U.S. patent application number 15/881695 was filed with the patent office on 2018-09-20 for host targeted inhibitors of dengue virus and other viruses.
This patent application is currently assigned to Dana-Farber Cancer Institute, Inc.. The applicant listed for this patent is Dana-Farber Cancer Institute, Inc., President and Fellows of Harvard College. Invention is credited to Melissanne de Wispelaere, Nathanael S. Gray, Qingsong Liu, Priscilla L. Yang.
Application Number | 20180265507 15/881695 |
Document ID | / |
Family ID | 49328039 |
Filed Date | 2018-09-20 |
United States Patent
Application |
20180265507 |
Kind Code |
A1 |
Gray; Nathanael S. ; et
al. |
September 20, 2018 |
HOST TARGETED INHIBITORS OF DENGUE VIRUS AND OTHER VIRUSES
Abstract
Novel antiviral compounds of Formulae (I)-(III) are provided:
##STR00001## The inventive compounds, pharmaceutical compositions
thereof, and kits including the inventive compounds are useful for
the prevention and treatment of infectious diseases caused by
viruses, for example, by Flaviviridae virus (e.g., Dengue virus
(DENV)), Kunjin virus, Japanese encephalitis virus, vesicular
stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), human
cytomegalovirus (HCMV), poliovirus, Junin virus, Ebola virus,
Marburg virus (MARV), Lassa fever virus (LASV), Venezuelan equine
encephalitis virus (VEEV), or Rift Valley Fever virus (RVFV).
Inventors: |
Gray; Nathanael S.; (Boston,
MA) ; Yang; Priscilla L.; (Boston, MA) ; Liu;
Qingsong; (Brookline, MA) ; de Wispelaere;
Melissanne; (Paris, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Dana-Farber Cancer Institute, Inc.
President and Fellows of Harvard College |
Boston
Cambridge |
MA
MA |
US
US |
|
|
Assignee: |
Dana-Farber Cancer Institute,
Inc.
Boston
MA
President and Fellows of Harvard College
Cambridge
MA
|
Family ID: |
49328039 |
Appl. No.: |
15/881695 |
Filed: |
January 26, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14391638 |
Oct 9, 2014 |
9879003 |
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PCT/US2013/032488 |
Mar 15, 2013 |
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15881695 |
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61622828 |
Apr 11, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 519/00 20130101;
C07D 471/04 20130101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 519/00 20060101 C07D519/00 |
Goverment Interests
GOVERNMENT SUPPORT
[0002] This invention was made with government support under grant
numbers HG006097, R01 AI076442, U54 CA156732-01, and U54 AI057159
awarded by the National Institutes of Health. The government has
certain rights in the invention.
Claims
1. A compound of Formula (I): ##STR00218## or a pharmaceutically
acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,
stereoisomer, isotopically labeled derivative, or prodrug thereof;
wherein: Ring A is heteroaryl; each instance of R.sup.A is
independently selected from the group consisting of hydrogen,
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
carbocyclyl, optionally substituted heterocyclyl, optionally
substituted aryl, optionally substituted heteroaryl, --OR.sup.A1,
--N(R.sup.A1).sub.2, --SR.sup.A1, --CN,
--C(.dbd.NR.sup.A1)R.sup.A1, --C(.dbd.NR.sup.A1)OR.sup.A1,
--C(.dbd.NR.sup.A1)SR.sup.A1, --C(.dbd.NR.sup.A1)N(R.sup.A1).sub.2,
--C(.dbd.O)NR.sup.A1--, --NR.sup.A1C(.dbd.O)--,
--C(.dbd.O)R.sup.A1, --C(.dbd.S)R.sup.A1, --C(.dbd.S)OR.sup.A1,
--C(.dbd.S)SR.sup.A1, --C(.dbd.S)N(R.sup.A1).sub.2, --NO.sub.2,
--N.sub.3, --N(R.sup.A1).sub.3.sup.+F.sup.-,
--N(R.sup.A1).sub.3.sup.+Cl.sup.-,
--N(R.sup.A1).sub.3.sup.+Br.sup.-,
--N(R.sup.A1).sub.3.sup.+I.sup.-, --N(OR.sup.A1)R.sup.A1,
--NR.sup.A1C(.dbd.O)R.sup.A1, --NR.sup.A1C(.dbd.O)OR.sup.A1,
--NR.sup.A1C(.dbd.O)SR.sup.A1,
--NR.sup.A1C(.dbd.O)N(R.sup.A1).sub.2,
--NR.sup.A1C(.dbd.S)R.sup.A1, --NR.sup.A1C(.dbd.S)OR.sup.A1,
--NR.sup.A1C(.dbd.S)SR.sup.A1,
--NR.sup.A1C(.dbd.S)N(R.sup.A1).sub.2,
--NR.sup.A1C(.dbd.NR.sup.A1)R.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)OR.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)SR.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)N(R.sup.A1).sub.2,
--NR.sup.A1S(.dbd.O).sub.2R.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2OR.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2SR.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2N(R.sup.A1).sub.2,
--NR.sup.A1S(.dbd.O)R.sup.A1, --NR.sup.A1S(.dbd.O)OR.sup.A1,
--NR.sup.A1S(.dbd.O)SR.sup.A1,
--NR.sup.A1S(.dbd.O)N(R.sup.A1).sub.2, --NR.sup.A1P(.dbd.O),
--NR.sup.A1P(.dbd.O).sub.2, --NR.sup.A1P(.dbd.O)(R.sup.A1).sub.2,
--NR.sup.A1P(.dbd.O)R.sup.A1(OR.sup.A1),
--NR.sup.A1P(.dbd.O)(OR.sup.A1).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A1).sub.2, --OC(.dbd.NR.sup.A1)R.sup.A1,
--OC(.dbd.NR.sup.A1)OR.sup.A1,
--OC(.dbd.NR.sup.A1)N(R.sup.A1).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A1).sub.2, --ON(R.sup.A1).sub.2,
--OS(.dbd.O)R.sup.A1, --OS(.dbd.O)OR.sup.A1, --OS(.dbd.O)SR.sup.A1,
--OS(.dbd.O)N(R.sup.A1).sub.2, --OS(.dbd.O).sub.2R.sup.A1,
--OS(.dbd.O).sub.2OR.sup.A1, --OS(.dbd.O).sub.2SR.sup.A1,
--OS(.dbd.O).sub.2N(R.sup.A1).sub.2, --OP(.dbd.O).sub.2,
--OP(.dbd.O)(R.sup.A1).sub.2, --OP(.dbd.O)R.sup.A1(OR.sup.A1),
--OP(.dbd.O)(OR.sup.A1).sub.2, --OP(.dbd.O), --OP(R.sup.A1).sub.2,
--OPR.sup.A1(OR.sup.A1), --OP(OR.sup.A1).sub.2,
--OSi(R.sup.A1).sub.3, --OSi(R.sup.A1).sub.2OR.sup.A1,
--OSi(R.sup.A1)(OR.sup.A1).sub.2, --OSi(OR.sup.A1).sub.3,
--SSR.sup.A1, --S(.dbd.O)R.sup.A1, --S(.dbd.O)OR.sup.A1,
--S(.dbd.O)N(R.sup.A1).sub.2, --S(.dbd.O).sub.2R.sup.A1,
--S(.dbd.O).sub.2OR.sup.A1, --S(.dbd.O).sub.2N(R.sup.A1).sub.2,
--SC(.dbd.O)R.sup.A1, --SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A1).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A1).sub.2, --P(R.sup.A1).sub.2,
--PR.sup.A1(OR.sup.A1), --P(OR.sup.A1).sub.2, --P(.dbd.O),
--P(.dbd.O)(R.sup.A1).sub.2, --P(.dbd.O)(OR.sup.A1).sub.2,
--P(.dbd.O)R.sup.A1(OR.sup.A1), --P(.dbd.O).sub.2,
--B(R.sup.A1).sub.2, --B(OR.sup.A1).sub.2, --BR.sup.A1(OR.sup.A1),
--Si(R.sup.A1).sub.3, --Si(R.sup.A1).sub.2OR.sup.A1,
--SiR.sup.A1(OR.sup.A1).sub.2, and --Si(OR.sup.A).sub.3, wherein
each occurrence of R.sup.A1 is independently selected from the
group consisting of hydrogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, a nitrogen protecting group when
attached to a nitrogen atom, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, or two R.sup.A1 groups are joined to form an
optionally substituted heterocyclic ring; k is 0, 1, 2, 3, 4, or 5;
Ring C is a carbocyclic, heterocyclic, aryl, or heteroaryl ring;
each instance of R.sup.C is independently selected from the group
consisting of hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.C1, --N(R.sup.C1).sub.2, --SR.sup.C1, --CN,
--C(.dbd.NR.sup.C1)R.sup.C1, --C(.dbd.NR.sup.C1)OR.sup.C1,
--C(.dbd.NR.sup.C1)SR.sup.C1, --C(.dbd.NR.sup.C1)N(R.sup.C1).sub.2,
--C(.dbd.O)R.sup.C1, --C(.dbd.S)R.sup.C1, --C(.dbd.S)OR.sup.C1,
--C(.dbd.S)SR.sup.C1, --C(.dbd.S)N(R.sup.C1).sub.2, --NO.sub.2,
--N.sub.3, --N(R.sup.C1).sub.3.sup.+F.sup.-,
--N(R.sup.C1).sub.3.sup.+Cl.sup.-,
--N(R.sup.C1).sub.3.sup.+Br.sup.-,
--N(R.sup.C1).sub.3.sup.+I.sup.-, --N(OR.sup.C1)R.sup.C1,
--NR.sup.C1C(.dbd.O)R.sup.C1, --NR.sup.C1C(.dbd.O)OR.sup.C1,
--NR.sup.C1C(.dbd.O)SR.sup.C1,
--NR.sup.C1C(.dbd.O)N(R.sup.C1).sub.2,
--NR.sup.C1C(.dbd.S)R.sup.C1, --NR.sup.C1C(.dbd.S)OR.sup.C1,
--NR.sup.C1C(.dbd.S)SR.sup.C1,
--NR.sup.C1C(.dbd.S)N(R.sup.C1).sub.2,
--NR.sup.C1C(.dbd.NR)R.sup.C1,
--NR.sup.C1C(.dbd.NR.sup.C1)OR.sup.C1,
--NR.sup.C1C(.dbd.NR.sup.C1)SR.sup.C1,
--NR.sup.C1C(.dbd.NR.sup.C1)N(R.sup.C1).sub.2,
--NR.sup.C1S(.dbd.O).sub.2R.sup.C1,
--NR.sup.C1S(.dbd.O).sub.2OR.sup.C1,
--NR.sup.C1S(.dbd.O).sub.2SR.sup.C1,
--NR.sup.C1S(.dbd.O).sub.2N(R.sup.C1).sub.2,
--NR.sup.C1S(.dbd.O)R.sup.C1, --NR.sup.C1S(.dbd.O)OR.sup.C1,
--NR.sup.C1S(.dbd.O)SR.sup.C1,
--NR.sup.C1S(.dbd.O)N(R.sup.C1).sub.2, --NR.sup.C1P(.dbd.O),
--NR.sup.C1P(.dbd.O).sub.2, --NR.sup.C1P(.dbd.O)(R.sup.C1).sub.2,
--NR.sup.C1P(.dbd.O)R.sup.C1(OR.sup.C1),
--NR.sup.C1P(.dbd.O)(OR.sup.C1).sub.2, --OC(.dbd.O)R.sup.C1,
--OC(.dbd.O)OR.sup.C1, --OC(.dbd.O)SR.sup.C1,
--OC(.dbd.O)N(R.sup.C1).sub.2, --OC(.dbd.NR.sup.C1)R.sup.C1,
--OC(.dbd.NR.sup.C1)OR.sup.C1,
--OC(.dbd.NR.sup.C1)N(R.sup.C1).sub.2, --OC(.dbd.S)R.sup.C1,
--OC(.dbd.S)OR.sup.C1, --OC(.dbd.S)SR.sup.C1,
--OC(.dbd.S)N(R.sup.C1).sub.2, --ON(R.sup.C1).sub.2,
--OS(.dbd.O)R.sup.C1, --OS(.dbd.O)OR.sup.C1, --OS(.dbd.O)SR.sup.C1,
--OS(.dbd.O)N(R.sup.C1).sub.2, --OS(.dbd.O).sub.2R.sup.C1,
--OS(.dbd.O).sub.2OR.sup.C1, --OS(.dbd.O).sub.2SR.sup.C1,
--OS(.dbd.O).sub.2N(R.sup.C1).sub.2, --OP(.dbd.O).sub.2,
--OP(.dbd.O)(R.sup.C1).sub.2, --OP(.dbd.O)R.sup.C1(OR.sup.C1),
--OP(.dbd.O)(OR.sup.C1).sub.2, --OP(.dbd.O), --OP(R.sup.C1).sub.2,
--OPR.sup.C1(OR.sup.C1), --OP(OR.sup.C1).sub.2,
--OSi(R.sup.C1).sub.3, --OSi(R.sup.C1).sub.2OR.sup.C1,
--OSi(R.sup.C1)(OR.sup.C1).sub.2, --OSi(OR.sup.C1).sub.3,
--SSR.sup.C1, --S(.dbd.O)R.sup.C1, --S(.dbd.O)OR.sup.C1,
--S(.dbd.O)N(R.sup.C1).sub.2, --S(.dbd.O).sub.2R.sup.C1,
--S(.dbd.O).sub.2OR.sup.C1, --S(.dbd.O).sub.2N(R.sup.C1).sub.2,
--SC(.dbd.O)R.sup.C1, --SC(.dbd.O)OR.sup.C1, --SC(.dbd.O)SR.sup.C1,
--SC(.dbd.O)N(R.sup.C1).sub.2, --SC(.dbd.S)R.sup.C1,
--SC(.dbd.S)OR.sup.C1, --SC(.dbd.S)SR.sup.C1,
--SC(.dbd.S)N(R.sup.C1).sub.2, --P(R.sup.C1).sub.2,
--PR.sup.C1(OR.sup.C1), --P(OR.sup.C1).sub.2, --P(.dbd.O),
--P(.dbd.O)(R.sup.C1).sub.2, --P(.dbd.O)(OR.sup.C1).sub.2,
--P(.dbd.O)R.sup.C1(OR.sup.C1), --P(.dbd.O).sub.2,
--B(R.sup.C1).sub.2, --B(OR.sup.C1).sub.2, --BR.sup.C1(OR.sup.C1),
--Si(R.sup.C1).sub.3, --Si(R.sup.C1).sub.2OR.sup.C1,
--SiR.sup.C1(OR.sup.C1).sub.2, and --Si(OR.sup.C1).sub.3, wherein
each occurrence of R.sup.C1 is independently selected from the
group consisting of hydrogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, a nitrogen protecting group when
attached to a nitrogen atom, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, or two R.sup.C1 groups are joined to form an
optionally substituted heterocyclic ring or optionally substituted
heteroaryl ring; n is 0, 1, 2, 3, or 4; L is a bond or an
optionally substituted, branched or unbranched C.sub.1-6
hydrocarbon chain; R.sup.D is any one of Formulae (i-1)-(i-43):
##STR00219## ##STR00220## ##STR00221## ##STR00222## ##STR00223##
wherein: each instance of R.sup.D1 is independently hydrogen,
halogen, acyl, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --CN, --NO.sub.2,
--OR.sup.D1a, --N(R.sup.D1a).sub.2, --SR.sup.D1a,
--CH.sub.2OR.sup.D1a, --CH.sub.2N(R.sup.D1a).sub.2,
--CH.sub.2SR.sup.D1a, --C(.dbd.O)R.sup.D1a, --C(.dbd.O)OR.sup.D1a,
--C(.dbd.O)SR.sup.D1a, --C(.dbd.O)N(R.sup.D1a).sub.2,
--C(.dbd.S)R.sup.D1a, --C(.dbd.S)OR.sup.D1a, --C(.dbd.S)SR.sup.D1a,
--C(.dbd.S)N(R.sup.D1a).sub.2, --C(.dbd.NR.sup.D1a)R.sup.D1a,
--C(.dbd.NR.sup.D1a)OR.sup.D1a, --C(.dbd.NR.sup.D1a)SR.sup.D1a, or
--C(.dbd.NR.sup.D1a)N(R.sup.D1a).sub.2, wherein each occurrence of
R.sup.D1a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
or two R.sup.D1a groups are joined to form an substituted or
unsubstituted heterocyclic ring; each instance of R.sup.D2 is
independently hydrogen, halogen, acyl, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, --CN,
--NO.sub.2, --OR.sup.D2a, --N(R.sup.D2a).sub.2, --SR.sup.D2a,
--CH.sub.2OR.sup.D2aCH.sub.2N(R.sup.D2a).sub.2,
--CH.sub.2SR.sup.D2a, --C(.dbd.O)R.sup.D2a, --C(.dbd.O)OR.sup.D2a,
--C(.dbd.O)SR.sup.D2a, --C(.dbd.O)N(R.sup.D2a).sub.2,
--C(.dbd.S)R.sup.D2a, --C(.dbd.S)OR.sup.D2a, --C(.dbd.S)SR.sup.D2a,
--C(.dbd.S)N(R.sup.D2a).sub.2, --C(.dbd.NR.sup.D2a)R.sup.D2a,
--C(.dbd.NR.sup.D2a)OR.sup.D2a, --C(.dbd.NR.sup.D2a)SR.sup.D2a, and
--C(.dbd.NR.sup.D2a)N(R.sup.D2a).sub.2, wherein each occurrence of
R.sup.D2a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, and substituted or unsubstituted heteroaryl,
or two R.sup.D2a groups are joined to form an substituted or
unsubstituted heterocyclic ring; each instance of R.sup.D3 is
independently hydrogen, halogen, acyl, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.D3a, --N(R.sup.D3a).sub.2, --SR.sup.D3a,
--CH.sub.2OR.sup.D3a, --CH.sub.2N(R.sup.D3a).sub.2,
--CH.sub.2SR.sup.D3a, --C(.dbd.O)R.sup.D3a, --C(.dbd.O)OR.sup.D3a,
--C(.dbd.O)SR.sup.D3a, --C(.dbd.O)N(R.sup.D3a).sub.2,
--C(.dbd.S)R.sup.D3a, --C(.dbd.S)OR.sup.D3a, --C(.dbd.S)SR.sup.D3a,
--C(.dbd.S)N(R.sup.D3a).sub.2, --C(.dbd.NR.sup.D3a)R.sup.D3a,
--C(.dbd.NR.sup.D3a)OR.sup.D3a, --C(.dbd.NR.sup.D3a)SR.sup.D3a, or
--C(.dbd.NR.sup.D3a)N(R.sup.D3a).sub.2 wherein each occurrence of
R.sup.D3a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
or two R.sup.D3a groups are joined to form an substituted or
unsubstituted heterocyclic ring; optionally R.sup.D1 and R.sup.D3,
or R.sup.D2 and R.sup.D3, or R.sup.D1 and R.sup.D2 are joined to
form an substituted or unsubstituted carbocyclic or substituted or
unsubstituted heterocyclic ring; R.sup.D4 is a leaving group
selected from the group consisting of --Br, --Cl, --I, and
--OS(.dbd.O).sub.wR.sup.D4a, wherein w is 1 or 2, and R.sup.D4a is
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl; each instance of X.sup.1 is independently
a bond, --C(.dbd.O)--, --SO.sub.2--, --NR.sup.D5--, optionally
substituted alkylene, or optionally substituted heteroarylene,
wherein R.sup.D5 is hydrogen, C.sub.1-6 alkyl, or a nitrogen
protecting group; each instance of Y is independently O, S, or
NR.sup.D6, wherein R.sup.D6 is hydrogen, C.sub.1-6 alkyl, or a
nitrogen protecting group; and each instance of z and z.sub.1 is
independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.
2. A compound of Formula (II): ##STR00224## or a pharmaceutically
acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,
stereoisomer, isotopically labeled derivative, or prodrug thereof;
wherein: Ring A is aryl, arylalkenyl, or heteroaryl; each instance
of R.sup.A is independently selected from the group consisting of
hydrogen, halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.A1, --N(R.sup.A1).sub.2, --SR.sup.A1, --CN,
--C(.dbd.NR.sup.A1)R.sup.A1, --C(.dbd.NR.sup.A1)OR.sup.A1,
--C(.dbd.NR.sup.A1)SR.sup.A1, --C(.dbd.NR.sup.A1)N(R.sup.A1).sub.2,
--C(.dbd.O)NR.sup.A1--, --NR.sup.A1C(.dbd.O)--,
--C(.dbd.O)R.sup.A1, --C(.dbd.S)R.sup.A1, --C(.dbd.S)OR.sup.A1,
--C(.dbd.S)SR.sup.A1, --C(.dbd.S)N(R.sup.A1).sub.2, --NO.sub.2,
--N.sub.3, --N(R.sup.A1).sub.3.sup.+F.sup.-,
--N(R.sup.A1).sub.3.sup.+Cl.sup.-,
--N(R.sup.A1).sub.3.sup.+Br.sup.-,
--N(R.sup.A1).sub.3.sup.+I.sup.-, --N(OR.sup.A1)R.sup.A1,
--NR.sup.A1C(.dbd.O)R.sup.A1, --NR.sup.A1C(.dbd.O)OR.sup.A1,
--NR.sup.A1C(.dbd.O)SR.sup.A1,
--NR.sup.A1C(.dbd.O)N(R.sup.A1).sub.2,
--NR.sup.A1C(.dbd.S)R.sup.A1, --NR.sup.A1C(.dbd.S)OR.sup.A1,
--NR.sup.A1C(.dbd.S)SR.sup.A1,
--NR.sup.A1C(.dbd.S)N(R.sup.A1).sub.2,
--NR.sup.A1C(.dbd.NR.sup.A1)R.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)OR.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)SR.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)N(R.sup.A1).sub.2,
--NR.sup.A1S(.dbd.O).sub.2R.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2OR.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2SR.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2N(R.sup.A1).sub.2,
--NR.sup.A1S(.dbd.O)R.sup.A1, --NR.sup.A1S(.dbd.O)OR.sup.A1,
--NR.sup.A1S(.dbd.O)SR.sup.A1,
--NR.sup.A1S(.dbd.O)N(R.sup.A1).sub.2, --NR.sup.A1P(.dbd.O),
--NR.sup.A1P(.dbd.O).sub.2, --NR.sup.A1P(.dbd.O)(R.sup.A1).sub.2,
--NR.sup.A1P(.dbd.O)R.sup.A1(OR.sup.A1),
--NR.sup.A1P(.dbd.O)(OR.sup.A1).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A1).sub.2, --OC(.dbd.NR.sup.A1)R.sup.A1,
--OC(.dbd.NR.sup.A1)OR.sup.A1,
--OC(.dbd.NR.sup.A1)N(R.sup.A1).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A1).sub.2, --ON(R.sup.A1).sub.2,
--OS(.dbd.O)R.sup.A1, --OS(.dbd.O)OR.sup.A1, --OS(.dbd.O)SR.sup.A1,
--OS(.dbd.O)N(R.sup.A1).sub.2, --OS(.dbd.O).sub.2R.sup.A1,
--OS(.dbd.O).sub.2OR.sup.A1, --OS(.dbd.O).sub.2SR.sup.A1,
--OS(.dbd.O).sub.2N(R.sup.A1).sub.2, --OP(.dbd.O).sub.2,
--OP(.dbd.O)(R.sup.A1).sub.2, --OP(.dbd.O)R.sup.A1(OR.sup.A1),
--OP(.dbd.O)(OR.sup.A1).sub.2, --OP(.dbd.O), --OP(R.sup.A1).sub.2,
--OPR.sup.A1(OR.sup.A1), --OP(OR.sup.A1).sub.2,
--OSi(R.sup.A1).sub.3, --OSi(R.sup.A1).sub.2OR.sup.A1,
--OSi(R.sup.A1)(OR.sup.A1).sub.2, --OSi(OR.sup.A1).sub.3,
--SSR.sup.A1, --S(.dbd.O)R.sup.A1, --S(.dbd.O)OR.sup.A1,
--S(.dbd.O)N(R.sup.A1).sub.2, --S(.dbd.O).sub.2R.sup.A1,
--S(.dbd.O).sub.2OR.sup.A1, --S(.dbd.O).sub.2N(R.sup.A1).sub.2,
--SC(.dbd.O)R.sup.A1, --SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A1).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A1).sub.2, --P(R.sup.A1).sub.2,
--PR.sup.A1(OR.sup.A1), --P(OR.sup.A1).sub.2, --P(.dbd.O),
--P(.dbd.O)(R.sup.A1).sub.2, --P(.dbd.O)(OR.sup.A1).sub.2,
--P(.dbd.O)R.sup.A1(OR.sup.A1), --P(.dbd.O).sub.2,
--B(R.sup.A1).sub.2, --B(OR.sup.A1).sub.2, --BR.sup.A1(OR.sup.A1),
--Si(R.sup.A1).sub.3, --Si(R.sup.A1).sub.2OR.sup.A1,
--SiR.sup.A1(OR.sup.A1).sub.2, and --Si(OR.sup.A1).sub.3, wherein
each occurrence of R.sup.A1 is independently selected from the
group consisting of hydrogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, a nitrogen protecting group when
attached to a nitrogen atom, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, or two R.sup.A1 groups are joined to form an
optionally substituted heterocyclic ring; k is 0, 1, 2, 3, 4, or 5;
Ring C is a carbocyclic, heterocyclic, aryl, or heteroaryl ring;
each instance of R.sup.j1, R.sup.j2, R.sup.j3, and R.sup.C is
independently selected from the group consisting of hydrogen,
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
carbocyclyl, optionally substituted heterocyclyl, optionally
substituted aryl, optionally substituted heteroaryl, --OR.sup.C1,
--N(R.sup.C1).sub.2, --SR.sup.C1, --CN,
--C(.dbd.NR.sup.C1)R.sup.C1, --C(.dbd.NR.sup.C1)OR.sup.C1,
--C(.dbd.NR.sup.C1)SR.sup.C1, --C(.dbd.NR.sup.C1)N(R.sup.C1).sub.2,
--C(.dbd.O)R.sup.C1, --C(.dbd.S)R.sup.C1, --C(.dbd.S)OR.sup.C1,
--C(.dbd.S)SR.sup.C1, --C(.dbd.S)N(R.sup.C1).sub.2, --NO.sub.2,
--N.sub.3, --N(R.sup.C1).sub.3.sup.+F.sup.-,
--N(R.sup.C1).sub.3.sup.+Cl.sup.-,
--N(R.sup.C1).sub.3.sup.+Br.sup.-,
--N(R.sup.C1).sub.3.sup.+F.sup.-, --N(OR.sup.C1)R.sup.C1,
--NR.sup.C1C(.dbd.O)R.sup.C1, --NR.sup.C1C(.dbd.O)OR.sup.C1,
--NR.sup.C1C(.dbd.O)SR.sup.C1,
--NR.sup.C1C(.dbd.O)N(R.sup.C1).sub.2,
--NR.sup.C1C(.dbd.S)R.sup.C1, --NR.sup.C1C(.dbd.S)OR.sup.C1,
--NR.sup.C1C(.dbd.S)SR.sup.C1,
--NR.sup.C1C(.dbd.S)N(R.sup.C1).sub.2,
--NR.sup.C1C(.dbd.NR.sup.C1)R.sup.C1,
--NR.sup.C1C(.dbd.NR.sup.C1)OR.sup.C1,
--NR.sup.C1C(.dbd.NR.sup.C1)SR.sup.C1,
--NR.sup.C1C(.dbd.NR.sup.C1)N(R.sup.C1).sub.2,
--NR.sup.C1S(.dbd.O).sub.2R.sup.C1,
--NR.sup.C1S(.dbd.O).sub.2OR.sup.C1,
--NR.sup.C1S(.dbd.O).sub.2SR.sup.C1,
--NR.sup.C1S(.dbd.O).sub.2N(R.sup.C1).sub.2,
--NR.sup.C1S(.dbd.O)R.sup.C1, --NR.sup.C1S(.dbd.O)OR.sup.C1,
--NR.sup.C1S(.dbd.O)SR.sup.C1,
--NR.sup.C1S(.dbd.O)N(R.sup.C1).sub.2, --NR.sup.C1P(.dbd.O),
--NR.sup.C1P(.dbd.O).sub.2, --NR.sup.C1P(.dbd.O)(R.sup.C1).sub.2,
--NR.sup.C1P(.dbd.O)R.sup.C1(OR.sup.C1),
--NR.sup.C1P(.dbd.O)(OR.sup.1).sub.2, --OC(.dbd.O)R.sup.C1,
--OC(.dbd.O)OR.sup.C1, --OC(.dbd.O)SR.sup.C1,
--OC(.dbd.O)N(R.sup.C1).sub.2, --OC(.dbd.NR.sup.C1)R.sup.C1,
--OC(.dbd.NR.sup.C1)OR.sup.C1,
--OC(.dbd.NR.sup.C1)N(R.sup.C1).sub.2, --OC(.dbd.S)R.sup.C1,
--OC(.dbd.S)OR.sup.C1, --OC(.dbd.S)SR.sup.C1,
--OC(.dbd.S)N(R.sup.C1).sub.2, --ON(R.sup.C1).sub.2,
--OS(.dbd.O)R.sup.C1, --OS(.dbd.O)OR.sup.C1, --OS(.dbd.O)SR.sup.C1,
--OS(.dbd.O)N(R.sup.C1).sub.2, --OS(.dbd.O).sub.2R.sup.C1,
--OS(.dbd.O).sub.2OR.sup.C1, --OS(.dbd.O).sub.2SR.sup.C1,
--OS(.dbd.O).sub.2N(R.sup.C1).sub.2, --OP(.dbd.O).sub.2,
--OP(.dbd.O)(R.sup.C1).sub.2, --OP(.dbd.O)R.sup.C1(OR.sup.C1),
--OP(.dbd.O)(OR.sup.C1).sub.2, --OP(.dbd.O), --OP(R.sup.C1).sub.2,
--OPR.sup.C1(OR.sup.C1), --OP(OR.sup.C1).sub.2,
--OSi(R.sup.C1).sub.3, --OSi(R.sup.C1).sub.2OR.sup.C1,
--OSi(R.sup.C1)(OR.sup.C1).sub.2, --OSi(OR.sup.C1).sub.3,
--SSR.sup.C1, --S(.dbd.O)R.sup.C1, --S(.dbd.O)OR.sup.C1,
--S(.dbd.O)N(R.sup.C1).sub.2, --S(.dbd.O).sub.2R.sup.C1,
--S(.dbd.O).sub.2OR.sup.C1, --S(.dbd.O).sub.2N(R.sup.C1).sub.2,
--SC(.dbd.O)R.sup.C1, --SC(.dbd.O)OR.sup.C1, --SC(.dbd.O)SR.sup.C1,
--SC(.dbd.O)N(R.sup.C1).sub.2, --SC(.dbd.S)R.sup.C1,
--SC(.dbd.S)OR.sup.C1, --SC(.dbd.S)SR.sup.C1,
--SC(.dbd.S)N(R.sup.C1).sub.2, --P(R.sup.C1).sub.2,
--PR.sup.C1(OR.sup.C1), --P(OR.sup.C1).sub.2, --P(.dbd.O),
--P(.dbd.O)(R.sup.C1).sub.2, --P(.dbd.O)(OR.sup.C1).sub.2,
--P(.dbd.O)R.sup.C1(OR.sup.C1), --P(.dbd.O).sub.2,
--B(R.sup.C1).sub.2, --B(OR.sup.C1).sub.2, --BR.sup.C1(OR.sup.C1),
--Si(R.sup.C1).sub.3, --Si(R.sup.C1).sub.2OR.sup.C1,
--SiR.sup.C1(OR.sup.C1).sub.2, and --Si(OR.sup.C1).sub.3, wherein
each occurrence of R.sup.Cd is independently selected from the
group consisting of hydrogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, a nitrogen protecting group when
attached to a nitrogen atom, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, or two R.sup.C1 groups are joined to form an
optionally substituted heterocyclic ring or optionally substituted
heteroaryl ring; n is 0, 1, 2, 3, or 4; L is a bond or an
optionally substituted, branched or unbranched C.sub.1-6
hydrocarbon chain; R.sup.D is any one of Formulae (i-1)-(i-43):
##STR00225## ##STR00226## ##STR00227## ##STR00228## ##STR00229##
wherein: each instance of R.sup.D1 is independently hydrogen,
halogen, acyl, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --CN, --NO.sub.2,
--OR.sup.D1a, --N(R.sup.D1a).sub.2, --SR.sup.D1a,
--CH.sub.2OR.sup.D1a, --CH.sub.2N(R.sup.D1a).sub.2,
--CH.sub.2SR.sup.D1a, --C(.dbd.O)R.sup.D1a, --C(.dbd.O)OR.sup.D1a,
--C(.dbd.O)SR.sup.D1a, --C(.dbd.O)N(R.sup.D1a).sub.2,
--C(.dbd.S)R.sup.D1a, --C(.dbd.S)OR.sup.D1a, --C(.dbd.S)SR.sup.D1a,
--C(.dbd.S)N(R.sup.D1a).sub.2, --C(.dbd.NR.sup.D1a)R.sup.D1a,
--C(.dbd.NR.sup.D1a)OR.sup.D1a, --C(.dbd.NR.sup.D1a)SR.sup.D1, or
--C(.dbd.NR.sup.D1a)N(R.sup.D1a).sub.2, wherein each occurrence of
R.sup.D1a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
or two R.sup.D1a, groups are joined to form an substituted or
unsubstituted heterocyclic ring; each instance of R.sup.D2 is
independently hydrogen, halogen, acyl, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, --CN,
--NO.sub.2, --OR.sup.D2a, --N(R.sup.D2a).sub.2, --SR.sup.D2a,
--CH.sub.2OR.sup.D2a, --CH.sub.2N(R.sup.D2a).sub.2,
--CH.sub.2SR.sup.D2a, --C(.dbd.O)R.sup.D2a, --C(.dbd.O)OR.sup.D2a,
--C(.dbd.O)SR.sup.D2a, --C(.dbd.O)N(R.sup.D2a).sub.2,
--C(.dbd.S)R.sup.D2a, --C(.dbd.S)OR.sup.D2a, --C(.dbd.S)SR.sup.D2a,
--C(.dbd.S)N(R.sup.D2a).sub.2, --C(.dbd.NR.sup.D2a)R.sup.D2a,
--C(.dbd.NR.sup.D2a)OR.sup.D2a, --C(.dbd.NR.sup.D2a)SR.sup.D2a, and
--C(.dbd.NR.sup.D2a)N(R.sup.D2a).sub.2, wherein each occurrence of
R.sup.D2a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, and substituted or unsubstituted heteroaryl,
or two R.sup.D2a groups are joined to form an substituted or
unsubstituted heterocyclic ring; each instance of R.sup.D3 is
independently hydrogen, halogen, acyl, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.D3a, --N(R.sup.D3a).sub.2, --SR.sup.D3a,
--CH.sub.2OR.sup.D3a, --CH.sub.2N(R.sup.D3a).sub.2,
--CH.sub.2SR.sup.D3a, --C(.dbd.O)R.sup.D3a, --C(.dbd.O)OR.sup.D3a,
--C(.dbd.O)SR.sup.D3a, --C(.dbd.O)N(R.sup.D3a).sub.2,
--C(.dbd.S)R.sup.D3a, --C(.dbd.S)OR.sup.D3a, --C(.dbd.S)SR.sup.D3a,
--C(.dbd.S)N(R.sup.D3a).sub.2, --C(.dbd.NR.sup.D3a)R.sup.D3a,
--C(.dbd.NR.sup.D3a)OR.sup.D3a, --C(.dbd.NR.sup.D3a)SR.sup.D3a, or
--C(.dbd.NR.sup.D3a)N(R.sup.D3a).sub.2 wherein each occurrence of
R.sup.D3a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
or two R.sup.D3a groups are joined to form an substituted or
unsubstituted heterocyclic ring; optionally R.sup.D1 and R.sup.D3,
or R.sup.D2 and R.sup.D3, or R.sup.D1 and R.sup.D2 are joined to
form an substituted or unsubstituted carbocyclic or substituted or
unsubstituted heterocyclic ring; R.sup.D4 is a leaving group
selected from the group consisting of --Br, --Cl, --I, and
--OS(.dbd.O).sub.wR.sup.D4a, wherein w is 1 or 2, and R.sup.D4a is
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl; each instance of X.sup.1 is independently
a bond, --C(.dbd.O)--, --SO.sub.2--, --NR.sup.D5--, optionally
substituted alkylene, or optionally substituted heteroarylene,
wherein R.sup.D5 is hydrogen, C.sub.1-6 alkyl, or a nitrogen
protecting group; each instance of Y is independently O, S, or
NR.sup.D6, wherein R.sup.D6 is hydrogen, C.sub.1-6 alkyl, or a
nitrogen protecting group; and each instance of z and z.sub.1 is
independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.
3. A compound of Formula (III): ##STR00230## or a pharmaceutically
acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,
stereoisomer, isotopically labeled derivative, or prodrug thereof;
wherein: Ring A is aryl, arylalkenyl, or heteroaryl; each instance
of R.sup.A is independently selected from the group consisting of
hydrogen, halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.A1, --N(R.sup.A1).sub.2, --SR.sup.A1, --CN,
--C(.dbd.NR.sup.A1)R.sup.A1, --C(.dbd.NR.sup.A1)OR.sup.A1,
--C(.dbd.NR.sup.A1)SR.sup.A1, --C(.dbd.NR.sup.A1)N(R.sup.A1).sub.2,
--C(.dbd.O)NR.sup.A1--, --NR.sup.A1C(.dbd.O)--,
--C(.dbd.O)R.sup.A1, --C(.dbd.S)R.sup.A1, --C(.dbd.S)OR.sup.A1,
--C(.dbd.S)SR.sup.A1, --C(.dbd.S)N(R.sup.A1).sub.2, --NO.sub.2,
--N.sub.3, --N(R.sup.A1).sub.3+F--,
--N(R.sup.A1).sub.3.sup.+Cl.sup.-,
--N(R.sup.A1).sub.3.sup.+Br.sup.-,
--N(R.sup.A1).sub.3.sup.+I.sup.-, --N(OR.sup.A1)R.sup.A1,
--NR.sup.A1C(.dbd.O)R.sup.A1, --NR.sup.A1C(.dbd.O)OR.sup.A1,
--NR.sup.A1C(.dbd.O)SR.sup.A1,
--NR.sup.A1C(.dbd.O)N(R.sup.A1).sub.2,
--NR.sup.A1C(.dbd.S)R.sup.A1, --NR.sup.A1C(.dbd.S)OR.sup.A1,
--NR.sup.A1C(.dbd.S)SR.sup.A1,
--NR.sup.A1C(.dbd.S)N(R.sup.A1).sub.2,
--NR.sup.A1C(.dbd.NR.sup.A1)R.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)OR.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)SR.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)N(R.sup.A1).sub.2,
--NR.sup.A1S(.dbd.O).sub.2R.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2OR.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2SR.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2N(R.sup.A1).sub.2,
--NR.sup.A1S(.dbd.O)R.sup.A1, --NR.sup.A1S(.dbd.O)OR.sup.A1,
--NR.sup.A1S(.dbd.O)SR.sup.A1,
--NR.sup.A1S(.dbd.O)N(R.sup.A1).sub.2, --NR.sup.A1P(.dbd.O),
--NR.sup.A1P(.dbd.O).sub.2, --NR.sup.A1P(.dbd.O)(R.sup.A1).sub.2,
--NR.sup.A1P(.dbd.O)R.sup.A1(OR.sup.A1),
--NR.sup.A1P(.dbd.O)(OR.sup.A1).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A1).sub.2, --OC(.dbd.NR.sup.A1)R.sup.A1,
--OC(.dbd.NR.sup.A1)OR.sup.A1,
--OC(.dbd.NR.sup.A1)N(R.sup.A1).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A1).sub.2, --ON(R.sup.A1).sub.2,
--OS(.dbd.O)R.sup.A1, --OS(.dbd.O)OR.sup.A1, --OS(.dbd.O)SR.sup.A1,
--OS(.dbd.O)N(R.sup.A1).sub.2, --OS(.dbd.O).sub.2R.sup.A1,
--OS(.dbd.O).sub.2OR.sup.A1, --OS(.dbd.O).sub.2SR.sup.A1,
--OS(.dbd.O).sub.2N(R.sup.A1).sub.2, --OP(.dbd.O).sub.2,
--OP(.dbd.O)(R.sup.A1).sub.2, --OP(.dbd.O)R.sup.A1(OR.sup.A1),
--OP(.dbd.O)(OR.sup.A1).sub.2, --OP(.dbd.O), --OP(R.sup.A1).sub.2,
--OPR.sup.A1(OR.sup.A1), --OP(OR.sup.A1).sub.2,
--OSi(R.sup.A1).sub.3, --OSi(R.sup.A1).sub.2OR.sup.A1,
--OSi(R.sup.A1)(OR.sup.A1).sub.2, --OSi(OR.sup.A1).sub.3,
--SSR.sup.A1, --S(.dbd.O)R.sup.A1, --S(.dbd.O)OR.sup.A1,
--S(.dbd.O)N(R.sup.A1).sub.2, --S(.dbd.O).sub.2R.sup.A1,
--S(.dbd.O).sub.2OR.sup.A, --S(.dbd.O).sub.2N(R.sup.A1).sub.2,
--SC(.dbd.O)R.sup.A1, --SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A1).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A1).sub.2, --P(R.sup.A1).sub.2,
--PR.sup.A1(OR.sup.A1), --P(OR.sup.A1).sub.2, --P(.dbd.O),
--P(.dbd.O)(R.sup.A1).sub.2, --P(.dbd.O)(OR.sup.A1).sub.2,
--P(.dbd.O)R.sup.A1(OR.sup.A1), --P(.dbd.O).sub.2,
--B(R.sup.A1).sub.2, --B(OR.sup.A1).sub.2, --BR.sup.A1(OR.sup.A1),
--Si(R.sup.A1).sub.3, --Si(R.sup.A1).sub.2OR.sup.A1,
--SiR.sup.A1(OR.sup.A1).sub.2, and --Si(OR.sup.A1).sub.3, wherein
each occurrence of R.sup.A1 is independently selected from the
group consisting of hydrogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, a nitrogen protecting group when
attached to a nitrogen atom, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, or two R.sup.A1 groups are joined to form an
optionally substituted heterocyclic ring; k is 0, 1, 2, 3, 4, or 5;
Ring C is a carbocyclic, heterocyclic, aryl, or heteroaryl ring;
each instance of R.sup.C is independently selected from the group
consisting of hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.C1, --N(R.sup.C1).sub.2, --SR.sup.C1, --CN,
--C(.dbd.NR.sup.C1)R.sup.C1, --C(.dbd.NR.sup.C1)OR.sup.q,
--C(.dbd.NR.sup.C1)SR.sup.C1, --C(.dbd.NR.sup.C1)N(R.sup.C1).sub.2,
--C(.dbd.O)R.sup.C1, --C(.dbd.S)R.sup.C1, --C(.dbd.S)OR.sup.C1,
--C(.dbd.S)SR.sup.C1, --C(.dbd.S)N(R.sup.C1).sub.2, --NO.sub.2,
--N.sub.3, --N(R.sup.C1).sub.3.sup.+F.sup.-,
--N(R.sup.C1).sub.3.sup.+Cl.sup.-,
--N(R.sup.C1).sub.3.sup.+Br.sup.-,
--N(R.sup.C1).sub.3.sup.+I.sup.-, --N(OR.sup.C1)R.sup.C1,
--NR.sup.C1C(.dbd.O)R.sup.C1, --NR.sup.C1C(.dbd.O)OR.sup.C1,
--NR.sup.C1C(.dbd.O)SR.sup.C1,
--NR.sup.C1C(.dbd.O)N(R.sup.C1).sub.2,
--NR.sup.C1C(.dbd.S)R.sup.C1, --NR.sup.C1C(.dbd.S)OR.sup.C1,
--NR.sup.C1C(.dbd.S)SR.sup.C1,
--NR.sup.C1C(.dbd.S)N(R.sup.C1).sub.2,
--NR.sup.C1C(.dbd.NR)R.sup.C1,
--NR.sup.C1C(.dbd.NR.sup.C1)OR.sup.C1,
--NR.sup.C1C(.dbd.NR.sup.C1)SR.sup.C1,
--NR.sup.C1C(.dbd.NR.sup.C1)N(R.sup.C1).sub.2,
--NR.sup.C1S(.dbd.O).sub.2R.sup.C1,
--NR.sup.C1S(.dbd.O).sub.2OR.sup.C1,
--NR.sup.C1S(.dbd.O).sub.2SR.sup.C1,
--NR.sup.C1S(.dbd.O).sub.2N(R.sup.C1).sub.2,
--NR.sup.C1S(.dbd.O)R.sup.C1, --NR.sup.C1S(.dbd.O)OR.sup.C1,
--NR.sup.C1S(.dbd.O)SR.sup.C1,
--NR.sup.C1S(.dbd.O)N(R.sup.C1).sub.2, --NR.sup.C1P(.dbd.O),
--NR.sup.C1P(.dbd.O).sub.2, --NR.sup.C1P(.dbd.O)(R.sup.C1).sub.2,
--NR.sup.C1P(.dbd.O)R.sup.C1(OR.sup.C1),
--NR.sup.C1P(.dbd.O)(OR.sup.C1).sub.2, --OC(.dbd.O)R.sup.C1,
--OC(.dbd.O)OR.sup.C1, --OC(.dbd.O)SR.sup.C1,
--OC(.dbd.O)N(R.sup.C1).sub.2, --OC(.dbd.NR.sup.C1)R.sup.C1,
--OC(.dbd.NR.sup.C1)OR.sup.C1,
--OC(.dbd.NR.sup.C1)N(R.sup.C1).sub.2, --OC(.dbd.S)R.sup.C1,
--OC(.dbd.S)OR.sup.C1, --OC(.dbd.S)SR.sup.C1,
--OC(.dbd.S)N(R.sup.C1).sub.2, --ON(R.sup.C1).sub.2,
--OS(.dbd.O)R.sup.C1, --OS(.dbd.O)OR.sup.C1, --OS(.dbd.O)SR.sup.C1,
--OS(.dbd.O)N(R.sup.C1).sub.2, --OS(.dbd.O).sub.2R.sup.C1,
--OS(.dbd.O).sub.2OR.sup.C1, --OS(.dbd.O).sub.2SR.sup.C1,
--OS(.dbd.O).sub.2N(R.sup.C1).sub.2, --OP(.dbd.O).sub.2,
--OP(.dbd.O)(R.sup.C1).sub.2, --OP(.dbd.O)R.sup.C1(OR.sup.C1),
--OP(.dbd.O)(OR.sup.C1).sub.2, --OP(.dbd.O), --OP(R.sup.C1).sub.2,
--OPR.sup.C1(OR.sup.C1), --OP(OR.sup.C1).sub.2,
--OSi(R.sup.C1).sub.3, --OSi(R.sup.C1).sub.2OR.sup.C1,
--OSi(R.sup.C1)(OR.sup.C1).sub.2, --OSi(OR.sup.C1).sub.3,
--SSR.sup.C1, --S(.dbd.O)R.sup.C1, --S(.dbd.O)OR.sup.C1,
--S(.dbd.O)N(R.sup.C1).sub.2, --S(.dbd.O).sub.2R.sup.C1,
--S(.dbd.O).sub.2OR.sup.C1, --S(.dbd.O).sub.2N(R.sup.C1).sub.2,
--SC(.dbd.O)R.sup.C1, --SC(.dbd.O)OR.sup.C1, --SC(.dbd.O)SR.sup.C1,
--SC(.dbd.O)N(R.sup.C1).sub.2, --SC(.dbd.S)R.sup.C1,
--SC(.dbd.S)OR.sup.C1, --SC(.dbd.S)SR.sup.C1,
--SC(.dbd.S)N(R.sup.C1).sub.2, --P(R.sup.C1).sub.2,
--PR.sup.C1(OR.sup.C1), --P(OR.sup.C1).sub.2, --P(.dbd.O),
--P(.dbd.O)(R.sup.C1).sub.2, --P(.dbd.O)(OR.sup.C1).sub.2,
--P(.dbd.O)R.sup.C1(OR.sup.C1), --P(.dbd.O).sub.2,
--B(R.sup.C1).sub.2, --B(OR.sup.C1).sub.2, --BR.sup.C1(OR.sup.C1),
--Si(R.sup.C1).sub.3, --Si(R.sup.C1).sub.2OR.sup.C1,
--SiR.sup.C1(OR.sup.C1).sub.2, and --Si(OR.sup.C1).sub.3, wherein
each occurrence of R.sup.C1 is independently selected from the
group consisting of hydrogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, a nitrogen protecting group when
attached to a nitrogen atom, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, or two R.sup.C1 groups are joined to form an
optionally substituted heterocyclic ring or optionally substituted
heteroaryl ring; R.sup.q is independently hydrogen, halogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, or a nitrogen protecting group;
n is 0, 1, 2, 3, or 4; L is a bond or an optionally substituted,
branched or unbranched C.sub.1-6 hydrocarbon chain; R.sup.D is any
one of Formulae (i-1)-(i-43): ##STR00231## ##STR00232##
##STR00233## ##STR00234## ##STR00235## wherein: each instance of
R.sup.D1 is independently hydrogen, halogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
--CN, --NO.sub.2, --OR.sup.D1a, --N(R.sup.D1a).sub.2, --SR.sup.D1a,
--CH.sub.2OR.sup.D1a, --CH.sub.2N(R.sup.D1a).sub.2,
--CH.sub.2SR.sup.D1a, --C(.dbd.O)R.sup.D1a, --C(.dbd.O)OR.sup.D1a,
--C(.dbd.O)SR.sup.D1a, --C(.dbd.O)N(R.sup.D1a).sub.2,
--C(.dbd.S)R.sup.D1a, --C(.dbd.S)OR.sup.D1a, --C(.dbd.S)SR.sup.D1a,
--C(.dbd.S)N(R.sup.D1a).sub.2, --C(.dbd.NR.sup.D1a)R.sup.D1a,
--C(.dbd.NR.sup.D1a)OR.sup.D1a C(.dbd.NR.sup.D1a)SR.sup.D1a, or
--C(.dbd.NR.sup.D1a)N(R.sup.D1a).sub.2, wherein each occurrence of
R.sup.D1a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
or two R.sup.D1a groups are joined to form an substituted or
unsubstituted heterocyclic ring; each instance of R.sup.D2 is
independently hydrogen, halogen, acyl, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, --CN,
--NO.sub.2, --OR.sup.D2a, --N(R.sup.D2a).sub.2, --SR.sup.D2a,
--CH.sub.2OR.sup.D2aCH.sub.2N(R.sup.D2a).sub.2,
--CH.sub.2SR.sup.D2a, --C(.dbd.O)R.sup.D2a, --C(.dbd.O)OR.sup.D2a,
--C(.dbd.O)SR.sup.D2a, --C(.dbd.O)N(R.sup.D2a).sub.2,
--C(.dbd.S)R.sup.D2a, --C(.dbd.S)OR.sup.D2a, --C(.dbd.S)SR.sup.D2a,
--C(.dbd.S)N(R.sup.D2a).sub.2, --C(.dbd.NR.sup.D2a)R.sup.D2a,
--C(.dbd.NR.sup.D2a)OR.sup.D2a, --C(.dbd.NR.sup.D2a)SR.sup.D2a, and
--C(.dbd.NR.sup.D2a)N(R.sup.D2a).sub.2, wherein each occurrence of
R.sup.D2a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, and substituted or unsubstituted heteroaryl,
or two R.sup.D2a groups are joined to form an substituted or
unsubstituted heterocyclic ring; each instance of R.sup.D3 is
independently hydrogen, halogen, acyl, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.D3a, --N(R.sup.D3a).sub.2, --SR.sup.D3a,
--CH.sub.2OR.sup.D3a, --CH.sub.2N(R.sup.D3a).sub.2,
--CH.sub.2SR.sup.D3a, --C(.dbd.O)R.sup.D3a, --C(.dbd.O)OR.sup.D3a,
--C(.dbd.O)SR.sup.D3a, --C(.dbd.O)N(R.sup.D3a).sub.2,
--C(.dbd.S)R.sup.D3a, --C(.dbd.S)OR.sup.D3a, --C(.dbd.S)SR.sup.D3a,
--C(.dbd.S)N(R.sup.D3a).sub.2, --C(.dbd.NR.sup.D3a)R.sup.D3a,
--C(.dbd.NR.sup.D3a)OR.sup.D3a, --C(.dbd.NR.sup.D3a)SR.sup.D3a, or
--C(.dbd.NR.sup.D3a)N(R.sup.D3a).sub.2 wherein each occurrence of
R.sup.D3a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
or two R.sup.D3a groups are joined to form an substituted or
unsubstituted heterocyclic ring; optionally R.sup.D1 and R.sup.D3,
or R.sup.D2 and R.sup.D3, or R.sup.D1 and R.sup.D2 are joined to
form an substituted or unsubstituted carbocyclic or substituted or
unsubstituted heterocyclic ring; R.sup.D4 is a leaving group
selected from the group consisting of --Br, --Cl, --I, and
--OS(.dbd.O).sub.wR.sup.D4a, wherein w is 1 or 2, and R.sup.D4a is
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl; each instance of X.sup.1 is independently
a bond, --C(.dbd.O)--, --SO.sub.2--, --NR.sup.D5--, optionally
substituted alkylene, or optionally substituted heteroarylene,
wherein R.sup.D5 is hydrogen, C.sub.1-6 alkyl, or a nitrogen
protecting group; each instance of Y is independently O, S, or
NR.sup.D6, wherein R.sup.D6 is hydrogen, C.sub.1-6 alkyl, or a
nitrogen protecting group; and each instance of z and z.sub.1 is
independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.
