. Topoisomerase II ("topo II")
plays important roles in DNA replication, chromosome segregation
and the maintenance of the nuclear scaffold in eukaryotic cells.
The enzyme acts by creating breaks in DNA, thereby allowing the DNA
strands to unravel and separate. Due to the important roles of the
enzyme in dividing cells, the enzyme is a highly attractive target
for chemotherapeutic agents, especially in human cancers. The
inhibition of topo II can be determined by any method known in the
art such as that described in Gadelle, D., et al., Biochemical
Pharmacology, (2006), doi:10.1016/j.bcp.2006.07.040.
[0258] The glucocorticoid receptor is a member of the steroid
hormone nuclear receptor family which includes glucocorticoid
receptors (GR), androgen receptors (AR), mineralocorticoid
receptors (MR), estrogen receptors (ER), and progesterone receptors
(PR). Glucocorticoid receptors bind glucocorticoids such as
cortisol, corticosterone, and cortisone.
[0259] "Immunosuppression" refers to impairment of any component of
the immune system resulting in decreased immune function. This
impairment may be measured by any conventional means including
whole blood assays of lymphocyte function, detection of lymphocyte
proliferation and assessment of the expression of T cell surface
antigens. The antisheep red blood cell (SRBC) primary (IgM)
antibody response assay (usually referred to as the plaque assay)
is one specific method. This and other methods are described in
Luster, M. I., Portier, C., Pait, D. G., White, K. L., Jr.,
Gennings, C., Munson, A. E., and Rosenthal, G. J. (1992). "Risk
Assessment in Immunotoxicology I: Sensitivity and Predictability of
Immune Tests." Fundam. Appl. Toxicol., 18, 200-210. Measuring the
immune response to a T-cell dependent immunogen is another
particularly useful assay (Dean, J. H., House, R. V., and Luster,
M. I. (2001). "Immunotoxicology: Effects of, and Responses to,
Drugs and Chemicals." In Principles and Methods of Toxicology:
Fourth Edition (A. W. Hayes, Ed.), pp. 1415-1450, Taylor &
Francis, Philadelphia, Pa.). In one embodiment, a decrease in the
expression of glucocorticoid receptors in PBMCs indicates
impairment of immune function. A patient in need of
immunosuppression is within the judgment of a physician, and can
include patients with immune or inflammatory disorders. In one
embodiment, patients that have undergone or will be undergoing an
organ, tissue, bone marrow, or stem cell transplantation are in
need of immunosuppression to prevent inflammation and/or rejection
of the transplanted organ or tissue.
[0260] The compounds of this invention can be used to treat
subjects with immune disorders. As used herein, the term "immune
disorder" and like terms means a disease, disorder or condition
caused by the immune system of an animal, including autoimmune
disorders. Immune disorders include those diseases, disorders or
conditions that have an immune component and those that are
substantially or entirely immune system-mediated. Autoimmune
disorders are those wherein the animal's own immune system
mistakenly attacks itself, thereby targeting the cells, tissues,
and/or organs of the animal's own body. For example, the autoimmune
reaction is directed against the nervous system in multiple
sclerosis and the gut in Crohn's disease. In other autoimmune
disorders such as systemic lupus erythematosus (lupus), affected
tissues and organs may vary among individuals with the same
disease. One person with lupus may have affected skin and joints
whereas another may have affected skin, kidney, and lungs.
Ultimately, damage to certain tissues by the immune system may be
permanent, as with destruction of insulin-producing cells of the
pancreas in Type 1 diabetes mellitus. Specific autoimmune disorders
that may be ameliorated using the compounds and methods of this
invention include without limitation, autoimmune disorders of the
nervous system (e.g., multiple sclerosis, myasthenia gravis,
autoimmune neuropathies such as Guillain-Barre, and autoimmune
uveitis), autoimmune disorders of the blood (e.g., autoimmune
hemolytic anemia, pernicious anemia, and autoimmune
thrombocytopenia), autoimmune disorders of the blood vessels (e.g.,
temporal arteritis, anti-phospholipid syndrome, vasculitides such
as Wegener's granulomatosis, and Behcet's disease), autoimmune
disorders of the skin (e.g., psoriasis, dermatitis herpetiformis,
pemphigus vulgaris, and vitiligo), autoimmune disorders of the
gastrointestinal system (e.g., Crohn's disease, ulcerative colitis,
primary biliary cirrhosis, and autoimmune hepatitis), autoimmune
disorders of the endocrine glands (e.g., Type 1 or immune-mediated
diabetes mellitus, Grave's disease. Hashimoto's thyroiditis,
autoimmune oophoritis and orchitis, and autoimmune disorder of the
adrenal gland); and autoimmune disorders of multiple organs
(including connective tissue and musculoskeletal system diseases)
(e.g., rheumatoid arthritis, systemic lupus erythematosus,
scleroderma, polymyositis, dermatomyositis, spondyloarthropathies
such as ankylosing spondylitis, and Sjogren's syndrome). In
addition, other immune system mediated diseases, such as
graft-versus-host disease and allergic disorders, are also included
in the definition of immune disorders herein. Because a number of
immune disorders are caused by inflammation, there is some overlap
between disorders that are considered immune disorders and
inflammatory disorders. For the purpose of this invention, in the
case of such an overlapping disorder, it may be considered either
an immune disorder or an inflammatory disorder. "Treatment of an
immune disorder" herein refers to administering a compound
represented by any of the formulas disclosed herein to a subject,
who has an immune disorder, a symptom of such a disease or a
predisposition towards such a disease, with the purpose to cure,
relieve, alter, affect, or prevent the autoimmune disorder, the
symptom of it, or the predisposition towards it.
[0261] As used herein, the term "allergic disorder" means a
disease, condition or disorder associated with an allergic response
against normally innocuous substances. These substances may be
found in the environment (such as indoor air pollutants and
aeroallergens) or they may be non-environmental (such as those
causing dermatological or food allergies). Allergens can enter the
body through a number of routes, including by inhalation,
ingestion, contact with the skin or injection (including by insect
sting). Many allergic disorders are linked to atopy, a
predisposition to generate the allergic antibody IgE. Because IgE
is able to sensitize mast cells anywhere in the body, atopic
individuals often express disease in more than one organ. For the
purpose of this invention, allergic disorders include any
hypersensitivity that occurs upon re-exposure to the sensitizing
allergen, which in turn causes the release of inflammatory
mediators. Allergic disorders include without limitation, allergic
rhinitis (e.g., hay fever), sinusitis, rhinosinusitis, chronic or
recurrent otitis media, drug reactions, insect sting reactions,
latex reactions, conjunctivitis, urticaria, anaphylaxis and
anaphylactoid reactions, atopic dermatitis, asthma and food
allergies.
[0262] As used herein, the term "asthma" means a pulmonary disease,
disorder or condition characterized by reversible airway
obstruction, airway inflammation, and increased airway
responsiveness to a variety of stimuli.
[0263] Compounds represented by any of the formulas disclosed
herein can be used to prevent or to treat subjects with
inflammatory disorders. As used herein, an "inflammatory disorder"
means a disease, disorder or condition characterized by
inflammation of body tissue or having an inflammatory component.
These include local inflammatory responses and systemic
inflammation. Examples of such inflammatory disorders include:
transplant rejection, including skin graft rejection; chronic
inflammatory disorders of the joints, including arthritis,
rheumatoid arthritis, osteoarthritis and bone diseases associated
with increased bone resorption; inflammatory bowel diseases such as
ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's
disease; inflammatory lung disorders such as asthma, adult
respiratory distress syndrome, and chronic obstructive airway
disease; inflammatory disorders of the eye including corneal
dystrophy, trachoma, onchocerciasis, uveitis, sympathetic
ophthalmitis and endophthalmitis; chronic inflammatory disorders of
the gums, including gingivitis and periodontitis; tuberculosis;
leprosy; inflammatory diseases of the kidney including uremic
complications, glomerulonephritis and nephrosis; inflammatory
disorders of the skin including sclerodermatitis, psoriasis and
eczema; inflammatory diseases of the central nervous system,
including chronic demyelinating diseases of the nervous system,
multiple sclerosis, AIDS-related neurodegeneration and Alzheimer's
disease, infectious meningitis, encephalomyelitis, Parkinson's
disease, Huntington's disease, amyotrophic lateral sclerosis and
viral or autoimmune encephalitis; autoimmune disorders,
immune-complex vasculitis, systemic lupus and erythematodes;
systemic lupus erythematosus (SLE); and inflammatory diseases of
the heart such as cardiomyopathy, ischemic heart disease
hypercholesterolemia, atherosclerosis; as well as various other
diseases with significant inflammatory components, including
preeclampsia; chronic liver failure, brain and spinal cord trauma.
There may also be a systemic inflammation of the body, exemplified
by gram-positive or gram negative shock, hemorrhagic or
anaphylactic shock, or shock induced by cancer chemotherapy in
response to pro-inflammatory cytokines, e.g., shock associated with
pro-inflammatory cytokines. Such shock can be induced, e.g., by a
chemotherapeutic agent used in cancer chemotherapy. "Treatment of
an inflammatory disorder" herein refers to administering a compound
or a composition of the invention to a subject, who has an
inflammatory disorder, a symptom of such a disorder or a
predisposition towards such a disorder, with the purpose to cure,
relieve, alter, affect, or prevent the inflammatory disorder, the
symptom of it, or the predisposition towards it.
[0264] As used herein, the term "pharmaceutically acceptable salt,"
is a salt formed from, for example, an acid and a basic group of
one of the compounds of formula (I)-(XV) or Table 1. Illustrative
salts include, but are not limited, to sulfate, citrate, acetate,
oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate,
acid phosphate, isonicotinate, lactate, salicylate, acid citrate,
tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,
succinate, maleate, besylate, gentisinate, fumarate, gluconate,
glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term
"pharmaceutically acceptable salt" also refers to a salt prepared
from a compound of formula (I)-(XV) or Table 1 having an acidic
functional group, such as a carboxylic acid functional group, and a
pharmaceutically acceptable inorganic or organic base. Suitable
bases include, but are not limited to, hydroxides of alkali metals
such as sodium, potassium, and lithium; hydroxides of alkaline
earth metal such as calcium and magnesium; hydroxides of other
metals, such as aluminum and zinc; ammonia, and organic amines,
such as unsubstituted or hydroxy-substituted mono-, di-, or
trialkylamines; dicyclohexylamine; tributyl amine; pyridine;
N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-,
or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or
tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or
tris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy
lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine,
or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids
such as arginine, lysine, and the like. The term "pharmaceutically
acceptable salt" also refers to a salt prepared from a compound of
formula (I)-(XV) or Table 1 having a basic functional group, such
as an amine functional group, and a pharmaceutically acceptable
inorganic or organic acid. Suitable acids include, but are not
limited to, hydrogen sulfate, citric acid, acetic acid, oxalic
acid, hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen
iodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid,
lactic acid, salicylic acid, tartaric acid, bitartratic acid,
ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric
acid, gluconic acid, glucaronic acid, formic acid, benzoic acid,
glutamic acid, methanesulfonic acid, ethanesulfonic acid,
benzenesulfonic acid, and p-toluenesulfonic acid.
[0265] As used herein, the term "pharmaceutically acceptable
solvate," is a solvate formed from the association of one or more
pharmaceutically acceptable solvent molecules to one of the
compounds of formula (I)-(XV) or Table 1. The term solvate includes
hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate,
tetrahydrate, and the like).
[0266] A pharmaceutically acceptable carrier may contain inert
ingredients which do not unduly inhibit the biological activity of
the compounds. The pharmaceutically acceptable carriers should be
biocompatible, i.e., non-toxic, non-inflammatory, non-immunogenic
and devoid of other undesired reactions upon the administration to
a subject. Standard pharmaceutical formulation techniques can be
employed, such as those described in Remington's Pharmaceutical
Sciences, ibid. Suitable pharmaceutical carriers for parenteral
administration include, for example, sterile water, physiological
saline, bacteriostatic saline (saline containing about 0.9% mg/ml
benzyl alcohol), phosphate-buffered saline, Hank's solution,
Ringer's-lactate and the like. Methods for encapsulating
compositions (such as in a coating of hard gelatin or cyclodextran)
are known in the art (Baker, et al., "Controlled Release of
Biological Active Agents", John Wiley and Sons, 1986).
[0267] As used herein, the term "effective amount" refers to an
amount of a compound of this invention which is sufficient to
reduce or ameliorate the severity, duration, progression, or onset
of a disease or disorder, e.g. a proliferative disorder, prevent
the advancement of a disease or disorder, e.g. a proliferative
disorder, cause the regression of a disease or disorder, e.g. a
proliferative disorder, prevent the recurrence, development, onset
or progression of a symptom associated with a disease or disorder,
e.g. a proliferative disorder, or enhance or improve the
prophylactic or therapeutic effect(s) of another therapy. The
precise amount of compound administered to a subject will depend on
the mode of administration, the type and severity of the disease or
condition and on the characteristics of the subject, such as
general health, age, sex, body weight and tolerance to drugs. It
will also depend on the degree, severity and type of cell
proliferation, and the mode of administration. The skilled artisan
will be able to determine appropriate dosages depending on these
and other factors. When co-administered with other agents, e.g.,
when co-administered with an anti-cancer agent, an "effective
amount" of the second agent will depend on the type of drug used.
Suitable dosages are known for approved agents and can be adjusted
by the skilled artisan according to the condition of the subject,
the type of condition(s) being treated and the amount of a compound
of the invention being used. In cases where no amount is expressly
noted, an effective amount should be assumed.
[0268] Non-limiting examples of an effective amount of a compound
of the invention are provided herein below. In a specific
embodiment, the invention provides a method of preventing,
treating, managing, or ameliorating a disease or disorder, e.g. a
proliferative disorder or one or more symptoms thereof, said
methods comprising administering to a subject in need thereof a
dose of at least 150 .mu.g/kg, preferably at least 250 .mu.g/kg, at
least 500 .mu.g/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10
mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at
least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at
least 200 mg/kg or more of one or more compounds of the invention
once every day, preferably, once every 2 days, once every 3 days,
once every 4 days, once every 5 days, once every 6 days, once every
7 days, once every 8 days, once every 10 days, once every two
weeks, once every three weeks, or once a month.
[0269] The dosages of a chemotherapeutic agents other than
compounds of the invention, which have been or are currently being
used to prevent, treat, manage, or ameliorate a disease or
disorder, e.g. a proliferative disorder, or one or more symptoms
thereof, can be used in the combination therapies of the invention.
Preferably, dosages lower than those which have been or are
currently being used to prevent, treat, manage, or ameliorate a
disease or disorder, e.g. a proliferative disorder, or one or more
symptoms thereof, are used in the combination therapies of the
invention. The recommended dosages of agents currently used for the
prevention, treatment, management, or amelioration of a disease or
disorder, e.g. a proliferative disorder, or one or more symptoms
thereof, can obtained from any reference in the art including, but
not limited to, Hardman et al., eds., 1996, Goodman & Gilman's
The Pharmacological Basis Of Basis Of Therapeutics 9.sup.th Ed,
Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57.sup.th
Ed., 2003, Medical Economics Co., Inc., Montvale, N.J., which are
incorporated herein by reference in its entirety.
[0270] As used herein, the terms "treat", "treatment" and
"treating" refer to the reduction or amelioration of the
progression, severity and/or duration of a disease or disorder,
e.g. a proliferative disorder, or the amelioration of one or more
symptoms (preferably, one or more discernible symptoms) of a
disease or disorder, e.g. a proliferative disorder resulting from
the administration of one or more therapies (e.g., one or more
therapeutic agents such as a compound of the invention). In
specific embodiments, the terms "treat", "treatment" and "treating"
refer to the amelioration of at least one measurable physical
parameter of a disease or disorder, e.g. a proliferative disorder,
such as growth of a tumor, not necessarily discernible by the
patient. In other embodiments the terms "treat", "treatment" and
"treating" refer to the inhibition of the progression of a disease
or disorder, e.g. a proliferative disorder, either physically by,
e.g., stabilization of a discernible symptom, physiologically by,
e.g., stabilization of a physical parameter, or both. In other
embodiments the terms "treat", "treatment" and "treating" refer to
the reduction or stabilization of tumor size or cancerous cell
count.
[0271] As used herein, the terms "prevent", "prevention" and
"preventing" refer to the reduction in the risk of acquiring or
developing a disease or disorder, e.g. a given proliferative
disorder, or the reduction or inhibition of the recurrence or a
disease or disorder, e.g. a proliferative disorder. In one
embodiment, a compound of the invention is administered as a
preventative measure to a patient, preferably a human, having a
genetic predisposition to any of the disorders described
herein.
[0272] As used herein, the terms "therapeutic agent" and
"therapeutic agents" refer to any agent(s) which can be used in the
treatment, management, or amelioration of a disease or disorder,
e.g. a proliferative disorder or one or more symptoms thereof. In
certain embodiments, the term "therapeutic agent" refers to a
compound of the invention. In certain other embodiments, the term
"therapeutic agent" refers does not refer to a compound of the
invention. Preferably, a therapeutic agent is an agent which is
known to be useful for, or has been or is currently being used for
the treatment, management, prevention, or amelioration a disease or
disorder, e.g. a proliferative disorder or one or more symptoms
thereof.
[0273] As used herein, the term "synergistic" refers to a
combination of a compound of the invention and another therapy
(e.g., a prophylactic or therapeutic agent), which is more
effective than the additive effects of the therapies. A synergistic
effect of a combination of therapies (e.g., a combination of
prophylactic or therapeutic agents) permits the use of lower
dosages of one or more of the therapies and/or less frequent
administration of said therapies to a subject with a disease or
disorder, e.g. a proliferative disorder. The ability to utilize
lower dosages of a therapy (e.g., a prophylactic or therapeutic
agent) and/or to administer said therapy less frequently reduces
the toxicity associated with the administration of said therapy to
a subject without reducing the efficacy of said therapy in the
prevention, management or treatment of a disease or disorder, e.g.
a proliferative disorder. In addition, a synergistic effect can
result in improved efficacy of agents in the prevention, management
or treatment of a disease or disorder, e.g. a proliferative
disorder. Finally, a synergistic effect of a combination of
therapies (e.g., a combination of prophylactic or therapeutic
agents) may avoid or reduce adverse or unwanted side effects
associated with the use of either therapy alone.
[0274] As used herein, the phrase "side effects" encompasses
unwanted and adverse effects of a therapy (e.g., a prophylactic or
therapeutic agent). Side effects are always unwanted, but unwanted
effects are not necessarily adverse. An adverse effect from a
therapy (e.g., prophylactic or therapeutic agent) might be harmful
or uncomfortable or risky. Side effects include, but are not
limited to fever, chills, lethargy, gastrointestinal toxicities
(including gastric and intestinal ulcerations and erosions),
nausea, vomiting, neurotoxicities, nephrotoxicities, renal
toxicities (including such conditions as papillary necrosis and
chronic interstitial nephritis), hepatic toxicities (including
elevated serum liver enzyme levels), myelotoxicities (including
leukopenia, myelosuppression, thrombocytopenia and anemia), dry
mouth, metallic taste, prolongation of gestation, weakness,
somnolence, pain (including muscle pain, bone pain and headache),
hair loss, asthenia, dizziness, extra-pyramidal symptoms,
akathisia, cardiovascular disturbances and sexual dysfunction.
[0275] As used herein, the term "in combination" refers to the use
of more than one therapies (e.g., one or more prophylactic and/or
therapeutic agents). The use of the term "in combination" does not
restrict the order in which therapies (e.g., prophylactic and/or
therapeutic agents) are administered to a subject with a disease or
disorder, e.g. a proliferative disorder. A first therapy (e.g., a
prophylactic or therapeutic agent such as a compound of the
invention) can be administered prior to (e.g., 5 minutes, 15
minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours,
12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks,
3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before),
concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes,
30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12
hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3
weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the
administration of a second therapy (e.g., a prophylactic or
therapeutic agent such as an anti-cancer agent) to a subject with a
disease or disorder, e.g. a proliferative disorder, such as
cancer.
[0276] As used herein, the terms "therapies" and "therapy" can
refer to any protocol(s), method(s), and/or agent(s) that can be
used in the prevention, treatment, management, or amelioration of a
disease or disorder, e.g. a proliferative disorder or one or more
symptoms thereof.
[0277] A used herein, a "protocol" includes dosing schedules and
dosing regimens. The protocols herein are methods of use and
include prophylactic and therapeutic protocols.
[0278] As used herein, the terms "manage," "managing," and
"management" refer to the beneficial effects that a subject derives
from a therapy (e.g., a prophylactic or therapeutic agent), which
does not result in a cure of the disease. In certain embodiments, a
subject is administered one or more therapies (e.g., one or more
prophylactic or therapeutic agents) to "manage" a disease so as to
prevent the progression or worsening of the disease.
[0279] As used herein, a composition that "substantially" comprises
a compound means that the composition contains more than about 80%
by weight, more preferably more than about 90% by weight, even more
preferably more than about 95% by weight, and most preferably more
than about 97% by weight of the compound.
[0280] As used herein, a reaction that is "substantially complete"
means that the reaction contains more than about 80% by weight of
the desired product, more preferably more than about 90% by weight
of the desired product, even more preferably more than about 95% by
weight of the desired product, and most preferably more than about
97% by weight of the desired product.
[0281] As used herein, a racemic mixture means about 50% of one
enantiomer and about 50% of is corresponding enantiomer relative to
a chiral center in the molecule. The invention encompasses all
enantiomerically-pure, enantiomerically-enriched,
diastereomerically pure, diastereomerically enriched, and racemic
mixtures of the compounds of the invention.
[0282] Enantiomeric and diastereomeric mixtures can be resolved
into their component enantiomers or diastereomers by well known
methods, such as chiral-phase gas chromatography, chiral-phase high
performance liquid chromatography, crystallizing the compound as a
chiral salt complex, or crystallizing the compound in a chiral
solvent. Enantiomers and diastereomers can also be obtained from
diastereomerically- or enantiomerically-pure intermediates,
reagents, and catalysts by well known asymmetric synthetic
methods.
[0283] The compounds of the invention are defined herein by their
chemical structures and/or chemical names. Where a compound is
referred to by both a chemical structure and a chemical name, and
the chemical structure and chemical name conflict, the chemical
structure is determinative of the compound's identity.
[0284] When administered to a patient, e.g., to a non-human animal
for veterinary use or for improvement of livestock, or to a human
for clinical use, the compounds of the invention are administered
in isolated form or as the isolated form in a pharmaceutical
composition. As used herein, "isolated" means that the compounds of
the invention are separated from other components of either (a) a
natural source, such as a plant or cell, preferably bacterial
culture, or (b) a synthetic organic chemical reaction mixture.
Preferably, the compounds of the invention are purified via
conventional techniques. As used herein, "purified" means that when
isolated, the isolate contains at least 95%, preferably at least
98%, of a compound of the invention by weight of the isolate either
as a mixture of stereoisomers or as a diastereomeric or
enantiomeric pure isolate.
[0285] As used herein, a composition that is "substantially free"
of a compound means that the composition contains less than about
20% by weight, more preferably less than about 10% by weight, even
more preferably less than about 5% by weight, and most preferably
less than about 3% by weight of the compound.
[0286] Only those choices and combinations of substituents that
result in a stable structure are contemplated. Such choices and
combinations will be apparent to those of ordinary skill in the art
and may be determined without undue experimentation.
[0287] The invention can be understood more fully by reference to
the following detailed description and illustrative examples, which
are intended to exemplify non-limiting embodiments of the
invention.
B. THE COMPOUNDS OF THE INVENTION
[0288] The present invention encompasses compounds having Formulas
(I), (II), (III), (IV), (V), (VI), (VII) and those set forth in
Table 1 and tautomers, pharmaceutically acceptable salts, solvates,
clathrates, hydrates, polymorphs and prodrugs thereof.
[0289] Compounds of formulas (I)-(VII) inhibit the activity of
Hsp90 and are particularly useful for treating or preventing
proliferative disorders, such as cancer. In addition, compounds of
formula (I)-(XV) are particularly useful in treating cancer when
given in combination with another anti-cancer agent.
[0290] In one embodiment, the invention provides compounds of
formula (I) as set forth below:
##STR00016##
[0291] or a tautomer, pharmaceutically acceptable salt, solvate,
clathrate or a prodrug thereof, wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.5, Z, L, and n are defined as above.
[0292] In one embodiment of compounds of formula (I) one or more of
the following provisos apply: [0293] when L is --S--CH.sub.2--,
--CH.sub.2--O--, or --O--CH.sub.2--, R.sub.1 is not optionally
substituted lower alkyl; [0294] when L is --S--CH.sub.2-- and
R.sub.5 is a methoxy phenyl, R.sub.1 is not
tetrahydro-2H-pyran-2-yl; [0295] when L is --S--CH.sub.2-- and
R.sub.5 is --H, R.sub.1 is not optionally substituted pyridyl;
[0296] when L is --O-- or --S--, R.sub.1 is not
--C(O)N(R.sub.13).sub.2 or optionally substituted lower alkyl;
[0297] when L is --N(CH.sub.3)-- or --O--, R.sub.1 is not
optionally substituted fluorophenyl; when L is --CH.sub.2--,
R.sub.1 is not a 1,2,3-triazolyl; [0298] when L is --CH.sub.2-- or
--CH.sub.2--CH.sub.2--, R.sub.1 is not an optionally substituted
C1-C7 alkyl; and [0299] when L is --CH.sub.2--S--, R.sub.1 is not a
chlorophenyl.
[0300] In one embodiment of compounds of formula (I) one or more of
the following provisos apply: [0301] when L is --S--CH.sub.2--,
--CH.sub.2--O--, or --O--CH.sub.2--, R.sub.1 is not optionally
substituted lower alkyl; [0302] when L is --S--CH.sub.2-- and
R.sub.5 is a methoxy phenyl, R.sub.1 is not
tetrahydro-2H-pyran-2-yl; [0303] when L is --S--CH.sub.2-- and
R.sub.5 is --H, R.sub.1 is not optionally substituted pyridyl;
[0304] when L is --O-- or --S--, R.sub.1 is not
--C(O)N(R.sub.13).sub.2 or optionally substituted lower alkyl;
[0305] when L is --N(CH.sub.3)-- or --O--, R.sub.1 is not
optionally substituted fluorophenyl; when L is --CH.sub.2--,
R.sub.1 is not a 1,2,3-triazolyl; [0306] when L is --S--CH.sub.2--
and R.sub.5 is --H, R.sub.1 is not optionally substituted pyridyl
or a fluorophenyl; [0307] when L is --CH.sub.2-- or
--CH.sub.2--CH.sub.2--, R.sub.1 is not an optionally substituted
C1-C7 alkyl; and [0308] when L is --CH.sub.2--S--, R.sub.1 is not a
chlorophenyl.
[0309] In another embodiment, the invention provides compounds of
formula (II) as set forth below:
##STR00017## [0310] or a tautomer, pharmaceutically acceptable
salt, solvate, clathrate or a prodrug thereof, wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.5, Z, and L are defined as above.
[0311] In another embodiment, the invention provides compounds of
formula (III) as set forth below:
##STR00018## [0312] or a tautomer, pharmaceutically acceptable
salt, solvate, clathrate or a prodrug thereof, wherein R'.sub.1,
R.sub.2, R.sub.3, Z, and L' are defined as above.
[0313] In another embodiment of compounds of formula (III), one or
more of the following provisos apply: [0314] when L' is
--S--CH.sub.2-- and R'.sub.5 is a methoxy phenyl, R'.sub.1 is not
tetrahydro-2H-pyran-2-yl; [0315] when L' is --O-- or --S--,
R'.sub.1 is not --C(O)N(R.sub.13).sub.2.
[0316] In another embodiment, the invention provides compounds of
formula (IV) as set forth below:
##STR00019## [0317] or a tautomer, pharmaceutically acceptable
salt, solvate, clathrate or a prodrug thereof, wherein L',
R'.sub.1, R.sub.41, X.sub.41, X.sub.42, Y.sub.40, Y.sub.41, and
Y.sub.42 are defined as above.
[0318] In another embodiment, the invention provides compounds of
formula (V) as set forth below:
##STR00020## [0319] or a tautomer, pharmaceutically acceptable
salt, solvate, clathrate or a prodrug thereof, wherein L',
R'.sub.1, R.sub.41, R.sub.42, R.sub.43, R.sub.45, and X.sub.42 are
defined as above.
[0320] In another embodiment, the invention provides compounds of
formula (VI) as set forth below:
##STR00021## [0321] or a tautomer, pharmaceutically acceptable
salt, solvate, clathrate or a prodrug thereof, wherein L',
R'.sub.1, R.sub.52, R.sub.53, R.sub.55, R.sub.56, and X.sub.45 are
defined as above.
[0322] In another embodiment, the invention provides compounds of
formula (VII) as set forth below:
##STR00022## [0323] or a tautomer, pharmaceutically acceptable
salt, solvate, clathrate or a prodrug thereof, wherein L',
R'.sub.1, R.sub.41, and R.sub.42 are defined as above.
[0324] In another embodiment, the invention provides compounds of
formula (VIII) as set forth below:
##STR00023##
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate
or a prodrug thereof, wherein R.sub.3, R.sub.5, R.sub.35, R.sub.36,
Y, Z and t are defined as above.
[0325] In another embodiment, the invention provides compounds of
formula (IX) as set forth below:
##STR00024##
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate
or a prodrug thereof, wherein R.sub.2, R.sub.3, R.sub.5, R.sub.35,
R.sub.36, Y, Z and n are defined as above.
[0326] In another embodiment, the invention provides compounds of
formula (X) as set forth below:
##STR00025##
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate
or a prodrug thereof, wherein R.sub.2, R.sub.3, R.sub.5, R.sub.35,
R.sub.36, Y, and Z are defined as above.
[0327] In another embodiment, the invention provides compounds of
formula (XI) as set forth below:
##STR00026##
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate
or a prodrug thereof, wherein R.sub.35, R.sub.36, R.sub.40,
X.sub.40, X.sub.41, Y.sub.40, Y.sub.41, and Y.sub.42, are defined
as above.
[0328] In another embodiment, the invention provides compounds of
formula (XII) as set forth below:
##STR00027##
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate
or a prodrug thereof, wherein R.sub.35, R.sub.36, R.sub.41,
R.sub.42, R.sub.43, R.sub.45, and X.sub.42 are defined as
above.
[0329] In another embodiment, the invention provides compounds of
formula (XIII) as set forth below:
##STR00028##
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate
or a prodrug thereof, wherein R.sub.35, R.sub.36, R.sub.52,
R.sub.53, R.sub.55, R.sub.56, and X.sub.45 are defined as
above.
[0330] In another embodiment, the invention provides compounds of
formula (XIV) as set forth below:
##STR00029##
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate
or a prodrug thereof, wherein R.sub.35, R.sub.36, R.sub.41, and
R.sub.42 are defined as above.
[0331] In another embodiment, the invention provides compounds of
formula (XV) as set forth below:
##STR00030## [0332] or a tautomer, pharmaceutically acceptable
salt, solvate, clathrate or a prodrug thereof, wherein R'.sub.3,
R'.sub.5, R.sub.1, R.sub.6, Y, Z, and n are defined as above.
[0333] In one embodiment of compounds of formula (XV) one or more
of the following provisos apply: [0334] provided that when Y is
--S-- and R.sub.1 is an optionally substituted C1-C3 alkyl, then
R'.sub.3 is not --OCH.sub.2OMe; [0335] provided that when Y is
--S--, R.sub.1 is Me and R'.sub.5 is lower alkyl, then R.sub.6 is
not halo.
[0336] In one embodiment, in the compounds represented by formula
(I), (II), (III), (IX), or (X), R.sub.2 and R.sub.3 are each
independently --OH, --SH, or --NHR.sub.7. In one aspect, both
R.sub.2 and R.sub.3 are --OH.
[0337] In one embodiment, in the compounds represented by formula
(I), (II), (III), (VIII), (IX), (X), (XV), Z, for each occurrence,
is independently an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a
heteroalkyl, alkoxy, haloalkoxy, --NR.sub.10R.sub.11, --OR.sub.7,
--C(O)R.sub.7, --C(O)OR.sub.7, --C(S)R.sub.7, --C(O)SR.sub.7,
--C(S)SR.sub.7, --C(S)OR.sub.7, --C(S)NR.sub.10R.sub.11,
--C(NR.sub.8)OR.sub.7, --C(NR.sub.8)R.sub.7,
--C(NR.sub.8)NR.sub.10R.sub.11, --C(NR.sub.8)SR.sub.7,
--OC(O)R.sub.7, --OC(O)OR.sub.7, --OC(S)OR.sub.7,
--OC(NR.sub.8)OR.sub.7, --SC(O)R.sub.7, --SC(O)OR.sub.7,
--SC(NR.sub.8)OR.sub.7, --OC(S)R.sub.7, --SC(S)R.sub.7,
--SC(S)OR.sub.7, --OC(O)NR.sub.10R.sub.11,
--OC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)NR.sub.10R.sub.11,
--SC(O)NR.sub.10R.sub.11, --SC(NR.sub.8)NR.sub.10R.sub.11,
--SC(S)NR.sub.10R.sub.11, --OC(NR.sub.8)R.sub.7,
--SC(NR.sub.8)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --NR.sub.7C(S)R.sub.7,
--NR.sub.7C(S)OR.sub.7, --NR.sub.7C(NR.sub.8)R.sub.7,
--NR.sub.7C(O)OR.sub.7, --NR.sub.7C(NR.sub.8)OR.sub.7,
--NR.sub.7C(O)NR.sub.10R.sub.11, --NR.sub.7C(S)NR.sub.10R.sub.11,
--NR.sub.7C(NR.sub.8)NR.sub.10R.sub.11, --SR.sub.7,
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --OS(O).sub.pOR.sub.7,
--OS(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, --NR.sub.7S(O).sub.pNR.sub.10R.sub.11,
--NR.sub.7S(O).sub.pOR.sub.7, --S(O).sub.pNR.sub.10R.sub.11,
--SS(O).sub.pR.sub.7, --SS(O).sub.pOR.sub.7,
--SS(O).sub.pNR.sub.10R.sub.11, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2. In one aspect, Z is a C1-C6 alkyl, a C1-C6
haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl
sulfanyl or a C3-C6 cycloalkyl. In one aspect, Z is a C1-C6
alkyl.
[0338] In one embodiment, in the compounds represented by formula
(I) or (II), L is null, --S--CR.sub.12--, --O--CR.sub.12--,
--NR.sub.14--CR.sub.12--, --CR.sub.12--CR.sub.12--, --CR.sub.12--,
--O--, --S--, or --NR.sub.14--. In one aspect, L is
--S--CH.sub.2--. In one aspect, L is --S--.
[0339] In one embodiment, in the compounds represented by formula
(I), (II) or (XV), R.sub.1 is an optionally substituted phenyl, an
optionally substituted thiazolyl, an optionally substituted
pyridinyl, an optionally substituted dihydrofuranone, an optionally
substituted pyrimidine-dione, an optionally substituted imidazolyl,
or --C(O)N(R.sub.13).sub.2.
[0340] In one embodiment, in the compounds represented by formula
(I) or (II), L is --S--CH.sub.2-- or --S-- and R.sub.1 is an
optionally substituted phenyl, an optionally substituted thiazolyl,
an optionally substituted pyridinyl, an optionally substituted
dihydrofuranone, an optionally substituted pyrimidine-dione, an
optionally substituted imidazolyl, or --C(O)N(R.sub.13).sub.2.
[0341] In one embodiment, in the compounds represented by formula
(I), (IX) or (XV), n is 1.
[0342] In one embodiment, in the compounds represented by formula
(I), (IX) or (XV), n is 0.
[0343] In one embodiment, in the compounds represented by formula
(I), (II), (VIII), (IX), or (X), R.sub.5 is represented by the
following formula:
##STR00031## [0344] wherein: [0345] R.sub.9, for each occurrence,
is independently a substituent selected from the group consisting
of an optionally substituted alkyl, an optionally substituted
alkenyl, an optionally substituted alkynyl, an optionally
substituted cycloalkyl, an optionally substituted cycloalkenyl, an
optionally substituted heterocyclyl, an optionally substituted
aryl, an optionally substituted heteroaryl, an optionally
substituted aralkyl, an optionally substituted heteraralkyl,
hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a
haloalkyl, a heteroalkyl, --OR.sub.7, --C(O)R.sub.7,
--C(O)OR.sub.7, --OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --SR.sub.7, --S(O).sub.pR.sub.7,
--OS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, or --S(O).sub.pNR.sub.10R.sub.11,
--S(O).sub.pOR.sub.7, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2; [0346] or two R.sub.9 groups taken
together with the carbon atoms to which they are attached form a
fused ring; and [0347] q is zero or an integer from 1 to 7.
