U.S. patent number RE46,724 [Application Number 15/156,580] was granted by the patent office on 2018-02-20 for haloalkyl heteroaryl benzamide compounds.
This patent grant is currently assigned to Romark Laboratories, L.C.. The grantee listed for this patent is Romark Laboratories, L.C.. Invention is credited to Jean-Francois Rossignol, J. Edward Semple.
United States Patent |
RE46,724 |
Rossignol , et al. |
February 20, 2018 |
Haloalkyl heteroaryl benzamide compounds
Abstract
A new class of haloalkyl heteroaryl benzamides is described.
These compounds show strong activity against hepatitis viruses.
Inventors: |
Rossignol; Jean-Francois (St.
Petersburg, FL), Semple; J. Edward (Tampa, FL) |
Applicant: |
Name |
City |
State |
Country |
Type |
Romark Laboratories, L.C. |
Tampa |
FL |
US |
|
|
Assignee: |
Romark Laboratories, L.C.
(Tampa, FL)
|
Family
ID: |
1000002870875 |
Appl.
No.: |
15/156,580 |
Filed: |
May 17, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
12777383 |
May 11, 2010 |
8846727 |
|
|
|
61177626 |
May 12, 2009 |
|
|
|
Reissue of: |
14451637 |
Aug 5, 2014 |
9126992 |
Sep 8, 2015 |
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D
249/14 (20130101); C07D 275/03 (20130101); C07D
233/90 (20130101); A61K 31/427 (20130101); A61P
31/12 (20180101); C07D 231/40 (20130101); C07D
271/113 (20130101); A61P 31/14 (20180101); A61P
31/22 (20180101); C07D 263/48 (20130101); A61P
31/18 (20180101); A61P 31/20 (20180101); C07D
285/08 (20130101); C07D 277/56 (20130101); C07D
413/12 (20130101); A61K 31/433 (20130101); C07D
417/12 (20130101); C07D 231/44 (20130101); C07D
271/07 (20130101); C07D 405/12 (20130101); A61K
31/4196 (20130101); A61K 31/454 (20130101); C07D
409/06 (20130101); C07D 285/135 (20130101); A61K
45/06 (20130101); C07D 261/14 (20130101); C07D
277/46 (20130101); A61K 31/506 (20130101); C07D
233/88 (20130101); C07D 401/12 (20130101); C07D
403/12 (20130101); A61P 31/16 (20180101); A61K
31/4245 (20130101); A61P 43/00 (20180101); C07D
403/06 (20130101); C07D 417/06 (20130101); A61K
31/497 (20130101); C07D 261/14 (20130101); C07D
231/40 (20130101); C07D 231/44 (20130101); A61K
31/4245 (20130101); C07D 271/113 (20130101); C07D
271/07 (20130101); A61K 31/454 (20130101); C07D
233/88 (20130101); C07D 403/12 (20130101); A61K
31/427 (20130101); A61K 31/433 (20130101); A61K
31/497 (20130101); C07D 277/46 (20130101); C07D
405/12 (20130101); C07D 275/03 (20130101); C07D
277/56 (20130101); C07D 417/06 (20130101); A61K
31/4196 (20130101); A61K 45/06 (20130101); C07D
403/06 (20130101); C07D 413/12 (20130101); C07D
285/135 (20130101); C07D 401/12 (20130101); C07D
285/08 (20130101); C07D 417/12 (20130101); A61K
31/506 (20130101); C07D 409/06 (20130101); C07D
233/90 (20130101); C07D 249/14 (20130101); C07D
263/48 (20130101) |
Current International
Class: |
A61K
31/415 (20060101); C07D 271/07 (20060101); C07D
263/48 (20060101); C07D 417/12 (20060101); C07D
233/88 (20060101); C07D 233/90 (20060101); C07D
271/113 (20060101); C07D 275/03 (20060101); C07D
277/46 (20060101); C07D 277/56 (20060101); C07D
285/08 (20060101); C07D 285/135 (20060101); C07D
403/06 (20060101); C07D 403/12 (20060101); C07D
405/12 (20060101); C07D 409/06 (20060101); C07D
413/12 (20060101); C07D 417/06 (20060101); A61K
31/506 (20060101); A61K 31/497 (20060101); A61K
31/454 (20060101); C07D 401/12 (20060101); A61K
45/06 (20060101); C07D 231/40 (20060101); C07D
231/44 (20060101); C07D 285/125 (20060101); A61K
31/4168 (20060101); A61K 31/4196 (20060101); A61K
31/421 (20060101); C07D 261/14 (20060101); C07D
249/14 (20060101); C07D 233/38 (20060101); C07D
231/38 (20060101); A61K 31/433 (20060101); A61K
31/427 (20060101); A61K 31/4245 (20060101) |
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Sep 2010 |
|
WO |
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|
Primary Examiner: Johnson; Jerry D
Attorney, Agent or Firm: Foley & Lardner LLP
Government Interests
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
This invention was funded by NIAID contract NO1-AI-30046. The
United States government has certain rights in the invention.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application .Iadd.is a Reissue Application of U.S. Pat. No.
9,126,992, which issued on Sep. 8, 2015 from U.S. application Ser.
No. 14/658,409, which .Iaddend.is a Divisional of U.S. application
Ser. No. 12/777,383, filed May 11, 2010, .Iadd.which issued as U.S.
Pat. No. 8,846,727, on Sep. 30, 2014, .Iaddend.which claims benefit
of U.S. Provisional Application No. 61/177,626, filed May 12, 2009,
the entire contents of which are incorporated herein by reference.
Claims
The invention claimed is:
1. A pharmaceutical composition comprising a compound of Formula I:
##STR00400## wherein: R.sub.1 through R.sub.5 and R.sub.10 are,
independently, hydrogen, CN, NO.sub.2, F, Cl, Br, I, hydroxy,
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenyl,
cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl,
alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl,
alkoxyalkynyl, alkenyloxyalkyl, alkenyloxyalkenyl,
alkenyloxyalkynyl, alkynyloxyalkyl, alkenyloxyalkenyl,
alkenyloxyalkynyl, cycloalkoxy, cycloalkylalkoxy,
cycloalkylalkenyloxy, cycloalkylalkynyloxy, cycloalkenyloxy,
cycloalkenylalkoxy, cycloalkenylalkenyloxy, cycloalkenylalkynyloxy,
alkoxyalkylamino, hydroxyalkyl, acyl, acyloxy, aroyloxy,
arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, alkoxycarbonyloxy, carbamoyl,
carbamoyloxy, alkylamino, dialkylamino, alkylaminoalkyl, amido,
alkylamido, dialkylamido, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl,
alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl,
cycloalkylalkylsulfonyl, cycloalkylsulfonylalkyl,
cycloalkylalkylsulfonylalkyl, arylsulfonyl, arylalkylsulfonyl,
arylalkenylsulfonyl, heteroarylsulfonyl, heteroarylalkylsulfonyl,
heteroarylalkenylsulfonyl, alkylsulfonamido,
N,N'-dialkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl,
sulfonamidoarylalkyl, sulfonamidoarylalkenyl, aryl, arylalkyl,
aryloxy, arylalkoxy, arylthio, arylalkylthio, arylamino,
arylalkylamino, arylalkenyl, arylalkynyl, heteroaryl,
heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl,
heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, or heterocycloalkenyloxy, any of which may be
optionally substituted wherein R.sub.6 is selected from the group
consisting of haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy,
S(O).sub.mC(R.sub.7R.sub.8).sub.nCF.sub.3, and
C(R.sub.7R.sub.8).sub.nCF.sub.3; wherein W, X and Y are,
independently, S, O, N, NR.sub.9 or CR.sub.10 where at least two of
W, X, and Y are S, O, N, or NR.sub.9; wherein R.sub.7, R.sub.8, and
R.sub.9 are, independently, hydrogen, fluoro, chloro, alkyl,
perhaloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, or
together with the atoms to which they are attached, may be joined
to form an optionally substituted 4-to 8-membered heterocycloalkyl
or an optionally substituted 3- to 8-membered cycloalkyl ring, any
of which may be optionally substituted; m is an integer between 0
and 2; and n is an integer between 0 and 5; or a pharmaceutically
acceptable salt or ester thereof, and a pharmaceutically acceptable
carrier, wherein the composition comprises an effective amount of
the compound for treating a viral pathogen.
2. The pharmaceutical composition of claim 1, wherein the viral
pathogen is Hepatitis B or Hepatitis C Virus infection.
3. The pharmaceutical composition of claim 1, wherein the viral
pathogen is a parainfluenza, an influenza A, or an influenza B
infection.
4. A method for treating a viral infection comprising administering
the pharmaceutical composition of claim 1 to a patient in need
thereof.
5. A method for treating a viral infection comprising administering
the pharmaceutical composition as claimed in claim 1, to a patient
in need thereof, in combination with another antiviral
composition.
6. The method of claim 4, wherein the viral infection is selected
from the group consisting of respiratory viruses, herpes viruses,
and gastrointestinal viruses.
7. The method of claim 6, wherein said respiratory viral infection
is selected from the group consisting of parainfluenza, influenza
A, influenza B, coronavirus, rhinovirus (RHV), and respiratory
syncytial virus (RSV).
8. The method of claim 6, wherein said gastrointestinal virus is
selected from the group consisting of rotavirus and adenovirus.
9. A method for treating rhabdovirus comprising administering the
pharmaceutical composition of claim 1 to a patient in need
thereof.
10. The pharmaceutical composition of claim 1, wherein: R.sub.1
through R.sub.5 and R.sub.10 are, independently, hydrogen, cyano,
nitro, halo, hydroxy. alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy,
alkynyloxy, acyl, acyloxy, aroyloxy, heteroaroyloxy,
alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,
alkoxycarbonyloxy, carbamoyl, carbamoyloxy, alkylamino, haloalkyl,
perhaloalkyl, perhaloalkoxy, alkylthio, perhaloalkylthio,
alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonyl,
heteroarylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, aryl,
aryloxy, arylalkoxy, arylthio, arylalkylthio, arylamino,
arylalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylalkoxy, heteroarylamino, heteroarylalkylamino,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, and
heterocycloalkoxy, all optionally substituted with substituents
selected independently from carbonyl (oxo), carboxyl, lower alkyl
carboxylate, lower alkyl carbonate, lower alkyl carbamate, halogen,
hydroxy, amino, amido, cyano, hydrazinyl, hydrazinylcarbonyl,
alkylhydrazinyl, dialkylhydrazinyl, arylhydrazinyl,
heteroarylhydrazinyl, nitro, thiol, sulfonic acid, trisubstituted
silyl, urea, acyl, acyloxy, acylamino, arylthio, lower alkyl, lower
alkylamino, lower dialkylamino, lower alkyloxy, lower alkoxyalkyl,
lower alkylthio, lower alkylsulfonyl, lower alkenyl, lower
alkenylamino, lower dialkenylamino, lower alkenyloxy, lower
alkenylthio, lower alkenyl sulfonyl, lower alkynyl, lower
alkynylamino, lower dialkynylamino, lower alkynyloxy, lower
alkynylthio, lower alkynylsulfonyl, lower cycioalkyl, lower
cycioalkyloxy, lower cycioalkylamino, lower cycloalkylthio, lower
cycioalkylsulfonyl, lower cycioalkylalkyl, lower
cycioalkylalkyloxy, lower cycioalkylalkylamino, lower
cycioalkylalkylthio, lower cycioalkylalkylsulfonyl, aryl, aryloxy,
arylamino, arylthio, arylsulfonyl, arylalkyl, arylalkyloxy,
arylalkylamino, arylalkylthio, arylalkylsulfonyl, heteroaryl,
heteroaryloxy, heteroarylamino, heteroarylthio, heteroarylsulfonyl,
heteroarylalkyl, heteroarylalkyloxy, heteroarylalkylamino,
heteroarylalkylthio, heteroarylalkylsulfonyl, heterocycioalkyl,
heterocycioalkyloxy, heterocycioalkylamino, heterocycioalkylthio,
heterocycloalkylsulfonyl, lower haloalkyl, lower haloalkenyl, lower
haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower
haloalkoxy, and lower acyloxy; R.sub.6 is selected from the group
consisting of haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy,
S(O).sub.mC(R.sub.7R.sub.8).sub.nCF.sub.3, and
C(R.sub.7R.sub.8).sub.nCF.sub.3; wherein W, X and Y are
independently chosen from the group consisting of S, O, N, NR.sub.9
and CR.sub.10 and at least two of W, X and Y are heteroatoms;
wherein R.sub.7, R.sub.8, and R.sub.9 are independently selected
from the group consisting of hydrogen, fluoro, chloro, alkyl,
perhaloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, or
together with the atoms to which they are attached, may be joined
to form an optionally substituted 4- to 8-membered heterocycioalkyl
or an optionally substituted 3- to 8-membered cycioalkyl ring, any
of which may be optionally substituted as for R.sub.1 through
R.sub.5 and R.sub.10; m is an integer between 0 and 2; and n is an
integer between 0 and 5.
11. The pharmaceutical composition of claim 1, wherein R.sub.1
through R.sub.5 are, independently, hydrogen, CN, F, Cl, Br,
hydroxy, alkyl, alkoxy, hydroxyalkyl, acyloxy, aroyloxy,
arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally substituted
with halogen, alkoxy, perhalo-C.sub.1-C.sub.3-alkyl, or
C.sub.1-C.sub.3 alkyl; R.sub.6 is selected from the group
consisting of perhaloalkyl,
S(O).sub.mC(R.sub.7R.sub.8).sub.nCF.sub.3, and
C(R.sub.7R.sub.8).sub.nCF.sub.3; R.sub.7, R.sub.8, and R.sub.9 are
independently selected from the group consisting of hydrogen,
fluoro, chloro, alkyl, and perhaloalkyl, any of which may be
optionally substituted; R.sub.10 is selected from the group
consisting of hydrogen, CN, NO.sub.2, F, Cl, Br, alkyl, cycloalkyl,
cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy,
cycloalkylalkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl,
arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy; and n is an integer
between 0 and 2.