4. (canceled)
5. The compound of claim 1, wherein Ring A is a 5-membered or
6-membered, monocyclic heteroaryl ring.
6. The compound of claim 5, wherein ##STR00236## is of formula:
##STR00237##
7. (canceled)
8. The compound of claim 5, wherein ##STR00238## is of formula:
##STR00239## ##STR00240##
9. (canceled)
10. The compound of claim 1, wherein ##STR00241## is one of the
following formulae: ##STR00242##
11-12. (canceled)
13. The compound of claim 1, wherein Ring C is aryl.
14. (canceled)
15. The compound of claim 1, wherein Ring C is indoline.
16. (canceled)
17. The compound of claim 1, wherein L is a bond or
--CH.sub.2--.
18. (canceled)
19. The compound of claim 1, wherein R.sup.D is of formula:
##STR00243##
20. (canceled)
21. The compound of claim 1, wherein R.sup.D is of formula:
##STR00244##
22-25. (canceled)
26. The compound of claim 1, wherein the compound is of formula:
##STR00245## or a pharmaceutically acceptable salt thereof.
27-31. (canceled)
32. The compound of claim 1, wherein the compound is of formula:
##STR00246## or a pharmaceutically acceptable salt thereof.
33-41. (canceled)
42. The compound of claim 1, wherein the compound is of formula:
##STR00247## or a pharmaceutically acceptable salt thereof.
43-48. (canceled)
49. A pharmaceutical composition comprising a therapeutically or
prophylactically effective amount of a compound of claim 1, or a
pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof, and optionally a pharmaceutically
acceptable excipient.
50. A method of treating or preventing an infectious disease in a
subject suffering therefrom, the method comprising: administering
to the subject a therapeutically or prophylactically effective
amount of a compound of claim 1, or a pharmaceutically acceptable
salt, solvate, hydrate, polymorph, co-crystal, tautomer,
stereoisomer, isotopically labeled derivative, or prodrug
thereof.
51-58. (canceled)
59. A method of preventing a viral infection in a subject who was
or may be exposed to a virus, the method comprising: administering
to the subject a prophylactically effective amount of a compound of
claim 1, or a pharmaceutically acceptable salt, solvate, hydrate,
polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
60-69. (canceled)
70. A kit for treating or preventing an infectious disease, the kit
comprising: a first container comprising a compound of claim 1, or
a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof; and instructions for administering
the compound, or a pharmaceutically acceptable salt, solvate,
hydrate, polymorph, co-crystal, tautomer, stereoisomer,
isotopically labeled derivative, or prodrug thereof, to a subject
to treat or prevent the infectious disease.
71. The compound of claim 1, wherein the compound is of the
formula: ##STR00248## ##STR00249## ##STR00250## or a
pharmaceutically acceptable salt thereof.
Description
RELATED APPLICATIONS
[0001] The present invention is a continuation of and claims
priority under 35 U.S.C. .sctn. 120 to U.S. application, U.S. Ser.
No. 14/391,638, filed Oct. 9, 2014, which is a national stage
filing under 35 U.S.C. .sctn. 371 of international PCT application,
PCT/US2013/032488, filed Mar. 15, 2013, which claims priority under
35 U.S.C. .sctn. 119(e) to U.S. provisional application, U.S. Ser.
No. 61/622,828, filed Apr. 11, 2012, each of which is incorporated
herein by reference.
BACKGROUND OF THE INVENTION
[0003] Dengue virus (DENV) is one of the most significant
mosquito-borne viral infections affecting humans today and is an
NIAID (National Institute of Allergy and Infectious Diseases)
Category A Biodefense pathogen. DENV is a plus-stranded RNA virus
and a member of the Flaviviridae family. The four Dengue virus
serotypes (DENV1, DENV2, DENV3, and DENV4) are defined by the viral
envelope protein (E) and share 60% sequence homology at the amino
acid level. Due to the large number of people at risk for
infection, DENV is the most widespread mosquito-borne virus
affecting humans today. An estimated 2.5 billion people live in
areas at risk for epidemic transmission, and an estimated 100
million people are infected with DENV annually. Infection with DENV
is responsible for diseases ranging from Dengue fever to the much
more severe and life-threatening Dengue hemorrhagic fever (DHF) and
Dengue shock syndrome (DSS) that are characterized by vascular
leakage. An estimated 500,000 cases of DHF and DSS occur annually
and are associated with 2.5% fatality although fatality rates for
DHF and DSS can exceed 20% if untreated (Dengue and Dengue
haemorrhagic fever. Vol. 2010 (WHO Media Centre, 2010)).
[0004] The determinants of disease severity for DENV infection and
the pathogenesis mechanisms underlying DHF and DSS are poorly
understood. Vascular leakage, which is the hallmark of DHF, is
largely believed to be caused by a host-mounted "cytokine storm"
but is correlated with high levels of viremia, particularly early
in infection (Halstead, Science (1988) 239:476-481; Gubler, Dengue
and Dengue Hemorrhagic Fever; Guple et al., ed.; CAB International:
New York, 1997; Vol. 1; pp. 1-22; Vaughn et al., J. Infect. Dis.
(2000) 181:2-9; Libraty et al., J. Infect. Dis. (2002)
185:1213-1221; Wang et al., Virology (2003) 305:330-338; and Endy
et al., J. Infect. Dis. (2004) 189:990-1000). In vivo data have
suggested that therapies that lower Dengue viral burden can
ameliorate the inflammatory "cytokine storm" associated with DHF or
DSS.
[0005] The strong correlation between viral load and disease
severity suggests that antivirals that inhibit DENV and reduce
viral burden might reduce the severity of DENV-associated disease.
Peak virus titers on the order of 10.sup.7 to 10.sup.8
MID.sub.50/mL (median infectious dose/mL plasma) were found in
patients with Dengue fever; patients with DHF or DSS exhibited
titers 100-fold and 1000-fold higher, respectively (Vaughn et al.,
J. Infect. Dis. (2000) 181:2-9; and Libraty et al., J. Infect. Dis.
(2002) 185:1213-1221). Additional studies of viremia and estimated
infected cell mass confirm this (Libraty et al., J. Infect. Dis.
(2002) 185:1213-1221; Wang et al., Virology (2003) 305:330-338;
Libraty et al., J. Infect. Dis. (2002) 186:1165-1168; Wang et al.,
Clin. Infect. Dis. (2006) 43:1023-1030; and Halstead, Dengue.
Lancet (2007) 370:1644-1652). Recent experimental support for the
potential efficacy of anti-DENV therapeutics includes the
demonstration that reduction of virus titers by 70-93% was
associated with a reduction in serum levels of inflammatory
cytokines (i.e., IL6, TNF.alpha., IL12p70, and MCP-1) in a mouse
model of Dengue fever (Schul et al., J. Infect. Dis. (2007)
195:665-674). These effects were observed with 7-DMA, a compound
with modest activity against the DENV RNA-dependent polymerase
(EC.sub.50 15 .mu.M) (Wu et al., J. Virology (2002)
76:3596-3604).
[0006] Despite the spread of the four DENV serotypes worldwide and
the increasing incidence of DHF and DSS over the past fifty years,
there currently are no specific therapeutics to combat DENV
infection or a vaccine that protects against all four DENV
serotypes. It remains an open question whether immunization
directed towards a limited set of epitopes conserved across all
DENV serotypes can elicit tetravalent protective immunity or if a
successful vaccine will require four distinct type-specific
responses. Further complicating DENV vaccine development is the
potential for non-neutralizing antibody responses to enhance the
infection of immune cells and to exacerbate the disease due to the
interaction of the antibody Fc region with activating Fc.gamma.
receptors (Fc.gamma.R) on immune cells, a phenomenon known as
antibody-dependent enhancement of infection (ADE). Currently, the
only treatment for DHF or DSS is supportive care primarily
maintaining the patient's circulating fluid volume. Thus, while
continuing efforts to develop a protective tetravalent vaccine are
imperative, alternative strategies to prevent and control DENV
infection are also urgently needed.
SUMMARY OF THE INVENTION
[0007] Antiviral agents that act via a host target may have higher
barriers to resistance and broader inhibitory activity against
multiple viral pathogens, compared with antivirals that act via a
viral target. Novel compounds are provided that show efficacy
against Flaviviridae viruses (e.g., all four Dengue serotypes
(DENV1, DENV2, DENV3, and DENV4)), Kunjin virus, Japanese
encephalitis virus, vesicular stomatitis virus, Junin virus, Ebola
virus, Marburg virus (MARV), Lassa fever virus (LASV), Venezuelan
equine encephalitis virus (VEEV), Rift Valley Fever virus (RVFV),
and other viruses. Without wishing to be bound by a particular
theory, these compounds are thought to covalently modify cysteine
residues of a host target. These compounds suggest a new paradigm
for developing broad-based antiviral agents.
[0008] The present invention provides compounds of Formula (I), and
pharmaceutically acceptable salts, solvates, hydrates, polymorphs,
co-crystals, tautomers, stereoisomers, isotopically labeled
derivatives, prodrugs, and compositions thereof. The present
invention further provides methods of using the inventive
compounds, and pharmaceutically acceptable salts, solvates,
hydrates, polymorphs, co-crystals, tautomers, stereoisomers,
isotopically labeled derivatives, prodrugs, and compositions
thereof, to study the inhibition of viruses, to treat or prevent
infectious diseases caused by viruses, to reduce viral load in a
subject, and to screen a compound library to identify compounds
that prevent or inhibit entry of viruses into host cells. Also
provided are kits, containing one or more inventive compounds, or
compositions thereof, for treating or preventing infectious
diseases.
[0009] In one aspect, the present invention provides compounds of
Formula (I):
##STR00002##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof; wherein Ring A, Ring C, R.sup.A,
R.sup.C, R.sup.D, L, k, and n are as defined herein.
[0010] In one aspect, the present invention provides compounds of
Formula (II):
##STR00003##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof; wherein Ring A, Ring C, R.sup.A,
R.sup.C, R.sup.D, R.sup.j1, R.sup.j2, R.sup.j3, L, k, and n are as
defined herein.
[0011] In one aspect, the present invention provides compounds of
Formula (III):
##STR00004##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof; wherein Ring A, Ring C, R.sup.A,
R.sup.C, R.sup.D, R.sup.q, L, k, and n are as defined herein.
[0012] Exemplary compounds of Formula (I) include, but are not
limited to:
##STR00005##
[0013] In another aspect, the present invention provides
pharmaceutical compositions including a compound of Formula (I),
(II), or (III), or a pharmaceutically acceptable salt, solvate,
hydrate, polymorph, co-crystal, tautomer, stereoisomer,
isotopically labeled derivative, or prodrug thereof, and optionally
a pharmaceutically acceptable excipient.
[0014] In still another aspect, the invention provides methods for
the treatment of infectious diseases in a subject caused by
viruses, methods for reducing viral load in a subject, and methods
of preventing viral infections in a subject who was or may be
exposed to viruses. The viruses, the infection of which may be
treated or prevented by the inventive methods, include Flaviviridae
viruses (e.g., Dengue virus (DENV), including Dengue virus 1
(DENV1), Dengue virus 2 (DENV2), Dengue virus 3 (DENV3), and Dengue
virus 4 (DENV4); West Nile virus; tick-borne encephalitis virus;
yellow fever virus; hepatitis C virus; hepatitis G virus; bovine
viral diarrhea; classical swine fever virus; and hog cholera
virus), Kunjin virus, Japanese encephalitis virus, vesicular
stomatitis virus (VSV), vesicular stomatitis virus (VSV)
pseudotyped with rabies glycoprotein, vesicular stomatitis virus
(VSV) pseudotyped with Ebola glycoprotein, herpes simplex virus 1
(HSV-1), human cytomegalovirus (HCMV), poliovirus, Junin virus,
Ebola virus, Marburg virus (MARV), Lassa fever virus (LASV),
Venezuelan equine encephalitis virus (VEEV), and Rift Valley Fever
virus (RVFV). The infectious diseases being treated or prevented by
the inventive methods include, but are not limited to, dengue
fever, dengue hemorrhagic fever, and dengue shock syndrome (DSS).
The methods of the invention include administering to the subject a
therapeutically or prophylactically effective amount of a compound
of the invention, or a pharmaceutically acceptable salt, solvate,
hydrate, polymorph, co-crystal, tautomer, stereoisomer,
isotopically labeled derivative, or prodrug thereof.
[0015] In yet another aspect, the present invention provides
methods of screening a library of compounds to identify one or more
compounds that prevent or inhibit entry of a virus into a host
cell. The methods of screening a library include providing at least
two different compounds of the invention, or pharmaceutically
acceptable salts, solvates, hydrates, polymorphs, co-crystals,
tautomers, stereoisomers, isotopically labeled derivatives, or
prodrugs thereof; and performing at least one assay using the
different compounds of the invention, or pharmaceutically
acceptable salts, solvates, hydrates, polymorphs, co-crystals,
tautomers, stereoisomers, isotopically labeled derivatives, or
prodrugs thereof, to detect entry of the virus into the host
cell.
[0016] Another aspect of the present invention relates to uses of
the inventive compounds, and pharmaceutically acceptable salts,
solvates, hydrates, polymorphs, co-crystals, tautomers,
stereoisomers, isotopically labeled derivatives, prodrugs, and
pharmaceutical compositions thereof, for treating or preventing an
infectious disease in a subject suffering therefrom.
[0017] In another aspect, the invention provides kits for treating
or preventing an infectious disease (e.g., a viral disease). The
inventive kits include a first container containing a
therapeutically effective amount of a compound of the invention, or
a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof; and instructions for administering
the compound to a subject to treat or prevent the infectious
disease. A kit may include multiple unit dosages, for example, for
multiple days of treatment.
[0018] The details of one or more embodiments of the invention are
set forth herein. Other features, objects, and advantages of the
invention will be apparent from the Detailed Description, the
Figures, the Examples, and the Claims.
Definitions
[0019] Definitions of specific functional groups and chemical terms
are described in more detail below. The chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed.,
inside cover, and specific functional groups are generally defined
as described therein. Additionally, general principles of organic
chemistry, as well as specific functional moieties and reactivity,
are described in Thomas Sorrell, Organic Chemistry, University
Science Books, Sausalito, 1999; Smith and March, March's Advanced
Organic Chemistry, 5.sup.th Edition, John Wiley & Sons, Inc.,
New York, 2001; Larock, Comprehensive Organic Transformations, VCH
Publishers, Inc., New York, 1989; and Carruthers, Some Modern
Methods of Organic Synthesis, 3.sup.rd Edition, Cambridge
University Press, Cambridge, 1987.
[0020] It is also to be understood that compounds that have the
same molecular formula but differ in the nature or sequence of
bonding of their atoms or the arrangement of their atoms in space
are termed "isomers." Isomers that differ in the arrangement of
their atoms in space are termed "stereoisomers." Stereoisomers that
are not mirror images of one another are termed "diastereomers,"
and those that are non-superimposable mirror images of each other
are termed "enantiomers". When a compound has an asymmetric center,
for example, a carbon atom of the compound is bonded to four
different groups, a pair of enantiomers is possible. An enantiomer
can be characterized by the absolute configuration of its
asymmetric center and is described by the R- and S-sequencing rules
of Cahn and Prelog, or by the manner in which the molecule rotates
plane polarized light and designated as dextrorotatory or
levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral
compound can exist as either individual enantiomer or as a mixture
thereof. A mixture containing equal proportions of the enantiomers
is called a "racemic mixture." For example, the compounds described
herein can be in the form of an individual enantiomer, diastereomer
or geometric isomer, or can be in the form of a mixture of
stereoisomers, including racemic mixtures and mixtures enriched in
one or more stereoisomer. Isomers can be isolated from mixtures by
methods known to those skilled in the art, including chiral high
pressure liquid chromatography (HPLC) and the formation and
crystallization of chiral salts; or preferred isomers can be
prepared by asymmetric syntheses. See, for example, Jacques et al.,
Enantiomers, Racemates and Resolutions (Wiley Interscience, New
York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel,
Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); and
Wilen, Tables of Resolving Agents and Optical Resolutions p. 268
(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind.
1972). The invention additionally encompasses compounds described
herein as individual isomers substantially free of other isomers,
and alternatively, as mixtures of various isomers.
[0021] When a range of values is listed, it is intended to
encompass each value and sub-range within the range. For example
"C.sub.1-6" is intended to encompass, C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5, C.sub.1-4,
C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4, C.sub.2-3,
C.sub.3-6, C.sub.3-5, C.sub.3-4, C.sub.4-6, C.sub.4-5, and
C.sub.5-6.
[0022] "Alkyl" refers to a radical of a straight-chain or branched
saturated hydrocarbon group having from 1 to 20 carbon atoms
("C.sub.1-20 alkyl"). In some embodiments, an alkyl group has 1 to
10 carbon atoms ("C.sub.1-10 alkyl"). In some embodiments, an alkyl
group has 1 to 9 carbon atoms ("C.sub.1-9 alkyl"). In some
embodiments, an alkyl group has 1 to 8 carbon atoms ("C.sub.1-8
alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon
atoms ("C.sub.1-7 alkyl"). In some embodiments, an alkyl group has
1 to 6 carbon atoms ("C.sub.1-6 alkyl"). In some embodiments, an
alkyl group has 1 to 5 carbon atoms ("C.sub.1-5 alkyl"). In some
embodiments, an alkyl group has 1 to 4 carbon atoms ("C.sub.1-4
alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon
atoms ("C.sub.1-3 alkyl"). In some embodiments, an alkyl group has
1 to 2 carbon atoms ("C.sub.1-2 alkyl"). In some embodiments, an
alkyl group has 1 carbon atom ("C.sub.1 alkyl"). In some
embodiments, an alkyl group has 2 to 6 carbon atoms ("C.sub.2-6
alkyl"). Examples of C.sub.1-6 alkyl groups include methyl
(C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), isopropyl
(C.sub.3), n-butyl (C.sub.4), tert-butyl (C.sub.4), sec-butyl
(C.sub.4), isobutyl (C.sub.4), n-pentyl (C.sub.5), 3-pentanyl
(C.sub.5), amyl (C.sub.5), neopentyl (C.sub.5), 3-methyl-2-butanyl
(C.sub.5), tertiary amyl (C.sub.5), and n-hexyl (C.sub.6).
Additional examples of alkyl groups include n-heptyl (C.sub.7),
n-octyl (C.sub.8) and the like. Unless otherwise specified, each
instance of an alkyl group is independently optionally substituted,
i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a
"substituted alkyl") with one or more substituents. In certain
embodiments, the alkyl group is unsubstituted C.sub.1-10 alkyl
(e.g., --CH.sub.3). In certain embodiments, the alkyl group is
substituted C.sub.1-10 alkyl.
[0023] "Alkenyl" refers to a radical of a straight-chain or
branched hydrocarbon group having from 2 to 20 carbon atoms, one or
more carbon-carbon double bonds, and no triple bonds ("C.sub.2-20
alkenyl"). In some embodiments, an alkenyl group has 2 to 10 carbon
atoms ("C.sub.2-10 alkenyl"). In some embodiments, an alkenyl group
has 2 to 9 carbon atoms ("C.sub.2-9 alkenyl"). In some embodiments,
an alkenyl group has 2 to 8 carbon atoms ("C.sub.2-8 alkenyl"). In
some embodiments, an alkenyl group has 2 to 7 carbon atoms
("C.sub.2-7 alkenyl"). In some embodiments, an alkenyl group has 2
to 6 carbon atoms ("C.sub.2-6 alkenyl"). In some embodiments, an
alkenyl group has 2 to 5 carbon atoms ("C.sub.2-5 alkenyl"). In
some embodiments, an alkenyl group has 2 to 4 carbon atoms
("C.sub.2-4 alkenyl"). In some embodiments, an alkenyl group has 2
to 3 carbon atoms ("C.sub.2-3 alkenyl"). In some embodiments, an
alkenyl group has 2 carbon atoms ("C.sub.2 alkenyl"). The one or
more carbon-carbon double bonds can be internal (such as in
2-butenyl) or terminal (such as in 1-butenyl). Examples of
C.sub.2-4 alkenyl groups include ethenyl (C.sub.2), 1-propenyl
(C.sub.3), 2-propenyl (C.sub.3), 1-butenyl (C.sub.4), 2-butenyl
(C.sub.4), butadienyl (C.sub.4), and the like. Examples of
C.sub.2-6 alkenyl groups include the aforementioned C.sub.2-4
alkenyl groups as well as pentenyl (C.sub.5), pentadienyl
(C.sub.5), hexenyl (C.sub.6), and the like. Additional examples of
alkenyl include heptenyl (C.sub.7), octenyl (C.sub.8), octatrienyl
(C.sub.8), and the like. Unless otherwise specified, each instance
of an alkenyl group is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted alkenyl") or substituted (a
"substituted alkenyl") with one or more substituents. In certain
embodiments, the alkenyl group is unsubstituted C.sub.2-10 alkenyl.
In certain embodiments, the alkenyl group is substituted C.sub.2-10
alkenyl.
[0024] "Alkynyl" refers to a radical of a straight-chain or
branched hydrocarbon group having from 2 to 20 carbon atoms, one or
more carbon-carbon triple bonds, and optionally one or more double
bonds ("C.sub.2-20 alkynyl"). In some embodiments, an alkynyl group
has 2 to 10 carbon atoms ("C.sub.2-10 alkynyl"). In some
embodiments, an alkynyl group has 2 to 9 carbon atoms ("C.sub.2-9
alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon
atoms ("C.sub.2-8 alkynyl"). In some embodiments, an alkynyl group
has 2 to 7 carbon atoms ("C.sub.2-7 alkynyl"). In some embodiments,
an alkynyl group has 2 to 6 carbon atoms ("C.sub.2-6 alkynyl"). In
some embodiments, an alkynyl group has 2 to 5 carbon atoms
("C.sub.2-5 alkynyl"). In some embodiments, an alkynyl group has 2
to 4 carbon atoms ("C.sub.2-4 alkynyl"). In some embodiments, an
alkynyl group has 2 to 3 carbon atoms ("C.sub.2-3 alkynyl"). In
some embodiments, an alkynyl group has 2 carbon atoms ("C.sub.2
alkynyl"). The one or more carbon-carbon triple bonds can be
internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
Examples of C.sub.2-4 alkynyl groups include, without limitation,
ethynyl (C.sub.2), 1-propynyl (C.sub.3), 2-propynyl (C.sub.3),
1-butynyl (C.sub.4), 2-butynyl (C.sub.4), and the like. Examples of
C.sub.2-6 alkenyl groups include the aforementioned C.sub.2-4
alkynyl groups as well as pentynyl (C.sub.5), hexynyl (C.sub.6),
and the like. Additional examples of alkynyl include heptynyl
(C.sub.7), octynyl (C.sub.8), and the like. Unless otherwise
specified, each instance of an alkynyl group is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
alkynyl") or substituted (a "substituted alkynyl") with one or more
substituents. In certain embodiments, the alkynyl group is
unsubstituted C.sub.2-10 alkynyl. In certain embodiments, the
alkynyl group is substituted C.sub.2-10 alkynyl.
[0025] As used herein, a "hydrocarbon chain" refers to a
substituted or unsubstituted divalent alkyl, alkenyl, or alkynyl
group. A hydrocarbon chain includes at least one chain, each node
("carbon unit") of which including at least one carbon atom,
between the two radicals of the hydrocarbon chain. For example,
hydrocarbon chain --C.sup.AH(C.sup.BH.sub.2C.sup.CH.sub.3)--
includes only one carbon unit C.sup.A. The term "C.sub.x
hydrocarbon chain," wherein x is a positive integer, refers to a
hydrocarbon chain that includes x number of carbon unit(s) between
the two radicals of the hydrocarbon chain. If there is more than
one possible value of x, the smallest possible value of x is used
for the definition of the hydrocarbon chain. For example,
--CH(C.sub.2H.sub.5)-- is a C.sub.1 hydrocarbon chain, and
##STR00006##
is a C.sub.3 hydrocarbon chain. When a range of values is used,
e.g., a C.sub.1-6 hydrocarbon chain, the meaning of the range is as
described herein. A hydrocarbon chain may be saturated (e.g.,
--(CH.sub.2).sub.4--). A hydrocarbon chain may also be unsaturated
and include one or more C.dbd.C and/or C.ident.C bonds anywhere in
the hydrocarbon chain. For instance,
--CH.dbd.CH--(CH.sub.2).sub.2--, --CH.sub.2--C.ident.C--CH.sub.2--,
and --C.ident.C--CH.dbd.CH-- are all examples of a unsubstituted
and unsaturated hydrocarbon chain. In certain embodiments, the
hydrocarbon chain is unsubstituted (e.g., --(CH.sub.2).sub.4--). In
certain embodiments, the hydrocarbon chain is substituted (e.g.,
--CH(C.sub.2H.sub.5)-- and --CF.sub.2--). Any two substituents on
the hydrocarbon chain may be joined to form an optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, or optionally substituted heteroaryl
ring. For instance,
##STR00007##
are all examples of a hydrocarbon chain. In contrast, in certain
embodiments
##STR00008##
are not within the scope of the hydrocarbon chains described
herein. In certain embodiments, the hydrocarbon chains is alkylene.
In certain embodiments, the hydrocarbon chains is alkenylene. In
certain embodiments, the hydrocarbon chains is alkynylene.
[0026] "Carbocyclyl" or "carbocyclic" refers to a radical of a
non-aromatic cyclic hydrocarbon group having from 3 to 10 ring
carbon atoms ("C.sub.3-10 carbocyclyl") and zero heteroatoms in the
non-aromatic ring system. In some embodiments, a carbocyclyl group
has 3 to 8 ring carbon atoms ("C.sub.3-8 carbocyclyl"). In some
embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms
("C.sub.3-6 carbocyclyl"). In some embodiments, a carbocyclyl group
has 3 to 6 ring carbon atoms ("C.sub.3-6 carbocyclyl"). In some
embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms
("C.sub.5-10 carbocyclyl"). Exemplary C.sub.3-6 carbocyclyl groups
include, without limitation, cyclopropyl (C.sub.3), cyclopropenyl
(C.sub.3), cyclobutyl (C.sub.4), cyclobutenyl (C.sub.4),
cyclopentyl (C.sub.5), cyclopentenyl (C.sub.5), cyclohexyl
(C.sub.6), cyclohexenyl (C.sub.6), cyclohexadienyl (C.sub.6), and
the like. Exemplary C.sub.3-8 carbocyclyl groups include, without
limitation, the aforementioned C.sub.3-6 carbocyclyl groups as well
as cycloheptyl (C.sub.7), cycloheptenyl (C.sub.7), cycloheptadienyl
(C.sub.7), cycloheptatrienyl (C.sub.7), cyclooctyl (C.sub.8),
cyclooctenyl (C.sub.8), bicyclo[2.2.1]heptanyl (C.sub.7),
bicyclo[2.2.2]octanyl (C.sub.8), and the like. Exemplary C.sub.3-10
carbocyclyl groups include, without limitation, the aforementioned
C.sub.3-8 carbocyclyl groups as well as cyclononyl (C.sub.9),
cyclononenyl (C.sub.9), cyclodecyl (C.sub.10), cyclodecenyl
(C.sub.10), octahydro-1H-indenyl (C.sub.9), decahydronaphthalenyl
(C.sub.10), spiro[4.5]decanyl (C.sub.10), and the like. As the
foregoing examples illustrate, in certain embodiments, the
carbocyclyl group is either monocyclic ("monocyclic carbocyclyl")
or contain a fused, bridged or spiro ring system such as a bicyclic
system ("bicyclic carbocyclyl") and can be saturated or can be
partially unsaturated. "Carbocyclyl" also includes ring systems
wherein the carbocyclic ring, as defined above, is fused with one
or more aryl or heteroaryl groups wherein the point of attachment
is on the carbocyclic ring, and in such instances, the number of
carbons continue to designate the number of carbons in the
carbocyclic ring system. Unless otherwise specified, each instance
of a carbocyclyl group is independently optionally substituted,
i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted
(a "substituted carbocyclyl") with one or more substituents. In
certain embodiments, the carbocyclyl group is unsubstituted
C.sub.3-10 carbocyclyl. In certain embodiments, the carbocyclyl
group is a substituted C.sub.3-10 carbocyclyl.
[0027] In some embodiments, "carbocyclyl" is a monocyclic,
saturated carbocyclyl group having from 3 to 10 ring carbon atoms
("C.sub.3-10 cycloalkyl"). In some embodiments, a cycloalkyl group
has 3 to 8 ring carbon atoms ("C.sub.3-8 cycloalkyl"). In some
embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms
("C.sub.3-6 cycloalkyl"). In some embodiments, a cycloalkyl group
has 5 to 6 ring carbon atoms ("C.sub.5-6 cycloalkyl"). In some
embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms
("C.sub.5-10 cycloalkyl"). Examples of C.sub.5-6 cycloalkyl groups
include cyclopentyl (C.sub.5) and cyclohexyl (C.sub.5). Examples of
C.sub.3-6 cycloalkyl groups include the aforementioned C.sub.5-6
cycloalkyl groups as well as cyclopropyl (C.sub.3) and cyclobutyl
(C.sub.4). Examples of C.sub.3-8 cycloalkyl groups include the
aforementioned C.sub.3-6 cycloalkyl groups as well as cycloheptyl
(C.sub.7) and cyclooctyl (C.sub.8). Unless otherwise specified,
each instance of a cycloalkyl group is independently unsubstituted
(an "unsubstituted cycloalkyl") or substituted (a "substituted
cycloalkyl") with one or more substituents. In certain embodiments,
the cycloalkyl group is unsubstituted C.sub.3-10 cycloalkyl. In
certain embodiments, the cycloalkyl group is substituted C.sub.3-10
cycloalkyl.
[0028] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3-
to 10-membered non-aromatic ring system having ring carbon atoms
and 1 to 4 ring heteroatoms, wherein each heteroatom is
independently selected from nitrogen, oxygen, sulfur, boron,
phosphorus, and silicon ("3-10 membered heterocyclyl"). In
heterocyclyl groups that contain one or more nitrogen atoms, the
point of attachment can be a carbon or nitrogen atom, as valency
permits. A heterocyclyl group can either be monocyclic ("monocyclic
heterocyclyl") or a fused, bridged or spiro ring system such as a
bicyclic system ("bicyclic heterocyclyl"), and can be saturated or
can be partially unsaturated. Heterocyclyl bicyclic ring systems
can include one or more heteroatoms in one or both rings.
"Heterocyclyl" also includes ring systems wherein the heterocyclic
ring, as defined above, is fused with one or more carbocyclyl
groups wherein the point of attachment is either on the carbocyclyl
or heterocyclic ring, or ring systems wherein the heterocyclic
ring, as defined above, is fused with one or more aryl or
heteroaryl groups, wherein the point of attachment is on the
heterocyclic ring, and in such instances, the number of ring
members continue to designate the number of ring members in the
heterocyclic ring system. Unless otherwise specified, each instance
of heterocyclyl is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted heterocyclyl") or substituted (a
"substituted heterocyclyl") with one or more substituents. In
certain embodiments, the heterocyclyl group is unsubstituted 3-10
membered heterocyclyl. In certain embodiments, the heterocyclyl
group is substituted 3-10 membered heterocyclyl.
[0029] In some embodiments, a heterocyclyl group is a 5-10 membered
non-aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms, wherein each heteroatom is independently selected from
nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10
membered heterocyclyl"). In some embodiments, a heterocyclyl group
is a 5-8 membered non-aromatic ring system having ring carbon atoms
and 1-4 ring heteroatoms, wherein each heteroatom is independently
selected from nitrogen, oxygen, and sulfur ("5-8 membered
heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6
membered non-aromatic ring system having ring carbon atoms and 1-4
ring heteroatoms, wherein each heteroatom is independently selected
from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In
some embodiments, the 5-6 membered heterocyclyl has 1-3 ring
heteroatoms selected from nitrogen, oxygen, and sulfur. In some
embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms
selected from nitrogen, oxygen, and sulfur. In some embodiments,
the 5-6 membered heterocyclyl has one ring heteroatom selected from
nitrogen, oxygen, and sulfur.
[0030] Exemplary 3-membered heterocyclyl groups containing one
heteroatom include, without limitation, azirdinyl, oxiranyl,
thiorenyl. Exemplary 4-membered heterocyclyl groups containing one
heteroatom include, without limitation, azetidinyl, oxetanyl and
thietanyl. Exemplary 5-membered heterocyclyl groups containing one
heteroatom include, without limitation, tetrahydrofuranyl,
dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl,
pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary
5-membered heterocyclyl groups containing two heteroatoms include,
without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and
oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups
containing three heteroatoms include, without limitation,
triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary
6-membered heterocyclyl groups containing one heteroatom include,
without limitation, piperidinyl, tetrahydropyranyl,
dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl
groups containing two heteroatoms include, without limitation,
piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered
heterocyclyl groups containing two heteroatoms include, without
limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups
containing one heteroatom include, without limitation, azepanyl,
oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups
containing one heteroatom include, without limitation, azocanyl,
oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups
fused to a C.sub.6 aryl ring (also referred to herein as a
5,6-bicyclic heterocyclic ring) include, without limitation,
indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,
benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl
groups fused to an aryl ring (also referred to herein as a
6,6-bicyclic heterocyclic ring) include, without limitation,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
[0031] "Aryl" refers to a radical of a monocyclic or polycyclic
(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g.,
having 6, 10, or 14 n electrons shared in a cyclic array) having
6-14 ring carbon atoms and zero heteroatoms provided in the
aromatic ring system ("C.sub.6-14 aryl"). In some embodiments, an
aryl group has six ring carbon atoms ("C.sub.6 aryl"; e.g.,
phenyl). In some embodiments, an aryl group has ten ring carbon
atoms ("C.sub.10 aryl"; e.g., naphthyl such as 1-naphthyl and
2-naphthyl). In some embodiments, an aryl group has fourteen ring
carbon atoms ("C.sub.14 aryl"; e.g., anthracyl). "Aryl" also
includes ring systems wherein the aryl ring, as defined above, is
fused with one or more carbocyclyl or heterocyclyl groups wherein
the radical or point of attachment is on the aryl ring, and in such
instances, the number of carbon atoms continue to designate the
number of carbon atoms in the aryl ring system. Unless otherwise
specified, each instance of an aryl group is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
aryl") or substituted (a "substituted aryl") with one or more
substituents. In certain embodiments, the aryl group is
unsubstituted C.sub.6-14 aryl. In certain embodiments, the aryl
group is substituted C.sub.6-14 aryl.
[0032] "Aralkyl" is a subset of alkyl and aryl, as defined herein,
and refers to an optionally substituted alkyl group substituted by
an optionally substituted aryl group.
[0033] "Heteroaryl" refers to a radical of a 5-10 membered
monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or
10 n electrons shared in a cyclic array) having ring carbon atoms
and 1-4 ring heteroatoms provided in the aromatic ring system,
wherein each heteroatom is independently selected from nitrogen,
oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl
groups that contain one or more nitrogen atoms, the point of
attachment can be a carbon or nitrogen atom, as valency permits.
Heteroaryl bicyclic ring systems can include one or more
heteroatoms in one or both rings. "Heteroaryl" includes ring
systems wherein the heteroaryl ring, as defined above, is fused
with one or more carbocyclyl or heterocyclyl groups wherein the
point of attachment is on the heteroaryl ring, and in such
instances, the number of ring members continue to designate the
number of ring members in the heteroaryl ring system. "Heteroaryl"
also includes ring systems wherein the heteroaryl ring, as defined
above, is fused with one or more aryl groups wherein the point of
attachment is either on the aryl or heteroaryl ring, and in such
instances, the number of ring members designates the number of ring
members in the fused (aryl/heteroaryl) ring system. Bicyclic
heteroaryl groups wherein one ring does not contain a heteroatom
(e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of
attachment can be on either ring, i.e., either the ring bearing a
heteroatom (e.g., 2-indolyl) or the ring that does not contain a
heteroatom (e.g., 5-indolyl).
[0034] In some embodiments, a heteroaryl group is a 5-10 membered
aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms provided in the aromatic ring system, wherein each
heteroatom is independently selected from nitrogen, oxygen, and
sulfur ("5-10 membered heteroaryl"). In some embodiments, a
heteroaryl group is a 5-8 membered aromatic ring system having ring
carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring
system, wherein each heteroatom is independently selected from
nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some
embodiments, a heteroaryl group is a 5-6 membered aromatic ring
system having ring carbon atoms and 1-4 ring heteroatoms provided
in the aromatic ring system, wherein each heteroatom is
independently selected from nitrogen, oxygen, and sulfur ("5-6
membered heteroaryl"). In some embodiments, the 5-6 membered
heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen,
and sulfur. In some embodiments, the 5-6 membered heteroaryl has
1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In
some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom
selected from nitrogen, oxygen, and sulfur. Unless otherwise
specified, each instance of a heteroaryl group is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
heteroaryl") or substituted (a "substituted heteroaryl") with one
or more substituents. In certain embodiments, the heteroaryl group
is unsubstituted 5-14 membered heteroaryl. In certain embodiments,
the heteroaryl group is substituted 5-14 membered heteroaryl.
[0035] Exemplary 5-membered heteroaryl groups containing one
heteroatom include, without limitation, pyrrolyl, furanyl and
thiophenyl. Exemplary 5-membered heteroaryl groups containing two
heteroatoms include, without limitation, imidazolyl, pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary
5-membered heteroaryl groups containing three heteroatoms include,
without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
Exemplary 5-membered heteroaryl groups containing four heteroatoms
include, without limitation, tetrazolyl. Exemplary 6-membered
heteroaryl groups containing one heteroatom include, without
limitation, pyridinyl. Exemplary 6-membered heteroaryl groups
containing two heteroatoms include, without limitation,
pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered
heteroaryl groups containing three or four heteroatoms include,
without limitation, triazinyl and tetrazinyl, respectively.
Exemplary 7-membered heteroaryl groups containing one heteroatom
include, without limitation, azepinyl, oxepinyl, and thiepinyl.
Exemplary 5,6-bicyclic heteroaryl groups include, without
limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,
benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,
benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and
purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without
limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,
cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
[0036] "Heteroaralkyl" is a subset of alkyl and heteroaryl, as
defined herein, and refers to an optionally substituted alkyl group
substituted by an optionally substituted heteroaryl group.
[0037] "Partially unsaturated" refers to a group that includes at
least one double or triple bond. A "partially unsaturated" ring
system is further intended to encompass rings having multiple sites
of unsaturation, but is not intended to include aromatic groups
(e.g., aryl or heteroaryl groups) as herein defined. Likewise,
"saturated" refers to a group that does not contain a double or
triple bond, i.e., contains all single bonds.
[0038] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,
and heteroaryl groups, as defined herein, which are divalent
bridging groups are further referred to using the suffix -ene,
e.g., alkylene, alkenylene, alkynylene, carbocyclylene,
heterocyclylene, arylene, and heteroarylene.
[0039] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,
and heteroaryl groups, as defined herein, are optionally
substituted (e.g., "substituted" or "unsubstituted" alkyl,
"substituted" or "unsubstituted" alkenyl, "substituted" or
"unsubstituted" alkynyl, "substituted" or "unsubstituted"
carbocyclyl, "substituted" or "unsubstituted" heterocyclyl,
"substituted" or "unsubstituted" aryl or "substituted" or
"unsubstituted" heteroaryl group). In general, the term
"substituted", whether preceded by the term "optionally" or not,
means that at least one hydrogen present on a group (e.g., a carbon
or nitrogen atom) is replaced with a permissible substituent, e.g.,
a substituent which upon substitution results in a stable compound,
e.g., a compound which does not spontaneously undergo
transformation such as by rearrangement, cyclization, elimination,
or other reaction. Unless otherwise indicated, a "substituted"
group has a substituent at one or more substitutable positions of
the group, and when more than one position in any given structure
is substituted, the substituent is either the same or different at
each position. The term "substituted" is contemplated to include
substitution with all permissible substituents of organic
compounds, any of the substituents described herein that results in
the formation of a stable compound. The present invention
contemplates any and all such combinations in order to arrive at a
stable compound. For purposes of this invention, heteroatoms such
as nitrogen may have hydrogen substituents and/or any suitable
substituent as described herein which satisfy the valencies of the
heteroatoms and results in the formation of a stable moiety.