[0348] In one embodiment, in the compounds represented by formula
(I), (II), (VIII), (IX), or (X), R.sub.5 is represented by the
following formula:
##STR00032## [0349] wherein: [0350] q is zero or an integer from 1
to 5; and [0351] u is zero or an integer from 1 to 5.
[0352] In one embodiment, in the compounds represented by formula
(I), (II), (VIII), (IX), or (X), R.sub.5 is represented by the
following formula:
##STR00033## [0353] wherein: [0354] R.sub.33 is a halo, lower
alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and
lower alkyl sulfanyl; [0355] R.sub.34 is H, a lower alkyl, or a
lower alkylcarbonyl; and [0356] Ring B and Ring C are optionally
substituted with one or more substituents.
[0357] In one embodiment, in the compounds represented by formula
(I), (II), (VIII), (IX), or (X), R.sub.5 is selected from the group
consisting of:
##STR00034## [0358] wherein: [0359] X.sub.6, for each occurrence,
is independently CH, CR.sub.9, N, N(O), N.sup.+(R.sub.17), provided
that at least three X.sub.6 groups are independently selected from
CH and CR.sub.9; [0360] X.sub.7, for each occurrence, is
independently CH, CR.sub.9, N, N(O), N.sup.+(R.sub.17), provided
that at least three X.sub.7 groups are independently selected from
CH and CR.sub.9; [0361] X.sub.8, for each occurrence, is
independently CH.sub.2, CHR.sub.9, C(R.sub.9).sub.2, S, S(O).sub.p,
NR.sub.7, or NR.sub.17; [0362] X.sub.9, for each occurrence, is
independently N or CH; [0363] X.sub.10, for each occurrence, is
independently CH, CR.sub.9, N, N(O), N.sup.+(R.sub.17), provided
that at least one X.sub.10 is selected from CH and CR.sub.9; [0364]
R.sub.9, for each occurrence, is independently a substituent
selected from the group consisting of an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, an optionally
substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano,
nitro, guanadino, a haloalkyl, a heteroalkyl, --OR.sub.7,
--C(O)R.sub.7, --C(O)OR.sub.7, --OC(O)R.sub.7,
--C(O)NR.sub.10R.sub.11, --NR.sub.8C(O)R.sub.7, --SR.sub.7,
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, or --S(O).sub.pNR.sub.10R.sub.11,
--S(O).sub.pOR.sub.7, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2, --S(O).sub.POR.sub.7,
--OP(O)(OR.sub.7).sub.2, or --SP(O)(OR.sub.7).sub.2; [0365] or two
R.sub.9 groups taken together with the carbon atoms to which they
are attached form a fused ring; and [0366] R.sub.17, for each
occurrence, is independently --H, an alkyl, an aralkyl,
--C(O)R.sub.7, --C(O)OR.sub.7, or --C(O)NR.sub.10R.sub.11.
[0367] In one embodiment, in the compounds represented by formula
(I), (II), (VIII), (IX), or (X), R.sub.5 is an optionally
substituted indolyl, an optionally substituted benzoimidazolyl, an
optionally substituted indazolyl, an optionally substituted
3H-indazolyl, an optionally substituted indolizinyl, an optionally
substituted quinolinyl, an optionally substituted isoquinolinyl, an
optionally substituted benzoxazolyl, an optionally substituted
benzo[1,3]dioxolyl, an optionally substituted benzofuryl, an
optionally substituted benzothiazolyl, an optionally substituted
benzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl,
an optionally substituted thiazolo[4,5-c]pyridinyl, an optionally
substituted thiazolo[5,4-c]pyridinyl, an optionally substituted
thiazolo[4,5-b]pyridinyl, an optionally substituted
thiazolo[5,4-b]pyridinyl, an optionally substituted
oxazolo[4,5-c]pyridinyl, an optionally substituted
oxazolo[5,4-c]pyridinyl, an optionally substituted
oxazolo[4,5-b]pyridinyl, an optionally substituted
oxazolo[5,4-b]pyridinyl, an optionally substituted
imidazopyridinyl, an optionally substituted benzothiadiazolyl,
benzoxadiazolyl, an optionally substituted benzotriazolyl, an
optionally substituted tetrahydroindolyl, an optionally substituted
azaindolyl, an optionally substituted quinazolinyl, an optionally
substituted purinyl, an optionally substituted
imidazo[4,5-a]pyridinyl, an optionally substituted
imidazo[1,2-a]pyridinyl, an optionally substituted
3H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-c]pyridinyl, an optionally substituted
3H-imidazo[4,5-c]pyridinyl, an optionally substituted
pyridopyrdazinyl, and optionally substituted pyridopyrimidinyl, an
optionally substituted pyrrolo[2,3]pyrimidyl, an optionally
substituted pyrazolo[3,4]pyrimidyl an optionally substituted
cyclopentaimidazolyl, an optionally substituted
cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an
optionally substituted pyrroloimidazolyl, an optionally substituted
pyrrolotriazolyl, or an optionally substituted benzo[b]thienyl.
[0368] In one embodiment, in the compounds represented by formula
(I), (II), (VIII), (IX), or (X), R.sub.5 is selected from the group
consisting of:
##STR00035## [0369] wherein: [0370] X.sub.11, for each occurrence,
is independently CH, CR.sub.9, N, N(O), or N.sup.+(R.sub.17);
[0371] X.sub.12, for each occurrence, is independently CH,
CR.sub.9, N, N(O), N.sup.+(R.sub.17), provided that at least one
X.sub.12 group is independently selected from CH and CR.sub.9;
[0372] X.sub.13, for each occurrence, is independently O, S, S(O)p,
NR.sub.7, or NR.sub.17; [0373] R.sub.9, for each occurrence, is
independently a substituent selected from the group consisting of
an optionally substituted alkyl, an optionally substituted alkenyl,
an optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, halo, cyano,
nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a hetero
alkyl, --NR.sub.10R.sub.11, --OR.sub.7, --C(O)R.sub.7,
--C(O)OR.sub.7, --OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11;
--NR.sub.8C(O)R.sub.7, --SR.sub.7, --S(O).sub.pR.sub.7,
--OS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, or --S(O).sub.pNR.sub.10R.sub.11,
--S(O).sub.pOR.sub.7, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2, --S(O).sub.pOR.sub.7,
--OP(O)(OR.sub.7).sub.2, or --SP(O)(OR.sub.7).sub.2; [0374] or two
R.sub.9 groups taken together with the carbon atoms to which they
are attached form a fused ring; and [0375] R.sub.17, for each
occurrence, is independently an alkyl or an aralkyl.
[0376] In one embodiment, in the compounds represented by formula
(I), (II), (VIII), (IX), or (X), [0377] R.sub.5 is
[0377] ##STR00036## [0378] wherein R.sub.27, for each occurrence,
is independently a substituent selected from the group consisting
of --H, an optionally substituted alkyl, an optionally substituted
alkenyl, an optionally substituted alkynyl, an optionally
substituted cycloalkyl, an optionally substituted cycloalkenyl, an
optionally substituted heterocyclyl, an optionally substituted
aryl, an optionally substituted heteroaryl, an optionally
substituted aralkyl, an optionally substituted heteraralkyl, halo,
cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a
heteroalkyl, --OR.sub.7, --C(O)R.sub.7, --C(O)OR.sub.7,
--OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11, --NR.sub.8C(O)R.sub.7,
--SR.sub.7, --S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7,
--S(O).sub.pOR.sub.7, --NR.sub.8S(O).sub.pR.sub.7, or
--S(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--OP(O)(OR.sub.7).sub.2, --SP(O)(OR.sub.7).sub.2,
--S(O).sub.pOR.sub.7, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2; [0379] or two R.sub.27 groups taken
together with the carbon atom to which they are attached form an
optionally substituted cycloalkyl or optionally substituted
heterocyclyl ring.
[0380] In one embodiment, in the compounds represented by formula
(I), (II), (VIII), (IX), or (X), R.sub.5 is X.sub.20R.sub.50. In
one aspect, X.sub.20 is a C1-C4 alkyl and R.sub.50 is an optionally
substituted phenyl.
[0381] In one embodiment, in the compounds represented by formula
(I), (II), (VIII), (IX), or (X), R.sub.5 is
--H.
[0382] In one embodiment, in the compounds represented by formula
(I), (II), (VIII), (IX), or (X), R.sub.5 is
##STR00037##
[0383] In one embodiment, in the compounds represented by formula
(I), (II), (VIII), (IX), or (X), R.sub.5 is
##STR00038##
wherein X.sub.1, X.sub.2, and X.sub.3 are each independently
C(R.sub.27).sub.2, NR.sub.77, C(O), S(O).sub.2, O or S; [0384]
R.sub.27, for each occurrence, is independently a substituent
selected from the group consisting of --H, an optionally
substituted alkyl, an optionally substituted alkenyl, an optionally
substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted
heterocyclyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted aralkyl, an
optionally substituted heteraralkyl, halo, cyano, nitro, guanadino,
a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, --OR.sub.7,
--C(O)R.sub.7, --C(O)OR.sub.7, --OC(O)R.sub.7,
--C(O)NR.sub.10R.sub.11, --NR.sub.8C(O)R.sub.7, --SR.sub.7,
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, or --S(O).sub.pNR.sub.10R.sub.11,
--S(O).sub.pOR.sub.7, --OP(O)(OR.sub.7).sub.2,
--SP(O)(OR.sub.7).sub.2, --S(O).sub.pOR.sub.7,
--OP(O)(OR.sub.7).sub.2, or --SP(O)(OR.sub.7).sub.2; [0385] or two
R.sub.27 groups taken together with the carbon atom to which they
are attached form an optionally substituted cycloalkyl or
optionally substituted heterocyclyl ring; R.sub.77, for each
occurrence, is independently a substituent selected from the group
consisting of --H, an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cycloalkyl, an optionally substituted
cycloalkenyl, an optionally substituted heterocyclyl, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted aralkyl, an optionally substituted
heteraralkyl, halo, guanadino, a hydroxyalkyl, alkoxyalkyl,
haloalkyl, a heteroalkyl, --OR.sub.7, --C(O)R.sub.7,
--C(O)OR.sub.7, --OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11,
--SR.sub.7, --S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7,
--S(O).sub.pOR.sub.7, --S(O).sub.pNR.sub.10R.sub.11,
--S(O).sub.pOR.sub.7, --OP(O)(OR.sub.7).sub.2,
--SP(O)(OR.sub.7).sub.2, --S(O).sub.pOR.sub.7,
--OP(O)(OR.sub.7).sub.2, or --SP(O)(OR.sub.7).sub.2; and [0386] r
is 0 or 1.
[0387] In one embodiment, in the compounds represented by formula
(I), (II), (VIII), (IX), or (X), R.sub.5 is an optionally
substituted alkyl. In one aspect, R.sub.5 is an optionally
substituted lower alkyl.
[0388] In one embodiment, in the compounds represented by formula
(III), (IV), (V), (VI), or (VII), R'.sub.1 is null,
--S--CR.sub.12--, --NR.sub.14--CR.sub.12--,
--CR.sub.12--CR.sub.12--, --CR.sub.12--, --O--, --S--, or
--NR.sub.14--. In one aspect, L' is --S--CH.sub.2--. In one aspect,
L' is --S--.
[0389] In one embodiment, in the compounds represented by formula
(III), (IV), (V), (VI), or (VII), R'.sub.1 is an optionally
substituted phenyl, an optionally substituted thiazolyl, an
optionally substituted pyridinyl, an optionally substituted
dihydrofuranone, an optionally substituted pyrimidine-dione, an
optionally substituted imidazolyl, or --C(O)N(R.sub.13).sub.2.
[0390] In one embodiment, in the compounds represented by formula
(III), (IV), (V), (VI), or (VII), L' is --S--CH.sub.2-- or --S--
and R'.sub.1 is an optionally substituted phenyl, an optionally
substituted thiazolyl, an optionally substituted pyridinyl, an
optionally substituted dihydrofuranone, an optionally substituted
pyrimidine-dione, an optionally substituted imidazolyl, or
--C(O)N(R.sub.13).sub.2.
[0391] In one embodiment, in the compounds represented by formula
(III) or (XV), R'.sub.5 is represented by the following
formula:
##STR00039## [0392] wherein: [0393] R.sub.9, for each occurrence,
is independently a substituent selected from the group consisting
of an optionally substituted alkyl, an optionally substituted
alkenyl, an optionally substituted alkynyl, an optionally
substituted cycloalkyl, an optionally substituted cycloalkenyl, an
optionally substituted heterocyclyl, an optionally substituted
aryl, an optionally substituted heteroaryl, an optionally
substituted aralkyl, an optionally substituted heteraralkyl,
hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a
haloalkyl, a heteroalkyl, --OR.sub.7, --C(O)R.sub.7,
--C(O)OR.sub.7, --OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --SR.sub.7, --S(O).sub.pR.sub.7,
--OS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, or --S(O).sub.pNR.sub.10R.sub.11,
--S(O).sub.pOR.sub.7, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2; [0394] or two R.sub.9 groups taken
together with the carbon atoms to which they are attached form a
fused ring; and [0395] q is zero or an integer from 1 to 7.
[0396] In one embodiment, in the compounds represented by formula
(III) or (XV), R'.sub.5 is represented by the following
formula:
##STR00040## [0397] wherein: [0398] q is zero or an integer from 1
to 5; and [0399] u is zero or an integer from 1 to 5.
[0400] In one embodiment, in the compounds represented by formula
(III) or (XV), R'.sub.5 is represented by the following
formula:
##STR00041## [0401] wherein: [0402] R.sub.33 is a halo, lower
alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and
lower alkyl sulfanyl; [0403] R.sub.34 is H, a lower alkyl, or a
lower alkylcarbonyl; and [0404] Ring B and Ring C are optionally
substituted with one or more substituents.
[0405] In one embodiment, in the compounds represented by formula
(III) or (XV), R'.sub.5 is selected from the group consisting
of:
##STR00042## [0406] wherein: [0407] X.sub.6, for each occurrence,
is independently CH, CR.sub.9, N, N(O), N.sup.+(R.sub.17), provided
that at least three X.sub.6 groups are independently selected from
CH and CR.sub.9; [0408] X.sub.7, for each occurrence, is
independently CH, CR.sub.9, N, N(O), N.sup.+(R.sub.17), provided
that at least three X.sub.7 groups are independently selected from
CH and CR.sub.9; [0409] X.sub.8, for each occurrence, is
independently CH.sub.2, CHR.sub.9, C(R.sub.9).sub.2, S, S(O).sub.p,
NR.sub.7, or NR.sub.17; [0410] X.sub.9, for each occurrence, is
independently N or CH; [0411] X.sub.10, for each occurrence, is
independently CH, CR.sub.9, N, N(O), N.sup.+(R.sub.17), provided
that at least one X.sub.10 is selected from CH and CR.sub.9; [0412]
R.sub.9, for each occurrence, is independently a substituent
selected from the group consisting of an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cycloalkyl, an optionally
substituted cycloalkenyl, an optionally substituted heterocyclyl,
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted aralkyl, an optionally
substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano,
nitro, guanadino, a haloalkyl, a heteroalkyl, --OR.sub.7,
--C(O)R.sub.7, --C(O)OR.sub.7, --OC(O)R.sub.7,
--C(O)NR.sub.10R.sub.11, --NR.sub.8C(O)R.sub.7, --SR.sub.7,
--S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, or --S(O).sub.pNR.sub.10R.sub.11,
--S(O).sub.pOR.sub.7, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2, --S(O).sub.pOR.sub.7,
--OP(O)(OR.sub.7).sub.2, or --SP(O)(OR.sub.7).sub.2; [0413] or two
R.sub.9 groups taken together with the carbon atoms to which they
are attached form a fused ring; and [0414] R.sub.17, for each
occurrence, is independently --H, an alkyl, an aralkyl,
--C(O)R.sub.7, --C(O)OR.sub.7, or --C(O)NR.sub.10R.sub.11.
[0415] In one embodiment, in the compounds represented by formula
(III) or (XV), R'.sub.5 is an optionally substituted indolyl, an
optionally substituted benzoimidazolyl, an optionally substituted
indazolyl, an optionally substituted 3H-indazolyl, an optionally
substituted indolizinyl, an optionally substituted quinolinyl, an
optionally substituted isoquinolinyl, an optionally substituted
benzoxazolyl, an optionally substituted benzo[1,3]dioxolyl, an
optionally substituted benzofuryl, an optionally substituted
benzothiazolyl, an optionally substituted benzo[d]isoxazolyl, an
optionally substituted benzo[d]isothiazolyl, an optionally
substituted thiazolo[4,5-c]pyridinyl, an optionally substituted
thiazolo[5,4-c]pyridinyl, an optionally substituted
thiazolo[4,5-b]pyridinyl, an optionally substituted
thiazolo[5,4-b]pyridinyl, an optionally substituted
oxazolo[4,5-c]pyridinyl, an optionally substituted
oxazolo[5,4-c]pyridinyl, an optionally substituted
oxazolo[4,5-b]pyridinyl, an optionally substituted
oxazolo[5,4-b]pyridinyl, an optionally substituted
imidazopyridinyl, an optionally substituted benzothiadiazolyl,
benzoxadiazolyl, an optionally substituted benzotriazolyl, an
optionally substituted tetrahydroindolyl, an optionally substituted
azaindolyl, an optionally substituted quinazolinyl, an optionally
substituted purinyl, an optionally substituted
imidazo[4,5-a]pyridinyl, an optionally substituted
imidazo[1,2-a]pyridinyl, an optionally substituted
3H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-b]pyridinyl, an optionally substituted
1H-imidazo[4,5-c]pyridinyl, an optionally substituted
3H-imidazo[4,5-c]pyridinyl, an optionally substituted
pyridopyrdazinyl, and optionally substituted pyridopyrimidinyl, an
optionally substituted pyrrolo[2,3]pyrimidyl, an optionally
substituted pyrazolo[3,4]pyrimidyl an optionally substituted
cyclopentaimidazolyl, an optionally substituted
cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an
optionally substituted pyrroloimidazolyl, an optionally substituted
pyrrolotriazolyl, or an optionally substituted benzo[b]thienyl.
[0416] In one embodiment, in the compounds represented by formula
(III) or (XV), R'.sub.5 is selected from the group consisting
of:
##STR00043## [0417] wherein: [0418] X.sub.11, for each occurrence,
is independently CH, CR.sub.9, N, N(O), or N.sup.+(R.sub.17);
[0419] X.sub.12, for each occurrence, is independently CH,
CR.sub.9, N, N(O), N.sup.+(R.sub.17), provided that at least one
X.sub.12 group is independently selected from CH and CR.sub.9;
[0420] X.sub.13, for each occurrence, is independently O, S, S(O)p,
NR.sub.7, or NR.sub.17; [0421] R.sub.9, for each occurrence, is
independently a substituent selected from the group consisting of
an optionally substituted alkyl, an optionally substituted alkenyl,
an optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, halo, cyano,
nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a
heteroalkyl, --NR.sub.10R.sub.11, --OR.sub.7, --C(O)R.sub.7,
--C(O)OR.sub.7, --OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --SR.sub.7, --S(O).sub.pR.sub.7,
--OS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, or --S(O).sub.pNR.sub.10R.sub.11,
--S(O).sub.pOR.sub.7, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2, --S(O).sub.pOR.sub.7,
--OP(O)(OR.sub.7).sub.2, or --SP(O)(OR.sub.7).sub.2; [0422] or two
R.sub.9 groups taken together with the carbon atoms to which they
are attached form a fused ring; and [0423] R.sub.17, for each
occurrence, is independently an alkyl or an aralkyl.
[0424] In one embodiment, in the compounds represented by formula
(III) or (XV), R'.sub.5 is
##STR00044## [0425] wherein R.sub.27, for each occurrence, is
independently a substituent selected from the group consisting of
--H, an optionally substituted alkyl, an optionally substituted
alkenyl, an optionally substituted alkynyl, an optionally
substituted cycloalkyl, an optionally substituted cycloalkenyl, an
optionally substituted heterocyclyl, an optionally substituted
aryl, an optionally substituted heteroaryl, an optionally
substituted aralkyl, an optionally substituted heteraralkyl, halo,
cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a
heteroalkyl, --NR.sub.10R.sub.11, --OR.sub.7, --C(O)R.sub.7,
--C(O)OR.sub.7, --OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11,
--NR.sub.8C(O)R.sub.7, --SR.sub.7, --S(O).sub.pR.sub.7,
--OS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--NR.sub.8S(O).sub.pR.sub.7, or --S(O).sub.pNR.sub.10R.sub.11,
--S(O).sub.pOR.sub.7, --OP(O)(OR.sub.7).sub.2,
--SP(O)(OR.sub.7).sub.2, --S(O).sub.pOR.sub.7,
--OP(O)(OR.sub.7).sub.2, or --SP(O)(OR.sub.7).sub.2;
[0426] or two R.sub.27 groups taken together with the carbon atom
to which they are attached form an optionally substituted
cycloalkyl or optionally substituted heterocyclyl ring.
[0427] In one embodiment, in the compounds represented by formula
(III) or (XV), R'.sub.5 is X.sub.20R.sub.50.
[0428] In one aspect, X.sub.20 is a C1-C4 alkyl and R.sub.50 is an
optionally substituted phenyl.
[0429] In one embodiment, in the compounds represented by formula
(III) or (XV), R'.sub.5 is
##STR00045##
[0430] In one embodiment, in the compounds represented by formula
(III) or (XV), R'.sub.5 is
##STR00046##
wherein X.sub.1, X.sub.2, and X.sub.3 are each independently
C(R.sub.27).sub.2, NR.sub.77, C(O), S(O).sub.2, O or S; [0431]
R.sub.27, for each occurrence, is independently a substituent
selected from the group consisting of --H, an optionally
substituted alkyl, an optionally substituted alkenyl, an optionally
substituted alkynyl, an optionally substituted cycloalkyl, an
optionally substituted cycloalkenyl, an optionally substituted
heterocyclyl, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted aralkyl, an
optionally substituted heteraralkyl, halo, cyano, nitro, guanadino,
a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl,
--NR.sub.10R.sub.11, --OR.sub.7, --C(O)R.sub.7, --C(O)OR.sub.7,
--OC(O)R.sub.7, --C(O)NR.sub.10R.sub.11, --NR.sub.8C(O)R.sub.7,
--SR.sub.7, --S(O).sub.pR.sub.7, --OS(O).sub.pR.sub.7,
--S(O).sub.pOR.sub.7, --NR.sub.8S(O).sub.pR.sub.7, or
--S(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--OP(O)(OR.sub.7).sub.2, --SP(O)(OR.sub.7).sub.2,
--S(O).sub.pOR.sub.7, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.2; [0432] or two R.sub.27 groups taken
together with the carbon atom to which they are attached form an
optionally substituted cycloalkyl or optionally substituted
heterocyclyl ring; R.sub.77, for each occurrence, is independently
a substituent selected from the group consisting of --H, an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cycloalkyl, an optionally substituted cycloalkenyl, an optionally
substituted heterocyclyl, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted
aralkyl, an optionally substituted heteraralkyl, halo, guanadino, a
hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, --OR.sub.7,
--C(O)R.sub.7, --C(O)OR.sub.7, --OC(O)R.sub.7,
--C(O)NR.sub.10R.sub.11, --SR.sub.7, --S(O).sub.pR.sub.7,
--OS(O).sub.pR.sub.7, --S(O).sub.pOR.sub.7,
--S(O).sub.pNR.sub.10R.sub.11, --S(O).sub.pOR.sub.7,
--OP(O)(OR.sub.7).sub.2, --SP(O)(OR.sub.7).sub.2,
--S(O).sub.pOR.sub.7, --OP(O)(OR.sub.7).sub.2, or
--SP(O)(OR.sub.7).sub.27 and r is 0 or 1.
[0433] In one embodiment, in the compounds represented by formula
(IV), (V), (VII), (XI), (XII), or (XIV), R.sub.41 is selected from
the group consisting of --H, lower alkyl, lower alkoxy, lower
cycloalkyl, and lower cycloalkoxy.
[0434] In one embodiment, in the compounds represented by formula
(IV), (V), (VII), (XI), (XII), or (XIV), R.sub.41 is selected from
the group consisting of --H, methyl, ethyl, propyl, isopropyl,
cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
[0435] In one embodiment, in the compounds represented by formula
(IV) or (XI), X.sub.41 is NR.sub.42 and X.sub.42 is CR.sub.44.
[0436] In one embodiment, in the compounds represented by formula
(IV) or (XI), X.sub.41 is NR.sub.42 and X.sub.42 is N.
[0437] In one embodiment, in the compounds represented by formula
(IV) or (XI), X.sub.41 is NR.sub.42, and R.sub.42 is selected from
the group consisting of --H, a lower alkyl, a lower cycloalkyl,
--C(O)N(R.sub.27).sub.2, and --C(O)OH, wherein each R.sub.27 is
independently --H or a lower alkyl.
[0438] In one embodiment, in the compounds represented by formula
(IV) or (XI), X.sub.41 is NR.sub.42, and R.sub.42 is selected from
the group consisting of --H, methyl, ethyl, n-propyl, isopropyl,
cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl,
--C(O)OH, --(CH.sub.2).sub.mC(O)OH, --CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2OCH.sub.3, and --C(O)N(CH.sub.3).sub.2.
[0439] In one embodiment, in the compounds represented by formula
(IV) or (XI), R.sub.43 and R.sub.44 are, independently, selected
from the group consisting of --H, methyl, ethyl, propyl, isopropyl,
cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
[0440] In one embodiment, in the compounds represented by formula
(IV) or (XI), X.sub.42 is CR.sub.44; Y.sub.40 is CR.sub.43; and
R.sub.43 and R.sub.44 together with the carbon atoms to which they
are attached form a cycloalkenyl, an aryl, heterocyclyl, or
heteroaryl ring.
[0441] In one embodiment, in the compounds represented by formula
(IV) or (XI), R.sub.43 and R.sub.44 together with the carbon atoms
to which they are attached form a C.sub.5-C.sub.8 cycloalkenyl or a
C.sub.5-C.sub.8 aryl.
[0442] In one embodiment, in the compounds represented by formula
(IV) or (XI), R.sub.45 or CR.sub.45 is selected from the group
consisting of --H, --OH, --SH, --NH.sub.2, a lower alkoxy, a lower
alkyl amino, and a lower dialkyl amino.
[0443] In one embodiment, in the compounds represented by formula
(IV) or (XI), R.sub.45 is selected from the group consisting of
--H, --OH, methoxy and ethoxy.
[0444] In one embodiment, in the compounds represented by formula
(IV) or (XI), X.sub.41 is O.
[0445] In one embodiment, in the compounds represented by formula
(V) or (XII), X.sub.42 is CR.sub.44, and R.sub.43 and R.sub.44 are,
independently, selected from the group consisting of --H, methyl,
ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy,
and cyclopropoxy.
[0446] In one embodiment, in the compounds represented by formula
(V) or (XII), X.sub.42 is CR.sub.44, and [0447] R.sub.43 and
R.sub.44, taken together with the carbon atoms to which they are
attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl
ring.
[0448] In one embodiment, in the compounds represented by formula
(V) or (XII), R.sub.43 and R.sub.44, taken together with the carbon
atoms to which they are attached, form a C.sub.5-C.sub.8
cycloalkenyl or a C.sub.5-C.sub.8 aryl.
[0449] In one embodiment, in the compounds represented by formula
(V) or (XII), X.sub.42 is CR.sub.44.
[0450] In one embodiment, in the compounds represented by formula
(V) or (XII), X.sub.42 is N.
[0451] In one embodiment, in the compounds represented by formula
(VII) or (XIV), R.sub.42 is --H or an optionally substituted lower
alkyl.
[0452] In one embodiment, in the compounds represented by formula
(VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), one of R.sub.35
or R.sub.36 is --H. In one aspect, both R.sub.35 and R.sub.36 are
--H. In one aspect, the other one of R.sub.35 or R.sub.36 is an
optionally substituted alkyl or an optionally substituted
cycyloalkyl. In one aspect, the other one of R.sub.35 or R.sub.36
is an optionally substituted lower alkyl or an optionally
substituted lower cycyloalkyl. In one aspect, the other one of
R.sub.35 or R.sub.36 is an optionally substituted C4-C6
cycyloalkyl.
[0453] In one embodiment, in the compounds represented by formula
(VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), R.sub.35 and
R.sub.36, together with N to which they are attached form a 5 or 6
membered heterocyclic ring.
[0454] In one embodiment, in the compounds represented by formula
(VIII), (IX), or (X), Y is S.
[0455] In one embodiment, in the compounds represented by formula
(VIII), (IX), or (X), Y is O.
[0456] In one embodiment, in the compounds represented by formula
(VIII), R.sub.3 is --OH, --SH, or --NHR.sub.7. In one aspect,
R.sub.3 is --OH.
[0457] In one embodiment, in the compounds represented by formula
(VIII), t is 0.
[0458] In one embodiment, in the compounds represented by formula
(VIII), t is 1.
[0459] In one embodiment, in the compounds represented by formula
(VIII), t is 2.
[0460] In one embodiment, in the compounds represented by formula
(XV), Y is --O--.
[0461] In one embodiment, in the compounds represented by formula
(XV), Y is --S--.
[0462] In one embodiment, in the compounds represented by formula
(XV), R'.sub.3 is C1-C6 alkoxy or --OH. In one aspect, R'.sub.3 is
--OH.
[0463] In one embodiment, in the compounds represented by formula
(XV), R.sub.6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy,
a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6
cycloalkyl.
[0464] In another embodiment, the compound is selected from the
group consisting of [0465]
4-isopropyl-6-(5-(4-methoxybenzylthio)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,-
4-triazol-3-yl)benzene-1,3-diol; [0466]
4-(5-(2,6-difluorobenzylthio)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-
-3-yl)-6-isopropylbenzene-1,3-diol; [0467]
4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-(4-(trifluoromethyl)benzylthi-
o)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol; [0468]
6-((5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2-
,4-triazol-3-ylthio)methyl)pyrimidine-2,4-(1H,3H)-dione; [0469]
4-isopropyl-6-(4-(1-methyl-1-indol-5-yl)-5-((2-methylthiazol-4-yl)methylt-
hio)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol; [0470]
2-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,-
4-triazol-3-ylthio)acetamide; [0471]
4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-(pyridin-3-ylmethylthio)-4H-1-
,2,4-triazol-3-yl)benzene-1,3-diol; [0472]
4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-(pyridin-2-ylmethylthio)-4H-1-
,2,4-triazol-3-yl)benzene-1,3-diol; [0473]
4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-(pyridin-4-ylmethylthio)-4H-1-
,2,4-triazol-3-yl)benzene-1,3-diol; [0474]
3-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,-
4-triazol-3-ylthio)dihydrofuran-2(3H)-one; [0475]
4-(5-((2-aminothiazol-4-yl)methylthio)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,-
4-triazol-3-yl)-6-isopropylbenzene-1,3-diol; [0476]
4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-((6-(trifluoromethyl)pyridin--
3-yl)methylthio)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol; [0477]
4-isopropyl-6-(4-(4-(methoxymethyl)benzyl)-5-(pyridin-3-ylmethylthio)-4H--
1,2,4-triazol-3-yl)benzene-1,3-diol; [0478]
4-(4-(4-(2-(dimethylamino)ethyl)phenyl)-5-(pyridin-3-ylmethylthio)-4H-1,2-
,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol; [0479]
4-isopropyl-6-(4-(2-methoxy-2,3-dihydro-1H-inden-5-yl)-5-(pyridin-3-ylmet-
hylthio)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol; [0480]
4-isopropyl-6-(5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl)benzene-1,3-diol;
[0481]
4-(5-(4-hydroxyphenyl)-1H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1-
,3-diol; [0482]
4-ethyl-6-(5-(pyridin-3-ylmethylthio)-1H-1,2,4-triazol-3-yl)benzene-1,3-d-
iol; [0483]
4-ethyl-6-(5-((2-methylthiazol-4-yl)methylthio)-1H-1,2,4-triazol-3-yl)ben-
zene-1,3-diol; [0484]
4-(5-((1H-imidazol-1-yl)methyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triaz-
ol-3-yl)-6-isopropylbenzene-1,3-diol; [0485]
4-isopropyl-6-(4-methyl-5-(pyridin-3-ylmethylthio)-4H-1,2,4-triazol-3-yl)-
benzene-1,3-diol; [0486]
4-(5-(3-(dimethylamino)propyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazo-
l-3-yl)-6-isopropylbenzene-1,3-diol; [0487]
4-(4-fluorophenethyl)-6-(4-(2-methoxy-2,3-dihydro-1H-inden-5-yl)-5-(pyrid-
in-3-ylmethylthio)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol; [0488]
4-(4-fluorophenethyl)-6-(4-(2-methoxy-2,3-dihydro-1H-inden-5-yl)-5-(2-met-
hylthiazol-4-yl)methylthio)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol;
[0489]
4-(4-(1',3'-dihydrospiro[[1,3]dioxolane-2,2'-indene]-5'-yl)-5-(pyridin-3--
ylmethylthio)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol;
[0490]
4-(5-(benzylthio)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-6-iso-
propylbenzene-1,3-diol; [0491]
4-(4-(benzo[d][1,3]dioxol-5-yl)-5-(pyridin-4-ylmethoxy)-4H-1,2,4-triazol--
3-yl)-6-isopropylbenzene-1,3-diol; [0492]
4-(5-(4-(benzyloxy)benzylthio)-1H-1,2,4-triazol-3-yl)-6-ethylbenzene-1,3--
diol; [0493]
4-(5-(biphenyl-2-ylmethylthio)-1H-1,2,4-triazol-3-yl)-6-ethylbenzene-1,3--
diol; [0494]
4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-(2-(pyridin-3-yl)ethyl)-4H-1,-
2,4-triazol-3-yl)benzene-1,3-diol; [0495]
4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(1-methylpiperidin-4-yloxy)-4H-1,2,4-t-
riazol-3-yl)-6-isopropylbenzene-1,3-diol; [0496]
4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(2-(2-(dimethylamino)ethoxy)ethoxy)-4H-
-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol; [0497]
4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(2-morpholinoethoxy)-4H-1,2,4-triazol--
3-yl)-6-isopropylbenzene-1,3-diol; [0498]
4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(1,4-dimethylpiperazin-2-yl)methoxy)-4-
H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol; [0499]
4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(2-(dimethylamino)ethoxy)-4H-1,2,4-tri-
azol-3-yl)-6-isopropylbenzene-1,3-diol; [0500]
4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(3-methoxy-3-methylbutoxy)-4H-1,2,4-tr-
iazol-3-yl)-6-isopropylbenzene-1,3-diol; [0501]
(S)-4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(1-methylpyrrolidin-2-yl)methoxy)--
4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol; [0502]
4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-4H-1,2,4-
-triazol-3-yl)-6-isopropylbenzene-1,3-diol; [0503]
4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(2-isopropoxyethoxy)-4H-1,2,4-triazol--
3-yl)-6-isopropylbenzene-1,3-diol; [0504]
4-(5-(cyclohexyloxy)-4-(2,3-dihydro-1H-inden-5-yl)-4H-1,2,4-triazol-3-yl)-
-6-isopropylbenzene-1,3-diol; [0505]
4-(5-(benzo[d][1,3]dioxol-5-yloxy)-4-(2,3-dihydro-1H-inden-5-yl)-4H-1,2,4-
-triazol-3-yl)-6-isopropylbenzene-1,3-diol; [0506]
4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(4-methoxyphenoxy)-4H-1,2,4-triazol-3--
yl)-6-isopropylbenzene-1,3-diol; [0507]
4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(3-(dimethylamino)phenoxy)-4H-1,2,4-tr-
iazol-3-yl)-6-isopropylbenzene-1,3-diol; [0508]
4-(5-(cyclopentylmethoxy)-4-(2,3-dihydro-1H-inden-5-yl)-4H-1,2,4-triazol--
3-yl)-6-isopropylbenzene-1,3-diol; [0509]
1-(2-(4-(2,3-dihydro-1H-inden-5-yl)-5-(2,4-dihydroxy-5-isopropylphenyl)-4-
H-1,2,4-triazol-3-yloxy)ethyl)imidazolidin-2-one; [0510]
4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(pyridin-3-yloxy)-4H-1,2,4-triazol-3-y-
l)-6-isopropylbenzene-1,3-diol; [0511]
4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(2-(pyrrolidin-1-yl)ethoxy)-4H-1,2,4-t-
riazol-3-yl)-6-isopropylbenzene-1,3-diol; [0512]
4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(1-ethylpiperidin-3-yloxy)-4H-1,2,4-tr-
iazol-3-yl)-6-isopropylbenzene-1,3-diol; [0513]
4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(2-(piperidin-1-yl)ethoxy)-4H-1,2,4-tr-
iazol-3-yl)-6-isopropylbenzene-1,3-diol; or [0514]
4-(4-(benzo[d][1,3]dioxol-5-yl)-5-(pyridin-3-ylmethoxy)-4H-1,2,4-triazol--
3-yl)-6-isopropylbenzene-1,3-diol; or a tautomer, pharmaceutically
acceptable salt, solvate, clathrate, or a prodrug thereof.
