U.S. patent application number 17/077025 was filed with the patent office on 2021-02-11 for 3,3 disubstituted 19-nor pregnane compounds, compositions, and uses thereof.
The applicant listed for this patent is Sage Therapeutics, Inc.. Invention is credited to Benny C. Askew, JR., Boyd L. Harrison, Albert Jean Robichaud, Francesco G. Salituro, Ravindra B. Upasani.
Application Number | 20210040141 17/077025 |
Document ID | / |
Family ID | 1000005164456 |
Filed Date | 2021-02-11 |
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United States Patent
Application |
20210040141 |
Kind Code |
A1 |
Upasani; Ravindra B. ; et
al. |
February 11, 2021 |
3,3 DISUBSTITUTED 19-NOR PREGNANE COMPOUNDS, COMPOSITIONS, AND USES
THEREOF
Abstract
Provided herein are 3,3-disubstituted 19-nor-steroidal compounds
according to Formula (I) and (III): ##STR00001## where R.sup.1,
R.sup.2, R.sup.3, R.sup.3', R.sup.4, R.sup.6a, R.sup.6a, R.sup.11a,
and R.sup.11b areas defined herein. Compounds of the present
invention are contemplated useful for the prevention and treatment
of a variety of CNS-related conditions, for example, treatment of
sleep disorders, mood disorders, insomnia, anxiety, depression,
traumatic brain injury (TBI), stress, and epilepsy.
Inventors: |
Upasani; Ravindra B.; (San
Jose, CA) ; Askew, JR.; Benny C.; (Marshfield,
MA) ; Harrison; Boyd L.; (Princeton Junction, NJ)
; Salituro; Francesco G.; (Marlborough, MA) ;
Robichaud; Albert Jean; (Boston, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sage Therapeutics, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
1000005164456 |
Appl. No.: |
17/077025 |
Filed: |
October 22, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16548248 |
Aug 22, 2019 |
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17077025 |
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15681983 |
Aug 21, 2017 |
10435431 |
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16548248 |
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14351449 |
Apr 11, 2014 |
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PCT/US2012/060136 |
Oct 12, 2012 |
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15681983 |
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61698204 |
Sep 7, 2012 |
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61547291 |
Oct 14, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07J 31/006 20130101;
C07J 9/005 20130101; C07J 43/003 20130101; C07J 7/008 20130101;
C07J 7/0085 20130101; C07J 7/002 20130101; C07J 5/0015
20130101 |
International
Class: |
C07J 43/00 20060101
C07J043/00; C07J 5/00 20060101 C07J005/00; C07J 7/00 20060101
C07J007/00; C07J 31/00 20060101 C07J031/00; C07J 9/00 20060101
C07J009/00 |
Claims
1. A compound of Formula (I): ##STR00152## or a pharmaceutically
acceptable salt thereof; wherein: R.sup.1 is hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.A1, --SR.sup.A1,
--N(R.sup.A1).sub.2, --OC(.dbd.O)R.sup.A1, --OC(.dbd.O)OR.sup.A1,
--OC(.dbd.O)SR.sup.A1, --OC(.dbd.O)N(R.sup.A1).sub.2,
--SC(.dbd.O)R.sup.A2, --SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A,
--SC(.dbd.O)N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1,
--NHC(.dbd.O)OR.sup.A1, --NHC(.dbd.O)SR.sup.A1,
--NHC(.dbd.O)N(R.sup.A1).sub.2, --OS(.dbd.O).sub.2R.sup.A2,
--OS(.dbd.O).sub.2OR.sup.A1, --S--S(.dbd.O).sub.2R.sup.A2,
--S--S(.dbd.O).sub.2OR.sup.A1, --S(.dbd.O)R.sup.A2,
--SO.sub.2R.sup.A2, or --S(.dbd.O).sub.2OR.sup.A1, wherein each
instance of R.sup.A1 is independently hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl, an
oxygen protecting group when attached to an oxygen atom, a sulfur
protecting group when attached to a sulfur atom, a nitrogen