[0040] Exemplary carbon atom substituents include, but are not
limited to, halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H,
--SO.sub.3H, --OH, --OR.sup.aa, --ON(R.sup.bb).sub.2,
--N(R.sup.bb).sub.2, --N(R.sup.bb).sub.3.sup.+X.sup.-,
--N(OR.sup.cc)R.sup.bb, --SH, --SR.sup.aa, --SSR.sup.cc,
--C(.dbd.O)R.sup.aa, --CO.sub.2H, --CHO, --C(OR.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --OC(.dbd.O)R.sup.aa, --OCO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --OC(.dbd.O)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.O)R.sup.aa, --NR.sup.bbCO.sub.2R.sup.aa,
--NR.sup.bbC(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --OC(.dbd.NR.sup.bb)R.sup.aa,
--OC(.dbd.NR.sup.bb)OR.sup.aa,
--C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--OC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa, --NR.sup.bbSO.sub.2R,
--SO.sub.2N(R.sup.bb).sub.2, --SO.sub.2R.sup.aa, --SO.sub.2OR,
--OSO.sub.2R.sup.aa, --S(.dbd.O)R.sup.aa, --OS(.dbd.O)R.sup.aa,
--Si(R.sup.aa).sub.3,
--OSi(R.sup.aa).sub.3--C(.dbd.S)N(R.sup.bb).sub.2,
--C(.dbd.O)SR.sup.aa, --C(.dbd.S)SR.sup.aa, --SC(.dbd.S)SR.sup.aa,
--SC(.dbd.O)SR.sup.aa, --OC(.dbd.O)SR.sup.aa,
--SC(.dbd.O)OR.sup.aa, --SC(.dbd.O)R.sup.aa,
--P(.dbd.O).sub.2R.sup.aa, --OP(.dbd.O).sub.2R.sup.aa,
--P(.dbd.O)(R.sup.aa).sub.2, --OP(.dbd.O)(R.sup.aa).sub.2,
--OP(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2,
--OP(.dbd.O).sub.2N(R.sup.bb).sub.2, --P(.dbd.O)(NR.sup.bb).sub.2,
--OP(.dbd.O)(NR.sup.bb).sub.2,
--NR.sup.bbP(.dbd.O)(OR.sup.cc).sub.2,
--NR.sup.bbP(.dbd.O)(NR.sup.bb).sub.2, --P(R.sup.cc).sub.2,
--P(R.sup.cc).sub.3, --OP(R.sup.cc).sub.2, --OP(R.sup.cc).sub.3,
--B(R.sup.aa).sub.2, --B(OR.sup.cc).sub.2, --BR.sup.aa(OR.sup.cc),
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, and heteroaryl is independently substituted with 0, 1, 2, 3,
4, or 5 R.sup.dd groups;
[0041] or two geminal hydrogens on a carbon atom are replaced with
the group .dbd.O, .dbd.S, .dbd.NN(R.sup.bb).sub.2,
.dbd.NNR.sup.bbC(.dbd.O)R.sup.aa,
.dbd.NNR.sup.bbC(.dbd.O)OR.sup.aa,
.dbd.NNR.sup.bbS(.dbd.O).sub.2R.sup.aa, .dbd.NR.sup.bb, or
.dbd.NOR.sup.cc; each instance of R.sup.aa is, independently,
selected from C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.aa groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups;
each instance of R.sup.bb is, independently, selected from
hydrogen, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2, --CN,
--C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa,
--C(.dbd.NR.sup.ccC)N(R.sup.cc).sub.2, --SO.sub.2N(R.sup.cc).sub.2,
--SO.sub.2R.sup.cc, --SO.sub.2OR.sup.cc, --SOR.sup.aa,
--C(.dbd.S)N(R.sup.cc).sub.2, --C(.dbd.O)SR.sup.cc,
--C(.dbd.S)SR.sup.cc, --P(.dbd.O).sub.2R.sup.aa,
--P(.dbd.O)(R.sup.aa).sub.2, --P(.dbd.O).sub.2N(R.sup.cc).sub.2,
--P(.dbd.O)(NR.sup.cc).sub.2, C.sub.1-10 alkyl, C.sub.1-10
perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10
carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14
membered heteroaryl, or two R.sup.bb groups are joined to form a
3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, and heteroaryl is independently substituted with 0, 1, 2, 3,
4, or 5 R.sup.dd groups;
[0042] each instance of R.sup.cc is, independently, selected from
hydrogen, C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.cc groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0043] each instance of R.sup.dd is, independently, selected from
halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H,
--OH, --OR.sup.ee, --ON(R.sup.ff).sub.2, --N(R.sup.ff).sub.2,
--N(R.sup.ff).sub.3.sup.+X.sup.-, --N(OR.sup.ee)R.sup.ff, --SH,
--SR.sup.ee, --SSR.sup.ee, --C(.dbd.O)R.sup.ee, --CO.sub.2H,
--CO.sub.2R.sup.ee, --OC(.dbd.O)R.sup.ee, --OCO.sub.2R.sup.ee,
--C(.dbd.O)N(R.sup.ff).sub.2, --OC(.dbd.O)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.O)R.sup.ee, --NR.sup.ffCO.sub.2R.sup.ee,
--NR.sup.ffC(.dbd.O)N(R.sup.ff).sub.2,
--C(.dbd.NR.sup.ff)OR.sup.ee, --OC(.dbd.NR.sup.ff)R.sup.ee,
--OC(.dbd.NR.sup.ff)OR.sup.ee,
--C(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--OC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffSO.sub.2R.sup.ee, SO.sub.2N(R.sup.ff).sub.2,
--SO.sub.2R.sup.ee, --SO.sub.2OR.sup.ee, --OSO.sub.2R.sup.ee,
--S(.dbd.O)R.sup.ee, --Si(R.sup.ee).sub.3, --OSi(R.sup.ee).sub.3,
--C(.dbd.S)N(R.sup.ff).sub.2, --C(.dbd.O)SR.sup.ee,
--C(.dbd.S)SR.sup.ee, --SC(.dbd.S)SR.sup.ee,
--P(.dbd.O).sub.2R.sup.ee, --P(.dbd.O)(R.sup.ee).sub.2,
--OP(.dbd.O)(R.sup.ee).sub.2, --OP(.dbd.O)(OR.sup.ee).sub.2,
C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered
heterocyclyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, wherein
each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5
R.sup.gg groups, or two geminal R.sup.dd substituents can be joined
to form .dbd.O or .dbd.S;
[0044] each instance of R.sup.ee is, independently, selected from
C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10
membered heterocyclyl, and 3-10 membered heteroaryl, wherein each
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5
R.sup.gg groups;
[0045] each instance of R.sup.ff is, independently, selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered
heterocyclyl, C.sub.6-10 aryl and 5-10 membered heteroaryl, or two
R.sup.ff groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups;
and
[0046] each instance of R.sup.gg is, independently, halogen, --CN,
--NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H, --OH, --OC.sub.1-6
alkyl, --ON(C.sub.1-6 alkyl).sub.2, --N(C.sub.1-6 alkyl).sub.2,
--N(C.sub.1-6 alkyl).sub.3.sup.+X.sup.-, --NH(C.sub.1-6
alkyl).sub.2.sup.+X.sup.-, --NH.sub.2(C.sub.1-6
alkyl).sup.+X.sup.-, --NH.sub.3.sup.+X.sup.-, --N(OC.sub.1-6
alkyl)(C.sub.1-6 alkyl), --N(OH)(C.sub.1-6 alkyl), --NH(OH), --SH,
--SC.sub.1-6 alkyl, --SS(C.sub.1-6 alkyl), --C(.dbd.O)(C.sub.1-6
alkyl), --CO.sub.2H, --CO.sub.2(C.sub.1-6 alkyl),
--OC(.dbd.O)(C.sub.1-6 alkyl), --OCO.sub.2(C.sub.1-6 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)N(C.sub.1-6 alkyl).sub.2,
--OC(.dbd.O)NH(C.sub.1-6 alkyl), --NHC(.dbd.O)(C.sub.1-6 alkyl),
--N(C.sub.1-6 alkyl)C(.dbd.O)(C.sub.1-6 alkyl),
--NHCO.sub.2(C.sub.1-6 alkyl), --NHC(.dbd.O)N(C.sub.1-6
alkyl).sub.2, --NHC(.dbd.O)NH(C.sub.1-6 alkyl),
--NHC(.dbd.O)NH.sub.2, --C(.dbd.NH)O(C.sub.1-6 alkyl),
--OC(.dbd.NH)(C.sub.1-6 alkyl), --OC(.dbd.NH)OC.sub.1-6 alkyl,
--C(.dbd.NH)N(C.sub.1-6 alkyl).sub.2, --C(.dbd.NH)NH(C.sub.1-6
alkyl), --C(.dbd.NH)NH.sub.2, --OC(.dbd.NH)N(C.sub.1-6
alkyl).sub.2, --OC(NH)NH(C.sub.1-6 alkyl), --OC(NH)NH.sub.2,
--NHC(NH)N(C.sub.1-6 alkyl).sub.2, --NHC(.dbd.NH)NH.sub.2,
--NHSO.sub.2(C.sub.1-6 alkyl), --SO.sub.2N(C.sub.1-6 alkyl).sub.2,
--SO.sub.2NH(C.sub.1-6 alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2C.sub.1-6 alkyl, --SO.sub.2OC.sub.1-6 alkyl,
--OSO.sub.2C.sub.1-6 alkyl, --SOC.sub.1-6 alkyl, --Si(C.sub.1-6
alkyl).sub.3, --OSi(C.sub.1-6 alkyl).sub.3-C(.dbd.S)N(C.sub.1-6
alkyl).sub.2, --C(.dbd.S)NH(C.sub.1-6 alkyl), --C(.dbd.S)NH.sub.2,
--C(.dbd.O)S(C.sub.1-6 alkyl), --C(.dbd.S)SC.sub.1-6 alkyl,
--SC(.dbd.S)SC.sub.1-6 alkyl, --P(.dbd.O).sub.2(C.sub.1-6 alkyl),
--P(.dbd.O)(C.sub.1-6 alkyl).sub.2, --OP(.dbd.O)(C.sub.1-6
alkyl).sub.2, --OP(.dbd.O)(OC.sub.1-6 alkyl).sub.2, C.sub.1 alkyl,
C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10 membered
heterocyclyl, 5-10 membered heteroaryl; or two geminal R.sup.gg
substituents can be joined to form .dbd.O or .dbd.S; wherein X is a
counterion.
[0047] A "counterion" or "anionic counterion" is a negatively
charged group associated with a cationic quaternary amino group in
order to maintain electronic neutrality. Exemplary counterions
include halide ions (e.g., F.sup.-, Cl.sup.-, Br.sup.-, F.sup.-),
NO.sub.3.sup.-, ClO.sub.4.sup.-, OH.sup.-, H.sub.2PO.sub.4.sup.-,
HSO.sub.4.sup.-, sulfonate ions (e.g., methansulfonate,
trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate,
10-camphor sulfonate, naphthalene-2-sulfonate,
naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic
acid-2-sulfonate, and the like), and carboxylate ions (e.g.,
acetate, ethanoate, propanoate, benzoate, glycerate, lactate,
tartrate, glycolate, and the like). "Halo" or "halogen" refers to
fluorine (fluoro, --F), chlorine (chloro, --Cl), bromine (bromo,
--Br), or iodine (iodo, --I).
[0048] "Acyl" as used herein refers to a moiety selected from the
group consisting of --C(.dbd.O)R.sup.aa, --CHO, --CO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa, --C(.dbd.S)N(R.sup.bb).sub.2,
--C(.dbd.O)SR.sup.aa, or --C(.dbd.S)SR.sup.aa, wherein R.sup.aa and
R.sup.bb are as defined herein.
[0049] Nitrogen atoms can be substituted or unsubstituted as
valency permits, and include primary, secondary, tertiary, and
quarternary nitrogen atoms. Exemplary nitrogen atom substituents
include, but are not limited to, hydrogen, --OH, --OR.sup.aa,
--N(R.sup.cc).sub.2, --CN, --C(.dbd.O)R.sup.aa,
--C(.dbd.O)N(R.sup.cc).sub.2, --CO.sub.2R.sup.aa,
--SO.sub.2R.sup.aa, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O).sub.2N(R.sup.cc).sub.2, --P(.dbd.O)(NR.sup.cc).sub.2,
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.cc groups attached to a nitrogen atom are joined to form a
3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, and heteroaryl is independently substituted with 0, 1, 2, 3,
4, or 5 R.sup.dd groups, and wherein R.sup.aa, R.sup.bb, R.sup.cc,
and R.sup.dd are as defined above.
[0050] In certain embodiments, the substituent present on a
nitrogen atom is a nitrogen protecting group (also referred to as
an amino protecting group). Nitrogen protecting groups include, but
are not limited to, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2,
--C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa,
--C(.dbd.NR.sup.cc)R.sup.aa, --C(.dbd.NR.sup.cc)OR.sup.aa,
--C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2, --SO.sub.2N(R.sup.cc).sub.2,
--SO.sub.2R.sup.cc, --SO.sub.2OR.sup.cc, --SOR.sup.aa,
--C(.dbd.S)N(R.sup.cc).sub.2, --C(.dbd.O)SR.sup.cc,
--C(.dbd.S)SR.sup.cc, C.sub.1-10 alkyl (e.g., aralkyl,
heteroaralkyl), C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10
carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14
membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups,
and wherein R.sup.aa, R.sup.bb, R.sup.cc and R.sup.dd are as
defined herein. Nitrogen protecting groups are well known in the
art and include those described in detail in Protecting Groups in
Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3.sup.rd
edition, John Wiley & Sons, 1999, incorporated herein by
reference.
[0051] For example, nitrogen protecting groups such as amide groups
(e.g., --C(.dbd.O)R.sup.aa) include, but are not limited to,
formamide, acetamide, chloroacetamide, trichloroacetamide,
trifluoroacetamide, phenylacetamide, 3-phenylpropanamide,
picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl
derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide,
o-nitrophenoxyacetamide, acetoacetamide,
(N'-dithiobenzyloxyacylamino)acetamide,
3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,
2-methyl-2-(o-nitrophenoxy)propanamide,
2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,
3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine
derivative, o-nitrobenzamide, and
o-(benzoyloxymethyl)benzamide.
[0052] Nitrogen protecting groups such as carbamate groups (e.g.,
--C(.dbd.O)OR.sup.aa) include, but are not limited to, methyl
carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc),
9-(2-sulfo)fluorenylmethyl carbamate,
9-(2,7-dibromo)fluoroenylmethyl carbamate,
2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10,10-tetrahydrothioxanthyl)]meth-
yl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),
2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl
carbamate (Teoc), 2-phenylethyl carbamate (hZ),
1-(1-adamantyl)-1-methylethyl carbamate (Adpoc),
1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl
carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate
(TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),
1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'-
and 4'-pyridyl)ethyl carbamate (Pyoc),
2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate
(t-butoxycarbonyl, BOC, or Boc), 1-adamantyl carbamate (Adoc),
vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl
carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl
carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl
carbamate, alkyldithio carbamate, benzyl carbamate (Cbz),
p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate,
p-bromobenzyl carbamate, p-chlorobenzyl carbamate,
2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate
(Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,
2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,
2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl
carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),
2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl
carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),
1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl
carbamate, p-(dihydroxyboryl)benzyl carbamate,
5-benzisoxazolylmethyl carbamate,
2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc),
m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate,
o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate,
phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl
thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate,
cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl
carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl
carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate,
1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,
1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,
2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl
carbamate, isobutyl carbamate, isonicotinyl carbamate,
p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl
carbamate, 1-methylcyclohexyl carbamate,
1-methyl-1-cyclopropylmethyl carbamate,
1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,
1-methyl-1-(p-phenylazophenyl)ethyl carbamate,
1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl
carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate,
2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl
carbamate, and 2,4,6-trimethylbenzyl carbamate.
[0053] Nitrogen protecting groups such as sulfonamide groups (e.g.,
--S(.dbd.O).sub.2R.sup.aa) include, but are not limited to,
p-toluenesulfonamide (Ts), benzenesulfonamide,
2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr),
2,4,6-trimethoxybenzenesulfonamide (Mtb),
2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),
2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),
4-methoxybenzenesulfonamide (Mbs),
2,4,6-trimethylbenzenesulfonamide (Mts),
2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),
2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc),
methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES),
9-anthracenesulfonamide,
4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),
benzylsulfonamide, trifluoromethylsulfonamide, and
phenacylsulfonamide. Other nitrogen protecting groups include, but
are not limited to, phenothiazinyl-(10)-acyl derivative,
N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl
derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine
derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,
N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide,
N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane
adduct (STABASE), 5-substituted
1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted
1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted
3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,
N-[2-(trimethylsilyl)ethoxy]methylamine (SEM),
N-3-acetoxypropylamine,
N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary
ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,
N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),
N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),
N-9-phenylfluorenylamine (PhF),
N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino
(Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine,
N-benzylideneamine, N-p-methoxybenzylideneamine,
N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,
N--(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine,
N-p-nitrobenzylideneamine, N-salicylideneamine,
N-5-chlorosalicylideneamine,
N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,
N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,
N-borane derivative, N-diphenylborinic acid derivative,
N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper
chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine
N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide
(Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates,
dibenzyl phosphoramidate, diphenyl phosphoramidate,
benzenesulfenamide, o-nitrobenzenesulfenamide (Nps),
2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide,
2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide,
and 3-nitropyridinesulfenamide (Npys).
[0054] In certain embodiments, the substituent present on an oxygen
atom is an oxygen protecting group (also referred to as a hydroxyl
protecting group). Oxygen protecting groups include, but are not
limited to, --R.sup.aa, --N(R.sup.bb).sub.2, --C(.dbd.O)SR.sup.aa,
--C(.dbd.O)R.sup.aa, --CO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R)N(R.sup.bb2,
--C(.dbd.NR.sup.bb)R.sup.aa, --C(.dbd.NR.sup.bb)OR.sup.aa,
--C(NR.sup.bbN(R.sup.bb).sub.2, --S(.dbd.O)R.sup.aa,
--SO.sub.2R.sup.aa, --Si(R.sup.aa).sub.3, --P(R.sup.cc).sub.2,
--P(R.sup.cc).sub.3, --P(.dbd.O).sub.2R.sup.aa,
--P(.dbd.O)(R.sup.aa).sub.2, --P(.dbd.O)(OR.sup.cc).sub.2,
--P(.dbd.O).sub.2N(R.sup.bb).sub.2, and
--P(.dbd.O)(NR.sup.bb).sub.2, wherein R.sup.aa, R.sup.bb, and
R.sup.cc are as defined herein. Oxygen protecting groups are well
known in the art and include those described in detail in
Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, incorporated
herein by reference.
[0055] Exemplary oxygen protecting groups include, but are not
limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM),
t-butylthiomethyl, t-butoxycarbonyl (BOC or Boc),
(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),
p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),
guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),
siloxymethyl, 2-methoxyethoxymethyl (MEM),
2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl,
2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP),
3-bromotetrahydropyranyl, tetrahydrothiopyranyl,
1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP),
4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl
S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl
(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,
2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,
1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,
1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl,
2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl,
p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl,
3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,
2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl,
4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl,
p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,
a-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,
di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl,
4-(4'-bromophenacyloxyphenyl)diphenylmethyl,
4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl,
4,4',4''-tris(levulinoyloxyphenyl)methyl,
4,4',4''-tris(benzoyloxyphenyl)methyl,
3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl,
1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl,
9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,
1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido,
trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl
(TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl
(DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS),
t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl,
triphenylsilyl, diphenylmethylsilyl (DPMS),
t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate,
acetate, chloroacetate, dichloroacetate, trichloroacetate,
trifluoroacetate, methoxyacetate, triphenylmethoxyacetate,
phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate,
4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate
(levulinoyldithioacetal), pivaloate, adamantoate, crotonate,
4-methoxycrotonate, benzoate, p-phenylbenzoate,
2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,
9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl
2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl
carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),
2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl
carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl
p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl
p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate,
alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl
S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl
dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate,
4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,
2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,
4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,
2,6-dichloro-4-methylphenoxyacetate,
2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,
2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,
isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,
o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl
N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,
borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,
sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate
(Ts).
[0056] In certain embodiments, the substituent present on an sulfur
atom is an sulfur protecting group (also referred to as a thiol
protecting group). Sulfur protecting groups include, but are not
limited to, --R.sup.aa, --N(R.sup.bb).sub.2, --C(.dbd.O)SR.sup.aa,
--C(.dbd.O)R.sup.aa, --CO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--S(.dbd.O)R.sup.aa, --SO.sub.2R.sup.aa, --Si(R.sup.aa).sub.3,
--P(R.sup.cc).sub.2, --P(R.sup.cc).sub.3,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R'').sub.2,
--P(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2,
and --P(.dbd.O)(NR.sup.bb).sub.2, wherein R.sup.aa, R.sup.bb, and
R.sup.cc are as defined herein. Sulfur protecting groups are well
known in the art and include those described in detail in
Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, incorporated
herein by reference.
[0057] A "leaving group" is a molecular fragment that departs with
a pair of electrons in heterolytic bond cleavage. As used herein,
the term "leaving group" is given its ordinary meaning in the art
of synthetic organic chemistry and refers to an atom or a group
capable of being displaced by a nucleophile. Usually a leaving
group is a substituent that is present on a chemical compound that
is capable of being displaced by another group. Leaving groups can
be anions or neutral molecules. Examples of suitable leaving groups
include, but are not limited to, halides (such as fluoride,
chloride, bromide, and iodide), esters, thioesters, phosphates,
sulfates, sulfinates, sulfonates, alkoxycarbonyloxy,
aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy,
alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy,
methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In
some cases, the leaving group is a sulfonic acid ester, such as
para-toluenesulfonate ("tosylate,"-OTs), methanesulfonate
("mesylate,"-OMs), p-bromobenzenesulfonyloxy (brosylate, --OBs), or
trifluoromethanesulfonate ("triflate,"-OTf). In some cases, the
leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In
some cases, the leaving group is a nosylate, such as
2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group
is a sulfonate-containing group. In some embodiments, the leaving
group is a tosylate group. The leaving group may also be a
phosphineoxide (e.g., formed during a Mitsunobu reaction) or an
internal leaving group such as an epoxide or cyclic sulfate. Other
non-limiting examples of leaving groups are water, ammonia,
alcohols, ether moieties, thioether moieties, zinc halides,
magnesium moieties, diazonium salts, copper moieties, and boron
moieties (such as boronic acids and trihaloborate salts such as
trifluoroborate salts). These and other exemplary substituents are
described in more detail in the Detailed Description, Figures,
Examples, and claims. The invention is not intended to be limited
in any manner by the above exemplary listing of substituents.
Other Definitions
[0058] The following definitions are more general terms used
throughout the present application:
[0059] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. Pharmaceutically acceptable salts are well
known in the art. For example, Berge et al., describe
pharmaceutically acceptable salts in detail in J. Pharmaceutical
Sciences, 1977, 66, 1-19, incorporated herein by reference.
Pharmaceutically acceptable salts of the compounds of this
invention include those derived from suitable inorganic and organic
acids and bases. Examples of pharmaceutically acceptable, nontoxic
acid addition salts are salts of an amino group formed with
inorganic acids such as hydrochloric acid, hydrobromic acid,
phosphoric acid, sulfuric acid, and perchloric acid or with organic
acids such as acetic acid, oxalic acid, maleic acid, tartaric acid,
citric acid, succinic acid, or malonic acid or by using other
methods known in the art such as ion exchange. Other
pharmaceutically acceptable salts include adipate, alginate,
ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,
borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N+(C1-4alkyl)4 salts. Representative
alkali or alkaline earth metal salts include sodium, lithium,
potassium, calcium, magnesium, and the like. Further
pharmaceutically acceptable salts include, when appropriate,
nontoxic ammonium, quaternary ammonium, and amine cations formed
using counterions such as halide, hydroxide, carboxylate, sulfate,
phosphate, nitrate, loweralkyl sulfonate, and aryl sulfonate.
[0060] The term "polymorphs" means crystal structures in which a
compound (or a salt, hydrate, or solvate thereof) can crystallize
in different crystal packing arrangements, all of which have the
same elemental composition. Different crystal forms usually have
different X-ray diffraction patterns, infrared spectra, melting
points, density, hardness, crystal shape, optical and electrical
properties, stability, and solubility. Recrystallization solvent,
rate of crystallization, storage temperature, and other factors may
cause one crystal form to dominate. Crystalline polymorphs of a
compound can be prepared by crystallization under different
conditions.
[0061] The term "co-crystal" refers to a crystalline structure
composed of at least two components, where the components may be
atoms, ions, or molecules. Typically, the components interact with
one another to form the crystalline structure through ionic or,
more commonly, non-ionic interactions. For a specific co-crystal
form, all its components can be found within a single crystal
lattice (unit cell) and are usually in a definite stoichiometric
ratio. A component of a co-crystal may be a solid or liquid when
the component is in its pure form. Crystalline salts, crystalline
hydrates, and crystalline solvates are also within the meaning of
co-crystals.
[0062] "Solvate" refers to forms of the compound that are
associated with a solvent or water (also referred to as a
"hydrate"), usually by a solvolysis reaction. This physical
association includes hydrogen bonding. Conventional solvents
include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl
ether, and the like. The compounds of the invention may be
prepared, e.g., in crystalline form, and may be solvated or
hydrated. Suitable solvates include pharmaceutically acceptable
solvates, such as hydrates, and further include both stoichiometric
solvates and non-stoichiometric solvates. In certain instances, the
solvate will be capable of isolation, for example, when one or more
solvent molecules are incorporated in the crystal lattice of the
crystalline solid. "Solvate" encompasses both solution-phase and
isolable solvates. Representative solvates include hydrates,
ethanolates, and methanolates.
[0063] "Tautomers" refer to compounds that are interchangeable
forms of a particular compound structure, and that vary in the
displacement of hydrogen atoms and electrons. Thus, two structures
may be in equilibrium through the movement of .pi. electrons and an
atom (usually H). For example, enols and ketones are tautomers
because they are rapidly interconverted by treatment with either
acid or base. Another example of tautomerism is the aci- and
nitro-forms of phenylnitromethane, that are likewise formed by
treatment with acid or base.
[0064] Tautomeric forms may be relevant to the attainment of the
optimal chemical reactivity and biological activity of a compound
of interest.
[0065] As used herein, "isotopically labeled derivatives" of a
compound refer to derivatives of the compound wherein at least one
atom of the compound is enriched for an isotope that is higher or
lower in molecular weight than the most abundant isotope of the
atom found in nature.
[0066] "Prodrugs" refers to compounds, including derivatives of the
compounds of the invention, which have cleavable groups and become
by solvolysis or under physiological conditions the compounds of
the invention which are pharmaceutically active in vivo. Such
examples include, but are not limited to, choline ester derivatives
and the like, N-alkylmorpholine esters and the like. Other
derivatives of the compounds of this invention have activity in
both their acid and acid derivative forms, but in the acid
sensitive form often offers advantages of solubility, tissue
compatibility, or delayed release in the mammalian organism (see,
Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier,
Amsterdam 1985). Prodrugs include acid derivatives well know to
practitioners of the art, such as, for example, esters prepared by
reaction of the parent acid with a suitable alcohol, or amides
prepared by reaction of the parent acid compound with a substituted
or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
Simple aliphatic or aromatic esters, amides and anhydrides derived
from acidic groups pendant on the compounds of this invention are
particular prodrugs. In some cases it is desirable to prepare
double ester type prodrugs such as (acyloxy)alkyl esters or
((alkoxycarbonyl)oxy)alkylesters. Particularly the C.sub.1 to
C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
aryl, C.sub.7-C.sub.12 substituted aryl, and C.sub.7-C.sub.12
arylalkyl esters of the compounds of the invention.
[0067] A "subject" to which administration is contemplated
includes, but is not limited to, humans (i.e., a male or female of
any age group, e.g., a pediatric subject (e.g, infant, child,
adolescent) or adult subject (e.g., young adult, middle-aged adult,
or senior adult)) and/or other non-human animals, for example,
mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys);
commercially relevant mammals such as cattle, pigs, horses, sheep,
goats, cats, and/or dogs), fish, and birds (e.g., commercially
relevant birds such as chickens, ducks, geese, and/or turkeys). In
certain embodiments, the animal is a mammal. The animal may be a
male or female and at any stage of development. A non-human animal
may be a transgenic animal, such as a transgenic mouse or
transgenic pig.
[0068] "Treat," "treating," and "treatment" contemplate an action
that occurs while a subject is suffering from a condition, e.g., an
infectious disease caused by a virus, and that reduces the severity
of the condition or retards or slows the progression of the
condition ("therapeutic treatment"), and also contemplates an
action that occurs before a subject begins to suffer from the
condition and that inhibits or reduces the severity of the
condition ("prophylactic treatment").
[0069] As used herein, "condition," "disease," and "disorder" are
used interchangeably.
[0070] An "effective amount" of a compound of the present invention
refers to an amount sufficient to elicit the desired biological
response, i.e., treating the condition. As will be appreciated by
those of ordinary skill in this art, the effective amount of a
compound of the invention may vary depending on such factors as the
desired biological endpoint, the pharmacokinetics of the compound,
the condition being treated, the mode of administration, and the
age and health of the subject. An effective amount encompasses
therapeutic and prophylactic treatment.
[0071] A "therapeutically effective amount" of a compound of the
present invention is an amount sufficient to provide a therapeutic
benefit in the treatment of a condition, e.g., an infectious
disease caused by a virus, or to delay or minimize one or more
symptoms associated with the condition. A therapeutically effective
amount of a compound means an amount of therapeutic agent, alone or
in combination with other therapies, which provides a therapeutic
benefit in the treatment of the condition. The term
"therapeutically effective amount" can encompass an amount that
improves overall therapy, reduces or avoids symptoms or causes of
the condition, or enhances the therapeutic efficacy of another
therapeutic agent.
[0072] A "prophylactically effective amount" of a compound of the
present invention is an amount sufficient to prevent a condition,
e.g., an infectious disease caused by a virus, or one or more
symptoms associated with the condition or prevent its recurrence. A
prophylactically effective amount of a compound means an amount of
a therapeutic agent, alone or in combination with other agents,
which provides a prophylactic benefit in the prevention of the
condition. The term "prophylactically effective amount" can
encompass an amount that improves overall prophylaxis or enhances
the prophylactic efficacy of another prophylactic agent.
[0073] A "host factor," as used herein, refers to a biomolecule of
a host wherein the biomolecule contributes to a viral infection in
the host. An example of the host factor is a membrane receptor.
BRIEF DESCRIPTION OF THE DRAWINGS
[0074] FIG. 1 illustrates the chemical structures of certain
selective kinase inhibitors.
[0075] FIGS. 2A to 2G show the structures and anti-DENV activity of
QL-XII-47 and analogs used in the study. All infections were
performed in Huh7 cells at an MOI (multiplicity of infection) of 1.
Illustrated in FIG. 2A are the chemical structures of exemplary
compounds. FIG. 2B includes a dose response curve of QL-XII-47 in a
viral yield reduction assay measured against DENV2 NGC (strain New
Guinea C), in Huh7 cells. Shown in FIG. 2C is the inhibitory effect
of the compounds in yield reduction assays. Compounds were present
at 3 .mu.M at 0-24 hours post-infection with DENV2 NGC. Viral yield
at 24 hours was quantified by plaque formation assay. QL-XII-47's
anti-DENV activity is not due to host cell toxicity since no
cytotoxicity is observed at 20 .mu.M, the highest concentration
tested in a highly sensitive luminescent assay of cell viability
(FIG. 2D). QL-XII-47 exhibits potent activity against strains DENV1
WP74, DENV2 NGC, DENV3 THD3, and DENV4 TVP360 (FIG. 2E). 2 .mu.M
QL-XII-47 causes a greater than 10-fold reduction in Kunjin virus
yield (FIG. 2F). Negative control compound QL-XI-76 exhibits
minimal anti-DENV activity at concentrations up to 10 .mu.M, the
highest concentration tested (FIG. 2G).
[0076] FIGS. 3A to 3E demonstrate that QL-XII-47 inhibits a step
early in the DENV life cycle via a host target. All infections were
with DENV2 NGC in Huh7 cells at an MOI of 1. (FIG. 3A)
Preincubation of cells with QL-XII-47 for 6 hours prior to
infection with DENV results in inhibition comparable to that
observed when infected cells are treated with QL-XII-47 at 0-24
hours post-infection. (FIG. 3B) QL-XII-47 exhibits maximal
anti-DENV activity when added 0-3 hours post-infection and begins
to lose anti-DENV activity when added at later time points. (FIG.
3C) QL-XII-47 inhibits DENV in a single-cycle reporter virus assay
(Ansarah-Sobrinho et al., Virology (2008) 381:67-74) that measures
successful entry and translation of the viral RNA. Negative control
QL-XI-76 does not inhibit DENV in this system. (FIG. 3D) QL-XII-47
does not inhibit gene expression or replication of a reporter
replicon RNA5 electroporated into Huh7 cells. (FIG. 3E) QL-XII-47
does not inhibit expression or secretion of DENV virus-like
particles (VLPs).
[0077] FIGS. 4A and 4B demonstrate that QL-XII-47 blocks a late
step in DENV entry. Huh7 cells were infected with DENV2 NGC at an
MOI of 1 for 1 h and then washed exhaustively to remove
extracellular virus (FIG. 4A). Cells were lysed at various time
points post-infection; intracellular genomic DENV RNA and GAPDH
mRNA were quantified by qRT-PCR assay. A DENV2-derived stem peptide
was used as a control to block viral fusion during entry. At 24 h
post-infection, DENV genomic RNA is increasing due to replication
(shown in black), and the DENV RNA in the fusion-inhibited sample
is decreasing due to degradation since the virus cannot escape the
endosome (shown in blue). DENV genomic RNA in the QL-XII-47-treated
sample is relatively unchanged (shown in red), suggesting that the
nucleocapsid escapes the endosome but the viral RNA is protected
from cytoplasmic nucleases. Huh7 cells were infected at an MOI of
10 and then stained at various times post-transfection by in situ
hybridization using a ViewRNA probe (Panomics) specific for a
sequence in the 3'UTR of the DENV genome (FIG. 4B). The probe has
been validated to detect single copy RNA. In the presence of
QL-XII-47, DENV RNA persists in a punctate localization pattern
suggesting that it is protected from cytoplasmic nucleases and that
the viral entry process is blocked.
[0078] FIGS. 5A to 5V illustrate that QL-XII-47 and QL-XII-56
inhibit viruses outside the Flaviviridae family. 2 .mu.M QL-XII-47
inhibits infection of Bsc1 and Vero cells with VSV and VSV
pseudotyped with rabies virus glycoprotein (RABV) and Ebola
glycoprotein (EboV), as evidenced by immunostaining for viral
proteins (FIG. 5A). Inhibition is maximal when QL-XII-47 is present
before (-1 hpi) or at the time of infection (0 hpi). Inhibition is
lost when addition of QL-XII-47 is delayed to 1 (1 hpi) or 3 hours
post-infection (3 hpi). QL-XII-47 but not QL-XI-76 inhibits:
infection of human foreskin fibroblasts by a reporter HCMV that
expresses luciferase under the control of the UL97 promoter (FIG.
5B); infection and plaque formation of HSV-1 in Vero cells (FIG.
5C); and poliovirus infection and viral gene expression in Vero
cells (FIG. 5D). QL-XII-47 also inhibits the cytopathic effects of
Japanese Encephalitis Virus (JEV) (FIG. 5E) and Junin virus (FIG.
5F). * indicates that no plaques were detected at 8 .mu.M of
QL-XII-47. ** indicates that no plaques were detected at 8 .mu.M of
acyclovir and that lower concentrations were not tested. Data in
FIGS. 5A to 5V were generated in generous collaboration with S.
Piccinotti and S. Whelan (VSV pseudotypes); H. Chen and D. Coen
(HCMV and HSV-1); E. Sun and X. Zhuang (polio); and IBT Bioservices
(JEV and Junin). FIGS. 5G to 5J show the inhibitory activities of
QL-XII-47 and QL-XII-56 against Ebola glycoprotein (EBOV) at an MOI
of 1 (FIGS. 5G and 5I) or 10 (FIGS. 5H and 5J). FIGS. 5K to 5N show
the inhibitory activities of QL-XII-47 and QL-XII-56 against
Marburg virus (MARV) at an MOI of 1 (FIGS. 5K and 5M) or 10 (FIGS.
5L and 5N). FIGS. 5O and 5P show the inhibitory activities of
QL-XII-47 and QL-XII-56 against Junin virus (JUNV) at an MOI of 1
(FIG. 5O) or 10 (FIG. 5P). FIGS. 5Q and 5R show the inhibitory
activities of QL-XII-47 and QL-XII-56 against Lassa fever virus
(LASV) at an MOI of 1 (FIG. 5Q) or 10 (FIG. 5R). FIGS. 5S and 5T
show the inhibitory activities of QL-XII-47 and QL-XII-56 against
Venezuelan equine encephalitis virus (VEEV) at an MOI of 0.5 (FIG.
5S) or 1 (FIG. 5T). FIGS. 5U and 5V show the inhibitory activities
of QL-XII-47 and QL-XII-56 against Rift Valley fever virus (RVFV)
at an MOI of 1 (FIG. 5U) or 5 (FIG. 5V).
[0079] FIGS. 6A and 6B show that Bmx is not the target mediating
QL-XII-47's anti-DENV activity. RNAi-mediated depletion of Bmx
kinase with a MISSION siRNA pool (Sigma) has no effect on DENV
yield (FIG. 6A). PCI-32765 also has no effect on DENV yield (FIG.
6B). Compounds were added 1 hour post-infection with DENV2 NGC at
an MOI of 1. Viral yield was quantified by FFA at 24 h
post-infection.
[0080] FIG. 7 depicts a crystal structure of QL-X-138 with T790M
EGFR. A covalent bond formed between QL-X-138 and Cys797 is
indicated.
[0081] FIGS. 8A and 8B illustrate the identification of candidate
targets by "click-chemistry." FIG. 8A shows that QL-XII-47AL
retains potent anti-DENV activity. Huh7 cells were infected with
DENV2 NGC at an MOI of 1; compounds were added at a final
concentration of 3 .mu.M at 1 h post-infection. Viral yields were
quantified by FFA at 24 h post-infection. FIG. 8B illustrates the
treatment of DENV-infected cells with QL-XII-47AL followed by
labeling of covalently modified targets with biotinylated azide,
capture, and identification by mass spectrometry.
[0082] FIGS. 9A and 9B show the result of modeling the inventive
compounds with ALH1. FIG. 9A shows the chemical structures of the
compounds used in the modeling. FIG. 9B depicts a molecular
modeling of QL-XII-47 with ALDH1. The result shows that the
acrylamide moiety of QL-XII-47 is positioned towards Cys302.
[0083] FIGS. 10A to 10C show that QL-XII-47 inhibited DENV2 viral
production. Huh7 cells were infected with DENV virus. Values of FFU
(focus forming units)/ml were decreased for the infected cells
treated with QL-XII-47 after about 12 hours of infection compared
to the infected cells not treated with a compound of the invention
(FIG. 10A). Viral count was also decreased for the infected cells
treated with QL-XII-47 after about 12 hours of infection compared
to the infected cells not treated with a compound of the invention
(FIG. 10B). FIG. 10C shows Western blot analysis of DENV proteins
NS3 and core, demonstrating reduced steady-state expression of both
viral proteins in the presence of QL-XII-47 and suggesting that
QL-XII-47 may prevent their expression and/or promote their
degradation.
[0084] FIG. 11 shows a schematic of the replicon experiment used to
examine the effects of QL-XII-47 on translation of the dengue RNA.
Plasmid pDV2-Fluc(WT) or pDV2-FlucGDV encode dengue virus serotype
2 RNAs in which a luciferase reporter gene replaces most of the
genes encoding core, prM, and E. In vitro transcripts of the
wildtype replicon (WT) and a mutant that cannot replicate RNA due
to mutations in the active site of the viral polymerase (GDV
mutant) were produced. Huh7 cells were electroporated with the
respective DV2-replicon RNAs. Directly after electroporation cells
are incubated with the indicated drug (QL-XII-47 2 .mu.M,
cycloheximide 30 .mu.g/ml, MPA 5 .mu.M). At the indicated time
post-electroporation, luminescence was measured as a marker of
translation. For the WT construct, luc activity at an early time
point (12 hours or less) reflect translation of the input RNA
delivered by electroporation; luc activity at later time points
reflects luc translated from both input and newly synthesized
replicon RNA. Since the GDV mutant cannot synthesize new viral RNA,
luciferase activity observed at all time points is the product of
the input RNA delivered by electroporation.
[0085] FIGS. 12A and 12B show luciferase measurements taken in the
experiment described in FIG. 11. FIG. 12A shows the luciferase
activity measured at 6 hours post-electroporation for Huh7 cells
electroporated with the wildtype (WT) or mutant (MUT) replicon RNAs
and then treated with 2 .mu.M QL-XII-47, 2 .mu.M QL-XII-56, 30
.mu.g/mL cycloheximide (CHX) as general inhibitor of translation,
or DMSO as a negative control. FIG. 12B shows luciferase activity
measured at the indicated time point for cells electroporated with
the WT or GVD replicon RNA and then treated with DMSO, QL-XII-47,
QL-XII-56, or cycloheximide as indicated.
[0086] FIGS. 13A to 13C show that QL-XII-47 inhibited EMCV-IRES
dependant translation in Huh7 cells. Huh7 cells were electroporated
with an in vitro transcribed RNA encoding luciferase under the
control of the EMCV IRES. Following electroporation, cell were
treated with QL-XII-47 2 .mu.M, cycloheximide 30 .mu.g/ml, MPA 5
.mu.M as indicated on the plot. Cells were lysed and luciferase
activity measured at the indicated time points
post-electroporation. FIG. 13A shows the WT results. FIG. 13B shows
the GDV results. FIG. 13C shows the EMC-Luc results.
[0087] FIG. 14 shows cytotoxicity evaluation of the exemplary
compounds.
[0088] FIGS. 15A and 15B show that QL-XII-47 and QL-XII-56
inhibited encephalomyocarditis virus (EMCV) IRES-dependant
translation. FIG. 15A shows the Cap-dependent results. FIG. 15B
shows the IRES-dependent results.
[0089] FIG. 16 shows that conjugation of QL-XII-47 to biotin
significantly reduces the antiviral activity.
[0090] FIGS. 17A and 17B show the effects of RNAi-mediated
depletion of Prdx-1 on dengue virus. Cells were treated with
individual (sil-si4) and pooled siRNAs against Prdx-1 for 48 hours
and then infected with DV2 at moi 1. Cells were lysed, and culture
supernatants were harvested at 24 hours post-infection. FIG. 17A
shows that RNAi-mediated depletion of Prdx-1 does not reduce
steady-state expression of dengue NS3 protein (left); moreover,
combination treatment of cells with siRNAs against Prdx-1 and
QL-XII-47 does not reduce steady-state expression of NS3 beyond
what is observed with QL-XII-47 alone. FIG. 17B shows the
quantitation of infectious viral particles released to the culture
supernatants at 24 hours post-infection showing that RNAi-mediated
depletion of Prdx-1 does not appear to inhibit dengue virus.
[0091] FIGS. 18A and 18B show that QL-XII-47 and QL-XII-56
inhibited vesicular stomatitis virus (VSV). FIG. 18A shows the VSV
6 hpi results. FIG. 18B shows the RTqPCR results.
[0092] FIGS. 19A and 19B show that QL-XII-47 and QL-XII-56
inhibited poliovirus Type 1 (PV1). FIG. 19A shows the PV1 6 hpi
results. FIG. 19B shows the RTqPCR results.
[0093] FIGS. 20A to 20H show the exemplary compounds prepared
according to formulae (I)-(III) and (a)-(c). The blue bonds in the
structures of the second column and the red bonds in the structures
of the third column indicate the point of attachment to the
scaffold formulae.
[0094] FIGS. 21A and 21B show recombinant viral particle or
reporter viral particle (RVP) screening of the exemplary compounds.
FIG. 21A shows the results when the concentration of each compound
was 5.3 .mu.M or 1.9 .mu.M. FIG. 21B shows the results when the
concentration of each compound was 2.5 .mu.M. Used in the system
are the particles with dengue structural proteins (E, prM/M, and
core) and then an RNA derived from West Nile virus that encodes the
nonstructural proteins as well as a luciferase reporter
(Ansarah-Sobrinho et al., Virology, 2008, 381, 67-74). The
resulting particle can infect new cells. Upon viral entry and
release and translation of the WNV RNA, luc expression is obtained.
The luc activity is a marker of steady-state viral RNA. Decreased
luc activity can reflect inhibition of the initial entry step OR
inhibition of translation of the viral RNA OR inhibition of
steady-state RNA replication (increased synthesis and/or decreased
turnover).
[0095] FIG. 22 shows FFA evaluation of the exemplary compounds.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
[0096] The present invention provides compounds, and pharmaceutical
compositions thereof, for the prevention and treatment of
infectious diseases in a subject. The infectious disease may be
caused by a virus, for example, Flaviviridae virus (e.g., Dengue
virus (DENV), including Dengue virus 1 (DENV1), Dengue virus 2
(DENV2), Dengue virus 3 (DENV3), and Dengue virus 4 (DENV4); West
Nile virus; tick-borne encephalitis virus; yellow fever virus;
hepatitis C virus; hepatitis G virus; bovine viral diarrhea;
classical swine fever virus; and hog cholera virus), Kunjin virus,
Japanese encephalitis virus, vesicular stomatitis virus (VSV),
vesicular stomatitis virus (VSV) pseudotyped with rabies
glycoprotein, vesicular stomatitis virus (VSV) pseudotyped with
Ebola glycoprotein, herpes simplex virus 1 (HSV-1), human
cytomegalovirus (HCMV), poliovirus, Junin virus, Ebola virus,
Marburg virus (MARV), Lassa fever virus (LASV), Venezuelan equine
encephalitis virus (VEEV), Rift Valley Fever virus (RVFV),
hepatitis B virus, cytomegalovirus, papillomavirus, coronavirus,
Epstein-Barr virus (EBV), human immunodeficiency virus (HIV),
orthomyxovirus, paramyxovirus, arenavirus, bunyavirus, adenovirus,
poxvirus, retrovirus, rhabdovirus, picornavirus, or herpesvirus. In
certain embodiments, the compound inhibits the activity of the
virus. In certain embodiments, the compound inhibits the activity
of the virus by covalently modifying one or more cysteine residues
of a host factor. In certain embodiments, the compound prevents or
inhibits entry of the virus into a host cell. The present invention
further provides methods of using the compounds described herein,
e.g., as biological probes to study the inhibition of the activity
of a virus, to study viral entry, and to screen a library of
compounds to identify antiviral compounds, and as therapeutics,
e.g., in the prevention and treatment of infectious diseases caused
by a virus. The infectious diseases include, but are not limited
to, Dengue fever, Dengue hemorrhagic fever (DHF), Dengue shock
syndrome (DSS), hepatitis B, hepatitis C, fulminant viral
hepatitis, severe acute respiratory syndrome (SARS), viral
myocarditis, influenza A virus infection, influenza B virus
infection, parainfluenza virus infection, RS virus (RSV) infections
(e.g., RSV bronchiolitis, RSV pneumonia, especially infant and
childhood RSV infections and RSV pneumonia in the patients with
cardiopulmonary disorders), measles virus infection, vesicular
stomatitis virus infection, rabies virus infection, Ebola virus
infection, Japanese encephalitis, Junin virus infection, human
cytomegalovirus infection, herpes simplex virus 1 infection,
poliovirus infection, Marburg virus infection, Lassa fever virus
infection, Venezuelan equine encephalitis, Rift Valley Fever virus
infection, Korean hemorrhagic fever virus infection, Crimean-Congo
hemorrhagic fever virus infection, HIV infection, encephalitis,
Saint Louise encephalitis, Kyasanur Forest disease, Murray Valley
encephalitis, tick-borne encephalitis, West Nile encephalitis,
yellow fever, and viral infections in subjects with immune
disorders. Novel compounds have been identified and optimized that
target essential host factors to further the understanding of
host-virus interactions and to validate host targets and lead
compounds for further development as a potential new class of
antiviral agents. Importantly, because the novel compounds act via
a host target, they have the potential to have activity against
multiple pathogens that utilize the same host factor or pathway and
to circumvent the rapid selection for resistance observed with
agents that act via a viral target.