[0515] In another embodiment, the compound is selected from the
group consisting of [0516]
4-(5-(cyclopentyloxy)-4-(2,3-dihydro-1H-inden-5-yl)-4H-1,2,4-triazol-3-yl-
)-6-isopropylbenzene-1,3-diol; [0517]
4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(pyridin-3-ylmethylthio)-4H-1,2,4-tria-
zol-3-yl)-6-isopropylbenzene-1,3-diol; [0518]
4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(pyridin-4-ylmethylthio)-4H-1,2,4-tria-
zol-3-yl)-6-isopropylbenzene-1,3-diol; [0519]
4-isopropyl-6-(4-phenyl-5-(pyridin-3-ylmethylthio)-4H-1,2,4-triazol-3-yl)-
benzene-1,3-diol; [0520]
4-(4-(4-(diethylamino)phenyl)-5-(pyridin-3-ylmethylthio)-4H-1,2,4-triazol-
-3-yl)-6-isopropylbenzene-1,3-diol; [0521]
4-isopropyl-6-(4-phenyl-5-(pyridin-2-ylmethylthio)-4H-1,2,4-triazol-3-yl)-
benzene-1,3-diol; [0522]
4-(4-(4-(diethylamino)phenyl)-5-(pyridin-2-ylmethylthio)-4H-1,2,4-triazol-
-3-yl)-6-isopropylbenzene-1,3-diol; [0523]
4-(4-(4-(diethylamino)phenyl)-5-(pyridin-4-ylmethylthio)-4H-1,2,4-triazol-
-3-yl)-6-isopropylbenzene-1,3-diol; [0524]
4-isopropyl-6-(4-phenyl-5-(pyridin-4-ylmethylthio)-4H-1,2,4-triazol-3-yl)-
benzene-1,3-diol; [0525]
4-(4-(4-chlorophenyl)-5-(pyridin-2-ylmethylthio)-4H-1,2,4-triazol-3-yl)-6-
-isopropylbenzene-1,3-diol; [0526]
4-(4-(4-chlorophenyl)-5-(pyridin-3-ylmethylthio)-4H-1,2,4-triazol-3-yl)-6-
-isopropylbenzene-1,3-diol; [0527]
4-(4-(4-chlorophenyl)-5-(pyridin-4-ylmethylthio)-4H-1,2,4-triazol-3-yl)-6-
-isopropylbenzene-1,3-diol; [0528] ethyl
4-(2,3-dihydro-1H-inden-5-yl)-5-(2,4-dihydroxy-5-isopropylphenyl)-4H-1,2,-
4-triazole-3-carboxylate; [0529]
4-(2,3-dihydro-1H-inden-5-yl)-5-(2,4-dihydroxy-5-isopropylphenyl)-4H-1,2,-
4-triazole-3-carboxylic acid; [0530]
4-(4-(benzo[d][1,3]dioxol-5-yl)-5-(pyridin-3-ylmethylthio)-4H-1,2,4-triaz-
ol-3-yl)-6-isopropylbenzene-1,3-diol; [0531]
4-isopropyl-6-(4-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-5-(pyridin-3-yl-
methylthio)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol; [0532]
4-isopropyl-6-(4-(4-(pyridin-3-ylmethyl)phenyl)-5-(pyridin-3-ylmethylthio-
)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol; [0533]
4-isopropyl-6-(4-(6-((2-methoxyethyl)(methyl)amino)pyridin-3-yl)-5-(pyrid-
in-3-ylmethylthio)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol; [0534]
4-(4-(3,4-dimethoxyphenyl)-5-(pyridin-3-ylmethylthio)-4H-1,2,4-triazol-3--
yl)-6-isopropylbenzene-1,3-diol; [0535]
4-(4-(benzo[d][1,3]dioxol-5-yl)-5-(thiazol-4-ylmethylthio)-4H-1,2,4-triaz-
ol-3-yl)-6-isopropylbenzene-1,3-diol; [0536]
4-isopropyl-6-(4-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-5-(thiazol-4-yl-
methylthio)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol; [0537]
4-isopropyl-6-(4-(4-(pyridin-3-ylmethyl)phenyl)-5-(thiazol-4-ylmethylthio-
)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol; [0538]
4-isopropyl-6-(4-(6-((2-methoxyethyl)(methyl)amino)pyridin-3-yl)-5-(thiaz-
ol-4-ylmethylthio)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol; [0539]
4-(4-(3,4-dimethoxyphenyl)-5-(thiazol-4-ylmethylthio)-4H-1,2,4-triazol-3--
yl)-6-isopropylbenzene-1,3-diol; [0540]
4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-(thiazol-4-ylmethylthio)-4H-1-
,2,4-triazol-3-yl)benzene-1,3-diol; [0541]
4-(4-(2,3-dihydro-1H-inden-5-yl)-5-(thiazol-4-ylmethylthio)-4H-1,2,4-tria-
zol-3-yl)-6-isopropylbenzene-1,3-diol; [0542]
4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-(3-(pyridin-3-yl)propylthio)--
4H-1,2,4-triazol-3-yl)benzene-1,3-diol; [0543]
4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-(2-(pyridin-3-yl)ethylthio)-4-
H-1,2,4-triazol-3-yl)benzene-1,3-diol; [0544]
4-(4-(benzo[d][1,3]dioxol-5-yl)-5-(2-(pyridin-3-yl)ethylthio)-4H-1,2,4-tr-
iazol-3-yl)-6-isopropylbenzene-1,3-diol; [0545]
2-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,-
4-triazol-3-ylthio) acetic acid; [0546] methyl
3-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,-
4-triazol-3-ylthio)propanoate; [0547]
2-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,-
4-triazol-3-ylthio)-N-methylacetamide; [0548]
3-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,-
4-triazol-3-ylthio)-N-methylpropan amide; [0549]
4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-(pyridin-2-ylthio)-4H-1,2,4-t-
riazol-3-yl)benzene-1,3-diol; [0550]
4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-(pyridin-3-ylthio)-4H-1,2,4-t-
riazol-3-yl)benzene-1,3-diol; [0551]
2-((5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2-
,4-triazol-3-ylthio)methyl)benzenaminium chloride; [0552]
4-(5-(2-aminobenzylthio)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl-
)-6-isopropylbenzene-1,3-diol; [0553] tert-butyl
2-((5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2-
,4-triazol-3-ylthio)methyl)phenylcarbamate; [0554]
2-((5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2-
,4-triazol-3-ylthio)methyl)benzenaminium 2,2,2-trifluoroacetate;
[0555] tert-butyl
3-((5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2-
,4-triazol-3-ylthio)methyl)phenylcarbamate; [0556]
4-(5-(3-aminobenzylthio)-4-(1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-6-isopr-
opylbenzene-1,3-diol; [0557]
4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-(phenylthio)-4H-1,2,4-triazol-
-3-yl)benzene-1,3-diol; [0558]
N-(2-((5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H--
1,2,4-triazol-3-ylthio)methyl)phenyl)acetamide; [0559]
N-(3-((5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H--
1,2,4-triazol-3-ylthio)methyl)phenyl)acetamide; [0560]
4-isopropyl-6-(4-(4-morpholinophenyl)-5-(pyridin-2-ylthio)-4H-1,2,4-triaz-
ol-3-yl)benzene-1,3-diol; [0561]
4-isopropyl-6-(4-phenyl-5-(pyridin-2-ylthio)-4H-1,2,4-triazol-3-yl)benzen-
e-1,3-diol; [0562]
4-(5-(2-aminoethylthio)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-
-6-isopropylbenzene-1,3-diol 2,2,2-trifluoroacetate; [0563]
4-(5-(2-(ethylamino)benzylthio)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triaz-
ol-3-yl)-6-isopropylbenzene-1,3-diol 2,2,2-trifluoroacetate; [0564]
ethyl
4-(benzo[d][1,3]dioxol-5-yl)-5-(2,4-dihydroxy-5-isopropylphenyl)-4H-1,2,4-
-triazole-3-carboxylate; [0565]
N-(2-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1-
,2,4-triazol-3-ylthio)ethyl)acetamide; [0566]
4-(4-(4-((dimethylamino)methyl)phenyl)-5-(pyridin-2-ylthio)-4H-1,2,4-tria-
zol-3-yl)-6-isopropylbenzene-1,3-diol; [0567]
4-(4-(4-((tert-butyl(methyl)amino)methyl)phenyl)-5-(pyridin-2-ylthio)-4H--
1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol; [0568]
4-(4-(4-(dimethylamino)phenyl)-5-(pyridin-2-ylthio)-4H-1,2,4-triazol-3-yl-
)-6-isopropylbenzene-1,3-diol; [0569]
4-isopropyl-6-(4-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-5-(pyridin-2-yl-
thio)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol; [0570]
4-(4-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-fluorophenyl)-5-(pyridi-
n-2-ylthio)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol;
[0571]
(R)-4-isopropyl-6-(4-(6-morpholinopyridin-3-yl)-5-(pyrrolidin-2-yl)-4H-1,-
2,4-triazol-3-yl)benzene-1,3-diol; [0572]
4-(4-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-fluorophenyl)-5-(phenyl-
thio)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol; [0573]
4-(4-(4-(dimethylamino)phenyl)-5-(pyridin-3-ylmethylthio)-4H-1,2,4-triazo-
l-3-yl)-6-isopropylbenzene-1,3-diol; [0574]
4-(4-(4-((dimethylamino)methyl)phenyl)-5-(pyridin-3-ylmethylthio)-4H-1,2,-
4-triazol-3-yl)-6-isopropylbenzene-1,3-diol [0575]
4-(4-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-fluorophenyl)-5-(pyridi-
n-3-ylmethylthio)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol;
[0576]
4-isopropyl-6-(4-(4-morpholinophenyl)-5-(pyridin-3-ylmethylthio)-4-
H-1,2,4-triazol-3-yl)benzene-1,3-diol; [0577]
2-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,-
4-triazol-3-yl)acetic acid; [0578]
4-(4-(4-(2-(dimethylamino)ethyl)phenyl)-5-(pyridin-3-ylmethylthio)-4H-1,2-
,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol; or [0579]
4-(4-(benzo[d][1,3]dioxol-5-yl)-5-(pyridin-3-ylmethoxy)-4H-1,2,4-triazol--
3-yl)-6-isopropylbenzene-1,3-diol; or a tautomer, pharmaceutically
acceptable salt, solvate, clathrate, or a prodrug thereof.
[0580] In another embodiment, the compound is
2-(4-(benzo[d][1,3]dioxol-5-yl)-5-(pyridin-3-ylmethylthio)-4H-1,2,4-triaz-
ol-3-yl)-4-methoxyphenol or a tautomer, pharmaceutically acceptable
salt, solvate, clathrate, or a prodrug thereof.
[0581] In another embodiment, the compound is selected from the
group consisting of: [0582]
4-(2,3-dihydro-1H-inden-5-yl)-5-(2,4-dihydroxy-5-isopropylphenyl)-4H-1,2,-
4-triazole-3-carboxamide; [0583]
4-(benzo[d][1,3]dioxol-5-yl)-5-(2,4-dihydroxy-5-isopropylphenyl)-4H-1,2,4-
-triazole-3-carboxamide; [0584]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(dimethylamino)phenyl)-4H-1,2,4--
triazole-3-carboxamide; [0585]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholinophenyl)-4H-1,2,4-triaz-
ole-3-carboxamide; [0586]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-t-
riazole-3-carboxamide; [0587]
4-(3-acetamido-4-methoxyphenyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-4H-1,-
2,4-triazole-3-carboxamide; [0588]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(methylsulfonamido)phenyl)-4H-1,-
2,4-triazole-3-carboxamide; [0589]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(pyrrolidin-1-ylmethyl)phenyl)-4-
H-1,2,4-triazole-3-carboxamide; [0590]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(6-morpholinopyridin-3-yl)-4H-1,2,4-
-triazole-3-carboxamide; [0591]
4-(4-((tert-butyl(methyl)amino)methyl)phenyl)-5-(2,4-dihydroxy-5-isopropy-
lphenyl)-4H-1,2,4-triazole-3-carboxamide; [0592]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(pyridin-2-ylmethyl)phenyl)-4H-1-
,2,4-triazole-3-carboxamide; [0593]
4-(4-((diethylamino)methyl)phenyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-4H-
-1,2,4-triazole-3-carboxamide; [0594]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((dimethylamino)methyl)phenyl)-4-
H-1,2,4-triazole-3-carboxamide; [0595]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(3-(N,N-dimethylsulfamoyl)-4-methyl-
phenyl)-4H-1,2,4-triazole-3-carboxamide; [0596]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholinomethyl)phenyl)-4H-1,2-
,4-triazole-3-carboxamide; [0597]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(6-morpholinopyridin-3-yl)--
4H-1,2,4-triazole-3-carboxamide; [0598]
N-cyclohexyl-5-(2,4-dihydroxy-5-isopropylphenyl)-4-(6-morpholinopyridin-3-
-yl)-4H-1,2,4-triazole-3-carboxamide; [0599]
N-cyclopropyl-5-(2,4-dihydroxy-5-isopropylphenyl)-4-(6-morpholinopyridin--
3-yl)-4H-1,2,4-triazole-3-carboxamide; [0600]
N-benzyl-5-(2,4-dihydroxy-5-isopropylphenyl)-4-(6-morpholinopyridin-3-yl)-
-4H-1,2,4-triazole-3-carboxamide; [0601]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-isopropyl-4-(6-morpholinopyridin-3--
yl)-4H-1,2,4-triazole-3-carboxamide; [0602]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(6-morpholinopyridin-3-yl)-N-propyl-
-4H-1,2,4-triazole-3-carboxamide; [0603]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-(dimethylamino)ethyl)-4-(6-morph-
olinopyridin-3-yl)-4H-1,2,4-triazole-3-carboxamide; [0604]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-isobutyl-4-(6-morpholinopyridin-3-y-
l)-4H-1,2,4-triazole-3-carboxamide; [0605]
N-cyclopentyl-5-(2,4-dihydroxy-5-isopropylphenyl)-4-(6-morpholinopyridin--
3-yl)-4H-1,2,4-triazole-3-carboxamide; [0606]
(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(6-morpholinopyridin-3-yl)-4H-1,2,-
4-triazol-3-yl)(morpholino)methanone; [0607]
(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(6-morpholinopyridin-3-yl)-4H-1,2,-
4-triazol-3-yl)(piperidin-1-yl)methanone; [0608]
(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(6-morpholinopyridin-3-yl)-4H-1,2,-
4-triazol-3-yl)(pyrrolidin-1-yl)methanone; [0609]
4-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-4H-
-1,2,4-triazole-3-carboxamide; [0610]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(1-hydroxyethyl)benzyl)-4H-1,2,4-
-triazole-3-carboxamide; [0611]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(methylsulfonamido)phenyl)-4H-1,-
2,4-triazole-3-carboxamide; [0612]
4-(3-acetamido-4-methoxyphenyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-4H-1,-
2,4-triazole-3-carboxamide; [0613]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-isopropyl-4H-1,2,4-triazole-3-carbo-
xamide; [0614]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-methoxyphenyl)-4H-1,2,4-triazole-
-3-carboxamide; [0615]
4-(2,3-dihydro-1H-inden-5-yl)-5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-
-4H-1,2,4-triazole-3-carboxamide; [0616]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(hydroxymethyl)benzyl)-4H-1,2,4--
triazole-3-carboxamide; [0617]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-methylbenzyl)-4H-1,2,4-triazole--
3-carboxamide; [0618]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(((2-methoxyethyl)(methyl)amino)-
methyl)phenyl)-4H-1,2,4-triazole-3-carboxamide; [0619]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methylindolin-5-yl)-4H-1,2,4-tri-
azole-3-carboxamide; [0620]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(3-(N-(2-methoxyethyl)-N-methylsulf-
amoyl)phenyl)-4H-1,2,4-triazole-3-carboxamide; [0621]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(6-morpholinopyridin-3-yl)--
4H-1,2,4-triazole-3-carboxamide; [0622]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(3-(N-(2-(dimethylamino)ethyl)-N-me-
thylsulfamoyl)-4-methylphenyl)-4H-1,2,4-triazole-3-carboxamide;
[0623]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-methoxy-3-(N-methylpropionamido)-
phenyl)-4H-1,2,4-triazole-3-carboxamide; [0624]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(3,3-dimethylureido)phenyl)-4H-1-
,2,4-triazole-3-carboxamide; [0625]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(indolin-5-yl)-4H-1,2,4-triazole-3--
carboxamide; [0626]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-methylpiperidin-1-yl)-methyl-
)phenyl)-4H-1,2,4-triazole-3-carboxamide; [0627]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(6-morpholinopyridin-3-yl)-N-neopen-
tyl-4H-1,2,4-triazole-3-carboxamide; [0628]
N-sec-butyl-5-(2,4-dihydroxy-5-isopropylphenyl)-4-(6-morpholinopyridin-3--
yl)-4H-1,2,4-triazole-3-carboxamide; [0629]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((2-methoxyethyl)(methyl)amino)p-
henyl)-4H-1,2,4-triazole-3-carboxamide; [0630]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-(methylsulfonyl)indolin-5-yl)-4H-
-1,2,4-triazole-3-carboxamide; [0631]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1H-indol-5-yl)-4H-1,2,4-triazole-3-
-carboxamide; [0632]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((2-(dimethylamino)ethyl)(methyl-
)amino)phenyl)-4H-1,2,4-triazole-3-carboxamide; [0633]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(6-((2-methoxyethyl)(methyl)amino)p-
yridin-3-yl)-4H-1,2,4-triazole-3-carboxamide; [0634]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(6-(dimethylamino)pyridin-3-yl)-4H--
1,2,4-triazole-3-carboxamide; [0635]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((ethyl(methyl)amino)methyl)phen-
yl)-4H-1,2,4-triazole-3-carboxamide; [0636]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-morpholinoethyl)-4-(6-morpholino-
pyridin-3-yl)-4H-1,2,4-triazole-3-carboxamide; [0637]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(4-methylpiperazin-1-yl)-phenyl)-
-4H-1,2,4-triazole-3-carboxamide; [0638]
4-(benzo[d][1,3]dioxol-5-yl)-5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-(di-
methylamino)ethyl)-4H-1,2,4-triazole-3-carboxamide; [0639]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-isopropyl-4-(4-(morpholinomethyl)ph-
enyl)-4H-1,2,4-triazole-3-carboxamide; [0640]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-(dimethylamino)ethyl)-4-(4-(morp-
holinomethyl)phenyl)-4H-1,2,4-triazole-3-carboxamide; [0641]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(pyrrolidin-1-yl)phenyl)-4H-1,2,-
4-triazole-3-carboxamide; [0642]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(hydroxymethyl)benzyl)-4H-1,2,4--
triazole-3-carboxamide; [0643]
4-(benzo[d][1,3]dioxol-5-yl)-5-(2,4-dihydroxy-5-isopropylphenyl)-N-isopro-
pyl-4H-1,2,4-triazole-3-carboxamide; [0644]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-(dimethylamino)ethyl)-4-(4-((2-(-
dimethylamino)ethyl)(methyl)amino)phenyl)-4H-1,2,4-triazole-3-carboxamide;
[0645]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((2-(dimethylamino)ethyl)-
(methyl)amino)phenyl)-N-isopropyl-4H-1,2,4-triazole-3-carboxamide
[0646]
4-(4-((diethylamino)methyl)phenyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-N--
(2-(dimethylamino)ethyl)-4H-1,2,4-triazole-3-carboxamide; [0647]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4((2-(dimethylamino)ethyl)(methyl)-
amino)phenyl)-N-(2-hydroxyethyl)-4H-1,2,4-triazole-3-carboxamide;
[0648]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-methoxyethyl)-4-(4-(morpholinome-
thyl)phenyl)-4H-1,2,4-triazole-3-carboxamide; [0649]
4-(benzo[d][1,3]dioxol-5-yl)-5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-met-
hoxyethyl)-4H-1,2,4-triazole-3-carboxamide; [0650]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-(dimethylamino)ethyl)-4-(4-morph-
olinophenyl)-4H-1,2,4-triazole-3-carboxamide; [0651]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-hydroxyethyl)-4-(4-(morpholinome-
thyl)phenyl)-4H-1,2,4-triazole-3-carboxamide [0652]
4-(benzo[d][1,3]dioxol-5-yl)-5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-hyd-
roxyethyl)-4H-1,2,4-triazole-3-carboxamide; [0653]
4-(benzo[d][1,3]dioxol-5-yl)-N-cyclohexyl-5-(2,4-dihydroxy-5-isopropylphe-
nyl)-4H-1,2,4-triazole-3-carboxamide; [0654]
4-(benzo[d][1,3]dioxol-5-yl)-5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-mor-
pholinoethyl)-4H-1,2,4-triazole-3-carboxamide; [0655]
4-(benzo[d][1,3]dioxol-5-yl)-5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-(py-
rrolidin-1-yl)ethyl)-4H-1,2,4-triazole-3-carboxamide; [0656]
4-(4-((diethylamino)methyl)phenyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-N--
isopropyl-4H-1,2,4-triazole-3-carboxamide; [0657]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-isobutyl-4-(4-(morpholinomethyl)phe-
nyl)-4H-1,2,4-triazole-3-carboxamide; [0658]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholinomethyl)phenyl)-N-prop-
yl-4H-1,2,4-triazole-3-carboxamide; [0659]
N-cyclohexyl-5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholinomethyl)p-
henyl)-4H-1,2,4-triazole-3-carboxamide; [0660]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-isopropyl-4-(4-morpholinophenyl)-4H-
-1,2,4-triazole-3-carboxamide; [0661]
4-(4-((diethylamino)methyl)phenyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-4H-
-1,2,4-triazole-3-carboxamide; [0662]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-morpholinoethyl)-4-(4-morpholino-
phenyl)-4H-1,2,4-triazole-3-carboxamide; [0663]
N-(2-(diethylamino)ethyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morph-
olinomethyl)phenyl)-4H-1,2,4-triazole-3-carboxamide; [0664]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl-
)-4H-1,2,4-triazole-3-carboxamide; [0665]
N-(2-(diethylamino)ethyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-4-(6-morpho-
linopyridin-3-yl)-4H-1,2,4-triazole-3-carboxamide; [0666]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(6-morpholinopyridin-3-yl)-N-(2-(pi-
peridin-1-yl)ethyl)-4H-1,2,4-triazole-3-carboxamide; [0667]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-ethoxyethyl)-4-(6-morpholinopyri-
din-3-yl)-4H-1,2,4-triazole-3-carboxamide; [0668]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)-4-
-(6-morpholinopyridin-3-yl)-4H-1,2,4-triazole-3-carboxamide; [0669]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-thiomorpholinophenyl)-4H-1,2,4-t-
riazole-3-carboxamide; [0670]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-(pyrrolidin-1-yl)ethyl)-4-(4-(py-
rrolidin-1-ylmethyl)phenyl)-4H-1,2,4-triazole-3-carboxamide; [0671]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-morpholinoethyl)-4-(4-(pyrrolidi-
n-1-ylmethyl)phenyl)-4H-1,2,4-triazole-3-carboxamide; [0672]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholinomethyl)phenyl)-N-(2-(-
pyrrolidin-1-yl)ethyl)-4H-1,2,4-triazole-3-carboxamide; [0673]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(2-morpholinoethylamino)phenyl)--
4H-1,2,4-triazole-3-carboxamide; [0674]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)-4-
-(4-(morpholinomethyl)phenyl)-4H-1,2,4-triazole-3-carboxamide;
[0675]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(6-morpholinopyridin-3-yl)-N-(2-(py-
rrolidin-1-yl)ethyl)-4H-1,2,4-triazole-3-carboxamide; [0676]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(4-methylpiperazin-1-yl)-phenyl)-
-N-(2-morpholinoethyl)-4H-1,2,4-triazole-3-carboxamide; [0677]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-morpholinoethyl)-4-(4-(morpholin-
omethyl)phenyl)-4H-1,2,4-triazole-3-carboxamide; [0678]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)-4-
-(4-(pyrrolidin-1-ylmethyl)phenyl)-4H-1,2,4-triazole-3-carboxamide;
[0679]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)-4-
-(4-morpholinophenyl)-4H-1,2,4-triazole-3-carboxamide; [0680]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholinophenyl)-N-(2-(pyrrolid-
in-1-yl)ethyl)-4H-1,2,4-triazole-3-carboxamide; [0681]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(2-(pyrrolidin-1-yl)ethylamino)p-
henyl)-4H-1,2,4-triazole-3-carboxamide; [0682]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(4-methylpiperazin-1-yl)-phenyl)-
-N-(2-(pyrrolidin-1-yl)ethyl)-4H-1,2,4-triazole-3-carboxamide;
[0683]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(2-(4-methylpiperazin-1-yl)ethyl-
amino)phenyl)-4H-1,2,4-triazole-3-carboxamide; [0684]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-(methylsulfonyl)ethyl)-4-(4-morp-
holinophenyl)-4H-1,2,4-triazole-3-carboxamide; [0685]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)-4-
-(4-(4-methylpiperazin-1-yl)phenyl)-4H-1,2,4-triazole-3-carboxamide;
[0686]
5-(2,4-dihydroxy-5-isopropylphenyl)-N-isopropyl-4-(4-((4-methylpip-
erazin-1-yl)methyl)phenyl)-4H-1,2,4-triazole-3-carboxamide; or
[0687]
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-ethylpiperazin-1-yl)methyl)p-
henyl)-N-isopropyl-4H-1,2,4-triazole-3-carboxamide; or a tautomer,
pharmaceutically acceptable salt, solvate, clathrate, or a prodrug
thereof.
[0688] Exemplary compounds of the invention are depicted in Table 1
below, including tautomers, pharmaceutically acceptable salts,
solvates, clathrates, hydrates, polymorphs or prodrugs thereof.