12. The pharmaceutical composition of claim 11, wherein: R.sub.1,
R.sub.2, and R.sub.3 are, independently, hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy, or
carbamoyloxy, any of which may be optionally substituted; R.sub.6
is selected from the group consisting of perhaloalkyl and
C(R.sub.7R.sub.8)--CF.sub.3; R.sub.7 and R.sub.8 are independently
selected from the group consisting of hydrogen, fluoro, and chloro;
and R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkoxy, acyl,
alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl,
amido, dialkylamido, perhaloalkyl, alkylthio, alkylsulfonyl,
alkylsulfonylalkyl, cycloalkylsulfonyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, heteroarylthio, heteroarylalkylthio,
heterocycloalkyl, and heterocycloalkenyl.
13. The pharmaceutical composition of claim 12 comprising a
compound of Formula II or III or V or VI or VII or VIII or IX or X
or XI or XII or XIII or XVI or XVII or XVIII or XIX ##STR00401##
##STR00402## ##STR00403## wherein: R.sub.10 is selected from the
group consisting of hydrogen, CN, NO.sub.2, F, Cl, Br, alkyl,
cycloalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl,
heteroaryloxycarbonyl, carbamoyl, amido, dialkylamido,
perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
14. The pharmaceutical composition of claim 1, wherein the compound
is of Formula IV ##STR00404## wherein: R.sub.10 is selected from
the group consisting of hydrogen, CN, NO.sub.2, F, Cl, alkyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl; and with the proviso that
when R.sub.4 is Br, R.sub.10 may not be unsubstituted phenyl.
15. The pharmaceutical composition of claim 1, wherein the salt is
selected from the group consisting of acetate, adipate, alginate,
aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,
citrate, camphorate, camphorsulfonate, cyclopentanepropionate,
digluconate, dodecylsulfate, ethanesulfonate, fumarate,
glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,
hexanoate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxyethanesulfonate, lactate, malate, maleate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate,
thiocyanate, tosylate, undecanoate, lithium, sodium, calcium,
potassium, aluminum, ammonium, tetraethylammonium, methylammonium,
dimethylammonium, N-methylmorpholinium, and ethanolammonium.
16. The pharmaceutical composition of claim 1, wherein the
pharmaceutical composition is a solid.
.Iadd.17. The method of claim 5, wherein the patient is a
human..Iaddend.
.Iadd.18. The method of claim 9, wherein the patient is a
human..Iaddend.
Description
FIELD OF THE INVENTION
The present invention is directed to new heterocyclic compounds,
pharmaceutically acceptable salts thereof, compositions comprising
such compounds and salts, and methods of using those compounds,
salts, and compositions for the treatment of viral disease. It is
also directed to methods of inhibition of viral pathogen activity
in humans and animals. It is also directed to treatment of
hepatitis C virus (HCV), hepatitis B virus (HBV), and related viral
pathogen infection in humans and animals.
BACKGROUND
The present application relates generally to the field of
thiazolide compounds. In particular, the application relates to
haloalkyl-substituted thiazolide compounds.
Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) are major
public health problems, causing more than an estimated 500 million
chronic infections worldwide. Both viruses cause significant
progressive liver disease and are major risk factors for primary
hepatocellular carcinoma. Current standards of care for both HBV
and HCV infections, while effective in many cases, are sub-optimal
and fail to produce either a virologic or a clinical `cure` in
most. The development of drug-resistance in HBV, including strains
carrying resistance to multiple currently used agents, is an
emerging clinical problem, and drug-resistance for future HCV
therapies is predicted to be a significant clinical issue
SUMMARY
This invention provides novel compounds and pharmaceutical
compositions that treat viral pathogens, as well as methods of
synthesizing and using the compounds to treat and inhibit viral
infection. The compounds of this invention are haloalkyl heteroaryl
benzamides
In one embodiment, this invention provides compounds of Formula I
and
##STR00001## pharmaceutically acceptable salts thereof wherein:
R.sub.1 through R.sub.5 and R.sub.10 are, independently chosen
hydrogen, CN, NO.sub.2, halogen, hydroxy, alkyl, alkenyl, alkynyl,
alkoxy, alkenyloxy, alkynyloxy, alkoxyalkynyl, alkenyloxyalkyl,
alkenyloxyalkenyl, alkenyloxyalkynyl, alkynyloxyalkyl,
alkoxyalkylamino, hydroxyalkyl, acyl, acyloxy, aroyloxy,
arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, heteroarylalkoxycarbonyl,
alkoxycarbonyloxy, carbamoyl, carbamoyloxy, alkylamino,
dialkylamino, alkylaminoalkyl, amido, alkylamido, dialkylamido,
perhaloalkoxy, alkylthio, perhaloalkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, alkenylsulfonyl,
alkynylsulfonyl, cycloalkylsulfonylalkyl,
cycloalkylalkylsulfonylalkyl, arylsulfonyl, arylalkylsulfonyl,
arylalkenylsulfonyl, heteroarylsulfonyl, heteroarylalkylsulfonyl,
heteroarylalkenylsulfonyl, aryl, aryloxy, arylthio, arylalkylthio,
alkylthio, perhaloalkylthio, arylamino, arylalkylamino,
arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl,
heteroarylalkenyl, heteroarylalkynyl, heteroaryloxy,
heteroarylalkoxy, heteroarylamino, heteroarylalkylamino,
heteroarylthio, heteroarylalkylthio, heteroarylalkylamino,
heterocycloalkyl, heterocycloalkenyl, heterocycloalkoxy, or
heterocycloalkenyloxy, all optionally substituted as described
below
wherein R.sub.6 is selected from the group consisting of haloalkyl,
perhaloalkyl, haloalkoxy, perhaloalkoxy,
S(O).sub.mC(R.sub.7R.sub.8).sub.nCF.sub.3, and
C(R.sub.7R.sub.8).sub.nCF.sub.3;
wherein W, X and Y are, independently, S, O, N, NR.sub.9 or
CR.sub.10 where at least two of W, X, and Y are S, O, N, or
NR.sub.9;
wherein R.sub.7, R.sub.8, and R.sub.9 are independently selected
from the group consisting of hydrogen, fluoro, chloro, alkyl,
perhaloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, or
R.sub.7 and R.sub.8, together with the atoms to which they are
attached, are joined to form a 3- to 8-membered cycloalkyl ring or
a 4- to 8-membered heterocycloalkyl, either ring optionally
substituted as described below;
m is an integer between 0 and 2; and
n is an integer between 0 and 5;
or a pharmaceutically acceptable salt or ester thereof
These compounds are useful in treating disorders and conditions
caused by viral pathogens.
In another embodiment, this invention provides or contemplates a
composition comprising a compound of formula I and a carrier.
In another embodiment, this invention provides or contemplates a
pharmaceutical composition comprising a compound of Formula I and a
pharmaceutically acceptable carrier.
In another embodiment, this invention provides or contemplates a
method of treatment of viral infection comprising administering to
a human or animal afflicted with viral infection a therapeutically
effective amount of a compound of Formula I.
In a more specific embodiment, this invention provides or
contemplates a method of treatment of HCV infection comprising
administering to a human or animal afflicted with viral infection a
therapeutically effective amount of a compound of Formula I.
In a more specific embodiment, this invention provides or
contemplates a method of treatment of HBV infection comprising
administering to a human or animal afflicted with viral infection a
therapeutically effective amount of a compound of Formula I.
In other embodiments, the present invention provides or
contemplates methods for inhibiting or modulating a viral pathogen.
In other embodiments, the present invention provides or
contemplates methods for treating a viral-mediated disorder in a
patient in need of such treatment comprising administering to said
patient a therapeutically effective amount of a compound or
composition of compounds of this invention. In other embodiments,
this invention provides or contemplates methods for treating HCV,
HBV, and other viral infections comprising administering
pharmaceutical compositions of the invention to a patient in need
thereof. For example, the patient may have a chronic HCV infection.
The present invention also contemplates the use of compounds
disclosed herein for use in the manufacture of a medicament for the
treatment of a disease or condition ameliorated by the inhibition
or modulation of viral activity.
DETAILED DESCRIPTION
Unless otherwise specified, "a" or "an" means "one or more."
In one embodiment, this invention provides or contemplates a
compound of Formula I, wherein R.sub.1 through R.sub.5 are,
independently, hydrogen, cyano, fluoro, chloro, bromo, hydroxy,
alkyl, alkoxy, aryloxy, aroyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino,
haloalkyl, perhaloalkyl, perhaloalkylthio, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, all optionally substituted as described
below.
R.sub.6 is selected from the group consisting of perhaloalkyl,
S(O).sub.mC(R.sub.7R.sub.8).sub.nCF.sub.3, and
C(R.sub.7R.sub.8).sub.nCF.sub.3;
R.sub.7, R.sub.8, and R.sub.9 are, independently, hydrogen, fluoro,
chloro, alkyl, or perhaloalkyl, any of which may be optionally
substituted;
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, alkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, heteroarylalkoxycarbonyl,
carbamoyl, alkylamino, amido, alkylamido, dialkylamido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
alkylsulfonylalkyl, cycloalkylsulfonyl, alkylsulfonamido, aryl,
arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylamino,
arylalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylalkoxy, heteroarylamino, heteroarylalkylamino,
heteroarylthio, heteroarylalkylthio, heteroarylalkylamino,
heterocycloalkyl, heterocycloalkenyl, heterocycloalkoxy, and
heterocycloalkenyloxy; and
m and n are, independently, integers equal to 0, 1, or 2.
In a more specific embodiment, this invention provides or
contemplates a compound of Formula I wherein R.sub.1, R.sub.2, or
R.sub.3 are, independently, hydroxy, acyloxy, aroyloxy,
arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy, or
carbamoyloxy, any of which may be optionally substituted.
In another more specific embodiment, this invention provides or
contemplates a compound of Formula I wherein one of R.sub.1,
R.sub.2 and R.sub.3 is hydroxy or acetoxy.
In another more specific embodiment, this invention provides or
contemplates a compound of Formula I wherein either R.sub.3 or
R.sub.4 is halogen.
In a still more specific embodiment, this invention provides or
contemplates a compound of Formula I wherein one of R.sub.1,
R.sub.2 and R.sub.3 is hydroxy or acetoxy and wherein R.sub.4 is
halogen.
In a still more specific embodiment, this invention provides or
contemplates a compound of Formula I wherein R.sub.1 is hydroxy or
acetoxy and wherein R.sub.2, R.sub.3 or R.sub.4 is halogen.
In another more specific embodiment, this invention provides or
contemplates a compound of Formula I wherein R.sub.3 or R.sub.4 is
methyl or methoxy.
In another more specific embodiment, this invention provides or
contemplates a compound of Formula I wherein one of R.sub.1,
R.sub.2 and R.sub.3 is hydroxy or acetoxy.
In another embodiment, this invention provides or contemplates a
compound of Formula I wherein R.sub.6 is selected from the group
consisting of perhaloalkyl and C(R.sub.7R.sub.8).sub.nCF.sub.3,
wherein R.sub.7 and R.sub.8 are as defined above.
In another embodiment, this invention provides or contemplates a
compound of Formula I wherein R.sub.6 is perfluoroalkyl or
perchloroalkyl.
In another embodiment, this invention provides or contemplates a
compound of Formula I wherein R.sub.6 is perfluoro or perchloro
C.sub.1-C.sub.3 alkyl.
In another embodiment, this invention provides or contemplates a
compound of Formula I wherein R.sub.6 is trifluoromethyl.
In another embodiment this invention provides or contemplates
pharmaceutical compositions comprising one or more compounds of the
present invention together with a pharmaceutically acceptable
carrier (e.g., a diluent or excipient). It other embodiments this
invention provides or contemplates methods of making and using the
compounds and compositions. In more specific embodiments, the
invention provides or contemplates pharmaceutical compositions
which comprise therapeutically effective amounts of the compound of
this invention and methods of using such compositions for treating
HCV, HBV, and other viral infections.
In one subgeneric embodiment, this invention provides or
contemplates a compound of Formula I in which W is O and either X
or Y is N or NR.sub.9.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W is O and both X and Y are N or
NR.sub.9.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W is S and either X or Y is N or
NR.sub.9.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W is S and both X and Y are N or
NR.sub.9.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W is N and either X or Y is O.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W is N and either X or Y is S.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W is N and either X or Y is N or
NR.sub.9
In another embodiment, this invention provides or contemplates a
compound of Formula I in which two of W, X, and Y are N or
NR.sub.9.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W, X, and Y are N or NR.sub.9.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W is CR.sub.10, one of X or Y is O,
and the other is N or NR.sub.9.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W is CR.sub.10, one of X or Y is O
and the other is N or NR.sub.9.
In one subgeneric embodiment, this invention provides or
contemplates a compound of Formula I in which W is O and either X
or Y is N or NR.sub.9.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W is O and both X and Y are N or
NR.sub.9.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W is S and either X or Y is N or
NR.sub.9.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W is S and both X and Y are N or
NR.sub.9.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W is N or NR.sub.9 and either X or Y
is O.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W is N or NR.sub.9 and either X or Y
is S.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W is N; either X or Y is N or
NR.sub.9; and R.sub.6 is SO.sub.2CF.sub.3 or
SO.sub.2CH.sub.2CF.sub.3.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W is N; either X or Y is N or
NR.sub.9; and R.sub.6 is CF.sub.2CH.sub.3, CF.sub.2CF.sub.3 or
CH.sub.2CF.sub.3.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W is N, in which either X or Y is N
or NR.sub.9, and wherein R.sub.6 is SO.sub.2CF.sub.3 or
SO.sub.2CH.sub.2CF.sub.3.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W is N, in which either X or Y is N
or NR.sub.9, and wherein R.sub.6 is CF.sub.2CH.sub.3,
CF.sub.2CF.sub.3 or CH.sub.2CF.sub.3.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which two of W, X, and Y are N or NR.sub.9
and wherein R.sub.6 is CF.sub.2CH.sub.3, CF.sub.2CF.sub.3 or
CH.sub.2CF.sub.3.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which two of W, X, and Y are N or NR.sub.9
and wherein R.sub.6 is SO.sub.2CF.sub.3 or
SO.sub.2CH.sub.2CF.sub.3.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W, .times., and Y are N or NR.sub.9
and wherein R.sub.6 is SO.sub.2CF.sub.3 or
SO.sub.2CH.sub.2CF.sub.3.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which W, X, and Y are N or NR.sub.9 and
wherein R.sub.6 is CF.sub.2CH.sub.3, CF.sub.2CF.sub.3 or
CH.sub.2CF.sub.3.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which one of X or Y is O and the other is
N or NR.sub.9 and wherein R.sub.6 is methyl, fluoromethyl, or
trifluoromethyl.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which one of X or Y is O and the other is
N or NR.sub.9 and wherein R.sub.6 is SO.sub.2CF.sub.3 or
SO.sub.2CH.sub.2CF.sub.3.