[0097] Successful antiviral drug development efforts have
traditionally focused on inhibition of viral enzymes that are
responsible for catalyzing viral genome replication and polyprotein
processing during viral assembly. Lessons from HIV drug development
efforts teach that, due to the high mutation rates of RNA viruses
and the associated rapid development of resistance to
monotherapies, combination therapies targeting multiple stages of
the viral life cycle are necessary for effective treatment without
the rapid development of resistance. As demonstrated by CCR5
antagonists such as the anti-HIV drug maraviroc, host-targeted
antivirals can also contribute to combination antiviral therapies
and, in some cases, may prove superior over the long term because
the host-targeted antivirals have the potential to be effective
against multiple viral pathogens and because their barriers to
resistance are higher than those of drugs that act via viral
targets.
[0098] A large number of cellular proteins have a reactive cysteine
that is important as a catalytic residue or as a site of
post-translational modification and that can be selectively
targeted by a compound that binds and places a reactive group in
close proximity to the targeted cysteine. Chemical proteomic
studies have identified a large number of proteins that contain
reactive cysteines (the reactive "cysteinome") and have established
that reactivity in most cases corresponds to residues of
significant biological function (Weerapana et al., Nature Chem.
Biol. (2008) 4:405-407; and Weerapana et al., Nature (2010)
468:790-795). The strategy of the present invention is to target
essential host factors by developing selective, covalent
cysteine-directed inhibitors. Covalent inhibition has several
potential benefits, including (1) irreversible inactivation of the
target protein that mitigates the need to extensively optimize for
potency; (2) full modification of the target with transient
exposure of the drug in vivo, which can reduce the need to achieve
high and sustained drug exposure and therefore mitigate toxicology
concerns; and (3) facilitation of target identification by affinity
approaches. The success of covalent inhibitors is well-illustrated
by the thirty-nine FDA-approved drugs that are highly effective in
humans, including aspirin (Warner et al., Proc. Nat. Acad. Sci. USA
(2002) 99:13371-13373) (Cox-1, Cox-2, and Cox-3) and the large
penicillin-class of antibiotics (bacterial DD-transpeptidase
inhibitors) (Waxman et al., Ann. Rev. Biochem. (1983) 52:825-869),
amongst many others (Johnson et al., Future Med. Chem. (2010)
2:949-964; and Singh et al., Nat. Rev. Drug Discov. (2011)
10:307-317).
[0099] Small molecule inhibitors have been developed that form a
covalent bond to a free cysteine of a target protein. While this
strategy has been applied to the development of covalent kinase
inhibitors, a significant opportunity exists to apply this approach
to discover novel antiviral targets as well as to develop and
validate potent antiviral compounds that act via these targets.
This approach complements on-going efforts to develop non-covalent
inhibitors targeting essential viral proteins.
[0100] Although structure-guided drug discovery approaches have
traditionally been biased against covalent inhibitors due to
concerns about off-target effects and potential toxicity, this
belies the historical success of drugs that act via covalent
mechanisms, including thirty-nine FDA-approved drugs (Johnson et
al., Future Med. Chem. (2010) 2:949-964; and Singh et al., Nat.
Rev. Drug Discov. (2011) 10:307-317). These include compounds
targeting enzyme and non-enzyme targets such as, rasagiline
(Hubalek et al., J. Med. Chem. (2004) 47:1760-1766) (monoamine
oxidase), clopidogrel (Herbert et al., Seminars in Vascular
Medicine (2003) 3:113-122) (G protein coupled receptor), omeprazole
(Im et al., J. Biol. Chem. (1985) 260:4591-4597) (proton pump
inhibitor), amongst many others (Johnson et al., Future Med. Chem.
(2010) 2:949-964; and Singh et al., Nat. Rev. Drug Discov. (2011)
10:307-317). Importantly, covalent inhibitors are not simply highly
reactive electrophiles. Specific covalent inhibitors typically have
warheads that are only weakly reactive compared to the quinones and
acyl halides typically present in highly reactive compounds and
electrophilic metabolites. In addition, covalent inhibitors usually
must form specific, non-covalent interactions and bind in a
particular orientation in order to undergo covalent reaction with a
nucleophile whereas highly reactive compounds more commonly react
non-specifically with the nucleophiles that are most accessible to
solution on the protein surface.
[0101] Covalent inhibitors, when properly deployed, have several
potential advantages over non-covalent inhibitors. First, the
covalent attachment means that the inhibitor has a kinetic off-rate
of essentially zero. This can boost potency by several orders of
magnitude. For example, WZ4002 (see FIG. 1 for the chemical
structure) inhibits T790M EGFR-dependent cellular proliferation
with an EC.sub.50 of 10 nM, while the corresponding non-covalent
inhibitor has an EC.sub.50 higher than 10 .mu.M (Zhou et al.,
Nature (2009) 462:1070-1074). Second, transient exposure is often
sufficient to achieve complete modification of the target. Third,
if designed and screened appropriately, very potent target
modulation can be achieved with covalent inhibitors. For example,
WZ4002 was identified from an acrylamide-containing library and
found to be efficacious in T790M EGFR-dependent lung tumor models
(Zhou et al., Nature (2009) 462:1070-1074). Fourth, since the
potency of the inhibitors of the present invention relies upon
their covalent modification of a cysteine residue, the
pharmacological selectivity of the inhibitors can be established by
introducing a cysteine to serine mutation into the target enzyme
and looking for reversal of the inhibitor-induced pharmacology.
This approach has been used previously to prove that the functional
target of WZ4002 is T790M EGFR and that the functional target of
FIIN1 is FGFR (Zhou et al., Nature (2009) 462:1070-1074; and Zhou
et al., Chem. Biol. (2010) 17:285-295). Fifth, covalent attachment
of the inhibitor can facilitate identification of the inhibitor's
target by affinity purification. Identification of the target(s) of
non-covalent inhibitors following phenotypic, cell-based screens
can be more challenging in comparison. It is noted that while a
cysteine-directed inhibitor of the HCV protease has recently been
disclosed (Hagel et al., Nature Chem. Biol. (2011) 7:22-24).
[0102] Cysteines are functionally important as catalytic residues
as well as sites for numerous types of post-translational
modification including disulfide formation, oxidation,
nitrosolyation, and alkylation. Although thiol groups are
predominantly protonated at physiological pH ranges, the pK.sub.a
of the thiol groups is greatly affected by the surrounding amino
acids. Consequently, a thiolate can act as an extremely potent
nucleophile even at physiological pH and can serve as a key
catalytic residue in several large enzyme families, including
cysteine proteases, phosphatases, acyl transferases, and E2
ubiquitin transferases. Small molecules that are capable of
covalently modifying the thiol group of cysteine are quite
frequently found in nature, and the nucleophilicity of active-site
cysteines has been exploited to develop potent, irreversible
inhibitors that covalently modify catalytic cysteines of proteases,
phosphatases, and E2 ubiquitin transferases (Singh et al., Nat.
Rev. Drug Discov. (2011) 10:307-317). In addition, cysteine
residues located in or near small molecule binding clefts outside
of the active site have been successfully targeted with small
molecule inhibitors.
[0103] Cysteine-targeted covalent inhibitors take advantage of
non-covalent interactions to selectively target a particular
protein binding site and to position the electrophilic moiety in a
conformation that permits bond formation with a specific cysteine
residue. This strategy prevents non-selective reaction of an
electrophile with the cysteine-containing proteome (the
"cysteineome") and has successfully yielded inhibitors with a
remarkable level of functional selectivity in cellular assays and
in vivo. For example, several inhibitors that function by this
mechanism are in clinical trials, including four different
compounds targeting a unique cysteine located in the periphery of
the ATP-binding site of EGFR kinases. This approach has been
recently applied to develop selective covalent inhibitors of a
number of different human kinases, including inhibitors of Rsk
(CMK, FMK) (Cohen et al., Science (2005) 308:1318-1321 and Cohen et
al., Nature Chem. Biol. (2007) 3:156-160), BTK (PCI-32765)
(Honigberg et al., Proc. Nat. Acad. Sci. USA (2010)
107:13075-13080), c-kit (Leproult et al., J. Med. Chem. (2011)
54:1347-1355), Nek2 (Henise et al., J. Med. Chem. (2011)
54:4133-4146), and a subset of the MAPKs (resorcylic acid lactone
polyketides (Schirmer et al., Proc. Nat. Acad. Sci. USA (2006)
103:4234-4239)). Studies suggest that this strategy might be
applied more broadly to identify selective, irreversible inhibitors
of not only additional kinases, but other protein classes as well.
In a recent quantitative chemoproteomic study, Cravatt and
colleagues utilized an alkynylated iodoacetamide probe and
quantitative mass spectrometry to identify the reactive cysteinome
(Weerapana et al., Nature (2010) 468:790-795). Out of a total of
8,910 cysteines present on the 890 human proteins detected in this
analysis, 1,082 cysteines were found to be hyper-reactive.
Importantly, hyper-reactivity was found to be a good predictor of a
cysteine's function as a catalytic residue, as a non-catalytic
residue present in an enzyme active site, or as a site of
post-translational oxidative modification.
Compounds
[0104] In one aspect of the present invention, provided are
compounds of Formula (I):
##STR00009##
or a pharmaceutically acceptable salt thereof; wherein:
[0105] Ring A is aryl, arylalkenyl, or heteroaryl;
[0106] each instance of R.sup.A is independently selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A1).sub.2, --SR.sup.A1, --CN,
--C(.dbd.NR.sup.A1)R.sup.A1, --C(.dbd.NR.sup.A1)OR.sup.A1,
--C(.dbd.NR.sup.A1)SR.sup.A1, --C(.dbd.NR.sup.A1)N(R.sup.A1).sub.2,
--C(.dbd.O)NR.sup.A1, --NR.sup.A1C(.dbd.O)--, --C(.dbd.O)R.sup.A1,
--C(.dbd.S)R.sup.A1, --C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A1).sub.2, --NO.sub.2, --N.sub.3,
--N(R.sup.A1).sub.3.sup.+F.sup.-,
--N(R.sup.A1).sub.3.sup.+Cl.sup.-,
--N(R.sup.A1).sub.3.sup.+Br.sup.-,
--N(R.sup.A1).sub.3.sup.+I.sup.-, --N(OR.sup.A1)R.sup.A1,
--NR.sup.A1C(.dbd.O)R.sup.A1, --NR.sup.A1C(.dbd.O)OR.sup.A1,
--NR.sup.A1C(.dbd.O)SR.sup.A1,
--NR.sup.A1C(.dbd.O)N(R.sup.A1).sub.2,
--NR.sup.A1C(.dbd.S)R.sup.A1, --NR.sup.A1C(.dbd.S)OR.sup.A1,
--NR.sup.A1C(.dbd.S)SR.sup.A1,
--NR.sup.A1C(.dbd.S)N(R.sup.A1).sub.2,
--NR.sup.A1C(.dbd.NR.sup.A1)R.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)OR.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)SR.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)N(R.sup.A1).sub.2,
--NR.sup.A1S(.dbd.O).sub.2R.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2OR.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2SR.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2N(R.sup.A1).sub.2,
--NR.sup.A1S(.dbd.O)R.sup.A1, --NR.sup.A1S(.dbd.O)OR.sup.A1,
--NR.sup.A1S(.dbd.O)SR.sup.A1, --NR.sup.A1
S(.dbd.O)N(R.sup.A1).sub.2, --NR.sup.A1P(.dbd.O),
--NR.sup.A1P(.dbd.O).sub.2, --NR.sup.A1P(.dbd.O)(R.sup.A1).sub.2,
--NR.sup.A1P(.dbd.)R.sup.A1(OR.sup.A1),
--NR.sup.A1P(.dbd.O)(OR.sup.A1).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A1).sub.2, --OC(.dbd.NR.sup.A1)R.sup.A1,
--OC(.dbd.NR.sup.A1)OR.sup.A1,
--OC(.dbd.NR.sup.A1)N(R.sup.A1).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A1).sub.2, --ON(R.sup.A1).sub.2,
--OS(.dbd.O)R.sup.A1, --OS(.dbd.O)OR.sup.A1, --OS(.dbd.O)SR.sup.A1,
--OS(.dbd.O)N(R.sup.A1).sub.2, --OS(.dbd.O).sub.2R.sup.A1,
--OS(.dbd.O).sub.2OR.sup.A1, --OS(.dbd.O).sub.2SR.sup.A1,
--OS(.dbd.O).sub.2N(R.sup.A1).sub.2, --OP(.dbd.O).sub.2,
--OP(.dbd.O)(R.sup.A1).sub.2, --OP(.dbd.O)R.sup.A1(OR.sup.A1),
--OP(.dbd.O)(OR.sup.A1).sub.2, --OP(.dbd.O), --OP(R.sup.A1).sub.2,
--OPR.sup.A1(OR.sup.A1), --OP(OR.sup.A1).sub.2,
--OSi(R.sup.A1).sub.3, --OSi(R.sup.A1).sub.2OR.sup.A1,
--OSi(R.sup.A1)(OR.sup.A1).sub.2, --OSi(OR.sup.A1).sub.3,
--SSR.sup.A1, --S(.dbd.O)R.sup.A1, --S(.dbd.O)OR.sup.A1,
--S(.dbd.O)N(R.sup.A1).sub.2, --S(.dbd.O).sub.2R.sup.A1,
--S(.dbd.O).sub.2OR.sup.A1, --S(.dbd.O).sub.2N(R.sup.A1).sub.2,
--SC(.dbd.O)R.sup.A1, --SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A1).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A1).sub.2, --P(R.sup.A1).sub.2,
--PR.sup.A(OR.sup.A1), --P(OR.sup.A1).sub.2, --P(.dbd.O),
--P(.dbd.O)(R.sup.A1).sub.2, --P(.dbd.O)(OR.sup.A1).sub.2,
--P(.dbd.O)R.sup.A1(OR.sup.A1), --P(.dbd.O).sub.2,
--B(R.sup.A1).sub.2, --B(OR.sup.A1).sub.2, --BR.sup.A1(OR.sup.A1),
--Si(R.sup.A1).sub.3, --Si(R.sup.A1).sub.2R.sup.A1,
--SiR.sup.A1(OR.sup.A1).sub.2, and --Si(OR.sup.A1).sub.3, wherein
each occurrence of R.sup.A1 is independently selected from the
group consisting of hydrogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, a nitrogen protecting group when
attached to a nitrogen atom, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, or two R.sup.A1 groups are joined to form an
optionally substituted heterocyclic ring;
[0107] k is 0, 1, 2, 3, 4, or 5;
[0108] Ring C is a carbocyclic, heterocyclic, aryl, or heteroaryl
ring;
[0109] each instance of R.sup.C is independently selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.C1, --N(R.sup.C1).sub.2, --SR.sup.C1, --CN,
--C(.dbd.NR.sup.C1)R.sup.C1, --C(.dbd.NR.sup.C1)OR.sup.C1,
--C(.dbd.NR.sup.C1)SR.sup.C1, --C(.dbd.NR.sup.C1)N(R.sup.C1).sub.2,
--C(.dbd.O)R.sup.C1, --C(.dbd.S)R.sup.C1, --C(.dbd.S)OR.sup.C1,
--C(.dbd.S)SR.sup.C1, --C(.dbd.S)N(R.sup.C1).sub.2, --NO.sub.2,
--N.sub.3, --N(R.sup.C1).sub.3.sup.+F.sup.-,
--N(R.sup.C1).sub.3.sup.+Cl.sup.-,
--N(R.sup.C1).sub.3.sup.+Br.sup.-, --N(R.sup.C1).sub.3+,
--N(OR.sup.C1)R.sup.C1, --NR.sup.C1C(.dbd.O)R.sup.C1,
--NR.sup.C1C(.dbd.O)OR.sup.C1, --NR.sup.C1C(.dbd.O)SR.sup.C1,
--NR.sup.C1C(.dbd.O)N(R.sup.C1).sub.2,
--NR.sup.C1C(.dbd.S)R.sup.C1, --NR.sup.C1C(.dbd.S)OR.sup.C1,
--NR.sup.C1C(.dbd.S)SR.sup.C1,
--NR.sup.C1C(.dbd.S)N(R.sup.C1).sub.2,
--NR.sup.C1C(.dbd.NR.sup.C1)R.sup.C1,
--NR.sup.C1C(.dbd.NR.sup.C1)OR.sup.C1,
--NR.sup.C1C(.dbd.NR.sup.C1)SR.sup.C1,
--NR.sup.C1C(.dbd.NR.sup.C1)N(R.sup.C1).sub.2,
--NR.sup.C1S(.dbd.O).sub.2R.sup.C1,
--NR.sup.C1S(.dbd.O).sub.2OR.sup.C1,
--NR.sup.C1S(.dbd.O).sub.2SR.sup.C1,
--NR.sup.C1S(.dbd.O).sub.2N(R.sup.C1).sub.2,
--NR.sup.C1S(.dbd.O)R.sup.C1, --NR.sup.CS(.dbd.O)OR.sup.C1,
--NR.sup.CS(.dbd.O)SR.sup.C1,
--NR.sup.C1S(.dbd.O)N(R.sup.C1).sub.2, --NR.sup.C1P(.dbd.O),
--NR.sup.C1P(.dbd.O).sub.2, --NR.sup.C1P(.dbd.O)(R.sup.C1).sub.2,
--NR.sup.C1P(.dbd.O)R.sup.C1(OR),
--NR.sup.C1P(.dbd.O)(OR.sup.C1).sub.2, --OC(.dbd.O)R.sup.C1,
--OC(.dbd.O)OR.sup.C1, --OC(.dbd.O)SR.sup.C1,
--OC(.dbd.O)N(R.sup.C1).sub.2, --OC(.dbd.NR.sup.C1)R.sup.C1,
--OC(.dbd.NR.sup.C1)OR.sup.C1,
--OC(.dbd.NR.sup.C1)N(R.sup.C1).sub.2, --OC(.dbd.S)R.sup.C1,
--OC(.dbd.S)OR.sup.C1, --OC(.dbd.S)SR.sup.C1,
--OC(.dbd.S)N(R.sup.C1).sub.2, --ON(R.sup.C1).sub.2,
--OS(.dbd.O)R.sup.C1, --OS(.dbd.O)OR.sup.C1, --OS(.dbd.O)SR.sup.C1,
--OS(.dbd.O)N(R.sup.C1).sub.2, --OS(.dbd.O).sub.2R.sup.C1,
--OS(.dbd.O).sub.2OR.sup.C1, --OS(.dbd.O).sub.2SR.sup.C1,
--OS(.dbd.O).sub.2N(R.sup.C1).sub.2, --OP(.dbd.O).sub.2,
--OP(.dbd.O)(R.sup.C1).sub.2, --OP(.dbd.O)R1(OR.sup.C1),
--OP(.dbd.O)(OR.sup.C1).sub.2, --OP(.dbd.O), --OP(R.sup.C1).sub.2,
--OPR.sup.C1(OR.sup.C1), --OP(OR.sup.C1).sup.2,
--OSi(R.sup.C1).sub.3, --OSi(R.sup.C1).sub.2OR.sup.C1,
--OSi(R.sup.C1)(OR.sup.C1).sub.2, --OSi(OR.sup.C1).sub.3,
--SSR.sup.C1, --S(.dbd.O)R.sup.C1, --S(.dbd.O)OR.sup.C1,
--S(.dbd.O)N(R.sup.C1).sub.2, --S(.dbd.O).sub.2R.sup.C1,
--S(.dbd.O).sub.2R.sup.C1, --S(.dbd.O).sub.2R.sup.C1,
--S(.dbd.O).sub.2N(R.sup.C1).sub.2, --SC(.dbd.O)R.sup.C1,
--SC(.dbd.O)OR.sup.C1, --SC(.dbd.O)SR.sup.C1,
--SC(.dbd.O)N(R.sup.C1).sub.2, --SC(.dbd.S)R.sup.C1,
--SC(.dbd.S)OR.sup.C1, --SC(.dbd.S)SR.sup.C1,
--SC(.dbd.S)N(R.sup.C1).sub.2, --P(R.sup.C1).sub.2,
--PR.sup.C1(OR.sup.C1), --P(OR.sup.C1).sub.2, --P(.dbd.O),
--P(.dbd.O)(R.sup.C1).sub.2, --P(.dbd.O)(OR.sup.C1).sub.2,
--P(.dbd.O)R.sup.C1(OR.sup.C1), --P(.dbd.O).sub.2,
--B(R.sup.C1).sub.2, --B(OR.sup.C1).sub.2, --BR.sup.C1(OR.sup.C1),
--Si(R.sup.C1).sub.3, --Si(R.sup.C1).sub.2OR.sup.C1,
--SiR.sup.C1(OR.sup.C1).sub.2, and --Si(OR.sup.C1).sub.3, wherein
each occurrence of R.sup.C1 is independently selected from the
group consisting of hydrogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, a nitrogen protecting group when
attached to a nitrogen atom, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, or two R.sup.C1 groups are joined to form an
optionally substituted heterocyclic ring or optionally substituted
heteroaryl ring;
[0110] n is 0, 1, 2, 3, or 4;
[0111] L is a bond or an optionally substituted, branched or
unbranched C.sub.1-6 hydrocarbon chain;
[0112] R.sup.D is any one of Formulae (i-1)-(i-43):
##STR00010## ##STR00011## ##STR00012## ##STR00013##
##STR00014##
wherein:
[0113] each instance of R.sup.D1 is independently hydrogen,
halogen, acyl, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --CN, --NO.sub.2,
--OR.sup.D1a, --N(R.sup.D1a).sub.2, --SR.sup.D1a,
--CH.sub.2OR.sup.D1a, --CH.sub.2N(R.sup.D1a).sub.2,
--CH.sub.2SR.sup.D1a, --C(.dbd.O)R.sup.D1a, --C(.dbd.O)OR.sup.D1a,
--C(.dbd.O)SR.sup.D1a, --C(.dbd.O)N(R.sup.D1a).sub.2,
--C(.dbd.S)R.sup.D1a, --C(.dbd.S)OR.sup.D1a, --C(.dbd.S)SR.sup.D1a,
--C(.dbd.S)N(R.sup.D1a).sub.2, --C(.dbd.NR.sup.D1a)R.sup.D1a,
--C(.dbd.NR.sup.D1a)OR.sup.D1a, --C(.dbd.NR.sup.D1a)SR.sup.D1a, or
--C(.dbd.NR.sup.D1a)N(R.sup.D1a).sub.2, wherein each occurrence of
R.sup.D1a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
or two R.sup.D1a groups are joined to form an substituted or
unsubstituted heterocyclic ring;
[0114] each instance of R.sup.D2 is independently hydrogen,
halogen, acyl, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --CN, --NO.sub.2,
--OR.sup.D2a, --N(R.sup.D2a).sub.2, --SR.sup.D2a,
--CH.sub.2OR.sup.D2a, --CH.sub.2N(R.sup.D2a).sub.2,
--CH.sub.2SR.sup.D2a, --C(.dbd.O)R.sup.D2a, --C(.dbd.O)OR.sup.D2a,
--C(.dbd.O)SR.sup.D2a, --C(.dbd.O)N(R.sup.D2a).sub.2,
--C(.dbd.S)R.sup.D2a, --C(.dbd.S)OR.sup.D2a, --C(.dbd.S)SR.sup.D2a,
--C(.dbd.S)N(R.sup.D2a).sub.2, --C(.dbd.NR.sup.D2a)R.sup.D2a,
--C(.dbd.NR.sup.D2a)OR.sup.D2a, --C(.dbd.NR.sup.D2a)SR.sup.D2a, and
--C(.dbd.NR.sup.D2a)N(R.sup.D2a).sub.2, wherein each occurrence of
R.sup.D2a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, and substituted or unsubstituted heteroaryl,
or two R.sup.D2a groups are joined to form an substituted or
unsubstituted heterocyclic ring;
[0115] each instance of R.sup.D3 is independently hydrogen,
halogen, acyl, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.D3a,
--N(R.sup.D3a).sub.2, --SR.sup.D3a, --CH.sub.2OR.sup.D3a,
--CH.sub.2N(R.sup.D3a).sub.2, --CH.sub.2SR.sup.D3a,
--C(.dbd.O)R.sup.D3a, --C(.dbd.O)OR.sup.D3a, --C(.dbd.O)SR.sup.D3a,
--C(.dbd.O)N(R.sup.D3a).sub.2, --C(.dbd.S)R.sup.D3a,
--C(.dbd.S)OR.sup.D3a, --C(.dbd.S)SR.sup.D3a,
--C(.dbd.S)N(R.sup.D3a).sub.2, --C(.dbd.NR.sup.D3a)R.sup.D3,
--C(.dbd.NR.sup.D3a)OR.sup.D3a, --C(.dbd.NR.sup.D3a)SR.sup.D3a, or
--C(.dbd.NR.sup.D3a)N(R.sup.D3a).sub.2 wherein each occurrence of
R.sup.D3a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
or two R.sup.D3a groups are joined to form an substituted or
unsubstituted heterocyclic ring;
[0116] optionally R.sup.D1 and R.sup.D3, or R.sup.D2 and R.sup.D3,
or R.sup.D1 and R.sup.D2 are joined to form an substituted or
unsubstituted carbocyclic or substituted or unsubstituted
heterocyclic ring;
[0117] R.sup.D4 is a leaving group selected from the group
consisting of --Br, --Cl, --I, and --OS(.dbd.O).sub.wR.sup.D4a,
wherein w is 1 or 2, and R.sup.D4a is substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[0118] each instance of X.sup.1 is independently a bond,
--C(.dbd.O)--, --SO.sub.2--, --NR.sup.D5--, optionally substituted
alkylene, or optionally substituted heteroarylene, wherein R.sup.D5
is hydrogen, C.sub.1-6 alkyl, or a nitrogen protecting group;
[0119] each instance of Y is independently O, S, or NR.sup.D6,
wherein R.sup.D6 is hydrogen, C.sub.1-6 alkyl, or a nitrogen
protecting group; and
[0120] each instance of z and z.sub.1 is independently 0, 1, 2, 3,
4, 5, or 6, as valency permits.
[0121] In another aspect of the present invention, provided are
compounds of Formula (II):
##STR00015##
or a pharmaceutically acceptable salt thereof; wherein:
[0122] Ring A is aryl, arylalkenyl, or heteroaryl;
[0123] each instance of R.sup.A is independently selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A1).sub.2, --SR.sup.A1, --CN,
--C(.dbd.NR.sup.A1)R.sup.A1, --C(.dbd.NR.sup.A1)OR.sup.A1,
--C(.dbd.NR.sup.A1)SR.sup.A1, --C(.dbd.NR.sup.A1)N(R.sup.A1).sub.2,
--C(.dbd.O)NR.sup.A1--, --NR.sup.A1C(.dbd.O)--,
--C(.dbd.O)R.sup.A1, --C(.dbd.S)R.sup.A1, --C(.dbd.S)OR.sup.A1,
--C(.dbd.S)SR.sup.A1, --C(.dbd.S)N(R.sup.A1).sub.2, --NO.sub.2,
--N.sub.3, --N(R.sup.A1).sub.3.sup.+F.sup.-,
--N(R.sup.A1).sub.3.sup.+Cl.sup.-,
--N(R.sup.A1).sub.3.sup.+Br.sup.-,
--N(R.sup.A1).sub.3.sup.+I.sup.-, --N(OR.sup.A1)R.sup.A1,
--NR.sup.A1C(.dbd.O)R.sup.A1, --NR.sup.A1C(.dbd.O)OR.sup.A1,
--NR.sup.A1C(.dbd.O)SR.sup.A1,
--NR.sup.A1C(.dbd.O)N(R.sup.A1).sub.2,
--NR.sup.A1C(.dbd.S)R.sup.A1, --NR.sup.A1C(.dbd.S)OR.sup.A1,
--NR.sup.A1C(.dbd.S)SR.sup.A1,
--NR.sup.A1C(.dbd.S)N(R.sup.A1).sub.2,
--NR.sup.A1C(.dbd.NR.sup.A1)R.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)OR.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)SR.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)N(R.sup.A1).sub.2,
--NR.sup.A1S(.dbd.O).sub.2R.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2OR.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2SR.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2N(R.sup.A1).sub.2,
--NR.sup.A1S(.dbd.O)R.sup.A1, --NR.sup.A1S(.dbd.O)OR.sup.A1,
--NR.sup.A1S(.dbd.O)SR.sup.A1,
--NR.sup.A1S(.dbd.O)N(R.sup.A1).sub.2, --NR.sup.A1P(.dbd.O),
--NR.sup.A1P(.dbd.O).sub.2, --NR.sup.A1P(.dbd.O)(R.sup.A1).sub.2,
--NR.sup.A1P(.dbd.)R.sup.A1(OR.sup.A1),
--NR.sup.A1P(.dbd.O)(OR.sup.A1).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A1).sub.2, --OC(.dbd.NR.sup.A1)R.sup.A1,
--OC(.dbd.NR.sup.A1)OR.sup.A1,
--OC(.dbd.NR.sup.A1)N(R.sup.A1).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A1).sub.2, --ON(R.sup.A1).sub.2,
--OS(.dbd.O)R.sup.A1, --OS(.dbd.O)OR.sup.A1, --OS(.dbd.O)SR.sup.A1,
--OS(.dbd.O)N(R.sup.A1).sub.2, --OS(.dbd.O).sub.2R.sup.A1,
--OS(.dbd.O).sub.2OR.sup.A1, --OS(.dbd.O).sub.2SR.sup.A1,
--OS(.dbd.O).sub.2N(R.sup.A1).sub.2, --OP(.dbd.O).sub.2,
--OP(.dbd.O)(R.sup.A1).sub.2, --OP(.dbd.O)R.sup.A1(OR.sup.A1),
--OP(.dbd.O)(OR.sup.A1).sub.2, --OP(.dbd.O), --OP(R.sup.A1).sub.2,
--OPR.sup.A1(OR.sup.A1), --OP(OR.sup.A1).sub.2,
--OSi(R.sup.A1).sub.3, --OSi(R.sup.A1).sub.2OR.sup.A1,
--OSi(R.sup.A1)(OR.sup.A1).sub.2, --OSi(OR.sup.A1).sub.3,
--SSR.sup.A1, --S(.dbd.O)R.sup.A1, --S(.dbd.O)OR.sup.A1,
--S(.dbd.O)N(R.sup.A1).sub.2, --S(.dbd.O).sub.2R.sup.A1,
--S(.dbd.O).sub.2OR.sup.A1, --S(.dbd.O).sub.2N(R.sup.A1).sub.2,
--SC(.dbd.O)R.sup.A1, --SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A1).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A1).sub.2, --P(R.sup.A1).sub.2,
--PR.sup.A(OR.sup.A1), --P(OR.sup.A1).sub.2, --P(.dbd.O),
--P(.dbd.O)(R.sup.A1).sub.2, --P(.dbd.O)(OR.sup.A1).sub.2,
--P(.dbd.O)R.sup.A1(OR.sup.A1), --P(.dbd.O).sub.2,
--B(R.sup.A1).sub.2, --B(OR.sup.A1).sub.2, --BR.sup.A1(OR.sup.A1),
--Si(R.sup.A1).sub.3, --Si(R.sup.A1).sub.2R.sup.A1,
--SiR.sup.A1(OR.sup.A1).sub.2, and --Si(OR.sup.A1).sub.3, wherein
each occurrence of R.sup.A1 is independently selected from the
group consisting of hydrogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, a nitrogen protecting group when
attached to a nitrogen atom, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, or two R.sup.A1 groups are joined to form an
optionally substituted heterocyclic ring;
[0124] k is 0, 1, 2, 3, 4, or 5;
[0125] Ring C is a carbocyclic, heterocyclic, aryl, or heteroaryl
ring;
[0126] each instance of R.sup.j1, R.sup.j2, R.sup.j3, and R.sup.C
is independently selected from the group consisting of hydrogen,
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
carbocyclyl, optionally substituted heterocyclyl, optionally
substituted aryl, optionally substituted heteroaryl, --OR.sup.C1,
--N(R.sup.C1).sub.2, --SR.sup.C1, --CN,
--C(.dbd.NR.sup.C1)R.sup.C1, --C(.dbd.NR.sup.C1)OR.sup.C1,
--C(.dbd.NR.sup.C1)SR.sup.C1, --C(.dbd.NR.sup.C1)N(R.sup.C1).sub.2,
--C(.dbd.O)R.sup.C1, --C(.dbd.S)R.sup.C1, --C(.dbd.S)OR.sup.C1,
--C(.dbd.S)SR.sup.C1, --C(.dbd.S)N(R.sup.C1).sub.2, --NO.sub.2,
--N.sub.3, --N(R.sup.C1).sub.3.sup.+F.sup.-,
--N(R.sup.C1).sub.3.sup.+Cl.sup.-,
--N(R.sup.C1).sub.3.sup.+Br.sup.-,
--N(R.sup.C1).sub.3.sup.+I.sup.-, --N(OR.sup.C1)R.sup.C1,
--NR.sup.C1C(.dbd.O)R.sup.C1, --NR.sup.C1C.sub.(.dbd.O)OR.sup.C1,
--NR.sup.CC(.dbd.O)SR.sup.C1,
--NR.sup.C1C(.dbd.O)N(R.sup.C1).sub.2,
--NR.sup.C1C(.dbd.S)R.sup.C1, --NR.sup.C1C(.dbd.S)OR.sup.C1,
--NR.sup.C1C(.dbd.S)SR.sup.C1,
--NR.sup.C1C(.dbd.S)N(R.sup.C1).sub.2,
--NR.sup.C1C(.dbd.NR.sup.C1)R.sup.C1,
--NR.sup.C1C(.dbd.NR.sup.C1)OR.sup.C1,
--NR.sup.C1C(.dbd.NR.sup.C1)SR.sup.C1
NR.sup.C1C(.dbd.NR.sup.C1)N(R.sup.C1).sub.2,
--NR.sup.C1S(.dbd.O).sub.2R.sup.C1,
--NR.sup.C1S(.dbd.O).sub.2OR.sup.C1,
--NR.sup.C1S(.dbd.O).sub.2SR.sup.C1,
--NR.sup.C1S(.dbd.O).sub.2N(R.sup.C1).sub.2,
--NR.sup.C1S(.dbd.O)R.sup.C1, --NR.sup.CS(.dbd.O)OR.sup.C1,
--NR.sup.CS(.dbd.O)SR.sup.C1,
--NR.sup.C1S(.dbd.O)N(R.sup.C1).sub.2, --NR.sup.C P(.dbd.O),
--NR.sup.C P(.dbd.O).sub.2, --NR.sup.C1P(.dbd.O)(R.sup.C1).sub.2,
--NR.sup.C1P(.dbd.O)R(OR.sup.C1),
--NR.sup.C1P(.dbd.O)(OR.sup.C1).sub.2, --OC(.dbd.O)R.sup.C1,
--OC(.dbd.O)OR.sup.C1, --OC(.dbd.O)SR.sup.C1,
--OC(.dbd.O)N(R.sup.C1).sub.2, --OC(.dbd.NR.sup.C1)R.sup.C1,
--OC(.dbd.NR.sup.C1)OR.sup.C1,
--OC(.dbd.NR.sup.C1)N(R.sup.C1).sub.2, --OC(.dbd.S)R.sup.C1,
--OC(.dbd.S)OR.sup.C1, --OC(.dbd.S)SR.sup.C1,
--OC(.dbd.S)N(R.sup.C1).sub.2, --ON(R.sup.C1).sub.2,
--OS(.dbd.O)R.sup.C1, --OS(.dbd.O)OR.sup.C1, --OS(.dbd.O)SR.sup.C1,
--OS(.dbd.O)N(R.sup.C1).sub.2, --OS(.dbd.O).sub.2R.sup.C1,
--OS(.dbd.O).sub.2OR.sup.C1, --OS(.dbd.O).sub.2SR.sup.C1,
--OS(.dbd.O).sub.2N(R.sup.C1).sub.2, --OP(.dbd.O).sub.2,
--OP(.dbd.O)(R.sup.C1).sub.2, --OP(.dbd.O)R.sup.C1(OR.sup.C1),
--OP(.dbd.O)(OR.sup.C1).sub.2, --OP(.dbd.O), --OP(R.sup.C1).sub.2,
--OPR.sup.C1(OR.sup.C1), --OP(OR.sup.C1).sub.2,
--OSi(R.sup.C1).sub.3, --OSi(R.sup.C1).sub.2OR.sup.C1,
--OSi(R.sup.C1)(OR.sup.C1).sup.2, --OSi(OR.sup.C1).sub.3,
--SSR.sup.C1, --S(.dbd.O)R.sup.C1, --S(.dbd.O)OR.sup.C1,
--S(.dbd.O)N(R.sup.C1).sub.2, --S(.dbd.O).sub.2R.sup.C1,
--S(.dbd.O).sub.2R.sup.C1, --S(.dbd.O).sub.2R.sup.C1,
--S(.dbd.O).sub.2N(R.sup.C1).sub.2, --SC(.dbd.O)R.sup.C1,
--SC(.dbd.O)OR.sup.C1, --SC(.dbd.O)SR.sup.C1,
--SC(.dbd.O)N(R.sup.C1).sub.2, --SC(.dbd.S)R.sup.C1,
--SC(.dbd.S)OR.sup.C1, --SC(.dbd.S)SR.sup.C1,
--SC(.dbd.S)N(R.sup.C1).sub.2, --P(R.sup.C1).sub.2,
--PR.sup.C1(OR.sup.C1), --P(OR.sup.C1).sub.2, --P(.dbd.O),
--P(.dbd.O)(R.sup.C1).sub.2, --P(.dbd.O)(OR.sup.C1).sub.2,
--P(.dbd.O)R.sup.C1(OR.sup.C1), --P(.dbd.O).sub.2,
--B(R.sup.C1).sub.2, --B(OR.sup.C1).sub.2, --BR.sup.C1(OR.sup.C1),
--Si(R.sup.C1).sub.3, --Si(R.sup.C1).sub.2OR.sup.C1,
--SiR.sup.C1(OR.sup.C1).sub.2, and --Si(OR.sup.C1).sub.3, wherein
each occurrence of R.sup.C1 is independently selected from the
group consisting of hydrogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, a nitrogen protecting group when
attached to a nitrogen atom, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, or two R.sup.C1 groups are joined to form an
optionally substituted heterocyclic ring or optionally substituted
heteroaryl ring;
[0127] n is 0, 1, 2, 3, or 4;
[0128] L is a bond or an optionally substituted, branched or
unbranched C.sub.1-6 hydrocarbon chain;
[0129] R.sup.D is any one of Formulae (i-1)-(i-43):
##STR00016## ##STR00017## ##STR00018## ##STR00019##
##STR00020##
wherein:
[0130] each instance of R.sup.D1 is independently hydrogen,
halogen, acyl, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --CN, --NO.sub.2,
--OR.sup.D1a, --N(R.sup.D1a).sub.2, --SR.sup.D1a,
--CH.sub.2OR.sup.D1a, --CH.sub.2N(R.sup.D1a).sub.2,
--CH.sub.2SR.sup.D1a, --C(.dbd.O)R.sup.D1a, --C(.dbd.O)OR.sup.D1a,
--C(.dbd.O)SR.sup.D1a, --C(.dbd.O)N(R.sup.D1a).sub.2,
--C(.dbd.S)R.sup.D1a, --C(.dbd.S)OR.sup.D1a, --C(.dbd.S)SR.sup.D1a,
--C(.dbd.S)N(R.sup.D1a).sub.2, --C(.dbd.NR.sup.D1a)R.sup.D1a,
--C(.dbd.NR.sup.D1a)OR.sup.D1a, --C(.dbd.NR.sup.D1a)SR.sup.D1, or
--C(.dbd.NR.sup.D1a)N(R.sup.D1a).sub.2, wherein each occurrence of
R.sup.D1a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
or two R.sup.D1a groups are joined to form an substituted or
unsubstituted heterocyclic ring;
[0131] each instance of R.sup.D2 is independently hydrogen,
halogen, acyl, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --CN, --NO.sub.2,
--OR.sup.D2a, --N(R.sup.D2a).sub.2, --SR.sup.D2a,
--CH.sub.2OR.sup.D2a, --CH.sub.2N(R.sup.D2a).sub.2,
--CH.sub.2SR.sup.D2a, --C(.dbd.O)R.sup.D2a, --C(.dbd.O)OR.sup.D2a,
--C(.dbd.O)SR.sup.D2a, --C(.dbd.O)N(R.sup.D2a).sub.2,
--C(.dbd.S)R.sup.D2a, --C(.dbd.S)OR.sup.D2a, --C(.dbd.S)SR.sup.D2a,
--C(.dbd.S)N(R.sup.D2a).sub.2, --C(.dbd.NR.sup.D2a)R.sup.D2a,
--C(.dbd.NR.sup.D2a)OR.sup.D2a, --C(.dbd.NR.sup.D2a)SR.sup.D2a, and
--C(.dbd.NR.sup.D2a)N(R.sup.D2a).sub.2, wherein each occurrence of
R.sup.D2a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, and substituted or unsubstituted heteroaryl,
or two R.sup.D2a groups are joined to form an substituted or
unsubstituted heterocyclic ring;
[0132] each instance of R.sup.D3 is independently hydrogen,
halogen, acyl, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.D3a,
--N(R.sup.D3a).sub.2, --SR.sup.D3a, --CH.sub.2OR.sup.D3a,
--CH.sub.2N(R.sup.D3a).sub.2, --CH.sub.2SR.sup.D3a,
--C(.dbd.O)R.sup.D3a, --C(.dbd.O)OR.sup.D3a, --C(.dbd.O)SR.sup.D3a,
--C(.dbd.O)N(R.sup.D3a).sub.2, --C(.dbd.S)R.sup.D3a,
--C(.dbd.S)OR.sup.D3a, --C(.dbd.S)SR.sup.D3a,
--C(.dbd.S)N(R.sup.D3a).sub.2, --C(.dbd.NR.sup.D3a)R.sup.D3a,
--C(.dbd.NR.sup.D3a)OR.sup.D3a, --C(.dbd.NR.sup.D3a)SR.sup.D3a, or
--C(.dbd.NR.sup.D3a)N(R.sup.D3a).sub.2 wherein each occurrence of
R.sup.D3a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
or two R.sup.D3a groups are joined to form an substituted or
unsubstituted heterocyclic ring;
[0133] optionally R.sup.D1 and R.sup.D3, or R.sup.D2 and R.sup.D3,
or R.sup.D1 and R.sup.D2 are joined to form an substituted or
unsubstituted carbocyclic or substituted or unsubstituted
heterocyclic ring;
R.sup.D4 is a leaving group selected from the group consisting of
--Br, --Cl, --I, and --OS(.dbd.O).sub.wR.sup.D4a, wherein w is 1 or
2, and R.sup.D4a is substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl;
[0134] each instance of X.sup.1 is independently a bond,
--C(.dbd.O)--, --SO.sub.2--, --NR.sup.D5--, optionally substituted
alkylene, or optionally substituted heteroarylene, wherein R.sup.D5
is hydrogen, C14 alkyl, or a nitrogen protecting group;
[0135] each instance of Y is independently O, S, or NR.sup.D6,
wherein R.sup.D6 is hydrogen, C.sub.1-6 alkyl, or a nitrogen
protecting group; and
[0136] each instance of z and z.sub.1 is independently 0, 1, 2, 3,
4, 5, or 6, as valency permits.