TABLE-US-00001 NO. Structure Name 1 ##STR00047##
4-isopropyl-6-(5-(4- methoxybenzylthio)-4-(1-methyl-
1H-indol-5-yl)-4H-1,2,4-triazol-3- yl)benzene-1,3-diol 2
##STR00048## 4-(5-(2,6-difluorobenzylthio)-4-
(1-methyl-1H-indol-5-yl)-4H- 1,2,4-triazol-3-yl)-6-
isopropylbenzene-1,3-diol 3 ##STR00049##
4-isopropyl-6-(4-(1-methyl-1H- indol-5-yl)-5-(4-
(trifluoromethyl)benzylthio)-4H-
1,2,4-triazol-3-yl)benzene-1,3-diol 4 ##STR00050##
6-((5-(2,4-dihydroxy-5- isopropylphenyl)-4-(1-methyl-1H-
indol-5-yl)-4H-1,2,4-triazol-3- ylthio)methyl)pyrimidine-
2,4(1H,3H)-dione 5 ##STR00051## 4-isopropyl-6-(4-(1-methyl-1H-
indol-5-yl)-5-((2-methylthiazol-4-
yl)methylthio)-4H-1,2,4-triazol-3- yl)benzene-1,3-diol 6
##STR00052## 2-(5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(1-methyl-1H- indol-5-yl)-4H-1,2,4-triazol-3-
ylthio)acetamide 7 ##STR00053## 4-isopropyl-6-(4-(1-methyl-1H-
indol-5-yl)-5-(pyridin-3- ylmethylthio)-4H-1,2,4-triazol-3-
yl)benzene-1,3-diol 8 ##STR00054## 4-isopropyl-6-(4-(1-methyl-1H-
indol-5-yl)-5-(pyridin-2- ylmethylthio)-4H-1,2,4-triazol-3-
yl)benzene-1,3-diol 9 ##STR00055## 4-isopropyl-6-(4-(1-methyl-1H-
indol-5-yl)-5-(pyridin-4- ylmethylthio)-4H-1,2,4-triazol-3-
yl)benzene-1,3-diol 10 ##STR00056## 3-(5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(1-methyl-1H- indol-5-yl)-4H-1,2,4-triazol-3-
ylthio)dihydrofuran-2(3H)-one 11 ##STR00057##
4-(5-((2-aminothiazol-4- yl)methylthio)-4-(1-methyl-1H-
indol-5-yl)-4H-1,2,4-triazol-3-yl)- 6-isopropylbenzene-1,3-diol 12
##STR00058## 4-isopropyl-6-(4-(1-methyl-1H- indol-5-yl)-5-((6-
(trifluoromethyl)pyridin-3- yl)methylthio)-4H-1,2,4-triazol-3-
yl)benzene-1,3-diol 13 ##STR00059## 4-isopropyl-6-(4-(4-
(methoxymethyl)benzyl)-5- (pyridin-3-ylmethylthio)-4H-
1,2,4-triazol-3-yl)benzene-1,3-diol 14 ##STR00060## 4-(4-(4-(2-
(dimethylamino)ethyl)phenyl)-5- (pyridin-3-ylmethylthio)-4H-
1,2,4-triazol-3-yl)-6- isopropylbenzene-1,3-diol 15 ##STR00061##
4-isopropyl-6-(4-(2-methoxy-2,3- dihydro-1H-inden-5-yl)-5-
(pyridin-3-ylmethylthio)-4H- 1,2,4-triazol-3-yl)benzene-1,3-diol 16
##STR00062## 4-isopropyl-6-(5-(pyridin-4-yl)-
1H-1,2,4-triazol-3-yl)benzene-1,3- diol 17 ##STR00063##
4-(5-(4-hydroxyphenyl)-1H-1,2,4- triazol-3-yl)-6-isopropylbenzene-
1,3-diol 18 ##STR00064## 4-ethyl-6-(5-(pyridin-3-
yl)methylthio)-1H-1,2,4-triazol-3- yl)benzene-1,3-diol 19
##STR00065## 4-ethyl-6-(5-((2-methylthiazol-4-
yl)methylthio)-1H-1,2,4-triazol-3- yl)benzene-1,3-diol 20
##STR00066## 4-(5-((1H-imidazol-1-yl)methyl)-
4-(1-methyl-1H-indol-5-yl)-4H- 1,2,4-triazol-3-yl)-6-
isopropylbenzene-1,3-diol 21 ##STR00067##
4-(4-(1-(2-(dimethylamino)ethyl)- 1H-indol-5-yl)-5-(pyridin-3-
ylmethylthio)-4H-1,2,4-triazol-3- yl)-6-isopropylbenzene-1,3-diol
22 ##STR00068## 4-(2,3-dihydroxy-1H-inden-5-yl)-5-
(2,4-dihydroxy-5- isopropylphenyl)-4H-1,2,4- triazole-3-carboxamide
23 ##STR00069## 4-(benzo[d][1,3]dioxol-5-yl)-5- (2,4-dihydroxy-5-
isopropylphenyl)-4H-1,2,4- triazole-3-carboxamide 24 ##STR00070##
5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-
(dimethylamino)phenyl)-4H- 1,2,4-triazole-3-carboxamide 25
##STR00071## 5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-
morpholinophenyl)-4H-1,2,4- triazole-3-carboxamide 26 ##STR00072##
5-(2,4-dihydroxy-5- isopropylphenyl)-4-(1-methyl-1H-
indol-5-yl)-4H-1,2,4-triazole-3- carboxamide 27 ##STR00073##
4-(3-acetamido-4- methoxyphenyl)-5-(2,4-
dihydroxy-5-isopropylphenyl)- 4H-1,2,4-triazole-3-carboxamide 28
##STR00074## 5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-
(methylsulfonamido)phenyl)-4H- 1,2,4-triazole-3-carboxamide 29
##STR00075## 5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-(pyrrolidin-
1-ylmethyl)phenyl)-4H-1,2,4- triazole-3-carboxamide 30 ##STR00076##
5-(2,4-dihydroxy-5- isopropylphenyl-4-(6-
morpholinopyridin-3-yl)-4H- 1,2,4-triazole-3-carboxamide 31
##STR00077## 4-(4-((tert-butyl (methyl)amino)methyl)phenyl)-
5-(2,4-dihydroxy-5- isopropylphenyl)-4H-1,2,4-
triazole-3-carboxamide 32 ##STR00078## 5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(4-(pyridin-2- ylmethyl)phenyl)-4H-1,2,4-
triazole-3-carboxamide 33 ##STR00079## 4-(4-
((diethylamino)methyl)phenyl)-5- (2,4-dihydroxy-5-
isopropylphenyl)-4H-1,2,4- triazole-3-carboxamide 34 ##STR00080##
5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-
((dimethylamino)methyl)phenyl)- 4H-1,2,4-triazole-3-carboxamide 35
##STR00081## 5-(2,4-dihydroxy-5- isopropylphenyl)-4-(3-(N,N-
dimethylsulfamoyl)-4- methylphenyl)-4H-1,2,4-triazole-
3-carboxamide 36 ##STR00082## 5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(4- (morpholinomethyl)phenyl)-4H-
1,2,4-triazole-3-carboxamide 37 ##STR00083## 5-(2,4-dihydroxy-5-
isopropylphenyl)-N-ethyl-4-(6- morpholinopyridin-3-yl)-4H-
1,2,4-triazole-3-carboxamide 38 ##STR00084##
N-cyclohexyl-5-(2,4-dihydroxy-5- isopropylphenyl)-4-(6-
morpholinopyridin-3-yl)-4H- 1,2,4-triazole-3-carboxamide 39
##STR00085## N-cyclopropyl-5-(2,4-dihydroxy-5-
5-isopropylphenyl)-4-(6- morpholinopyridin-3-yl)-4H-
1,2,4-triazole-3-carboxamide 40 ##STR00086##
N-benzyl-5-(2,4-dihydroxy-5- isopropylphenyl)-4-(6-
morpholinopyridin-3-yl)-4H- 1,2,4-triazole-3-carboxamide 41
##STR00087## 5-(2,4-dihydroxy-5- isopropylphenyl)-N-isopropyl-4-
(6-morpholinopyridin-3-yl)-4H- 1,2,4-triazole-3-carboxamide 42
##STR00088## 5-(2,4-dihydroxy-5- isopropylphenyl)-4-(6-
morpholinopyridin-3-yl)-N- propyl-4H-1,2,4-triazole-3- carboxamide
43 ##STR00089## 5-(2,4-dihydroxy-5- isopropylphenyl)-N-(2-
(dimethylamino)ethyl)-4-(6- morpholinopyridin-3-yl)-4H-
1,2,4-triazole-3-carboxamide 44 ##STR00090## 5-(2,4-dihydroxy-5-
isopropylphenyl)-N-isobutyl-4-(6- morpholinopyridin-3-yl)-4H-
1,2,4-triazole-3-carboxamide 45 ##STR00091##
N-cyclopentyl-5-(2,4-dihydroxy- 5-isopropylphenyl)-4-(6-
morpholinopyridin-3-yl)-4H- 1,2,4-triazole-3-carboxamide 46
##STR00092## (5-(2,4-dihydroxy-5- isopropylphenyl)-4-(6-
morpholinopyridin-3-yl)-4H- 1,2,4-triazol-3-
yl)(morpholino)methanone 47 ##STR00093## (5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(6- morpholinopyridin-3-yl)-4H-
1,2,4-triazol-3-yl)(piperidin-1- yl)methanone 48 ##STR00094##
(5-(2,4-dihydroxy-5- isopropylphenyl)-4-(6-
morpholinopyridin-3-yl)-4H- 1,2,4-triazol-3-yl)(pyrrolidin-1-
yl)methanone 49 ##STR00095## 4-(benzo[d][1,3]dioxol-5-
ylmethyl)-5-(2,4-dihydroxy-5- isopropylphenyl)-4H-1,2,4-
triazole-3-carboxamide 50 ##STR00096## 5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(4-(1- hydroxyethyl)benzyl)-4H-1,2,4-
triazole-3-carboxamide 51 ##STR00097## 4-isopropyl-6-(4-methyl-5-
(pyridin-3-ylmethylthio)-4H- 1,2,4-triazol-3-yl)benzene-1,3-diol 52
##STR00098## 2-(4-(benzo[d][1,3]dioxol-5-yl)-5-
(pyridin-3-ylmethylthio)-4H- 1,2,4-triazol-3-yl)-4- methoxyphenol
53 ##STR00099## 4-(5-(3-(dimethylamino)propyl)-
4-(1-methyl-1H-indol-5-yl)-4H- 1,2,4-triazol-3-yl)-6-
isopropylbenzene-1,3-diol 54 ##STR00100##
4-(4-fluorophenethyl)-6-(4-(2- methoxy-2,3-dihydro-1H-inden-5-
yl)-5-(pyridin-3-ylmethylthio)- 4H-1,2,4-triazol-3-yl)benzene-1,3-
diol 55 ##STR00101## 4-(4-fluorophenethyl)-6-(4-(2-
methoxy-2,3-dihydro-1H-inden-5- yl)-5-((2-methylthiazol-4-
yl)methylthio)-4H-1,2,4-triazol-3- yl)benzene-1,3-diol 56
##STR00102## 4-(4-(1',3'- dihydrospiro[[1,3]dioxolane-2,2'-
indene]-5'-yl)-5-(pyridin-3- ylmethylthio)-4H-1,2,4-triazol-4-
yl)-6-isopropylbenzene-1,3-diol 57 ##STR00103##
4-(5-(benzylthio)-4-(1-methyl-1H-
indol-5-yl)-4H-1,2,4-triazol-3-yl)- 6-isopropylbenzene-1,3-diol 58
##STR00104## 4-(4-(benzo[d][1,3]dioxol-5-yl)-5-
(pyridin-4-ylmethoxy)-4H-1,2,4- triazol-3-yl)-6-isopropylbenzene-
1,3-diol 59 ##STR00105## 4-(5-(4-(benzyloxy)benzylthio)-
1H-1,2,4-triazol-3-yl)-6- ethylbenzene-1,3-diol 60 ##STR00106##
4-(5-(biphenyl-2-ylmethylthio)- 1H-1,2,4-triazol-3-yl)-6-
ethylbenzene-1,3-diol 61 ##STR00107##
4-isopropyl-6-(4-(1-methyl-1H- indol-5-yl)-5-(2-(pyridin-3-
yl)ethyl)-4H-1,2,4-triazol-3- yl)benzene-1,3-diol 62 ##STR00108##
4-(4-(2,3-dihydro-1H-inden-5-yl)- 5-(1-methylpiperidin-4-yloxy)-
4H-1,2,4-triazol-3-yl)-6- isopropylbenzene-1,3-diol 63 ##STR00109##
4-(4-(2,3-dihydro-1H-inden-5-yl)- 5-(2-(2-
(dimethylamino)ethoxy)ethoxy)- 4H-1,2,4-triazol-3-yl)-6-
isopropylbenzene-1,3-diol 64 ##STR00110##
4-(4-(2,3-dihydro-1H-inden-5-yl)- 5-(2-morpholinoethoxy)-4H-1,2,4-
triazol-3-yl)-6-isopropylbenzene- 1,3-diol 65 ##STR00111##
4-(4-(2,3-dihydro-1H-inden-5-yl)- 5-((1,4-dimethylpiperazin-2-
yl)methoxy)-4H-1,2,4-triazol-3- yl)-6-isopropylbenzene-1,3-diol 66
##STR00112## 4-(4-(2,3-dihydro-1H-inden-5-yl)-
5-(2-(dimethylamino)ethoxy)-4H- 1,2,4-triazol-3-yl)-6-
isopropylbenzene-1,3-diol 67 ##STR00113##
4-(4-(2,3-dihydro-1H-inden-5-yl)- 5-(3-methoxy-3-methylbutoxy)-
4H-1,2,4-triazol-3-yl)-6- isopropylbenzene-1,3-diol 68 ##STR00114##
(S)-4-(4-(2,3-dihydro-1H-inden-5- yl)-5-((1-methylpyrrolidin-2-
yl)methoxy)-4H-1,2,4-triazol-3- yl)-6-isopropylbenzene-1,3-diol 69
##STR00115## 4-(4-(2,3-dihydro-1H-inden-5-yl)-
5-(tetrahydro-2H-pyran-4-yloxy)- 4H-1,2,4-triazol-3-yl)-6-
isopropylbenzene-1,3-diol 70 ##STR00116##
4-(4-(2,3-dihydro-1H-inden-5-yl)- 5-(2-isopropoxyethoxy)-4H-1,2,4-
triazol-3-yl)-6-isopropylbenzene- 1,3-diol 71 ##STR00117##
4-(5-(cyclohexyloxy)-4-(2,3- dihydro-1H-inden-5-yl)-4H-1,2,4-
triazol-3-yl)-6-isopropylbenzene- 1,3-diol 72 ##STR00118##
4-(5-(benzo[d][1,3]dioxol-5- yloxy)-4-(2,3-dihydro-1H-inden-
5-yl)-4H-1,2,4-triazol-3-yl)-6- isopropylbenzene-1,3-diol 73
##STR00119## 4-(4-(2,3-dihydro-1H-inden-5-yl)-
5-(4-methoxyphenoxy)-4H-1,2,4- triazol-3-yl)-6-isopropylbenzene-
1,3-diol 74 ##STR00120## 4-(4-(2,3-dihydro-1H-inden-5-yl)-
5-(3-(dimethylamino)phenoxy)- 4H-1,2,4-triazol-3-yl)-6-
isopropylbenzene-1,3-diol 75 ##STR00121##
4-(5-(cyclopentylmethoxy)-4-(2,3- dihydro-1H-inden-5-yl)-4H-1,2,4-
triazol-3-yl)-6-isopropylbenzene- 1,3-diol 76 ##STR00122##
1-(2-(4-(2,3-dihydro-1H-inden-5- yl)-5-(2,4-dihydroxy-5-
isopropylphenyl)-4H-1,2,4-triazol- 3-yloxy)ethyl)imidazolidin-2-one
77 ##STR00123## 4-(4-(2,3-dihydro-1H-inden-5-yl)-
5-(pyridin-3-yloxy)-4H-1,2,4- triazol-3-yl)-6-isopropylbenzene-
1,3-diol 78 ##STR00124## 4-(4-(2,3-dihydro-1H-inden-5-yl)-
5-(2-(pyrrolidin-1-yl)ethoxy)-4H- 1,2,4-triazol-3-yl)-6-
isopropylbenzene-1,3-diol 79 ##STR00125##
4-(4-(2,3-dihydro-1H-inden-5-yl)- 5-(1-ethylpiperidin-3-yloxy)-4H-
1,2,4-triazol-3-yl)-6- isopropylbenzene-1,3-diol 80 ##STR00126##
4-(4-(2,3-dihydro-1H-inden-5-yl)- 5-(2-(piperidin-1-yl)ethoxy)-4H-
1,2,4-triazol-3-yl)-6- isopropylbenzene-1,3-diol 81 ##STR00127##
4-(4-(benzo[d][1,3]dioxol-5-yl)-5- (pyridin-3-ylmethoxy)-4H-1,2,4-
triazol-3-yl)-6-isopropylbenzene- 1,3-diol 82 ##STR00128##
4-(5-(cyclopentyloxy)-4-(2,3- dihydro-1H-inden-5-yl)-4H-1,2,4-
triazol-3-yl)-6-isopropylbenzene- 1,3-diol 83 ##STR00129##
5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-
(methylsulfonamido)phenyl)-4H- 1,2,4-triazole-3-carboxamide 84
##STR00130## 4-(3-acetamido-4- methoxyphenyl)-5-(2,4-
dihydroxy-5-isopropylphenyl)- 4H-1,2,4-triazole-3-carboxamide 85
##STR00131## 4-(4-(2,3-dihydro-1H-inden-5-yl)-
5-(pyridin-3-ylmethylthio)-4H- 1,2,4-triazol-3-yl)-6-
isopropylbenzene-1,3-diol 86 ##STR00132##
4-(4-(2,3-dihydro-1H-inden-5-yl)- 5-(pyridin-4-ylmethylthio)-4H-
1,2,4-triazol-3-yl)-6- isopropylbenzene-1,3-diol 87 ##STR00133##
4-isopropyl-6-(4-phenyl-5- (pyridin-3-ylmethylthio)-4H-
1,2,4-triazol-3-yl)benzene-1,3-diol 88 ##STR00134##
4-(4-(4-(diethylamino)phenyl)-5- (pyridin-3-ylmethylthio)-4H-
1,2,4-triazol-3-yl)-6- isopropylbenzene-1,3-diol 89 ##STR00135##
4-isopropyl-6-(4-phenyl-5- (pyridin-2-ylmethylthio)-4H-
1,2,4-triazol-3-yl)benzene-1,3-diol 90 ##STR00136##
4-(4-(4-(diethylamino)phenyl)-5- (pyridin-2-ylmethylthio)-4H-
1,2,4-triazol-3-yl)-6- isopropylbenzene-1,3-diol 91 ##STR00137##
4-(4-(4-(diethylamino)phenyl)-5- (pyridin-4-ylmethylthio)-4H-
1,2,4-triazol-3-yl)-6- isopropylbenzene-1,3-diol 92 ##STR00138##
4-isopropyl-6-(4-phenyl-5- (pyridin-4-ylmethylthio)-4H-
1,2,4-triazol-3-yl)benzene-1,3-diol 93 ##STR00139##
4-(4-(4-chlorophenyl)-5-(pyridin- 2-ylmethylthio)-4H-1,2,4-triazol-
3-yl)-6-isopropylbenzene-1,3-diol 94 ##STR00140##
4-(4-(4-chlorophenyl)-5-(pyridin- 3-ylmethylthio)-4H-1,2,4-triazol-
3-yl)-6-isopropylbenzene-1,3-diol 95 ##STR00141##
4-(4-(4-chlorophenyl)-5-(pyridin- 4-ylmethylthio)-4H-1,2,4-triazol-
3-yl)-6-isopropylbenzene-1,3-diol 96 ##STR00142## ethyl
4-(2,3-dihydro-1H-inden-5- yl)-5-(2,4-dihydroxy-5-
isopropylphenyl)-4H-1,2,4- triazole-3-carboxylate 97 ##STR00143##
4-(2,3-dihydro-1H-inden-5-yl)-5- (2,4-dihydroxy-5-
isopropylphenyl)-4H-1,2,4- triazole-3-carboxylic acid 98
##STR00144## 5-(2,4-dihydroxy-5- isopropylphenyl)-4-isopropyl-4H-
1,2,4-triazole-3-carboxamide 99 ##STR00145## 5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(4- methoxyphenyl)-4H-1,2,4-
triazole-3-carboxamide 100 ##STR00146##
4-(2,3-dihydro-1H-inden-5-yl)-5- (2,4-dihydroxy-5-
isopropylphenyl)-N-ethyl-4H- 1,2,4-triazole-3-carboxamide 101
##STR00147## 4-(4-(benzo[d][1,3]dioxol-5-yl)-5-
(pyidin-3-ylmethylthio)-4H- 1,2,4-triazol-3-yl)-6-
isopropylbenzene-1,3-diol 102 ##STR00148## 4-isopropyl-6-(4-(6-(4-
methylpiperazin-1-yl)pyridin-3- yl)-5-(pyridin-3-ylmethylthio)-
4H-1,2,4-triazol-3-yl)benzene-1,3- diol 103 ##STR00149##
4-isopropyl-6-(4-(4-(pyridin-3- ylmethyl)phenyl)-5-(pyridin-3-
ylmethylthio)-4H-1,2,4-triazol-3- yl)benzene-1,3-diol 104
##STR00150## 4-isopropyl-6-(4-(6-((2- methoxyethyl)(methyl)amino)
pyridin-3-yl)-5-(pyridin-3- ylmethylthio)-4H-1,2,4-triazol-3-
yl)benzene-1,3-diol 105 ##STR00151## 4-(4-(3,4-dimethoxyphenyl)-5-
(pyridin-3-ylmethylthio)-4H- 1,2,4-triazol-3-yl)-6-
isopropylbenzene-1,3-diol 106 ##STR00152##
4-(4-benzo[d][1,3]dioxol-5-yl)-5-
(thiazol-4-ylmethylthio)-4H-1,2,4-
triazol-3-yl)-6-isopropylbenzene- 1,3-diol 107 ##STR00153##
4-isopropyl-6-(4-(6-(4- methylpiperazin-1-yl)pyridin-3-
yl)-5-(thiazol-4-ylmethylthio)-4H-
1,2,4-triazol-3-yl)benzene-1,3-diol 108 ##STR00154##
4-isopropyl-6-(4-(4-(pyridin-3- ylmethyl)phenyl)-5-(thiazol-4-
ylmethylthio)-4H-1,2,4-triazol-3- yl)benzene-1,3-diol 109
##STR00155## 4-isopropyl-6-(4-(6-((2- methoxyethyl)(methyl)amino)
pyridin-3-yl)-5-(thiazol-4- ylmethylthio)-4H-1,2,4-triazol-3-
yl)benzene-1,3-diol 110 ##STR00156## 4-(4-(3,4-dimethoxyphenyl)-5-
(thiazol-4-ylmethylthio)-4H-1,2,4-
triazol-3-yl)-6-isopropylbenzene- 1,3-diol 111 ##STR00157##
4-isopropyl-6-(4-(1-methyl-1H- indol-5-yl)-5-(thiazol-4-
ylmethylthio)-4H-1,2,4-triazol-3- yl)benzene-1,3-diol 112
##STR00158## 4-(4-(2,3-dihydro-1H-inden-5-yl)-
5-(thiazol-4-ylmethylthio)-4H- 1,2,4-triazol-3-yl)-6-
isopropylbenzene-1,3-diol 113 ##STR00159##
4-isopropyl-6-(4-(1-methyl-1H- indol-5-yl)-5-(3-(pyridin-3-
yl)propylthio)-4H-1,2,4-triazol-3- yl)benzene-1,3-diol 114
##STR00160## 4-isopropyl-6-(4-(1-methyl-1H-
indol-5-yl)-5-(2-(pyridin-3- yl)ethylthio)-4H-1,2,4-triazol-3-
yl)benzene-1,3-diol 115 ##STR00161##
4-(4-(benzo[d][1,3]dioxol-5-yl)-5- (2-(pyridin-3-yl)ethylthio)-4H-
1,2,4-triazol-3-yl)-6- isopropylbenzene-1,3-diol 116 ##STR00162##
5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-
(hydroxymethyl)benzyl)-4H- 1,2,4-triazole-3-carboxamide 117
##STR00163## 5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-
methylbenzyl)-4H-1,2,4-triazole- 3-carboxamide 118 ##STR00164##
5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-(((2-
methoxyethyl)(methyl)amino) methyl)phenyl)-4H-1,2,4-triazole-3-
carboxamide 119 ##STR00165## 5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(1- methylindolin-5-yl)-4H-1,2,4-
triazole-3-carboxamide 120 ##STR00166## 5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(3-(N-(2- methoxyethyl)-N-
methylsulfamoyl)phenyl)-4H- 1,2,4-triazole-3-carboxamide 121
##STR00167## 2-(5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(1-methyl-1H- indol-5-yl)-4H-1,2,4-triazol-3-
ylthio)acetic acid 122 ##STR00168## methyl 3-(5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(1-methyl-1H- indol-5-yl)-4H-1,2,4-triazol-3-
ylthio)propanoate 123 ##STR00169## 2-(5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(1-methyl-1H- indol-5-yl)-4H-1,2,4-triazol-3-
ylthio)-N-methylacetamide 124 ##STR00170## 5-(2,4-dihydroxy-5-
isopropylphenyl)-N-methyl-4-(6- morpholinopyridin-3-yl)-4H-
1,2,4-triazole-3-carboxamide 125 ##STR00171##
3-(5-(2,4-dihydroxy-5- isopropylphenyl)-4-(1-methyl-1H-
indol-5-yl)-4H-1,2,4-triazol-3- ylthio)-N-methylpropanamide 126
##STR00172## 4-isopropyl-6-(4-(1-methyl-1H-
indol-5-yl)-5-(pyridin-2-ylthio)-
4H-1,2,4-triazol-3-yl)benzene-1,3- diol 127 ##STR00173##
5-(2,4-dihydroxy-5- isopropylphenyl)-4-(3-(N-(2-
(dimethylamino)ethyl)-N- methylsulfamoyl)-4-
methylphenyl)-4H-1,2,4-triazole- 3-carboxamide 128 ##STR00174##
5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-methoxy-3-
(N-methylpropionamido)phenyl)- 4H-1,2,4-triazole-3-carboxamide 129
##STR00175## 5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-(3,3-
dimethylureido)phenyl)-4H-1,2,4- triazole-3-carboxamide 130
##STR00176## 5-(2,4-dihydroxy-5- isopropylphenyl)-4-(indolin-5-yl)-
4H-1,2,4-triazole-3-carboxamide 131 ##STR00177##
5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-((4- methylpiperidin-1-
yl)methyl)phenyl)-4H-1,2,4- triazole-3-carboxamide 132 ##STR00178##
5-(2,4-dihydroxy-5- isopropylphenyl)-4-(6-
morpholinopyridin-3-yl)-N- neopentyl-4H-1,2,4-triazole-3-
carboxamide 133 ##STR00179## N-sec-butyl-5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(6- morpholinopyridin-3-yl)-4H-
1,2,4-triazole-3-carboxamide 134 ##STR00180##
4-isopropyl-6-(4-(1-methyl-1H- indol-5-yl)-5-(pyridin-3-ylthio)-
4H-1,2,4-triazol-3-yl)benzene-1,3- diol 135 ##STR00181##
5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-((2-
methoxyethyl)(methyl)amino) phenyl)-4H-1,2,4-triazole-3-
carboxamide 136 ##STR00182## 5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(1- (methylsulfonyl)indolin-5-yl)-4H-
1,2,4-triazole-3-carboxamide 137 ##STR00183## 5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(1H-indol-5- yl)-4H-1,2,4-triazole-3-
carboxamide 138 ##STR00184## 5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(4-((2- (dimethylamino)ethyl)(methyl)
amino)phenyl)-4H-1,2,4-triazole-3- carboxamide 139 ##STR00185##
5-(2,4-dihydroxy-5- isopropylphenyl)-4-(6-((2-
methoxyethyl)(methyl)amino) pyridin-3-yl)-4H-1,2,4-triazole-3-
carboxamide 140 ##STR00186## 5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(6- (dimethylamino)pyridin-3-yl)-4H-
1,2,4-triazole-3-carboxamide 141 ##STR00187## 5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(4- ((ethyl(methyl)amino)methyl)
phenyl)-4H-1,2,4-triazole-3- carboxamide 142 ##STR00188##
2-((5-(2,4-dihydroxy-5- isopropylphenyl)-4-(1-methyl-1H-
indol-5-yl)-4H-1,2,4-triazol-3- ylthio)methyl)benzenaminium
chloride 143 ##STR00189## 4-(5-(2-aminobenzylthio)-4-(1-
methyl-1H-indol-5-yl)-4H-1,2,4- triazol-3-yl)-6-isopropylbenzene-
1,3-diol 144 ##STR00190## 5-(2,4-dihydroxy-5-
isopropylphenyl)-N-(2- morpholinoethyl)-4-(6-
morpholinopyridin-3-yl)-4H- 1,2,4-triazole-3-carboxamide
145 ##STR00191## tert-butyl 2-((5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(1-methyl-1H- indol-5-yl)-4H-1,2,4-triazol-3-
ylthio)methyl)phenylcarbamate 146 ##STR00192##
2-((5-(2,4-dihydroxy-5- isopropylphenyl)-4-(1-methyl-1H-
indol-5-yl)-4H-1,2,4-triazol-3- ylthio)methyl)benzenaminium
2,2,2-trifluoroacetate 147 ##STR00193## tert-butyl
3-((5-(2,4-dihydroxy-5- isopropylphenyl)-4-(1-methyl-1H-
indol-5-yl)-4H-1,2,4-triazol-3- ylthio)methyl)phenylcarbamate 148
##STR00194## 4-(5-(3-aminobenzylthio)-4-(1H-
indol-5-yl)-4H-1,2,4-triazol-3-yl)- 6-isopropylbenzene-1,3-diol 149
##STR00195## 4-isopropyl-6-(4-(1-methyl-1H-
indol-5-yl)-5-(phenylthio)-4H- 1,2,4-triazol-3-yl)benzene-1,3-diol
150 ##STR00196## N-(2-((5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(1-methyl-1H- indol-5-yl)-4H-1,2,4-triazol-3-
ylthio)methyl)phenyl)acetamide 151 ##STR00197##
N-(3-((5-(2,4-dihydroxy-5- isopropylphenyl)-4-(1-methyl-1H-
indol-5-yl)-4H-1,2,4-triazol-3- ylthio)methyl)phenyl)acetamide 152
##STR00198## 5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-(4-
methylpiperazin-1-yl)phenyl)-4H- 1,2,4-triazole-3-carboxamide 153
##STR00199## 4-(benzo[d][1,3]dioxol-5-yl)-5- (2,4-dihydroxy-5-
isopropylphenyl)-N-(2- (dimethylamino)ethyl)-4H-1,2,4-
triazole-3-carboxamide 154 ##STR00200## 4-isopropyl-6-(4-(4-
morpholinophenyl)-5-(pyridin-2- ylthio)-4H-1,2,4-triazol-3-
yl)benzene-1,3-diol 155 ##STR00201## 4-isopropyl-6-(4-phenyl-5-
(pyridin-2-ylthio)-4H-1,2,4- triazol-3-yl)benzene-1,3-diol 156
##STR00202## 5-(2,4-dihydroxy-5- isopropylphenyl)-N-isopropyl-4-
(4-(morpholinomethyl)phenyl)- 4H-1,2,4-triazole-3-carboxamide 157
##STR00203## 5-(2,4-dihydroxy-5- isopropylphenyl)-N-(2-
(dimethylamino)ethyl)-4-(4- (morpholinomethyl)phenyl)-4H-
1,2,4-triazole-3-carboxamide 158 ##STR00204##
4-(5-(2-aminoethylthio)-4-(1- methyl-1H-indol-5-yl)-4H-1,2,4-
triazol-3-yl)-6-isopropylbenzene- 1,3-diol 2,2,2-trifluoroacetate
159 ##STR00205## 4-(5-(2-(ethylamino)benzylthio)-
4-(1-methyl-1H-indol-5-yl)-4H- 1,2,4-triazol-3-yl)-6-
isopropylbenzene-1,3-diol 2,2,2- trifluoroacetate 160 ##STR00206##
ethyl 4-(benzo[d][1,3]dioxol-5- yl)-5-(2,4-dihydroxy-5-
isopropylphenyl)-4H-1,2,4- triazole-3-carboxylate 161 ##STR00207##
5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-(pyrrolidin-
1-yl)phenyl)-4H-1,2,4-triazole-3- carboxamide 162 ##STR00208##
5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-
(hydroxymethyl)benzyl)-4H- 1,2,4-triazole-3-carboxamide 163
##STR00209## 4-(benzo[d][1,3]dioxol-5-yl)-5- (2,4-dihydroxy-5-
isopropylphenyl)-N-isopropyl-4H- 1,2,4-triazole-3-carboxamide 164
##STR00210## 5-(2,4-dihydroxy-5- isopropylphenyl)-N-(2-
(dimethylamino)ethyl)-4-(4-((2- (dimethylamino)ethyl)(methyl)
amino)phenyl)-4H-1,2,4-triazole-3- carboxamide 165 ##STR00211##
N-(2-(5-(2,4-dihydroxy-5- isopropylphenyl)-4-(1-methyl-1H-
indol-5-yl)-4H-1,2,4-triazol-3- ylthio)ethyl)acetamide 166
##STR00212## 4-(4-(4- ((dimethylamino)methyl)phenyl)-
5-(pyridin-2-ylthio)-4H-1,2,4- triazol-3-yl)-6-isopropylbenzene-
1,3-diol 167 ##STR00213## 4-(4-(4-((tert-
butyl(methyl)amino)methyl) phenyl)-5-(pyridin-2-ylthio)-4H-
1,2,4-triazol-3-yl)-6-isopropyl- benzene-1,3-diol 168 ##STR00214##
5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-((2-
(dimethylamino)ethyl)(methyl) amino)phenyl)-N-isopropyl-4H-
1,2,4-triazole-3-carboxamide 169 ##STR00215## 4-(4-
((diethylamino)methyl)phenyl)-5- (2,4-dihydroxy-5-
isopropylphenyl)-N-(2- (dimethylamino)ethyl)-4H-1,2,4-
triazole-3-carboxamide 170 ##STR00216## 5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(4-((2- (dimethylamino)ethyl)(methyl)
amino)phenyl)-N-(2-hydroxyethyl)- 4H-1,2,4-triazole-3-carboxamide
171 ##STR00217## 5-(2,4-dihydroxy-5- isopropylphenyl)-N-(2-
methoxyethyl)-4-(4- (morpholinomethyl)phenyl)-4H-
1,2,4-triazole-3-carboxamide 172 ##STR00218##
4-(benzo[d][1,3]dioxol-5-yl)-5- (2,4-dihydroxy-5-
isopropylphenyl)-N-(2- methoxyethyl)-4H-1,2,4-triazole-
3-carboxamide 173 ##STR00219## 5-(2,4-dihydroxy-5-
isopropylphenyl)-N-(2- (dimethylamino)ethyl)-4-(4-
morpholinophenyl)-4H-1,2,4- triazole-3-carboxamide 174 ##STR00220##
5-(2,4-dihydroxy-5- isopropylphenyl)-N-(2- hydroxyethyl)-4-(4-
(morpholinomethyl)phenyl)-4H- 1,2,4-triazole-3-carboxamide 175
##STR00221## 4-(benzo[d][1,3]dioxol-5-yl)-5- (2,4-dihydroxy-5-
isopropylphenyl)-N-(2- hydroxyethyl)-4H-1,2,4-triazole-
3-carboxamide 176 ##STR00222## 4-(benzo[d][1,3]dioxol-5-yl)-N-
cyclohexyl-5-(2,4-dihydroxy-5- isopropylphenyl)-4H-1,2,4-
triazole-3-carboxamide 177 ##STR00223##
4-(4-(4-(dimethylamino)phenyl)- 5-(pyridin-2-ylthio)-4H-1,2,4-
triazol-3-yl)-6-isopropylbenzene- 1,3-diol 178 ##STR00224##
4-(benzo[d][1,3]dioxol-5-yl)-5- (2,4-dihydroxy-5-
isopropylphenyl)-N-(2- morpholinoethyl)-4H-1,2,4-
triazole-3-carboxamide 179 ##STR00225##
4-(benzo[d][1,3]dioxol-5-yl)-5- (2,4-dihydroxy-5-
isopropylphenyl)-N-(2- (pyrrolidin-1-yl)ethyl)-4H-1,2,4-
triazole-3-carboxamide 180 ##STR00226## 4-(4-
((diethylamino)methyl)phenyl)-5- (2,4-dihydroxy-5-
isopropylphenyl)-N-isopropyl-4H- 1,2,4-triazole-3-carboxamide 181
##STR00227## 5-(2,4-dihydroxy-5- isopropylphenyl)-N-isobutyl-4-(4-
(morpholinomethyl)phenyl)-4H- 1,2,4-triazole-3-carboxamide 182
##STR00228## 5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-
(morpholinomethyl)phenyl)-N- propyl-4H-1,2,4-triazole-3-
carboxamide 183 ##STR00229## N-cyclohexyl-5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(4- (morpholinomethyl)phenyl)-4H-
1,2,4-triazole-3-carboxamide 184 ##STR00230## 5-(2,4-dihydroxy-5-
isopropylphenyl)-N-isopropyl-4- (4-morpholinophenyl)-4H-1,2,4-
triazole-3-carboxamide 185 ##STR00231## 4-(4-
((diethylamino)methyl)phenyl)-5- isopropylphenyl)-4H-1,2,4-
triazole-3-carboxamide 186 ##STR00232## 5-(2,4-dihydroxy-5-
isopropylphenyl)-N-(2- morpholinoethyl)-4-(4-
morpholinophenyl)-4H-1,2,4- triazole-3-carboxamide 187 ##STR00233##
4-isopropyl-6-(4-(6-(4- methylpiperazin-1-yl)pyridin-3-
yl)-5-(pyridin-2-ylthio)-4H-1,2,4- triazol-3-yl)benzene-1,3-diol
188 ##STR00234## N-(2-(diethylamino)ethyl)-5-(2,4-
dihydroxy-5-isopropylphenyl)-4- (4-(morpholinomethyl)phenyl)-
4H-1,2,4-triazole-3-carboxamide 189 ##STR00235##
5-(2,4-dihydroxy-5- isopropylphenyl)-N-ethyl-4-(4-
(morpholinomethyl)phenyl)-4H- 1,2,4-triazole-3-carboxamide 190
##STR00236## 4-(4-(4-((2- (dimethylamino)ethyl)(methyl)
amino)-3-fluorophenyl)-5-(pyridin-
2-ylthio)-4H-1,2,4-triazol-3-yl)-6- isopropylbenzene-1,3-diol 191
##STR00237## (R)-4-isopropyl-5-(4-(6- morpholinopyridin-3-yl)-5-
(pyrrolidin-2-yl)-4H-1,2,4-triazol- 3-yl)benzene-1,3-diol 192
##STR00238## N-(2-(diethylamino)ethyl)-5-(2,4-
dihydroxy-5-isopropylphenyl)-4- (6-morpholinopyridin-3-yl)-4H-
1,2,4-triazole-3-carboxamide 193 ##STR00239## 5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(6- morpholinopyridin-3-yl)-N-(2-
(piperidin-1-yl)ethyl)-4H-1,2,4- triazole-3-carboxamide 194
##STR00240## 5-(2,4-dihydroxy-5- isopropylphenyl)-N-(2-
ethoxyethyl)-4-(6- morpholinopyridin-3-yl)-4H-
1,2,4-triazole-3-carboxamide 195 ##STR00241## 5-(2,4-dihydroxy-5-
isopropylphenyl)-N-(2-(4- methylpiperazin-1-yl)ethyl)-4-(6-
morpholinopyridin-3-yl)-4H- 1,2,4-triazole-3-carboxamide 196
##STR00242## 5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-
thiomorpholinophenyl)-4H-1,2,4- triazole-3-carboxamide 197
##STR00243## 5-(2,4-dihydroxy-5- isopropylphenyl)-N-(2-
(pyrrolidin-1-yl)ethyl)-4-(4- (pyrrolidin-1-ylmethyl)phenyl)-
4H-1,2,4-triazole-3-carboxamide 198 ##STR00244##
5-(2,4-dihydroxy-5- isopropylphenyl)-N-(2- morpholinoethyl)-4-(4-
(pyrrolidin-1-ylmethyl)phenyl)- 4H-1,2,4-triazole-3-carboxamide 199
##STR00245## 5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-
(morpholinomethyl)phenyl)-N-(2- (pyrrolidin-1-yl)ethyl)-4H-1,2,4-
triazole-3-carboxamide 200 ##STR00246## 201 ##STR00247##
5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-(2-
morpholinoethylamino)phenyl)- 4H-1,2,4-triazole-3-carboxamide 202
##STR00248## 5-(2,4-dihydroxy-5- isopropylphenyl)-N-(2-(4-
methylpiperazin-1-yl)ethyl)-4-(4- (morpholinomethyl)phenyl)-4H-
1,2,4-triazole-3-carboxamide 203 ##STR00249## 5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(6- morpholinopyridin-3-yl)-N-(2-
(pyrrolidin-1-yl)ethyl)-4H-1,2,4- triazole-3-carboxamide 204
##STR00250## 5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-(4-
methylpiperazin-1-yl)phenyl)-N- (2-morpholinoethyl)-4H-1,2,4-
triazole-3-carboxamide 205 ##STR00251## 5-(2,4-dihydroxy-5-
isopropylphenyl)-N-(2- morpholinoethyl)-4-(4-
(morpholinomethyl)phenyl)-4H- 1,2,4-triazole-3-carboxamide 206
##STR00252## 5-(2,4-dihydroxy-5- isopropylphenyl)-N-(2-(4-
methylpiperazin-1-yl)ethyl)-4-(4- (pyrrolidin-1-ylmethyl)phenyl)-
4H-1,2,4-triazole-3-carboxamide 207 ##STR00253##
5-(2,4-dihydroxy-5- isopropylphenyl)-N-(2-(4-
methylpiperazin-1-yl)ethyl)-4-(4- morpholinophenyl)-4H-1,2,4-
triazole-3-carboxamide 208 ##STR00254## 5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(4- morpholinophenyl)-N-(2-
(pyrrolidin-1-yl)ethyl)-4H-1,2,4- triazole-3-carboxamide 209
##STR00255## 210 ##STR00256## 4-(4-(4-((2-
(dimethylamino)ethyl)(methyl) amino)-3-fluorophenyl)-5-
(phenylthio)-4H-1,2,4-triazol-3- yl)-6-isopropylbenzene-1,3-diol
211 ##STR00257## 5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-(2-
(pyrrolidin-1- yl)ethylamino)phenyl)-4H-1,2,4-
triazole-3-carboxamide 212 ##STR00258## 5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(4-(4- methylpiperazin-1-yl)phenyl)-N-
(2-(pyrrolidin-1-yl)ethyl)-4H- 1,2,4-triazole-3-carboxamide 213
##STR00259## 5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-(2-(4-
methylpiperazin-1- yl)ethylamino)phenyl)-4H-1,2,4-
triazole-3-carboxamide 214 ##STR00260## 5-(2,4-dihydroxy-5-
isopropylphenyl)-N-(2- (methylsulfonyl)ethyl)-4-(4-
morpholinophenyl)-4H-1,2,4-
triazole-3-carboxamide 215 ##STR00261## 5-(2,4-dihydroxy-5-
isopropylphenyl)-N-(2-(4- methylpiperazin-1-yl)ethyl)-4-(4-
(4-methylpiperazin-1-yl)phenyl)- 4H-1,2,4-triazole-3-carboxamide
216 ##STR00262## 5-(2,4-dihydroxy-5-
isopropylphenyl)-N-isopropyl-4- (4-((4-methylpiperazin-1-
yl)methyl)phenyl)-4H-1,2,4- triazole-3-carboxamide 217 ##STR00263##
5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-((4- ethylpiperazin-1-
yl)methyl)phenyl)-N-isopropyl- 4H-1,2,4-triazole-3-carboxamide 218
##STR00264## 4-(4-(4-(dimethylamino)phenyl)-
5-(pyridin-3-ylmethylthio)-4H- 1,2,4-triazol-3-yl)-6-
isopropylbenzene-1,3-diol 219 ##STR00265## 4-(4-(4-
((dimethylamino)methyl)phenyl)- 5-(pyridin-3-ylmethylthio)-4H-
1,2,4-triazol-3-yl)-6- isopropylbenzene-1,3-diol 220 ##STR00266##
4-(4-(4-((2- (dimethylamino)ethyl)(methyl)
amino)-3-fluorophenyl)-5-(pyridin-
3-ylmethylthio)-4H-1,2,4-triazol-3- yl)-6-isopropylbenzene-1,3-diol
221 ##STR00267## 4-isopropyl-6-(4-(4-
morpholinophenyl)-5-(pyridin-3- ylmethylthio)-4H-1,2,4-triazol-3-
yl)benzene-1,3-diol 222 ##STR00268## 2-(5-(2,4-dihydroxy-5-
isopropylphenyl)-4-(1-methyl-1H- indol-5-yl)-4H-1,2,4-triazol-3-
yl)acetic acid 223 ##STR00269## 4-(4-(4-(2-
(dimethylamino)ethyl)phenyl)-5- (pyridin-3-ylmethylthio)-4H-
1,2,4-triazol-3-yl)-6- isopropylbenzene-1,3-diol 224 ##STR00270##
4-(4-(benzo[d][1,3]dioxol-5-yl)-5- (pyridin-3-ylmethoxy)-4H-1,2,4-
triazol-3-yl)-6-isopropylbenzene- 1,3-diol
[0689] In certain instances tautomeric forms of the disclosed
compound exist, such as the tautomeric structures shown below:
##STR00271## [0690] X.sub.15.dbd.O, S or NR.sub.7
[0691] It is to be understood that when a compound is represented
by a structural formula herein, all other tautomeric forms which
may exist for the compound are encompassed the structural formula.
Compounds represented by formulas disclosed herein that can form
analogous tautomeric structures to the one shown above are also
preferred.
[0692] Similarly, prodrugs, i.e. compounds which can be metabolized
or hydrolyzed in vivo to a compound of the present invention are
encompassed by the present description. For example, the following
embodiments of a compound of the present invention can be produced
in vivo in the following reaction:
##STR00272## ##STR00273##
[0693] One skilled in the art will understand that other
hydrolyzable protecting groups can be employed with the compounds
of the present invention to obtain prodrugs encompassed by the
present description.
[0694] Without wishing to be bound by any theory, it is believed
that the compounds of the invention preferentially bind to Hsp90 in
the tautomeric form shown above, and thereby inhibit the activity
of Hsp90.
C. METHODS FOR MAKING COMPOUNDS OF THE INVENTION
[0695] Compounds of the invention can be obtained via standard,
well-known synthetic methodology, see e.g., March, J. Advanced
Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed.,
1992. In particular, compounds of the invention can be obtained by
heating a benzoic acid (1) with an aminophenyl (2) to give a phenyl
benzamide (3) which can then be reacted with hydrazine to give a
triazole (4) (see Scheme I below). Starting materials useful for
preparing compounds of the invention and intermediates therefore,
are commercially available or can be prepared from commercially
available materials using known synthetic methods and reagents.