In another embodiment, this invention provides or contemplates a
compound of Formula I wherein one of X or Y is O and the other is N
or NR.sub.9 and wherein R.sub.6 is methyl, fluoromethyl, or
trifluoromethyl.
In another embodiment, this invention provides or contemplates a
compound of Formula I wherein one of X or Y is O and the other is N
or NR.sub.9 and wherein R.sub.6 is SO.sub.2CF.sub.3 or
SO.sub.2CH.sub.2CF.sub.3.
In another embodiment, this invention provides or contemplates a
compound of Formula I wherein R.sub.6 is methyl, fluoromethyl, or
trifluoromethyl.
In another embodiment, this invention provides or contemplates a
compound of Formula I wherein R.sub.6 is SO.sub.2CF.sub.3 or
SO.sub.2CH.sub.2CF.sub.3.
In another embodiment, this invention provides or contemplates a
compound of Formula I wherein R.sub.6 is CF.sub.2CH.sub.3,
CF.sub.2CF.sub.3 or CH.sub.2CF.sub.3.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which three of R.sub.1-R.sub.5-- are
H.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which two of R.sub.2-R.sub.5-- are H.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which three of R.sub.2-R.sub.5-- are
H.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which R.sub.2-R.sub.5-- are H.
In another embodiment, this invention provides or contemplates a
compound of Formula I in which one of R.sub.1-R.sub.5 is
O--R.sub.12, where R.sub.12 is H or C.sub.1-C.sub.6 alkanoyl, the
latter optionally substituted with 1-3 halogens
In another embodiment, this invention provides or contemplates a
compound of Formula I in which R.sub.6 is C.sub.1-C.sub.3 alkyl,
optionally substituted with 1-3 halogens.
In another embodiment, this invention provides or contemplates a
compound of Formula I wherein R.sub.6 is methyl, fluoromethyl, or
trifluoromethyl.
In another embodiment, this invention provides or contemplates a
compound of Formula I wherein R.sub.6 is SO.sub.2CF.sub.3 or
SO.sub.2CH.sub.2CF.sub.3.
In another embodiment, this invention provides or contemplates a
compound of Formula I wherein R.sub.6 is CF.sub.2CH.sub.3,
CF.sub.2CF.sub.3 or CH.sub.2CF.sub.3.
In another embodiment, this invention provides or contemplates a
compound of Formula I wherein R.sub.1 is hydroxy or
alkanoyloxy.
In a more specific embodiment, this invention provides or
contemplates a compound of Formula I wherein R.sub.1 is hydroxy or
C.sub.1-C.sub.3 alkanoyloxy.
In another embodiment, this invention provides or contemplates a
compound of Formula II
##STR00002## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy.
In additional embodiments, this invention provides or contemplates
a compound of Formula II wherein:
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
In a still more specific embodiment, this invention provides or
contemplates a compound of Formula II wherein
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In a more specific embodiment, this invention provides or
contemplates a compound of Formula II wherein R.sub.1 is hydroxy or
C.sub.1-C.sub.3 alkanoyloxy.
In a still more specific embodiment, this invention provides or
contemplates a compound of Formula II wherein R.sub.1 is hydroxy or
acetoxy; and
and 3, 4, or all of R.sub.2-R.sub.5 and R.sub.10 are hydrogen.
In a still more specific embodiment, this invention provides or
contemplates the following compounds of Formula I:
2-(5-(trifluoromethyl)thiazol-2-ylcarbamoyl)phenyl acetate and
2-hydroxy-N-(5-(trifluoromethyl)thiazol-2-yl)benzamide.
In another subgeneric embodiment, this invention provides or
contemplates a compound of Formula III:
##STR00003## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy.
In a more specific embodiment, this invention provides or
contemplates a compound of Formula III wherein:
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
In a still more specific embodiment, this invention provides or
contemplates a compound of Formula III wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In another more specific embodiment, this invention provides or
contemplates a compound of Formula III wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In a more specific embodiment, this invention provides or
contemplates a compound of Formula III wherein R.sub.1 is hydroxy
or C.sub.1-C.sub.3 alkanoyloxy.
In another embodiment, this invention provides or contemplates a
compound of Formula III wherein:
R.sub.1 is chosen from the group consisting of hydroxy and acetoxy;
and 3, 4, or all of
R.sub.2-R.sub.5 and R.sub.10 are hydrogen.
In another subgeneric embodiment, this invention provides or
contemplates a compound of Formula IV:
##STR00004## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy.
In a more specific embodiment, this invention provides or
contemplates a compound of Formula IV wherein:
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, alkyl, aryloxycarbonyl, heteroaryloxycarbonyl,
carbamoyl, amido, dialkylamido, perhaloalkyl, alkylsulfonyl,
alkylsulfonylalkyl, cycloalkylsulfonyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, heterocycloalkyl, and
heterocycloalkenyl; an with the proviso that when R.sub.4 is Br,
R.sub.10 may not be unsubstituted phenyl.
In a more specific subgeneric embodiment, this invention provides
or contemplates a compound of Formula IV wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In a still more specific embodiment, this invention provides or
contemplates a compound of Formula IV wherein R.sub.1 is hydroxy or
acetoxy; and 3, 4, or all of R.sub.2-R.sub.5 and R.sub.10 are
hydrogen.
Examples of this more specific embodiment include the compounds
include 2-(4-(trifluoromethyl)thiazol-2-ylcarbamoyl)phenyl acetate
and 2-hydroxy-N-(4-(trifluoromethyl)thiazol-2-yl)benzamide.
In another embodiment, this invention provides or contemplates a
compound of Formula V:
##STR00005## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy.
In a more specific embodiment, this invention provides or
contemplates a compound of Formula V wherein:
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
In additional embodiments, this invention provides or contemplates
a compound of Formula V wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In more specific embodiments, this invention provides or
contemplates compounds of Formula V wherein:
R.sub.1 is hydroxy or acetoxy; and
3, 4, or all of R.sub.2 through R.sub.5 and R.sub.10 are
hydrogen.
In another embodiment, this invention provides or contemplates a
compound of Formula VI:
##STR00006## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy.
In a more specific embodiment, this invention provides or
contemplates a compound of Formula VI wherein:
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
In a still more specific embodiment, this invention provides or
contemplates a compound of Formula VI wherein:
R.sub.1 is chosen from the group consisting of hydroxy, aryloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In more specific embodiments, this invention provides or
contemplates compounds of Formula VI wherein R.sub.1 is hydroxy or
acetoxy; and 3, 4, or all of R.sub.2 through R.sub.5 and R.sub.10
are hydrogen.
In a still more specific embodiment, this invention provides or
contemplates a compound of Formula VI wherein:
R.sub.1 is hydroxy or acetoxy; and
R.sub.2 through R.sub.5 and R.sub.10 are hydrogen.
In additional embodiments, this invention provides or contemplates
a compound of Formula VII:
##STR00007## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy.
In more specific subgeneric embodiments, the invention provides or
contemplates a compound of Formula VII wherein:
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
In more specific embodiments, this invention provides or
contemplates a compound of Formula VII wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In more specific embodiments, this invention provides or
contemplates compounds of Formula VII wherein R.sub.1 is hydroxy or
acetoxy; and 3, 4, or all of R.sub.2 through R.sub.5 and R.sub.10
are hydrogen.
In a still more specific embodiment, this invention provides or
contemplates a compound of Formula VII wherein:
R.sub.1 is hydroxy or acetoxy; and
R.sub.2 through R.sub.5 and R.sub.10 are hydrogen.
In another embodiment, this invention provides or contemplates a
compound of Formula VIII:
##STR00008## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy;
In some embodiments, the compounds of the present invention have
structural Formula VIII wherein:
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
In other embodiments, the compounds of the present invention have
structural Formula VIII wherein:
R.sub.1 is chosen from the group consisting of hydroxy, aryloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In more specific embodiments, this invention provides or
contemplates compounds of Formula VIII wherein R.sub.1 is hydroxy
or acetoxy; and 3, 4, or all of R.sub.2 through R.sub.5 and
R.sub.10 are hydrogen.
In a still more specific embodiment, this invention provides or
contemplates a compound of Formula VIII wherein: R.sub.1 is hydroxy
or acetoxy; and R.sub.2 through R.sub.5 and R.sub.10 are
hydrogen.
In certain embodiments, the compounds of the present invention have
structural Formula IX:
##STR00009## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy;
In some embodiments, the compounds of the present invention have
structural Formula IX wherein:
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
In other embodiments, the compounds of the present invention have
structural Formula IX wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula IX wherein:
R.sub.1 is chosen from the group consisting of hydroxy and acetoxy;
and R.sub.2 through R.sub.5 and R.sub.10 are hydrogen.
In certain embodiments, the compounds of the present invention have
structural Formula X:
##STR00010## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted;
R.sub.9 is selected from the group consisting of hydrogen, fluoro,
chloro, alkyl, and perhaloalkyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy.
In some embodiments, the compounds of the present invention have
structural Formula X wherein:
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
In other embodiments, the compounds of the present invention have
structural Formula X wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted;
and
R.sub.9 is selected from the group consisting of hydrogen, alkyl,
and perhaloalkyl, any of which may be optionally substituted.
In other embodiments, the compounds of the present invention have
structural Formula X wherein:
R.sub.1 is chosen from the group consisting of hydroxy and
acetoxy;
R.sub.2 through R.sub.5 and R.sub.10 are hydrogen; and
R.sub.9 is alkyl, which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XI:
##STR00011## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted;
R.sub.9 is selected from the group consisting of hydrogen, fluoro,
chloro, alkyl, and perhaloalkyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy.
In some embodiments, the compounds of the present invention have
structural Formula XI wherein:
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
In further embodiments, the compounds of the present invention have
structural Formula XI wherein:
R.sub.1 is chosen from the group consisting of hydroxy, aryloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted;
and
R.sub.9 is selected from the group consisting of hydrogen, alkyl,
and perhaloalkyl, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XI wherein R.sub.1 is chosen from the group
consisting of hydroxy and acetoxy;
R.sub.2 through R.sub.5 and R.sub.10 are hydrogen; and
R.sub.9 is alkyl, which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XII:
##STR00012## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted;
R.sub.9 is selected from the group consisting of hydrogen, fluoro,
chloro, alkyl, and perhaloalkyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy.
In some embodiments, the compounds of the present invention have
structural Formula XII wherein:
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
In other embodiments, the compounds of the present invention have
structural Formula XII wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted;
and
R.sub.9 is selected from the group consisting of hydrogen, alkyl,
and perhaloalkyl, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XII wherein:
R.sub.1 is chosen from the group consisting of hydroxy and
acetoxy;
R.sub.2 through R.sub.5 and R.sub.10 are hydrogen; and
R.sub.9 is alkyl, which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XIII:
##STR00013## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted;
R.sub.9 is selected from the group consisting of hydrogen, fluoro,
chloro, alkyl, and perhaloalkyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy;
In some embodiments, the compounds of the present invention have
structural Formula XIII wherein:
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
In some embodiments, the compounds of the present invention have
structural Formula XIII wherein:
R.sub.1 is chosen from the group consisting of hydroxy, aryloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted;
and
R.sub.9 is selected from the group consisting of hydrogen, alkyl,
and perhaloalkyl, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XIII wherein:
R.sub.1 is chosen from the group consisting of hydroxy and
acetoxy;
R.sub.2 through R.sub.5 and R.sub.10 are hydrogen; and
R.sub.9 is alkyl, which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XIV:
##STR00014## wherein:
R.sub.1 through R.sub.5 or, hydrogen, CN, F, Cl, Br, hydroxy,
alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl,
cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy, aroyloxy,
arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, and
cycloalkylalkylsulfonyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy.
In some embodiments, the compounds of the present invention have
structural Formula XIV wherein:
R.sub.1 and R.sub.2 are, independently, hydroxy, acyloxy, aroyloxy,
arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy, or
carbamoyloxy, any of which may be optionally substituted;
R.sub.3 is selected from the group consisting of acyloxy, aroyloxy,
arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
In other embodiments, the compounds of the present invention have
structural Formula XIV wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XIV wherein:
R.sub.1 is chosen from the group consisting of hydroxy and acetoxy;
and
R.sub.2 through R.sub.5 and R.sub.10 are hydrogen.
In certain embodiments, the compounds of the present invention have
structural Formula XV:
##STR00015## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy.
In some embodiments, the compounds of the present invention have
structural Formula XV wherein:
R.sub.1 and R.sub.2 are, independently, hydroxy, acyloxy, aroyloxy,
arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy, or
carbamoyloxy, any of which may be optionally substituted;
R.sub.3 is selected from the group consisting of acyloxy, aroyloxy,
arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
In other embodiments, the compounds of the present invention have
structural Formula XV wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XV wherein:
R.sub.1 is chosen from the group consisting of hydroxy and acetoxy;
and
R.sub.2 through R.sub.5 and R.sub.10 are hydrogen.
In certain embodiments, the compounds of the present invention have
structural Formula XVI:
##STR00016## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy.
In some embodiments, the compounds of the present invention have
structural Formula XVI wherein:
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
In further embodiments, the compounds of the present invention have
structural Formula XVI wherein:
R.sub.1 is chosen from the group consisting of hydroxy, aryloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XVI wherein:
R.sub.1 is chosen from the group consisting of hydroxy and acetoxy;
and
R.sub.2 through R.sub.5 and R.sub.10 are hydrogen.
In certain embodiments, the compounds of the present invention have
structural Formula XVII:
##STR00017## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy.
In some embodiments, the compounds of the present invention have
structural Formula XVII wherein:
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
In other embodiments, the compounds of the present invention have
structural Formula XVII wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XVII wherein:
R.sub.1 is chosen from the group consisting of hydroxy and acetoxy;
and
R.sub.2 through R.sub.5 and R.sub.10 are hydrogen.