[0137] In another aspect of the present invention, provided are
compounds of Formula (III):
##STR00021##
or a pharmaceutically acceptable salt thereof; wherein:
[0138] Ring A is aryl, arylalkenyl, or heteroaryl;
[0139] each instance of R.sup.A is independently selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A1).sub.2, --SR.sup.A1, --CN,
--C(.dbd.NR.sup.A1)R.sup.A1, --C(.dbd.NR.sup.A1)OR.sup.A1,
--C(.dbd.NR.sup.A1)SR.sup.A1, --C(.dbd.NR.sup.A1)N(R.sup.A1).sub.2,
--C(.dbd.O)NR.sup.A1--, --NR.sup.A1C(.dbd.O)--,
--C(.dbd.O)R.sup.A1, --C(.dbd.S)R.sup.A1, --C(.dbd.S)OR.sup.A1,
--C(.dbd.S)SR.sup.A1, --C(.dbd.S)N(R.sup.A1).sub.2, --NO.sub.2,
--N.sub.3, --N(R.sup.A1).sub.3.sup.+F.sup.-,
--N(R.sup.A1).sub.3.sup.+Cl.sup.-,
--N(R.sup.A1).sub.3.sup.+Br.sup.-,
--N(R.sup.A1).sub.3.sup.+I.sup.-, --N(OR.sup.A1)R.sup.A1,
--NR.sup.A1C(.dbd.O)R.sup.A1, --NR.sup.A1C(.dbd.O)OR.sup.A1,
--NR.sup.A1C(.dbd.O)SR.sup.A1,
--NR.sup.A1C(.dbd.O)N(R.sup.A1).sub.2,
--NR.sup.A1C(.dbd.S)R.sup.A1, --NR.sup.A1C(.dbd.S)OR.sup.A1,
--NR.sup.A1C(.dbd.S)SR.sup.A1,
--NR.sup.A1C(.dbd.S)N(R.sup.A1).sub.2,
--NR.sup.A1C(.dbd.NR.sup.A1)R.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)OR.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)SR.sup.A1,
--NR.sup.A1C(.dbd.NR.sup.A1)N(R.sup.A1).sub.2,
--NR.sup.A1S(.dbd.O).sub.2R.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2OR.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2SR.sup.A1,
--NR.sup.A1S(.dbd.O).sub.2N(R.sup.A1).sub.2,
--NR.sup.A1S(.dbd.O)R.sup.A1, --NR.sup.A1S(.dbd.O)OR.sup.A1,
--NR.sup.A1S(.dbd.O)SR.sup.A1,
--NR.sup.A1S(.dbd.O)N(R.sup.A1).sub.2, --NR.sup.A1P(.dbd.O),
--NR.sup.A1P(.dbd.O).sub.2, --NR.sup.A1P(.dbd.O)(R.sup.A1).sub.2,
--NR.sup.A1P(.dbd.O)R.sup.A1(OR.sup.A1),
--NR.sup.A1P(.dbd.O)(OR.sup.A1).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.AC1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A1).sub.2, --OC(.dbd.NR.sup.A1)R.sup.A1,
--OC(.dbd.NR.sup.A1)OR.sup.A1,
--OC(.dbd.NR.sup.A1)N(R.sup.A1).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A1).sub.2, --ON(R.sup.A1).sub.2,
--OS(.dbd.O)R.sup.A1, --OS(.dbd.O)OR.sup.A1, --OS(.dbd.O)SR.sup.A1,
--OS(.dbd.O)N(R.sup.A1).sub.2, --OS(.dbd.O).sub.2R.sup.A1,
--OS(.dbd.O).sub.2OR.sup.A1, --OS(.dbd.O).sub.2SR.sup.A1,
--OS(.dbd.O).sub.2N(R.sup.A1).sub.2, --OP(.dbd.O).sub.2,
--OP(.dbd.O)(R.sup.A1).sub.2, --OP(.dbd.O)R.sup.A1(OR.sup.A1),
--OP(.dbd.O)(OR.sup.A1).sub.2, --OP(.dbd.O), --OP(R.sup.A1).sub.2,
--OPR.sup.A1(OR.sup.A1), --OP(OR.sup.A1).sub.2,
--OSi(R.sup.A1).sub.3, --OSi(R.sup.A1).sub.2OR.sup.A1,
--OSi(R.sup.A1)(OR.sup.A1).sub.2, --OSi(OR.sup.A1).sub.3,
--SSR.sup.A1, --S(.dbd.O)R.sup.A1, --S(.dbd.O)OR.sup.A1,
--S(.dbd.O)N(R.sup.A1).sub.2, --S(.dbd.O).sub.2R.sup.A1,
--S(.dbd.O).sub.2OR.sup.A1, --S(.dbd.O).sub.2N(R.sup.A1).sub.2,
--SC(.dbd.O)R.sup.A1, --SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A1).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A1).sub.2, --P(R.sup.A1).sub.2,
--PR.sup.A1(OR.sup.A1), --P(OR.sup.A1).sub.2, --P(.dbd.O),
--P(.dbd.O)(R.sup.A1).sub.2, --P(.dbd.O)(OR.sup.A1).sub.2,
--P(.dbd.O)R.sup.A1(OR.sup.A1), --P(.dbd.O).sub.2,
--B(R.sup.A1).sub.2, --B(OR.sup.A1).sub.2, --BRA(OR.sup.A1),
--Si(R.sup.A1).sub.3, --Si(R.sup.A1).sub.2OR.sup.A1,
--SiR.sup.A1(OR.sup.A1).sub.2, and --Si(OR.sup.A1).sub.3, wherein
each occurrence of R.sup.A1 is independently selected from the
group consisting of hydrogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, a nitrogen protecting group when
attached to a nitrogen atom, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, or two R.sup.A1 groups are joined to form an
optionally substituted heterocyclic ring;
[0140] k is 0, 1, 2, 3, 4, or 5;
[0141] Ring C is a carbocyclic, heterocyclic, aryl, or heteroaryl
ring;
[0142] each instance of R.sup.C is independently selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.C1, --N(R.sup.C1).sub.2, --SR.sup.C1, --CN,
--C(.dbd.NR.sup.C1)R.sup.C1, --C(.dbd.NR.sup.C1)OR.sup.C1,
--C(.dbd.NR.sup.C1)SR.sup.C1, --C(.dbd.NR.sup.C1)N(R.sup.C1).sub.2,
--C(.dbd.O)R.sup.C1, --C(.dbd.S)R.sup.C1, --C(.dbd.S)OR.sup.C1,
--C(.dbd.S)SR.sup.C1, --C(.dbd.S)N(R.sup.C1) 2, --NO.sub.2,
--N.sub.3, --N(R.sup.C1).sub.3+F--,
--N(R.sup.C1).sub.3.sup.+Cl.sup.-,
--N(R.sup.C1).sub.3.sup.+Br.sup.-, --N(R.sup.C1).sub.3+,
--N(OR.sup.C1)R.sup.C1, --NR.sup.C1C(.dbd.O)R.sup.C1,
--NR.sup.C1C(.dbd.O)OR.sup.C1, --NR.sup.C1C(.dbd.O)SR.sup.C1,
--NR.sup.C1C(.dbd.O)N(R.sup.C1).sub.2,
--NR.sup.C1C(.dbd.S)R.sup.C1, --NR.sup.C1C(.dbd.S)OR.sup.C1,
--NR.sup.C1C(.dbd.S)SR.sup.C1,
--NR.sup.C1C(.dbd.S)N(R.sup.C1).sub.2,
--NR.sup.C1C(.dbd.NR.sup.C1)R.sup.C1,
--NR.sup.C1C(.dbd.NR.sup.C1)OR.sup.C1,
--NR.sup.C1C(.dbd.NR.sup.C1)SR.sup.C1
NR.sup.C1C(.dbd.NR.sup.C1)N(R.sup.C1).sub.2,
--NR.sup.C1S(.dbd.O).sub.2R1, --NR.sup.C1S(.dbd.O).sub.2OR.sup.C1,
--NR.sup.C1S(.dbd.O).sub.2SR.sup.C1,
--NR.sup.C1S(.dbd.O).sub.2N(R.sup.C1).sub.2,
--NR.sup.C1S(.dbd.O)R.sup.C1, --NR.sup.C1S(.dbd.O)OR.sup.C1,
--NR.sup.C1S(.dbd.O)SR.sup.C1,
--NR.sup.C1S(.dbd.O)N(R.sup.C1).sub.2, --NR.sup.C P(.dbd.O),
--NR.sup.C P(.dbd.O).sub.2, --NR.sup.C1P(.dbd.O)(R.sup.C1).sub.2,
--NR.sup.C P(.dbd.O)R.sup.C(OR.sup.C1),
--NR.sup.C1P(.dbd.O)(OR.sup.C1).sub.2, --OC(.dbd.O)R.sup.C1,
--OC(.dbd.O)OR.sup.C1, --OC(.dbd.O)SR.sup.C1,
--OC(.dbd.O)N(R.sup.C1).sub.2, --OC(.dbd.NR.sup.C1)R.sup.C1,
--OC(.dbd.NR.sup.C1)OR.sup.C1,
--OC(.dbd.NR.sup.C1)N(R.sup.C1).sub.2, --OC(.dbd.S)R.sup.C1,
--OC(.dbd.S)OR.sup.C1, --OC(.dbd.S)SR.sup.C1,
--OC(.dbd.S)N(R.sup.C1).sub.2, --ON(R.sup.C1).sub.2,
--OS(.dbd.O)R.sup.C1, --OS(.dbd.O)OR.sup.C1, --OS(.dbd.O)SR.sup.C1,
--OS(.dbd.O)N(R.sup.C1).sub.2, --OS(.dbd.O).sub.2R.sup.C1,
--OS(.dbd.O).sub.2OR.sup.C1, --OS(.dbd.O).sub.2SR.sup.C1,
--OS(.dbd.O).sub.2N(R.sup.C1).sub.2, --OP(.dbd.O).sub.2,
--OP(.dbd.O)(R.sup.C1).sub.2, --OP(.dbd.O)R.sup.C1(OR.sup.C1),
--OP(.dbd.O)(OR.sup.C1).sub.2, --OP(.dbd.O), --OP(R.sup.C1).sub.2,
--OPR.sup.C1(OR.sup.C1), --OP(OR.sup.C1).sub.2,
--OSi(R.sup.C1).sub.3, --OSi(R.sup.C1).sub.2OR.sup.C1,
--OSi(R.sup.C1)(OR.sup.C1).sub.2, --OSi(OR.sup.C1).sub.3,
--SSR.sup.C1, --S(.dbd.O)R.sup.C1, --S(.dbd.O)OR.sup.C1,
--S(.dbd.O)N(R.sup.C1).sub.2, --S(.dbd.O).sub.2R.sup.C1,
--S(.dbd.O).sub.2OR.sup.C1, --S(.dbd.O).sub.2,
--S(.dbd.O).sub.2N(R.sup.C1).sub.2, --SC(.dbd.O)R.sup.C1,
--SC(.dbd.O)OR.sup.C1, --SC(.dbd.O)SR.sup.C1,
--SC(.dbd.O)N(R.sup.C1).sub.2, --SC(.dbd.S)R.sup.C1,
--SC(.dbd.S)OR.sup.C1, --SC(.dbd.S)SR.sup.C1,
--SC(.dbd.S)N(R.sup.C1).sub.2, --P(R.sup.C1).sub.2,
--PR.sup.C1(OR.sup.C1), --P(OR.sup.C1).sub.2, --P(.dbd.O),
--P(.dbd.O)(R.sup.C1).sub.2, --P(.dbd.O)(OR.sup.C1).sub.2,
--P(.dbd.O)R.sup.C1(OR.sup.C1), --P(.dbd.O).sub.2,
--B(R.sup.C1).sub.2, --B(OR.sup.C1).sub.2, --BR.sup.C1(OR.sup.C1),
--Si(R.sup.C1).sub.3, --Si(R.sup.C1).sub.2OR.sup.C1,
--SiR.sup.C1(OR.sup.C1).sub.2, and --Si(OR.sup.C1).sub.3, wherein
each occurrence of R.sup.C1 is independently selected from the
group consisting of hydrogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, a nitrogen protecting group when
attached to a nitrogen atom, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, or two R.sup.C1 groups are joined to form an
optionally substituted heterocyclic ring or optionally substituted
heteroaryl ring;
[0143] R.sup.q is independently hydrogen, halogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, or a nitrogen protecting group;
[0144] n is 0, 1, 2, 3, or 4;
[0145] L is a bond or an optionally substituted, branched or
unbranched C.sub.1-6 hydrocarbon chain;
[0146] R.sup.D is any one of Formulae (i-1)-(i-43):
##STR00022## ##STR00023## ##STR00024## ##STR00025##
##STR00026##
wherein:
[0147] each instance of R.sup.D1 is independently hydrogen,
halogen, acyl, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --CN, --NO.sub.2,
--OR.sup.D1a, --N(R.sup.D1a).sub.2, --SR.sup.D1a,
--CH.sub.2OR.sup.D1a, --CH.sub.2N(R.sup.D1a).sub.2,
--CH.sub.2SR.sup.D1a, --C(.dbd.O)R.sup.D1a, --C(.dbd.O)OR.sup.D1a,
--C(.dbd.O)SR.sup.D1a, --C(.dbd.O)N(R.sup.D1a).sub.2,
--C(.dbd.S)R.sup.D1a, --C(.dbd.S)OR.sup.D1a, --C(.dbd.S)SR.sup.D1a,
--C(.dbd.S)N(R.sup.D1a).sub.2, --C(.dbd.NR.sup.D1a)R.sup.D1a,
--C(.dbd.NR.sup.D1a)OR.sup.D1a, --C(.dbd.NR.sup.D1a)SR.sup.D1a, or
--C(.dbd.NR.sup.D1a)N(R.sup.D1a).sub.2, wherein each occurrence of
R.sup.D1a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
or two R.sup.D1a groups are joined to form an substituted or
unsubstituted heterocyclic ring;
[0148] each instance of R.sup.D2 is independently hydrogen,
halogen, acyl, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --CN, --NO.sub.2,
--OR.sup.D2a, --N(R.sup.D2a).sub.2, --SR.sup.D2a,
--CH.sub.2OR.sup.D2a, --CH.sub.2N(R.sup.D2a).sub.2,
--CH.sub.2SR.sup.D2a, --C(.dbd.O)R.sup.D2a, --C(.dbd.O)OR.sup.D2a,
--C(.dbd.O)SR.sup.D2a, --C(.dbd.O)N(R.sup.D2a).sub.2,
--C(.dbd.S)R.sup.D2a, --C(.dbd.S)OR.sup.D2a, --C(.dbd.S)SR.sup.D2a,
--C(.dbd.S)N(R.sup.D2a).sub.2, --C(.dbd.NR.sup.D2a)R.sup.D2a,
--C(.dbd.NR.sup.D2a)OR.sup.D2a, --C(.dbd.NR.sup.D2a)SR.sup.D2a, and
--C(.dbd.NR.sup.D2a)N(R.sup.D2a).sub.2, wherein each occurrence of
R.sup.D2a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, and substituted or unsubstituted heteroaryl,
or two R.sup.D2a groups are joined to form an substituted or
unsubstituted heterocyclic ring;
[0149] each instance of R.sup.D3 is independently hydrogen,
halogen, acyl, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.D3a,
--N(R.sup.D3a).sub.2, --SR.sup.D3a, --CH.sub.2OR.sup.D3a,
--CH.sub.2N(R.sup.D3a).sub.2, --CH.sub.2SR.sup.D3a,
--C(.dbd.O)R.sup.D3a, --C(.dbd.O)OR.sup.D3a, --C(.dbd.O)SR.sup.D3a,
--C(.dbd.O)N(R.sup.D3a).sub.2, --C(.dbd.S)R.sup.D3a,
--C(.dbd.S)OR.sup.D3a, --C(.dbd.S)SR.sup.D3a,
--C(.dbd.S)N(R.sup.D3a).sub.2, --C(.dbd.NR.sup.D3a)R.sup.D3,
--C(.dbd.NR.sup.D3a)OR.sup.D3a, --C(.dbd.NR.sup.D3a)SR.sup.D3a, or
--C(.dbd.NR.sup.D3a)N(R.sup.D3a).sub.2 wherein each occurrence of
R.sup.D3a is independently hydrogen, acyl, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
or two R.sup.D3a groups are joined to form an substituted or
unsubstituted heterocyclic ring;
[0150] optionally R.sup.D1 and R.sup.D3, or R.sup.D2 and R.sup.D3,
or R.sup.D1 and R.sup.D2 are joined to form an substituted or
unsubstituted carbocyclic or substituted or unsubstituted
heterocyclic ring;
R.sup.D4 is a leaving group selected from the group consisting of
--Br, --Cl, --I, and --OS(.dbd.O).sub.wR.sup.D4a, wherein w is 1 or
2, and R.sup.D4a is substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl;
[0151] each instance of X.sup.1 is independently a bond,
--C(.dbd.O)--, --SO.sub.2--, --NR.sup.D5--, optionally substituted
alkylene, or optionally substituted heteroarylene, wherein R.sup.D5
is hydrogen, C.sub.1-6 alkyl, or a nitrogen protecting group;
[0152] each instance of Y is independently O, S, or NR.sup.D6,
wherein R.sup.D6 is hydrogen, C.sub.1-6 alkyl, or a nitrogen
protecting group; and
[0153] each instance of z and z.sub.1 is independently 0, 1, 2, 3,
4, 5, or 6, as valency permits.
[0154] As generally defined above, Ring A is aryl, arylalkenyl, or
heteroaryl. In certain embodiments, Ring A is heteroaryl. In
certain embodiments, Ring A is arylalkenyl. In certain embodiments,
Ring A is aryl. Ring A may be substituted with one or more
substituents R.sup.A. The substituent R.sup.A may be attached to a
carbon atom or heteroatom of Ring A. In certain embodiments, Ring A
is a monocyclic heteroaryl ring. In certain embodiments, Ring A is
a bicyclic heteroaryl ring. In certain embodiments, Ring A is a
tricyclic heteroaryl ring. In certain embodiments, Ring A is a
substituted heteroaryl ring. In certain embodiments, Ring A is an
unsubstituted heteroaryl ring. In certain embodiments, Ring A is
substituted pyridyl. In certain embodiments, Ring A is
unsubstituted pyridyl. In certain embodiments, Ring A is a
heteroaryl ring fused with one or more carbocyclic, heterocyclic,
aryl, or heteroaryl groups wherein the point of attachment is on
the heteroaryl ring.
[0155] In certain embodiments, Ring A is a 6-membered heteroaryl
ring.
[0156] In certain embodiments,
##STR00027##
[0157] In certain embodiments,
##STR00028##
[0158] In certain embodiments,
##STR00029##
[0159] In certain embodiments,
##STR00030##
[0160] In certain embodiments,
##STR00031##
[0161] In certain embodiments,
##STR00032##
[0162] In certain embodiments,
##STR00033##
[0163] In certain embodiments,
##STR00034##
[0164] In certain embodiments,
##STR00035##
[0165] In certain embodiments,
##STR00036##
[0166] Ring A of Formula (I) may also be a 5-membered heteroaryl
ring. In certain embodiments, Ring A is a 5-membered heteroaryl
ring wherein one of the five ring carbon atoms is replaced by
nitrogen, oxygen, or sulfur.
[0167] In certain embodiments,
##STR00037##
[0168] In certain embodiments,
##STR00038##
[0169] In certain embodiments,
##STR00039##
[0170] In certain embodiments,
##STR00040##
[0171] In certain embodiments,
##STR00041##
[0172] In certain embodiments,
##STR00042##
[0173] In certain embodiments, Ring A is a 5-membered heteroaryl
ring wherein two of the five ring carbon atoms are independently
replaced by nitrogen, oxygen, or sulfur.
[0174] In certain embodiments,
##STR00043##
[0175] In certain embodiments,
##STR00044##
[0176] In certain embodiments,
##STR00045##
[0177] In certain embodiments,
##STR00046##
[0178] In certain embodiments,
##STR00047##
[0179] In certain embodiments,
##STR00048##
[0180] In certain embodiments,
##STR00049##
[0181] In certain embodiments,
##STR00050##
[0182] In certain embodiments,
##STR00051##
[0183] In certain embodiments,
##STR00052##
[0184] In certain embodiments,
##STR00053##
[0185] In certain embodiments,
##STR00054##
[0186] In certain embodiments,
##STR00055##
[0187] In certain embodiments,
##STR00056##
[0188] In certain embodiments,
##STR00057##
[0189] In certain embodiments,
##STR00058##
[0190] In certain embodiments, Ring A is a 5-membered heteroaryl
ring wherein three of the five ring carbon atoms are independently
replaced by nitrogen, oxygen, or sulfur.
[0191] In certain embodiments,
##STR00059##
[0192] In certain embodiments,
##STR00060##
[0193] In certain embodiments,
##STR00061##
[0194] In certain embodiments,
##STR00062##
[0195] In certain embodiments,
##STR00063##
[0196] In certain embodiments,
##STR00064##
[0197] In certain embodiments,
##STR00065##
[0198] In certain embodiments,
##STR00066##
[0199] In certain embodiments,
##STR00067##
[0200] In certain embodiments,
##STR00068##
[0201] In certain embodiments,
##STR00069##
[0202] In certain embodiments,
##STR00070##
[0203] In certain embodiments,
##STR00071##
[0204] In certain embodiments,
##STR00072##
[0205] In certain embodiments,
##STR00073##
[0206] In certain embodiments,
##STR00074##
[0207] In certain embodiments,
##STR00075##
[0208] In certain embodiments,
##STR00076##
[0209] In certain embodiments,
##STR00077##
[0210] In certain embodiments,
##STR00078##
[0211] In certain embodiments,
##STR00079##
[0212] In certain embodiments,
##STR00080##
[0213] In certain embodiments, Ring A is a 5-membered heteroaryl
ring wherein four of the five ring carbon atoms are independently
replaced by nitrogen, oxygen, or sulfur.
[0214] In certain embodiments,
##STR00081##
[0215] In certain embodiments,
##STR00082##
[0216] In certain embodiments,
##STR00083##
[0217] In certain embodiments,
##STR00084##
[0218] In certain embodiments,
##STR00085##
[0219] In certain embodiments,
##STR00086##
[0220] In certain embodiments,
##STR00087##
[0221] In certain embodiments,
[0222] In certain embodiments, Ring A is bicyclic heteroaryl. In
certain embodiments,
##STR00088##
is one of the following formulae:
##STR00089##
[0223] In certain embodiments, Ring A is unsubstituted, and thus k
is 0. In certain embodiments, k is 1. In certain embodiments, k is
2. In certain embodiments, k is 3. In certain embodiments, k is 4.
In certain embodiments, k is 5.
[0224] In certain embodiments, Ring A is aryl. In certain
embodiments, Ring A is phenyl. In certain embodiments, Ring A is
arylalkenyl. In certain embodiments, Ring A is phenylalkenyl. In
certain embodiments,
##STR00090##
is one of the following formulae:
##STR00091##
[0225] In certain embodiments, at least one R.sup.A is H. In
certain embodiments, at least one R.sup.A is halogen. In certain
embodiments, at least one R.sup.A is F. In certain embodiments, at
least one R.sup.A is Cl. In certain embodiments, at least one
R.sup.A is Br. In certain embodiments, at least one R.sup.A is I
(iodine). In certain embodiments, at least one R.sup.A is
substituted acyl. In certain embodiments, at least one R.sup.A is
unsubstituted acyl. In certain embodiments, at least one R.sup.A is
acetyl. In certain embodiments, at least one R.sup.A is substituted
alkyl. In certain embodiments, at least one R.sup.A is
unsubstituted alkyl. In certain embodiments, at least one R.sup.A
is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.A is
methyl. In certain embodiments, at least one R.sup.A is ethyl. In
certain embodiments, at least one R.sup.A is propyl. In certain
embodiments, at least one R.sup.A is optionally substituted
-alkyl-O-alkyl. In certain embodiments, at least one R.sup.A is
optionally substituted alkylene-O-aryl. In certain embodiments, at
least one R.sup.A is optionally substituted alkylene-O-phenyl. In
certain embodiments, at least one R.sup.A is optionally substituted
alkylene-O-(p-CF.sub.3-phenyl). In certain embodiments, at least
one R.sup.A is optionally substituted
alkylene-O-(o-CF.sub.3-phenyl). In certain embodiments, at least
one R.sup.A is optionally substituted
alkylene-O-(m-CF.sub.3-phenyl). In certain embodiments, at least
one R.sup.A is butyl. In certain embodiments, at least one R.sup.A
is substituted alkenyl. In certain embodiments, at least one
R.sup.A is unsubstituted alkenyl. In certain embodiments, at least
one R.sup.A is substituted alkynyl. In certain embodiments, at
least one R.sup.A is unsubstituted alkynyl. In certain embodiments,
at least one R.sup.A is substituted carbocyclyl. In certain
embodiments, at least one R.sup.A is unsubstituted carbocyclyl. In
certain embodiments, at least one R.sup.A is substituted
heterocyclyl. In certain embodiments, at least one R.sup.A is
unsubstituted heterocyclyl. In certain embodiments, at least one
R.sup.A is substituted aryl. In certain embodiments, at least one
R.sup.A is unsubstituted aryl. In certain embodiments, at least one
R.sup.A is substituted phenyl. In certain embodiments, at least one
R.sup.A is unsubstituted phenyl. In certain embodiments, at least
one R.sup.A is substituted heteroaryl. In certain embodiments, at
least one R.sup.A is unsubstituted heteroaryl. In certain
embodiments, at least one R.sup.A is substituted pyridyl. In
certain embodiments, at least one R.sup.A is unsubstituted pyridyl.
In certain embodiments, at least one R.sup.A is --OR.sup.A1. In
certain embodiments, at least one R.sup.A is --N(R.sup.A1).sub.2.
In certain embodiments, at least one R.sup.A is --SR.sup.A1. In
certain embodiments, at least one R.sup.A is --OH. In certain
embodiments, at least one R.sup.A is --NH.sub.2. In certain
embodiments, at least one R.sup.A is --SH.
[0226] In certain embodiments, when R.sup.A is --OR.sup.A1,
--N(R.sup.A1).sub.2, or --SR.sup.A1, at least one R.sup.A1 is H. In
certain embodiments, at least one R.sup.A1 is substituted acyl. In
certain embodiments, at least one R.sup.A1 is unsubstituted acyl.
In certain embodiments, at least one R.sup.A1 is acetyl. In certain
embodiments, at least one R.sup.A1 is substituted alkyl. In certain
embodiments, at least one R.sup.A1 is unsubstituted alkyl. In
certain embodiments, at least one R.sup.A1 is C.sub.1-6 alkyl. In
certain embodiments, at least one R.sup.A1 is methyl. In certain
embodiments, at least one R.sup.A1 is ethyl. In certain
embodiments, at least one R.sup.A1 is propyl. In certain
embodiments, at least one R.sup.A1 is butyl. In certain
embodiments, at least one R.sup.A1 is substituted alkenyl. In
certain embodiments, at least one R.sup.A1 is unsubstituted
alkenyl. In certain embodiments, at least one R.sup.A1 is
substituted alkynyl. In certain embodiments, at least one R.sup.A1
is unsubstituted alkynyl. In certain embodiments, at least one
R.sup.A1 is substituted carbocyclyl. In certain embodiments, at
least one R.sup.A1 is unsubstituted carbocyclyl. In certain
embodiments, at least one R.sup.A1 is substituted heterocyclyl. In
certain embodiments, at least one R.sup.A1 is unsubstituted
heterocyclyl. In certain embodiments, at least one R.sup.A1 is
substituted aryl. In certain embodiments, at least one R.sup.A1 is
unsubstituted aryl. In certain embodiments, at least one R.sup.A1
is substituted phenyl. In certain embodiments, at least one
R.sup.A1 is unsubstituted phenyl. In certain embodiments, at least
one R.sup.A1 is substituted heteroaryl. In certain embodiments, at
least one R.sup.A1 is unsubstituted heteroaryl. In certain
embodiments, at least one R.sup.A1 is substituted pyridyl. In
certain embodiments, at least one R.sup.A1 is unsubstituted
pyridyl. In certain embodiments, at least one R.sup.A1 is a
nitrogen protecting group when attached to a nitrogen atom. In
certain embodiments, at least one R.sup.A1 is an oxygen protecting
group when attached to an oxygen atom. In certain embodiments, at
least one R.sup.A1 is a sulfur protecting group when attached to a
sulfur atom. In certain embodiments, two R.sup.A1 groups are joined
to form a substituted heterocyclic ring. In certain embodiments,
two R.sup.A1 groups are joined to form an unsubstituted
heterocyclic ring.
[0227] In certain embodiments, R.sup.A is
--N(R.sup.A1)C(.dbd.O)R.sup.A1. In certain embodiments, R.sup.A is
--N(R.sup.A1)C(.dbd.O)-alkenyl. In certain embodiments, R.sup.A is
--N(R.sup.A1)C(.dbd.O)--CH.dbd.CH.sub.2. In certain embodiments,
R.sup.A is --C(.dbd.O)N(R.sup.A1).sub.2. In certain embodiments,
R.sup.A is --C(.dbd.O)NH.sub.2. In certain embodiments, R.sup.A is
--C(.dbd.O)NHCH.sub.3. In certain embodiments, R.sup.A is
--C(.dbd.O)R.sup.A1. In certain embodiments, R.sup.A is
--C(.dbd.O)-alkenyl. In certain embodiments, R.sup.A is
--C(.dbd.O)--CH.dbd.CH.sub.2. In certain embodiments, R.sup.A is
--N(R.sup.A1)C(.dbd.O)N(R.sup.A1).sub.2. In certain embodiments,
R.sup.A is --NHC(.dbd.O)N(R.sup.A1).sub.2. In certain embodiments,
R.sup.A is --NHC(.dbd.O)NHCH.sub.3. In certain embodiments, R.sup.A
is --N(R.sup.A1)SO.sub.2R.sup.A1. In certain embodiments, R.sup.A
is --NHSO.sub.2R.sup.A1. In certain embodiments, R.sup.A is
--NHSO.sub.2-alkyl. In certain embodiments, R.sup.A is
--NHSO.sub.2--CH.sub.3. In certain embodiments, R.sup.A is
--NHSO.sub.2--C.sub.2H.sub.5. In certain embodiments, R.sup.A is
--NHSO.sub.2-iPr. In certain embodiments, R.sup.A is
--NHSO.sub.2--Butyl. In certain embodiments, R.sup.A is
--NHSO.sub.2-tButyl.
[0228] In certain embodiments, R.sup.A is heterocyclic ring. In
certain embodiments, R.sup.A is optionally substituted piperazine.
In certain embodiments, R.sup.A is N-methyl-piperazine.
[0229] In certain embodiments, two R.sup.A on Ring A can optionally
form another ring. In certain embodiments, R.sup.A is --OR.sup.A1
and two R.sup.A1 can optionally form a heterocyclic ring.
[0230] In certain embodiments, R.sup.A is substituted C1-6 alkyl;
and k is 1. In certain embodiments, R.sup.A is unsubstituted
C.sub.1-6 alkyl; and k is 1. In certain embodiments, R.sup.A is
methyl; and k is 1. In certain embodiments, R.sup.A is ethyl; and k
is 1. In certain embodiments, R.sup.A is propyl; and k is 1. In
certain embodiments, R.sup.A is butyl; and k is 1.
[0231] In certain embodiments, R.sup.A is halogen; and k is 1. In
certain embodiments, R.sup.A is F; and k is 1. In certain
embodiments, R.sup.A is Cl; and k is 1. In certain embodiments,
R.sup.A is Br; and k is 1. In certain embodiments, R.sup.A is I
(iodine); and k is 1.
[0232] As generally defined above, Ring C is a carbocyclic,
heterocyclic, aryl, or heteroaryl ring. Ring C may be substituted
with one or more substituents R.sup.C. R.sup.A may be a substituent
on a carbon atom or heteroatom as valency permits. In certain
embodiments, Ring C is a carbocyclic ring. In certain embodiments,
Ring C is a monocyclic carbocyclic ring. In certain embodiments,
Ring C is a bicyclic carbocyclic ring. In certain embodiments, Ring
C is a substituted carbocyclic ring. In certain embodiments, Ring C
is an unsubstituted carbocyclic ring. In certain embodiments, Ring
C is a saturated carbocyclic ring. In certain embodiments, Ring C
is an unsaturated carbocyclic ring. In certain embodiments, Ring C
is a carbocyclic ring fused with one or more carbocyclic,
heterocyclic, aryl, or heteroaryl groups wherein the point of
attachment is on the carbocyclic ring.
[0233] In certain embodiments, Ring C is a heterocyclic ring. In
certain embodiments, Ring C is a monocyclic heterocyclic ring. In
certain embodiments, Ring C is a bicyclic heterocyclic ring. In
certain embodiments, Ring C is a substituted heterocyclic ring. In
certain embodiments, Ring C is an unsubstituted heterocyclic ring.
In certain embodiments, Ring C is a saturated heterocyclic ring. In
certain embodiments, Ring C is an unsaturated heterocyclic ring. In
certain embodiments, Ring C is a heterocyclic ring fused with one
or more carbocyclic, heterocyclic, aryl, or heteroaryl groups
wherein the point of attachment is on the heterocyclic ring.
[0234] In certain embodiments, Ring C is an aryl ring. In certain
embodiments, Ring C is a monocyclic aryl ring. In certain
embodiments, Ring C is a bicyclic aryl ring. In certain
embodiments, Ring C is a tricyclic aryl ring. In certain
embodiments, Ring C is a substituted aryl ring. In certain
embodiments, Ring C is an unsubstituted aryl ring. In certain
embodiments, Ring C is substituted phenyl. In certain embodiments,
Ring C is unsubstituted phenyl. In certain embodiments, Ring C is
an aryl ring fused with one or more carbocyclic, heterocyclic,
aryl, or heteroaryl groups wherein the point of attachment is on
the aryl ring. In certain embodiments, Ring C is substituted
naphthyl. In certain embodiments, Ring C is unsubstituted
naphthyl.
[0235] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00092##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0236] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00093##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0237] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00094##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0238] In certain embodiments, Ring C is a heteroaryl ring. In
certain embodiments, Ring C is a monocyclic heteroaryl ring. In
certain embodiments, Ring C is a bicyclic heteroaryl ring. In
certain embodiments, Ring C is a tricyclic heteroaryl ring. In
certain embodiments, Ring C is a substituted heteroaryl ring. In
certain embodiments, Ring C is an unsubstituted heteroaryl ring. In
certain embodiments, Ring C is substituted pyridyl. In certain
embodiments, Ring C is unsubstituted pyridyl. In certain
embodiments, Ring C is a heteroaryl ring fused with one or more
carbocyclic, heterocyclic, aryl, or heteroaryl groups wherein the
point of attachment is on the heteroaryl ring. In certain
embodiments, Ring C is a heteroaryl ring fused with a phenyl ring
wherein the point of attachment is on the phenyl ring. In certain
embodiments, Ring C is substituted indole. In certain embodiments,
Ring C is unsubstituted indole. In certain embodiments, Ring C is
substituted isoindole. In certain embodiments, Ring C is
unsubstituted isoindole. In certain embodiments, Ring C is
substituted indazole. In certain embodiments, Ring C is
unsubstituted indazole. In certain embodiments, Ring C is
substituted benzothiophene. In certain embodiments, Ring C is
unsubstituted benzothiophene. In certain embodiments, Ring C is
substituted isobenzothiophene. In certain embodiments, Ring C is
unsubstituted isobenzothiophene. In certain embodiments, Ring C is
substituted benzofuran. In certain embodiments, Ring C is
unsubstituted benzofuran. In certain embodiments, Ring C is
substituted benzoisofuran. In certain embodiments, Ring C is
unsubstituted benzoisofuran. In certain embodiments, Ring C is
substituted benzimidazole. In certain embodiments, Ring C is
unsubstituted benzimidazole. In certain embodiments, Ring C is
substituted benzoxazole. In certain embodiments, Ring C is
unsubstituted benzoxazole. In certain embodiments, Ring C is
substituted benzisoxazole. In certain embodiments, Ring C is
unsubstituted benzisoxazole. In certain embodiments, Ring C is
substituted benzothiazole. In certain embodiments, Ring C is
unsubstituted benzothiazole. In certain embodiments, Ring C is
substituted benzisothiazole. In certain embodiments, Ring C is
unsubstituted benzisothiazole. In certain embodiments, Ring C is
substituted benzotriazole. In certain embodiments, Ring C is
unsubstituted benzotriazole. In certain embodiments, Ring C is
substituted benzoxadiazole. In certain embodiments, Ring C is
unsubstituted benzoxadiazole. In certain embodiments, Ring C is
substituted quinoline. In certain embodiments, Ring C is
unsubstituted quinoline. In certain embodiments, Ring C is
substituted isoquinoline. In certain embodiments, Ring C is
unsubstituted isoquinoline. In certain embodiments, Ring C is
substituted cinnoline. In certain embodiments, Ring C is
unsubstituted cinnoline. In certain embodiments, Ring C is
substituted quinoxaline. In certain embodiments, Ring C is
unsubstituted quinoxaline. In certain embodiments, Ring C is
substituted phthalazine. In certain embodiments, Ring C is
unsubstituted phthalazine. In certain embodiments, Ring C is
substituted quinazoline. In certain embodiments, Ring C is
unsubstituted quinazoline.
[0239] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00095##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0240] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00096##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0241] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00097##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0242] In certain embodiments, Ring C is unsubstituted or
substituted with one or more R.sup.C. Substituent R.sup.C may be
attached to a carbon atom or heteroatom as valency permits. In
certain embodiments, Ring C is unsubstituted, and thus n is 0. In
certain embodiments, n is 1. In certain embodiments, n is 2. In
certain embodiments, n is 3. In certain embodiments, n is 4.
[0243] In certain embodiments, at least one R.sup.C is H. In
certain embodiments, at least one R.sup.C is halogen. In certain
embodiments, at least one R.sup.C is F. In certain embodiments, at
least one R.sup.C is Cl. In certain embodiments, at least one
R.sup.C is Br. In certain embodiments, at least one R.sup.C is I
(iodine). In certain embodiments, at least one R.sup.C is
substituted acyl. In certain embodiments, at least one R.sup.C is
unsubstituted acyl. In certain embodiments, at least one R.sup.C is
acetyl. In certain embodiments, at least one R.sup.C is substituted
alkyl. In certain embodiments, at least one R.sup.C is
unsubstituted alkyl. In certain embodiments, at least one R.sup.C
is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.C is
methyl. In certain embodiments, at least one R.sup.C is ethyl. In
certain embodiments, at least one R.sup.C is propyl. In certain
embodiments, at least one R.sup.C is butyl. In certain embodiments,
at least one R.sup.C is substituted alkenyl. In certain
embodiments, at least one R.sup.C is unsubstituted alkenyl. In
certain embodiments, at least one R.sup.C is substituted alkynyl.
In certain embodiments, at least one R.sup.C is unsubstituted
alkynyl. In certain embodiments, at least one R.sup.C is
substituted carbocyclyl. In certain embodiments, at least one
R.sup.C is unsubstituted carbocyclyl. In certain embodiments, at
least one R.sup.C is substituted heterocyclyl. In certain
embodiments, at least one R.sup.C is unsubstituted heterocyclyl. In
certain embodiments, at least one R.sup.C is substituted aryl. In
certain embodiments, at least one R.sup.C is unsubstituted aryl. In
certain embodiments, at least one R.sup.C is substituted phenyl. In
certain embodiments, at least one R.sup.C is unsubstituted phenyl.
In certain embodiments, at least one R.sup.C is substituted
heteroaryl. In certain embodiments, at least one R.sup.C is
unsubstituted heteroaryl. In certain embodiments, at least one
R.sup.C is substituted pyridyl. In certain embodiments, at least
one R.sup.C is unsubstituted pyridyl. In certain embodiments, at
least one R.sup.C is --OR.sup.C1. In certain embodiments, at least
one R.sup.C is --N(R.sup.C1).sub.2. In certain embodiments, at
least one R.sup.C is --SR.sup.C1. In certain embodiments, at least
one R.sup.C is --OH. In certain embodiments, at least one R.sup.C
is --NH.sub.2. In certain embodiments, at least one R.sup.C is
--SH.
[0244] In certain embodiments, when R.sup.C is --OR.sup.C1,
--N(R.sup.C1).sub.2, or --SR.sup.C1, at least one R.sup.C1 is H. In
certain embodiments, at least one R.sup.C1 is substituted acyl. In
certain embodiments, at least one R.sup.C1 is unsubstituted acyl.
In certain embodiments, at least one R.sup.C1 is acetyl. In certain
embodiments, at least one R.sup.C1 is substituted alkyl. In certain
embodiments, at least one R.sup.C1 is unsubstituted alkyl. In
certain embodiments, at least one R.sup.C1 is C.sub.1-6 alkyl. In
certain embodiments, at least one R.sup.C1 is methyl. In certain
embodiments, at least one R.sup.C1 is ethyl. In certain
embodiments, at least one R.sup.C1 is propyl. In certain
embodiments, at least one R.sup.C1 is butyl. In certain
embodiments, at least one R.sup.C1 is substituted alkenyl. In
certain embodiments, at least one R.sup.C1 is unsubstituted
alkenyl. In certain embodiments, at least one R.sup.C1 is
substituted alkynyl. In certain embodiments, at least one R.sup.C1
is unsubstituted alkynyl. In certain embodiments, at least one
R.sup.C1 is substituted carbocyclyl. In certain embodiments, at
least one R.sup.C1 is unsubstituted carbocyclyl. In certain
embodiments, at least one R.sup.C1 is substituted heterocyclyl. In
certain embodiments, at least one R.sup.C1 is unsubstituted
heterocyclyl. In certain embodiments, at least one R.sup.C1 is
substituted aryl. In certain embodiments, at least one R.sup.C1 is
unsubstituted aryl. In certain embodiments, at least one R.sup.C1
is substituted phenyl. In certain embodiments, at least one
R.sup.C1 is unsubstituted phenyl. In certain embodiments, at least
one R.sup.C1 is substituted heteroaryl. In certain embodiments, at
least one R.sup.C1 is unsubstituted heteroaryl. In certain
embodiments, at least one R.sup.C1 is substituted pyridyl. In
certain embodiments, at least one R.sup.C1 is unsubstituted
pyridyl. In certain embodiments, at least one R.sup.C1 is a
nitrogen protecting group when attached to a nitrogen atom. In
certain embodiments, at least one R.sup.C1 is an oxygen protecting
group when attached to an oxygen atom. In certain embodiments, at
least one R.sup.C1 is a sulfur protecting group when attached to a
sulfur atom. In certain embodiments, two R.sup.C1 groups are joined
to form a substituted heterocyclic ring. In certain embodiments,
two R.sup.C1 groups are joined to form an unsubstituted
heterocyclic ring.
[0245] In certain embodiments, R.sup.C is substituted C.sub.1-6
alkyl; and n is 1. In certain embodiments, R.sup.C is unsubstituted
C1-6 alkyl; and n is 1. In certain embodiments, R.sup.C is methyl;
and n is 1. In certain embodiments, R.sup.C is ethyl; and n is 1.
In certain embodiments, R.sup.C is propyl; and n is 1. In certain
embodiments, R.sup.C is butyl; and n is 1.
[0246] In certain embodiments, R.sup.C is halogen; and n is 1. In
certain embodiments, R.sup.C is F; and n is 1. In certain
embodiments, R.sup.C is C1; and n is 1. In certain embodiments,
R.sup.C is Br; and n is 1. In certain embodiments, R.sup.C is I
(iodine); and n is 1.
[0247] Linker L is a divalent linker moiety. L may contain 0-6
carbon atoms in the backbone of L. In certain embodiments, L
contains 0-4 carbon atoms in the backbone of L. In certain
embodiments, L contains 0-3 carbon atoms in the backbone of L. In
certain embodiments, L contains 0-2 carbon atoms in the backbone of
L. L may be saturated or unsaturated. L may be substituted or
unsubstituted. L may be branched or unbranched. In certain
embodiments, L is a bond directly connecting Ring C and R.sup.D. In
certain embodiments, L is a single bond. In certain embodiments, L
is a C.sub.1 hydrocarbon chain substituted with one or more R.sup.L
groups. In certain embodiments, L is --CH.sub.2--. In certain
embodiments, L is a C.sub.2 hydrocarbon chain substituted with one
or more R.sup.L groups. In certain embodiments, L is
--(CH.sub.2).sub.2--. In certain embodiments, L is
trans-CH.dbd.CH--. In certain embodiments, L is cis-CH.dbd.CH--. In
certain embodiments, L is --C--C--. In certain embodiments, L is a
C.sub.3 hydrocarbon chain substituted with one or more R.sup.L
groups. In certain embodiments, L is --(CH.sub.2).sub.3--. In
certain embodiments, L is a C.sub.4 hydrocarbon chain substituted
with one or more R.sup.L groups. In certain embodiments, L is
--(CH.sub.2).sub.4--. In certain embodiments, L is a C.sub.5
hydrocarbon chain substituted with one or more R.sup.L groups. In
certain embodiments, L is --(CH.sub.2).sub.5--. In certain
embodiments, L is a C.sub.6 hydrocarbon chain substituted with one
or more R.sup.L groups. In certain embodiments, L is
--(CH.sub.2).sub.6--. Each occurrence of R.sup.L is independently
selected from the group consisting of hydrogen, halogen, optionally
substituted acyl, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--CN, --C(.dbd.NR.sup.L1)R.sup.L1, --C(.dbd.NR.sup.L1)OR.sup.L1,
--C(.dbd.NR.sup.L1)SR.sup.L1, --C(.dbd.NR.sup.L1)N(R.sup.L1).sub.2,
--C(.dbd.S)R.sup.L1, --C(.dbd.S)OR.sup.L1, --C(.dbd.S)SR.sup.L1,
--C(.dbd.S)N(R.sup.L1).sub.2, --NO.sub.2, --N.sub.3,
--N(R.sup.L1).sub.3.sup.+F.sup.-,
--N(R.sup.L1).sub.3.sup.+Cl.sup.-,
--N(R.sup.L1).sub.3.sup.+Br.sup.-,
--N(R.sup.L1).sub.3.sup.+I.sup.-, --N(OR.sup.L1)R.sup.L1,
--NR.sup.L1C(.dbd.O)R.sup.L1, --NR.sup.L1C(.dbd.O)OR.sup.L1,
--NR.sup.L1C(.dbd.O)SR.sup.L1,
--NR.sup.L1C(.dbd.O)N(R.sup.L1).sub.2,
--NR.sup.L1C(.dbd.S)R.sup.L1, --NR.sup.L1C(.dbd.S)OR.sup.L1,
--NR.sup.L1C(.dbd.S)SR.sup.L1,
--NR.sup.L1C(.dbd.S)N(R.sup.L1).sub.2,
--NR.sup.L1C(.dbd.NR.sup.L1)R.sup.L1,
--NR.sup.L1C(.dbd.NR.sup.L1)OR.sup.L1, --NR.sup.L1
C(.dbd.NR.sup.L1)SR.sup.L1,
--NR.sup.L1C(.dbd.NR.sup.L1)N(R.sup.L1).sub.2, --NR.sup.L1
S(.dbd.O).sub.2R.sup.L1, --NR.sup.L1S(.dbd.O).sub.2OR.sup.L1,
--NR.sup.L1 S(.dbd.O).sub.2SR.sup.L1, --NR.sup.L1
S(.dbd.O).sub.2N(R.sup.L1).sub.2, --NR.sup.L1S(.dbd.O)R.sup.L1,
--NR.sup.L1S(.dbd.O)OR.sup.L1, --NR.sup.L1 S(.dbd.O)SR.sup.L1,
--NR.sup.L1S(.dbd.O)N(R.sup.L1).sub.2, --NR.sup.L1P(.dbd.O),
--NR.sup.L1P(.dbd.O).sub.2, --NR.sup.L1(.dbd.O)(R.sup.L1).sub.2,
NR.sup.L1P(.dbd.O)R.sup.L1(OR.sup.L1),
--NR.sup.L1P(.dbd.O)(OR.sup.L1).sub.2, --OC(.dbd.O)R.sup.L1,
--OC(.dbd.O)OR.sup.L1, --OC(.dbd.O)SR.sup.L1,
--OC(.dbd.O)N(R.sup.L1).sub.2, --OC(.dbd.NR.sup.L1)R.sup.L1,
--OC(.dbd.NR.sup.L1)OR.sup.L1,
--OC(.dbd.NR.sup.L1)N(R.sup.L1).sub.2, --OC(.dbd.S)R.sup.L1,
--OC(.dbd.S)OR.sup.L1, --OC(.dbd.S)SR.sup.L1,
--OC(.dbd.S)N(R.sup.L1).sub.2, --ON(R.sup.L1).sub.2,
--OS(.dbd.O)R.sup.L1, --OS(.dbd.O)OR.sup.L1, --OS(.dbd.O)SR.sup.L1,
--OS(.dbd.O)N(R.sup.L1).sub.2, --OS(.dbd.O).sub.2R.sup.L1,
--OS(.dbd.O).sub.2OR.sup.L1, --OS(.dbd.O).sub.2SR.sup.L1,
--OS(.dbd.O).sub.2N(R.sup.L1).sub.2, --OP(.dbd.O).sub.2,
--OP(.dbd.O)(R.sup.L1).sub.2, --OP(.dbd.O)R.sup.L1(OR.sup.L1),
--OP(.dbd.O)(OR.sup.L1).sub.2, --OP(.dbd.O), --OP(R.sup.L1).sub.2,
--OPR.sup.L1(OR.sup.L1), --OP(OR.sup.L1).sub.2,
--OSi(R.sup.L1).sub.3, --OSi(R.sup.L1).sub.2OR.sup.L1,
--OSi(R.sup.L1)(OR.sup.L1).sub.2, --OSi(OR.sup.L1).sub.3,
--SSR.sup.L1, --S(.dbd.O)R.sup.L1, --S(.dbd.O)OR.sup.L1,
--S(.dbd.O)N(R.sup.L1).sub.2, --S(.dbd.O).sub.2R.sup.L1,
--S(.dbd.O).sub.2OR.sup.L1, --S(.dbd.O).sub.2N(R.sup.L1).sub.2,
--SC(.dbd.O)R.sup.L1, --SC(.dbd.O)OR.sup.L1, --SC(.dbd.O)SR.sup.L1,
--SC(.dbd.O)N(R.sup.L1).sub.2, --SC(.dbd.S)R.sup.L1,
--SC(.dbd.S)OR.sup.L1, --SC(.dbd.S)SR.sup.L1,
--SC(.dbd.S)N(R.sup.L1).sub.2, --P(R.sup.L1).sub.2,
--PR.sup.L1(OR.sup.L1), --P(OR.sup.L1).sub.2, --P(.dbd.O),
--P(.dbd.O)(R.sup.L1).sub.2, --P(.dbd.O)(OR.sup.L1).sub.2,
--P(.dbd.O)R.sup.L1(OR.sup.L1), --P(.dbd.O).sub.2,
--B(R.sup.L1).sub.2, --B(OR.sup.L1).sub.2, --BR.sup.L1(OR.sup.L1),
--Si(R.sup.L1).sub.3, --Si(R.sup.L1).sub.2OR.sup.L1,
--SiR.sup.L1(OR.sup.L1).sub.2, and --Si(OR.sup.L1).sub.3, wherein
each occurrence of R.sup.L1 is independently selected from the
group consisting of hydrogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, a nitrogen protecting group when
attached to a nitrogen atom, an oxygen protecting group when
attached to an oxygen atom, a sulfur protecting group when attached
to a sulfur atom, or two R.sup.L1 groups are joined to form an
optionally substituted heterocyclic ring.