[0696] Additional methods of preparing the compounds of the
invention can be found in U.S. patent application Ser. No.
11/807,333, filed on May 25, 2007, U.S. patent application Ser. No.
11/807,201, filed on May 25, 2007, U.S. patent application Ser. No.
11/807,327, filed on May 25, 2007, and U.S. patent application Ser.
No. 11/807,331, filed on May 25, 2007; the entire teachings of each
of these applications are incorporated herein by reference.
[0697] Reactive functional groups can be protected during one or
more reaction step, then deprotected to restore the original
functionality. Examples of suitable protecting groups for hydroxyl
groups include benzyl, methoxymethyl, allyl, trimethylsilyl,
tert-butyldimethylsilyl, acetate, and the like. Examples of
suitable amine protecting groups include benzyloxycarbonyl,
tert-butoxycarbonyl, tert-butyl, benzyl and
fluorenylmethyloxy-carbonyl (Fmoc). Examples of suitable thiol
protecting groups include benzyl, tert-butyl, acetyl, methoxymethyl
and the like. Other suitable protecting groups are well known to
those of ordinary skill in the art and include those found in T. W.
Greene, Protecting Groups in Organic Synthesis, John Wiley &
Sons, Inc. 1981.
##STR00274##
[0698] In addition, compounds of the invention can also be prepared
as shown below in the Schemes below and Examples.
[0699] In one embodiment, the compounds can be prepared as shown in
Scheme II. A dihydroxy benzoic acid methyl ester is reacted with
benzyl chloride, to produce a Bis-benzyloxy benzoic acid methyl
ester (1). The Bis-benzyloxy benzoic acid methyl ester can then be
heated with LiOH to give a Bis-benzyloxy benzoic acid (2). The
Bis-benzyloxy benzoic acid (2) is then reacted with an aminophenyl
to produce a phenyl-benzamide (3). The phenyl-benzamide (3) is then
reacted with hydrazine to give a triazol (4). The hydroxy groups
can then be unprotected in the presence of palladium on charcoal to
give the final product.
##STR00275##
[0700] In another embodiment the compounds can be prepared as shown
in Scheme III. A nitroaniline (1) can be reacted with propionyl
chloride to yield nitro-phenyl-propionamide (2). NaH can then be
added to a solution of (2) in anhydrous THF followed by iodomethane
to give pure product nitro-phenyl-N-methyl-propionamide (3).
[0701] The nitro-phenyl-N-methyl-propionamide (3) and borane-methyl
sulfide complex are heated to give the
nitro-phenyl-methyl-propyl-amine (4). A solution of (4) in
MeOH/EtOAc containing Pd--C can be subjected to hydrogenation to
give the N-methyl-N-propyl-benzene-1,3-diamine (5).
[0702] To a stirred solution of (5) in CH.sub.2Cl.sub.2 can be
added 1,1'-thiocarbonyldiimidazole to give the
(5-Isothiocyanato-2-methoxy-phenyl)-methyl-propyl-amine (6).
[0703] The isothiocyanate (6) can be reacted with the hydrazide (7)
to give the intermediate (8). A solution of NaOH in water can be
added to the intermediate (8), which can then be flushed with
nitrogen and heated. The reaction mixture can then be cooled and
acidified. The mixture can then be filtered and purified to give
4-isopropyl-6-{5-mercapto-4-[4-methoxy-3-(methyl-propyl-amino)-phenyl]-4H-
-[1,2,4]triazol-3-yl}-benzene-1,3-diol.
##STR00276## ##STR00277##
[0704] In another embodiment the compounds can be prepared as shown
in Scheme IV. A bromo-nitrobenzene (1) can be reacted with
N.sup.1,N.sup.2,N.sup.2-trimethylethane-1,2-diamine to give
N.sup.1-(nitrophenyl)-N.sup.1,N.sup.2,N.sup.2-trimethylethane-1,2-diamine
(2). A solution of (2) in can be subjected to hydrogenation, passed
through a short pad of celite, washed with MeOH and evaporated
under reduced pressure. Thiocarbodiimidazole can then be added to
(2) to give the
N.sup.1-(isothiocyanato-phenyl)-)-N.sup.1,N.sup.2,N.sup.2-trimethylet-
hane-1,2-diamine (3).
[0705] The isothiocyanate (3) can then be reacted with a benzoic
acid hydrazide to give the final product
4-(4-(3-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-5-mercap-
to-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol (4).
##STR00278##
##STR00279##
##STR00280##
D. USES OF COMPOUNDS OF THE INVENTION
[0706] The present invention is directed to therapies which involve
administering one of more compounds of the invention, and
compositions comprising said compounds to a subject, preferably a
human subject, to inhibit the activity of Hsp90 or to prevent,
treat, manage, or ameliorate a proliferative disorder, such as
cancer, or one or more symptoms thereof.
[0707] In one embodiment, the present invention is directed to
treating cancers in which aberrant expression and/or activation of
c-kit has been implicated as a contributing factor. The method
comprises administering to a patient an effective amount of a
compound represented by formula (I), (II), (III), (IV), (V), (VI),
(VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) or any
embodiment thereof, or a compound shown in Table 1.
[0708] In one embodiment, the present invention is directed to
treating cancers in which expression of Bcr-Abl has been implicated
as a contributing factor. The method comprises administering to a
patient an effective amount of a compound represented by formula
(I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI),
(XII), (XIII), (XIV), (XV) or any embodiment thereof, or a compound
shown in Table 1.
[0709] In one embodiment, the present invention is directed to
treating cancers in which aberrant expression and/or activation of
flt-3 has been implicated as a contributing factor. The method
comprises administering to a patient an effective amount of a
compound represented by formula (I), (II), (III), (IV), (V), (VI),
(VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) or any
embodiment thereof, or a compound shown in Table 1.
[0710] In one embodiment, the present invention is directed to
treating cancers in which aberrant expression and/or activation of
EGFR has been implicated as a contributing factor. The method
comprises administering to a patient an effective amount of a
compound represented by formula (I), (II), (III), (IV), (V), (VI),
(VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) or any
embodiment thereof, or a compound shown in Table 1.
[0711] In one embodiment, the present invention is directed to
treating cancers in which Hsp90 is over expressed compared with
normal cells. The method comprises administering to a patient an
effective amount of a compound represented by formula (I), (II),
(III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII),
(XIII), (XIV), (XV) or any embodiment thereof, or a compound shown
in Table 1. Examples of cancers in which Hsp90 is over expressed
include diffuse large B-cell lymphomas (DLBCL).
[0712] In one aspect, the invention provides a method of inhibiting
the activity of Hsp90 in a cell, comprising administering to the
cell an effective amount of a compound represented by formula (I),
(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI),
(XII), (XIII), (XIV), (XV) or any embodiment thereof, or a compound
shown in Table 1. In one embodiment, the compound is administered
to a cell in a subject, preferably a mammal, and more preferably a
human.
[0713] In another aspect, the invention provides a method of
treating or preventing a proliferation disorder in a mammal,
comprising administering to the mammal an effective amount of a
compound represented by formula (I), (II), (III), (IV), (V), (VI),
(VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) or any
embodiment thereof, or a compound shown in Table 1. In one
embodiment, the compound is administered to a human to treat or
prevent a proliferative disorder. In another embodiment, the
proliferation disorder is cancer. In another embodiment, the
compound is administered with one or more additional therapeutic
agents. In a preferred embodiment, the additional therapeutic agent
is an anticancer agent.
[0714] In another aspect, the invention provides a method for
treating cancer in a mammal, comprising administering to the mammal
an effective amount of a compound represented by formula (I), (II),
(III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII),
(XIII), (XIV), (XV) or any embodiment thereof, or a compound shown
in Table 1. In one embodiment, the compound is administered to a
human to treat or prevent cancer. In another embodiment, the
compound is administered with one or more additional therapeutic
agents. In a preferred embodiment, the one or more additional
therapeutic agents are anticancer agents.
[0715] In another aspect, the invention provides a method for
treating a c-kit associated cancer in a mammal, comprising
administering to the mammal an effective amount of a compound
represented by formula (I), (II), (III), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) or any
embodiment thereof, or a compound shown in Table 1. In one
embodiment, the compound is administered to a human to treat or
prevent the c-kit associated cancer. In another embodiment, the
compound is administered with one or more additional therapeutic
agents. In a preferred embodiment, the one or more additional
therapeutic agents are anticancer agents.
[0716] In another aspect, the invention provides a method for
treating a Bcr-Abl associated cancer in a mammal, comprising
administering to the mammal an effective amount of a compound
represented by formula (I), (II), (III), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) or any
embodiment thereof, or a compound shown in Table 1. In one
embodiment, the compound is administered to a human to treat or
prevent the Bcr-Abl associated cancer. In another embodiment, the
compound is administered with one or more additional therapeutic
agents. In a preferred embodiment, the one or more additional
therapeutic agents are anticancer agents.
[0717] In another aspect, the invention provides a method for
treating a flt3 associated cancer in a mammal, comprising
administering to the mammal an effective amount of a compound
represented by formula (I), (II), (III), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) or any
embodiment thereof, or a compound shown in Table 1. In one
embodiment, the compound is administered to a human to treat or
prevent the flt3 associated cancer. In another embodiment, the
compound is administered with one or more additional therapeutic
agents. In a preferred embodiment, the one or more additional
therapeutic agents are anticancer agents.
[0718] In another aspect, the invention provides a method for
treating an EGFR associated cancer in a mammal, comprising
administering to the mammal an effective amount of a compound
represented by formula (I), (II), (III), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) or any
embodiment thereof, or a compound shown in Table 1. In one
embodiment, the compound is administered to a human to treat or
prevent the EGFR associated cancer. In another embodiment, the
compound is administered with one or more additional therapeutic
agents. In a preferred embodiment, the one or more additional
therapeutic agents are anticancer agents.
[0719] In another aspect, the invention provides a method for
treating a cancer in a mammal which is characterized by the
upregulation of Hsp90 compared to normal cells of the same type,
comprising administering to the mammal an effective amount of a
compound represented by formula (I), (II), (III), (IV), (V), (VI),
(VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) or any
embodiment thereof, or a compound shown in Table 1. In one
embodiment, the compound is administered to a human to treat or
prevent the cancer associated with the upregulation of Hsp90. In
another embodiment, the cancer associated with the upregulation of
Hsp90 is DLBCL. In another embodiment, the compound is administered
with one or more additional therapeutic agents. In a preferred
embodiment, the one or more additional therapeutic agents are
anticancer agents.
[0720] In another aspect, the invention provides a method for
treating or inhibiting angiogenesis in a subject in need thereof,
comprising administering to the subject an effective amount of a
compound represented by formula (I), (II), (III), (IV), (V), (VI),
(VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) or any
embodiment thereof, or a compound shown in Table 1.
[0721] In another aspect, the invention provides a method of
blocking, occluding, or otherwise disrupting blood flow in
neovasculature, comprising contacting the neovasculature with an
effective amount of a compound represented by formula (I), (II),
(III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII),
(XIII), (XIV), (XV) or any embodiment thereof, or a compound shown
in Table 1. In one aspect, the neovasculature is in a subject and
blood flow in the neovasculature is blocked, occluded, or otherwise
disrupted in the subject by administering to the subject an
effective amount of a compound represented by formula (I), (II),
(III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII),
(XIII), (XIV), (XV) or any embodiment thereof, or a compound shown
in Table 1. In one aspect, the subject is human.
[0722] The present invention provides a method for preventing,
treating, managing, or ameliorating an infection in a subject in
need thereof, comprising administering an effective amount of a
compound represented by formula (I), (II), (III), (IV), (V), (VI),
(VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) or any
embodiment thereof, or a compound shown in Table 1.
[0723] In one aspect, the invention is directed to a method of
treating or preventing a fungal infection.
[0724] In one aspect, the invention is directed to a method of
treating or preventing a yeast infection.
[0725] In one aspect, the invention is directed to a method of
treating or preventing a yeast infection caused by a Candida
yeast.
[0726] In another embodiment the invention is directed to a method
of treating or preventing fungal drug resistance. In one aspect,
the fungal drug resistance is associated with an azole drug.
[0727] In another aspect, the fungal drug resistance is associated
with a non-azole fungal drug. In one aspect, the non-azole drug is
an echinocandin. In one aspect, the azole fungal drug is
ketoconazole, miconazole, fluconazole, itraconazole, posaconazole,
ravuconazole, voriconazole, clotrimazole, econazole, oxiconazole,
sulconazole, terconazole, butoconazole, isavuconazole, or
tioconazole. In one aspect, the azole fugnal drug is
fluconazole.
[0728] In one aspect, the invention is directed to a method of
treating or preventing a bacterial infection.
[0729] In one aspect, the invention is directed to a method of
treating or preventing abacterial infection caused by a Gram
Positive Bacteria.
[0730] In one aspect, the invention is directed to a method of
treating or preventing abacterial infection caused by a Gram
Negative Bacteria.
[0731] In one aspect, the invention is directed to a method of
treating or preventing a viral infection.
[0732] In one aspect, the invention is directed to a method of
treating or preventing a viral infection caused by an influenza
virus, a herpes virus, a hepatitis virus, or an HIV virus.
[0733] In one aspect, the invention is directed to a method of
treating or preventing a viral infection caused by influenza A
virus, herpes simplex virus type 1, hepatitis C virus, hepatitis B
virus, HIV-1 virus, or Epstein-Barr Virus.
[0734] In one aspect, the invention is directed to a method of
treating or preventing a parasitic infection.
[0735] In one aspect, the invention is directed to a method of
treating or preventing a protozoal infection.
[0736] In one aspect, the invention is directed to a method of
treating or preventing an infection caused by plasmodium falciparum
or trypsanosoma cruzi.
[0737] In one aspect, the invention is directed to a method of
treating or preventing an infection caused by a leishmania
protozoa.
[0738] In one aspect, the invention is directed to a method of
treating or preventing an amoebic infection.
[0739] In one aspect, the invention is directed to a method of
treating or preventing a helminth infection.
[0740] In one aspect, the invention is directed to a method of
treating or preventing an infection caused by schistostoma
mansoni.
[0741] In one aspect, compounds of the invention are administered
in combination with one or more additional anti-infective
therapeutic agents.
[0742] The present invention provides a method for inhibiting
topoisomerase II, comprising administering an effective amount of a
compound represented by formula (I), (II), (III), (IV), (V), (VI),
(VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) or any
embodiment thereof, or a compound shown in Table 1.
[0743] In another embodiment, topoisomerase II is associated with a
disease and administering the compound will treat or prevent the
disease.
[0744] In one aspect, the disease is a proliferative disease.
[0745] In another aspect, the proliferative disease is cancer.
[0746] In one aspect, the disease is an infection.
[0747] The present invention provides a method of treating an
inflammatory disorder in a subject in need thereof, comprising
administering an effective amount of a compound represented by
formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX),
(X), (XI), (XII), (XIII), (XIV), (XV) or any embodiment thereof, or
a compound shown in Table 1. In one embodiment, the inflammatory
disorder is selected from the group consisting of transplant
rejection, skin graft rejection, arthritis, rheumatoid arthritis,
osteoarthritis and bone diseases associated with increased bone
resorption; inflammatory bowel disease, ileitis, ulcerative
colitis, Barrett's syndrome, Crohn's disease; asthma, adult
respiratory distress syndrome, chronic obstructive airway disease;
corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic
ophthalmitis, endophthalmitis; gingivitis, periodontitis;
tuberculosis; leprosy; uremic complications, glomerulonephritis,
nephrosis; sclerodermatitis, psoriasis, eczema; chronic
demyelinating diseases of the nervous system, multiple sclerosis,
AIDS-related neurodegeneration, Alzheimer's disease, infectious
meningitis, encephalomyelitis, Parkinson's disease, Huntington's
disease, amyotrophic lateral sclerosis viral or autoimmune
encephalitis; autoimmune disorders, immune-complex vasculitis,
systemic lupus and erythematodes; systemic lupus erythematosus
(SLE); cardiomyopathy, ischemic heart disease hypercholesterolemia,
atherosclerosis, preeclampsia; chronic liver failure, brain and
spinal cord trauma.
[0748] The present invention provides a method of treating an
immune disorder in a subject in need thereof, comprising
administering an effective amount of a compound represented by
formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX),
(X), (XI), (XII), (XIII), (XIV), (XV) or any embodiment thereof, or
a compound shown in Table 1. In one embodiment, the immune disorder
is selected from the group consisting of multiple sclerosis,
myasthenia gravis, Guillain-Barre, autoimmune uveitis, autoimmune
hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia,
temporal arteritis, anti-phospholipid syndrome, vasculitides such
as Wegener's granulomatosis, Behcet's disease, psoriasis,
dermatitis herpetiformis, pemphigus vulgaris, vitiligo, Crohn's
disease, ulcerative colitis, primary biliary cirrhosis, autoimmune
hepatitis, Type 1 or immune-mediated diabetes mellitus, Grave's
disease. Hashimoto's thyroiditis, autoimmune oophoritis and
orchitis, autoimmune disorder of the adrenal gland, rheumatoid
arthritis, systemic lupus erythematosus, scleroderma, polymyositis,
dermatomyositis, ankylosing spondylitis, and Sjogren's
syndrome.
[0749] The present invention provides a method of suppressing an
immune response in a subject in need thereof, comprising
administering an effective amount of a compound represented by
formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX),
(X), (XI), (XII), (XIII), (XIV), (XV) or any embodiment thereof, or
a compound shown in Table 1. In one embodiment, the subject in need
of immunosuppression is a subject that has received an organ or
tissue transplant, such as a skin graft, heart, kidney, lung,
liver, pancreas, cornea, bowel, stomach, and the like. In another
embodiment, the subject in need of immunosuppression is a subject
that has received stem cell transplantation. The transplant may be
a syngeneic transplant (i.e., from a donor that has the same
genetic make up), an allographic transplant (i.e., from a donor of
the same species) or a xenographic transplant (i.e., from a donor
that is a different species).
[0750] The present invention provides a method of inhibiting the
production of inflammatory cytokines, such as G-CSF, GM-CSF, IL-12,
IL-1.beta., IL-23, IL-6, IL-8, and TNF-.alpha., in a subject in
need of such treatment. The method comprises administering to the
subject an effective amount of a compound represented by formula
(I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI),
(XII), (XIII), (XIV), (XV) or any embodiment thereof, or a compound
shown in Table 1.
1. c-Kit Associated Cancers
[0751] SCF binding to the c-kit protects hematopoietic stem and
progenitor cells from apoptosis (Lee, et al., 1997, J. Immunol.,
159:3211-3219), thereby contributing to colony formation and
hematopoiesis. Expression of c-kit is frequently observed in acute
myelocytic leukemia (AML) and sometimes observed in acute
lymphocytic leukemia (ALL) (for reviews, see Sperling, et al.,
1997, Haemat., 82:617-621; Escribano, et al., 1998, Leuk. Lymph.,
30:459-466). Although c-kit is expressed in the majority of AML
cells, its expression does not appear to be prognostic of disease
progression (Sperling, et al, 1997, Haemat. 82:617-621). However,
SCF protected AML cells from apoptosis induced by chemotherapeutic
agents (Hassan, et al., 1996, Acta. Hem., 95:257-262). Therefore,
degradation of c-kit caused by the inhibition of Hsp90 by the
compounds of the invention will enhance the efficacy of these
agents and may induce apoptosis of AML cells.
[0752] The clonal growth of cells from patients with
myelodysplastic syndrome (Sawada, et al., 1996, Blood, 88:319-327)
or chronic myelogenous leukemia (CML) (Sawai, et al., 1996, Exp.
Hem., 2:116-122) was found to be significantly enhanced by SCF in
combination with other cytokines. CML is characterized by expansion
of Philadelphia chromosome positive cells of the marrow
(Verfaillie, et al., 1998, Leuk., 12:136-138), which appears to
primarily result from inhibition of apoptotic death (Jones, 1997,
Curr. Opin. One., 9:3-7). The product of the Philadelphia
chromosome, p210.sup.BCR-ABL, has been reported to mediate
inhibition of apoptosis (Bedi, et al., 1995, Blood, 86:1148-1158).
Since p210.sup.BCR-ABL and the c-kit RTK both inhibit apoptosis and
p62.sup.dok has been suggested as a substrate (Carpino, et al.,
1997, Cell, 88:197-204), it is possible that clonal expansion
mediated by these kinases occurs through a common signaling
pathway. However, c-kit has also been reported to interact directly
with p210.sup.BCR-ABL (Hallek, et al., 1996, Brit. J Haem.,
94:5-16), which suggests that c-kit may have a more causative role
in CML pathology. Therefore, degradation of c-kit caused by the
inhibition of Hsp90 by the compounds of the invention will prove
useful in the treatment of CML.
[0753] Normal colorectal mucosa does not express c-kit (Bellone, et
al., 1997, J. Cell Physiol., 172:1-11). However, c-kit is
frequently expressed in colorectal carcinoma (Bellone, et al.,
1997, J. Cell Physiol., 172: 1-11), and autocrine loops of SCF and
c-kit have been observed in several colon carcinoma cell lines
(Toyota, et al., 1993, Turn. Biol., 14:295-302; Lahm, et al., 1995,
Cell Growth & Differ., 6:1111-1118; Bellone, et al., 1997, J.
Cell Physiol., 172:1-11). Furthermore, disruption of the autocrine
loop by the use of neutralizing antibodies (Lahm, et al., 1995,
Cell Growth & Differ., 6:1111-1118) and downregulation of c-kit
and/or SCF significantly inhibits cell proliferation (Lahm, et al.,
1995, Cell Growth & Differl., 6:1111-1118; Bellone, et al.,
1997, J. Cell Physiol., 172:1-11).
[0754] SCF/c-kit autocrine loops have been observed in gastric
carcinoma cell lines (Turner, et al., 1992, Blood, 80:374-381;
Hassan, et al., 1998, Digest. Dis. Science, 43:8-14), and
constitutive c-kit activation also appears to be important for
gastrointestinal stromal tumors (GISTs). GISTs are the most common
mesenchymal tumor of the digestive system. More than 90% of GISTs
express c-kit, which is consistent with the putative origin of
these tumor cells from interstitial cells of Cajal (ICCs) (Hirota,
et al., 1998, Science, 279:577-580). The c-kit expressed in GISTs
from several different patients was observed to have mutations in
the intracellular juxtamembrane domain leading to constitutive
activation (Hirota, et al., 1998, Science 279:577-580). Therefore,
degradation of c-kit caused by the inhibition of Hsp90 by the
compounds of the invention will be an efficacious means for the
treatment of these cancers.
[0755] Male germ cell tumors have been histologically categorized
into seminomas, which retain germ cell characteristics, and
nonseminomas which can display characteristics of embryonal
differentiation. Both seminomas and nonseminomas are thought to
initiate from a preinvasive stage designated carcinoma in situ
(CIS) (Murty, et al., 1998, Sem. Oncol., 25:133-144). Both c-kit
and SCF have been reported to be essential for normal gonadal
development during embryogenesis (Loveland, et al., 1997, J.
Endocrinol., 153:337-344). Loss of either the receptor or the
ligand resulted in animals devoid of germ cells. In postnatal
testes, c-kit has been found to be expressed in Leydig cells and
spermatogonia, while SCF was expressed in Sertoli cells (Loveland,
et al., 1997, J. Endocrinol., 153:337-344). Testicular tumors
develop from Leydig cells with high frequency in transgenic mice
expressing human papilloma virus 16 (HPV16) E6 and E7 oncogenes
(Kondoh, et al., 1991, J. Virol., 65:3335-3339; Kondoh, et al.,
1994, J. Urol., 152:2151-2154). These tumors express both c-kit and
SCF, and an autocrine loop may contribute to the tumorigenesis
(Kondoh, et al., 1995, Oncogene, 10:341-347) associated with
cellular loss of functional p53 and the retinoblastoma gene product
by association with E6 and E7 (Dyson, et al., 1989, Science,
243:934-937; Werness, et al., 1990, Science, 248:76-79; Scheffner,
et al., 1990, Cell, 63:1129-1136). Defective signaling mutants of
SCF (Kondoh, et al., 1995, Oncogene, 10:341-347) or c-kit (Li, et
al., 1996, Canc. Res., 56:4343-4346) inhibited formation of
testicular tumors in mice expressing HPV16 E6 and E7. Since c-kit
kinase activation is pivotal to tumorigenesis in these animals, the
compounds of the invention which inhibit Hsp90 and thereby cause
the degradation of c-kit will be useful for preventing or treating
testicular tumors associated with human papilloma virus.
[0756] Expression of c-kit on germ cell tumors shows that the
receptor is expressed by the majority of carcinomas in situ and
seminomas, but c-kit is expressed in only a minority of
nonseminomas (Strohmeyer, et al., 1991, Canc. Res., 51:1811-1816;
Rajpert-de Meyts, et al., 1994, Int. J. Androl., 17:85-92;
Izquierdo, et al., 1995, J. Pathol., 177:253-258; Strohmeyer, et
al., 1995, J. Urol., 153:511-515; Bokenmeyer, et al., 1996, J.
Cance. Res., Clin. Oncol., 122:301-306; Sandlow, et al., 1996, J.
Androl., 17:403-408). Therefore, degradation of c-kit caused by the
inhibition of Hsp90 by the compounds of the invention will be an
efficacious means for the treatment of these cancers.
[0757] SCF and c-kit are expressed throughout the central nervous
system of developing rodents, and the pattern of expression
suggests a role in growth, migration and differentiation of
neuroectodermal cells. Expression of SCF and c-kit have also been
reported in the adult brain (Hamel, et al., 1997, J. Neuro-Onc.,
35:327-333). Expression of c-kit has also been observed in normal
human brain tissue (Tada, et al. 1994, J. Neuro., 80:1063-1073).
Glioblastoma and astrocytoma, which define the majority of
intracranial tumors, arise from neoplastic transformation of
astrocytes (Levin, et al., 1997, Principles & Practice of
Oncology, 2022-2082). Expression of c-kit has been observed in
glioblastoma cell lines and tissues (Berdel, et al., 1992, Canc.
Res., 52:3498-3502; Tada, et al., 1994, J. Neuro., 80:1063-1073;
Stanulla, et al., 1995, Act. Neuropath., 89:158-165).
[0758] The association of c-kit with astrocytoma pathology is less
clear. Reports of expression of c-kit in normal astrocytes have
been made (Natali, et al., 1992, Int. J. Canc., 52:197-201), (Tada,
et al. 1994, J. Neuro., 80:1063-1073), while others report it is
not expressed (Kristt, et al., 1993, Neuro., 33:106-115). In the
former case, high levels of c-kit expression in high grade tumors
were observed (Kristt, et al., 1993, Neuro., 33:106-115), whereas
in the latter case researchers were unable to detect any expression
in astrocytomas. In addition, contradictory reports of c-kit and
SCF expression in neuroblastomas also exist. One study found that
neuroblastoma cell lines often express SCF, but rarely express
c-kit. In primary tumors, c-kit was detected in about 8% of
neuroblastomas, while SCF was found in 18% of tumors (Beck, et al.,
1995, Blood, 86:3132-3138). In contrast, other studies (Cohen, et
al., 1994, Blood, 84:3465-3472) have reported that all 14
neuroblastoma cell lines examined contained c-kit/SCF autocrine
loops, and expression of both the receptor and ligand were observed
in 45% of tumor samples examined. In two cell lines, anti-c-kit
antibodies inhibited cell proliferation, suggesting that the
SCF/c-kit autocrine loop contributed to growth (Cohen, et al.,
1994, Blood, 84:3465-3472). Therefore, degradation of c-kit caused
by the inhibition of Hsp90 by the compounds of the invention will
be an efficacious means for treating some cancers of the central
nervous system.
2. Bcr-Abl Associated Cancers
[0759] The Philadelphia chromosome which generates the fusion
protein Bcr-Abl is associated with the bulk of chronic myelogenous
leukemia (CML) patients (more than 95%), 10-25% of acute
lymphocytic leukemia (ALL) patients, and about 2-3% of acute
myelogenous leukemias (AML). In addition, Bcr-Abl is a factor in a
variety of other hematological malignancies, including granulocytic
hyperplasia resembling CML, myelomonocytic leukemia, lymphomas, and
erythroid leukemia (see Lugo, et al., MCB (1989), 9:1263-1270;
Daley, et al., Science (1990), 247:824-830; and Honda, Blood
(1998), 91:2067-2075, the entire teachings of each of these
references are incorporated herein by reference).
[0760] A number of different kinds of evidence support the
contention that Bcr-Abl oncoproteins, such as p210 and p185
BCR-ABL, are causative factors in these leukemias (Campbell and
Arlinghaus, "Current Status of Bcr Gene Involvement with Human
Leukemia", In: Advances in Cancer Research, Eds. Klein, VandeWoude,
Orlando, Fla. Academic Press, Inc., 57:227-256, 1991, the entire
teachings of which are incorporated herein by reference). The
malignant activity is due in large part to the Bcr-Abl protein's
highly activated protein tyrosine kinase activity and its abnormal
interaction with protein substrates (Arlinghaus et al., In: UCLA
Symposia on Molecular and Cellular Biology New Series, Acute
Lymphoblastic Leukemia, Eds. R. P. Gale, D. Hoelzer, New York,
N.Y., Alan R. Liss, Inc., 108:81-90, 1990, the entire teachings of
which are incorporated herein by reference). The Bcr-Abl
oncoprotein p210 Bcr-Abl is associated with both CML and ALL,
whereas the smaller oncoprotein, p185 BCR-ABL, is associated with
ALL patients, although some CML patients also express p185
(Campbell et al., 1991).
3. FLT3 Associated Cancers
[0761] FLT3 associated cancers are cancers in which inappropriate
FLT3 activity is detected. FLT3 associated cancers include
hematologic malignancies such as leukemia and lymphoma. In some
embodiments FLT3 associated cancers include acute myelogenous
leukemia (AML), B-precursor cell acute lymphoblastic leukemia,
myelodysplastic leukemia, T-cell acute lymphoblastic leukemia,
mixed lineage leukemia (MLL), or chronic myelogenous leukemia
(CML).
4. EGFR Associated Cancers
[0762] EGFR associated cancers are cancers in which inappropriate
EGFR activity (e.g., overexpression of EGFR or mutation of EGFR
which causes constitutive tyrosine kinase activity) has been
implicated as a contributing factor. Inappropriate EGFR activity
has been associated with an adverse prognosis in a number of human
cancers, such as neuroblastoma, intestine carcinoma such as rectum
carcinoma, colon carcinoma, familiary adenomatous polyposis
carcinoma and hereditary non-polyposis colorectal cancer,
esophageal carcinoma, labial carcinoma, larynx carcinoma,
hypopharynx carcinoma, tong carcinoma, salivary gland carcinoma,
gastric carcinoma, adenocarcinoma, medullary thyroidea carcinoma,
papillary thyroidea carcinoma, renal carcinoma, kidney parenchym
carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus
carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic
carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma,
urinary carcinoma, melanoma, brain tumors such as glioblastoma,
astrocytoma, meningioma, medulloblastoma and peripheral
neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma,
Burkitt lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic
leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid
leukemia (CML), adult T-cell leukemia lymphoma, hepatocellular
carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell
lung carcinoma, non-small cell lung carcinoma, multiple myeloma,
basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma,
rhabdomyo sarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma,
myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma and
plasmocytoma.
[0763] In particular, EGFR appears to have an important role in the
development of human brain tumors. A high incidence of
overexpression, amplification, deletion and structural
rearrangement of the gene coding for EGFR has been found in
biopsies of brain tumors. In fact, the amplification of the EGFR
gene in glioblastoma multiforme tumors is one of the most
consistent genetic alterations known, with EGFR being overexpressed
in approximately 40% of malignant gliomas and EGFRvIII mutation
being found in about 50% of all glioblastomas.
[0764] In addition to gliomas, abnormal EGFR expression has also
been reported in a number of squamous epidermoid cancers and breast
cancers. Interestingly, evidence also suggests that many patients
with tumors that over-express EGFR have a poorer prognosis than
those having tumors that do not over-express EGFR.
[0765] Non-small cell lung cancer (NSCLC) includes squamous cell
carcinomas, adenocarcinoma, bronchioloalveolar carcinoma (BAC), and
large cell undifferentiated carcinoma. A subset of patients with
NSCLC have been shown to have mutations in the tyrosine kinase
domain of EGFR which is thought to be necessary for the maintenance
of the disease. Treatment of this subset of patients with NSCLC
with gefitinib, a tyrosine kinase inhibitor which targets EGFR, has
shown rapid and dramatic clinical response.
[0766] Consequently, therapeutic strategies that can potentially
inhibit or reduce the aberrant expression of EGFR are of great
interest as potential anti-cancer agents.
5. Combination Therapies and Treatment of Refractory Cancers
[0767] The prophylactic or therapeutic agents of the combination
therapies of the invention can be administered sequentially or
concurrently. In a specific embodiment, the combination therapies
of the invention comprise one or more compounds and at least one
other therapy (e.g., another prophylactic or therapeutic agent)
which has the same mechanism of action as said compounds. In
another specific embodiment, the combination therapies of the
invention comprise one or more compounds of the invention and at
least one other therapy (e.g., another prophylactic or therapeutic
agent) which has a different mechanism of action than said
compounds. In certain embodiments, the combination therapies of the
present invention improve the prophylactic or therapeutic effect of
one or more compounds of the invention by functioning together with
the compounds to have an additive or synergistic effect. In certain
embodiments, the combination therapies of the present invention
reduce the side effects associated with the therapies (e.g.,
prophylactic or therapeutic agents). In certain embodiments, the
combination therapies of the present invention reduce the effective
dosage of one or more of the therapies.
[0768] The prophylactic or therapeutic agents of the combination
therapies can be administered to a subject, preferably a human
subject, in the same pharmaceutical composition. In alternative
embodiments, the prophylactic or therapeutic agents of the
combination therapies can be administered concurrently to a subject
in separate pharmaceutical compositions. The prophylactic or
therapeutic agents may be administered to a subject by the same or
different routes of administration.
[0769] In a specific embodiment, a pharmaceutical composition
comprising one or more compounds of the invention is administered
to a subject, preferably a human, to prevent, treat, manage, or
ameliorate a proliferative disorder, such as cancer, or one or more
symptom thereof. In accordance with the invention, pharmaceutical
compositions of the invention may also comprise one or more other
agents (e.g., prophylactic or therapeutic agents which are
currently being used, have been used, or are known to be useful in
the prevention, treatment or amelioration of a proliferative
disorder or a symptom thereof).
[0770] The invention provides methods for preventing, managing,
treating or ameliorating a proliferative disorder, such as cancer,
or one or more symptoms thereof in a subject refractory (either
completely or partially) to existing agent therapies for such a
proliferative disorder, said methods comprising administering to
said subject a dose of an effective amount of one or more compounds
of the invention and a dose of an effective amount of one or more
therapies (e.g., one or more prophylactic or therapeutic agents
useful for the prevention, treatment, management, or amelioration
of a proliferative disorder or a symptom thereof). The invention
also provides methods for preventing, treating, managing, or
ameliorating a proliferative disorder or a symptom thereof by
administering one or more compounds of the invention in combination
with any other therapy(ies) to patients who have proven refractory
to other therapies but are no longer on these therapies.
[0771] The compounds of the invention and/or other therapies can be
administered to a subject by any route known to one of skill in the
art. Examples of routes of administration include, but are not
limited to, parenteral, e.g., intravenous, intradermal,
subcutaneous, oral (e.g., inhalation), intranasal, transdermal
(topical), transmucosal, and rectal administration.
6) Agents Useful in Combination with the Compounds of the
Invention
[0772] Without wishing to be bound by theory, it is believed that
the compounds of the invention can be particularly effective at
treating subjects whose cancer has become multi-drug resistant.
Although chemotherapeutic agents initially cause tumor regression,
most agents that are currently used to treat cancer target only one
pathway to tumor progression. Therefore, in many instances, after
treatment with one or more chemotherapeutic agents, a tumor
develops multidrug resistance and no longer responds positively to
treatment. One of the advantages of inhibiting Hsp90 activity is
that several of its client proteins, which are mostly protein
kinases or transcription factors involved in signal transduction,
have been shown to be involved in the progression of cancer. Thus,
inhibition of Hsp90 provides a method of short circuiting several
pathways for tumor progression simultaneously. Therefore, it is
believed that treatment of cancer with an Hsp90 inhibitor of the
invention either alone, or in combination with other
chemotherapeutic agents, is more likely to result in regression or
elimination of the tumor, and less likely to result in the
development of more aggressive multidrug resistant tumors than
other currently available therapies.