In certain embodiments, the compounds of the present invention have
structural Formula XVIII:
##STR00018## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted;
R.sub.9 is selected from the group consisting of hydrogen, fluoro,
chloro, alkyl, and perhaloalkyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy;
In some embodiments, the compounds of the present invention have
structural Formula XVIII wherein:
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
In other embodiments, the compounds of the present invention have
structural Formula XVIII wherein:
R.sub.1 is chosen from the group consisting of hydroxy, aryloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted;
and
R.sub.9 is selected from the group consisting of hydrogen, alkyl,
and perhaloalkyl, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XVIII wherein:
R.sub.1 is chosen from the group consisting of hydroxy and
acetoxy;
R.sub.2 through R.sub.5 and R.sub.10 are hydrogen; and
R.sub.9 is methyl.
In certain embodiments, the compounds of the present invention have
structural Formula XIX:
##STR00019## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted;
R.sub.9 is selected from the group consisting of hydrogen, fluoro,
chloro, alkyl, and perhaloalkyl, any of which may be optionally
substituted; and
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl,
heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido,
dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl,
alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl,
alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, arylamino, arylalkylamino, heteroaryl,
heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino,
heteroarylalkylamino, heteroarylthio, heteroarylalkylthio,
heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl,
heterocycloalkoxy, and heterocycloalkenyloxy.
In some embodiments, the compounds of the present invention have
structural Formula XIX wherein:
R.sub.10 is selected from the group consisting of hydrogen, CN,
NO.sub.2, F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl,
cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocycloalkyl, and heterocycloalkenyl.
In other embodiments, the compounds of the present invention have
structural Formula XIX wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted:
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, and
heterocycloalkoxy, any of which may be optionally substituted;
or
R.sub.9 is selected from the group consisting of hydrogen, alkyl,
and perhaloalkyl, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XIX wherein:
R.sub.1 is chosen from the group consisting of hydroxy and
acetoxy;
R.sub.2 through R.sub.5 and R.sub.10 are hydrogen; and
R.sub.9 is methyl.
In certain embodiments, the compounds of the present invention have
structural Formula XX:
##STR00020## wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted;
R.sub.6 is selected from the group consisting of perhaloalkyl,
S(O).sub.mC(R.sub.7R.sub.8).sub.nCF.sub.3, and
C(R.sub.7R.sub.8).sub.nCF.sub.3;
R.sub.7 and R.sub.8 are independently selected from the group
consisting of hydrogen, fluoro, chloro, alkyl, and perhaloalkyl,
any of which may be optionally substituted;
m is an integer between 0 and 2;
n is an integer between 0 and 2; and
with the following provisos when R.sub.6 is trifluoromethyl:
when R.sub.1 is selected from the group consisting of hydroxy, and
acetoxy, R.sub.2-R.sub.5 cannot be hydrogen;
when R.sub.1 is hydroxy, R.sub.4 cannot be selected from the group
consisting of Cl and Br; and
when R.sub.3 is acetoxy, R.sub.1, R.sub.2, R.sub.4 and R.sub.5 may
not be hydrogen.
In some embodiments, the compounds of the present invention have
structural Formula XX:
R.sub.1 is chosen from the group consisting of hydroxy and
acetoxy;
R.sub.2 through R.sub.5 are hydrogen; and
R.sub.6 is perfluoroethyl, CF.sub.3CH.sub.2--, and
CH.sub.3CF.sub.2--.
In certain embodiments, the compounds of the present invention have
structural Formula XXI:
##STR00021## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted.
In other embodiments, the compounds of the present invention have
structural Formula XXI, wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XXI, wherein:
R.sub.1 is chosen from the group consisting of hydroxy and acetoxy;
and
R.sub.2 through R.sub.5 are hydrogen.
In certain embodiments, the compounds of the present invention have
structural Formula XXII:
##STR00022## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted.
In other embodiments, the compounds of the present invention have
structural Formula XXII, wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XXII, wherein:
R.sub.1 is chosen from the group consisting of hydroxy and acetoxy;
and
R.sub.2 through R.sub.5 are hydrogen.
In certain embodiments, the compounds of the present invention have
structural Formula XXIII:
##STR00023## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted.
In other embodiments, the compounds of the present invention have
structural Formula XXIII, wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XXIII, wherein:
R.sub.1 is chosen from the group consisting of hydroxy and acetoxy;
and R.sub.2 through R.sub.5 are hydrogen.
In certain embodiments, the compounds of the present invention have
structural Formula XXIV:
##STR00024## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted.
In other embodiments, the compounds of the present invention have
structural Formula XXIV, wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XXIV, wherein:
R.sub.1 is chosen from the group consisting of hydroxy and acetoxy;
and
R.sub.2 through R.sub.5 are hydrogen.
In certain embodiments, the compounds of the present invention have
structural Formula XXV:
##STR00025## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted.
In other embodiments, the invention provides or contemplates a
compound of Formula XXV, wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XXV, wherein:
R.sub.1 is chosen from the group consisting of hydroxy and acetoxy;
and
R.sub.2 through R.sub.5 are hydrogen.
In certain embodiments, the compounds of the present invention have
structural Formula XXVI:
##STR00026## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted; and
R.sub.9 is selected from the group consisting of hydrogen, alkyl,
and perhaloalkyl, any of which may be optionally substituted.
In some embodiments, the compounds of the present invention have
structural Formula XXVI wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XXVI wherein:
R.sub.1 is chosen from the group consisting of hydroxy and
acetoxy;
R.sub.2 through R.sub.5 are hydrogen; and
R.sub.9 is methyl.
In certain embodiments, the compounds of the present invention have
structural Formula XXVII:
##STR00027## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted; and
R.sub.9 is selected from the group consisting of hydrogen, alkyl,
and perhaloalkyl, any of which may be optionally substituted.
In some embodiments, the compounds of the present invention have
structural Formula XXVII wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XXVII wherein:
R.sub.1 is chosen from the group consisting of hydroxy and
acetoxy;
R.sub.2 through R.sub.5 are hydrogen; and
R.sub.9 is methyl.
In certain embodiments, the compounds of the present invention have
structural Formula XXVIII:
##STR00028## wherein:
R.sub.1 through R.sub.5 are, independently, hydrogen, CN, F, Cl,
Br, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,
alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyalkyl, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or
cycloalkylalkylsulfonyl, any of which may be optionally
substituted; and
R.sub.9 is selected from the group consisting of hydrogen, alkyl,
and perhaloalkyl, any of which may be optionally substituted.
In some embodiments, the compounds of the present invention have
structural Formula XXVIII wherein:
R.sub.1 is chosen from the group consisting of hydroxy, acyloxy,
aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy,
heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy,
and carbamoyloxy, any of which may be optionally substituted;
and
R.sub.2 through R.sub.5 are, independently, hydrogen, CN, NO.sub.2,
F, Cl, Br, alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido,
perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio,
arylalkylthio, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkyl, or
heterocycloalkoxy, any of which may be optionally substituted.
In certain embodiments, the compounds of the present invention have
structural Formula XXVIII wherein:
R.sub.1 is chosen from the group consisting of hydroxy and
acetoxy;
R.sub.2 through R.sub.5 are hydrogen; and
R.sub.9 is methyl.
The disclosed compounds include compounds of formula (I), salts,
and solvates thereof. For example, in some embodiments, the
compound of the present invention may be a salt or a solvate.
Many compounds of this invention are capable of existing in more
than one stereoisomeric form. All depictions of and references to
compounds of this invention are intended to include all
diastereomeric and enantiomeric forms of those compounds.
Because compounds of this invention may be used in the diagnosis as
well as the treatment of disease, isotopically labeled versions of
these compounds are included in this disclosure and in the claims.
All references to elements in compounds of this invention are
intended to include all isotopes of those elements, including
unstable isotopes. For example, references to "hydrogen" or H in
formulas or in claims are intended to include deuterium, (D) and
tritium (T.)
In another embodiment, this invention provides or contemplates a
kit, comprising, in a compartment, at least one pharmaceutical
composition comprising, in a pharmaceutically acceptable carrier,
an effective amount of at least one compound of the invention. In
some embodiments, the kit further comprises written instructions
for administering the pharmaceutical composition. In some
embodiments, written instructions for administering concern
indications noted elsewhere in this disclosure. In some
embodiments, written instructions for administering concern an
administration regimen noted elsewhere in this disclosure.
As used in the present specification the following terms have the
meanings indicated:
The term "salts" is used in its broadest sense. For example, the
term salts includes hydrogen salts and hydroxide salts with ions of
the present compound. In some embodiments, the term salt may be a
subclass referred to as pharmaceutically acceptable salts, which
are salts of the present compounds having a pharmacological
activity and which are neither biologically nor otherwise
undesirable. In all embodiments, the salts can be formed with
acids, such as, without limitation, hydrogen, acetate, adipate,
alginate, aspartate, benzoate, benzenesulfonate, bisulfate
butyrate, citrate, camphorate, camphorsulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, glucoheptanoate, glycero-phosphate,
hemisulfate, heptanoate, hexanoate, hydrochloride hydrobromide,
hydroiodide, 2-hydroxyethane-sulfonate, lactate, maleate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate,
thiocyanate, tosylate and undecanoate. In all embodiments, the
salts can be formed with bases, such as, without limitation,
hydroxide, ammonium salts, alkali metal salts such as lithium,
sodium and potassium salts, alkaline earth metal salts such as
calcium, magnesium salts, aluminum salts, salts with organic bases
such as ammonia, methylamine, diethylamine, ethanolamine,
dicyclohexylamine, N-methylmorpholine, N-methyl-D-glucamine, and
salts with amino acids such as arginine and lysine. Basic
nitrogen-containing groups can be quarternized with agents
including lower alkyl halides such as methyl, ethyl, propyl and
butyl chlorides, bromides and iodides; dialkyl sulfates such as
dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides
such as decyl, lauryl, myristyl and stearyl chlorides, bromides and
iodides; and aralkyl halides such as benzyl and phenethyl
bromides.
The terms "therapeutically acceptable salt," and "pharmaceutically
acceptable salt," as used herein, represent salts or zwitterionic
forms of the compounds of the present invention which are water or
oil-soluble or dispersible; which are suitable for treatment of
diseases without undue toxicity, irritation, and allergic-response;
which are commensurate with a reasonable benefit/risk ratio; and
which are effective for their intended use. The salts can be
prepared during the final isolation and purification of the
compounds or separately by reacting the appropriate compound in the
form of the free base with a suitable acid. Representative acid
addition salts include acetate, adipate, alginate, L-ascorbate,
aspartate, benzoate, benzenesulfonate (besylate), bisulfate,
butyrate, camphorate, camphorsulfonate, citrate, digluconate,
formate, fumarate, gentisate, glutarate, glycerophosphate,
glycolate, hemisulfate, heptanoate, hexanoate, hippurate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate
(isethionate), lactate, maleate, malonate, DL-mandelate,
mesitylenesulfonate, methanesulfonate, naphthylenesulfonate,
nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate,
persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate,
propionate, pyroglutamate, succinate, sulfonate, tartrate,
L-tartrate, trichloroacetate, trifluoroacetate, phosphate,
glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and
undecanoate. Also, basic groups in the compounds of the present
invention can be quaternized with methyl, ethyl, propyl, and butyl
chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and
diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides,
bromides, and iodides; and benzyl and phenethyl bromides. Examples
of acids which can be employed to form therapeutically acceptable
addition salts include inorganic acids such as hydrochloric,
hydrobromic, sulfuric, and phosphoric, and organic acids such as
oxalic, maleic, succinic, and citric. Salts can also be formed by
coordination of the compounds with an alkali metal or alkaline
earth ion. Hence, the present invention contemplates sodium,
potassium, magnesium, and calcium salts of the compounds of the
compounds of the present invention and the like.
Basic addition salts can be prepared during the final isolation and
purification of the compounds by reacting a carboxy, phenol or
similar group with a suitable base such as the hydroxide,
carbonate, or bicarbonate of a metal cation or with ammonia or an
organic primary, secondary, or tertiary amine. The cations of
therapeutically acceptable salts include lithium, sodium,
potassium, calcium, magnesium, and aluminum, as well as nontoxic
quaternary amine cations such as ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, diethylamine, ethylamine, tributylamine, pyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,
dicyclohexylamine, procaine, dibenzylamine,
N,N-dibenzylphenethylamine, 1-ephenamine, and
N,N-dibenzylethylenediamine. Other representative organic amines
useful for the formation of base addition salts include
ethylenediamine, ethanolamine, diethanolamine, piperidine, and
piperazine.
The term "solvates" is used in its broadest sense. For example, the
term solvates includes hydrates formed when a compound of the
present invention contains one or more bound water molecules.
The term "acyl," as used herein, alone or in combination, refers to
a carbonyl attached to an alkyl, alkenyl, aryl, heteroaryl,
heterocycle, or any other moiety where the atom attached to the
carbonyl is carbon. An "acetyl" group refers to a --C(O)CH.sub.3
group. Examples of acyl groups include alkanoyl groups such as
formyl, acetyl, and propionyl, aroyl groups such as benzoyl, and
mixed alkyl-aryl groups such as cinnamoyl.
The term "acylamino" embraces an amino radical substituted with an
acyl group. An example of an "acylamino" radical is acetylamino
(CH.sub.3C(O)NH--) The term "alkenyl," as used herein, alone or in
combination, refers to a straight-chain, branched-chain, or cyclic
unsaturated hydrocarbon radical, or a radical containing any
combination of straight-chain or branched-chain, and cyclic
moieties, having one or more double bonds and containing from 2 to
20 carbon atoms, or, in the case of cyclic moieties, having from 3
to 20 ring members. In many embodiments alkenyl groups comprise
from 2 to 6 carbon atoms. The term "alkenyl groups" is used in its
broadest sense. Alkenylene refers to a carbon-carbon double bond
system attached at two or more positions such as ethenylene
[(--CH.dbd.CH--),(--C::C--)]. For example, the term
"(C.sub.2-C.sub.8) alkenyl groups" embraces straight, branched, and
cyclic hydrocarbon radicals containing 2 to 8 carbon atoms having
at least one double bond. Examples of suitable alkenyl radicals
include ethenyl, also known as vinyl, propenyl, iso-propenyl,
butenyl, iso-butenyl, sec-butenyl, tert-butenyl, 1,3-butadienyl,
n-pentenyl, n-hexenyl, cycloalkenyl radicals such as cyclohexenyl
and 1,3-cyclopentadienyl, cycloalkenylalkyl radicals such as
cyclohexenylmethyl, alkenylcycloalkyl radicals such as
methylenecyclohexyl, and the like. The term "alkoxy," as used
herein, alone or in combination, refers to an alkyl ether radical,
wherein the term alkyl is as defined herein. Examples of suitable
alkyl ether radicals include methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,
cyclopentoxy, and the like.