protecting group when attached to a nitrogen atom, or two R.sup.A1
groups are joined to form an substituted or unsubstituted
heterocyclic or heteroaryl ring; and R.sup.A2 is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R.sup.2 is hydrogen, halo, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OH, --OR.sup.B1,
--OC(.dbd.O)R.sup.B1, --NH.sub.2, --N(R.sup.B1).sub.2, or
--NR.sup.B1C(.dbd.O)R.sup.B1, wherein each instance of R.sup.B1 is
independently hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, an oxygen protecting group
when attached to an oxygen atom, a nitrogen protecting group when
attached to a nitrogen atom, or two R.sup.B1 groups are joined to
form an substituted or unsubstituted heterocyclic ring; R.sup.3 is
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl; R.sup.3' is hydrogen,
--C(.dbd.O)R.sup.C1, --C(.dbd.O)OR.sup.C1, --C(.dbd.O)SR.sup.C1,
--C(.dbd.O)N(R.sup.C1).sub.2, --S(.dbd.O).sub.2R.sup.C2,
--S(.dbd.O).sub.2OR.sup.C1, --P(.dbd.O).sub.2R.sup.C2,
--P(.dbd.O).sub.2OR.sup.C1, --P(.dbd.O)(OR.sup.C1),
--P(.dbd.O)(R.sup.C2).sub.2, or --P(.dbd.O)(R.sup.C2)(OR.sup.C1),
wherein R.sup.C1 is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, an oxygen protecting group
when attached to an oxygen atom, a sulfur protecting group when
attached to a sulfur atom, a nitrogen protecting group when
attached to a nitrogen atom, or two R.sup.C1 groups are joined to
form an substituted or unsubstituted heterocyclic ring; and
R.sup.C2 is substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; R.sup.4 is selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl; each of R.sup.6a and
R.sup.6b is independently hydrogen, halo, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or
substituted or unsubstituted alkynyl, or R.sup.6a and R.sup.6b are
joined to form an oxo (.dbd.O) group; each of R.sup.11a and
R.sup.11b is independently hydrogen, halo, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, --OH, --OR.sup.D1,
--OC(.dbd.O)R.sup.D1, --NH.sub.2, --N(R.sup.D1).sub.2, or
--NR.sup.DIC(.dbd.O)R.sup.D1, wherein each instance of R.sup.D1 is
independently hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, an oxygen protecting group
when attached to an oxygen atom, a nitrogen protecting group when
attached to a nitrogen atom, or two R.sup.D1 groups are joined to
form an substituted or unsubstituted heterocyclic ring; or
R.sup.11a and R.sup.11b are joined to form an oxo (.dbd.O) group;
wherein represents a single or double bond, provided if a double
bond is present in Ring B, then one of R.sup.6a or R.sup.6b is
absent, and provided if a single bond is present in Ring B, then
the hydrogen at C5 is in the alpha or beta position; provided that
the following compounds, and salts thereof, are specifically
excluded: ##STR00153## ##STR00154## ##STR00155##
2. A compound of Formula (III): ##STR00156## or a pharmaceutically
acceptable salt thereof; wherein: R.sup.1 is hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.A1, --SR.sup.A1,
--N(R.sup.A1).sub.2, --OC(.dbd.O)R.sup.A1, --OC(.dbd.O)OR.sup.A1,
--OC(.dbd.O)SR.sup.A1, --OC(.dbd.O)N(R.sup.A1).sub.2,
--SC(.dbd.O)R.sup.A2, --SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1,
--NHC(.dbd.O)OR.sup.A1, --NHC(.dbd.O)SR.sup.A1,
--NHC(.dbd.O)N(R.sup.A1).sub.2, --OS(.dbd.O).sub.2R.sup.A2,
--OS(.dbd.O).sub.2OR.sup.A1, --S--S(.dbd.O).sub.2R.sup.A2,
--S--S(.dbd.O).sub.2OR.sup.A1, --S(.dbd.O)R.sup.A2,
--SO.sub.2R.sup.A2, or --S(.dbd.O).sub.2OR.sup.A1, wherein each
instance of R.sup.A1 is independently hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl, an
oxygen protecting group when attached to an oxygen atom, a sulfur