[0773] In one embodiment, the compounds of the invention can be
administered with agents that are tyrosine kinase inhibitors (e.g.,
gefitinib or erlotinib which inhibit EGFR tyrosine kinase
activity). In another embodiment, the compounds of the invention
can be administered to patients whose cancer has become resistant
to a tyrosine kinase inhibitor (e.g., gefitinib or erlotinib). In
this embodiment, the compounds of the invention can be administered
either alone or in combination with the tyrosine kinase
inhibitor.
[0774] In another embodiment, the compounds of the invention are
useful for treating patients with hematological cancers that have
become resistant to Imatinib, a chemotherapeutic agent that acts by
inhibiting tyrosine kinase activity of Bcr-Abl. In patients with
CML in the chronic phase, as well as in a blast crisis, treatment
with Imatinib typically will induce remission. However, in many
cases, particularly in those patients who were in a blast crisis
before remission, the remission is not durable because the Bcr-Abl
fusion protein develops mutations in the tyrosine kinase domain
that cause it to be resistance to Imatinib. (See Nimmanapalli, et
al., Cancer Research (2001), 61:1799-1804; and Gone, et al., Blood
(2002), 100:3041-3044, the entire teachings of each of these
references are incorporated herein by reference). Compounds of the
invention act by inhibiting the activity of Hsp90 which disrupt
Bcr-Abl/Hsp90 complexes. When Bcr-Abl is not complex to Hsp90 it is
rapidly degraded. Therefore, compounds of the invention are
effective in treating Imatinib resistant leukemias since they act
through a different mechanism than Imatinib. Compounds of the
invention can be administered alone or with Imatinib in patients
who have a Bcr-Abl associated cancer that is not resistant to
Imatinib or to patients whose cancer has become resistant to
Imatinib.
[0775] Anticancer agents that can be co-administered with the
compounds of the invention include Taxol.TM., also referred to as
"paclitaxel", is a well-known anti-cancer drug which acts by
enhancing and stabilizing microtubule formation, and analogs of
Taxol.TM., such as Taxotere.TM.. Compounds that have the basic
taxane skeleton as a common structure feature, have also been shown
to have the ability to arrest cells in the G2-M phases due to
stabilization or inhibition of microtubules.
[0776] Other anti-cancer agents that can be employed in combination
with the compounds of the invention include Avastin, Adriamycin,
Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin;
aclarubicin; acodazole hydrochloride; acronine; adozelesin;
aldesleukin; altretamine; ambomycin; ametantrone acetate;
aminoglutethimide; amsacrine; anastrozole; anthramycin;
asparaginase; asperlin; azacitidine; azetepa; azotomycin;
batimastat; benzodepa; bicalutamide; bisantrene hydrochloride;
bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar
sodium; bropirimine; busulfan; cactinomycin; calusterone;
caracemide; carbetimer; carboplatin; carmustine; carubicin
hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;
cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;
dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;
dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin;
doxorubicin hydrochloride; droloxifene; droloxifene citrate;
dromostanolone propionate; duazomycin; edatrexate; eflornithine
hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine;
epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;
estramustine; estramustine phosphate sodium; etanidazole;
etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;
fazarabine; fenretinide; floxuridine; fludarabine phosphate;
fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;
gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin
hydrochloride; ifosfamide; ilmofosine; interleukin II (including
recombinant interleukin II, or rIL2), interferon alfa-2a;
interferon alfa-2b; interferon alfa-n1; interferon alfa-n3;
interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan
hydrochloride; lanreotide acetate; letrozole; leuprolide acetate;
liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone
hydrochloride; masoprocol; maytansine; mechlorethamine
hydrochloride; megestrol acetate; melengestrol acetate; melphalan;
menogaril; mercaptopurine; methotrexate; methotrexate sodium;
metoprine; meturedepa; mitindomide; mitocarcin; mitocromin;
mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazole; nogalamycin;
ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine;
peplomycin sulfate; perfosfamide; pipobroman; piposulfan;
piroxantrone hydrochloride; plicamycin; plomestane; porfimer
sodium; porfiromycin; prednimustine; procarbazine hydrochloride;
puromycin; puromycin hydrochloride; pyrazofurin; riboprine;
rogletimide; safingol; safingol hydrochloride; semustine;
simtrazene; sparfosate sodium; sparsomycin; spirogermanium
hydrochloride; spiromustine; spiroplatin; streptonigrin;
streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur;
teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;
testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;
tirapazamine; toremifene citrate; trestolone acetate; triciribine
phosphate; trimetrexate; trimetrexate glucuronate; triptorelin;
tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;
verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;
vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;
vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;
vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin
hydrochloride.
[0777] Other anti-cancer drugs that can be employed in combination
with the compounds of the invention include: 20-epi-1,25
dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;
acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK
antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam
derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; canarypox IL-2; capecitabine;
carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN
700; cartilage derived inhibitor; carzelesin; casein kinase
inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;
chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine;
docosanol; dolasetron; doxifluridine; droloxifene; dronabinol;
duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;
eflornithine; elemene; emitefur; epirubicin; epristeride;
estramustine analogue; estrogen agonists; estrogen antagonists;
etanidazole; etoposide phosphate; exemestane; fadrozole;
fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;
flezelastine; fluasterone; fludarabine; fluorodaunorunicin
hydrochloride; forfenimex; formestane; fostriecin; fotemustine;
gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;
gelatinase inhibitors; gemcitabine; glutathione inhibitors;
hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;
ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine;
ilomastat; imidazoacridones; imiquimod; immunostimulant peptides;
insulin-like growth factor-1 receptor inhibitor; interferon
agonists; interferons; interleukins; iobenguane; iododoxorubicin;
ipomeanol, 4-; iroplact; irsogladine; isobengazole;
isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;
lamellarin-N triacetate; lanreotide; leinamycin; lenograstim;
lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting
factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
lovastatin; loxoribine; lurtotecan; lutetium texaphyrin;
lysofylline; lytic peptides; maitansine; mannostatin A; marimastat;
masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase
inhibitors; menogaril; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor; mifepristone; miltefosine;
mirimostim; mismatched double stranded RNA; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
monoclonal antibody, human chorionic gonadotrophin; monophosphoryl
lipid A+myobacterium cell wall sk; mopidamol; multiple drug
resistance gene inhibitor; multiple tumor suppressor 1-based
therapy; mustard anticancer agent; mycaperoxide B; mycobacterial
cell wall extract; myriaporone; N-acetyldinaline; N-substituted
benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;
naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;
neutral endopeptidase; nilutamide; nisamycin; nitric oxide
modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine;
octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;
oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic
acid; panaxytriol; panomifene; parabactin; pazelliptine;
pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;
pentrozole; perflubron; perfosfamide; pennyl alcohol;
phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;
pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A;
placetin B; plasminogen activator inhibitor; platinum complex;
platinum compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylene conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII retinamide; rogletimide; rohitukine; romurtide;
roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU;
sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence
derived inhibitor 1; sense oligonucleotides; signal transduction
inhibitors; signal transduction modulators; single chain
antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate;
sodium phenylacetate; solverol; somatomedin binding protein;
sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stem cell inhibitor; stem-cell division
inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;
superactive vasoactive intestinal peptide antagonist; suradista;
suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;
tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;
tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;
temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;
thaliblastine; thiocoraline; thrombopoietin; thrombopoietin
mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan;
thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;
titanocene bichloride; topsentin; toremifene; totipotent stem cell
factor; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; vector system,
erythrocyte gene therapy; velaresol; veramine; verdins;
verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
Preferred anti-cancer drugs are 5-fluorouracil and leucovorin.
[0778] Other chemotherapeutic agents that can be employed in
combination with the compounds of the invention include but are not
limited to alkylating agents, antimetabolites, natural products, or
hormones. Examples of alkylating agents useful for the treatment or
prevention of T-cell malignancies in the methods and compositions
of the invention include but are not limited to, nitrogen mustards
(e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.),
alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine,
lomusitne, etc.), or triazenes (decarbazine, etc.). Examples of
antimetabolites useful for the treatment or prevention of T-cell
malignancies in the methods and compositions of the invention
include but are not limited to folic acid analog (e.g.,
methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine
analogs (e.g., mercaptopurine, thioguanine, pentostatin). Examples
of natural products useful for the treatment or prevention of
T-cell malignancies in the methods and compositions of the
invention include but are not limited to vinca alkaloids (e.g.,
vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide),
antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes
(e.g., L-asparaginase), or biological response modifiers (e.g.,
interferon alpha).
[0779] Examples of alkylating agents that can be employed in
combination with the compounds of the invention include but are not
limited to, nitrogen mustards (e.g., mechloroethamine,
cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and
methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl
sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine,
lomusitne, semustine, streptozocin, etc.), or triazenes
(decarbazine, etc.). Examples of antimetabolites useful for the
treatment or prevention of cancer in the methods and compositions
of the invention include but are not limited to folic acid analog
(e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil,
floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine,
thioguanine, pentostatin). Examples of natural products useful for
the treatment or prevention of cancer in the methods and
compositions of the invention include but are not limited to vinca
alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins
(e.g., etoposide, teniposide), antibiotics (e.g., actinomycin D,
daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin),
enzymes (e.g., L-asparaginase), or biological response modifiers
(e.g., interferon alpha). Examples of hormones and antagonists
useful for the treatment or prevention of cancer in the methods and
compositions of the invention include but are not limited to
adrenocorticosteroids (e.g., prednisone), progestins (e.g.,
hydroxyprogesterone caproate, megestrol acetate,
medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol,
ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens
(e.g., testosterone propionate, fluoxymesterone), antiandrogen
(e.g., flutamide), gonadotropin releasing hormone analog (e.g.,
leuprolide). Other agents that can be used in the methods and
compositions of the invention for the treatment or prevention of
cancer include platinum coordination complexes (e.g., cisplatin,
carboblatin), anthracenedione (e.g., mitoxantrone), substituted
urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g.,
procarbazine), adrenocortical suppressant (e.g., mitotane,
aminoglutethimide).
[0780] Examples of anti-cancer agents which act by arresting cells
in the G2-M phases due to stabilization or inhibition of
microtubules and which can be used in combination with the
compounds of the invention include without limitation the following
marketed drugs and drugs in development: Erbulozole (also known as
R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128),
Mivobulin isethionate (also known as CI-980), Vincristine,
NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751
(Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A
and Altorhyrtin C), Spongistatins (such as Spongistatin 1,
Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5,
Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin
9), Cemadotin hydrochloride (also known as LU-103793 and
NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B,
Epothilone C (also known as desoxyepothilone A or dEpoA),
Epothilone D (also referred to as KOS-862, dEpoB, and
desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B
N-oxide, Epothilone A N-oxide, 16-aza-epothilone B,
21-aminoepothilone B (also known as BMS-310705),
21-hydroxyepothilone D (also known as Desoxyepothilone F and
dEpoF), 26-fluoroepothilone), Auristatin PE (also known as
NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P
(Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known
as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378
(Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877
(Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198
(Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF,
also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis),
SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132
(Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),
Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also
known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known
as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A),
Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as
NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and
TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261
and WHI-261), H10 (Kansas State University), H16 (Kansas State
University), Oncocidin Al (also known as BTO-956 and DIME), DDE-313
(Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2
(Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also
known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of
Medicine, also known as MF-569), Narcosine (also known as
NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott),
Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine,
also known as MF-191), TMPN (Arizona State University), Vanadocene
acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also
known as NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School of
Medicine), A-204197 (Abbott), T-607 (Tularik, also known as
T-900607), RPR-115781 (Aventis), Eleutherobins (such as
Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and
Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131
(Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620
(Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis),
A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as
NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica),
Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099
(Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110,
trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318
(Zentaris), SC-12983 (NCl), Resverastatin phosphate sodium,
BPR-OY-007 (National Health Research Institutes), and SSR-250411
(Sanofi).
7) Anti-Infective Agents Useful in Combination with the Compounds
of the Invention
[0781] In one embodiment relating to infections, the other
therapeutic agent may be an anti-infective agent.
[0782] Other anti-fungal agents that can be co-administered with
the compounds of the invention include, but are not limited to,
polyene antifungals (e.g., amphotericin and nystatin), azole
antifungals (e.g., ketoconazole, miconazole, fluconazole,
itraconazole, posaconazole, ravuconazole, voriconazole,
clotrimazole, econazole, oxiconazole, sulconazole, terconazole,
butoconazole, and tioconazole), amorolfine, butenafine, naftifine,
terbinafine, flucytosine, nikkomycin Z, caspofungin, micafungin
(FK463), anidulafungin (LY303366), griseofulvin, ciclopiroxolamine,
tolnaftate, intrathecal, haloprogrin, and undecylenate.
[0783] Other anti-bacterial agents that can be co-administered with
the compounds of the invention include, but are not limited to,
sulfa drugs (e.g., sulfanilamide), folic acid analogs (e.g.,
trimethoprim), beta-lactams (e.g., penacillin, cephalosporins),
aminoglycosides (e.g., stretomycin, kanamycin, neomycin,
gentamycin), tetracyclines (e.g., chlorotetracycline,
oxytetracycline, and doxycycline), macrolides (e.g., erythromycin,
azithromycin, and clarithromycin), lincosamides (e.g.,
clindamycin), streptogramins (e.g., quinupristin and dalfopristin),
fluoroquinolones (e.g., ciprofloxacin, levofloxacin, and
moxifloxacin), polypeptides (e.g., polymixins), rifampin,
mupirocin, cycloserine, aminocyclitol (e.g., spectinomycin),
glycopeptides (e.g., vancomycin), oxazolidinones (e.g., linezolid),
ribosomes, chloramphenicol, fusidic acid, and metronidazole.
[0784] Other anti-viral agents that can be co-administered with the
compounds of the invention include, but are not limited to,
Emtricitabine (FTC); Lamivudine (3TC); Carbovir; Acyclovir;
Interferon; Famciclovir; Penciclovir; Zidovudine (AZT); Didanosine
(ddI); Zalcitabine (ddC); Stavudine (d4T); Tenofovir DF (Viread);
Abacavir (ABC); L-(-)--FMAU; L-DDA phosphate prodrugs;
.beta.-D-dioxolane nucleosides such as .beta.-D-dioxolanyl-guanine
(DG), .beta.-D-dioxolanyl-2,6-diaminopurine (DAPD), and
.beta.-D-dioxolanyl-6-chloropurine (ACP); non-nucleoside RT
inhibitors such as Nevirapine (Viramune), MKC-442, Efavirenz
(Sustiva), Delavirdine (Rescriptor); protease inhibitors such as
Amprenavir, Atazanavir, Fosamprenavir, Indinavir, Kaletra,
Nelfinavir, Ritonavir, Saquinavir, AZT, DMP-450; combination
treatments such as Epzicom (ABC+3TC), Trizivir (ABC+3TC+AZT),
Truvada (FTC+Viread); Omega IFN (BioMedicines Inc.); BILN-2061
(Boehringer Ingelheim); Summetrel (Endo Pharmaceuticals Holdings
Inc.); Roferon A (F. Hoffman-La Roche); Pegasys (F. Hoffman-La
Roche); Pegasys/Ribaravin (F. Hoffman-La Roche); CellCept (F.
Hoffman-La Roche); Wellferon (GlaxoSmithKline); Albuferon-.alpha.
(Human Genome Sciences Inc.); Levovirin (ICN Pharmaceuticals);
IDN-6556 (Idun Pharmaceuticals); IP-501 (Indevus Pharmaceuticals);
Actimmune (InterMune Inc.); Infergen A (InterMune Inc.); ISIS14803
(ISIS Pharmaceuticals Inc.); JTK-003 (Japan Tobacco Inc.);
Pegasys/Ceplene (Maxim Pharmaceuticals); Ceplene (Maxim
Pharmaceuticals); Civacir (Nabi Biopharmaceuticals Inc.); Intron
A/Zadaxin (RegeneRx); Levovirin (Ribapharm Inc.); Viramidine
(Ribapharm Inc.); Heptazyme (Ribozyme Pharmaceuticals); Intron A
(Schering-Plough); PEG-Intron (Schering-Plough); Rebetron
(Schering-Plough); Ribavirin (Schering-Plough);
PEG-Intron/Ribavirin (Schering-Plough); Zadazim (SciClone); Rebif
(Serono); IFN-.beta./EMZ701 (Transition Therapeutics); T67 (Tularik
Inc.); VX-497 (Vertex Pharmaceuticals Inc.); VX-950/LY-570310
(Vertex Pharmaceuticals Inc.); Omniferon (Viragen Inc.); XTL-002
(XTL Biopharmaceuticals); SCH 503034 (Schering-Plough); isatoribine
and its prodrugs ANA971 and ANA975 (Anadys); R1479 (Roche
Biosciences); Valopicitabine (Idenix); NIM811 (Novartis); Actilon
(Coley Pharmaceuticals); Pradefovir (Metabasis Therapeutics);
zanamivir; adefovir, adefovir dipivoxil, oseltamivir; vidarabine;
gancyclovir; valganciclovir; amantadine; rimantadine; relenza;
tamiflu; amantadine; entecavir; and pleconaril.
[0785] Other anti-parasitic agents that can be co-administered with
the compounds of the invention include, but are not limited to,
avermectins, milbemycins, lufenuron, imidacloprid,
organophosphates, pyrethroids, sufanamides, iodquinol, diloxanide
furoate, metronidazole, paromycin, azithromycin, quinacrine,
furazolidone, timidazole, ornidazole, bovine, colostrum, bovine
dialyzable leukocyte extract, chloroquine, chloroquine phosphate,
diclazuril, eflornithine, paromomycin, pentamidine, pyrimethamine,
spiramycin, trimethoprim-sulfamethoxazole, albendazole, quinine,
quinidine, tetracycline, pyrimethamine-sulfadoxine, mefloquine,
doxycycline, proguanil, clindamycin, suramin, melarsoprol,
diminazene, nifurtimox, spiroarsoranes, ketoconazole, terbinafine,
lovastatin, sodium stibobgluconate, N-methylglucamine antimonate,
amphotericin B, allopurinol, itraconazole, sulfadiazine, dapsone,
trimetrexate, clarithromycin, roxithromycin, atovaquone, aprinocid,
timidazole, mepacrine hydrochloride, emetine, polyaminopropyl
biguanide, paromomycin, benzimidazole, praziquantel, or
albendazole.
8) Steroid or Non-Steroidal Anti-Inflammatory Agents Useful in
Combination with the Compounds of the Invention
[0786] In one embodiment relating to autoimmune, allergic and
inflammatory conditions, the other therapeutic agent may be a
steroid or a non-steroidal anti-inflammatory agent. Particularly
useful non-steroidal anti-inflammatory agents, include, but are not
limited to, aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen,
flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen,
piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,
trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,
bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac,
tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac,
mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid,
tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam,
isoxicam; salicylic acid derivatives, including aspirin, sodium
salicylate, choline magnesium trisalicylate, salsalate, diflunisal,
salicylsalicylic acid, sulfasalazine, and olsalazin;
para-aminophennol derivatives including acetaminophen and
phenacetin; indole and indene acetic acids, including indomethacin,
sulindac, and etodolac; heteroaryl acetic acids, including
tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates),
including mefenamic acid, and meclofenamic acid; enolic acids,
including oxicams (piroxicam, tenoxicam), and pyrazolidinediones
(phenylbutazone, oxyphenthartazone); and alkanones, including
nabumetone and pharmaceutically acceptable salts thereof and
mixtures thereof. For a more detailed description of the NSAIDs,
see Paul A. Insel, Analgesic-Antipyretic and Antiinflammatory
Agents and Drugs Employed in the Treatment of Gout, in Goodman
& Gilman's The Pharmacological Basis of Therapeutics 617-57
(Perry B. Molinhoff and Raymond W. Ruddon eds., 9.sup.th ed 1996)
and Glen R. Hanson, Analgesic, Antipyretic and Anti-Inflammatory
Drugs in Remington: The Science and Practice of Pharmacy Vol II
1196-1221 (A. R. Gennaro ed. 19th ed. 1995) which are hereby
incorporated by reference in their entireties.
[0787] Of particular relevance to allergic disorders, the other
therapeutic agent may be an antihistamine. Useful antihistamines
include, but are not limited to, loratadine, cetirizine,
fexofenadine, desloratadine, diphenhydramine, chlorpheniramine,
chlorcyclizine, pyrilamine, promethazine, terfenadine, doxepin,
carbinoxamine, clemastine, tripelennamine, brompheniramine,
hydroxyzine, cyclizine, meclizine, cyproheptadine, phenindamine,
acrivastine, azelastine, levocabastine, and mixtures thereof. For a
more detailed description of antihistamines, see Goodman &
Gilman's The Pharmacological Basis of Therapeutics (2001) 651-57,
10.sup.th ed).
[0788] Immunosuppressive agents include glucocorticoids,
corticosteroids (such as Prednisone or Solumedrol), T cell blockers
(such as cyclosporin A and FK506), purine analogs (such as
azathioprine (Imuran)), pyrimidine analogs (such as cytosine
arabinoside), alkylating agents (such as nitrogen mustard,
phenylalanine mustard, buslfan, and cyclophosphamide), folic acid
antagonsists (such as aminopterin and methotrexate), antibiotics
(such as rapamycin, actinomycin D, mitomycin C, puramycin, and
chloramphenicol), human IgG, antilymphocyte globulin (ALG), and
antibodies (such as anti-CD3 (OKT3), anti-CD4 (OKT4), anti-CD5,
anti-CD7, anti-IL-2 receptor, anti-alpha/beta TCR, anti-ICAM-1,
anti-CD20 (Rituxan), anti-IL-12 and antibodies to
immunotoxins).
E. COMPOSITIONS AND METHODS FOR ADMINISTERING THERAPIES
[0789] The present invention provides compositions for the
treatment, prophylaxis, and amelioration of proliferative
disorders, such as cancer. In a specific embodiment, a composition
comprises one or more compounds of the invention, or a
pharmaceutically acceptable salt, solvate, clathrate, hydrate or
prodrug thereof. In another embodiment, a composition of the
invention comprises one or more prophylactic or therapeutic agents
other than a compound of the invention, or a pharmaceutically
acceptable salt, solvate, clathrate, hydrate, prodrug thereof. In
another embodiment, a composition of the invention comprises one or
more compounds of the invention, or a pharmaceutically acceptable
salt, solvate, clathrate, hydrate or prodrug thereof, and one or
more other prophylactic or therapeutic agents. In another
embodiment, the composition comprises a compound of the invention,
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate,
or prodrug thereof, and a pharmaceutically acceptable carrier,
diluent or excipient.
[0790] In a preferred embodiment, a composition of the invention is
a pharmaceutical composition or a single unit dosage form.
Pharmaceutical compositions and dosage forms of the invention
comprise one or more active ingredients in relative amounts and
formulated in such a way that a given pharmaceutical composition or
dosage form can be used to treat or prevent proliferative
disorders, such as cancer. Preferred pharmaceutical compositions
and dosage forms comprise a compound of formula (I)-(XV) or a
pharmaceutically acceptable prodrug, salt, solvate, clathrate,
hydrate, or prodrug thereof, optionally in combination with one or
more additional active agents.
[0791] The pharmaceutical compositions can be used in therapy,
e.g., to treat a mammal with an infection. In one embodiment, the
pharmaceutical composition includes one or more additional
therapeutic agents, such as one or more additional anti-infective
agents.
[0792] In another embodiment, the present invention is the use of a
compound of anyone of the formulas disclosed herein for the
manufacture of a medicament for treating a mammal with an
infection.
[0793] The pharmaceutical compositions can be used in therapy,
e.g., to treat a mammal with an inflammatory or immune disorder. In
one embodiment, the pharmaceutical composition includes one or more
additional therapeutic agent, such as one or more additional
anti-inflammatory agent or one or more immunosuppressant.
[0794] In another embodiment, the present invention is the use of a
compound of anyone of the formulas disclosed herein for the
manufacture of a medicament for treating a mammal with an
inflammatory or autoimmune disorder or for treatment of a mammal in
need of immunosuppression.
[0795] A pharmaceutical composition of the invention is formulated
to be compatible with its intended route of administration.
Examples of routes of administration include, but are not limited
to, parenteral, e.g., intravenous, intradermal, subcutaneous, oral
(e.g., inhalation), intranasal, transdermal (topical),
transmucosal, and rectal administration. In a specific embodiment,
the composition is formulated in accordance with routine procedures
as a pharmaceutical composition adapted for intravenous,
subcutaneous, intramuscular, oral, intranasal or topical
administration to human beings. In a preferred embodiment, a
pharmaceutical composition is formulated in accordance with routine
procedures for subcutaneous administration to human beings.
[0796] Single unit dosage forms of the invention are suitable for
oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or
rectal), parenteral (e.g., subcutaneous, intravenous, bolus
injection, intramuscular, or intraarterial), or transdermal
administration to a patient. Examples of dosage forms include, but
are not limited to: tablets; caplets; capsules, such as soft
elastic gelatin capsules; cachets; troches; lozenges; dispersions;
suppositories; ointments; cataplasms (poultices); pastes; powders;
dressings; creams; plasters; solutions; patches; aerosols (e.g.,
nasal sprays or inhalers); gels; liquid dosage forms suitable for
oral or mucosal administration to a patient, including suspensions
(e.g., aqueous or non-aqueous liquid suspensions, oil-in-water
emulsions, or a water-in-oil liquid emulsions), solutions, and
elixirs; liquid dosage forms suitable for parenteral administration
to a patient; and sterile solids (e.g., crystalline or amorphous
solids) that can be reconstituted to provide liquid dosage forms
suitable for parenteral administration to a patient.
[0797] The composition, shape, and type of dosage forms of the
invention will typically vary depending on their use. For example,
a dosage form suitable for mucosal administration may contain a
smaller amount of active ingredient(s) than an oral dosage form
used to treat the same indication. This aspect of the invention
will be readily apparent to those skilled in the art. See, e.g.,
Remington's Pharmaceutical Sciences (1990) 18th ed., Mack
Publishing, Easton Pa.
[0798] Typical pharmaceutical compositions and dosage forms
comprise one or more excipients. Suitable excipients are well known
to those skilled in the art of pharmacy, and non-limiting examples
of suitable excipients are provided herein. Whether a particular
excipient is suitable for incorporation into a pharmaceutical
composition or dosage form depends on a variety of factors well
known in the art including, but not limited to, the way in which
the dosage form will be administered to a patient. For example,
oral dosage forms such as tablets may contain excipients not suited
for use in parenteral dosage forms.
[0799] The suitability of a particular excipient may also depend on
the specific active ingredients in the dosage form. For example,
the decomposition of some active ingredients can be accelerated by
some excipients such as lactose, or when exposed to water. Active
ingredients that comprise primary or secondary amines (e.g.,
N-desmethylvenlafaxine and N,N-didesmethylvenlafaxine) are
particularly susceptible to such accelerated decomposition.
Consequently, this invention encompasses pharmaceutical
compositions and dosage forms that contain little, if any, lactose.
As used herein, the term "lactose-free" means that the amount of
lactose present, if any, is insufficient to substantially increase
the degradation rate of an active ingredient. Lactose-free
compositions of the invention can comprise excipients that are well
known in the art and are listed, for example, in the U.S.
Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose-free
compositions comprise active ingredients, a binder/filler, and a
lubricant in pharmaceutically compatible and pharmaceutically
acceptable amounts. Preferred lactose-free dosage forms comprise
active ingredients, microcrystalline cellulose, pre-gelatinized
starch, and magnesium stearate.
[0800] This invention further encompasses anhydrous pharmaceutical
compositions and dosage forms comprising active ingredients, since
water can facilitate the degradation of some compounds. For
example, the addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of simulating long-term storage in
order to determine characteristics such as shelf-life or the
stability of formulations over time. See, e.g., Jens T. Carstensen
(1995) Drug Stability: Principles & Practice, 2d. Ed., Marcel
Dekker, NY, N.Y., 379-80. In effect, water and heat accelerate the
decomposition of some compounds. Thus, the effect of water on a
formulation can be of great significance since moisture and/or
humidity are commonly encountered during manufacture, handling,
packaging, storage, shipment, and use of formulations.
[0801] Anhydrous pharmaceutical compositions and dosage forms of
the invention can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms that comprise lactose
and at least one active ingredient that comprises a primary or
secondary amine are preferably anhydrous if substantial contact
with moisture and/or humidity during manufacturing, packaging,
and/or storage is expected.
[0802] An anhydrous pharmaceutical composition should be prepared
and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions are preferably packaged using
materials known to prevent exposure to water such that they can be
included in suitable formulary kits. Examples of suitable packaging
include, but are not limited to, hermetically sealed foils,
plastics, unit dose containers (e.g., vials), blister packs, and
strip packs.
[0803] The invention further encompasses pharmaceutical
compositions and dosage forms that comprise one or more compounds
that reduce the rate by which an active ingredient will decompose.
Such compounds, which are referred to herein as "stabilizer"
include, but are not limited to, antioxidants such as ascorbic
acid, pH buffers, or salt buffers.
1) Oral Dosage Forms
[0804] Pharmaceutical compositions of the invention that are
suitable for oral administration can be presented as discrete
dosage forms, such as, but are not limited to, tablets (e.g.,
chewable tablets), caplets, capsules, and liquids (e.g., flavored
syrups). Such dosage forms contain predetermined amounts of active
ingredients, and may be prepared by methods of pharmacy well known
to those skilled in the art. See generally, Remington's
Pharmaceutical Sciences (1990) 18th ed., Mack Publishing, Easton
Pa.
[0805] Typical oral dosage forms of the invention are prepared by
combining the active ingredient(s) in an admixture with at least
one excipient according to conventional pharmaceutical compounding
techniques. Excipients can take a wide variety of forms depending
on the form of preparation desired for administration. For example,
excipients suitable for use in oral liquid or aerosol dosage forms
include, but are not limited to, water, glycols, oils, alcohols,
flavoring agents, preservatives, and coloring agents. Examples of
excipients suitable for use in solid oral dosage forms (e.g.,
powders, tablets, capsules, and caplets) include, but are not
limited to, starches, sugars, micro-crystalline cellulose,
diluents, granulating agents, lubricants, binders, and
disintegrating agents.
[0806] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit forms, in
which case solid excipients are employed. If desired, tablets can
be coated by standard aqueous or nonaqueous techniques. Such dosage
forms can be prepared by any of the methods of pharmacy. In
general, pharmaceutical compositions and dosage forms are prepared
by uniformly and intimately admixing the active ingredients with
liquid carriers, finely divided solid carriers, or both, and then
shaping the product into the desired presentation if necessary.
[0807] For example, a tablet can be prepared by compression or
molding. Compressed tablets can be prepared by compressing in a
suitable machine the active ingredients in a free-flowing form such
as powder or granules, optionally mixed with an excipient. Molded
tablets can be made by molding in a suitable machine a mixture of
the powdered compound moistened with an inert liquid diluent.
[0808] Examples of excipients that can be used in oral dosage forms
of the invention include, but are not limited to, binders, fillers,
disintegrants, and lubricants. Binders suitable for use in
pharmaceutical compositions and dosage forms include, but are not
limited to, corn starch, potato starch, or other starches, gelatin,
natural and synthetic gums such as acacia, sodium alginate, alginic
acid, other alginates, powdered tragacanth, guar gum, cellulose and
its derivatives (e.g., ethyl cellulose, cellulose acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),
polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,
hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910),
microcrystalline cellulose, and mixtures thereof.
[0809] Suitable forms of microcrystalline cellulose include, but
are not limited to, the materials sold as AVICEL-PH-101,
AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC
Corporation, American Viscose Division, Avicel Sales, Marcus Hook,
Pa.), and mixtures thereof. One specific binder is a mixture of
microcrystalline cellulose and sodium carboxymethyl cellulose sold
as AVICEL RC-581. Suitable anhydrous or low moisture excipients or
additives include AVICEL-PH-103J and Starch 1500 LM.
[0810] Examples of fillers suitable for use in the pharmaceutical
compositions and dosage forms disclosed herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof. The binder or filler in pharmaceutical
compositions of the invention is typically present in from about 50
to about 99 weight percent of the pharmaceutical composition or
dosage form.
[0811] Disintegrants are used in the compositions of the invention
to provide tablets that disintegrate when exposed to an aqueous
environment. Tablets that contain too much disintegrant may
disintegrate in storage, while those that contain too little may
not disintegrate at a desired rate or under the desired conditions.
Thus, a sufficient amount of disintegrant that is neither too much
nor too little to detrimentally alter the release of the active
ingredients should be used to form solid oral dosage forms of the
invention. The amount of disintegrant used varies based upon the
type of formulation, and is readily discernible to those of
ordinary skill in the art. Typical pharmaceutical compositions
comprise from about 0.5 to about 15 weight percent of disintegrant,
preferably from about 1 to about 5 weight percent of
disintegrant.
[0812] Disintegrants that can be used in pharmaceutical
compositions and dosage forms of the invention include, but are not
limited to, agar-agar, alginic acid, calcium carbonate,
microcrystalline cellulose, croscarmellose sodium, crospovidone,
polacrilin potassium, sodium starch glycolate, potato or tapioca
starch, other starches, pre-gelatinized starch, other starches,
clays, other algins, other celluloses, gums, and mixtures
thereof.
[0813] Lubricants that can be used in pharmaceutical compositions
and dosage forms of the invention include, but are not limited to,
calcium stearate, magnesium stearate, mineral oil, light mineral
oil, glycerin, sorbitol, mannitol, polyethylene glycol, other
glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated
vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil,
sesame oil, olive oil, corn oil, and soybean oil), zinc stearate,
ethyl oleate, ethyl laureate, agar, and mixtures thereof.
Additional lubricants include, for example, a syloid silica gel
(AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, Md.), a
coagulated aerosol of synthetic silica (marketed by Degussa Co. of
Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold
by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at
all, lubricants are typically used in an amount of less than about
1 weight percent of the pharmaceutical compositions or dosage forms
into which they are incorporated.
2) Controlled Release Dosage Forms
[0814] Active ingredients of the invention can be administered by
controlled release means or by delivery devices that are well known
to those of ordinary skill in the art. Examples include, but are
not limited to, those described in U.S. Pat. Nos. 3,845,770;
3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533,
5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556,
and 5,733,566, each of which is incorporated herein by reference.
Such dosage forms can be used to provide slow or controlled-release
of one or more active ingredients using, for example,
hydropropylmethyl cellulose, other polymer matrices, gels,
permeable membranes, osmotic systems, multilayer coatings,
microparticles, liposomes, microspheres, or a combination thereof
to provide the desired release profile in varying proportions.
Suitable controlled-release formulations known to those of ordinary
skill in the art, including those described herein, can be readily
selected for use with the active ingredients of the invention. The
invention thus encompasses single unit dosage forms suitable for
oral administration such as, but not limited to, tablets, capsules,
gelcaps, and caplets that are adapted for controlled-release.
[0815] All controlled-release pharmaceutical products have a common
goal of improving drug therapy over that achieved by their
non-controlled counterparts. Ideally, the use of an optimally
designed controlled-release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled-release formulations include extended activity of the
drug, reduced dosage frequency, and increased patient
compliance.
[0816] Most controlled-release formulations are designed to
initially release an amount of drug (active ingredient) that
promptly produces the desired therapeutic effect, and gradually and
continually release of other amounts of drug to maintain this level
of therapeutic or prophylactic effect over an extended period of
time. In order to maintain this constant level of drug in the body,
the drug must be released from the dosage form at a rate that will
replace the amount of drug being metabolized and excreted from the
body. Controlled-release of an active ingredient can be stimulated
by various conditions including, but not limited to, pH,
temperature, enzymes, water, or other physiological conditions or
compounds.
[0817] A particular extended release formulation of this invention
comprises a therapeutically or prophylactically effective amount of
a compound of formula (I)-(XV), or a pharmaceutically acceptable
salt, solvate, hydrate, clathrate, or prodrug thereof, in spheroids
which further comprise microcrystalline cellulose and, optionally,
hydroxypropylmethylcellulose coated with a mixture of ethyl
cellulose and hydroxypropylmethylcellulose. Such extended release
formulations can be prepared according to U.S. Pat. No. 6,274,171,
the entirely of which is incorporated herein by reference.
[0818] A specific controlled-release formulation of this invention
comprises from about 6% to about 40% a compound of formula
(I)-(XV), or a pharmaceutically acceptable salt, solvate, hydrate,
clathrate, or prodrug thereof, by weight, about 50% to about 94%
microcrystalline cellulose, NF, by weight, and optionally from
about 0.25% to about 1% by weight of hydroxypropyl-methylcellulose,
USP, wherein the spheroids are coated with a film coating
composition comprised of ethyl cellulose and
hydroxypropylmethylcellulose.