The term "alkoxyalkoxy," as used herein, alone or in combination,
refers to one or more alkoxy groups attached to the parent
molecular moiety through another alkoxy group. Examples include
ethoxyethoxy, methoxypropoxyethoxy, ethoxypentoxyethoxyethoxy and
the like.
The term "alkoxyalkyl," as used herein, alone or in combination,
refers to an alkoxy group attached to the parent molecular moiety
through an alkyl group. The term "alkoxyalkyl" also embraces
alkoxyalkyl groups having one or more alkoxy groups attached to the
alkyl group, that is, to form monoalkoxyalkyl and dialkoxyalkyl
groups.
The term "alkoxycarbonyl," as used herein, alone or in combination,
refers to an alkoxy group attached to the parent molecular moiety
through a carbonyl group. Examples of such "alkoxycarbonyl" groups
include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
butoxycarbonyl and hexyloxycarbonyl.
The term "alkoxycarbonylalkyl" embraces radicals having
"alkoxycarbonyl," as defined above substituted to an alkyl radical.
More preferred alkoxycarbonylalkyl radicals are "lower
alkoxycarbonylalkyl" having lower alkoxycarbonyl radicals as
defined above attached to one to six carbon atoms. Examples of such
lower alkoxycarbonylalkyl radicals include
methoxycarbonylmethyl.
The term "alkyl," as used herein, alone or in combination, refers
to a straight-chain, branched, or cyclic alkyl radical, or a
radical consisting of any combination of straight, branched, and/or
cyclic radicals, which is a saturated aliphatic hydrocarbon group
containing from 1-20 carbon atoms. In many embodiments, alkyl
groups comprise 1-10 carbon atoms. In many other embodiments, alkyl
groups comprise 1-6 carbon atoms. The term "alkyl groups" is used
in its broadest sense. Alkyl groups may be optionally substituted
as defined herein. Examples of alkyl radicals include methyl,
ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl,
neopentyl, iso-amyl, hexyl, cyclohexyl,
trans-1,2-di-ethylcyclohexyl, octyl, nonyl and the like. For
example, the abbreviation "(C.sub.1-C.sub.6)-alkyl groups" includes
(C.sub.3-C.sub.6)-cycloalkyl groups as well as straight and
branched alkyl groups, and "O(C.sub.1-C.sub.8)-alkyl groups"
includes the straight-chain O(C.sub.1-C.sub.8)-alkyl groups,
branched O(C.sub.1-C.sub.6'')-alkyl groups, and cyclic
O(C.sub.1-C.sub.6)-alkyl groups. The term "alkylene," as used
herein, alone or in combination, refers to a saturated aliphatic
group derived from a straight or branched chain saturated
hydrocarbon attached at two or more positions, such as methylene
(--CH.sub.2--), ethylene, and 1,3-cyclobutylene.
The term "alkylamino," as used herein, alone or in combination,
refers to an amino group attached to the parent molecular moiety
through an alkyl group.
The term "alkylaminocarbonyl" as used herein, alone or in
combination, refers to an alkylamino group attached to the parent
molecular moiety through a carbonyl group. Examples of such
radicals include N-methylaminocarbonyl and
N,N-dimethylcarbonyl.
The term "alkylcarbonyl" and "alkanoyl," as used herein, alone or
in combination, refers to an alkyl group attached to the parent
molecular moiety through a carbonyl group. Examples of such groups
include methylcarbonyl, also known as acetyl; ethylcarbonyl, also
known as propionyl; and 2-methyl-cyclopentylcarbonyl, etc.
The term "alkylidene," as used herein, alone or in combination,
refers to an alkenyl group in which one carbon atom of the
carbon-carbon double bond belongs to the moiety to which the
alkenyl group is attached.
The term "alkylsulfinyl," as used herein, alone or in combination,
refers to an alkyl group attached to the parent molecular moiety
through a sulfinyl group. Examples of alkylsulfinyl groups include
methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl.
The term "alkylsulfonyl," as used herein, alone or in combination,
refers to an alkyl group attached to the parent molecular moiety
through a sulfonyl group. Examples of alkylsulfinyl groups include
methanesulfonyl, ethanesulfonyl, tert-butanesulfonyl, and the
like.
The term "alkylthio," as used herein, alone or in combination,
refers to an alkyl thioether (R--S--) radical wherein the term
alkyl is as defined above. Examples of suitable alkyl thioether
radicals include methylthio, ethylthio, n-propylthio,
isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,
tert-butylthio, ethoxyethylthio, methoxypropoxyethylthio,
ethoxypentoxyethoxyethylthio and the like.
The term "alkylthioalkyl" embraces alkylthio radicals attached to
an alkyl radical. Alkylthioalkyl radicals include "lower
alkylthioalkyl" radicals having alkyl radicals of one to six carbon
atoms and an alkylthio radical as described above. Examples of such
radicals include methylthiomethyl.
The term "alkynyl," as used herein in its broadest sense, alone or
in combination, refers to a straight-chain, branched chain, or
cyclic unsaturated hydrocarbon radical, as well as a radical which
contains any combination of straight, branched, and/or cyclic
radicals, having one or more carbon-carbon triple bonds and
containing from 2 to 20 carbon atoms. In many embodiments alkynyl
groups contain from 2 to 6 carbon atoms. In many other embodiments
alkynyl groups contain from 2 to 4 carbon atoms. "Alkynylene"
refers to a carbon-carbon triple bond attached at two positions
such as ethynylene (--C:::C--, --C.ident.C--). For example,
(C.sub.2-C.sub.8) alkynyl groups embraces straight, branched, and
cyclic hydrocarbon chains containing 2 to 8 carbon atoms having at
least one triple bond, and the term includes but is not limited to
substituents such as ethynyl, propynyl, hydroxypropynyl,
butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl,
4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl,
hexyn-3-yl, 3,3-dimethylbutyn-1-yl, and the like, unless otherwise
indicated.
The term "amido," as used herein, alone or in combination, refers
to an amino group as described below attached to the parent
molecular moiety through a carbonyl or sulfonyl group. The term
"C-amido" as used herein, alone or in combination, refers to a
--C(.dbd.O)--NR.sub.2 group with R as defined herein. The term
"N-amido" as used herein, alone or in combination, refers to a
RC(.dbd.O)NH-- group, with R as defined herein.
The term "amino," as used herein, alone or in combination, refers
to --NRR', wherein R and R' are independently selected from the
group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkenyl, arylalkyl,
cycloalkyl, haloalkylcarbonyl, heteroaryl, heteroarylalkenyl,
heteroarylalkyl, heterocycle, heterocycloalkenyl, and
heterocycloalkyl, wherein the aryl, the aryl part of the
arylalkenyl, the arylalkyl, the heteroaryl, the heteroaryl part of
the heteroarylalkenyl and the heteroarylalkyl, the heterocycle, and
the heterocycle part of the heterocycloalkenyl and the
heterocycloalkyl can be optionally substituted with one, two,
three, four, or five substituents independently selected from the
group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano,
halo, haloalkoxy, haloalkyl, hydroxy, hydroxy-alkyl, nitro, and
oxo.
The term "aminoalkyl," as used herein, alone or in combination,
refers to an amino group attached to the parent molecular moiety
through an alkyl group. Examples include aminomethyl, aminoethyl
and aminobutyl. The term "alkylamino" denotes amino groups which
have been substituted with one or two alkyl radicals. Suitable
"alkylamino" groups may be mono- or dialkylated, forming groups
such as, for example, N-methylamino, N-ethylamino,
N,N-dimethylamino, N,N-diethylamino and the like.
The terms "aminocarbonyl" and "carbamoyl," as used herein, alone or
in combination, refer to an amino-substituted carbonyl group,
wherein the amino group can be a primary or secondary amino group
containing substituents selected from alkyl, aryl, aralkyl,
cycloalkyl, cycloalkylalkyl radicals and the like.
The term "aminocarbonylalkyl," as used herein, alone or in
combination, refers to an aminocarbonyl radical attached to an
alkyl radical, as described above. An example of such radicals is
aminocarbonylmethyl. The term "amidino" denotes an --C(NH)NH.sub.2
radical. The term "cyanoamidino" denotes an --C(N--CN)NH.sub.2
radical.
The term "aralkenyl" or "arylalkenyl," as used herein, alone or in
combination, refers to an aryl group attached to the parent
molecular moiety through an alkenyl group.
The term "aralkoxy" or "arylalkoxy," as used herein, alone or in
combination, refers to an aryl group attached to the parent
molecular moiety through an alkoxy group.
The term "aralkyl" or "arylalkyl," as used herein, alone or in
combination, refers to an aryl group attached to the parent
molecular moiety through an alkyl group.
The term "aralkylamino" or "arylalkylamino," as used herein, alone
or in combination, refers to an arylalkyl group attached to the
parent molecular moiety through a nitrogen atom, wherein the
nitrogen atom is substituted with hydrogen.
The term "aralkylidene" or "arylalkylidene," as used herein, alone
or in combination, refers to an aryl group attached to the parent
molecular moiety through an alkylidene group
The term "aralkylthio" or "arylalkylthio," as used herein, alone or
in combination, refers to an arylalkyl group attached to the parent
molecular moiety through a sulfur atom.
The term "aralkynyl" or "arylalkynyl," as used herein, alone or in
combination, refers to an aryl group attached to the parent
molecular moiety through an alkynyl group.
The term "aralkoxycarbonyl," as used herein, alone or in
combination, refers to a radical of the formula aralkyl-O--C(O)--
in which the term "aralkyl," has the significance given above.
Examples of an aralkoxycarbonyl radical are benzyloxycarbonyl ("Z"
or "Cbz") and 4-methoxyphenylmethoxycarbonyl ("MOS").
The term "aralkanoyl," as used herein, alone or in combination,
refers to an acyl radical derived from an aryl-substituted
alkanecarboxylic acid such as benzoyl, phenylacetyl,
3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,
(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl,
4-methoxyhydrocinnamoyl, and the like. The term "aroyl" refers to
an acyl radical derived from an arylcarboxylic acid, "aryl" having
the meaning given below. Examples of such aroyl radicals include
substituted and unsubstituted benzoyl or napthoyl such as benzoyl,
4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl,
1-naphthoyl, 2-naphthoyl, 6-carboxy-2-naphthoyl,
6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,
3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the
like.
The term "aryl," as used herein, alone or in combination, means a
carbocyclic aromatic system containing one, two or three rings
wherein such rings may be attached together in a pendent manner or
may be fused. The term "aryl" embraces aromatic radicals such as
phenyl, naphthyl, anthracenyl, phenanthryl, and biphenyl. The aryl
groups of the present invention can be optionally substituted with
one, two, three, four, or five substituents independently selected
from the groups as defined herein.
The term "arylamino" as used herein, alone or in combination,
refers to an aryl group attached to the parent moiety through an
amino group, such as N-phenylamino, and the like.
The terms "arylcarbonyl" and "aroyl," as used herein, alone or in
combination, refer to an aryl group attached to the parent
molecular moiety through a carbonyl group.
The term "aryloxy," as used herein, alone or in combination, refers
to an aryl group attached to the parent molecular moiety through an
oxygen atom.
The term "arylsulfonyl," as used herein, alone or in combination,
refers to an aryl group attached to the parent molecular moiety
through a sulfonyl group.
The term "arylthio," as used herein, alone or in combination,
refers to an aryl group attached to the parent molecular moiety
through a sulfur atom.
The terms "carboxy" or "carboxyl," whether used alone or with other
terms, such as "carboxyalkyl," denotes --CO.sub.2H.
The terms "benzo" and "benz," as used herein, alone or in
combination, refer to the divalent radical C.sub.6H.sub.4.dbd.
derived from benzene. Examples include benzothiophene and
benzimidazole.
The term "carbamoyloxy," as used herein, alone or in combination,
refers to an amino-substituted carbonyl group attached to the
parent molecular moiety through a oxygen atom (e.g.
RR'NC(.dbd.O)O--), wherein the amino group can be a primary or
secondary amino group containing substituents selected from alkyl,
aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the
like.
The term "O-carbamyl" as used herein, alone or in combination,
refers to a --OC(O)NR, group--with R as defined herein.
The term "C-linked" as used herein, alone or in combination, refers
to any substituent that is attached to the parent molecular moiety
through a carbon-carbon bond.
The term "N-carbamyl" as used herein, alone or in combination,
refers to a ROC(O)NH-- group, with R as defined herein.
The term "carbonate" as used herein, alone or in combination,
refers to a --O--C(.dbd.O)OR group, with R as defined herein.
The term "carbonyl," as used herein, when alone includes formyl
[--C(O)H] and in combination is a --C(O)-- group.
The term "carboxy," as used herein, refers to --C(O)OH or the
corresponding "carboxylate" such as a carboxylic acid salt
derivative or ester derivative. An "O-carboxy" group refers to a
RC(O)O-- group, where R is as defined herein. A "C-carboxy" group
refers to a --C(O)OR groups where R is as defined herein.
The term "cyano," as used herein, alone or in combination, refers
to --CN.
The term "cycloalkyl," as used herein, alone or in combination,
refers to a saturated or partially saturated monocyclic, bicyclic
or tricyclic alkyl radical wherein each cyclic moiety contains from
3 to 12, preferably three to seven, carbon atom ring members and
which may optionally be a benzo fused ring system which is
optionally substituted as defined herein. Examples of such
cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl,
adamantyl and the like. "Bicyclic" and "tricyclic" as used herein
are intended to include both fused ring systems, such as
decahydonapthalene, octahydronapthalene as well as the multicyclic
(multicentered) saturated or partially unsaturated type. The latter
type of isomer is exemplified in general by bicyclo[2,2,2]octane,
bicyclo[2,2,2]octane, bicyclo[1,1,1]pentane, camphor and
bicyclo[3,2,1]octane.
The term "cycloalkenyl," as used herein, alone or in combination,
refers to a partially unsaturated monocyclic, bicyclic or tricyclic
radical wherein each cyclic moiety contains from 3 to 12,
preferably five to eight, carbon atom ring members and which may
optionally be a benzo fused ring system which is optionally
substituted as defined herein. Examples of such cycloalkenyl
radicals include cyclopentenyl, cyclohexenyl, cyclohexadienyl,
cycloheptenyl, cyclooctadienyl, -1H-indenyl and the like.