[0248] Each of R.sup.j1, R.sup.j2, R.sup.j3 is an independent
substituent on the double bond in Formula (II). In certain
embodiments, each of R.sup.j1, R.sup.j2, R.sup.j3 is independently
hydrogen or substituted C.sub.1-6 alkyl. In certain embodiments,
each of R.sup.j1, R.sup.j2, R.sup.j3 is independently hydrogen. In
certain embodiments, each of R.sup.j1, R.sup.j2, R.sup.j3 is
independently unsubstituted C1-6 alkyl. In certain embodiments,
each of R.sup.j1, R.sup.j2, R.sup.j3 is independently methyl,
ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments,
each of R.sup.j1, R.sup.j2, R.sup.j3 is independently halogen. In
certain embodiments, In certain embodiments, each of R.sup.j1,
R.sup.j2, R.sup.j3 is independently F. In certain embodiments, In
certain embodiments, each of R.sup.j1, R.sup.j2, R.sup.j3 is
independently Cl. In certain embodiments, each of R.sup.j1,
R.sup.j2, R.sup.j3 is independently Br. In certain embodiments,
each of R.sup.j1, R.sup.j2, R.sup.j3 is independently I.
[0249] As generally defined herein, R.sup.q is independently
hydrogen, halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
a nitrogen protecting group. In certain embodiments, R.sup.q is
hydrogen. In some embodiments, R.sup.q is optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, or optionally substituted carbocyclyl. In certain
embodiments, R.sup.q is optionally substituted C.sub.1-6 alkyl,
optionally substituted C.sub.2-6 alkenyl, optionally substituted
C.sub.2-6 alkynyl, or optionally substituted C.sub.3-6 carbocyclyl.
In certain embodiments, R.sup.q is optionally substituted C1-6
alkyl. In certain embodiments, R.sup.q is substituted C1-6 alkyl.
In certain embodiments, R.sup.q is unsubstituted C1-6 alkyl. In
certain embodiments, R.sup.q is methyl, ethyl, propyl, butyl,
pentyl, or hexyl. In certain embodiments, R.sup.q is isopropyl,
isobutyl, or isoamyl. In certain embodiments, R.sup.q is isobutyl.
In certain embodiments, R.sup.q is tert-butyl. In certain
embodiments, R.sup.q is a nitrogen protecting group.
[0250] R.sup.D is a substituent on Ring C through linker L. In
certain embodiments, R.sup.D includes a Michael acceptor moiety.
This Michael acceptor moiety may react with a cysteine residue of a
host factor to allow covalent attachment of the compound to the
host factor. In certain embodiments, the covalent attachment is
irreversible, and viral entry and/or infection is reduced. In
certain embodiments, the covalent attachment is reversible, and
viral entry and/or infection is reduced.
[0251] In certain embodiments, R.sup.D is a group selected from the
group consisting of:
##STR00098## ##STR00099## ##STR00100## ##STR00101##
##STR00102##
[0252] In certain embodiments, at least one R.sup.D1 is H. In
certain embodiments, at least one R.sup.D1 is halogen. In certain
embodiments, at least one R.sup.D1 is F. In certain embodiments, at
least one R.sup.D1 is Cl. In certain embodiments, at least one
R.sup.D1 is Br. In certain embodiments, at least one R.sup.D1 is I
(iodine). In certain embodiments, at least one R.sup.D1 is
substituted acyl. In certain embodiments, at least one R.sup.D1 is
unsubstituted acyl. In certain embodiments, at least one R.sup.D1
is acetyl. In certain embodiments, at least one R.sup.D1 is
substituted alkyl. In certain embodiments, at least one R.sup.D1 is
unsubstituted alkyl. In certain embodiments, at least one R.sup.D1
is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.D1
is methyl. In certain embodiments, at least one R.sup.D1 is ethyl.
In certain embodiments, at least one R.sup.D1 is propyl. In certain
embodiments, at least one R.sup.D1 is butyl. In certain
embodiments, at least one R.sup.D1 is substituted alkenyl. In
certain embodiments, at least one R.sup.D1 is unsubstituted
alkenyl. In certain embodiments, at least one R.sup.D1 is
substituted alkynyl. In certain embodiments, at least one R.sup.D1
is unsubstituted alkynyl. In certain embodiments, at least one
R.sup.D1 is substituted carbocyclyl. In certain embodiments, at
least one R.sup.D1 is unsubstituted carbocyclyl. In certain
embodiments, at least one R.sup.D1 is substituted heterocyclyl. In
certain embodiments, at least one R.sup.D1 is unsubstituted
heterocyclyl. In certain embodiments, at least one R.sup.D1 is
substituted aryl. In certain embodiments, at least one R.sup.D1 is
unsubstituted aryl. In certain embodiments, at least one R.sup.D1
is substituted phenyl. In certain embodiments, at least one
R.sup.D1 is unsubstituted phenyl. In certain embodiments, at least
one R.sup.D1 is substituted heteroaryl. In certain embodiments, at
least one R.sup.D1 is unsubstituted heteroaryl. In certain
embodiments, at least one R.sup.D1 is substituted pyridyl. In
certain embodiments, at least one R.sup.D1 is unsubstituted
pyridyl. In certain embodiments, at least one R.sup.D1 is
--OR.sup.D1a. In certain embodiments, at least one R.sup.D1 is
--N(R.sup.D1a).sub.2. In certain embodiments, at least one R.sup.D1
is --SR.sup.D1aIn certain embodiments, at least one R.sup.D1 is
--OH. In certain embodiments, at least one R.sup.D1 is --NH.sub.2.
In certain embodiments, at least one R.sup.D1 is --SH. In certain
embodiments, at least one R.sup.D1 is --CH.sub.2OR.sup.D1a. In
certain embodiments, at least one R.sup.D1 is
--CH.sub.2N(R.sup.D1a).sub.2. In certain embodiments, at least one
R.sup.D1 is --CH.sub.2SR.sup.D1a. In certain embodiments, at least
one R.sup.D1 is --CH.sub.2OH. In certain embodiments, at least one
R.sup.D1 is --CH.sub.2NH.sub.2. In certain embodiments, at least
one R.sup.D1 is --CH.sub.2SH.
[0253] In certain embodiments, at least one R.sup.D1a is H. In
certain embodiments, at least one R.sup.D1a is substituted acyl. In
certain embodiments, at least one R.sup.D1a is unsubstituted acyl.
In certain embodiments, at least one R.sup.D1a is acetyl. In
certain embodiments, at least one R.sup.D1a is substituted alkyl.
In certain embodiments, at least one R.sup.D1a is unsubstituted
alkyl. In certain embodiments, at least one R.sup.D1a is C.sub.1-6
alkyl. In certain embodiments, at least one R.sup.D1a is methyl. In
certain embodiments, at least one R.sup.D1a is ethyl. In certain
embodiments, at least one R.sup.D1a is propyl. In certain
embodiments, at least one R.sup.D1a is butyl. In certain
embodiments, at least one R.sup.D1a is substituted alkenyl. In
certain embodiments, at least one R.sup.D1a is unsubstituted
alkenyl. In certain embodiments, at least one R.sup.D1a is
substituted alkynyl. In certain embodiments, at least one R.sup.D1a
is unsubstituted alkynyl. In certain embodiments, at least one
R.sup.D1a is substituted carbocyclyl. In certain embodiments, at
least one R.sup.D1a is unsubstituted carbocyclyl. In certain
embodiments, at least one R.sup.D1a is substituted heterocyclyl. In
certain embodiments, at least one R.sup.D1a is unsubstituted
heterocyclyl. In certain embodiments, at least one R.sup.D1a is
substituted aryl. In certain embodiments, at least one R.sup.D1a is
unsubstituted aryl. In certain embodiments, at least one R.sup.D1a
is substituted phenyl. In certain embodiments, at least one
R.sup.D1a is unsubstituted phenyl. In certain embodiments, at least
one R.sup.D1a is substituted heteroaryl. In certain embodiments, at
least one R.sup.D1a is unsubstituted heteroaryl. In certain
embodiments, at least one R.sup.D1a is substituted pyridyl. In
certain embodiments, at least one R.sup.D1a is unsubstituted
pyridyl. In certain embodiments, at least one R.sup.D1a is a
nitrogen protecting group when attached to a nitrogen atom. In
certain embodiments, at least one R.sup.D1a is an oxygen protecting
group when attached to an oxygen atom. In certain embodiments, at
least one R.sup.D1a is a sulfur protecting group when attached to a
sulfur atom. In certain embodiments, two R.sup.D1a groups are
joined to form a substituted heterocyclic ring. In certain
embodiments, two R.sup.D1a groups are joined to form an
unsubstituted heterocyclic ring.
[0254] In certain embodiments, at least one R.sup.D2 is H. In
certain embodiments, at least one R.sup.D2 is halogen. In certain
embodiments, at least one R.sup.D2 is F. In certain embodiments, at
least one R.sup.D2 is Cl. In certain embodiments, at least one
R.sup.D2 is Br. In certain embodiments, at least one R.sup.D2 is I
(iodine). In certain embodiments, at least one R.sup.D2 is
substituted acyl. In certain embodiments, at least one R.sup.D2 is
unsubstituted acyl. In certain embodiments, at least one R.sup.D2
is acetyl. In certain embodiments, at least one R.sup.D2 is
substituted alkyl. In certain embodiments, at least one R.sup.D2 is
unsubstituted alkyl. In certain embodiments, at least one R.sup.D2
is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.D2
is methyl. In certain embodiments, at least one R.sup.D2 is ethyl.
In certain embodiments, at least one R.sup.D2 is propyl. In certain
embodiments, at least one R.sup.D2 is butyl. In certain
embodiments, at least one R.sup.D2 is substituted alkenyl. In
certain embodiments, at least one R.sup.D2 is unsubstituted
alkenyl. In certain embodiments, at least one R.sup.D2 is
substituted alkynyl. In certain embodiments, at least one R.sup.D2
is unsubstituted alkynyl. In certain embodiments, at least one
R.sup.D2 is substituted carbocyclyl. In certain embodiments, at
least one R.sup.D2 is unsubstituted carbocyclyl. In certain
embodiments, at least one R.sup.D2 is substituted heterocyclyl. In
certain embodiments, at least one R.sup.D2 is unsubstituted
heterocyclyl. In certain embodiments, at least one R.sup.D2 is
substituted aryl. In certain embodiments, at least one R.sup.D2 is
unsubstituted aryl. In certain embodiments, at least one R.sup.D2
is substituted phenyl. In certain embodiments, at least one
R.sup.D2 is unsubstituted phenyl. In certain embodiments, at least
one R.sup.D2 is substituted heteroaryl. In certain embodiments, at
least one R.sup.D2 is unsubstituted heteroaryl. In certain
embodiments, at least one R.sup.D2 is substituted pyridyl. In
certain embodiments, at least one R.sup.D2 is unsubstituted
pyridyl. In certain embodiments, at least one R.sup.D2 is
--OR.sup.D2a. In certain embodiments, at least one R.sup.D2 is
--N(R.sup.D2a).sub.2. In certain embodiments, at least one R.sup.D2
is --SR.sup.D2a. In certain embodiments, at least one R.sup.D2 is
--OH. In certain embodiments, at least one R.sup.D2 is --NH.sub.2.
In certain embodiments, at least one R.sup.D2 is --SH. In certain
embodiments, at least one R.sup.D2 is --CH.sub.2OR.sup.D2a. In
certain embodiments, at least one R.sup.D2 is
--CH.sub.2N(R.sup.D2a).sub.2. In certain embodiments, at least one
R.sup.D2 is --CH.sub.2SR.sup.D1a. In certain embodiments, at least
one R.sup.D2 is --CH.sub.2OH. In certain embodiments, at least one
R.sup.D2 is --CH.sub.2NH.sub.2. In certain embodiments, at least
one R.sup.D2 is --CH.sub.2SH.
[0255] In certain embodiments, at least one R.sup.D2a is H. In
certain embodiments, at least one R.sup.D2a is substituted acyl. In
certain embodiments, at least one R.sup.D2a is unsubstituted acyl.
In certain embodiments, at least one R.sup.D2a is acetyl. In
certain embodiments, at least one R.sup.D2a is substituted alkyl.
In certain embodiments, at least one R.sup.D2a is unsubstituted
alkyl. In certain embodiments, at least one R.sup.D2a is C.sub.1-6
alkyl. In certain embodiments, at least one R.sup.D2a is methyl. In
certain embodiments, at least one R.sup.D2a is ethyl. In certain
embodiments, at least one R.sup.D2a is propyl. In certain
embodiments, at least one R.sup.D2a is butyl. In certain
embodiments, at least one R.sup.D2a is substituted alkenyl. In
certain embodiments, at least one R.sup.D2a is unsubstituted
alkenyl. In certain embodiments, at least one R.sup.D2a is
substituted alkynyl. In certain embodiments, at least one R.sup.D2a
is unsubstituted alkynyl. In certain embodiments, at least one
R.sup.D2a is substituted carbocyclyl. In certain embodiments, at
least one R.sup.D2a is unsubstituted carbocyclyl. In certain
embodiments, at least one R.sup.D2a is substituted heterocyclyl. In
certain embodiments, at least one R.sup.D2a is unsubstituted
heterocyclyl. In certain embodiments, at least one R.sup.D2a is
substituted aryl. In certain embodiments, at least one R.sup.D2a is
unsubstituted aryl. In certain embodiments, at least one R.sup.D2a
is substituted phenyl. In certain embodiments, at least one
R.sup.D2a is unsubstituted phenyl. In certain embodiments, at least
one R.sup.D2a is substituted heteroaryl. In certain embodiments, at
least one R.sup.D2a is unsubstituted heteroaryl. In certain
embodiments, at least one R.sup.D2a is substituted pyridyl. In
certain embodiments, at least one R.sup.D2a is unsubstituted
pyridyl. In certain embodiments, at least one R.sup.D2a is a
nitrogen protecting group when attached to a nitrogen atom. In
certain embodiments, at least one R.sup.D2a is an oxygen protecting
group when attached to an oxygen atom. In certain embodiments, at
least one R.sup.D2a is a sulfur protecting group when attached to a
sulfur atom. In certain embodiments, two R.sup.D2a groups are
joined to form a substituted heterocyclic ring. In certain
embodiments, two R.sup.D2a groups are joined to form an
unsubstituted heterocyclic ring.
[0256] In certain embodiments, at least one R.sup.D3 is H. In
certain embodiments, at least one R.sup.D3 is halogen. In certain
embodiments, at least one R.sup.D3 is F. In certain embodiments, at
least one R.sup.D3 is Cl. In certain embodiments, at least one
R.sup.D3 is Br. In certain embodiments, at least one R.sup.D3 is I
(iodine). In certain embodiments, at least one R.sup.D3 is
substituted acyl. In certain embodiments, at least one R.sup.D3 is
unsubstituted acyl. In certain embodiments, at least one R.sup.D3
is acetyl. In certain embodiments, at least one R.sup.D3 is
substituted alkyl. In certain embodiments, at least one R.sup.D3 is
unsubstituted alkyl. In certain embodiments, at least one R.sup.D3
is C.sub.1-6 alkyl. In certain embodiments, at least one R.sup.D3
is methyl. In certain embodiments, at least one R.sup.D3 is ethyl.
In certain embodiments, at least one R.sup.D3 is propyl. In certain
embodiments, at least one R.sup.D3 is butyl. In certain
embodiments, at least one R.sup.D3 is substituted alkenyl. In
certain embodiments, at least one R.sup.D3 is unsubstituted
alkenyl. In certain embodiments, at least one R.sup.D3 is
substituted alkynyl. In certain embodiments, at least one R.sup.D3
is unsubstituted alkynyl. In certain embodiments, at least one
R.sup.D3 is substituted carbocyclyl. In certain embodiments, at
least one R.sup.D3 is unsubstituted carbocyclyl. In certain
embodiments, at least one R.sup.D3 is substituted heterocyclyl. In
certain embodiments, at least one R.sup.D3 is unsubstituted
heterocyclyl. In certain embodiments, at least one R.sup.D3 is
substituted aryl. In certain embodiments, at least one R.sup.D3 is
unsubstituted aryl. In certain embodiments, at least one R.sup.D3
is substituted phenyl. In certain embodiments, at least one
R.sup.D3 is unsubstituted phenyl. In certain embodiments, at least
one R.sup.D3 is substituted heteroaryl. In certain embodiments, at
least one R.sup.D3 is unsubstituted heteroaryl. In certain
embodiments, at least one R.sup.D3 is substituted pyridyl. In
certain embodiments, at least one R.sup.D3 is unsubstituted
pyridyl. In certain embodiments, at least one R.sup.D3 is
--OR.sup.D3a. In certain embodiments, at least one R.sup.D3 is
--N(R.sup.D3a).sub.2. In certain embodiments, at least one R.sup.D3
is --SR.sup.D3a. In certain embodiments, at least one R.sup.D is
--OH. In certain embodiments, at least one R.sup.D3 is --NH.sub.2.
In certain embodiments, at least one R.sup.D3 is --SH. In certain
embodiments, at least one R.sup.D3 is --CH.sub.2OR.sup.D3a. In
certain embodiments, at least one R.sup.D is
--CH.sub.2N(R.sup.D3a).sub.2. In certain embodiments, at least one
R.sup.D3 is --CH.sub.2SR.sup.D3a. In certain embodiments, at least
one R.sup.D3 is --CH.sub.2OH. In certain embodiments, at least one
R.sup.D3 is --CH.sub.2NH.sub.2. In certain embodiments, at least
one R.sup.D3 is --CH.sub.2SH.
[0257] In certain embodiments, at least one R.sup.D3a is H. In
certain embodiments, at least one R.sup.D3a is substituted acyl. In
certain embodiments, at least one R.sup.D3a is unsubstituted acyl.
In certain embodiments, at least one R.sup.D3a is acetyl. In
certain embodiments, at least one R.sup.D3a is substituted alkyl.
In certain embodiments, at least one R.sup.D3a is unsubstituted
alkyl. In certain embodiments, at least one R.sup.D3a is C.sub.1-6
alkyl. In certain embodiments, at least one R.sup.D3a is methyl. In
certain embodiments, at least one R.sup.D3a is ethyl. In certain
embodiments, at least one R.sup.D3a is propyl. In certain
embodiments, at least one R.sup.D3a is butyl. In certain
embodiments, at least one R.sup.D3a is substituted alkenyl. In
certain embodiments, at least one R.sup.D3a is unsubstituted
alkenyl. In certain embodiments, at least one R.sup.D3a is
substituted alkynyl. In certain embodiments, at least one R.sup.D3a
is unsubstituted alkynyl. In certain embodiments, at least one
R.sup.D3a is substituted carbocyclyl. In certain embodiments, at
least one R.sup.D3a is unsubstituted carbocyclyl. In certain
embodiments, at least one R.sup.D3a is substituted heterocyclyl. In
certain embodiments, at least one R.sup.D3a is unsubstituted
heterocyclyl. In certain embodiments, at least one R.sup.D3a is
substituted aryl. In certain embodiments, at least one R.sup.D3a is
unsubstituted aryl. In certain embodiments, at least one R.sup.D3a
is substituted phenyl. In certain embodiments, at least one
R.sup.D3a is unsubstituted phenyl. In certain embodiments, at least
one R.sup.D3a is substituted heteroaryl. In certain embodiments, at
least one R.sup.D3a is unsubstituted heteroaryl. In certain
embodiments, at least one R.sup.D3a is substituted pyridyl. In
certain embodiments, at least one R.sup.D3a is unsubstituted
pyridyl. In certain embodiments, at least one R.sup.D3a is a
nitrogen protecting group when attached to a nitrogen atom. In
certain embodiments, at least one R.sup.D3a is an oxygen protecting
group when attached to an oxygen atom. In certain embodiments, at
least one R.sup.D3a is a sulfur protecting group when attached to a
sulfur atom. In certain embodiments, two R.sup.D3a groups are
joined to form a substituted heterocyclic ring. In certain
embodiments, two R.sup.D3a groups are joined to form an
unsubstituted heterocyclic ring.
[0258] In certain embodiments, R.sup.m is a leaving group. In
certain embodiments, R.sup.D4 is Cl. In certain embodiments,
R.sup.D4 is Br. In certain embodiments, R.sup.D4 is I (iodine). In
certain embodiments, R.sup.D4 is --OS(.dbd.O).sub.wR.sup.D4a. In
certain embodiments, R.sup.D4 is --OMs. In certain embodiments,
R.sup.D4 is --OTf. In certain embodiments, R.sup.D4 is --OTs.
[0259] In certain embodiments, w is 1. In certain embodiments, w is
2.
[0260] In certain embodiments, R.sup.D4a is substituted alkyl. In
certain embodiments, R.sup.D4a is unsubstituted alkyl. In certain
embodiments, R.sup.D4a is substituted alkenyl. In certain
embodiments, R.sup.D4a is unsubstituted alkenyl. In certain
embodiments, R.sup.D4a is substituted alkynyl. In certain
embodiments, R.sup.D4a is unsubstituted alkynyl. In certain
embodiments, R.sup.D4a is substituted carbocyclyl. In certain
embodiments, R.sup.D4a is unsubstituted carbocyclyl. In certain
embodiments, R.sup.D4a is substituted heterocyclyl. In certain
embodiments, R.sup.D4a is unsubstituted heterocyclyl. In certain
embodiments, R.sup.D4a is substituted aryl. In certain embodiments,
R.sup.D4a is unsubstituted aryl. In certain embodiments, R.sup.D4a
is substituted heteroaryl. In certain embodiments, R.sup.D4a is
unsubstituted heteroaryl.
[0261] In certain embodiments, R.sup.D5 is H. In certain
embodiments, R.sup.D5 is substituted alkyl. In certain embodiments,
R.sup.D5 is unsubstituted alkyl. In certain embodiments, R.sup.D5
is C.sub.1-6 alkyl. In certain embodiments, R.sup.D5 is methyl. In
certain embodiments, R.sup.D5 is ethyl. In certain embodiments,
R.sup.D5 is propyl. In certain embodiments, R.sup.D5 is butyl. In
certain embodiments, R.sup.D5 is a nitrogen protecting group. In
certain embodiments, R.sup.D5 is BOC. In certain embodiments,
R.sup.D5 is Cbz. In certain embodiments, R.sup.D5 is Fmoc. In
certain embodiments, R.sup.D5 is Bn.
[0262] In certain embodiments, a is 1. In certain embodiments, a is
2.
[0263] In certain embodiments, Y is --O--. In certain embodiments,
Y is .dbd.O. In certain embodiments, Y is --S--. In certain
embodiments, Y is .dbd.S. In certain embodiments, Y is
--NR.sup.D6-, wherein R.sup.D6 is hydrogen, C.sub.1-6 alkyl, or a
nitrogen protecting group. In certain embodiments, Y is --NH--. In
certain embodiments, Y is --NCH.sub.3--. In certain embodiments, Y
is --N(BOC)--. In certain embodiments, Y is --N(Fmoc)-. In certain
embodiments, Y is --N(Cbz)-. In certain embodiments, Y is --N(Bn)-.
In certain embodiments, Y is .dbd.NR.sup.D6, wherein R.sup.D6 is
hydrogen, C.sub.1-6 alkyl, or a nitrogen protecting group. In
certain embodiments, Y is .dbd.NH. In certain embodiments, Y is
.dbd.NCH.sub.3. In certain embodiments, Y is =NTs. In certain
embodiments, Y is =NBn. In certain embodiments, Y is
.dbd.NCH(Ph).sub.2.
[0264] As used herein, each of z and z1 is independently 0, 1, 2,
3, 4, 5, or 6, as valency permits. In certain embodiments, z is 0.
In certain embodiments, z is 1. In certain embodiments, z is 2. In
certain embodiments, z is 3. In certain embodiments, z is 4. In
certain embodiments, z is 5. In certain embodiments, z is 6. In
certain embodiments, z1 is 0. In certain embodiments, z1 is 1. In
certain embodiments, z1 is 2. In certain embodiments, z1 is 3. In
certain embodiments, z1 is 4. In certain embodiments, z1 is 5. In
certain embodiments, z1 is 6.
[0265] In certain embodiments, R.sup.D is
##STR00103##
[0266] In certain embodiments, R.sup.D is
##STR00104##
[0267] In certain embodiments, R.sup.D is
##STR00105##
[0268] In certain embodiments, R.sup.D is
##STR00106##
[0269] In certain embodiments, R.sup.D is
##STR00107##
[0270] In certain embodiments, R.sup.D is
##STR00108##
[0271] In certain embodiments, R.sup.D is
##STR00109##
[0272] In certain embodiments, R.sup.D is
##STR00110##
[0273] In certain embodiments, R.sup.D is
##STR00111##
[0274] In certain embodiments, R.sup.D is
##STR00112##
[0275] In certain embodiments, R.sup.D is
##STR00113##
[0276] In certain embodiments, R.sup.D is
##STR00114##
[0277] In certain embodiments, R.sup.D is
##STR00115##
[0278] In certain embodiments, R.sup.D is
##STR00116##
[0279] In certain embodiments, R.sup.D is
##STR00117##
[0280] In certain embodiments, R.sup.D is
##STR00118##
[0281] In certain embodiments, R.sup.D is
##STR00119##
[0282] In certain embodiments, R.sup.D is
##STR00120##
[0283] In certain embodiments, R.sup.D is
##STR00121##
[0284] In certain embodiments, R.sup.D is
##STR00122##
[0285] In certain embodiments, R.sup.D is
##STR00123##
[0286] In certain embodiments, R.sup.D is
##STR00124##
[0287] In certain embodiments, R.sup.D is
##STR00125##
[0288] In certain embodiments, R.sup.D is
##STR00126##
[0289] In certain embodiments, R.sup.D is
##STR00127##
[0290] In certain embodiments, R.sup.D is
##STR00128##
[0291] In certain embodiments, R.sup.D is
##STR00129##
[0292] In certain embodiments, R.sup.D is a group of Formula (i-1),
(i-3), or (i-20):
##STR00130##
wherein each instance of X.sup.1 is bond or NR.sup.D5, Y is
independently O, S, or NR.sup.D6, and R.sup.D1, R.sup.D2, and
R.sup.D3 are as defined herein. In certain embodiments, X.sup.1 is
a bond. In certain embodiments, X.sup.1 is NR.sup.D5. In certain
embodiments, Y is O. In certain embodiments, R.sup.D1 is hydrogen.
In certain embodiments, R.sup.D1 is --CN. In certain embodiments,
R.sup.D2 is hydrogen. In certain embodiments, R.sup.D3 is hydrogen.
In certain embodiments, R.sup.D2 is --CH.sub.2N(R.sup.D2a).sub.2,
and R.sup.D3 is hydrogen. In certain embodiments, R.sup.D2 is
--CH.sub.2N(R.sup.D3a).sub.2, and R.sup.D3 is hydrogen. In certain
embodiments, R.sup.D2 and R.sup.D3 are hydrogen. In certain
embodiments, R.sup.D1, R.sup.D2 and R.sup.D3 are hydrogen.
[0293] In certain embodiments, R.sup.D is a group of Formula
(i-19), (i-17), or (i-18):
##STR00131##
wherein Y is independently O, S, or NR.sup.D6; and R.sup.D1,
R.sup.D2, and R.sup.D3 are as defined herein. In certain
embodiments, Y is O. In certain embodiments, R.sup.D1 is hydrogen.
In certain embodiments, R.sup.D2 is hydrogen. In certain
embodiments, R.sup.D2 is --CN. In certain embodiments, R.sup.D3 is
substituted or unsubstituted alkyl.
[0294] In certain embodiments, R.sup.D is a group of Formula (i-7)
or (i-8):
##STR00132##
wherein Y is independently O, S, or NR.sup.D6; and R.sup.D1,
R.sup.D2, and R.sup.D3 are as defined herein. In certain
embodiments, Y is O. In certain embodiments, R.sup.D1 is hydrogen.
In certain embodiments, R.sup.D2 is hydrogen. In certain
embodiments, R.sup.D3 is hydrogen.
[0295] In certain embodiments, R.sup.D is a group of Formula (i-13)
or (i-14):
##STR00133##
wherein each instance of X.sup.1 is bond or NR.sup.D5; Y is
independently O, S, or NR.sup.D6; and R.sup.D1 and R.sup.D2 are as
defined herein. In certain embodiments, X.sup.1 is a bond. In
certain embodiments, X.sup.1 is NR.sup.D5. In certain embodiments,
Y is O. In certain embodiments, R.sup.D1 is hydrogen. In certain
embodiments, R.sup.D1 is halogen, e.g., --F or --Cl. In certain
embodiments, R.sup.D2 is hydrogen. In certain embodiments, R.sup.D2
is halogen, e.g., --F or --Cl.
[0296] In certain embodiments, R.sup.D is a group of Formula (i-11)
or (i-12):
##STR00134##
wherein each instance of X.sup.1 is bond or NR.sup.D5; Y is
independently O, S, or NR.sup.D6; z is 0, 1, 2, 3, 4, 5, or 6; and
R.sup.D1 is as defined herein. In certain embodiments, X.sup.1 is a
bond. In certain embodiments, X.sup.1 is NR.sup.D5. In certain
embodiments, Y is O. In certain embodiments z is 0 or 1. In certain
embodiments, R.sup.D1 is substituted or unsubstituted alkyl.
[0297] In certain embodiments, R.sup.D is a group of Formula
(i-10), (i-16), or (i-9):
##STR00135##
wherein each instance of X.sup.1 is bond or NR.sup.D5; Y is
independently O, S, or NR.sup.D6; z is 0, 1, 2, 3, 4, 5, or 6; and
R.sup.D4 is a leaving group selected from the group consisting of
--Br, --Cl, --I, and --OS(.dbd.O).sub.wR.sup.D4a, wherein w is 1 or
2. In certain embodiments, X.sup.1 is a bond. In certain
embodiments, X.sup.1 is NR.sup.D5. In certain embodiments, Y is O.
In certain embodiments, z is 0. In certain embodiments, z is 1.
[0298] In certain embodiments, R.sup.D is a group of Formula (i-4)
or (i-5):
##STR00136##
wherein each instance of X.sup.1 is bond or NR.sup.D5; and R.sup.D1
is as defined herein. In certain embodiments, X.sup.1 is a bond. In
certain embodiments, X.sup.1 is NR.sup.D5. In certain embodiments,
R.sup.D1 is hydrogen.
[0299] In certain embodiments, R.sup.D is a group of Formula
(i-6):
##STR00137##
wherein each instance of X.sup.1 is bond or NR.sup.D5; Y is
independently O, S, or NR.sup.D6; and R.sup.D1 is as defined
herein. In certain embodiments, X.sup.1 is a bond. In certain
embodiments, X.sup.1 is NR.sup.D5. In certain embodiments, Y is O.
In certain embodiments, R.sup.D1 is hydrogen.
[0300] In certain embodiments, R.sup.D is a group of Formula
(i-21)-(i-32), (i-39) and (i-40), wherein each instance of X.sup.1
is independently a bond, --C(.dbd.O)--, --SO.sub.2--, --NR.sup.D5,
optionally substituted alkylene, or optionally substituted
heteroarylene, wherein R.sup.D5 is hydrogen, C.sub.1-6 alkyl, or a
nitrogen protecting group; Y is independently O, S, or NR.sup.D6;
and R.sup.D1, R.sup.D2, and R.sup.D3 are as defined herein. In
certain embodiments, X.sup.1 is a bond. In certain embodiments,
X.sup.1 is --C(.dbd.O)--. In certain embodiments, X.sup.1 is
--SO.sub.2--. In certain embodiments, X.sup.1 is --NR.sup.D5. In
certain embodiments, X.sup.1 is optionally substituted alkylene. In
certain embodiments, X.sup.1 is substituted alkylene. In certain
embodiments, X.sup.1 is unsubstituted alkylene. In certain
embodiments, Y is O. In certain embodiments, Y is S. In certain
embodiments, Y is NR.sup.D6. In certain embodiments, R.sup.D1 is
hydrogen. In certain embodiments, R.sup.D2 is hydrogen. In certain
embodiments, R.sup.D2 is --CN. In certain embodiments, R.sup.D3 is
substituted or unsubstituted alkyl.
[0301] In certain embodiments, R.sup.D is a group of Formulae
(i-33) and (i-36)-(i-38), wherein each instance of X.sup.1 is
independently a bond, --C(.dbd.O)--, --SO.sub.2--, --NR.sup.D,
optionally substituted alkylene, or optionally substituted
heteroarylene, wherein R.sup.D5 is hydrogen, C.sub.1-6 alkyl, or a
nitrogen protecting group; and R.sup.D1 is as defined herein. In
certain embodiments, X.sup.1 is optionally substituted
heteroarylene. In certain embodiments, X.sup.1 is optionally
substituted heteroarylene. In certain embodiments, X.sup.1 is
optionally substituted five-membered heteroarylene. In certain
embodiments, X.sup.1 is optionally substituted five-membered
heteroarylene with at least one S, O, and N. In certain
embodiments, X.sup.1 is optionally substituted six-membered
heteroarylene. In certain embodiments, X.sup.1 is optionally
substituted six-membered heteroarylene with at least one S, O, and
N.
[0302] In certain embodiments, R.sup.D is a group of Formula
(i-34), wherein each instance of z and R.sup.D1 are as defined
herein. In certain embodiments, R.sup.D1 is halogen. In certain
embodiments, R.sup.D1 is F. In certain embodiments, R.sup.D1 is Cl.
In certain embodiments, R.sup.D1 is Br. In certain embodiments,
R.sup.D1 is I In certain embodiments, R.sup.D1 is CN. In certain
embodiments, R.sup.D1 is NO.sub.2.
[0303] In certain embodiments, R.sup.D is
##STR00138##
In certain embodiments, R.sup.D is
##STR00139##
In certain embodiments, R.sup.D is
##STR00140##
In certain embodiments, R.sup.D is
##STR00141##
[0304] In certain embodiments, R.sup.D is selected from one of the
following formulae:
##STR00142## ##STR00143## ##STR00144## ##STR00145##
[0305] In certain embodiments, the invention provides intermediates
of formulae (a)-(c) or salts thereof to prepare formulae (I)-(III),
wherein R.sup.D, L, Ring C, R.sup.C, n, R.sup.j1, R.sup.j2,
R.sup.j3, R.sup.q are as defined above; and M is halogen. In
certain embodiments, M is F. In certain embodiments, M is Cl. In
certain embodiments, M is Br. In certain embodiments, M is I.
##STR00146##
[0306] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00147##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0307] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00148##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0308] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00149##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0309] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00150##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0310] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00151##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0311] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00152## ##STR00153##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0312] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00154##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0313] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00155##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0314] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00156##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0315] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00157##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0316] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00158##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0317] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00159## ##STR00160##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0318] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00161##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0319] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00162##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0320] R.sup.D5 and one R.sup.C may be joined to form a substituted
heteroaryl ring. R.sup.D5 and one R.sup.C, may also be joined to
form an unsubstituted heteroaryl ring. In certain embodiments,
R.sup.D5 and one R.sup.C are joined to form a substituted
7-membered heteroaryl ring. In certain embodiments, R.sup.D5 and
one R.sup.C are joined to form an unsubstituted 7-membered
heteroaryl ring. In certain embodiments, R.sup.D5 and one R.sup.C
are joined to form a substituted 5-membered heteroaryl ring. In
certain embodiments, R.sup.D5 and one R.sup.C are joined to form an
unsubstituted 5-membered heteroaryl ring.
[0321] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00163##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0322] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00164##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0323] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00165##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0324] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00166##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0325] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00167##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0326] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00168##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0327] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00169##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, and prodrug thereof.
[0328] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00170##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0329] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00171##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0330] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00172##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0331] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00173##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0332] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00174##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0333] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00175##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0334] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00176##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0335] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00177##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0336] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00178##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0337] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00179##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0338] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00180##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0339] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00181##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0340] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00182##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0341] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00183##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0342] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00184##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0343] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00185##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0344] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00186##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0345] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00187##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0346] R.sup.D5 and one R.sup.C may be joined to form a substituted
heterocyclic ring. R.sup.D5 and one R.sup.C, may also be joined to
form an unsubstituted heterocyclic ring. In certain embodiments,
R.sup.D5 and one R.sup.C are joined to form a substituted
6-membered heterocyclic ring. In certain embodiments, R.sup.D5 and
one R.sup.C are joined to form an unsubstituted 6-membered
heterocyclic ring.
[0347] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00188##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0348] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00189##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0349] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00190##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0350] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00191##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0351] R.sup.D5 and one R.sup.C may be joined to form a substituted
or unsubstituted 5-membered heterocyclic ring.
[0352] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00192##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0353] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00193##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0354] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00194##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0355] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00195##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0356] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00196##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0357] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00197##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0358] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00198##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0359] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00199##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0360] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00200##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0361] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00201##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0362] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00202##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0363] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00203##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0364] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00204##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0365] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00205##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0366] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00206##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0367] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00207##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0368] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00208##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0369] In certain embodiments, the compound of Formula (I) is of
formula:
##STR00209##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0370] In certain embodiments, the compound of Formula (II) is of
formula: [0371] (QL-XII-47), or a pharmaceutically acceptable salt,
solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer,
isotopically labeled derivative, or prodrug thereof.
Pharmaceutical Compositions, Kits, and Administration
[0372] The present invention provides pharmaceutical compositions
comprising a compound of the present invention, e.g., a compound of
Formula (I), and pharmaceutically acceptable salts, solvates,
hydrates, polymorphs, co-crystals, tautomers, stereoisomers,
isotopically labeled derivatives, and prodrugs thereof, as
described herein, and optionally a pharmaceutically acceptable
excipient. In certain embodiments, the compound of the present
invention, or a pharmaceutically acceptable salt thereof, is
provided in an effective amount in the pharmaceutical composition.
In certain embodiments, the effective amount is a therapeutically
effective amount. In certain embodiments, the effective amount is a
prophylactically effective amount.
[0373] Pharmaceutical compositions described herein can be prepared
by any method known in the art of pharmacology. In general, such
preparatory methods include the steps of bringing the compound of
the present invention (the "active ingredient") into association
with a carrier or excipient, and/or one or more other accessory
ingredients, and then, if necessary and/or desirable, shaping,
and/or packaging the product into a desired single- or multi-dose
unit.
[0374] Pharmaceutical compositions can be prepared, packaged,
and/or sold in bulk, as a single unit dose, and/or as a plurality
of single unit doses. As used herein, a "unit dose" is a discrete
amount of the pharmaceutical composition comprising a predetermined
amount of the active ingredient. The amount of the active
ingredient is generally equal to the dosage of the active
ingredient which would be administered to a subject and/or a
convenient fraction of such a dosage such as, for example, one-half
or one-third of such a dosage.
[0375] Relative amounts of the active ingredient, the
pharmaceutically acceptable excipient, and/or any additional
ingredients in a pharmaceutical composition of the invention will
vary, depending upon the identity, size, and/or condition of the
subject treated and further depending upon the route by which the
composition is to be administered. By way of example, the
composition may comprise between 0.1% and 100% (w/w) active
ingredient.
[0376] Pharmaceutically acceptable excipients used in the
manufacture of provided pharmaceutical compositions include inert
diluents, dispersing and/or granulating agents, surface active
agents and/or emulsifiers, disintegrating agents, binding agents,
preservatives, buffering agents, lubricating agents, and/or oils.
Excipients such as cocoa butter and suppository waxes, coloring
agents, coating agents, sweetening, flavoring, and perfuming agents
may also be present in the composition.
[0377] Exemplary diluents include calcium carbonate, sodium
carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate,
calcium hydrogen phosphate, sodium phosphate lactose, sucrose,
cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol,
inositol, sodium chloride, dry starch, cornstarch, powdered sugar,
and mixtures thereof.
[0378] Exemplary granulating and/or dispersing agents include
potato starch, corn starch, tapioca starch, sodium starch
glycolate, clays, alginic acid, guar gum, citrus pulp, agar,
bentonite, cellulose, and wood products, natural sponge,
cation-exchange resins, calcium carbonate, silicates, sodium
carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone),
sodium carboxymethyl starch (sodium starch glycolate),
carboxymethyl cellulose, cross-linked sodium carboxymethyl
cellulose (croscarmellose), methylcellulose, pregelatinized starch
(starch 1500), microcrystalline starch, water insoluble starch,
calcium carboxymethyl cellulose, magnesium aluminum silicate
(Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and
mixtures thereof.
[0379] Exemplary surface active agents and/or emulsifiers include
natural emulsifiers (e.g. acacia, agar, alginic acid, sodium
alginate, tragacanth, chondrux, cholesterol, xanthan, pectin,
gelatin, egg yolk, casein, wool fat, cholesterol, wax, and
lecithin), colloidal clays (e.g. bentonite (aluminum silicate) and
Veegum (magnesium aluminum silicate)), long chain amino acid
derivatives, high molecular weight alcohols (e.g. stearyl alcohol,
cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene
glycol distearate, glyceryl monostearate, and propylene glycol
monostearate, polyvinyl alcohol), carbomers (e.g. carboxy
polymethylene, polyacrylic acid, acrylic acid polymer, and
carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.
carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl
cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene
sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween
60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan
monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan
tristearate (Span 65), glyceryl monooleate, sorbitan monooleate
(Span 80)), polyoxyethylene esters (e.g. polyoxyethylene
monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil,
polyethoxylated castor oil, polyoxymethylene stearate, and
Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid
esters (e.g. Cremophor.TM.), polyoxyethylene ethers, (e.g.
polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone),
diethylene glycol monolaurate, triethanolamine oleate, sodium
oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate,
sodium lauryl sulfate, Pluronic F-68, Poloxamer 188, cetrimonium
bromide, cetylpyridinium chloride, benzalkonium chloride, docusate
sodium, and/or mixtures thereof.
[0380] Exemplary binding agents include starch (e.g. cornstarch and
starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose,
dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and
synthetic gums (e.g. acacia, sodium alginate, extract of Irish
moss, panwar gum, ghatti gum, mucilage of isapol husks,
carboxymethylcellulose, methylcellulose, ethylcellulose,
hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, microcrystalline cellulose, cellulose acetate,
poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and
larch arabogalactan), alginates, polyethylene oxide, polyethylene
glycol, inorganic calcium salts, silicic acid, polymethacrylates,
waxes, water, alcohol, and/or mixtures thereof.
[0381] Exemplary preservatives include antioxidants, chelating
agents, antimicrobial preservatives, antifungal preservatives,
alcohol preservatives, acidic preservatives, and other
preservatives.
[0382] Exemplary antioxidants include alpha tocopherol, ascorbic
acid, acorbyl palmitate, butylated hydroxyanisole, butylated
hydroxytoluene, monothioglycerol, potassium metabisulfite,
propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite,
sodium metabisulfite, and sodium sulfite.
[0383] Exemplary chelating agents include
ethylenediaminetetraacetic acid (EDTA) and salts and hydrates
thereof (e.g., sodium edetate, disodium edetate, trisodium edetate,
calcium disodium edetate, dipotassium edetate, and the like),
citric acid and salts and hydrates thereof (e.g., citric acid
monohydrate), fumaric acid and salts and hydrates thereof, malic
acid and salts and hydrates thereof, phosphoric acid and salts and
hydrates thereof, and tartaric acid and salts and hydrates thereof.
Exemplary antimicrobial preservatives include benzalkonium
chloride, benzethonium chloride, benzyl alcohol, bronopol,
cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol,
chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin,
hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol,
phenylmercuric nitrate, propylene glycol, and thimerosal.
[0384] Exemplary antifungal preservatives include butyl paraben,
methyl paraben, ethyl paraben, propyl paraben, benzoic acid,
hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium
benzoate, sodium propionate, and sorbic acid.
[0385] Exemplary alcohol preservatives include ethanol,
polyethylene glycol, phenol, phenolic compounds, bisphenol,
chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
[0386] Exemplary acidic preservatives include vitamin A, vitamin C,
vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic
acid, ascorbic acid, sorbic acid, and phytic acid.
[0387] Other preservatives include tocopherol, tocopherol acetate,
deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA),
butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl
sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium
bisulfite, sodium metabisulfite, potassium sulfite, potassium
metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115,
Germaben II, Neolone, Kathon, and Euxyl. In certain embodiments,
the preservative is an anti-oxidant. In other embodiments, the
preservative is a chelating agent.
[0388] Exemplary buffering agents include citrate buffer solutions,
acetate buffer solutions, phosphate buffer solutions, ammonium
chloride, calcium carbonate, calcium chloride, calcium citrate,
calcium glubionate, calcium gluceptate, calcium gluconate,
D-gluconic acid, calcium glycerophosphate, calcium lactate,
propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium
phosphate, phosphoric acid, tribasic calcium phosphate, calcium
hydroxide phosphate, potassium acetate, potassium chloride,
potassium gluconate, potassium mixtures, dibasic potassium
phosphate, monobasic potassium phosphate, potassium phosphate
mixtures, sodium acetate, sodium bicarbonate, sodium chloride,
sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic
sodium phosphate, sodium phosphate mixtures, tromethamine,
magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free
water, isotonic saline, Ringer's solution, ethyl alcohol, and
mixtures thereof.
[0389] Exemplary lubricating agents include magnesium stearate,
calcium stearate, stearic acid, silica, talc, malt, glyceryl
behanate, hydrogenated vegetable oils, polyethylene glycol, sodium
benzoate, sodium acetate, sodium chloride, leucine, magnesium
lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
[0390] Exemplary natural oils include almond, apricot kernel,
avocado, babassu, bergamot, black current seed, borage, cade,
camomile, canola, caraway, carnauba, castor, cinnamon, cocoa
butter, coconut, cod liver, coffee, corn, cotton seed, emu,
eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd,
grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui
nut, lavandin, lavender, lemon, litsea cubeba, macademia nut,
mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,
orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,
pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,
sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,
soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut,
and wheat germ oils. Exemplary synthetic oils include, but are not
limited to, butyl stearate, caprylic triglyceride, capric
triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360,
isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol,
silicone oil, and mixtures thereof.