3) Parenteral Dosage Forms
[0819] Parenteral dosage forms can be administered to patients by
various routes including, but not limited to, subcutaneous,
intravenous (including bolus injection), intramuscular, and
intraarterial. Because their administration typically bypasses
patients' natural defenses against contaminants, parenteral dosage
forms are preferably sterile or capable of being sterilized prior
to administration to a patient. Examples of parenteral dosage forms
include, but are not limited to, solutions ready for injection, dry
products ready to be dissolved or suspended in a pharmaceutically
acceptable vehicle for injection, suspensions ready for injection,
and emulsions.
[0820] Suitable vehicles that can be used to provide parenteral
dosage forms of the invention are well known to those skilled in
the art. Examples include, but are not limited to: Water for
Injection USP; aqueous vehicles such as, but not limited to, Sodium
Chloride Injection, Ringer's Injection, Dextrose Injection,
Dextrose and Sodium Chloride Injection, and
[0821] Lactated Ringer's Injection; water-miscible vehicles such
as, but not limited to, ethyl alcohol, polyethylene glycol, and
polypropylene glycol; and non-aqueous vehicles such as, but not
limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl
oleate, isopropyl myristate, and benzyl benzoate.
[0822] Compounds that increase the solubility of one or more of the
active ingredients disclosed herein can also be incorporated into
the parenteral dosage forms of the invention.
4) Transdermal, Topical, and Mucosal Dosage Forms
[0823] Transdermal, topical, and mucosal dosage forms of the
invention include, but are not limited to, ophthalmic solutions,
sprays, aerosols, creams, lotions, ointments, gels, solutions,
emulsions, suspensions, or other forms known to one of skill in the
art. See, e.g., Remington's Pharmaceutical Sciences (1980 &
1990) 16th and 18th eds., Mack Publishing, Easton Pa. and
Introduction to Pharmaceutical Dosage Forms (1985) 4th ed., Lea
& Febiger, Philadelphia. Dosage forms suitable for treating
mucosal tissues within the oral cavity can be formulated as
mouthwashes or as oral gels. Further, transdermal dosage forms
include "reservoir type" or "matrix type" patches, which can be
applied to the skin and worn for a specific period of time to
permit the penetration of a desired amount of active ingredients.
Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide transdermal, topical, and
mucosal dosage forms encompassed by this invention are well known
to those skilled in the pharmaceutical arts, and depend on the
particular tissue to which a given pharmaceutical composition or
dosage form will be applied. With that fact in mind, typical
excipients include, but are not limited to, water, acetone,
ethanol, ethylene glycol, propylene glycol, butane-1,3-diol,
isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures
thereof to form lotions, tinctures, creams, emulsions, gels or
ointments, which are non-toxic and pharmaceutically acceptable.
Moisturizers or humectants can also be added to pharmaceutical
compositions and dosage forms if desired. Examples of such
additional ingredients are well known in the art. See, e.g.,
Remington's Pharmaceutical Sciences (1980 & 1990) 16th and 18th
eds., Mack Publishing, Easton Pa.
[0824] Depending on the specific tissue to be treated, additional
components may be used prior to, in conjunction with, or subsequent
to treatment with active ingredients of the invention. For example,
penetration enhancers can be used to assist in delivering the
active ingredients to the tissue. Suitable penetration enhancers
include, but are not limited to: acetone; various alcohols such as
ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as
dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide;
polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone;
Kollidon grades (Povidone, Polyvidone); urea; and various
water-soluble or insoluble sugar esters such as Tween 80
(polysorbate 80) and Span 60 (sorbitan monostearate).
[0825] The pH of a pharmaceutical composition or dosage form, or of
the tissue to which the pharmaceutical composition or dosage form
is applied, may also be adjusted to improve delivery of one or more
active ingredients. Similarly, the polarity of a solvent carrier,
its ionic strength, or tonicity can be adjusted to improve
delivery. Compounds such as stearates can also be added to
pharmaceutical compositions or dosage forms to advantageously alter
the hydrophilicity or lipophilicity of one or more active
ingredients so as to improve delivery. In this regard, stearates
can serve as a lipid vehicle for the formulation, as an emulsifying
agent or surfactant, and as a delivery-enhancing or
penetration-enhancing agent. Different salts, hydrates or solvates
of the active ingredients can be used to further adjust the
properties of the resulting composition.
5) Dosage & Frequency of Administration
[0826] The amount of the compound or composition of the invention
which will be effective in the prevention, treatment, management,
or amelioration of a disease or disorder, e.g. a proliferative
disorders, such as cancer, or one or more symptoms thereof, will
vary with the nature and severity of the disease or condition, and
the route by which the active ingredient is administered. The
frequency and dosage will also vary according to factors specific
for each patient depending on the specific therapy (e.g.,
therapeutic or prophylactic agents) administered, the severity of
the disorder, disease, or condition, the route of administration,
as well as age, body, weight, response, and the past medical
history of the patient. Effective doses may be extrapolated from
dose-response curves derived from in vitro or animal model test
systems. Suitable regiments can be selected by one skilled in the
art by considering such factors and by following, for example,
dosages reported in the literature and recommended in the
Physician's Desk Reference (57th ed., 2003).
[0827] Exemplary doses of a small molecule include milligram or
microgram amounts of the small molecule per kilogram of subject or
sample weight (e.g., about 1 microgram per kilogram to about 500
milligrams per kilogram, about 100 micrograms per kilogram to about
5 milligrams per kilogram, or about 1 microgram per kilogram to
about 50 micrograms per kilogram).
[0828] In general, the recommended daily dose range of a compound
of the invention for the conditions described herein lie within the
range of from about 0.01 mg to about 1000 mg per day, given as a
single once-a-day dose preferably as divided doses throughout a
day. In one embodiment, the daily dose is administered twice daily
in equally divided doses. Specifically, a daily dose range should
be from about 5 mg to about 500 mg per day, more specifically,
between about 10 mg and about 200 mg per day. In managing the
patient, the therapy should be initiated at a lower dose, perhaps
about 1 mg to about 25 mg, and increased if necessary up to about
200 mg to about 1000 mg per day as either a single dose or divided
doses, depending on the patient's global response. It may be
necessary to use dosages of the active ingredient outside the
ranges disclosed herein in some cases, as will be apparent to those
of ordinary skill in the art. Furthermore, it is noted that the
clinician or treating physician will know how and when to
interrupt, adjust, or terminate therapy in conjunction with
individual patient response.
[0829] Different therapeutically effective amounts may be
applicable for different disease or disorder, e.g. a proliferative
disorders, as will be readily known by those of ordinary skill in
the art. Similarly, amounts sufficient to prevent, manage, treat or
ameliorate such a disease or disorder, e.g. proliferative
disorders, but insufficient to cause, or sufficient to reduce,
adverse effects associated with the compounds of the invention are
also encompassed by the above described dosage amounts and dose
frequency schedules. Further, when a patient is administered
multiple dosages of a compound of the invention, not all of the
dosages need be the same. For example, the dosage administered to
the patient may be increased to improve the prophylactic or
therapeutic effect of the compound or it may be decreased to reduce
one or more side effects that a particular patient is
experiencing.
[0830] In a specific embodiment, the dosage of the composition of
the invention or a compound of the invention administered to
prevent, treat, manage, or ameliorate a disorders, such as cancer,
or one or more symptoms thereof in a patient is 150 .mu.g/kg,
preferably 250 .mu.g/kg, 500 .mu.g/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg,
25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, or
200 mg/kg or more of a patient's body weight. In another
embodiment, the dosage of the composition of the invention or a
compound of the invention administered to prevent, treat, manage,
or ameliorate a proliferative disorders, such as cancer, or one or
more symptoms thereof in a patient is a unit dose of 0.1 mg to 20
mg, 0.1 mg to 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8
mg, 0.1 mg to 7 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20
mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25
mg to 7m g, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg
to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg,
1 mg to 5 mg, or 1 mg to 2.5 mg.
[0831] The dosages of prophylactic or therapeutic agents other than
compounds of the invention, which have been or are currently being
used to prevent, treat, manage, or ameliorate diseases or
disorders, e.g. proliferative disorders, such as cancer, or one or
more symptoms thereof can be used in the combination therapies of
the invention. Preferably, dosages lower than those which have been
or are currently being used to prevent, treat, manage, or
ameliorate a disease or disorder, e.g. proliferative disorders, or
one or more symptoms thereof, are used in the combination therapies
of the invention. The recommended dosages of agents currently used
for the prevention, treatment, management, or amelioration of a
disease or disorder, e.g. proliferative disorders, such as cancer,
or one or more symptoms thereof, can obtained from any reference in
the art including, but not limited to, Hardman et al., eds., 1996,
Goodman & Gilman's The Pharmacological Basis Of Basis Of
Therapeutics 9.sup.th Ed, Mc-Graw-Hill, New York; Physician's Desk
Reference (PDR) 57.sup.th Ed., 2003, Medical Economics Co., Inc.,
Montvale, N.J., which are incorporated herein by reference in its
entirety.
[0832] In certain embodiments, when the compounds of the invention
are administered in combination with another therapy, the therapies
(e.g., prophylactic or therapeutic agents) are administered less
than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at
about 1 hour apart, at about 1 to about 2 hours apart, at about 2
hours to about 3 hours apart, at about 3 hours to about 4 hours
apart, at about 4 hours to about 5 hours apart, at about 5 hours to
about 6 hours apart, at about 6 hours to about 7 hours apart, at
about 7 hours to about 8 hours apart, at about 8 hours to about 9
hours apart, at about 9 hours to about 10 hours apart, at about 10
hours to about 11 hours apart, at about 11 hours to about 12 hours
apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours
apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48
hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72
hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours
apart, or 96 hours to 120 hours part. In one embodiment, two or
more therapies (e.g., prophylactic or therapeutic agents) are
administered within the same patent visit.
[0833] In certain embodiments, one or more compounds of the
invention and one or more other the therapies (e.g., prophylactic
or therapeutic agents) are cyclically administered. Cycling therapy
involves the administration of a first therapy (e.g., a first
prophylactic or therapeutic agents) for a period of time, followed
by the administration of a second therapy (e.g., a second
prophylactic or therapeutic agents) for a period of time, followed
by the administration of a third therapy (e.g., a third
prophylactic or therapeutic agents) for a period of time and so
forth, and repeating this sequential administration, i.e., the
cycle in order to reduce the development of resistance to one of
the agents, to avoid or reduce the side effects of one of the
agents, and/or to improve the efficacy of the treatment.
[0834] In certain embodiments, administration of the same compound
of the invention may be repeated and the administrations may be
separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15
days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
In other embodiments, administration of the same prophylactic or
therapeutic agent may be repeated and the administration may be
separated by at least at least 1 day, 2 days, 3 days, 5 days, 10
days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6
months.
[0835] In a specific embodiment, the invention provides a method of
preventing, treating, managing, or ameliorating proliferative
disorders, such as cancer, or one or more symptoms thereof, said
methods comprising administering to a subject in need thereof a
dose of at least 150 .mu.g/kg, preferably at least 250 .mu.g/kg, at
least 500 .mu.g/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10
mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at
least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at
least 200 mg/kg or more of one or more compounds of the invention
once every day, preferably, once every 2 days, once every 3 days,
once every 4 days, once every 5 days, once every 6 days, once every
7 days, once every 8 days, once every 10 days, once every two
weeks, once every three weeks, or once a month.
F. OTHER EMBODIMENTS
[0836] The compounds of the invention may be used as research tools
(for example, to evaluate the mechanism of action of new drug
agents, to isolate new drug discovery targets using affinity
chromatography, as antigens in an ELISA or ELISA-like assay, or as
standards in in vitro or in vivo assays). These and other uses and
embodiments of the compounds and compositions of this invention
will be apparent to those of ordinary skill in the art.
[0837] The invention is further defined by reference to the
following examples describing in detail the preparation of
compounds of the invention. It will be apparent to those skilled in
the art that many modifications, both to materials and methods, may
be practiced without departing from the purpose and interest of
this invention. The following examples are set forth to assist in
understanding the invention and should not be construed as
specifically limiting the invention described and claimed herein.
Such variations of the invention, including the substitution of all
equivalents now known or later developed, which would be within the
purview of those skilled in the art, and changes in formulation or
minor changes in experimental design, are to be considered to fall
within the scope of the invention incorporated herein.
EXAMPLES
Example 1
Compound 7
General Procedure:
##STR00281##
[0839] To a stirred suspension of 1.10 g (2.90 mmols) of
4-isopropyl-6-(5-mercapto-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-y-
l)benzene-1,3-diol, 2.0 g (14.45 mmols) of K.sub.2CO.sub.3 in 25 mL
of anhydrous DMF was added 0.48 g (2.89 mmols) of 3-picolyl
chloride hydrochloride portion wise, over 2 min. The reaction
mixture was stirred at room temperature for 2 h and diluted with 50
mL of water. The resultant solution was then adjusted to pH 7
approximately with saturated NH.sub.4Cl solution and the white
precipitate was extracted with ethyl acetate (15 mL.times.3) and
the combined extracts were washed with water (10 mL.times.4) and
dried over anhydrous Na.sub.2SO.sub.4. The solution was then
filtered through a short pad of silica gel and concentrated. The
crude product thus obtained was then reprecipitated using anhydrous
ether to obtain 1.0 g (74%) of the product Compound 7 as an off
white solid.
[0840] .sup.1H NMR (300 MHz, DMSO-D6) .delta. 10.91 (s, 1H), 9.71
(s, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.46 (dd, J=1.8 Hz, 5.1 Hz, 1H)
7.79 (dd, J=1.8, 6.3 Hz, 1H), 0.60 (d, J=8.4 Hz, 1H), 7.51-7.49 (m,
2H), 7.34 (dd, J=4.5, 8.1 Hz, 1H), 7.02 (dd, J=2.1, 8.4 Hz, 1H),
6.50 (d, J=3.0 Hz, 1H), 6.43 (s, 1H), 6.31 (s, 1H), 4.41 (s, 2H),
3.84 (s, 3H), 2.90 (sept., J=6.9 Hz, 1H), 0.56 (d, J=6.9 Hz,
6H).
[0841] ESMS clcd for C.sub.26H.sub.25N.sub.5O.sub.2S: 471.17.
Found: 472.2 (M+H).sup.+.
Compound 1
[0842] .sup.1H NMR (300 MHz, DMSO-D6) .delta. 10.97 (s, 1H), 9.70
(s, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.47 (d, J=3.0 Hz, 1H), 7.46 (s,
1H), 7.25 (d, J=8.7 Hz, 2H), 7.00 (dd, J=2.1 Hz, 8.7 Hz, 1H), 6.83
(d, J=8.7 Hz, 2H), 6.46 (d, J=3.0 Hz, 1H), 6.40 (s, 1H), 6.30 (s,
1H), 4.32 (s, 2H), 3.81 (s, 3H), 3.70 (s, 3H), 2.76 (sept., J=6.9
Hz, 1H), 0.54 (d, J=6.9 Hz, 6H).
[0843] ESMS clcd for C.sub.28H.sub.28N.sub.4O.sub.3S: 500.19.
Found: 501.2 (M+H).sup.+.
Compound 2
[0844] .sup.1H NMR (300 MHz, DMSO-D6) .delta. 10.94 (s, 1H), 9.74
(s, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.50 (d, J=2.4 Hz, 2H), 7.47-7.37
(m, 1H), 7.10 (t, J=8.1 Hz, 2H), 7.05 (dd, J=2.4, 8.4 Hz, 1H), 6.50
(d, J=3.0 Hz, 1H), 6.43 (s, 1H), 6.32 (s, 1H), 4.33 (s, 2H), 3.84
(s, 3H), 2.79 (sept., J=6.9 Hz, 1H), 0.57 (d, J=6.9 Hz, 6H).
[0845] ESMS clcd for C.sub.27H.sub.24F.sub.2N.sub.4O.sub.2S:
506.16. Found: 507.2 (M+H).sup.+.
Compound 3
[0846] .sup.1H NMR (300 MHz, DMSO-D6) .delta. 10.88 (s, 1H), 9.72
(s, 1H), 7.69-7.57 (m, 5H), 7.49 (d, J=3.3 Hz, 1H), 7.46 (d, J=2.4
Hz, 1H), 7.02 (dd, J=2.1, 8.4 Hz, 1H), 6.47 (d, J=3.3 Hz, 1H), 6.43
(s, 1H), 6.31 (s, 1H), 4.47 (s, 2H), 3.84 (s, 3H), 2.79 (sept,
J=6.9 Hz, 1H), 0.57 (d, J=6.9 Hz, 6H).
[0847] ESMS clcd for C.sub.28H.sub.25F.sub.3N.sub.4O.sub.2S:
538.17. Found: 539.2 (M+H).sup.+.
Compound 4
[0848] .sup.1H NMR (300 MHz, DMSO-D6) .delta. 10.76 (s, 1H), 9.75
(bs, 1H), 7.62 (s, 1H), 7.61 (d, J=6.3 Hz, 1H), 7.51 (d, J=3.0 Hz,
1H), 7.10 (dd, J=2.1, 8.4 Hz, 1H), 6.51 (d, J=3.0 Hz, 1H), 6.49 (s,
1H), 6.31 (s, 1H), 5.52 (s, 1H), 4.00 (s, 2H), 3.84 (s, 3H), 2.80
(sept, J=7.2 Hz, 1H), 0.61 (d, J=7.2H, 6H).
[0849] ESMS clcd for C.sub.25H.sub.24N.sub.6O.sub.4S: 504.16.
Found: 505.2 (M+H).sup.+.
Compound 5
[0850] .sup.1H NMR (300 MHz, DMSO-D6) .delta. 10.97 (s, 1H), 9.75
(bs, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.50 (d,
J=3.3 Hz, 1H), 7.38 (s, 1H), 7.07 (dd, J=1.8, 8.7 Hz, 1H), 6.50 (d,
J=3.3 Hz, 1H), 6.44 (s, 1H), 6.33 (s, 1H), 4.43 (s, 2H), 3.84 (s,
3H), 2.79 (sept, J=6.9 Hz, 1H), 2.58 (s, 3H), 0.57 (d, J=6.9 Hz,
6H).
[0851] ESMS clcd for C.sub.25H.sub.25N.sub.5O.sub.2S.sub.2: 491.14.
Found: 492.3 (M+H).sup.+.
Compound 6
[0852] .sup.1H NMR (300 MHz, DMSO-D6) .delta. 10.92 (s, 1H), 9.71
(s, 1H), 7.70 (bs, 1H), 7.65-7.63 (m, 2H), 7.52 (d, J=3.0 Hz, 1H),
7.27 (bs, 1H), 7.13 (dd, J=2.1, 8.7 Hz, 1H), 6.53 (d, J=3.0 Hz,
1H), 6.46 (s, 1H), 6.31 (s, 1H), 3.93 (s, 2H), 3.85 (s, 3H), 2.79
(sept. J=6.9 Hz, 1H), 0.58 (d, J=6.9 Hz, 6H).
[0853] ESMS clcd for C.sub.22H.sub.23N.sub.5O.sub.3S: 437.15.
Found: 438.3 (M+H).+-..
Compound 8
[0854] .sup.1H NMR (300 MHz, DMSO-D6) .delta. 10.97 (s, 1H), 9.72
(s, 1H), 8.46 (dq, J=0.9, 5.1 Hz, 1H), 7.76 (td, J=1.8, 7.5 Hz,
1H), 7.61 (d, J=8.4 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.51-7.48 (m,
2H), 7.29 (ddd, J=1.2, 4.8, 7.5 Hz, 1H), 7.09 (dd, J=2.1, 8.7 Hz,
1H), 6.51 (dd, J=0.9, 3.0 Hz, 1H), 6.44 (s, 1H), 6.32 (s, 1H), 4.52
(s, 2H), 3.85 (s, 3H), 2.79 (sept., J=6.9 Hz, 1H), 0.57 (d, J=6.9
Hz, 6H).
[0855] ESMS clcd for C.sub.26H.sub.25N.sub.5O.sub.2S: 471.17.
Found: 472.3 (M+H).sup.+.
Compound 9
[0856] .sup.1H NMR (300 MHz, DMSO-D6) .delta. 10.87 (s, 1H), 9.71
(s, 1H), 8.50 (d, J=6.0 Hz, 2H), 7.61 (d, J=8.7 Hz, 1H), 7.53 (d,
J=1.8 Hz, 1H), 7.50 (d, J=3.0 Hz, 1H), 7.39 (d, J=6.0 Hz, 2H), 7.05
(dd, J=2.1, 8.7 Hz, 1H), 6.50 (d, J=3.0 Hz, 1H), 6.44 (s, 1H), 6.30
(s, 1H), 4.39 (s, 2H), 3.84 (s, 3H), 2.79 (sept., J=6.9 Hz, 1H),
0.57 (d, J=6.9 Hz, 6H).
[0857] ESMS clcd for C.sub.26H.sub.25N.sub.5O.sub.2S: 471.17.
Found: 472.3 (M+H).sup.+.
Compound 10
[0858] .sup.1H NMR (300 MHz, DMSO-D6) .delta. 10.76 (s, 1H), 9.72
(s, 1H), 7.67-7.62 (m, 2H), 7.51 (d, J=3.0 Hz, 1H), 7.13 (dd,
J=2.1, 8.7 Hz, 1H), 7.53 (d, J=3.0 Hz, 1H), 6.50 (s, 1H), 6.31 (s,
1H), 4.64 (t, J=9.3 Hz, 1H), 4.45-4.26 (m, 2H), 3.85 (s, 3H),
2.83-2.71 (m, 2H), 2.55-2.45 (m, 1H), 0.61 (d, J=6.6 Hz, 6H).
[0859] ESMS clcd for C.sub.24H.sub.24N.sub.4O.sub.4S: 464.15.
Found: 465.3 (M+H).sup.+.
Compound 11
[0860] .sup.1H NMR (300 MHz, DMSO-D6) .delta. 11.02 (s, 1H), 9.72
(s, 1H), 7.61 (d, J=9.0 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H), 7.50 (d,
J=3.3 Hz, 1H), 7.09 (dd, J=2.1, 9.0 Hz, 1H), 6.97 (s, 2H), 6.51 (d,
J=3.0 Hz, 1H), 6.44 (s, 1H), 6.43 (s, 1H), 6.32 (s, 1H), 4.20 (s,
2H), 3.85 (s, 3H), 2.79 (sept., J=6.9 Hz, 1H), 0.56 (d, J=6.9 Hz,
6H).
[0861] ESMS clcd for C.sub.24H.sub.24N.sub.6O.sub.2S.sub.2: 492.14.
Found: 493.2 (M+H).sup.+.
Compound 12
[0862] .sup.1H NMR (300 MHz, DMSO-D6) .delta. 10.82 (s, 1H), 9.71
(s, 1H), 8.78 (s, 1H), 8.11 (d, J=7.8 Hz, 1H), 7.87 (d, J=8.1 Hz,
1H), 7.79 (d, J=8.7 Hz, 1H), 7.51-7.49 (m, 2H), 7.04 (dd, J=2.1,
8.7 Hz, 1H), 6.48 (d, J=3.0 Hz, 1H), 6.45 (s, 1H), 6.30 (s, 1H),
4.50 (s, 2H), 3.84 (s, 3H), 2.79 (sept., J=6.9 Hz, 1H), 0.58 (d,
J=6.9 Hz, 6H).
[0863] ESMS clcd for C.sub.27H.sub.24F.sub.3N.sub.5O.sub.2S:
539.16. Found: 540.3 (M+H).sup.+.
Compound 14
[0864] ESMS clcd for C.sub.27H.sub.31N.sub.5O.sub.2S: 489.22.
Found: 490.4 (M+H).sup.+.
Compound 13
[0865] .sup.1H NMR (300 MHz, DMSO-D6) .delta. 9.94 (s, 1H), 9.71
(s, 1H), 8.54 (d, J=2.1 Hz, 1H), 8.46 (d, J=3.6 Hz, 1H), 7.74 (d,
J=7.8 Hz, 1H), 7.33 (dd, J=4.5, 7.5 Hz, 1H), 7.15 (d, J=8.1 Hz,
2H), 6.82 (s, 1H), 6.81 (d, J=8.1 Hz, 2H), 6.47 (s, 1H), 4.97 (s,
2H), 4.37 (s, 2H), 4.31 (s, 2H), 3.21 (s, 3H), 2.70 (sept., J=6.9
Hz, 1H), 1.01 (d, J=6.9 Hz, 6H).
[0866] ESMS clcd for C.sub.26H.sub.28N.sub.4O.sub.3S: 476.19.
Found: 477.3 (M+H).sup.+.
Compound 15
[0867] .sup.1H NMR (300 MHz, DMSO-D6) .delta. 10.80 (s, 1H), 9.77
(s, 1H), 9.57 (d, J=1.5 Hz, 1H), 8.46 (dd, J=1.8, 4.8 Hz, 1H), 7.79
(dt, J=2.1, 8.1 Hz, 1H), 7.39-7.32 (m, 2H), 7.14 (s, 1H), 7.08 (dd,
J=2.1, 7.8 Hz, 1H), 6.51 (s, 1H), 6.33 (s, 1H), 4.40 (s, 2H),
4.24-4.20 (m, 1H), 3.24 (s, 3H), 3.17-3.04 (m, 2H), 2.95-2.84 (m,
3H), 0.76 (dd, J=3.3, 6.9 Hz, 6H).
[0868] ESMS clcd for C.sub.27H.sub.28N.sub.4O.sub.3S: 488.19.
Found: 489.3 (M+H).sup.+.
Compound 21
[0869] .sup.1H NMR (300 MHz, DMSO-D6) .delta. 11.08 (s, 1H), 9.75
(s, 1H), 8.58 (d, J=1.8 Hz, 1H), 8.46 (dd, J=1.5, 4.8 Hz, 1H), 7.79
(d, J=7.8 Hz, 1H), 7.67 (d, J=9.3 Hz, 1H), 7.56 (d, J=3.0 Hz, 1H),
7.52 (d, J=1.8 Hz, 1H), 7.34 (dd, J=4.8, 7.8 Hz, 1H), 7.03 (dd,
J=2.1, 8.7 Hz, 1H), 6.50 (d, J=3.3 Hz, 1H), 6.37 (s, 1H), 6.32 (s,
1H), 4.42 (s, 2H), 4.32 (t, J=6.6 Hz, 2H), 2.77 (sept., J=6.6 Hz,
1H), 2.58 (t, J=6.9 Hz, 2H), 0.52 (d, J=6.6 Hz, 6H).
[0870] ESMS clcd for C.sub.29H.sub.32N.sub.6O.sub.2S: 528.23.
Found: 529.5 (M+H).sup.+.
Compound 20
##STR00282##
[0871] Procedure:
[0872] 2,4-Dibenzyloxy-5-isopropylbenzoic acid (5.64 g, 15.0 mmol,
1.00 equiv.) in 80 mL dichloromethane at room temperature was
treated with oxalyl chloride (2.00 g, 15.75 mmol, 1.05 equiv.) and
catalytic amount of DMF (0.1 mL) for 1 hour. Solvent and excess
(COCl).sub.2 were removed on rotary evaporator. The residue was
dissolved in 100 mL dichloromethane, and treated with
1,3-dimethyl-5-aminoindole (2.40 g, 15.0 mmol, 1.00 equiv.) and
triethylamine (2.28 g, 22.5 mmol, 1.50 equiv.) at 0.degree. C. for
one hour. Normal aqueous workup and removal of solvent gave a light
brown solid that was washed with ether to yield
2,4-dibenzyloxy-5-isopropyl-N-(1-methyl-1H-indol-5-yl)-benzamide
(A) as off-white solid (7.20 g, 14.3 mmol, 95%)
[0873] Benzamide (A) was treated with Lawesson's reagent (3.46 g,
8.58 mmol, 0.6 equiv.) in 80 mL toluene at 110.degree. C. for three
hours. The reaction mixture was cooled to 0.degree. C., and treated
with hydrazine hydrate (1.50 g, 30 mmol) at 0.degree. C. for 10
minutes to decompose by-product and excess reagent. Normal
EtOAc/water workup, followed by recrystallization in EtOAc/hexane
yielded
2,4-dibenzyloxy-5-isopropyl-N-(1-methyl-1H-indol-5-yl)-thiobenzamide
(B) as yellow solid (6.20 g, 12. mmol, 83%).
[0874] Thiobenzamide (B) (4.68 g, 9.0 mmol, 1.0 equiv.) was
dissolved in 50 mL dioxane at 80.degree. C. Anhydrous hydrazine
(1.2 g, 36 mmol, 40.0 equiv.) was added under vigorous stirring and
heated at 80.degree. C. for 30 minutes. The mixture was cooled to
0.degree. C., and subjected to EtOAc/water workup. Flash column
purification yielded desired intermediate (C) as light yellow solid
(3.96 g, 7.64 mmol, 85%)
[0875] Chloroacetyl chloride (0.056 g, 0.5 mmol, 1.0 equiv.) in 10
mL CH.sub.2Cl.sub.2 at 0.degree. C. was treated with imidazole
(0.068 g, 1.0 mmol, 2.0 equiv.) for 10 minutes. Solvent was
removed, and the residue was mixed with intermediate (C) (0.26 g,
0.50 mmol, 1.0 equiv.) in 10 mL THF at 0.degree. C. for 30 minutes,
then heated at reflux for 30 minutes. Solvent was removed. The
residue was purified by chromatography to yield
5-[3-imidazol-1-ylmethyl-5-(2,4-dibenzyloxy-5-isopropyl-phenyl)-[1,2,4]tr-
iazol-4-yl]-1-methyl-1H-indole (D) as light brown solid (0.12 g,
0.20 mmol, 40%) ESMS calcd. for C.sub.38H.sub.37N.sub.6O.sub.2
(M+H).sup.+: 609.4. Found: 609.4.
[0876] Intermediate (D) obtained above was subjected to Pd (10%)
catalyzed hydrogenation in 10 mL EtOH for 24 hours. Removal of Pd/C
and solvent gave
5-[3-imidazol-1-ylmethyl-5-(2,4-dihydroxy-5-isopropyl-phenyl)-[1,2,4-
]triazol-4-yl]-1-methyl-1H-indole (E) as light brown solid (0.07 g,
0.16 mmol, 80%). .sup.1H NMR (300 MHz, DMSO-d6), .delta. (ppm):
11.06 (s, 1H); 9.75 (s, 1H); 7.63 (d, J=8.1 Hz, 1H); 7.57 (d, J=2.1
Hz, 1H); 7.52 (d, J=3.0 Hz, 1H); 7.28 (s, 1H); 7.03 (dd, J=8.1 Hz,
2.1 Hz, 1H); 6.94 (d, J=1.2 Hz, 1H); 6.84 (d, J=1.2 Hz, 1H); 6.51
(d, J=3.0 Hz, 1H); 6.37 (s, 1H); 6.33 (s, 1H); 5.27 (s, 2H); 3.86
(s, 3H); 2.78 (hept, J=6.6 Hz, 1H); 0.55 (d, J=6.6 Hz, 6H). ESMS
calcd. for C.sub.24H.sub.25N.sub.6O.sub.2 (M+H).sup.+: 429.3.
Found: 429.3.
Compound 22
##STR00283##
[0877] Step-1:
[0878] To a stirred solution of 15.20 g (0.10 mols) of
4-Isopropylresorcinol in 50 mL of 2N NaOH and 50 mL of EtOH was
added 6 mL (0.1 mol) of carbon disulfide drop wise (5 min.) and the
resultant mixture was mildly refluxed at 75.degree. C. for 3 h with
a condenser. Approximately 25 mL of EtOH was removed from the
mixture and to the resultant mixture was added 50 mL of cold water
and acidified with 2N HCl till ph 4-5. The precipitate thus
obtained was filtered and drained. (This can be vacuum dried).
However, it was further dissolved in 95:5 EtOAc:MeOH mixture, dried
over Na.sub.2SO.sub.4 and concentrated to obtain 8.5 g of the
product 2 as brown solid.
Step-2:
[0879] Through a stirred solution of 7.0 g (30 mmols) of 2 in 120
mL of anhydrous Et.sub.2O at 5.degree. C. was bubbled CO.sub.2 gas
for 10 min. To the resultant mixture was added 7.29 g (61 mmols) of
SOCl.sub.2 drop wise (carefully!), while a strong red precipitate
was formed. After the addition, the mixture was stirred at RT for 1
h and the precipitates filtered, washed with Et.sub.2O and dried.
Yield=7.0 g.
Step-3:
[0880] A mixture of 1 eq. of intermediate 3 and 1.1 eq. of the
amine 4 was heated in MeOH for 30 min at 70.degree. C. and
concentrated. The residue was dissolved in 9:1 DCM:MeOH and passed
through a plug of silica gel eluting with EtOAc. The resultant
yellow solution was concentrated and product was further
reprecipitated using Et.sub.2O.
Step-4:
[0881] To a stirred suspension of 0.30 g (0.92 mmols) of thioamide
5, 0.14 g (1.37 mmols) of oxamic hydrazide 6, 0.15 g (1.83 mmols)
of pyridine in 8 mL of anhydrous dioxane was added 0.30 g (1.09
mmos) of HgCl.sub.2 and heated at microwave at 160.degree. C. for 1
h. After cooling the mixture the solids were filtered off and the
filtrate was concentrated. The residue was then chromatographed to
obtain 0.1 g of the product as off white solid.
[0882] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz): 10.74 (s, 1H), 9.76 (s,
1H), 8.26 (s, 1H), 7.74 (s, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.21 (s,
1H), 7.08 (d, J=7.8 Hz, 1H), 6.48 (s, 1H), 6.32 (s, 1H), 2.93-2.82
(m, 5H), 2.10-1.99 (m, 2H), 0.80 (d, J=6.9 Hz, 6H).
[0883] ESMS clcd for C21H22N4O3: 378.17. Found: 379.2
(M+H).sup.+.
Compound 41
##STR00284##
[0884] Preparation of hydrazonamide 2
[0885] To a solution of 2.0 g (5.36 mmol) of thioamide 1 in 100 mL
of dioxanes was added dropwise anhydrous hydrazine (0.7 mL, 21.4
mmol). The mixture was stirred at 80.degree. C. for 1 h, and then
an additional equivalent of hydrazine (0.2 mL) was added. After
stirring for 30 min at 80.degree. C., the mixture was cooled to
room temperature, and poured into 80 mL of water. The aqueous
solution was extracted twice with ethyl acetate. The combined
organic fractions were dried (Na.sub.2SO.sub.4) and concentrated to
afford 2.0 g of product as an orange foam. The product was used
immediately in the next reaction.
Preparation of triazole acid/ester mixture 4
[0886] To a solution of 2.0 g of hydrazonamide 2 (5.39 mmol) in 25
mL of THF at 0.degree. C. was added dropwise a solution of ethyl
chloroxoacetate (0.6 mL) in 2 mL of THF and then 1.4 mL of
diisopropylethylamine (8.09 mmol). The reaction was stirred at
0.degree. C. for 1 h and then was quenched by adding water. The
aqueous solution was extracted twice with ethyl acetate. The
combined organic fractions were dried (Na.sub.2SO.sub.4), and
concentrated to afford a mixture of acid and ester an orange oil
(about 1:2 ratio). The mixture can be separated by filtering
through a plug of silica gel by eluting with 1:1 hexanes-ethyl
acetate and then 1:2 hexanes-ethyl acetate to isolate ester. Acid
is isolated by rinsing the silica gel plug with ethyl acetate or
ethyl acetate with 10% methanol.
Preparation of amido-triazole Compound 41
[0887] To a solution of 100 mg (0.235 mol) of acid 4 in 8 mL of DMF
was added 0.5 mL of isopropylamine. The mixture was stirred while
heated via microwave to 180.degree. C. for 45 min After cooling to
room temperature, the mixture was poured into 18 mL of water, and
was extracted three times with 15-mL portions of ethyl acetate. The
combined organic fractions were washed three times with water,
dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was
chromatographed (SiO.sub.2, 1:1, hexanes-ethyl acetate) to then
precipitated from ethyl ether to afford 54 mg (50%) of Compound 41
as an off-white solid.
Example 4
Inhibition of Hsp90
[0888] Hsp90 protein is obtained from Stressgen (Cat#SPP-770).
Assay buffer: 100 mM Tris-HCl, Ph7.4, 20 mM KCl, 6 mM MgCl.sub.2.
Malachite green (0.0812% w/v) (M9636) and polyvinyl alcohol USP
(2.32% w/v) (P1097) are obtained from Sigma. A Malachite Green
Assay (see Methods Mol Med, 2003, 85:149 for method details) is
used for examination of ATPase activity of Hsp90 protein. Briefly,
Hsp90 protein in assay buffer (100 mM Tris-HCl, Ph7.4, 20 mM KCl, 6
mM MgCl.sub.2) is mixed with ATP alone (negative control) or in the
presence of Geldanamycin (a positive control) or a compound of the
invention in a 96-well plate. Malachite green reagent is added to
the reaction. The mixtures are incubated at 37.degree. C. for 4
hours and sodium citrate buffer (34% w/v sodium citrate) is added
to the reaction. The plate is read by an ELISA reader with an
absorbance at 620 nm.