The term "cycloalkylalkyl," as used herein, alone or in
combination, refers to an alkyl radical as defined above which is
substituted by a cycloalkyl radical as defined above. Examples of
such cycloalkylalkyl radicals include cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,
1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentylethyl,
2-cyclohexylethyl, cyclobutylpropyl, cyclopentylpropyl,
cyclohexylbutyl and the like.
The term "cycloalkenylalkyl," as used herein, alone or in
combination, refers to an alkyl radical as defined above which is
substituted by a cycloalkenyl radical as defined above. Examples of
such cycloalkenylalkyl radicals include 1-methylcyclohex-1-enyl-,
4-ethylcyclohex-1-enyl-, 1-butylcyclopent-1-enyl-,
3-methylcyclopent-1-enyl- and the like.
The term "ester," as used herein, alone or in combination, refers
to a carbonyloxy --(C.dbd.O)O-- group bridging two moieties linked
at carbon atoms. Examples include ethyl benzoate, n-butyl
cinnamate, phenyl acetate and the like.
The term "ether," as used herein, alone or in combination, refers
to an oxy group bridging two moieties linked at carbon atoms.
The term "halo," or "halogen," as used herein, alone or in
combination, refers to fluorine, chlorine, bromine, or iodine.
The term "haloalkoxy," as used herein, alone or in combination,
refers to a haloalkyl group attached to the parent molecular moiety
through an oxygen atom.
The term "haloalkyl," as used herein, alone or in combination,
refers to an alkyl radical having the meaning as defined above
wherein one or more hydrogens are replaced with a halogen.
Specifically embraced are monohaloalkyl, dihaloalkyl and
polyhaloalkyl radicals. A monohaloalkyl radical, for one example,
may have either an iodo, bromo, chloro or fluoro atom within the
radical. Dihalo and polyhaloalkyl radicals may have two or more of
the same halo atoms or a combination of different halo radicals.
Examples of haloalkyl radicals include fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, trichloroethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
"Haloalkylene" refers to a halohydrocarbyl group attached at two or
more positions. Examples include fluoromethylene (--CFH--),
difluoromethylene (--CF.sub.2--), chloromethylene (--CHCl--) and
the like. Examples of such haloalkyl radicals include chloromethyl,
1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl,
1,1,1-trifluoroethyl, perfluorodecyl and the like.
The term "heteroalkyl," as used herein, alone or in combination,
refers to a stable straight or branched chain, or cyclic
hydrocarbon radical, or combinations thereof, fully saturated or
containing from 1 to 3 degrees of unsaturation, consisting of the
stated number of carbon atoms and from one to three heteroatoms
selected from the group consisting of O, N, and S, and wherein the
nitrogen and sulfur atoms may optionally be oxidized and the
nitrogen heteroatom may optionally be quaternized. The
heteroatom(s) O, N and S may be placed at any interior position of
the heteroalkyl group. Up to two heteroatoms may be consecutive,
such as, for example, --CH.sub.2--NH--OCH.sub.3.
The term "heteroaryl," as used herein, alone or in combination,
refers to an aromatic five- or six-membered ring, where at least
one atom is selected from the group consisting of N, O, and S, and
the remaining ring atoms are carbon. The five-membered rings have
two double bonds, and the six-membered rings have three double
bonds. The heteroaryl groups are connected to the parent molecular
group through a substitutable carbon or nitrogen atom in the ring.
The term "heteroaryl" also includes systems where a heteroaryl ring
is fused to an aryl group, as defined herein, a heterocycle group,
as defined herein, or an additional heteroaryl group. Heteroaryls
are exemplified by benzothienyl, benzoxazolyl, benzofuranyl,
benzimidazolyl, benzthiazolyl benzotriazolyl, cinnolinyl, furyl,
imidazolyl, triazolyl [e.g., 4H-1,2,4-triazolyl,
1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.], tetrazolyl [e.g.
1H-tetrazolyl, 2H-tetrazolyl, etc.], indazolyl, indolyl,
isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl,
oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,5-oxadiazolyl, etc.], oxazolyl, isoxazolyl, purinyl, thiazolyl,
isothiazolyl, thienopyridinyl, thienyl, thiadiazolyl [e.g.,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.],
pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl,
pyrrolyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl,
quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, tetrazolyl,
triazinyl, and the like. The heteroaryl groups of the present
invention can be optionally substituted with one, two, three, four,
or five substituents independently selected from the groups as
defined herein.
Examples of preferred heteroaryl groups include, without
limitation, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl,
pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,
indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl,
thiazolyl, triazolyl, and isoxazolyl
The term "heteroaralkyl" or "heteroarylalkyl," as used herein,
alone or in combination, refers to a heteroaryl group attached to
the parent molecular moiety through an alkyl group.
The term "heteroaralkenyl" or "heteroarylalkenyl," as used herein,
alone or in combination, refers to a heteroaryl group attached to
the parent molecular moiety through an alkenyl group.
The term "heteroaralkoxy" or "heteroarylalkoxy," as used herein,
alone or in combination, refers to a heteroaryl group attached to
the parent molecular moiety through an alkoxy group.
The term "heteroaralkylidene" or "heteroarylalkylidene," as used
herein, alone or in combination, refers to a heteroaryl group
attached to the parent molecular moiety through an alkylidene
group.
The term "heteroaryloxy," as used herein, alone or in combination,
refers to a heteroaryl group attached to the parent molecular
moiety through an oxygen atom.
The term "heteroarylsulfonyl," as used herein, alone or in
combination, refers to a heteroaryl group attached to the parent
molecular moiety through a sulfonyl group.
The terms "heterocycloalkyl" and, interchangeably, "heterocycle,"
as used herein, alone or in combination, each refer to a saturated,
partially unsaturated, or fully unsaturated monocyclic, bicyclic,
or tricyclic heterocyclic radical containing one or more
heteroatoms as ring members, wherein each said heteroatom may be
independently selected from the group consisting of nitrogen,
oxygen, and sulfur, and wherein there are typically 3 to 8 ring
members in each ring. Most commonly heterocyclic rings contain 5 to
6 ring members. In some embodiments of this invention heterocyclic
rings contain 1 to 4 heteroatoms; in other embodiments,
heterocyclic rings contain 1 to 2 heteroatoms. "Heterocycloalkyl"
and "heterocycle" are intended to include sulfones, sulfoxides,
N-oxides of tertiary nitrogen ring members, and carbocyclic fused
and benzo fused ring systems; additionally, both terms also include
systems where a heterocycle ring is fused to an aryl group, as
defined herein, or an additional heterocycle group. Heterocycle
groups of the invention are exemplified by aziridinyl, azetidinyl,
1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl,
dihydrocinnolinyl, dihydrobenzodioxinyl,
dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl,
dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl,
1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl,
pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl,
and the like. The heterocycle groups may be optionally substituted
unless specifically prohibited.
The term "heterocycloalkenyl," as used herein, alone or in
combination, refers to a heterocycle group attached to the parent
molecular moiety through an alkenyl group.
The term "heterocycloalkoxy," as used herein, alone or in
combination, refers to a heterocycle group attached to the parent
molecular group through an oxygen atom.
The term "heterocycloalkylalkyl," as used herein, alone or in
combination, refers to an alkyl radical as defined above in which
at least one hydrogen atom is replaced by a heterocycloalkyl
radical as defined above, such as pyrrolidinylmethyl,
tetrahydrothienylmethyl, pyridylmethyl and the like.
The term "heterocycloalkylidene," as used herein, alone or in
combination, refers to a heterocycle group attached to the parent
molecular moiety through an alkylidene group.
The term "hydrazinyl" as used herein, alone or in combination,
refers to two amino groups joined by a single bond, i.e.,
--N--N--.
The term "hydroxy," as used herein, alone or in combination, refers
to --OH.
The term "hydroxyalkyl" as used herein, alone or in combination,
refers to a linear or branched alkyl group having one to about ten
carbon atoms any one of which may be substituted with one or more
hydroxyl radicals. Examples of such radicals include hydroxymethyl,
hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.
The term "hydroxyalkyl," as used herein, alone or in combination,
refers to a hydroxy group attached to the parent molecular moiety
through an alkyl group.
The term "imino," as used herein, alone or in combination, refers
to .dbd.N--.
The term "iminohydroxy," as used herein, alone or in combination,
refers to .dbd.N(OH) and .dbd.N--O--.
The phrase "in the main chain" refers to the longest contiguous or
adjacent chain of carbon atoms starting at the point of attachment
of a group to the compounds of this invention.
The term "isocyanato" refers to a --NCO group.
The term "isothiocyanato" refers to a --NCS group.
The phrase "linear chain of atoms" refers to the longest straight
chain of atoms independently selected from carbon, nitrogen, oxygen
and sulfur.
The term "lower," as used herein in such terms as "lower alkyl,"
alone or in combination, means containing from 1 to and including 6
carbon atoms.
The term "mercaptoalkyl" as used herein, alone or in combination,
refers to an R'SR-- group, where R and R' are as defined
herein.
The term "mercaptomercaptyl" as used herein, alone or in
combination, refers to a RSR'S-- group, where R is as defined
herein.
The term "mercaptyl" as used herein, alone or in combination,
refers to an RS-- group, where R is as defined herein.
The term "null" refers to a lone electron pair.
The term "nitro," as used herein, alone or in combination, refers
to --NO.sub.2.
The term "optionally substituted" means the anteceding group may be
substituted or unsubstituted. When substituted, the hydrogen atoms
bound to the carbon, nitrogen, sulfur, or oxygen atoms are replaced
by "substituents" which may include carbonyl (oxo), carboxyl, lower
alkyl carboxylate, lower alkyl carbonate, lower alkyl carbamate,
halogen, hydroxy, amino, amido, cyano, hydrazinyl,
hydrazinylcarbonyl, alkylhydrazinyl, dialkylhydrazinyl,
arylhydrazinyl, heteroarylhydrazinyl, nitro, thiol, sulfonic acid,
trisubstituted silyl, urea, acyl, acyloxy, acylamino, acylthio,
lower alkyl, lower alkylamino, lower dialkylamino, lower alkyloxy,
lower alkoxyalkyl, lower alkylthio, lower alkylsulfonyl, lower
alkenyl, lower alkenylamino, lower dialkenylamino, lower
alkenyloxy, lower alkenylthio, lower alkenyl sulfonyl, lower
alkynyl, lower alkynylamino, lower dialkynylamino, lower
alkynyloxy, lower alkynylthio, lower alkynylsulfonyl, lower
cycloalkyl, lower cycloalkyloxy, lower cycloalkylamino, lower
cycloalkylthio, lower cycloalkylsulfonyl, lower cycloalkylalkyl,
lower cycloalkylalkyloxy, lower cycloalkylalkylamino, lower
cycloalkylalkylthio, lower cycloalkylalkylsulfonyl, aryl, aryloxy,
arylamino, arylthio, arylsulfonyl, arylalkyl, arylalkyloxy,
arylalkylamino, arylalkylthio, arylalkylsulfonyl, heteroaryl,
heteroaryloxy, heteroarylamino, heteroarylthio, heteroarylsulfonyl,
heteroarylalkyl, heteroarylalkyloxy, heteroarylalkylamino,
heteroarylalkylthio, heteroarylalkylsulfonyl, heterocycloalkyl,
heterocycloalkyloxy, heterocycloalkylamino, heterocycloalkylthio,
heterocycloalkylsulfonyl, lower haloalkyl, lower haloalkenyl, lower
haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower
haloalkoxy, and lower acyloxy. Two substituents may be joined
together to form a fused four-, five-, six-, or seven-membered
carbocyclic or heterocyclic ring consisting of zero to three
heteroatoms, for example forming methylenedioxy or ethylenedioxy.
An optionally substituted group may be unsubstituted (e.g.,
--CH.sub.2CH.sub.3), fully substituted (e.g., --CF.sub.2CF.sub.3),
monosubstituted (e.g., --CH.sub.2CH.sub.2F) or substituted at a
level anywhere in-between fully substituted and monosubstituted
(e.g., --CH.sub.2CF.sub.3). Where substituents are recited without
qualification as to substitution, both substituted and
unsubstituted forms are encompassed. Where a substituent is
qualified as "substituted," the substituted form is specifically
intended. All pendant aryl, heteroaryl, and heterocyclo moieties
can be further optionally substituted with one, two, three, four,
or five substituents independently selected from the groups listed
above.
The terms "oxy" or "oxa," as used herein, alone or in combination,
refer to --O--.
The term "oxo" as used herein, alone or in combination, refers to a
doubly bonded oxygen .dbd.O.
The term "perhaloalkoxy" refers to an alkoxy group where all of the
hydrogen atoms are replaced by halogen atoms.
The term "perhaloalkyl" as used herein, alone or in combination,
refers to an alkyl group where all of the hydrogen atoms are
replaced by halogen atoms.
The term "phosphonate" as used herein, alone or in combination,
refers to the --P(.dbd.O)(OG)(OG1) group, where G and G1 are chosen
from H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, etc.
The term "phosphinate" as used herein, alone or in combination,
refers to the --P(.dbd.O)(G)(OG1) group, where G and G1 are chosen
from H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, etc.
The terms "sulfonate," "sulfonic acid," and "sulfonic," as used
herein, alone or in combination, refer the --SO.sub.3H group and
its anion as the sulfonic acid is used in salt formation.
The term "sulfanyl," as used herein, alone or in combination,
refers to --S and --S--.
The term "sulfinyl," as used herein, alone or in combination,
refers to --S(O)--.
The term "sulfonyl," as used herein, alone or in combination,
refers to --SO.sub.2--.
The term "N-sulfonamido" refers to a RS(.dbd.O).sub.2NH-- group
with R as defined herein.
The term "S-sulfonamido" refers to a --S(.dbd.O).sub.2NR.sub.2,
group, with R as defined herein.
The terms "thia" and "thio," as used herein, alone or in
combination, refer to a --S-- group or an ether wherein the oxygen
is replaced with sulfur. The oxidized derivatives of the thio
group, namely sulfinyl and sulfonyl, are included in the definition
of thia and thio.
The term "thioether," as used herein, alone or in combination,
refers to a thio group bridging two moieties linked at carbon
atoms.
The term "thiol," as used herein, alone or in combination, refers
to an --SH group.