[0391] Liquid dosage forms for oral and parenteral administration
include pharmaceutically acceptable emulsions, microemulsions,
solutions, suspensions, syrups and elixirs. In addition to the
active ingredients, the liquid dosage forms may comprise inert
diluents commonly used in the art such as, for example, water or
other solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ,
olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl
alcohol, polyethylene glycols and fatty acid esters of sorbitan,
and mixtures thereof. Besides inert diluents, the oral compositions
can include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents. In
certain embodiments for parenteral administration, the conjugates
of the invention are mixed with solubilizing agents such as
Cremophor.TM., alcohols, oils, modified oils, glycols,
polysorbates, cyclodextrins, polymers, and mixtures thereof.
[0392] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions can be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation can be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that can be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0393] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0394] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This can be accomplished by the use of a
liquid suspension of crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution which, in turn, may depend upon
crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle.
[0395] Compositions for rectal or vaginal administration are
typically suppositories which can be prepared by mixing the
conjugates of this invention with suitable non-irritating
excipients or carriers such as cocoa butter, polyethylene glycol or
a suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active ingredient.
[0396] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active ingredient is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or (a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
(b) binders such as, for example, carboxymethylcellulose,
alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia,
(c) humectants such as glycerol, (d) disintegrating agents such as
agar, calcium carbonate, potato or tapioca starch, alginic acid,
certain silicates, and sodium carbonate, (e) solution retarding
agents such as paraffin, (f) absorption accelerators such as
quaternary ammonium compounds, (g) wetting agents such as, for
example, cetyl alcohol and glycerol monostearate, (h) absorbents
such as kaolin and bentonite clay, and (i) lubricants such as talc,
calcium stearate, magnesium stearate, solid polyethylene glycols,
sodium lauryl sulfate, and mixtures thereof. In the case of
capsules, tablets and pills, the dosage form may comprise buffering
agents.
[0397] Solid compositions of a similar type can be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally comprise opacifying agents and can be of a composition
that they release the active ingredient(s) only, or preferentially,
in a certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions which can be used
include polymeric substances and waxes. Solid compositions of a
similar type can be employed as fillers in soft and hard-filled
gelatin capsules using such excipients as lactose or milk sugar as
well as high molecular weight polethylene glycols and the like.
[0398] The active ingredient can be in micro-encapsulated form with
one or more excipients as noted above. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active ingredient can be admixed with at least one inert diluent
such as sucrose, lactose or starch. Such dosage forms may comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may comprise
buffering agents. They may optionally comprise opacifying agents
and can be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions which can be used include polymeric
substances and waxes.
[0399] Dosage forms for topical and/or transdermal administration
of a compound of this invention may include ointments, pastes,
creams, lotions, gels, powders, solutions, sprays, inhalants and/or
patches. Generally, the active ingredient is admixed under sterile
conditions with a pharmaceutically acceptable carrier or excipient
and/or any needed preservatives and/or buffers as can be required.
Additionally, the present invention contemplates the use of
transdermal patches, which often have the added advantage of
providing controlled delivery of an active ingredient to the body.
Such dosage forms can be prepared, for example, by dissolving
and/or dispensing the active ingredient in the proper medium.
Alternatively or additionally, the rate can be controlled by either
providing a rate controlling membrane and/or by dispersing the
active ingredient in a polymer matrix and/or gel.
[0400] Suitable devices for use in delivering intradermal
pharmaceutical compositions described herein include short needle
devices such as those described in U.S. Pat. Nos. 4,886,499;
5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496;
and 5,417,662. Intradermal compositions can be administered by
devices which limit the effective penetration length of a needle
into the skin, such as those described in PCT publication WO
99/34850 and functional equivalents thereof. Jet injection devices
which deliver liquid vaccines to the dermis via a liquid jet
injector and/or via a needle which pierces the stratum corneum and
produces a jet which reaches the dermis are suitable. Jet injection
devices are described, for example, in U.S. Pat. Nos. 5,480,381;
5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911;
5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627;
5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460;
and PCT publications WO 97/37705 and WO 97/13537. Ballistic
powder/particle delivery devices which use compressed gas to
accelerate vaccine in powder form through the outer layers of the
skin to the dermis are suitable. Alternatively or additionally,
conventional syringes can be used in the classical mantoux method
of intradermal administration.
[0401] Formulations suitable for topical administration include,
but are not limited to, liquid and/or semi-liquid preparations such
as liniments, lotions, oil in water and/or water in oil emulsions
such as creams, ointments and/or pastes, and/or solutions and/or
suspensions. Topically-administrable formulations may, for example,
comprise from about 1% to about 10% (w/w) active ingredient,
although the concentration of the active ingredient can be as high
as the solubility limit of the active ingredient in the solvent.
Formulations for topical administration may further comprise one or
more of the additional ingredients described herein.
[0402] A pharmaceutical composition of the invention can be
prepared, packaged, and/or sold in a formulation suitable for
pulmonary administration via the buccal cavity. Such a formulation
may comprise dry particles which comprise the active ingredient and
which have a diameter in the range from about 0.5 to about 7
nanometers, or from about 1 to about 6 nanometers. Such
compositions are conveniently in the form of dry powders for
administration using a device comprising a dry powder reservoir to
which a stream of propellant can be directed to disperse the powder
and/or using a self-propelling solvent/powder dispensing container
such as a device comprising the active ingredient dissolved and/or
suspended in a low-boiling propellant in a sealed container. Such
powders comprise particles wherein at least 98% of the particles by
weight have a diameter greater than 0.5 nanometers and at least 95%
of the particles by number have a diameter less than 7 nanometers.
Alternatively, at least 95% of the particles by weight have a
diameter greater than 1 nanometer and at least 90% of the particles
by number have a diameter less than 6 nanometers. Dry powder
compositions may include a solid fine powder diluent such as sugar
and are conveniently provided in a unit dose form.
[0403] Low boiling propellants generally include liquid propellants
having a boiling point of below 65.degree. F. at atmospheric
pressure. Generally the propellant may constitute 50 to 99.9% (w/w)
of the composition, and the active ingredient may constitute 0.1 to
20% (w/w) of the composition. The propellant may further comprise
additional ingredients such as a liquid non-ionic and/or solid
anionic surfactant and/or a solid diluent (which may have a
particle size of the same order as particles comprising the active
ingredient).
[0404] Pharmaceutical compositions of the invention formulated for
pulmonary delivery may provide the active ingredient in the form of
droplets of a solution and/or suspension. Such formulations can be
prepared, packaged, and/or sold as aqueous and/or dilute alcoholic
solutions and/or suspensions, optionally sterile, comprising the
active ingredient, and may conveniently be administered using any
nebulization and/or atomization device. Such formulations may
further comprise one or more additional ingredients including, but
not limited to, a flavoring agent such as saccharin sodium, a
volatile oil, a buffering agent, a surface active agent, and/or a
preservative such as methylhydroxybenzoate. The droplets provided
by this route of administration may have an average diameter in the
range from about 0.1 to about 200 nanometers.
[0405] Formulations described herein as being useful for pulmonary
delivery are useful for intranasal delivery of a pharmaceutical
composition of the invention. Another formulation suitable for
intranasal administration is a coarse powder comprising the active
ingredient and having an average particle from about 0.2 to 500
micrometers. Such a formulation is administered by rapid inhalation
through the nasal passage from a container of the powder held close
to the nares.
[0406] Formulations for nasal administration may, for example,
comprise from about as little as 0.1% (w/w) and as much as 100%
(w/w) of the active ingredient, and may comprise one or more of the
additional ingredients described herein. A pharmaceutical
composition of the invention can be prepared, packaged, and/or sold
in a formulation for buccal administration. Such formulations may,
for example, be in the form of tablets and/or lozenges made using
conventional methods, and may contain, for example, 0.1 to 20%
(w/w) active ingredient, the balance comprising an orally
dissolvable and/or degradable composition and, optionally, one or
more of the additional ingredients described herein. Alternately,
formulations for buccal administration may comprise a powder and/or
an aerosolized and/or atomized solution and/or suspension
comprising the active ingredient. Such powdered, aerosolized,
and/or aerosolized formulations, when dispersed, may have an
average particle and/or droplet size in the range from about 0.1 to
about 200 nanometers, and may further comprise one or more of the
additional ingredients described herein.
[0407] A pharmaceutical composition of the invention can be
prepared, packaged, and/or sold in a formulation for ophthalmic
administration. Such formulations may, for example, be in the form
of eye drops including, for example, a 0.1/1.0% (w/w) solution
and/or suspension of the active ingredient in an aqueous or oily
liquid carrier or excipient. Such drops may further comprise
buffering agents, salts, and/or one or more other of the additional
ingredients described herein. Other opthalmically-administrable
formulations which are useful include those which comprise the
active ingredient in microcrystalline form and/or in a liposomal
preparation. Ear drops and/or eye drops are contemplated as being
within the scope of this invention.
[0408] Although the descriptions of pharmaceutical compositions
provided herein are principally directed to pharmaceutical
compositions which are suitable for administration to humans, it
will be understood by the skilled artisan that such compositions
are generally suitable for administration to animals of all sorts.
Modification of pharmaceutical compositions suitable for
administration to humans in order to render the compositions
suitable for administration to various animals is well understood,
and the ordinarily skilled veterinary pharmacologist can design
and/or perform such modification with ordinary experimentation.
[0409] Compounds provided herein are typically formulated in dosage
unit form for ease of administration and uniformity of dosage. It
will be understood, however, that the total daily usage of the
compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific therapeutically effective dose level for any particular
subject or organism will depend upon a variety of factors including
the disease being treated and the severity of the disorder; the
activity of the specific active ingredient employed; the specific
composition employed; the age, body weight, general health, sex,
and diet of the subject; the time of administration, route of
administration, and rate of excretion of the specific active
ingredient employed; the duration of the treatment; drugs used in
combination or coincidental with the specific active ingredient
employed; and like factors well known in the medical arts.
[0410] The compounds and compositions provided herein can be
administered by any route, including enteral (e.g., oral),
parenteral, intravenous, intramuscular, intra-arterial,
intramedullary, intrathecal, subcutaneous, intraventricular,
transdermal, interdermal, rectal, intravaginal, intraperitoneal,
topical (as by powders, ointments, creams, and/or drops), mucosal,
nasal, bucal, sublingual; by intratracheal instillation, bronchial
instillation, and/or inhalation; and/or as an oral spray, nasal
spray, and/or aerosol. Specifically contemplated routes are oral
administration, intravenous administration (e.g., systemic
intravenous injection), regional administration via blood and/or
lymph supply, and/or direct administration to an affected site. In
general the most appropriate route of administration will depend
upon a variety of factors including the nature of the agent (e.g.,
its stability in the environment of the gastrointestinal tract),
and/or the condition of the subject (e.g., whether the subject is
able to tolerate oral administration).
[0411] The exact amount of a compound required to achieve an
effective amount will vary from subject to subject, depending, for
example, on species, age, and general condition of a subject,
severity of the side effects or disorder, identity of the
particular compound, mode of administration, and the like. The
desired dosage can be delivered three times a day, two times a day,
once a day, every other day, every third day, every week, every two
weeks, every three weeks, or every four weeks. In certain
embodiments, the desired dosage can be delivered using multiple
administrations (e.g., two, three, four, five, six, seven, eight,
nine, ten, eleven, twelve, thirteen, fourteen, or more
administrations).
[0412] In certain embodiments, an effective amount of a compound
for administration one or more times a day to a 70 kg adult human
may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to
about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to
about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to
about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100
mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg,
of a compound per unit dosage form.
[0413] In certain embodiments, the compounds of the invention may
be at dosage levels sufficient to deliver from about 0.001 mg/kg to
about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg,
preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from
about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about
10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more
preferably from about 1 mg/kg to about 25 mg/kg, of subject body
weight per day, one or more times a day, to obtain the desired
therapeutic effect.
[0414] It will be appreciated that dose ranges as described herein
provide guidance for the administration of provided pharmaceutical
compositions to an adult. The amount to be administered to, for
example, a child or an adolescent can be determined by a medical
practitioner or person skilled in the art and can be lower or the
same as that administered to an adult.
[0415] It will be also appreciated that a compound or composition,
as described herein, can be administered in combination with one or
more additional therapeutically active agents. The compounds or
compositions can be administered in combination with additional
therapeutically active agents that improve their bioavailability,
reduce and/or modify their metabolism, inhibit their excretion,
and/or modify their distribution within the body. It will also be
appreciated that the therapy employed may achieve a desired effect
for the same disorder, and/or it may achieve different effects.
[0416] The compound or composition can be administered concurrently
with, prior to, or subsequent to, one or more additional
therapeutically active agents. In general, each agent will be
administered at a dose and/or on a time schedule determined for
that agent. In will further be appreciated that the additional
therapeutically active agent utilized in this combination can be
administered together in a single composition or administered
separately in different compositions. The particular combination to
employ in a regimen will take into account compatibility of the
inventive compound with the additional therapeutically active agent
and/or the desired therapeutic effect to be achieved. In general,
it is expected that additional therapeutically active agents
utilized in combination be utilized at levels that do not exceed
the levels at which they are utilized individually. In some
embodiments, the levels utilized in combination will be lower than
those utilized individually.
[0417] Exemplary additional therapeutically active agents include,
but are not limited to, anti-cancer agents, anti-diabetic agents,
anti-inflammatory agents, immunosuppressant agents, and a
pain-relieving agent. Therapeutically active agents include small
organic molecules such as drug compounds (e.g., compounds approved
by the U.S. Food and Drug Administration as provided in the Code of
Federal Regulations (CFR)), peptides, proteins, carbohydrates,
monosaccharides, oligosaccharides, polysaccharides, nucleoproteins,
mucoproteins, lipoproteins, synthetic polypeptides or proteins,
small molecules linked to proteins, glycoproteins, steroids,
nucleic acids, DNAs, RNAs, nucleotides, nucleosides,
oligonucleotides, antisense oligonucleotides, lipids, hormones,
vitamins, and cells.
[0418] Also encompassed by the invention are kits (e.g.,
pharmaceutical packs). The kits provided may comprise an inventive
pharmaceutical composition or compound and a container (e.g., a
vial, ampule, bottle, syringe, and/or dispenser package, or other
suitable container). In some embodiments, provided kits may
optionally further include a second container comprising a
pharmaceutical excipient for dilution or suspension of an inventive
pharmaceutical composition or compound. In some embodiments, the
inventive pharmaceutical composition or compound provided in the
first container and the second container are combined to form one
unit dosage form.
[0419] Thus, in one aspect, provided are kits for preventing and/or
treating an infectious disease (e.g., a viral disease or viral
infection) of a subject. In certain embodiments, the kits include a
first container comprising a compound, or a pharmaceutically
acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,
stereoisomer, isotopically labeled derivative, prodrug, and
composition thereof; and an instruction for administering the
compound, or a pharmaceutically acceptable salt, solvate, hydrate,
polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, prodrug, and composition thereof, to a subject to
prevent or treat the infectious disease. The first container of the
provided kit may comprise a compound of the present invention. In
certain embodiments, the first container comprises QL-XII-47, or a
pharmaceutical salt thereof. In certain embodiments, the first
container comprises QL-XII-56, or a pharmaceutical salt thereof. In
certain embodiments, the first container comprises a
therapeutically effective amount of an inventive compound. In
certain embodiments, the first container comprises a
prophylactically effective amount of an inventive compound.
[0420] The kits of the present invention may be used for treating
or preventing Dengue fever, Dengue hemorrhagic fever (DHF), Dengue
shock syndrome (DSS), hepatitis B, hepatitis C, fulminant viral
hepatitis, severe acute respiratory syndrome (SARS), viral
myocarditis, influenza A virus infection, influenza B virus
infection, parainfluenza virus infection, RS virus (RSV) infections
(e.g., RSV bronchiolitis, RSV pneumonia, especially infant and
childhood RSV infections and RSV pneumonia in the patients with
cardiopulmonary disorders), measles virus infection, vesicular
stomatitis virus infection, rabies virus infection, Ebola virus
infection, Japanese encephalitis, Junin virus infection, human
cytomegalovirus infection, herpes simplex virus 1 infection,
poliovirus infection, Marburg virus infection, Lassa fever virus
infection, Venezuelan equine encephalitis, Rift Valley Fever virus
infection, Korean hemorrhagic fever virus infection, Crimean-Congo
hemorrhagic fever virus infection, HIV infection, encephalitis,
Saint Louise encephalitis, Kyasanur Forest disease, Murray Valley
encephalitis, tick-borne encephalitis, West Nile encephalitis,
yellow fever, and/or viral infections in subjects with immune
disorders. In certain embodiments, the provided kits are used for
treating or preventing Dengue fever. In certain embodiments, the
provided kits are used for treating or preventing Dengue
hemorrhagic fever (DHF). In certain embodiments, the provided kits
are used for treating or preventing Dengue shock syndrome (DSS).
The kits of the present invention may also be used for treating or
preventing a disease caused by Flaviviridae virus (e.g., Dengue
virus (DENV), including Dengue virus 1 (DENV1), Dengue virus 2
(DENV2), Dengue virus 3 (DENV3), and Dengue virus 4 (DENV4); West
Nile virus; tick-borne encephalitis virus; yellow fever virus;
hepatitis C virus; hepatitis G virus; bovine viral diarrhea;
classical swine fever virus; and hog cholera virus), Kunjin virus,
Japanese encephalitis virus, vesicular stomatitis virus (VSV),
vesicular stomatitis virus (VSV) pseudotyped with rabies
glycoprotein, vesicular stomatitis virus (VSV) pseudotyped with
Ebola glycoprotein, herpes simplex virus 1 (HSV-1), human
cytomegalovirus (HCMV), poliovirus, Junin virus, Ebola virus,
Marburg virus (MARV), Lassa fever virus (LASV), Venezuelan equine
encephalitis virus (VEEV), Rift Valley Fever virus (RVFV),
hepatitis B virus, cytomegalovirus, papillomavirus, coronavirus,
Epstein-Barr virus (EBV), human immunodeficiency virus (HIV),
orthomyxovirus, paramyxovirus, arenavirus, bunyavirus, adenovirus,
poxvirus, retrovirus, rhabdovirus, picornavirus, or herpesvirus. In
certain embodiments, the provided kits are used for treating or
preventing a disease caused by Flaviviridae virus. In certain
embodiments, the provided kits are used for treating or preventing
a disease caused by Dengue virus (DENV). In certain embodiments,
the provided kits are used for treating or preventing a disease
caused by Dengue virus 1 (DENV1), Dengue virus 2 (DENV2), Dengue
virus 3 (DENV3), or Dengue virus 4 (DENV4).
[0421] In certain embodiments, the subject administered the
inventive compound or composition is a mammal. In certain
embodiments, the subject is a human. In certain embodiments, the
subject is a domesticated animal, such as a dog, cat, cow, pig,
horse, sheep, or goat. In certain embodiments, the subject is a
companion animal such as a dog or cat. In certain embodiments, the
subject is a livestock animal such as a cow, pig, horse, sheep, or
goat. In certain embodiments, the subject is a zoo animal. In
another embodiment, the subject is a research animal such as a
rodent or non-human primate. In certain embodiments, the subject is
a non-human transgenic animal such as a transgenic mouse or
transgenic pig. In certain embodiments, the subject is a fish.
Methods of Treatment and Uses
[0422] In one aspect, the present invention provides methods for
the prevention and/or treatment of infectious diseases in a subject
suffered therefrom. In certain embodiments, the methods of
prevention and/or treatment include administering to a subject with
an infectious disease an effective amount of a compound of the
present invention (e.g., QL-XII-47 or QL-XII-56), or a
pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, prodrug, or pharmaceutical composition thereof. In
certain embodiments, the methods of prevention and/or treatment
comprise administering to a subject with an infectious disease an
effective amount of QL-XII-47, or a pharmaceutically acceptable
salt thereof. In certain embodiments, the methods of prevention
and/or treatment comprise administering to a subject with an
infectious disease an effective amount of QL-XII-56, or a
pharmaceutical salt thereof.
[0423] In certain embodiments, the effective amount is a
therapeutically effective amount. In certain embodiments, the
effective amount is a prophylactically effective amount.
[0424] The infectious disease prevented and/or treated by the
compounds or pharmaceutical compositions of the present invention
is typically caused by a virus. In certain embodiments, the
infectious disease is prevented and/or treated by blocking entry of
the virus into a host cell. Entry of a virus into a host cell
involves an early entry step that occurs before the uptake of the
virus by the host cell. Entry of a virus into a host cell also
involves a late entry step that occurs after the uptake of the
virus by the host cell but prior to the release of the genome of
the virus from the virus's nucleocapsid. In certain embodiments,
entry of the virus is blocked at an early entry step. In certain
embodiments, entry of the virus is blocked at a late entry step. In
certain embodiments, the infectious disease is prevented and/or
treated by reducing the count of the virus in the subject. In
certain embodiments, the infectious disease is prevented and/or
treated by inhibiting the activity of the virus in the subject. In
certain embodiments, the infectious disease is prevented and/or
treated by reducing the susceptibility of a host factor in the
subject to the virus. In certain embodiments, the infectious
disease is prevented and/or treated by attaching a compound of the
present invention to a cysteine residue of the host factor. In
certain embodiments, the infectious disease is prevented and/or
treated by irreversible binding of a compound of the present
invention to a cysteine residue of the host factor. In certain
embodiments, the infectious disease is prevented and/or treated by
covalently attaching a compound of the present invention to a
cysteine residue of the host factor.
[0425] In certain embodiments, the infectious disease prevented
and/or treated by the inventive compounds is caused by Flaviviridae
virus. In certain embodiments, the infectious disease prevented
and/or treated by the inventive compounds is caused by Dengue virus
(DENV). In certain embodiments, the infectious disease prevented
and/or treated by the inventive compounds is caused by Dengue virus
1 (DENV1). In certain embodiments, the infectious disease prevented
and/or treated by the inventive compounds is caused by Dengue virus
2 (DENV2). In certain embodiments, the infectious disease prevented
and/or treated by the inventive compounds is caused by Dengue virus
3 (DENV3). In certain embodiments, the infectious disease prevented
and/or treated by the inventive compounds is caused by Dengue virus
4 (DENV4). In certain embodiments, the infectious disease prevented
and/or treated by the inventive compounds is caused by Kunjin
virus. In certain embodiments, the infectious disease prevented
and/or treated by the inventive compounds is caused by Japanese
encephalitis virus. In certain embodiments, the infectious disease
prevented and/or treated by the inventive compounds is caused by
vesicular stomatitis virus (VSV). In certain embodiments, the
infectious disease prevented and/or treated by the inventive
compounds is caused by vesicular stomatitis virus (VSV) pseudotyped
with rabies glycoprotein. In certain embodiments, the infectious
disease prevented and/or treated by the inventive compounds is
caused by vesicular stomatitis virus (VSV) pseudotyped with Ebola
glycoprotein. In certain embodiments, the infectious disease
prevented and/or treated by the inventive compounds is caused by
herpes simplex virus 1 (HSV-1). In certain embodiments, the
infectious disease prevented and/or treated by the inventive
compounds is caused by human cytomegalovirus (HCMV). In certain
embodiments, the infectious disease prevented and/or treated by the
inventive compounds is caused by poliovirus. In certain
embodiments, the infectious disease prevented and/or treated by the
inventive compounds is caused by Junin virus. In certain
embodiments, the infectious disease prevented and/or treated by the
inventive compounds is caused by Ebola virus. In certain
embodiments, the infectious disease prevented and/or treated by the
inventive compounds is caused by Marburg virus (MARV). In certain
embodiments, the infectious disease prevented and/or treated by the
inventive compounds is caused by Lassa fever virus (LASV). In
certain embodiments, the infectious disease prevented and/or
treated by the inventive compounds is caused by Venezuelan equine
encephalitis virus (VEEV). In certain embodiments, the infectious
disease prevented and/or treated by the inventive compounds is
caused by Rift Valley Fever virus (RVFV). The infectious disease
prevented and/or treated by the inventive compounds may also be
caused by, without limitation, West Nile virus, tick-borne
encephalitis virus, yellow fever virus, hepatitis C virus,
hepatitis G virus, bovine viral diarrhea, classical swine fever
virus, hog cholera virus, hepatitis B virus, cytomegaloviruses,
papillomaviruses, coronaviruses, Epstein-Barr virus (EBV), human
immunodeficiency virus (HIV), orthomyxoviruses, paramyxoviruses,
arenaviruses, bunyaviruses, adenoviruses, poxviruses, retroviruses,
rhabdoviruses, picornaviruses, or herpesviruses.
[0426] In certain embodiments, the infectious disease prevented
and/or treated by the inventive compounds is Dengue fever. In
certain embodiments, the infectious disease prevented and/or
treated by the inventive compounds is Dengue hemorrhagic fever
(DHF). In certain embodiments, the infectious disease prevented
and/or treated by the inventive compounds is Dengue shock syndrome
(DSS). Other infectious disease that may be prevented and/or
treated by the inventive compounds include, but not limited to,
hepatitis B, hepatitis C, fulminant viral hepatitis, severe acute
respiratory syndrome (SARS), viral myocarditis, influenza A virus
infection, influenza B virus infection, parainfluenza virus
infection, RS virus (RSV) infections (e.g., RSV bronchiolitis, RSV
pneumonia, especially infant and childhood RSV infections and RSV
pneumonia in the patients with cardiopulmonary disorders), measles
virus infection, vesicular stomatitis virus infection, rabies virus
infection, Ebola virus infection, Japanese encephalitis, Junin
virus infection, human cytomegalovirus infection, herpes simplex
virus 1 infection, poliovirus infection, Marburg virus infection,
Lassa fever virus infection, Venezuelan equine encephalitis, Rift
Valley Fever virus infection, Korean hemorrhagic fever virus
infection, Crimean-Congo hemorrhagic fever virus infection, HIV
infection, encephalitis, Saint Louise encephalitis, Kyasanur Forest
disease, Murray Valley encephalitis, tick-borne encephalitis, West
Nile encephalitis, yellow fever, and viral infections in subjects
with immune disorders.
[0427] The present invention also provides methods of reducing
viral load in a subject. The methods of reducing viral load include
administering to the subject an effective amount of a compound of
the present invention (e.g., QL-XII-47 or QL-XII-56), or a
pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, prodrug, or pharmaceutical composition thereof. The
inventive compounds may be administered within 1 day, 2 days, 3
days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, or 1 month
of exposure to the virus. In certain embodiments, the time of viral
clearance is reduced. In certain embodiments, morbidity or
mortality of the subject, who may or may not have been infected
with the virus or has been exposed to the virus, is reduced.
[0428] Viral load may be determined by measuring the titer or level
of virus in a tissue or bodily fluid of the subject. Measuring the
viral load can be accomplished by any conventional assay, such as
ones described in the literature (see, e.g., Medical Microbiology;
3rd Ed.; Murray et al., eds.; Mosby, Inc.: Philadelphia, Pa.,
1998). In certain embodiments, viral load is reduced to a
undetectable level. In certain embodiments, viral load is reduced
to a low level of, for example, less than about 20,000 cpm (genome
copies per milliliter of serum of the subject), less than about
5000 cpm, less than about 2000 cpm, less than about 500 cpm, or
less than about 200 cpm. In certain embodiments, viral load is
reduced by at least about 5%, at least about 10%, at least about
25%, at least about 50%, at least about 75%, at least about 90%, at
least about 95%, or at least about 99%. In certain embodiments, the
inventive methods achieve a sustained viral response, e.g., the
viral load is reduced to an undetectable or low level for a period
of at least about one month, at least about two months, at least
about three months, at least about four months, at least about five
months, at least about six months, at least about one year, at
least about two years, at least about three years, at least about
four years, or at least about five years following cessation of
administering a compound of the present invention to the
subject.
[0429] The present invention also involves methods of preventing a
viral infection in a subject who was or may be exposed to a virus.
The methods of preventing a viral infection include administering
to the subject who was or may be exposed to a virus an effective
amount of a compound of the present invention (e.g., QL-XII-47 or
QL-XII-56), or a pharmaceutically acceptable salt, solvate,
hydrate, polymorph, co-crystal, tautomer, stereoisomer,
isotopically labeled derivative, prodrug, or pharmaceutical
composition thereof.
[0430] In certain embodiments, the subject was exposed to a virus.
In certain embodiments, the subject may be exposed to a virus. In
certain embodiments, the viral infection is prevented by blocking
entry of the virus into the cells of the subject.
[0431] In certain embodiments, the virus to which a subject was or
may be exposed is Flaviviridae virus. In certain embodiments, the
virus to which a subject was or may be exposed is Dengue virus
(DENV). In certain embodiments, the virus to which a subject was or
may be exposed is Dengue virus 1 (DENV1). In certain embodiments,
the virus to which a subject was or may be exposed is Dengue virus
2 (DENV2). In certain embodiments, the virus to which a subject was
or may be exposed is Dengue virus 3 (DENV3). In certain
embodiments, the virus to which a subject was or may be exposed is
Dengue virus 4 (DENV4). In certain embodiments, the virus to which
a subject was or may be exposed is Kunjin virus. In certain
embodiments, the virus to which a subject was or may be exposed is
Japanese encephalitis virus. In certain embodiments, the virus to
which a subject was or may be exposed is vesicular stomatitis virus
(VSV). In certain embodiments, the virus to which a subject was or
may be exposed is vesicular stomatitis virus (VSV) pseudotyped with
rabies glycoprotein. In certain embodiments, the virus to which a
subject was or may be exposed is vesicular stomatitis virus (VSV)
pseudotyped with Ebola glycoprotein. In certain embodiments, the
virus to which a subject was or may be exposed is herpes simplex
virus 1 (HSV-1). In certain embodiments, the virus to which a
subject was or may be exposed is human cytomegalovirus (HCMV). In
certain embodiments, the virus to which a subject was or may be
exposed is poliovirus. In certain embodiments, the virus to which a
subject was or may be exposed is Junin virus. In certain
embodiments, the virus to which a subject was or may be exposed is
Ebola virus. In certain embodiments, the virus to which a subject
was or may be exposed is Marburg virus (MARV). In certain
embodiments, the virus to which a subject was or may be exposed is
Lassa fever virus (LASV). In certain embodiments, the virus to
which a subject was or may be exposed is Venezuelan equine
encephalitis virus (VEEV). In certain embodiments, the virus to
which a subject was or may be exposed is Rift Valley Fever virus
(RVFV). The virus to which a subject was or may be exposed may also
include, but not limited to, West Nile virus, tick-borne
encephalitis virus, yellow fever virus, hepatitis C virus,
hepatitis G virus, bovine viral diarrhea, classical swine fever
virus, hog cholera virus, hepatitis B virus, cytomegaloviruses,
papillomaviruses, coronaviruses, Epstein-Barr virus (EBV), human
immunodeficiency virus (HIV), orthomyxoviruses, paramyxoviruses,
arenaviruses, bunyaviruses, adenoviruses, poxviruses, retroviruses,
rhabdoviruses, picornaviruses, and herpesviruses.
[0432] Another aspect of the present invention relates to methods
of inhibiting viral replication in vitro, in vivo, and/or ex
vitro.
[0433] Another aspect of the present invention relates to methods
of inhibiting viral production in vitro, in vivo, and/or ex
vitro.
[0434] Another aspect of the present invention relates to methods
of inhibiting viral activity in vitro, in vivo, and/or ex
vitro.
[0435] Another aspect of the present invention relates to methods
of killing a virus in vitro, in vivo, and/or ex vitro.
[0436] In certain embodiments, the methods of inhibiting viral
replication, viral production, inhibiting viral activity, or
killing a virus include contacting a virus in vitro, in vivo,
and/or ex vitro with an effective amount of a compound of the
present invention (e.g., QL-XII-47 or QL-XII-56), or a
pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, prodrug, or pharmaceutical composition thereof.
[0437] Another aspect of the invention relates to methods of
screening a library of compounds to identify one or more compounds
that are useful in the treatment and/or prevention of a viral
infection in a subject suffering therefrom, in inhibiting viral
replication in vitro, in vivo, and/or ex vitro, in inhibiting viral
production in vitro, in vivo, and/or ex vitro, in inhibiting viral
activity in vitro, in vivo, and/or ex vitro, and/or in killing a
virus in vitro, in vivo, and/or ex vitro. In certain embodiments,
the library of compounds is a library of compounds of the present
invention. The methods of screening a library include providing at
least two different compounds of the present invention, or
pharmaceutically acceptable salts, solvates, hydrates, polymorphs,
co-crystals, tautomers, stereoisomers, isotopically labeled
derivatives, or prodrugs thereof, or pharmaceutical compositions
thereof; and performing at least one assay using the different
compounds of the present invention, or pharmaceutically acceptable
salts, solvates, hydrates, polymorphs, co-crystals, tautomers,
stereoisomers, isotopically labeled derivatives, or prodrugs
thereof, or pharmaceutical compositions thereof, to detect one or
more characteristics. In certain embodiments, the methods of
screening a library include providing at least two different
compounds of the present invention, or pharmaceutically acceptable
salts thereof, or pharmaceutical compositions thereof; and
performing at least one assay using the different compounds of the
present invention, or pharmaceutically acceptable salts thereof, or
pharmaceutical compositions thereof, to detect one or more
characteristics. In certain embodiments, the characteristic is a
characteristic associated with the viral infection, the rival
replication, and/or the viral activity. In certain embodiments, the
characteristic is a desired characteristic. In certain embodiments,
the desired characteristic is usefulness in treating and/or
preventing the viral infection in the subject. In certain
embodiments, the desired characteristic is usefulness in reducing
the viral load in the subject. In certain embodiments, the desired
characteristic is usefulness in inhibiting the viral replication.
In certain embodiments, the desired characteristic is usefulness in
inhibiting the viral production. In certain embodiments, the
desired characteristic is usefulness in inhibiting the viral
activity. In certain embodiments, the desired characteristic is
usefulness in blocking entry of the virus into a host cell. In
certain embodiments, the desired characteristic is usefulness in
kill the virus. In certain embodiments, the desired characteristic
is usefulness in preventing or inhibiting entry of a virus into a
host cell. The characteristic to be detected may also be an
undesired characteristic associated with the viral infection, the
rival replication, and/or viral activity. In certain embodiments,
the undesired characteristic is increased viral load in a host
cell. In certain embodiments, the undesired characteristic is
increased viral replication. In certain embodiments, the undesired
characteristic is increased viral production. In certain
embodiments, the undesired characteristic is increased viral
activity. The present invention also provides methods of screening
a library of compounds to identify one or more compounds that
prevent or inhibit entry of a virus into a host cell. In certain
embodiments, the methods of screening include providing at least
two different compounds of the present invention, or
pharmaceutically acceptable salts, solvates, hydrates, polymorphs,
co-crystals, tautomers, stereoisomers, isotopically labeled
derivatives, or prodrugs thereof, and performing at least one assay
using the compounds of the present invention, or pharmaceutically
acceptable salts, solvates, hydrates, polymorphs, co-crystals,
tautomers, stereoisomers, isotopically labeled derivatives, or
prodrugs thereof, to detect entry of a virus into a host cell.
[0438] The different compounds of the present invention may be
provided from natural sources (see, e.g., Sternberg et al., Proc.
Nat. Acad. Sci. USA, (1995) 92:1609-1613) or generated by synthetic
methods such as combinatorial chemistry (see, e.g., Ecker et al.,
Bio/Technology, (1995) 13:351-360 and U.S. Pat. No. 5,571,902). In
certain embodiments, the different compounds are provided by
liquid-phase or solution synthesis. In certain embodiments, the
different compounds are provided by solid-phase synthesis. In
certain embodiments, the different compounds are provided by a
high-throughput, parallel, or combinatorial synthesis. In certain
embodiments, the different compounds are provided by a
low-throughput synthesis. In certain embodiments, the different
compounds are provided by a one-pot synthesis. The different
compounds may be provided robotically or manually. In certain
embodiments, the step of providing at least two different compounds
of the present invention include arraying into at least two vessels
at least two different compounds of the present invention wherein
the compounds are bound to solid supports, cleaving the compounds
from the solid supports, and dissolving the cleaved compounds in a
solvent. The solid supports include, but do not limit to, beads
(e.g., resin beads and magnetic beads), hollow fibers, solid
fibers, plates, dishes, flasks, meshes, screens, and membranes. In
certain embodiments, the solid supports are beads. In certain
embodiments, one solid support is capable of supporting at least 50
nmol of a compound. In certain embodiments, one solid support is
capable of supporting at least 100 nmol of a compound. In certain
embodiments, one solid support is capable of supporting at least
200 nmol of a compound. Each vessel may contain one or more
support-bound compounds of the present invention. In certain
embodiments, each vessel contains one support-bound compounds of
the present invention. The solid supports and/or the compounds may
be labeled with one or more labeling agents for the identification
or detection of the compounds. The vessels may be wells of a
microtiter plate. The solvent may be an inorganic solvent, organic
solvent, or a mixture thereof. The steps of arraying, cleaving, and
dissolving may be performed robotically or manually.
[0439] Typically, the methods of screening a compound library
involve at least one assay. In certain embodiments, the assay is
performed to detect entry of a virus into a host cell of a subject.
In certain embodiments, the assay is performed to determine the
extent of the interaction between a compound of the present
invention and a host factor of the subject using methods known in
the art (see, e.g., Chu et al., J. Am. Chem. Soc. (1996)
118:7827-7835). In certain embodiments, the assay is an
immunoassay, such as a sandwich-type assay, competitive binding
assay, one-step direct test, two-step test, or blot assay. The step
of performing at least one assay may be performed robotically or
manually. In certain embodiments, an early viral entry step is
prevented or inhibited. In certain embodiments, a late viral entry
step is prevented or inhibited. The virus whose entry into the host
cell may be prevented or inhibited include, but do not limit to,
Flaviviridae viruses (e.g., Dengue virus (DENV), including Dengue
virus 1 (DENV1), Dengue virus 2 (DENV2), Dengue virus 3 (DENV3),
and Dengue virus 4 (DENV4); West Nile virus; tick-borne
encephalitis virus; yellow fever virus; hepatitis C virus;
hepatitis G virus; bovine viral diarrhea; classical swine fever
virus; and hog cholera virus), Kunjin virus, Japanese encephalitis
virus, vesicular stomatitis virus (VSV), vesicular stomatitis virus
(VSV) pseudotyped with rabies glycoprotein, vesicular stomatitis
virus (VSV) pseudotyped with Ebola glycoprotein, herpes simplex
virus 1 (HSV-1), human cytomegalovirus (HCMV), poliovirus, Junin
virus, Ebola virus, Marburg virus (MARV), Lassa fever virus (LASV),
Venezuelan equine encephalitis virus (VEEV), Rift Valley Fever
virus (RVFV), hepatitis B virus, cytomegaloviruses,
papillomaviruses, coronaviruses, Epstein-Barr virus (EBV), human
immunodeficiency virus (HIV), orthomyxoviruses, paramyxoviruses,
arenaviruses, bunyaviruses, adenoviruses, poxviruses, retroviruses,
rhabdoviruses, picornaviruses, and herpesviruses. In certain
embodiments, the virus whose entry into the host cell may be
prevented or inhibited is Flaviviridae virus. In certain
embodiments, the virus whose entry into the host cell may be
prevented or inhibited is Dengue virus (DENV). In certain
embodiments, the virus whose entry into the host cell may be
prevented or inhibited is Dengue virus 1 (DENV1), Dengue virus 2
(DENV2), Dengue virus 3 (DENV3), or Dengue virus 4 (DENV4).
EXAMPLES
[0440] In order that the invention described herein may be more
fully understood, the following examples are set forth. The
synthetic and biological examples described in this application are
offered to illustrate the compounds, pharmaceutical compositions,
and inventive compounds provided herein and are not to be construed
in any way as limiting their scope.
Example 1. Synthesis of the Compounds
[0441] The compounds provided herein can be prepared from readily
available starting materials using the following general methods
and procedures. Various intermediates useful for preparation of the
compounds of the invention can be prepared in accordance with
methods described in the art (Upasani et al., J. Med. Chem. (1997)
40:73-84; and Hogenkamp et al., J. Med. Chem. (1997) 40:61-72) and
using the appropriate reagents, starting materials, and
purification methods known to those skilled in the art.
Representative methods are demonstrated in Schemes 1-4. The
compounds of the invention can be prepared using the intermediates
described above. For example, a general method for preparing
QL-XII-47 is illustrated in Scheme 1.
##STR00210## ##STR00211##
##STR00212## ##STR00213##
[0442] Compounds 1 (480 mg, 2 mmol, 1 equiv.) and 2 (470 mg, 2
mmol, 1 equiv.) were combined in 1,4-dioxane (13 mL) and heated at
100.degree. C. for 4 h, cooled to room temperature, poured into
brine, and extracted with ethyl acetate (3.times.). The organic
phase was dried over sodium sulfate, filtered, and concentrated.
The resulting residue was purified by flash chromatography on
SiO.sub.2 (methanol:dichloromethane; 1:15 to 1:9) to provide
compound 3 (560 mg, 64% yield, LC-MS m/z (M+H)=441.15).
[0443] Compound 3 (440 mg, 1 mmol, 1 equiv.) was dissolved in ethyl
acetate (7 mL) and treated with SnCl.sub.2 (950 mg, 5 mmol, 5
equiv.). The resulting mixture was heated at 65.degree. C. for 4 h
and then filtered through Celite.sup..COPYRGT.. The filtrate was
dried over sodium sulfate, filtered, and concentrated. The
resulting residue was purified by flash chromatography on SiO.sub.2
(methanol:dichloromethane; 1:10) to afford compound 4 (310 mg, 70%
yield, LC-MS m/z (M+H)=411.23).
[0444] Compound 4 (300 mg, 0.73 mmol, 1 equiv.) was dissolved in
dichloromethane (5 mL) and treated with carbonyl diimidazole (140
mg, 0.88 mmol, 1.2 equiv.) at room temperature. After 4 h, the
reaction mixture was quenched with brine and extracted with
dichloromethane (3.times.), and the combined organic layers were
dried over sodium sulfate. Following filtration and concentration
of the organic solution, the resulting crude residue was dissolved
in THF (5 mL) and treated with NaH (53 mg, 2.2 mmol, 3 equiv.) and
MeI (55 .mu.L, 0.88 mmol, 1.2 equiv.). After stirring at room
temperature for 12 h, the reaction was quenched with NH.sub.4Cl
(saturated) and extracted with dichloromethane (3.times.). The
organic solution was then dried over sodium sulfate, filtered, and
concentrated. The resulting residue was purified by flash
chromatography on SiO.sub.2 (methanol:dichloromethane; 1:10) to
afford compound 5 (147 mg, 45% yield, LC-MS m/z (M+H)=451.93).
[0445] Compounds 5 (135 mg, 0.3 mmol, 1 equiv.) and 6 (57 mg, 0.45
mmol, 1.5 equiv.) were dissolved in 1,4-dioxane (2 mL) and treated
with NaHCO.sub.3 (1.3 mL, 1 N, 3 equiv.) and
PdCl.sub.2(Ph.sub.3P).sub.2 (21 mg, 0.03 mmol, 0.1 equiv.). The
resulting solution was heated at 100.degree. C. for 3 h, cooled to
room temperature, and extracted with dichloromethane (3.times.).
The organic solution was then dried over sodium sulfate, filtered,
and concentrated. The resulting residue was purified by flash
chromatography on SiO.sub.2 (methanol:dichloromethane; 1:10) to
afford compound 7 (67 mg, 45% yield. LC-MS m/z (M+H)=497.24).
[0446] Compound 7 (50 mg, 0.1 mmol, 1 equiv.) was dissolved in
1,4-dioxane (3 mL), treated with HCl in 1,4-dioxane (0.2 mL of a 4
N solution, 8 equiv.), stirred at room temperature for 1 h, and
then treated with triethylamine (140 .mu.L, 1 mmol, 10 equiv.) and
acryloyl chloride (8 .mu.L, 0.105 mmol, 1.05 equiv.). The resulting
solution was stirred for 30 min, quenched with sodium bicarbonate
(saturated), and extracted with dichloromethane (3.times.). The
organic solution was then dried over sodium sulfate, filtered, and
concentrated. The residue was purified by flash chromatography on
SiO.sub.2 (methanol:dichloromethane; 1:30 to 1:10) to provide
compound 8 (13 mg, 30% yield, LC-MS m/z (M+H)=451.23).
##STR00214## ##STR00215##
[0447] Compounds 9 (1.35 g, 5 mmol, 1 equiv.) and 10 (760 mg, 5
mmol, 1 equiv.) were dissolved in 1,4-dioxane (10 mL) and heated at
100.degree. C. for 4 h. The reaction mixture was then cooled to
room temperature, washed with sodium bicarbonate (saturated) and
extracted with ethyl acetate (3.times.). The organic solution was
dried over sodium sulfate, filtered, and concentrated. The
resulting residue was purified by flash chromatography on SiO.sub.2
(methanol:dichloromethane; 1:10) to afford compound 11 (1.46 g, 76%
yield, LC-MS m/z (M+H)=386.13).
[0448] Compound 11 (1.4 g, 3.6 mmol, 1 equiv.) was dissolved in
ethanol (20 mL) at room temperature and treated with NaBH.sub.4
(680 mg, 18 mmol, 5 equiv.) in 5 portions. The resulting solution
was stirred for 4 h and filtered through celite. The filtrate was
then washed with NaHCO.sub.3 (saturated) and extracted with ethyl
acetate (3.times.). The organic solution was dried over sodium
sulfate, filtered, and concentrated. The resulting residue was
purified by flash chromatography on SiO.sub.2
(methanol:dichloromethane; 1:10) to afford compound 12 (620 mg, 50%
yield, LC-MS m/z (M+H)=344.14).
[0449] Compound 12 (620 mg, 1.8 mmol, 1 equiv.) was dissolved in
dichloromethane (20 mL) and treated with MnO.sub.2 (3.1 g, 5 equiv.
weights). After 4 hours, the reaction mixture was filtered through
Celite.sup..COPYRGT., and the filtrate was concentrated. The
residue was then dissolved in EtOH (20 mL) in a sealed tube,
treated with K.sub.2CO.sub.3 (745 mg, 5.4 mmol, 3 equiv.) followed
by triethylphophonoacetate (1 mL, 5.4 mmol, 3 equiv.), and heated
to 100.degree. C. for 12 h. The reaction mixture was cooled to room
temperature and filtered through Celite.COPYRGT., and the filtrate
was extracted with ethyl acetate (3.times.). The organic phase was
washed with water and brine, dried over sodium sulfate, filtered,
and concentrated. The resulting residue was purified by flash
chromatography on SiO.sub.2 (methanol:dichloromethane; 1:20) to
provide compound 13 (280 mg, 43% yield, LC-MS m/z
(M+H)=366.13).