Example 5
Degradation of Hsp90 Client Proteins via Inhibition of Hsp90
Activity
A. Cells and Cell Culture
[0889] Human high-Her2 breast carcinoma BT474 (HTB-20), SK-BR-3
(HTB-30) and MCF-7 breast carcinoma (HTB-22) from American Type
Culture Collection, VA, USA were grown in Dulbecco's modified
Eagle's medium with 4 mM L-glutamine and antibiotics (1001 U/ml
penicillin and 100 ug/ml streptomycine; GibcoBRL). To obtain
exponential cell growth, cells were trypsinized, counted and seeded
at a cell density of 0.5.times.10.sup.6 cells/ml regularly, every 3
days. All experiments were performed on day 1 after cell
passage.
B. Degradation of Her2 in Cells after Treatment with a Compound of
the Invention
[0890] 1. Method 1
[0891] BT-474 cells are treated with 0.5 .mu.M, 2 .mu.M, or 5 .mu.M
of 17AAG (a positive control) or 0.5 .mu.M, 2 .mu.M, or 5 .mu.M of
a compound of the invention overnight in DMEM medium. After
treatment, each cytoplasmic sample is prepared from
1.times.10.sup.6 cells by incubation of cell lysis buffer (#9803,
cell Signaling Technology) on ice for 10 minutes. The resulting
supernatant used as the cytosol fractions is dissolved with sample
buffer for SDS-PAGE and run on a SDS-PAGE gel, blotted onto a
nitrocellulose membrane by using semi-dry transfer. Non-specific
binding to nitrocellulose is blocked with 5% skim milk in TBS with
0.5% Tween at room temperature for 1 hour, then probed with
anti-Her2/ErB2 mAb (rabbit IgG, #2242, Cell Signaling) and
anti-Tubulin (T9026, Sigma) as housekeeping control protein.
HRP-conjugated goat anti-rabbit IgG (H+L) and HRP-conjugated horse
anti-mouse IgG (H+ L) are used as secondary Ab (#7074, #7076, Cell
Signaling) and LumiGLO reagent, 20.times. Peroxide (#7003, Cell
Signaling) is used for visualization.
[0892] Her2, an Hsp90 client protein, is expected to be degraded
when cells are treated with compounds of the invention. 0.5 .mu.M
of 17AAG, a known Hsp90 inhibitor which is used as a positive
control, causes partial degradation of Her2.
2. Method 2
[0893] MV-4-11 cells (20,000 cells/well) were cultured in 96-well
plates and maintained at 37.degree. C. for several hours. The cells
were treated with a compound of the invention or 17AAG (a positive
control) at various concentrations and incubated at 37.degree. C.
for 72 hours. Cell survival was measured with Cell Counting Kit-8
(Dojindo Laboratories, Cat. #CK04).
[0894] The IC.sub.50 range for Her2 degradation by compounds of the
invention are listed below in Table 2.
TABLE-US-00002 TABLE 2 IC.sub.50 range of compounds of the
invention for inhibition of Hsp90 IC.sub.50 (nM) Compound Number
.ltoreq.20 28, 32, 36, 49, 50, 83, 99, 137, 139, 141, 153 20 < x
.ltoreq. 50 22, 23, 24, 25, 26, 29, 30, 31, 33, 35, 37, 39, 41, 42,
42, 44, 45, 100, 118, 119, 120, 124, 130, 131, 133, 135, 152, 156,
157, 163, 171, 172, 173, 175, 178, 179, 180, 181, 182, 189, 190,
202, 206, 208 50 < x < 100 15, 20, 21, 34, 38, 127, 132, 138,
142, 161, 166, 168, 170, 174, 176, 186, 188, 193, 194, 196, 197,
198, 199, 201, 203, 205, 207, 209, 224 100 < x < 500 5, 7,
40, 47, 87, 126, 127, 128, 134, 136, 140, 143, 144, 146, 149, 154,
162, 164, 167, 169, 187, 192, 195, 200, 204, 210, 212, 220, 221,
223 500 < x < 1000 9, 98, 104, 177, 218 >1000 1, 2, 3, 4,
6, 8, 10, 12, 13, 16, 17, 18, 19, 46, 48, 85, 86, 88, 89, 90, 91,
92, 102, 109, 122, 145, 147, 148, 150, 155, 158, 160, 165, 219,
222
C. Fluorescent Staining of Her2 on the Surface of Cells Treated
with a Compound of the Invention
[0895] After treatment with a compound of the invention, cells are
washed twice with 1.times.PBS/1% FBS, and then stained with
anti-Her2-FITC (#340553, BD) for 30 min at 4.degree. C. Cells are
then washed three times in FACS buffer before the fixation in 0.5
ml 1% paraformadehydrede. Data is acquired on a FACSCalibur system.
Isotype-matched controls are used to establish the non-specific
staining of samples and to set the fluorescent markers. A total
10,000 events are recorded from each sample. Data are analyzed by
using CellQuest software (BD Biosciences).
D. Apoptosis Analysis
[0896] After treatment with the compounds of the invention, cells
are washed once with 1.times.PBS/1% FBS, and then stained in
binding buffer with FITC-conjugated Annexin V and Propidium iodide
(PI) (all obtained from BD Biosciences) for 30 min at 4.degree. C.
Flow cytometric analysis is performed with FACSCalibur (BD
Biosciences) and a total 10,000 events are recorded from each
sample. Data is analyzed by using CellQuest software (BD
Biosciences). The relative fluorescence is calculated after
subtraction of the fluorescence of control.
E. Degradation of c-Kit in Cells after Treatment with a Compound of
the Invention
[0897] Two leukemia cell lines, HEL92.1.7 and Kasumi-1, are used
for testing c-kit degradation induced by Hsp90 inhibitors of the
invention. The cells (3.times.10.sup.5 per well) are treated with
17AAG (0.5 .mu.M), or a compound of the invention for about 18 h.
The cells are collected and centrifuged (SORVALL RT 6000D) at 1200
rpm for 5 min. The supernatants are discarded, and the cells are
washed one time with 1.times.PBS. After centrifugation the cells
are stained with FITC conjugated c-kit antibody (MBL International,
Cat#K0105-4) in 100 ml 1.times.PBS at 4.degree. C. for 1 h. The
samples are read and analyzed with FACSCalibur flow cytometer
(Becton Dicknson).
[0898] c-Kit, a tyrosine kinase receptor and one of the Hsp90
client proteins, is selected and used in a FACS-based degradation
assay. Compounds of the invention are expected to induce c-kit
degradation in a dose-dependent manner. Compounds of the invention
are expected to be effective in the treatment of c-kit associated
tumors, such as leukemias, mast cell tumors, small cell lung
cancer, testicular cancer, some cancers of the gastrointestinal
tract (including GIST), and some central nervous system.
[0899] The results of the FACS analysis can be confirmed with
Western blot analysis.
F. Degradation of c-Met in Cells after Treatment with a Compound of
the Invention
[0900] The ability of the Hsp90 inhibitors of the invention to
induce the degradation of c-Met, an Hsp90 client protein that is
expressed at high levels in several types of non-small cell lung
cancer can be examined. NCI-H1993 (ATCC, cat#CRL-5909) are seeded
in 6-well plates at 5.times.10.sup.5 cells/well. The cells are
treated with 17AAG (100 nM or 400 nM) or a compound of the
invention (100 nM or 400 nM), and cell lysis is prepared 24 h after
treatment. Equal amount of proteins are used for Western blot
analysis. The compounds of the invention are expected to potently
induce degradation of c-Met in this cell line due to inhibition of
Hsp90.
Example 6
Anti-Tumor Activity Against the Human Tumor Cell Line MDA-MB-435S
in a nude Mouse Xenograft Model
[0901] The human tumor cell line, MDA-MB-435S (ATCC #HTB-129; G.
Ellison, et al., Mol. Pathol. 55:294-299, 2002), is obtained from
the American Type Culture Collection (Manassus, Va., USA). The cell
line is cultured in growth media prepared from 50% Dulbecco's
Modified Eagle Medium (high glucose), 50% RPMI Media 1640, 10%
fetal bovine serum (FBS), 1% 100.times.L-glutamine, 1% 100.times.
Penicillin-Streptomycin, 1% 100.times. sodium pyruvate and 1%
100.times.MEM non-essential amino acids. FBS is obtained from
Sigma-Aldrich Corp. (St. Louis, Mo., USA), and all other reagents
are obtained from Invitrogen Corp. (Carlsbad, Calif., USA).
Approximately 4-5.times.10(6) cells that have been cryopreserved in
liquid nitrogen are rapidly thawed at 37.degree. C. and transferred
to a 175 cm.sup.2 tissue culture flask containing 50 ml of growth
media and then incubated at 37.degree. C. in a 5% CO.sub.2
incubator. The growth media is replaced every 2-3 days until the
flask becomes 90% confluent, typically in 5-7 days. To passage and
expand the cell line, a 90% confluent flask is washed with 10 ml of
room temperature phosphate buffered saline (PBS) and the cells are
disassociated by adding 5 ml 1.times. Trypsin-EDTA (Invitrogen) and
incubating at 37.degree. C. until the cells detach from the surface
of the flask. To inactivate the trypsin, 5 ml of growth media is
added and then the contents of the flask are centrifuged to pellet
the cells. The supernatant is aspirated and the cell pellet is
resuspended in 10 ml of growth media and the cell number determined
using a hemocytometer. Approximately 1-3.times.10(6) cells per
flask are seeded into 175 cm.sup.2 flasks containing 50 ml of
growth media and incubated at 37.degree. C. in a 5% CO.sub.2
incubator. When the flasks reach 90% confluence, the above
passaging process is repeated until sufficient cells have been
obtained for implantation into mice.
[0902] Six to eight week old, female Crl:CD-1-nuBR (nude) mice are
obtained from Charles River Laboratories (Wilmington, Mass., USA).
Animals are housed 4-5/cage in micro-isolators, with a 12 hr/12 hr
light/dark cycle, acclimated for at least 1 week prior to use and
fed normal laboratory chow ad libitum. Studies are conducted on
animals between 7 and 12 weeks of age at implantation. To implant
tumor cells into nude mice, the cells are trypsinized as above,
washed in PBS and resusupended at a concentration of 50.times.10(6)
cells/ml in PBS. Using a 27 gauge needle and 1 cc syringe, 0.1 ml
of the cell suspension is injected into the corpus adiposum of nude
mice. The corpus adiposum is a fat body located in the ventral
abdominal vicera in the right quadrant of the abdomen at the
juncture of the os coxae (pelvic bone) and the os femoris (femur).
Tumors are then permitted to develop in vivo until they reach
approximately 150 mm.sup.3 in volume, which typically requires 2-3
weeks following implantation. Tumor volumes (V) are calculated by
caliper measurement of the width (W), length (L) and thickness (T)
of tumors using the following formula:
V=0.5326.times.(L.times.W.times.T). Animals are randomized into
treatment groups so that the average tumor volumes of each group
are similar at the start of dosing.
[0903] Sock solutions of test compounds are prepared by dissolving
the appropriate amounts of each compound in dimethyl sulfoxide
(DMSO) by sonication in an ultrasonic water bath. Stock solutions
are prepared at the start of the study, stored at -20.degree. C.
and diluted fresh each day for dosing. A solution of 20% Cremophore
RH40 (polyoxyl 40 hydrogenated castor oil; BASF Corp.,
Aktiengesellschaft, Ludwigshafen, Germany) in 80% D5W (5% dextrose
in water; Abbott Laboratories, North Chicago, Ill., USA) is also
prepared by first heating 100% Cremophore RH40 at 50-60.degree. C.
until liquefied and clear, diluting 1:5 with 100% D5W, reheating
again until clear and then mixing well. This solution is stored at
room temperature for up to 3 months prior to use. To prepare
formulations for daily dosing, DMSO stock solutions are diluted
1:10 with 20% Cremophore RH40. The final formulation for dosing
contains 10% DMSO, 18% Cremophore RH40, 3.6% dextrose and 68.4%
water and the appropriate amount of test article Animals are
intraperitoneal (IP) injected with this solution at 10 ml per kg
body weight on a schedule of 5 days per week (Monday thru Friday,
with no dosing on Saturday and Sunday) for 3 weeks.
[0904] Compounds of the invention are expected to result in
decreased the growth rate of MDA-MB-4355 cells in nude mice to a
greater extent than a dose of 100 mg/kg body weight of the Hsp90
inhibitor 17-AAG.
Example 7
Anti-tumor Activity Against Human
[0905] Tumor Cells in a nude Mouse Xenograft Model
[0906] The human squamous non-small cell lung cancer cell line,
RERF-LC-AI (RCB0444; S. Kyoizumi, et al., Cancer. Res.
45:3274-3281, 1985), is obtained from the Riken Cell Bank (Tsukuba,
Ibaraki, Japan). The cell line is cultured in growth media prepared
from 50% Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI
Media 1640, 10% fetal bovine serum (FBS), 1% 100.times.L-glutamine,
1% 100.times. penicillin-streptomycin, 1% 100.times. sodium
pyruvate and 1% 100.times.MEM non-essential amino acids. FBS is
obtained from American Type Culture Collection (Manassas, Va., USA)
and all other reagents are obtained from Invitrogen Corp.
(Carlsbad, Calif., USA). Approximately 4-5.times.10(6) cells that
have been cryopreserved in liquid nitrogen are rapidly thawed at
37.degree. C. and transferred to a 175 cm.sup.2 tissue culture
flask containing 50 ml of growth media and then incubated at
37.degree. C. in a 5% CO.sub.2 incubator.
[0907] The growth media is replaced every 2-3 days until the flask
becomes 90% confluent, typically in 5-7 days. To passage and expand
the cell line, a 90% confluent flask is washed with 10 ml of room
temperature phosphate buffered saline (PBS) and the cells are
disassociated by adding 5 ml 1.times. trypsin-EDTA (Invitrogen) and
incubating at 37.degree. C. until the cells detach from the surface
of the flask. To inactivate the trypsin, 5 ml of growth media is
added and then the contents of the flask are centrifuged to pellet
the cells. The supernatant is aspirated and the cell pellet is
resuspended in 10 ml of growth media and the cell number determined
using a hemocytometer. Approximately 1-3.times.10(6) cells per
flask are seeded into 175 cm.sup.2 flasks containing 50 ml of
growth media and incubated at 37.degree. C. in a 5% CO.sub.2
incubator. When the flasks reach 90% confluence, the above
passaging process is repeated until sufficient cells have been
obtained for implantation into mice.
[0908] Seven to eight week old, female Crl:CD-1-nuBR (nude) mice
are obtained from Charles River Laboratories (Wilmington, Mass.,
USA) Animals are housed 4-5/cage in micro-isolators, with a 12
hr/12 hr light/dark cycle, acclimated for at least 1 week prior to
use and fed normal laboratory chow ad libitum. Studies are
conducted on animals between 8 and 12 weeks of age at implantation.
To implant RERF-LC-AI tumor cells into nude mice, the cells are
trypsinized as above, washed in PBS and resuspended at a
concentration of 50.times.10(6) cells/ml in 50% non-supplemented
RPMI Media 1640 and 50% Matrigel Basement Membrane Matrix (#354234;
BD Biosciences; Bedford, Mass., USA). Using a 27 gauge needle and 1
cc syringe, 0.1 ml of the cell suspension is injected
subcutaneously into the flank of each nude mouse. Tumor volumes (V)
are calculated by caliper measurement of the width (W), length (L)
and thickness (T) of tumors using the following formula:
V=0.5236.times.(L.times.W.times.T).
[0909] In vivo passaged RERF-LC-AI tumor cells (RERF-LC-AI.sup.IVP)
are isolated to improve the rate of tumor implantation relative to
the parental cell line in nude mice. RERF-LC-AI tumors are
permitted to develop in vivo until they reach approximately 250
mm.sup.3 in volume, which requires approximately 3 weeks following
implantation. Mice are euthanized via CO.sub.2 asphyxiation and
their exteriors sterilized with 70% ethanol in a laminar flow hood.
Using sterile technique, tumors are excised and diced in 50 ml PBS
using a scalpel blade. A single cell suspension is prepared using a
55 ml Wheaton Safe-Grind tissue grinder (catalog #62400-358; VWR
International, West Chester, Pa., USA) by plunging the pestle up
and down 4-5 times without twisting. The suspension is strained
through a 70 .mu.M nylon cell strainer and then centrifuged to
pellet the cells. The resulting pellet is resuspended in 0.1 M
NH.sub.4Cl to lyse contaminating red blood cells and then
immediately centrifuged to pellet the cells. The cell pellet is
resuspended in growth media and seeded into 175 cm.sup.2 flasks
containing 50 ml of growth media at 1-3 tumors/flask or
approximately 10.times.10(6) cells/flask. After overnight
incubation at 37.degree. C. in a 5% CO.sub.2 incubator,
non-adherent cells are removed by rinsing two times with PBS and
then the cultures are fed with fresh growth media. When the flasks
reach 90% confluence, the above passaging process is repeated until
sufficient cells have been obtained for implantation into mice.
[0910] RERF-LC-AI.sup.IVP cells are then implanted as above and
tumors are permitted to develop in vivo until the majority reached
an average of 100-200 mm.sup.3 in tumor volume, which typically
requires 2-3 weeks following implantation. Animals with oblong or
very small or large tumors are discarded, and only animals carrying
tumors that display consistent growth rates are selected for
studies Animals are randomized into treatment groups so that the
average tumor volumes of each group are similar at the start of
dosing.
[0911] The HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin
(17-AAG), can be employed as a positive control (Albany Molecular
Research, Albany, N.Y., USA). Stock solutions of test articles are
prepared by dissolving the appropriate amounts of each compound in
dimethyl sulfoxide (DMSO) by sonication in an ultrasonic water
bath. Stock solutions are prepared weekly, stored at -20.degree. C.
and diluted fresh each day for dosing. A solution of 20% Cremophore
RH40 (polyoxyl 40 hydrogenated castor oil; BASF Corp.,
Aktiengesellschaft, Ludwigshafen, Germany) in 80% D5W (5% dextrose
in water; Abbott Laboratories, North Chicago, Ill., USA) is also
prepared by first heating 100% Cremophore RH40 at 50-60.degree. C.
until liquefied and clear, diluting 1:5 with 100% D5W, reheating
again until clear and then mixing well. This solution is stored at
room temperature for up to 3 months prior to use. To prepare
formulations for daily dosing, DMSO stock solutions are diluted
1:10 with 20% Cremophore RH40. The final formulation for dosing
contains 10% DMSO, 18% Cremophore RH40, 3.6% dextrose, 68.4% water
and the appropriate amount of test article Animals are
intraperitoneally (i.p.) injected with this solution at 10 ml per
kg body weight on a schedule of 5 days per week (Monday, Tuesday,
Wednesday, Thursday and Friday, with no dosing on Saturday and
Sunday) for a total of 15 doses.
[0912] Treatment with compounds of the invention is expected to
result in the decreased growth rate of RERF-LC-AI.sup.IVP human
lung tumor cells in nude mice.
Example 8
Necrosis in a Nude Mouse Tumor Model
[0913] The mouse mammary carcinoma cell line, EMT6 (ATCC
#CRL-2755), is obtained from the American Type Culture Collection
(ATCC; Manassas, Va., USA). The cell line is cultured in growth
media prepared from 50% Dulbecco's Modified Eagle Medium (high
glucose), 50% RPMI Media 1640, 10% fetal bovine serum (FBS), 1%
100.times.L-glutamine, 1% 100.times.Penicillin-Streptomycin, 1%
100.times. sodium pyruvate and 1% 100.times.MEM non-essential amino
acids. FBS is obtained from ATCC and all other reagents are
obtained from Invitrogen Corp. (Carlsbad, Calif., USA).
Approximately 4-5.times.10(6) cells that have been cryopreserved in
liquid nitrogen are rapidly thawed at 37.degree. C. and transferred
to a 175 cm.sup.2 tissue culture flask containing 50 ml of growth
media and then incubated at 37.degree. C. in a 5% CO.sub.2
incubator. The growth media is replaced every 2-3 days until the
flask became 90% confluent, typically in 5-7 days. To passage and
expand the cell line, a 90% confluent flask is washed with 10 ml of
room temperature phosphate buffered saline (PBS) and the cells are
disassociated by adding 5 ml 1.times. Trypsin-EDTA (Invitrogen) and
incubating at 37.degree. C. until the cells detach from the surface
of the flask. To inactivate the trypsin, 5 ml of growth media is
added and then the contents of the flask are centrifuged to pellet
the cells. The supernatant is aspirated and the cell pellet is
resuspended in 10 ml of growth media and the cell number determined
using a hemocytometer. Approximately 1-3.times.10(6) cells per
flask are seeded into 175 cm.sup.2 flasks containing 50 ml of
growth media and incubated at 37.degree. C. in a 5% CO.sub.2
incubator. When the flasks reach 90% confluence, the above
passaging process is repeated until sufficient cells have been
obtained for implantation into mice.
[0914] Seven to eight week old, female Crl:CD-1-nuBR (nude) mice
are obtained from Charles River Laboratories (Wilmington, Mass.,
USA) Animals are housed 4-5/cage in micro-isolators, with a 12
hr/12 hr light/dark cycle, acclimated for at least 1 week prior to
use and fed normal laboratory chow ad libitum. Studies are
conducted on animals between 8 and 10 weeks of age at implantation.
To implant EMT6 tumor cells into nude mice, the cells are
trypsinized as above, washed in PBS and resusupended at a
concentration of 10.times.10(6) cells/ml in PBS. Using a 27 gauge
needle and 1 cc syringe, 0.1 ml of the cell suspension is injected
subcutaneously into the flank of each nude mouse.
[0915] Tumors are then permitted to develop in vivo until the
majority reached 75-125 mm.sup.3 in tumor volume, which typically
requires 1 week following implantation Animals with oblong, very
small or large tumors are discarded, and only animals carrying
tumors that display consistent growth rates are selected for
studies. Tumor volumes (V) are calculated by caliper measurement of
the width (W), length (L) and thickness (T) of tumors using the
following formula: V=0.5236.times.(L.times.W.times.T). Animals are
randomized into treatment groups so that each group had median
tumor volumes of .about.100 mm.sup.3 at the start of dosing. To
formulate a compound of the invention in DRD, a stock solution of
the test article is prepared by dissolving an appropriate amount of
the compound in dimethyl sulfoxide (DMSO) by sonication in an
ultrasonic water bath. A solution of 20% Cremophore RH40 (polyoxyl
40 hydrogenated castor oil; BASF Corp., Aktiengesellschaft,
Ludwigshafen, Germany) in 5% dextrose in water (Abbott
Laboratories, North Chicago, Ill., USA) is also prepared by first
heating 100% Cremophore RH40 at 50-60.degree. C. until liquefied
and clear, diluting 1:5 with 100% D5W, reheating again until clear
and then mixing well. This solution is stored at room temperature
for up to 3 months prior to use. To prepare a DRD formulation for
dosing, the DMSO stock solution is diluted 1:10 with 20% Cremophore
RH40. The final DRD formulation for dosing contains 10% DMSO, 18%
Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate
amount of test article.
[0916] Tumor-bearing animals are given a single intravenous (i.v.)
bolus injections of either DRD vehicle or a compound of the
invention formulated in DRD, both at 10 mL per kg body weight.
Then, 4-24 hr after drug treatment, tumors are excised, cut in half
and fixed overnight in 10% neutral-buffered formalin. Each tumor is
embedded in paraffin with the cut surfaces placed downwards in the
block, and rough cut until a complete section is obtained. From
each tumor, 5 .mu.M serial sections are prepared and stained with
hematoxylin and eosin. Slides are evaluated manually using light
microscopy with a 10.times.10 square gridded reticle. The
percentage of necrosis in a tumor is quantified at 200.times.
magnification by scoring the total number of grid squares
containing necrosis and the total number of grid squares containing
viable tumor cells.
[0917] It is expected that compounds of the invention will result
in an increase in necrotic tissue in the center of EMT6 tumors
relative to the baseline necrosis observed in vehicle treated
tumors. As would be expected for a vascular targeting mechanism of
action, rapid onset of necrosis is consistent with there being a
loss of blood flow to tumors resulting in hypoxia and tumor cell
death.
Example 9
Vascular Disrupting Activities in a Nude Mouse Tumor Model
[0918] The mouse mammary carcinoma cell line, EMT6 (ATCC
#CRL-2755), is obtained from the American Type Culture Collection
(ATCC; Manassas, Va., USA). The cell line is cultured in growth
media prepared from 50% Dulbecco's Modified Eagle Medium (high
glucose), 50% RPMI Media 1640, 10% fetal bovine serum (FBS), 1%
100.times.L-glutamine, 1% 100.times. Penicillin-Streptomycin, 1%
100.times. sodium pyruvate and 1% 100.times.MEM non-essential amino
acids. FBS is obtained from ATCC and all other reagents are
obtained from Invitrogen Corp. (Carlsbad, Calif., USA).
Approximately 4-5.times.10.sup.6 cells that have been cryopreserved
in liquid nitrogen are rapidly thawed at 37.degree. C. and
transferred to a 175 cm.sup.2 tissue culture flask containing 50 mL
of growth media and then incubated at 37.degree. C. in a 5%
CO.sub.2 incubator. The growth media is replaced every 2-3 days
until the flask became 90% confluent, typically in 5-7 days. To
passage and expand the cell line, a 90% confluent flask is washed
with 10 mL of room temperature phosphate buffered saline (PBS) and
the cells are disassociated by adding 5 mL 1.times. Trypsin-EDTA
(Invitrogen) and incubating at 37.degree. C. until the cells detach
from the surface of the flask. To inactivate the trypsin, 5 mL of
growth media is added and then the contents of the flask are
centrifuged to pellet the cells. The supernatant is aspirated and
the cell pellet is resuspended in 10 mL of growth media and the
cell number determined using a hemocytometer. Approximately
1-3.times.10.sup.6 cells per flask are seeded into 175 cm.sup.2
flasks containing 50 mL of growth media and incubated at 37.degree.
C. in a 5% CO.sub.2 incubator. When the flasks reach 90%
confluence, the above passaging process is repeated until
sufficient cells have been obtained for implantation into mice.
[0919] Seven to eight week old, female Crl:CD-1-nuBR (nude) mice
are obtained from Charles River Laboratories (Wilmington, Mass.,
USA) Animals are housed 4-5/cage in micro-isolators, with a 12
hr/12 hr light/dark cycle, acclimated for at least 1 week prior to
use and fed normal laboratory chow ad libitum. Studies are
conducted on animals between 8 and 10 weeks of age at implantation.
To implant EMT6 tumor cells into nude mice, the cells are
trypsinized as above, washed in PBS and resusupended at a
concentration of 10.times.10.sup.6 cells/mL in PBS. Using a 27
gauge needle and 1 cc syringe, 0.1 mL of the cell suspension is
injected subcutaneously into the flank of each nude mouse.
[0920] For the Evans Blue dye assay, tumors are permitted to
develop in vivo until the majority reach 40-90 mm.sup.3 in tumor
volume (to minimize the extent of tumor necrosis), which typically
require 4-6 days following implantation. Animals with visibly
necrotic, oblong, very small or very large tumors are discarded and
only animals carrying tumors that display consistent growth rates
are selected for use. Tumor volumes (V) are calculated by caliper
measurement of the width (W), length (L) and thickness (T) of
tumors using the following formula:
V=0.5236.times.(L.times.W.times.T). Animals are randomized into
treatment groups so that at the start of dosing each group have
median tumor volumes of .about.125 mm.sup.3 or .about.55 mm.sup.3
for the Evans Blue dye assay.
[0921] To formulate compounds of the invention for dosing, the
appropriate amount of compound is dissolved in 5% dextrose in water
(D5W; Abbott Laboratories, North Chicago, Ill., USA).
Vehicle-treated animals are dosed with D5W.
[0922] To conduct the Evans Blue dye assay, tumor-bearing animals
are dosed with vehicle or test article at 0 hr, and then i.v.
injected with 100 .mu.L of a 1% (w/v) Evan's Blue dye (Sigma
#E-2129; St. Louis, Mo., USA) solution in 0.9% NaCl at +1 hr.
Tumors are excised at +4 hr, weighed and the tissue disassociated
by incubation in 50 .mu.L1 N KOH at 60.degree. C. for 16 hr. To
extract the dye, 125 .mu.L of a 0.6 N phosphoric acid and 325 .mu.L
acetone are added, and the samples vigorously vortexed and then
microcentrifuged at 3000 RPM for 15 min to pellet cell debris. The
optical absorbance of 200 .mu.L of supernatant is then measured at
620 nM in a Triad spectrophotometer (Dynex Technologies, Chantilly,
Va., USA). Background OD.sub.620 values from similarly sized groups
of vehicle or test article-treated animals that have not been
injected with dye are subtracted as background. OD.sub.620 values
are then normalized for tumor weight and dye uptake is calculated
relative to vehicle-treated tumors.
[0923] To examine the vascular disrupting activity of a compound of
the invention, the Evans Blue dye assay is employed as a
measurement of tumor blood volume (Graff et al., Eur J Cancer
36:1433-1440, 2000). Evans Blue dye makes a complex with serum
albumin by electrostatic interaction between the sulphonic acid
group of the dye and the terminal cationic nitrogens of the lysine
residues in albumin. The dye leaves the circulation very slowly,
principally by diffusion into extravascular tissues while still
bound to albumin Albumin-dye complex taken up by tumors is located
in the extracellular space of non-necrotic tissue, and
intracellular uptake and uptake in necrotic regions is negligible.
The amount of dye present in a tumor is a measurement of the tumor
blood volume and microvessel permeability. Compounds of the
invention are expected to result in substantially decreased tumor
dye uptake relative to vehicle-treated animals. Such a decrease in
dye penetration into the tumor is consistent with there being a
loss of blood flow to tumors due to blockage of tumor vasculature,
consistent with a vascular disrupting mechanism of action.
Example 10
Inhibition of the Production of Inflammatory Cytokines in Human
PBMCs
[0924] Human PBMC are isolated using Ficoll 400 and diatrizoate
sodium (density 1.077 g/ml) solution and purified with RosetteSep
(StemCell Technologies). The PBMCs are primed with human
IFN-.gamma. (800 U/ml, Pierce Biotechnology #R-IFNG-50), seeded at
0.5.times.10.sup.6/100 .mu.L/well in 96-well U-bottom plate with
culture medium (RPMI 1640, 10% FBS, 1% Pen/Strep), and incubated in
37.degree. C. for overnight. The cells are then stimulated with 1
.mu.g/ml of LPS (Lipopolysaccharide, Sigma#L2654-1MG) or 0.025% of
SAC (Staphylococcus Aureus Cowan, Calbiochem-Novabiochem Corp.
#507858), and treated with a test compound at different
concentrations with final DMSO concentration less than 0.5% for
16-18 hrs. About 180 .mu.l/well of supernatant is collected and
measured using ELISA kit or Bio-plex (Bio-Rad) to determine the
levels of cytokine production. The cell survival is determined
using Cell Counting Kit-8 (Dojindo Molecular Technologies, Inc.).
Compounds of the invention are expected to broadly inhibit the
production of proinflammatory cytokines.
Example 11
Suppression of Glucocorticoid Receptor Levels in Rat and Human
PBMCs
Cell Preparation:
[0925] Whole blood samples from healthy human volunteers and male
SD rats are collected and the PBMCs are isolated immediately as
follows. 5 ml of whole blood is diluted with an equal volume of
sterile 1.times.PBS. The diluted blood is overlayed carefully into
a sterile centrifuge tube without disturbing the bottom layer that
containing 5 ml of Ficoll-paque plus density gradient solution. The
layered blood is centrifuged at 1500.times.g for 30 minutes at room
temperature. The middle thin layer containing PBMCs is carefully
removed, transferred to another sterile centrifuge tube, and washed
twice with PBS to remove Percoll. Isolated rat and human PBMCs are
cultured in 10% fetal bovine serum/DMEM.
Treatment:
[0926] The rat and human PBMCs are treated with DMSO (control),
compounds of the invention, or 17-DMAG at concentrations of 0, 1,
5, 25, or 100 nM (in DMSO) for 16 hours. The cells are then
collected and rinsed in ice-cold PBS and stored in liquid nitrogen
until further analysis.
Immunoblot
[0927] PBMC are prepared in Western lysis buffer (10 mmol/L HEPES,
42 mmol/L KCl, 5 mmol/L MgCl.sub.2, 0.1 mmol/L EDTA, 0.1 mmol/L
EGTA, 1 mmol/L DTT, 1% Triton X-100, freshly supplemented with
1.times. protease inhibitor cocktail from Pierce, Rockford, Ill.).
Lysate protein concentrations are quantified by bicinchoninic acid
assay (Pierce) and normalized. Equal amounts of protein are loaded
onto 10% NuPAGE Bis-Tris Gels (Invitrogen) and subsequently
transferred onto polyvinylidene difluoride membranes. The membranes
are blocked in 5% milk in TBST. Primary antibody of glucocorticod
receptor from Santa Cruz Biotechnology, Inc. is added and incubated
at room temperature for 1 hour with shaking. The blots are washed
extensively in TBST before secondary antibodies are added for
overnight incubation at 4.degree. C. with gentle shaking. The blots
are again washed extensively and developed with SuperSignal West
Femto substrate (Pierce). The immunoblot analysis is performed to
measure the level of total GRs by Quantity One software from
Bio-Rad.
Example 12
Suppression of Glucocorticoid Receptor Levels in Human PBMCs and
Renal Cells, as well as in Several Human Cancer Cell Lines
Cell Preparation:
[0928] Normal human renal proximal tubule epithelial cells and
tumor cell lines of MV-4-11, Kasumi-1, and Hela are obtained from
Cambrex Bioproducts and American Type Culture Collection,
respectively. Cells are cultured with 10% fetal bovine
serum/DMEM.
[0929] The whole blood samples from healthy human volunteers are
collected and the PBMCs are isolated immediately as described in
Example 11. Isolated human PBMCs are cultured in 10% fetal bovine
serum/DMEM.
Treatment:
[0930] Human PBMCs, kasumi-1, My-4-11, Hela, and human renal
proximal tubule epithelial cells are treated with DMSO (control),
compounds of the invention, 17-DMAG at concentrations of 0, 5, 25,
or 100 nM (in DMSO) for 16 hours. The cells are then collected and
rinsed in ice-cold PBS and stored in liquid nitrogen until further
analysis.
Immunoblot
[0931] PBMC, renal and tumor cell pellets are prepared in Western
lysis buffer (10 mmol/L HEPES, 42 mmol/L KCl, 5 mmol/L MgCl.sub.2,
0.1 mmol/L EDTA, 0.1 mmol/L EGTA, 1 mmol/L DTT, 1% Triton X-100,
freshly supplemented with 1.times. protease inhibitor cocktail from
Pierce, Rockford, Ill.). Lysate protein concentrations are
quantified by bicinchoninic acid assay (Pierce) and normalized.
Equal amounts of protein are loaded onto 10% NuPAGE Bis-Tris Gels
(Invitrogen) and subsequently transferred onto polyvinylidene
difluoride membranes. The membranes are blocked in 5% milk in TBST.
Primary antibody of glucocorticod receptor from Santa Cruz
Biotechnology, Inc. is added and incubated at room temperature for
1 hour with shaking. The blots are washed extensively in TBST
before secondary antibodies are added for overnight incubation at
4.degree. C. with gentle shaking. The blots are again washed
extensively and developed with SuperSignal West Femto substrate
(Pierce). Compounds of the invention are expected to suppress the
expression of glucocorticoid receptors in cancer cells as well as
in normal PBMCs and renal cells.
Example 13
Suppression of Glucocorticoid Receptor Levels In Vivo
[0932] Male adult Sprague-Dawley (SD) rats, five per group, are
randomly assigned into five testing groups which received
treatments as shown in Table 3:
TABLE-US-00003 TABLE 3 Treatment group Treatment received G1 5
mL/kg of vehicle (5% DMSO/13.5% Cr-RH40/D5W) G2 6 mg/kg of 17-DMAG
G3 5 mg/kg of Paclitaxel G4 80 mg/kg of Compound of the invention
G5 50 mg/kg of Compound of the invention
[0933] The test compounds are administered daily intravenously via
tail vein for four days. All rats are sacrificed at the study day
5. About 1-2 mL of blood samples are collected per animal. The
blood samples are then pulled together as a group for PBMC
isolation. PBMCs are isolated and an immunoblot using an antibody
that recognizes the glucocorticoid receptor is prepared, as
described in Examples 11 and 12.
[0934] All publications, patent applications, patents, and other
documents cited herein are incorporated by reference in their
entirety. In case of conflict, the present specification, including
definitions, will control. In addition, the materials, methods, and
examples are illustrative only and not intended to be limiting.
[0935] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
scope of the invention encompassed by the appended claims.
* * * * *