The term "thiocarbonyl," as used herein, when alone includes
thioformyl --C(S)H and in combination is a --C(S)-- group.
The term "N-thiocarbamyl" refers to an ROC(S)NH-- group, with R as
defined herein.
The term "O-thiocarbamyl" refers to a --OC(S)NR, group with R as
defined herein.
The term "thiocyanato" refers to a --CNS group.
The term "trihalomethanesulfonamido" refers to a
X.sub.3CS(O).sub.2NR-- group with X is a halogen and R as defined
herein.
The term "trihalomethanesulfonyl" refers to a X.sub.3CS(O).sub.2--
group where X is a halogen.
The term "trihalomethoxy" refers to a X.sub.3CO-- group where X is
a halogen.
The term "trisubstituted silyl," as used herein, alone or in
combination, refers to a silicone group substituted at its three
free valences with groups as listed herein under the definition of
substituted amino. Examples include trimethysilyl,
tert-butyldimethylsilyl, triphenylsilyl and the like.
The term "urea," as used herein, alone or in combination, refers to
--N(R)C(.dbd.O)N(R)(R), with R as defined herein.
The term "carrier" is used in its broadest sense. For example, the
term carrier refers to any carriers, diluents, excipients, wetting
agents, buffering agents, suspending agents, lubricating agents,
adjuvants, vehicles, delivery systems, emulsifiers, disintegrants,
absorbents, preservatives, surfactants, colorants, flavorants, and
sweeteners. In some embodiments, the carrier may be a
pharmaceutically acceptable carrier, a term narrower than carrier,
because the term pharmaceutically acceptable carrier" means a
non-toxic that would be suitable for use in a pharmaceutical
composition.
The present invention also relates to a pharmaceutical composition
comprising, in a pharmaceutically acceptable carrier, an effective
amount of at least one compound of the invention.
The term effective amount is used in its broadest sense. The term,
for example, refers to the amount required to produce a desired
effect.
In some embodiments, the compound of the invention is present in a
pharmaceutical composition in an effective amount for treating HCV
infection (e.g., chronic HCV infection). "Treating HCV infection"
may refers to: (i) preventing HCV infection from occurring in an
animal that may be predisposed to HCV infection but has not yet
been diagnosed as having it; (ii) inhibiting or slowing HCV
infection, e.g. arresting its development; (iii) relieving chronic
infection, e.g. causing its regression; (iv) improving a symptom in
a subject having chronic infection; and/or (v) prolonging the
survival of a subject having chronic infection.
In any embodiment of the compounds of formula (I), R.sub.1 through
R.sub.5 may be the same, may be different, or some members of
R.sub.1 through R.sub.5 may be the same while the others are
different. Any combination is possible.
Examples of compounds of the present invention may include, but are
not limited to the following compounds listed in Table 1 below:
TABLE-US-00001 TABLE 1 No. Structure 1 ##STR00029## 2 ##STR00030##
3 ##STR00031## 4 ##STR00032## 5 ##STR00033## 6 ##STR00034## 7
##STR00035## 8 ##STR00036## 9 ##STR00037## 10 ##STR00038## 11
##STR00039## 12 ##STR00040## 13 ##STR00041## 14 ##STR00042## 15
##STR00043## 16 ##STR00044## 17 ##STR00045## 18 ##STR00046## 19
##STR00047## 20 ##STR00048## 21 ##STR00049## 22 ##STR00050## 23
##STR00051## 24 ##STR00052## 25 ##STR00053## 26 ##STR00054## 27
##STR00055## 28 ##STR00056## 29 ##STR00057## 30 ##STR00058## 31
##STR00059## 32 ##STR00060## 33 ##STR00061## 34 ##STR00062## 35
##STR00063## 36 ##STR00064## 37 ##STR00065## 38 ##STR00066## 39
##STR00067## 40 ##STR00068## 41 ##STR00069## 42 ##STR00070## 43
##STR00071## 44 ##STR00072## 45 ##STR00073## 46 ##STR00074## 47
##STR00075## 48 ##STR00076## 49 ##STR00077## 50 ##STR00078## 51
##STR00079## 52 ##STR00080## 53 ##STR00081## 54 ##STR00082## 55
##STR00083## 56 ##STR00084## 57 ##STR00085## 58 ##STR00086## 59
##STR00087## 60 ##STR00088## 61 ##STR00089## 62 ##STR00090## 63
##STR00091## 64 ##STR00092## 65 ##STR00093## 66 ##STR00094## 67
##STR00095## 68 ##STR00096## 69 ##STR00097## 70 ##STR00098## 71
##STR00099## 72 ##STR00100## 73 ##STR00101## 74 ##STR00102## 75
##STR00103## 76 ##STR00104## 77 ##STR00105## 78 ##STR00106## 79
##STR00107## 80 ##STR00108## 81 ##STR00109## 82 ##STR00110## 83
##STR00111## 84 ##STR00112## 85 ##STR00113## 86 ##STR00114## 87
##STR00115## 88 ##STR00116## 89 ##STR00117## 90 ##STR00118## 91
##STR00119## 92 ##STR00120## 93 ##STR00121## 94 ##STR00122## 95
##STR00123## 96 ##STR00124## 97 ##STR00125## 98 ##STR00126## 99
##STR00127## 100 ##STR00128## 101 ##STR00129## 102 ##STR00130## 103
##STR00131## 104 ##STR00132## 105 ##STR00133## 106 ##STR00134## 107
##STR00135## 108 ##STR00136## 109 ##STR00137## 110 ##STR00138## 111
##STR00139## 112 ##STR00140## 113 ##STR00141## 114 ##STR00142## 115
##STR00143## 116 ##STR00144## 117 ##STR00145## 118 ##STR00146## 119
##STR00147## 120 ##STR00148## 121 ##STR00149## 122 ##STR00150## 123
##STR00151##
124 ##STR00152## 125 ##STR00153## 126 ##STR00154## 127 ##STR00155##
128 ##STR00156## 129 ##STR00157## 130 ##STR00158## 131 ##STR00159##
132 ##STR00160## 133 ##STR00161## 134 ##STR00162## 135 ##STR00163##
136 ##STR00164## 137 ##STR00165## 138 ##STR00166## 139 ##STR00167##
140 ##STR00168## 141 ##STR00169## 142 ##STR00170## 143 ##STR00171##
144 ##STR00172## 145 ##STR00173## 146 ##STR00174## 147 ##STR00175##
148 ##STR00176## 149 ##STR00177## 150 ##STR00178## 151 ##STR00179##
152 ##STR00180## 153 ##STR00181## 154 ##STR00182## 155 ##STR00183##
156 ##STR00184## 157 ##STR00185## 158 ##STR00186## 159 ##STR00187##
160 ##STR00188## 161 ##STR00189## 162 ##STR00190## 163 ##STR00191##
164 ##STR00192## 165 ##STR00193## 166 ##STR00194## 167 ##STR00195##
168 ##STR00196## 169 ##STR00197## 170 ##STR00198## 171 ##STR00199##
172 ##STR00200## 173 ##STR00201## 174 ##STR00202## 175 ##STR00203##
176 ##STR00204## 177 ##STR00205## 178 ##STR00206## 179 ##STR00207##
180 ##STR00208## 181 ##STR00209## 182 ##STR00210## 183 ##STR00211##
184 ##STR00212## 185 ##STR00213## 186 ##STR00214## 187 ##STR00215##
188 ##STR00216## 189 ##STR00217## 190 ##STR00218## 191 ##STR00219##
192 ##STR00220## 193 ##STR00221## 194 ##STR00222## 195 ##STR00223##
196 ##STR00224## 197 ##STR00225## 198 ##STR00226## 199 ##STR00227##
200 ##STR00228## 201 ##STR00229## 202 ##STR00230## 203 ##STR00231##
204 ##STR00232## 205 ##STR00233## 206 ##STR00234## 207 ##STR00235##
208 ##STR00236## 209 ##STR00237## 210 ##STR00238## 211 ##STR00239##
212 ##STR00240## 213 ##STR00241## 214 ##STR00242## 215 ##STR00243##
216 ##STR00244## 217 ##STR00245## 218 ##STR00246## 219 ##STR00247##
220 ##STR00248## 221 ##STR00249## 222 ##STR00250## 223 ##STR00251##
224 ##STR00252## 225 ##STR00253## 226 ##STR00254## 227 ##STR00255##
228 ##STR00256## 229 ##STR00257## 230 ##STR00258## 231 ##STR00259##
232 ##STR00260## 233 ##STR00261## 234 ##STR00262## 235 ##STR00263##
236 ##STR00264## 237 ##STR00265## 238 ##STR00266## 239 ##STR00267##
240 ##STR00268## 241 ##STR00269## 242 ##STR00270## 243 ##STR00271##
244 ##STR00272## 245 ##STR00273## 246 ##STR00274## 247 ##STR00275##
248 ##STR00276##
249 ##STR00277## 250 ##STR00278## 251 ##STR00279## 252 ##STR00280##
253 ##STR00281## 254 ##STR00282## 255 ##STR00283## 256 ##STR00284##
257 ##STR00285## 258 ##STR00286## 259 ##STR00287## 260 ##STR00288##
261 ##STR00289## 262 ##STR00290## 263 ##STR00291## 264 ##STR00292##
265 ##STR00293## 266 ##STR00294## 267 ##STR00295## 268 ##STR00296##
269 ##STR00297## 270 ##STR00298## 271 ##STR00299## 272 ##STR00300##
273 ##STR00301## 274 ##STR00302## 275 ##STR00303## 276 ##STR00304##
277 ##STR00305## 278 ##STR00306## 279 ##STR00307## 280 ##STR00308##
281 ##STR00309## 282 ##STR00310## 283 ##STR00311## 284 ##STR00312##
285 ##STR00313## 286 ##STR00314## 287 ##STR00315## 288 ##STR00316##
289 ##STR00317## 290 ##STR00318## 291 ##STR00319## 292 ##STR00320##
293 ##STR00321## 294 ##STR00322## 295 ##STR00323## 296 ##STR00324##
297 ##STR00325## 298 ##STR00326## 299 ##STR00327## 300 ##STR00328##
301 ##STR00329## 302 ##STR00330## 303 ##STR00331## 304 ##STR00332##
305 ##STR00333## 306 ##STR00334## 307 ##STR00335## 308 ##STR00336##
309 ##STR00337## 310 ##STR00338## 311 ##STR00339## 312 ##STR00340##
313 ##STR00341## 314 ##STR00342## 315 ##STR00343## 316 ##STR00344##
317 ##STR00345## 318 ##STR00346## 319 ##STR00347## 320 ##STR00348##
321 ##STR00349## 322 ##STR00350## 323 ##STR00351## 324 ##STR00352##
325 ##STR00353## 326 ##STR00354## 327 ##STR00355## 328 ##STR00356##
329 ##STR00357## 330 ##STR00358## 331 ##STR00359## 332 ##STR00360##
333 ##STR00361## 334 ##STR00362## 335 ##STR00363## 336 ##STR00364##
337 ##STR00365## 338 ##STR00366## 339 ##STR00367## 340 ##STR00368##
341 ##STR00369## 342 ##STR00370## 343 ##STR00371## 344 ##STR00372##
345 ##STR00373## 346 ##STR00374## 347 ##STR00375## 348 ##STR00376##
349 ##STR00377## 350 ##STR00378## 351 ##STR00379## 352 ##STR00380##
353 ##STR00381## 354 ##STR00382## 355 ##STR00383## 356 ##STR00384##
357 ##STR00385## 358 ##STR00386## 359 ##STR00387## 360
##STR00388##
Table 2 designates the melting points of various compounds.
TABLE-US-00002 TABLE 2 Melting No. Structure Point (.degree. C.) 1
##STR00389## 127.5-129.0 2 ##STR00390## 260-264 (dec) 3
##STR00391## 126-128 4 ##STR00392## 254-257 5 ##STR00393## 172-174
6 ##STR00394## >300
For the above compounds that have a trifluoromethyl group
(--CF.sub.3), it is also envisioned by the inventors that in place
of the trifluoromethyl, a moiety selected from --CF.sub.2H,
--CH.sub.2CF.sub.3, --CF.sub.2CH.sub.3, --CF.sub.2CF.sub.3,
--SCF.sub.3, --SO.sub.2CF.sub.3, --OCF.sub.3 and
--CH.sub.2CH.sub.2CF.sub.3 may be used.
Compounds of Formula (I), where R.sub.6 is any of haloalkyl,
perhaloalkyl, haloalkoxy, perhaloalkoxy,
S(O).sub.mC(R.sub.7R.sub.8).sub.nCF.sub.3, and
C(R.sub.7R.sub.8).sub.nCF.sub.3, may be synthesized by reacting an
aroyl derivative, wherein G.sub.1 is hydroxy, chloro, fluoro,
bromo, alkoxy and the like with a heteroaromatic amine as shown
below, wherein W, X, and Y are as defined above, under suitable
reaction conditions. In some embodiments, the reaction may be
generically represented as follows:
##STR00395##
Examples of the invention, compounds (1) and (2), may be
synthesized by the method described in the following reaction
scheme. 2-Amino-5-trifluoromethyl-thiazole was prepared by a
modification of the procedure of Laduron et al. J. Fluorine Chem.
1995, 73, 83-86. Coupling of o-acetylsalicyloyl chloride and
2-Amino-5-trifluoromethylthiazole in the presence of a suitable
base, including tertiary amines like triethylamine, in a suitable
inert solvent like dichloromethane, at about 0.degree. C. to about
ambient room temperature, affords compound (1). Hydrolysis of the
acetyl moiety of compound (1) with dilute hydrochoric acid at room
temperature to about 50.degree. C. yields compound (2).
##STR00396##
Further examples of the invention, compounds (3) and (4), may be
synthesized via the synthetic pathway outlined in the scheme below,
using commercially available 2-amino-4-trifluoromethylthiazole as a
starting material.
##STR00397##
The compositions of the present invention may be formulated as
solid or liquid dosage forms, or as pastes or ointments, and may
optionally contain further active ingredients.
A pharmaceutical composition of the present invention comprises a
pharmaceutically acceptable carrier, which is not particularly
limited, and includes a wide range of carriers known to those of
ordinary skill in the art, and including wetting or dispersing
agents, starch derivatives, excipients, and the like. Tablet
embodiments may optionally comprise a coating of a substance that
constitutes an enteric coating, i.e., a coating that substantially
insoluble in gastric secretion but substantially soluble in
intestinal fluids.