[0450] Compound 13 (250 mg, 0.68 mmol, 1 equiv.) was dissolved in
ethyl acetate (10 mL) at room temperature, treated with
SnCl.sub.2.2H.sub.2O (765 mg, 3.4 mmol, 5 equiv.) and heated at
65.degree. C. for 4 h. The reaction mixture was cooled and filtered
through Celite.sup..COPYRGT.. The filtrate was washed with
NaHCO.sub.3 and brine, dried over sodium sulfate, filtered, and
concentrated. The resulting crude residue was dissolved in
dichloromethane (10 mL) and treated with Et.sub.3N (190 .mu.L, 1.36
mmol, 2 equiv.) and acryloyl chloride (27 .mu.L, 0.34 mmol, 0.5
equiv.). The reaction mixture was stirred at room temperature for
30 min, quenched with NaHCO.sub.3 (saturated) and extracted with
dichloromethane (3.times.). The organic phase was washed with water
and brine, dried over sodium sulfate, filtered, and concentrated.
The resulting residue was purified by flash chromatography on
SiO.sub.2 (methanol:dichloromethane; 1:30 to 1:10) to afford
compound 14 (78 mg, 30% yield, LC-MS m/z (M+H)=390.11).
[0451] Compound 14 (78 mg, 0.2 mmol, 1 equiv.) was dissolved in
1,4-dioxane (5 mL) and treated with compound 15 (26 mg, 0.24 mmol,
1.2 equiv.), NaHCO.sub.3 (0.6 mL, 1 N in water, 3 equiv.) and
PdCl.sub.2(Ph.sub.3P).sub.2 (14 mg, 0.02 mmol, 0.1 equiv.). The
reaction mixture was heated at 100.degree. C. for 3 h, cooled to
room temperature, filtered through Celite.sup..COPYRGT., and the
filtrate was extracted with ethyl acetate (3.times.). The organic
phase was then washed with water and brine, dried over sodium
sulfate, filtered, and concentrated. The resulting residue was
purified by flash chromatography on SiO.sub.2
(methanol:dichloromethane; 1:30 to 1:10) to afford compound 16 (40
mg, 48% yield, LC-MS m/z (M+H)=422.20).
##STR00216##
[0452] Compound 13 (360 mg, 1 mmol, 1 equiv.) was dissolved in
1,4-dioxane (5 mL) at room temperature and treated with compound 6
(190 mg, 1.5 mmol, 1.5 equiv.), PdCl.sub.2(Ph.sub.3P).sub.2 (70 mg,
0.1 mmol, 0.1 equiv.) and NaHCO.sub.3 (3 mL, 1 N in water, 3
equiv.). The reaction mixture was heated at 100.degree. C. for 3 h,
cooled to room temperature, filtered through celite, and the
filtrate was extracted with ethyl acetate (3.times.). The organic
phase was then washed with water and brine, dried over sodium
sulfate, filtered and concentrated. The resulting residue was
purified by flash chromatography on SiO.sub.2
(methanol:dichloromethane; 1:30 to 1:10) to afford compound 17 (210
mg, 52% yield, LC-MS m/z (M+H)=412.14).
[0453] Compound 17 (200 mg, 0.48 mmol, 1 equiv.) was dissolved in
ethyl acetate (10 mL) at room temperature, treated with
SnCl.sub.2.2H.sub.2O (540 mg, 2.4 mmol, 5 equiv.) and heated at
65.degree. C. for 4 h. Following, the reaction mixture was cooled
and filtered through celite. The resulting filtrate was washed with
NaHCO.sub.3 and brine, dried over sodium sulfate, filtered, and
concentrated. The residue was then purified by flash chromatography
on SiO.sub.2 (methanol:dichloromethane; 1:30 to 1:10) to afford
compound 18 (95 mg, 52% yield, LC-MS m/z (M+H)=382.24).
[0454] 4-Bromo-but-2-enoic acid (21 mg, 0.13 mmol, 1.3 equiv.) was
dissolved in dichloromethane (1 mL) and treated with (COCl).sub.2
(22 .mu.L, 0.26 mmol, 2 equiv.) and DMF (1 drop, 0.1 equiv.). After
1 h at room temperature, the solvents were evaporated. The crude
residue was then dissolved in dichloromethane (1 mL) and treated
with Et.sub.3N (36 .mu.L, 0.26 mmol, 2 equiv.), and compound 18 (38
mg, 0.1 mmol, 1 equiv.). After 2 h, the solvent was removed and the
crude residue was dissolved in THF (1 mL) and treated with
dimethylamine (0.13 mL in THF of 2 M solution, 0.26 mmol, 2
equiv.). The reaction mixture was stirred for 2 h, quenched with
NaHCO.sub.3 (saturated), and extracted with dichloromethane
(3.times.). The organic phase was washed with water and brine,
dried over sodium sulfate, filtered, and concentrated. The
resulting residue was purified by flash chromatography on SiO.sub.2
(methanol:dichloromethane; 1:30 to 1:10) to afford compound 19 (12
mg, 25% yield, LC-MS m/z (M+H)=493.34).
[0455] It will be appreciated that where typical or preferred
process conditions (i.e., reaction temperatures, times, mole ratios
of reactants, solvents, pressures, etc.) are given, other process
conditions can also be used unless otherwise stated. Optimum
reaction conditions may vary with the particular reactants or
solvent used, but such conditions can be determined by those
skilled in the art by routine optimization procedures.
[0456] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions. The
choice of a suitable protecting group for a particular functional
group as well as suitable conditions for protection and
deprotection are well known in the art. For example, numerous
protecting groups, and their introduction and removal, are
described in Greene et al., Protecting Groups in Organic Synthesis,
2.sup.nd Ed.; Wiley: New York, 1991, and references cited
therein.
[0457] The compounds provided herein may be isolated and purified
by known standard procedures. Such procedures include, but are not
limited to, trituration, recrystallization, column chromatography,
or HPLC.
Example 2. X-Ray Crystal Structure of QL-X-138
[0458] QL-X-138 (see FIG. 7 for the chemical structure), a
structural analog of QL-XII-47, has been successfully crystallized
with EGFR kinase that contains a cysteine in the same position as
the Tec-family kinases (FIG. 7). The structure shows the expected
hydrogen bond between the quinoline nitrogen and the "hinge" region
amino acid Met793. The pyrazole group is directed towards a
hydrophobic pocket at the back of the ATP-pocket which the
para-methyl aniline group is nestled beneath the P loop and a
covalent bond with Cys797 is apparent.
Example 3. Cell-Based Mini-Screen of Acrylamide-Containing
Compounds for the Identification of Novel Covalent Inhibitors of
DENV
Methods
[0459] Small molecule screens (Chu et al., Proc. Nat. Acad. Sci.
USA (2007) 104:3520-3525) and RNAi (Sessions et al., Nature (2009)
458:1047-1050) have been utilized to identify host factors that are
required for Dengue virus (DENV) replication, with a particular
interest in host kinases that modulate DENV replication. As an
extension of this work, a cell-based mini-screen of a 30-compound
subset of acrylamide-containing compounds was performed to identify
novel covalent inhibitors of DENV. The compounds were designed to
react covalently upon binding in the proper orientation near a
reactive cysteine.
[0460] Huh7 cells were seeded in 24-well plates and infected at an
MOI (multiplicity of infection) of 1 with 100 .mu.l of DENV2 New
Guinea C (DENV2-NGC). Plates were incubated for 1 hour at
37.degree. C. and rocked every 15 min. Unadsorbed virus was removed
by a PBS wash, after which 500 .mu.l of Dulbecco's modified Eagle's
medium (DMEM) supplemented with 2% FBS and the indicated
concentrations of small molecule was added to each well. After
incubation at 37.degree. C. for 24 hours, the supernatants were
collected for DENV2 titration using a focus forming assay,
described as follows. BHK-21 cells were seeded in 24-well plates.
Aliquots from infections were thawed at 37.degree. C. in a water
bath. Ten-fold dilutions in EBSS were prepared in duplicate, and
100 .mu.l of each dilution were added to the cells. Plates were
incubated for 1 hour at 37.degree. C. and rocked every 15 min.
Unadsorbed virus was removed by washes with PBS, after which 1 ml
of MEM-.alpha. supplemented with carboxymethylcellulose (CMC),
HEPES, and 2% FBS, was added to each well and incubated at
37.degree. C. for 3 days. The CMC overlay was aspirated, and cells
were washed with PBS and fixed with methanol for 15 min at
-20.degree. C. After fixation, the cells were washed with PBS and
incubated for 1 hour at room temperature with anti-DENV2 C antibody
(provided by John Aaskov), followed by incubation with
HRP-conjugated anti-mouse IgG antibody. The plates were revealed
with Vector VIP Peroxidase Substrate kit (Vector Laboratories
SK-4600) following manufacturer's instructions. The results are
shown in FIGS. 2B, 2C, and 2G.
[0461] Huh7 cells were seeded in 96-well plates and infected at an
MOI of 1 with 100 .mu.l of DENV2 supplemented with the indicated
concentrations of small molecule. As a positive control for
cytotoxicity, some wells were supplemented with 0.1% saponin. The
plates were incubated for 24 hours at 37.degree. C., and the cell
cytotoxicity was measured following the instructions of the
CellTiter-Glo Luminescent cell viability assay (Promega G7570). The
results are shown in FIG. 2D.
[0462] Huh7 cells were infected at an MOI of 1 with DENV1-WP74,
DENV2-NGC, DENV3-THD3, or DENV4-TVP360 as described in FIG. 2B. The
supernatants collected at 24 hours post-infection were analyzed by
focus forming assay in Vero cells. The experimental set up for
focus forming assay in Vero cells was similar to what was described
in FIG. 2B for BHK21 cells, except that the cells were incubated in
DMEM for 4 days at 37.degree. C. and revealed using anti-DENV E
antibody (4G2). The results are shown in FIG. 2E.
[0463] Huh7 cells were infected at an MOI of 1 with Kunjin virus as
described in FIG. 2B. The supernatants collected at 24 hours
post-infection were analyzed by plaque assay in BHK21 cells. The
experimental set up for plaque assay was similar to what was
described in FIG. 2B for focus forming assay, except that after 3
days incubation at 37.degree. C., the cells were stained with
crystal violet to reveal the plaques. The results are shown in FIG.
2F.
Results
[0464] This screen allowed the identification of QL-XII-47, a
tricyclic quinoline derivative, that causes >3-log.sub.10 unit
decrease in DENV2 New Guinea C (DENV2-NGC) yield at single-digit
micromolar concentrations (EC.sub.90 400 nM) (FIGS. 2A and 2B). It
was confirmed that QL-XII-47 is mostly likely functioning as a
covalent inhibitor by demonstrating that QL-XII-47R, in which the
reactive acrylamide has been replaced with an unreactive propyl
amide, results in a complete loss of activity (FIGS. 2A and 2C). No
cytotoxicity was observed for QL-XII-47 at 20 .mu.M, the highest
concentration tested (FIG. 2D). QL-XII-47 also inhibits additional
DENV strains representative of the four DENV serotypes (DENV1 to
DENV4) and Kunjin virus, another flavivirus, in yield reduction
assays (FIGS. 2E and 2F). In addition, QL-XI-76 was identified, in
which the pyrazole of QL-XII-47 is replaced with a furan, as a
negative control compound that is devoid of anti-DENV activity at
concentrations up to 10 .mu.M (FIGS. 2A and 2G). QL-XI-76
demonstrates that non-covalent interactions are also key to
QL-XII-47's activity and that the presence of an electrophilic
acrylamide moiety is not sufficient to confer anti-DENV
activity.
Example 4. Time-of-Addition Experiments for the Investigation of
the Stage(s) of the Viral Life Cycle Affected by QL-XII-47
Methods
[0465] In order to investigate the stage(s) of the viral life cycle
affected by QL-XII-47, time-of-addition experiments were
performed.
[0466] The results shown in FIGS. 3A and 3B were obtained by using
experiments performed essentially as described in Example 3. The
small molecule was diluted in media and added to the cells at the
indicated times pre- or post-DENV2 infection.
[0467] The plasmids used for recombinant viral particles (RVP)
production were provided by Ted Pierson (Ansarah-Sobrinho et al.,
Virology (2008) 381:67-74). To produce RVPs, HEK293T cells were
co-transfected with pCDNA6.2-D2.CprME (Ansarah-Sobrinho et al.,
Virology (2008) 381:67-74) and pWIIrep-REN-IB (Pierson et al.,
Virology (2006) 346:53-65) using Lipofectamine 2000 (Life
Technologies 11668-019) according to the manufacturer's
instructions. The supernatants were collected at 2 days
post-transfection and filtered through a 0.45 .mu.m filter to
remove contaminant cells in the supernatants. Huh7 cells seeded in
48-well plates were infected with 100 .mu.l of RVPs. The plates
were incubated for 1 hour at 37.degree. C. and rocked every 15 min.
Unadsorbed RVPs were removed by a PBS wash, after which 300 .mu.l
of DMEM supplemented with 2% FBS and the indicated concentrations
of small molecule was added to each well. After incubation at
37.degree. C. for 24 hours, the cells were collected and the
samples were processed following the instructions in the Renilla
luciferase assay system (Promega E2810). The Renilla luciferase
signal was read using Perkin Elmer EnVision plate reader. The
results are shown in FIG. 3C.
[0468] The plasmid containing a DENV2 replicon that expresses a
reporter firefly luciferase in place of DENV2 structural proteins
was provided by Eva Harris (Holden et al., Virology (2006)
344:439-452). In vitro transcripts were synthesized from PstI
linearized pDENrep-FH using T7-Scribe Standard RNA IVT kit
(CellScript C-AS3107) and m7G(5')ppp(5')A RNA cap structure analog
(New England Biolabs S 1405L) following the manufacturers
instructions. Huh7 cells were washed twice in PBS and 1.10.sup.6
cells were electroporated with DENV2 replicon in vitro transcripts
using ECM 830 electroporator (BTX Harvard Apparatus) at the
following settings: 5 pulses at 820 V, 100 s per pulse with 1.1 s
intervals. After electroporation, the cells were seeded in 24-well
plates and at 24 hours post-electroporation, and the media was
changed and supplemented with DMSO or 2 .mu.M of the indicated
small molecules. At 72 hours post-electroporation, the cells were
collected, and the samples were processed following the
instructions in the luciferase assay system (Promega E1483). The
firefly luciferase signal was read using Perkin Elmer EnVision
plate reader. The results are shown in FIG. 3D.
[0469] The plasmid used for virus-like particles (VLP) production
was provided by Stephen Harrison. Briefly, the codon optimized
sequence of DENV2-FGA/02 prM-E (Wang et al., PLoS ONE (2009)
4:e8325) was introduced in the pCDNA3.1 vector. To produce VLPs,
Huh7 cells were transfected with pCDNA3.1-D2.VLP using
Lipofectamine 2000 (Life Technologies 11668-019) according to the
manufacturer's instructions. At 4 hours post transfection, the
cells were treated with DMSO, 3 .mu.M of QL-XII-47, or 10 .mu.M of
Ki20227 or GNF2. The supernatants were collected at 24 hours
post-treatment and precipitated for 3 hours at 4.degree. C. by the
addition of 0.075% of PEG 8000. The VLPs were pelleted by
centrifugation at 10,000 g for 15 min at 4.degree. C. The pellet
was suspended in 200 .mu.l of 1.times.TNE (10 mM Tris-HCl pH 7.5,
2.5 mM EDTA, 50 mM NaCl), loaded over a sucrose cushion (800 .mu.l
of 12.5% sucrose in 1.times.TNE), and centrifuged at 100,000 g for
2 h at 4.degree. C. The supernatants were discarded, and the
purified VLPs were suspended in 50 .mu.l of 1.times.TNE. 25 .mu.l
of purified VLPs were analyzed for DENV2 E protein expression by
Western blotting using 4G2 antibody. An equal amount of purified
VLPs was loaded on a SDS-PAGE and submitted to Coomassie staining
to control for equal loading of the VLPs-enriched supernatants.
Steady state expression of DENV2 E protein in the cell lysates was
analyzed by Western blotting using 4G2 antibody. The results are
shown in FIG. 3E.
Results
[0470] It was discovered that potent inhibition of DENV is still
observed when cells are pretreated with QL-XII-47 for 6 hours and
then washed prior to infection with DENV (FIG. 3A). This strongly
suggests that QL-XII-47 acts via a host target and interferes with
a step early in the DENV life cycle. The time-of-addition
experiments show that the maximal anti-DENV effect was observed
when QL-XII-47 is present at 0-3 hours post-infection (FIG. 3B);
QL-XII-47's inhibitory activity is lost over time when QL-XII-47 is
added at later times post-infection. Consistent with the idea that
QL-XII-47 inhibits steps early in the DENV life cycle (e.g.,
entry), it was found that QL-XII-47 has potent inhibitory activity
in a single cycle reporter Dengue virus assay (RVP)
(Ansarah-Sobrinho et al., Virology (2008) 381:67-74) that expresses
a luciferase reporter upon successful entry and translation of a
subgenomic replicon RNA (FIG. 3C) but does not have activity in an
assay in which a subgenomic reporter replicon RNA is electroporated
into cells to bypass viral entry (FIG. 3D). Likewise, QL-XII-47 did
not inhibit the yield of virus-like particles (VLPs) produced when
a plasmid encoding the prM-E proteins was transfected into cells
(FIG. 3E), suggesting that QL-XII-47 does not inhibit viral
particle assembly or egress.
Example 5. Time-Course Experiments for the Determination of
QL-XII-47's Effect on the Different Stages of DENV Entry
Methods
[0471] To better understand QL-XII-47's effect on DENV entry, a
time course experiment was performed, and qRT-PCR and fluorescence
in situ hybridization were used to monitor the fate of the genomic
RNA of the DENV inoculum in the presence and absence of QL-XII-47
(FIGS. 4A and 4B).
[0472] Huh7 cells were seeded in 6-well plates and infected at an
MOI of 1 with 300 .mu.l of DENV2-NGC. As a positive control for
inhibition of viral fusion, DENV2-NGC was pre-incubated at
37.degree. C. for 15 min with 5 .mu.M of DENV2 stem-peptide
DENV2.sup.419-447, which was provided by Aaron Schmidt and Stephen
Harrison (Schmidt et al., PLoS Pathogens (2010) 6:e1000851). The
plates were incubated with the virus for 1 hour at 37.degree. C.
and rocked every 15 min. Unadsorbed virus was removed by a PBS
wash, after which 2 ml of media supplemented with DMSO or 2 .mu.M
of QL-XII-47 was added to each well. After incubation at 37.degree.
C. for the indicated time, total RNA was extracted from infected
cells using TRIzol reagent following manufacturer's instructions
(Life Technologies 15596-018). cDNA was generated on 500 ng of
total RNA using random hexamers to prime reverse transcription
reactions using iScript cDNA Synthesis kit (Bio-Rad 178-8890)
following manufacturer's instructions. cDNAs were then diluted 1:10
with nuclease-free water, and qPCR was performed with the cDNA
using the iQ SYBR Green Supermix kit (Bio-Rad 170-8880) according
to the manufacturer's instructions. Reactions were run on a MyiQ
iCycler (Bio-Rad) and analyzed with the MyiQ Optical System
Software (Bio-Rad, Hercules, Calif.). qPCR conditions were an
initial 95.degree. C. for 5 min, followed by 40 cycles of
95.degree. C. for 15 s and 60.degree. C. for 30 s. Primers used
were: DENV2 FW: 5'-AATATGCTGAAACGCGAGAGA-3' (SEQ ID NO: 1); DENV2
RV: 5'-GGGATTGTTAGGAAACGAAGG-3'(SEQ ID NO: 2); GAPDH FW:
5'-GAGTCAACGGATTTGGTCGT-3' (SEQ ID NO: 3); GAPDH RV:
5'-TTGATTTTGGAGGGATCTCG-3' (SEQ ID NO: 4). For each sample the
DENV2 RNA copy number was normalized to the GAPDH RNA copy number.
The results are shown in FIG. 4A.
[0473] Huh7 cells were seeded in 24-well plates on cover slips and
infected at an MOI of 10 with 100 .mu.l of DENV2-NGC. Plates were
incubated with the virus for 1 hour at 37.degree. C. and rocked
every 15 min. Unadsorbed virus was removed by a PBS wash, and mock-
or DENV2-infected cover slips were collected to serve as a
reference before addition of the small molecule. 1 ml of media
supplemented with DMSO or 2 .mu.M of QL-XII-47 was added to the
remaining wells, and the cells were incubated at 37.degree. C. The
remaining cover slips were collected at 3 h, 6 h, 9 h, 12 h, 15 h,
and 18 h post small molecule treatment. For each collection the
cover slips were fixed using 4% of paraformaldehyde. After
incubation for 15 min at room temperature, the cover slips were
washed with PBS and kept at 4.degree. C. until processing.
Detection of DENV2 viral RNA in the cells was done using QuantiGene
ViewRNA ISH Cell Assay kit (Panomics QVC0001) following
manufacturer's instructions using a DENV2 specific probe set
(Panomics VF1-10744). The cover slips were mounted with ProLong
Gold antifade reagent (Life Technologies P36930) prior to wide
field imaging (nearest neighbors analysis) using a Marianas
Spinning Disk confocal microscope. The results are shown in FIG.
4B.
Results
[0474] DENV genomic RNA persists at a relatively unchanged copy
number in the presence of QL-XII-47 and exhibits a punctate,
cytoplasmic localization. In untreated cells, this signal decays
and disappears by 12 hours followed by abundant perinuclear genomic
RNA at 18-24 hours due to synthesis of new viral RNA genomes. In
cells treated with a DENV-derived peptide that has been previously
demonstrated to block viral fusion (Schmidt et al., PLoS Pathogens
(2010) 6:e1000851), DENV RNA is decreasing by 24 hours
post-infection, presumably due to degradation of the virion in the
lysosome (FIG. 4A). These data suggest that DENV entry is blocked
at a "late entry step" that occurs after uptake of the virion but
prior to release of the genome from the nucleocapsid since the DENV
appears to be protected from cytoplasmic nucleases.
Example 6. Antiviral Activities of QL-XII-47 Against Additional
Viruses
[0475] To examine QL-XII-47 and QL-XII-56's spectrum of activity as
antiviral agents, QL-XII-47 and QL-XII-56 were tested against a
panel of additional viral pathogens using methods similar to what
are described in other Examples herein.
[0476] Potent inhibition of vesicular stomatitis virus (VSV), a
negative-strand RNA virus unrelated to DENV, was observed;
moreover, time-of-addition experiments indicate that QL-XII-47
inhibits VSV at a step early in the VSV life cycle (FIG. 5A).
Furthermore, imaging experiments using fluorescently labeled VSV
suggest that QL-XII-47 may interfere with a step late in VSV's
entry process since it does not affect VSV attachment or uptake.
QL-XII-47 also potently inhibits VSV pseudotyped with Ebola and
rabies virus glycoproteins (EboV and RABV, respectively) (FIG. 5A).
In general, the attachment, uptake, and fusion steps of pseudotyped
virus entry are expected to be directed by the Ebola and rabies
virus glycoproteins, while the steps of endosomal escape, genome
release, and initiation of viral gene expression are believed to
follow the mechanisms utilized by wildtype VSV. Therefore, current
data may suggest that QL-XII-47 inhibits entry of Ebola and rabies
viruses but may also suggest that QL-XII-47 acts at a post-fusion
step of viral entry that is shared between wildtype VSV and its
pseudotypes.
[0477] QL-XII-47 exhibits inhibitory activity against herpes
simplex virus 1 (HSV-1), human cytomegalovirus (HCMV), and
poliovirus (FIGS. 5B to 5D) in assays that quantify viral entry and
gene expression (HCMV and poliovirus) or plaque formation (HSV-1).
In less sensitive assays measuring virus-induced cytopathic effects
(CPE), QL-XII-47 was a modest inhibitor of Japanese Encephalitis
virus (JEV) and Junin virus (FIGS. 5E and 5F) but had no activity
against influenza virus or vaccinia virus. It was noted that since
QL-XII-47 is believed to act via a host target, the cell line and
species type used for testing is likely to affect the observed
antiviral activity. On a similar note, although cytotoxicity with
QL-XII-47 at concentrations up to 20 .mu.M in experiments using
Huh7, Vero, BHK21, and 3T3 cell lines was not observed,
single-digit micromolar cytotoxicity was observed in Hela and 293
cell lines. Therefore, while it is known that QL-XII-47's activity
against DENV and other viruses is not due to host cell death,
on-going studies have been designed to clarify and to better
understand QL-XII-47's range of antiviral activity and cytotoxicity
profile in additional cell lines.
[0478] Both QL-XII-47 and QL-XII-56 show inhibitory activity
against Ebola glycoprotein (EBOV) (FIGS. 5G to 5J), Marburg virus
(MARV) (FIGS. 5K to 5N), Junin virus (JUNV) (FIGS. 5O and 5P),
Lassa fever virus (LASV) (FIGS. 5Q and 5R), Venezuelan equine
encephalitis virus (VEEV) (FIGS. 5S and 5T), and Rift Valley fever
virus (RVFV) (FIGS. 5U and 5V).
Example 7. RNAi-Mediated Depletion Experiments and Cell-Based
Assays Showing Bmx is not the Target Mediating QL-XII-47's
Anti-DENV Activity
Methods
[0479] Huh7 cells were seeded in 24-well plates and concomitantly
transfected with 100 nM of non-targeting (Sigma SIC001) or Bmx
MISSION siRNAs (Sigma pool of SASI_Hs01_00019552,
SASI_Hs01_00019553 and SASI_Hs01_00185298) using Lipofectamine
RNAiMAX (Life Technologies 13778-075) and following the
manufacturer's instructions. At 48 hours post-siRNA transfection,
the cells were infected at an MOI of 1 with 100 .mu.l of DENV2-NGC.
The plates were incubated with the virus for 1 hour at 37.degree.
C. and rocked every 15 min. Unadsorbed virus was removed by a PBS
wash, after which 500 .mu.l of DMEM supplemented with 2% FBS was
added to each well. After incubation at 37.degree. C. for 24 hours,
the supernatants were collected for DENV2 titration using a focus
forming assay, as described in Example 3. The results are shown in
FIG. 6A.
[0480] The results shown in FIG. 6B were obtained by using the
methods described in Example 3.
Results
[0481] Extensive kinase profiling of QL-XII-47 using biochemical
and chemical proteomic approaches such as KiNativ50 identified two
Tec-family kinases, Bmx and Btk, as potent (IC.sub.50 7 nM)
biochemical and cellular targets of QL-XII-47. However, data
indicate that neither of these kinases is likely responsible for
the potent anti-DENV activity of the compound. Btk is a B
lymphocyte-specific kinase and not expressed in the Huh7 cells used
in the DENV experiments. While Bmx is known to be more widely
expressed, it was not detected in Huh7 by microarray expression
profiling (see, e.g., biogps.org/#goto=genereport&id=660) or by
Western blot. Moreover, RNAi-mediated depletion of any low level
Bmx expression had no effect on DENV replication (FIG. 6A). In
addition, DENV is not inhibited by PCI-32765, another covalent
inhibitor of Bmx and Btk (IC.sub.50 0.5 nM) (Honigberg et al.,
Proc. Nat. Acad. Sci. USA (2010) 107:13075-13080) (FIG. 6B).
Example 8. Identification of Candidate Targets by "Click"
Chemistry
[0482] To identify cellular proteins that are covalently targeted
by QL-XII-47, a chemical proteomics approach using
"click-chemistry" was performed.
[0483] QL-XII-47AL, an analog of QL-XII-47 modified with an alkyne
group, was designed which can undergo a copper-catalyzed
cyclo-addition reaction with an azide group (the so-called "click"
reaction) and which retains the antiviral activity of QL-XII-47
(FIGS. 8A and 8B). The advantage of "click-chemistry" relative to
conventional affinity chromatography is that the QL-XII-47AL can be
introduced to living cells infected with DENV thereby allowing bond
formation under more physiological conditions. Subsequent cell
lysis and reaction with desthiobiotin-PEG-azide, followed by
capture with streptavidin beads, trypsin digestion, and
mass-spectrometry allows identification of potential target
proteins. This approach is powerful because both host and viral
targets can be identified. Several potential targets have been
identified using this approach (FIGS. 8A and 8B). Analysis of the
sites labeled demonstrates that many of these targets were modified
on a cysteine residue located in the catalytic site, suggesting
that QL-XII-47 is likely to disable enzymatic activity as
predicted. This approach may be used to identify candidate targets
of QL-XII-47 and other inhibitors and to generate "clickable"
derivatives of compounds that are structurally similar to QL-XII-47
but that do not inhibit DENV (e.g., QL-XI-76, see FIGS. 2A and 2G).
Parallel proteomic analysis using the negative controls should help
to eliminate candidates that covalently react with the inhibitor
but that are not relevant to antiviral activity.
[0484] Molecular modeling may also be performed of the inventive
compounds bound to the targets identified by the click-chemistry
pull-down experiments in order to rationalize target-based SAR and
to guide potential chemical modifications. For example, QL-XII-47AL
covalently modifies Cys302 of aldehyde dehyrodenase 1 (ALH1), and
molecular docking suggests that QL-XII-47 fits well into the
nicotinamide binding site of ALDH1 with the acrylamide perfectly
poised to react with Cys302 (FIGS. 9A and 9B). Furthermore, the
methyl pyrazole side-chain of QL-XII-47 is predicted to form a key
hydrogen bond with the backbone NH of Cys302 and Cys303, an
interaction that is lost in negative control compound QL-XI-76,
which contains a non-hydrogen bond competent furan at this
position. Based on these models, compounds may be designed that
will disrupt key interactions, and this will allow for establishing
whether a correlation exists between inhibition of a potential
target (such as ALDH1) and the anti-DENV activity of the compound.
This is a classical approach to establishing the relevance of a
particular target that is complementary to the RNAi.
[0485] In sum, a class of substituted quinolones, exemplified by
QL-XII-47, has been discovered to show potent anti-DENV activity in
vitro. QL-XII-47 causes a >3-log.sub.10 unit drop in viral titer
at single-digit micromolar concentrations with no observed
cytotoxicity. QL-XII-47 has activity against strains representative
of all four DENV serotypes (DENV1-DENV4) as well as against Kunjin
virus (KUNV) and Japanese Encephalitis Virus (JEV), related members
of the Flaviviridae family. In addition, it has been found that
QL-XII-47 exhibits activity against vesicular stomatitis virus
(VSV) and VSV expressing rabies or Ebola glycoproteins, and other
viruses, suggesting that QL-XII-47 may have broad spectrum activity
against additional Category A, B, or C viral pathogens. Preliminary
experiments suggest strongly that QL-XII-47 inhibits a step early
in the DENV life cycle by covalently modifying a reactive cysteine
residue in a yet-to-be-identified host factor. QL-XII-47 (EC.sub.90
400 nM) is more than ten-fold more potent than 7-DMA, and thus it
is believed that inhibitors similar to QL-XII-47 will have
commensurately greater decreases in viral burden and the
inflammatory cytokine response.
Example 9. QL-XII-47 Inhibited DENV2 Viral Production
[0486] Huh7 cells were infected with DENV2 virus at MOI of about 1
during one hour at 37.degree. C. Then, at time (t)=0, the cells
were rinsed once with PBS and then medium (DMEM supplemented with
2% FBS and either 4 .mu.M QL-XII-47 or DMSO) was added. At each
indicated time, supernatants were harvested for titration in
FFU/ml, cell lysed for RNA extraction and reverse transcription
quantitative polymerase chain reaction (RTqPCR). Additional
duplicates were done in parallel for Western blotting.
[0487] The results, shown in FIGS. 10A to 10C, indicate that
QL-XII-47 inhibited DENV2 viral production. Values of FFU (focus
forming units)/ml were decreased for the infected cells treated
with QL-XII-47 after about 12 hours of infection compared to the
infected cells not treated with a compound of the invention (FIG.
10A). Viral count was also decreased for the infected cells treated
with QL-XII-47 after about 12 hours of infection compared to the
infected cells not treated with a compound of the invention (FIG.
10B).
Example 10. QL-XII-47 and QL-XII-56 Inhibited DENV2 Translation
[0488] Plasmid pDV2-Fluc(WT) or pDV2-FlucGDV encode dengue virus
serotype 2 RNAs in which a luciferase reporter gene replaces most
of the genes encoding core, prM, and E. In vitro transcripts of the
wildtype replicon (WT) and a mutant that cannot replicate RNA due
to mutations in the active site of the viral polymerase (GDV
mutant) were produced. Huh7 cells were electroporated with the
respective DV2-replicon RNAs. Directly after electroporation cells
are incubated with the indicated drug (QL-XII-47 2 .mu.M,
cycloheximide 30 .mu.g/ml, MPA 5 .mu.M). At the indicated time
post-electroporation, luminescence was measured as a marker of
translation. For the WT construct, luc activity at an early time
point (12 hours or less) reflect translation of the input RNA
delivered by electroporation; luc activity at later time points
reflects luc translated from both input and newly synthesized
replicon RNA. Since the GDV mutant cannot synthesize new viral RNA,
luciferase activity observed at all time points is the product of
the input RNA delivered by electroporation.
[0489] Linearized plasmid was used for in vitro Transcription (IVT)
and capped (no capping for IRES-EMC-Fluc). Those RNAs are then
electroporated in Huh7 cells. Directly after electroporation cells
are incubated with the indicated compound (QL-XII-47 (2 .mu.M),
cycloheximide (30 .mu.g/ml), or mycophenolic acid (MPA, 5 .mu.M)).
At the indicated time post electroporation, cells were washed with
PBS and lysed using the adapted lysis buffer (Firefly, Renilla or
Dual lysis buffer from Promega). Luminescence is measured using
Firefly, Renilla or Dual kit following recommendations, and read on
Envision instrument. The results are shown in FIG. 11.
[0490] Huh7 cells were electoporated with IVTs of DENV2-Fluc(WT) or
DENV2-Fluc (GDV). Some cells were treated with the indicated
compound (QL-XII-47 (2 .mu.M), QL-XII-56 (2 .mu.M), or
cycloheximide (CHX, 30 .mu.g/ml)), and other cells were not treated
with the indicated compound. Firefly Luciferase luminescence was
measured at indicated times. The results are shown in FIGS. 12A to
12B and Table 1. FIG. 12A shows the luciferase activity measured at
6 hours post-electroporation for Huh7 cells electroporated with the
wildtype (WT) or mutant (MUT) replicon RNAs and then treated with 2
.mu.M QL-XII-47, 2 .mu.M QL-XII-56, 30 .mu.g/mL cycloheximide (CHX)
as general inhibitor of translation, or DMSO as a negative control.
Luciferase at this time point is due to translation template by the
input RNA electroporated into cells. Reduced luciferase activity
for the cells treated with QL-XII-47, QL-XII-56, and cycloheximide
indicates reduced translation of both WT and GVD replicons. FIG.
12B shows luciferase activity measured at the indicated time point
for cells electroporated with the WT or GVD replicon RNA and then
treated with DMSO, QL-XII-47, QL-XII-56, or cycloheximide as
indicated. For the WT replicon, luciferase at early time points (6
h) reflects translation of the input RNA; luciferase activity at
later time points (24, 48, 72 h) reflects translation template by
newly synthesized RNA. For the GVD mutant, which cannot replicate
viral RNA due to mutation of the viral polymerase active site,
luciferase at all time points reflects the input RNA alone. The
data in column 3 indicate the p-value calculated by the student's
t-test for comparison of the compound-treated samples with the
DMSO-treated negative control, demonstrating the statistical
significance of the inhibition of viral RNA translation by
QL-XII-56, QL-XII-47, and CHX.
TABLE-US-00001 TABLE 1 P-values of compound-treated samples P-value
for student's t test comparison of compound-treated to untreated
negative control (Cap-driven) GDV QL-XII-56 0.000441 QL-XII-47
0.000121 CHX 0.000186 WT QL-XII-56 0.000181 QL-XII-47 0.000039 CHX
0.000111
[0491] These results indicate that QL-XII-47 and QL-XII-56
inhibited DENV2 RNA translation.
Example 11. QL-XII-47 and QL-XII-56 Inhibited Encephalomyocarditis
Virus (EMCV) IRES-Dependant Translation
[0492] Huh7 cells were electroporated with in vitro transcripts of
the DV2 WT and GVD replicon RNAs or an RNA encoding a luciferase
reporter under the control of the encephalomyocarditis virus (EMCV)
IRES element. Cells were treated QL-XII-47 or a combination of
cycloheximide (CHX) as a general inhibitor of translation and
mycophenolic acid (MPA) as an inhibitor of viral RNA replication or
with DMSO as a negative control immediately post-electroporation.
Luciferase activity was measured at 6 hours post-electroporation as
a measure of the translation of the different RNAs. Reduced
luciferase activity indicates reduction in translation of the RNA
in that sample. The data indicate that QL-XII-47 reduces
translation of WT and GVD DV replicon RNAs as well as translation
of the EMCV IRES; moreover, the reduction in translation is
comparable in magnitude to that caused by the CHX/MPA positive
control.
[0493] In order investigate Cap-dependent or IRES-dependent
translation of EMCV without DENV2 backbone, plasmid pFR-CrPV was
used. pFR-CrPV, a plasmid encoding the bicistronic expression
construct used to test cap-driven and IRES-driven translation from
the same RNA template. Firefly luciferase translation is cap-driven
while renilla luciferase expression is driven by the IRES element
of the Cricket paralysis virus (CrPV). When transfected into cells,
RNA pol II drives transcription to produce the bicistronic RNA.
Dual luciferase assay can be performed to measure translation of
both cap-dependent and IRES-driven translation. The plasmid was
previously published, see
www.pnas.org/content/early/2012/11/14/1216454109.abstract. Huh7
cells were retrotransfected with pFR-CrPV. 28 h post transfection,
the cells were treated with the indicated compound (QL-XII-47 (2
.mu.M), QL-XII-56 (2 .mu.M), CHX (30 .mu.g/ml)) for an additional
24 h. The cells were washed once with PBS and lysed with dual
luciferase assay buffer. The results are shown in FIGS. 15A and 15B
and Table 2. The data in column 3 of Table 2 indicate the value
calculated by the student's t-test for comparison of the
compound-treated samples with the DMSO-treated negative control,
demonstrating the statistical significance of the inhibition of
translation by QL-XII-56, QL-XII-47, and CHX.
TABLE-US-00002 TABLE 2 Statistical analysis of the reduction in
cap- dependent and IRES-dependent translation p-value for student's
p-value for student's t-test comparison of t-test comparison of
compound-treated to DMSO compound-treated to DMSO negative
control(Cap- negative control(IRES- driven translation) driven
translation QL-XII-47 0.019667 0.009291 QL-XII-56 0.026517 0.026662
CHX 0.013357 0.001974 Mock 0.00817 0.001656
[0494] These results indicate that QL-XII-47 and QL-XII-56
inhibited EMCV-IRES dependant translation in Huh7 cells.
Example 12. QL-XII-47 Biotin Test
[0495] Huh7 cells were infected with DENV2 virus at an MOI of about
1 during one hour at 37.degree. C. Then, at time (t)=0, the cells
were rinsed once with PBS. The cells were treated with the
indicated compound (QL-XII-47 or QL-XII-47 biotin) for 24 or 48 h.
Supernatants were harvested for titration in FFU/ml, cell lysed for
RNA extraction and RTqPCR. The structure of QL-XII-47 biotin is of
the following formula:
##STR00217##
[0496] The results, shown in FIG. 16, indicate that
QL-XII-47-biotin has significantly reduced inhibitory activity
against dengue virus.
Example 13. Test of the Effects of RNAi-Mediated Depletion of
Prdx1
[0497] Huh 7 cells were retrotransfected with siRNA Prdx1 and
plated in 12 well plates. At 48 h, the cells were infected with
DENV2 virus at an MOI of about 1 during one hour at 37.degree. C.
Some cells were treated for 24 h with 4 .mu.M of QL-XII-47 or
QL-XII-56, and other cells were not so treated. Supernatant were
harvested for titration and cells lysed for Western blotting.
[0498] The results are shown in FIGS. 17A to 17B. FIG. 17A shows
that RNAi-mediated depletion of Prdx-1 does not reduce steady-state
expression of dengue NS3 protein (left); moreover, combination
treatment of cells with siRNAs against Prdx-1 and QL-XII-47 does
not reduce steady-state expression of NS3 beyond what is observed
with QL-XII-47 alone. FIG. 17B shows the quantitation of infectious
viral particles released to the culture supernatants at 24 hours
post-infection showing that RNAi-mediated depletion of Prdx-1 does
not appear to inhibit dengue virus.
Example 14. QL-XII-47 and QL-XII-56 Inhibited Vesicular Stomatitis
Virus (VSV)
[0499] Vero cells were infected at an MOI of about 1 with VSV for 1
h at 37.degree. C. in Earle's balanced salt solution (EBSS). At
t=0, the cells were washed once with PBS and then medium (DMEM with
10% fetal bovine serum) containing the indicated compounds (N-(4
hydroxyphenyl)retinamide (4HPR, 5 .mu.M), QL-XII-47 (4 .mu.M), or
QL-XII-56 (4 .mu.M)) was added. At 6 h post infection (6 hpi),
supernatant were harvested for titration, and the cells were lysed
for RNA extraction and RTqPCR.
[0500] The results, shown in FIGS. 18A and 18B, demonstrate that
QL-XII-47 and QL-XII-56 inhibited VSV.
Example 15. QL-XII-47 and QL-XII-56 Inhibited Poliovirus Type 1
(PV1)
[0501] Vero cells were infected at an MOI of about 1 with PV1 for 1
h at 37.degree. C. in Earle's balanced salt solution (EBSS). At
t=0, the cells were washed once with PBS and then medium (DMEM with
10% fetal bovine serum) containing the indicated compound (N-(4
hydroxyphenyl)retinamide (4HPR, 5 .mu.M), QL-XII-47 (4 .mu.M), or
QL-XII-56 (4 .mu.M)) was added. At 6 h post infection (6 hpi),
supernatant were harvested for titration, and the cells were lysed
for RNA extraction and RTqPCR.
[0502] The results, shown in FIGS. 19A and 19B, demonstrate that
QL-XII-47 and QL-XII-56 inhibited PV1.
Example 16. Summary of FFA, RVP, Cytotoxicity Evaluation of the
Exemplary Compounds
[0503] Table 3 lists the results of FFA and RVP evaluation of the
exemplary compounds.
TABLE-US-00003 TABLE 3 FFA and RVP Evaluatin of Exemplary Compounds
FFA RVP RVP Compound Cytotox- (2 or (2 uM (2.5 uM No. icity 2.5 uM)
screen) pretreat) QL-XI-57 -- -- 2 -- QL-XI-55 NO 6 5 4 QL-VI-50 --
1 -- -- QL-XI-65 at 10 uM 77 6 12 QL-V-85 -- 1 -- -- QL-IX-97 -- 1
-- -- QL-X-39 -- 1 -- -- QL-X-132 -- -- 1 -- QL-XI-99 -- -- 1 --
QL-XI-100 -- -- 2 -- QL-XI-75 -- -- 1 -- QL-XII-01 -- -- 1 --
QL-XII-03 -- -- 1 -- QL-XII-37 -- -- 1 -- QL-XII-40 -- -- 1 --
QL-XII-58 -- 1 1 -- QL-XII-61 -- 1 1 -- QL-XI-76 -- 1 1 --
QL-XII-63 -- -- 2 -- QL-XII-66 -- -- 2 -- QL-XII-57 -- 1 2 --
QL-XI-77 NO 1 2 1 QL-X-138 NO 61 3 3 QL-X-134 NO 107 2 4 QL-XII-56
NO 62 1 6 QL-XII-115 NO 36000 5 43 QL-XII-54 NO 36000 70 95
QL-XII-38 -- -- 1 -- QL-XII-45 -- -- 1 -- QL-XII-46 -- -- 1 --
QL-XII-91 -- -- 1 -- QL-XII-48 -- -- 2 -- QL-XII-50 -- -- 2 --
QL-XII-51 at 5 uM 36000 2 -- QL-XII-47 NO 3600 19 106 QL-XII-44 at
10 uM 36000 8 125
OTHER EMBODIMENTS
[0504] The foregoing has been a description of certain non-limiting
embodiments of the invention. Those of ordinary skill in the art
will appreciate that various changes and modifications to this
description may be made without departing from the spirit or scope
of the present invention, as defined in the following claims.
[0505] All publications, including but not limited to journal
articles, books, patents, and patent applications, cited in this
specification are herein incorporated by reference as if each
individual publication were specifically and individually indicated
to be incorporated by reference herein as though fully set
forth.
EQUIVALENTS AND SCOPE
[0506] In the claims articles such as "a," "an," and "the" may mean
one or more than one unless indicated to the contrary or otherwise
evident from the context. Claims or descriptions that include "or"
between one or more members of a group are considered satisfied if
one, more than one, or all of the group members are present in,
employed in, or otherwise relevant to a given product or process
unless indicated to the contrary or otherwise evident from the
context. The invention includes embodiments in which exactly one
member of the group is present in, employed in, or otherwise
relevant to a given product or process. The invention includes
embodiments in which more than one, or all of the group members are
present in, employed in, or otherwise relevant to a given product
or process.
[0507] Furthermore, the invention encompasses all variations,
combinations, and permutations in which one or more limitations,
elements, clauses, and descriptive terms from one or more of the
listed claims is introduced into another claim. For example, any
claim that is dependent on another claim can be modified to include
one or more limitations found in any other claim that is dependent
on the same base claim. Where elements are presented as lists,
e.g., in Markush group format, each subgroup of the elements is
also disclosed, and any element(s) can be removed from the group.
It should it be understood that, in general, where the invention,
or aspects of the invention, is/are referred to as comprising
particular elements and/or features, certain embodiments of the
invention or aspects of the invention consist, or consist
essentially of, such elements and/or features. For purposes of
simplicity, those embodiments have not been specifically set forth
in haec verba herein. It is also noted that the terms "comprising"
and "containing" are intended to be open and permits the inclusion
of additional elements or steps. Where ranges are given, endpoints
are included. Furthermore, unless otherwise indicated or otherwise
evident from the context and understanding of one of ordinary skill
in the art, values that are expressed as ranges can assume any
specific value or sub-range within the stated ranges in different
embodiments of the invention, to the tenth of the unit of the lower
limit of the range, unless the context clearly dictates
otherwise.
[0508] This application refers to various issued patents, published
patent applications, journal articles, and other publications, all
of which are incorporated herein by reference. If there is a
conflict between any of the incorporated references and the instant
specification, the specification shall control. In addition, any
particular embodiment of the present invention that falls within
the prior art may be explicitly excluded from any one or more of
the claims. Because such embodiments are deemed to be known to one
of ordinary skill in the art, they may be excluded even if the
exclusion is not set forth explicitly herein. Any particular
embodiment of the invention can be excluded from any claim, for any
reason, whether or not related to the existence of prior art.
[0509] Those skilled in the art will recognize or be able to
ascertain using no more than routine experimentation many
equivalents to the specific embodiments described herein. The scope
of the present embodiments described herein is not intended to be
limited to the above Description, but rather is as set forth in the
appended claims. Those of ordinary skill in the art will appreciate
that various changes and modifications to this description may be
made without departing from the spirit or scope of the present
invention, as defined in the following claims.
Sequence CWU 1
1
4121DNAArtificial SequenceSynthetic Polynucleotide 1aatatgctga
aacgcgagag a 21221DNAArtificial SequenceSynthetic Polynucleotide
2gggattgtta ggaaacgaag g 21320DNAArtificial SequenceSynthetic
Polynucleotide 3gagtcaacgg atttggtcgt 20420DNAArtificial
SequenceSynthetic Polynucleotide 4ttgattttgg agggatctcg 20
* * * * *
References