Pharmaceutical compositions comprising the compounds of the present
invention are in some embodiments formulated for oral
administration and are optionally in the form of a liquid, for
example an emulsion or a solution or a suspension in water or oil
such as arachis oil, or other liquid. Formulations of non-aqueous
micellar solutions may be prepared according to the method
disclosed in U.S. Pat. No. 5,169,846. Alternatively, tablets can be
manufactured, for example, by performing the following steps: wet
granulation; drying; and compression. Film coating may generally be
performed with organic solvents.
The present invention is a method, comprising administering to a
subject at least one compound of the present invention in an amount
in an effective amount for treating HCV infection (e.g., chronic
HCV infection). In some embodiments, the method, comprising
administering to a subject at least one pharmaceutical composition
which comprises at least one compound of the present invention in
an amount in an effective amount for treating HCV infection (e.g.,
chronic HCV infection).
In some embodiments, the subject is chosen from animals. In some
embodiments, the subject is chosen from mammals. In some
embodiments, the subject is chosen from pets, such as mice, dogs,
cats, etc. In some embodiments, the subject is chosen from
humans.
In some embodiments, the invention provides a method of treating a
viral infection in a subject, comprising administering to the
subject at least one dose of an effective amount of at least one
compound of the present invention. In some embodiments, the
invention provides a method of treating a viral infection in a
subject, comprising administering to the subject at least one dose
of an effective amount of at least one pharmaceutical composition
comprising, in a pharmaceutically acceptable carrier, at least one
compound of the present invention.
In some embodiments the antiviral treatment or prophylactic dosages
of the compound of the present invention may depend upon the weight
of the subject, and may be inferred by one of ordinary skill
without undue experimentation by reference to the following
examples, which are set forth for purposes of illustration and are
not intended to be limiting.
The inventive compounds and compositions may be administered
locally or systemically by any means known to an ordinarily skilled
artisan. For example, the inventive compounds and compositions may
be administered orally, parenterally, by inhalation spray,
topically, rectally, nasally, buccally, vaginally or via an
implanted reservoir in dosage formulations containing conventional
non-toxic pharmaceutically acceptable carriers, adjuvants and
vehicles. The term parenteral as used herein includes subcutaneous,
intravenous, intraarterial, intramuscular, intraperitoneal,
intrathecal, intraventricular, intrasternal, intracranial or
intraosseous injection and infusion techniques. The exact
administration protocol will vary depending upon various factors
including the age, body weight, general health, sex and diet of the
patient; the determination of specific administration procedures
would be routine to an ordinarily skilled artisan.
Dose levels on the order of about 0.1 to about 100 mg/kg of the
active ingredient compound are useful in the treatment of the above
conditions (e.g., 0.1 mg/kg-day). In some embodiments, the amounts
range from about 1 to about 10 mg/kg, and in other embodiments, the
amounts range from about 2 to about 5 mg/kg. The specific dose
level for any particular patient will vary depending upon a variety
of factors, including the activity and the possible toxicity of the
specific compound employed; the age, body weight, general health,
sex and diet of the patient; the time of administration; the rate
of excretion; drug combination; the severity of the particular
disease being treated; and the form of administration. Typically,
in vitro dosage-effect results provide useful guidance on the
proper doses for patient administration. Studies in animal models
are also helpful. The considerations for determining the proper
dose levels are well known in the art.
Any administration regimen for regulating the timing and sequence
of drug delivery can be used and repeated as necessary to effect
treatment. Such regimen may include multiple uses or
preadministration and/or co-administration and/or
postadministration with food, liquid, or water.
As noted above, this invention provides or contemplates a kit,
comprising at least one compound of the invention. The kit could
take any form. By way of example, a kit includes one or more
containers for storing a pharmaceutical composition. In some
embodiments, a container contains written instructions for
administering the pharmaceutical composition. In some embodiments,
a container contains is the substrate for the written instructions
for administering the pharmaceutical composition. In some
embodiments, the written instructions for administering the
pharmaceutical composition are affixed to a container, for example,
as in a container for filling a prescription sometimes has written
instructions affixed on a surface.
Other embodiments of the invention will be apparent to those
skilled in the art from consideration of the specification and
practice of the invention disclosed herein. It is intended that the
specification and its examples be considered as exemplary only,
with a true scope and spirit of the invention being indicated by
what may eventually be claimed.
EXAMPLES
1. Materials and Methods
1.1 Materials.
All test compounds were provided by Romark Laboratories,
Nitazoxanide and Tizoxanide were used as standards.
1.2. HBV studies.
1.2.1. Antiviral Assays.
HBV antiviral assays were conducted as previous described [Korba
and Gerin, Antiviral Res. 19:55 (1992 Confluent cultures of 2.2.15
cells were maintained on 96-well flat-bottomed tissue culture
plates (confluence in this culture system is required for active,
high levels of HBV replication equivalent to that observed in
chronically-infected individuals [Sells et al. J. Virol. 62,
2836-2844 (1988); Korba and Gerin (1992)]. Cultures were treated
with nine consecutive daily doses of the test compounds. HBV DNA
levels were assessed by quantitative blot hybridization 24 hr.
after the last treatment. Cytotoxicity was assessed by uptake of
neutral red dye 24 hr. following the last treatment.
1.2.3. Production of HBV Proteins.
Cultures of 2.2.15 cells were treated under standard procedures and
semi-quantitative EIA-based analysis of HBV proteins was performed
as previously described [Korba and Gerin, Antivir. Res. 28, 225-242
(1995)], except that HBeAg was analyzed ETI-EBK Plus.RTM.(DiaSorin,
Inc., Stillwater, Minn. USA). Samples were diluted (2 to 10-fold)
to bring levels into the dynamic response ranges of the EIA's.
HBsAg, and HBeAg were analyzed from culture medium samples and
HBcAg was analyzed from intracellular lysates. Intracellular HBV
RNA was assessed by quantitative northern blot hybridization (Korba
and Gerin, 1995).
1.3. HCV Studies.
Antiviral activity of test compounds was assessed in a 3-day assay
using the stably-expressing HCV replicon cell line, AVA5
(sub-genomic CONI, genotype 1b) [Blight et al., Science 290,
1972-1974 (2000)] maintained as sub-confluent cultures on 96-well
plates as previously described (Okuse et al., Antiviral Research
65, 23-34 (2005)]. Antiviral activity was determined by blot
hybridization analysis of intracellular HCV RNA (normalized to the
level of cellular B-actin RNA in each culture sample) and
cytotoxicity was assessed by neutral red dye uptake after 3 days of
treatment. Additional studies were performed using Huh7 cells
containing another HCV replicon, H/FL-Neo, a genotype 1a full
length construct [Blight et al., J. Virol. 77, 3181-3190 (2003)].
For studies involving human serum, standard culture medium (which
contains 10% fetal bovine serum) and assay conditions were
maintained.
1.4. Presentation of Results.
EC.sub.50, EC.sub.90 and CC.sub.50 values (.+-.standard deviations
[S.D.]) were calculated by linear regression analysis using data
combined from all treated cultures (Korba and Gerin, 1992; Okuse et
al., 2005). EC.sub.50 and EC.sub.90 are drug concentrations at
which a 2-fold, or a 10-fold depression of intracellular HBV DNA or
HCV RNA (relative to the average levels in untreated cultures),
respectively, was observed. CC.sub.50 is the drug concentration at
which a 2-fold lower level of neutral red dye uptake (relative to
the average levels in untreated cultures) was observed. Selectivity
index (S.I.) was calculated as CC.sub.50/EC.sub.90 for HBV assays
and CC.sub.50/EC.sub.50 for HCV assays. EC.sub.90 values were used
for calculation of the S.I. in HBV assays since at least a 3-fold
depression of HBV DNA levels is typically required to achieve
statistical significance in this assay system (Korba and Gerin,
1992). For combination treatments, EC.sub.50, EC.sub.90, CC.sub.50
and S.I. are presented for the first compound listed. The molar
ratio of the compounds in each combination is also indicated.
2. Results
TABLE-US-00003 TABLE 3 HBV Extracellular Virion Assay Results.
EC.sub.50 EC.sub.90 CC.sub.50 (VIR) (VIR) SI Compd # (.mu.M)
(.mu.M) (.mu.M) (VIR) Nitazoxanide > 100.0 A C > 121
(reference) Tizoxanide > 100.0 A C > 172 (reference) 1 >
100.0 D E > 11 2 > 100.0 D E > 11 3 > 100.0 > E >
E 4 > 100.0 > E > E 5 > 100.0 > E > E 6 >
100.0 > E > E Legend: A: 0.05-0.2; B: 0.2-0.8; C: 0.8-3.2; D:
3.2-4.0; E: >4.0 ##STR00398## Nitazoxanide (reference)
##STR00399## Tizoxanide (reference)
Table 4 presents data from the primary HCV replicon cell assay.
TABLE-US-00004 TABLE 4 Primary HCV Replicon Cell Assay. PRIMARY
ASSAY, GENOTYPE 1B CC50 EC50 EC90 Compound (.mu.M) (.mu.M) (.mu.M)
SI Nitazoxanide (reference) 32.0 B C 169.0 Tizoxanide (reference)
15.0 B C 100.0 1 3.7 D E 0.9 2 0.46 A A 58.0 3 in test 4 in test 5
15.0 D E 15.0 6 5.3 D E 1.4 EC50 & EC90 Legand A: 0.005-0.05;
B: 0.05-0.5; C: 0.5-10; D: 0-5.0; E: >5.0
TABLE-US-00005 TABLE 5 Antiviral Activity of Thiazolides Against
Paramyxovirus, Influenza A and Coronavirus in Cell Assays
Paramyxovirus (Sendai virus)- Influenza A (PR8)- Coronavirus
(CCoV)- 37RC cells MDCK cells A72 cells Toxicity Toxicity Toxicity
Virus Yield LD.sub.50 S.I. Virus Yield LD.sub.50 S.I. Virus Yield
LD.sub.50 S.I. ID.sub.50 ID.sub.90 (MTT) LD.sub.50/ ID.sub.50
ID.sub.90 (MTT) LD.sub.50- / ID.sub.50 ID.sub.90 (MTT) LD.sub.50/
Compound RM# .mu.g/ml .mu.g/ml .mu.g/ml ID.sub.50 .mu.g/ml .mu.g/ml
.mu.g/- ml ID.sub.50 .mu.g/ml .mu.g/ml .mu.g/ml ID.sub.50
Nitazoxanide NTZ 1 6 >50 >50 1 7 >50 >50 (reference)
Tizoxanide TIZ 0.5 5 >50 >100 1 9 >50 >50 1 1.5 >50
>50 (reference) 1 RM5036 2 RM5037 3 RM5034 4 RM5035 5 RM4816 3 9
>50 >17 3 9 >50 >16.7 6 RM5033
TABLE-US-00006 TABLE 6 Antiviral Activity of Thiazolides Against
Rhinovirus, Respiratory Syncytial Virus and Herpesvirus in Cell
Assays Rhinovirus (RHV-2) Respiratory Syncytial Herpesvirus
(HSV-1)- HeLa R19 cells Virus (RV-A2)-HeLa cells Hep-2 cells
Toxicity Toxicity Virus Toxicity Virus Yield LD.sub.50 S.I. Virus
Yield LD.sub.50 S.I. Yield LD.sub.50 S.I. ID.sub.50 ID.sub.90 (MTT)
LD.sub.50/ ID.sub.50 ID.sub.90 (MTT) LD.sub.50- / ID.sub.50
ID.sub.90 (MTT) LD.sub.50/ Compound RM# .mu.g/ml .mu.g/ml .mu.g/ml
ID.sub.50 .mu.g/ml .mu.g/ml .mu.g/- ml ID.sub.50 .mu.g/ml .mu.g/ml
.mu.g/ml ID.sub.50 Nitazoxanide NTZ 2.5 >50 >50 >20 0.025
0.5 >50 >2000 (reference) Tizoxanide TIZ 0.3 40 >50
>167 0.5 -- 3 6 2 5 50 25 (reference) 1 RM5036 9 >50 >50
>5.5 0.2 2 >50 >250 2 RM5037 3 RM5034 0.03 1.5 >50
>1667 4 RM5035 0.15 1.5 >50 >333 5 RM4816 6 RM5033 0.2 1
>50 >250
TABLE-US-00007 TABLE 7 Antiviral Activity of Thiazolides Against
Rotavirus (2 strains) and Adenovirus in Cell Assays Rotavirus
(Simian SA11)- Rotavirus (WAG8P1)- Adenovirus (Ad5)- MA104 cells
MA104 cells HeLa R19 cells Toxicity Toxicity Toxicity Virus Yield
LD.sub.50 S.I. Virus Yield LD.sub.50 S.I. Virus Yield LD.sub.50
S.I. ID.sub.50 ID.sub.90 (MTT) LD.sub.50/ ID.sub.50 ID.sub.90 (MTT)
LD.sub.50- / ID.sub.50 ID.sub.90 (MTT) LD.sub.50/ Compound RM#
.mu.g/ml .mu.g/ml .mu.g/ml ID.sub.50 .mu.g/ml .mu.g/ml .mu.g/- ml
ID.sub.50 .mu.g/ml .mu.g/ml .mu.g/ml ID.sub.50 Nitazoxanide NTZ 1
10 >50 >50 10 40 >50 >5 1.5 15 >50 >3- 3.3
(reference) Tizoxanide TIZ 0.5 4 >50 >100 1 15 >50 >50
0.2 0.3 0.8 5 (reference) 1 RM5036 0.1 3.5 4 40 2 RM5037 3 RM5034 4
RM5035 5 RM4816 6 RM5033
TABLE-US-00008 TABLE 8 Antiviral Activity of thiazolides Against
Rhabdovirus in Cell Assays Rhabdovirus (VSV)-MA104 cells Toxicity
Virus Yield LD.sub.50 ID.sub.50 ID.sub.90 (MTT) S.I. Compound RM #
.mu.g/ml .mu.g/ml .mu.g/ml LD.sub.50/ID.sub.50 Nitazoxanide NTZ
(reference) Tizoxanide TIZ 2 15 50 25 (reference) 1 RM5036 2 RM5037
3 RM5034 4 RM5035 5 RM4816 6 RM5033
* * * * *
References