protecting group when attached to a sulfur atom, a nitrogen
protecting group when attached to a nitrogen atom, or two R.sup.A1
groups are joined to form an substituted or unsubstituted
heterocyclic or heteroaryl ring; and R.sup.A2 is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R.sup.2 is hydrogen, halo, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OH, --OR.sup.B1,
--OC(.dbd.O)R.sup.B1, --NH.sub.2, --N(R.sup.B1).sub.2, or
--NR.sup.BC(.dbd.O)R.sup.B1, wherein each instance of R.sup.B1 is
independently hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, an oxygen protecting group
when attached to an oxygen atom, a nitrogen protecting group when
attached to a nitrogen atom, or two R.sup.B1 groups are joined to
form an substituted or unsubstituted heterocyclic ring; R.sup.3 is
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl; R.sup.3' is hydrogen,
--C(.dbd.O)R.sup.C1, --C(.dbd.O)OR.sup.C1, --C(.dbd.O)SR.sup.C1,
--C(.dbd.O)N(R.sup.C1).sub.2, --S(.dbd.O).sub.2R.sup.C2,
--S(.dbd.O).sub.2OR.sup.C1, --P(.dbd.O).sub.2R.sup.C2,
--P(.dbd.O).sub.2OR.sup.C1, --P(.dbd.O)(OR.sup.C1),
--P(.dbd.O)(R.sup.C2).sub.2, or --P(.dbd.O)(R.sup.C2)(OR.sup.C1),
wherein R.sup.C1 is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, an oxygen protecting group
when attached to an oxygen atom, a sulfur protecting group when
attached to a sulfur atom, a nitrogen protecting group when
attached to a nitrogen atom, or two R.sup.C1 groups are joined to
form an substituted or unsubstituted heterocyclic ring; and
R.sup.C2 is substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; R.sup.4 is selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl; each of R.sup.6a and
R.sup.6b is independently hydrogen, halo, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or
substituted or unsubstituted alkynyl, or R.sup.6a and R.sup.6b are
joined to form an oxo (.dbd.O) group; each of R.sup.11a and
R.sup.11b is independently hydrogen, halo, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, --OH, --OR.sup.D1,
--OC(.dbd.O)R.sup.D1, --NH.sub.2, --N(R.sup.D1).sub.2, or
--NR.sup.D1C(.dbd.O)R.sup.D1, wherein each instance of R.sup.D1 is
independently hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, an oxygen protecting group
when attached to an oxygen atom, a nitrogen protecting group when
attached to a nitrogen atom, or two R.sup.D1 groups are joined to
form an substituted or unsubstituted heterocyclic ring; or
R.sup.11a and R.sup.11b are joined to form an oxo (.dbd.O) group;
wherein represents a single or double bond, provided if a double
bond is present in Ring B, then one of R.sup.6a or R.sup.6b is
absent, and provided if a single bond is present in Ring B, then
the hydrogen at C5 is in the alpha or beta position;
3. The compound of claim 1, wherein R.sup.1 is hydrogen, halogen,
--OR.sup.A1, --SR.sup.A1, --N(R.sup.A1).sub.2,
--OC(.dbd.O)R.sup.A1, --OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A1).sub.2, --SC(.dbd.O)R.sup.A2,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1,
--NHC(.dbd.O)OR.sup.A1, --NHC(.dbd.O)SR.sup.A1,
--NHC(.dbd.O)N(R.sup.A1).sub.2, --OS(.dbd.O).sub.2R.sup.A2,
--OS(.dbd.O).sub.2OR.sup.A1, --S--S(.dbd.O).sub.2R.sup.A2,
--S(.dbd.O).sub.2OR.sup.A1, --S(.dbd.O)R.sup.A2,
--SO.sub.2R.sup.A2, or --S(.dbd.O).sub.2OR.sup.A1.
4. The compound of claim 1, wherein R.sup.1 is hydrogen, halogen,
--OR.sup.A1, --N(R.sup.A1).sub.2, --S--S(.dbd.O).sub.2R.sup.A2,
substituted or unsubstituted hetercyclyl, or substituted or
unsubstituted heteroaryl.
5. The compound of claim 1, wherein R.sup.2 is hydrogen,
substituted or unsubstituted heterocyclyl, --OH, --OR.sup.B1,
--OC(.dbd.O)R.sup.BI, --NH.sub.2, --N(R.sup.B1).sub.2, or
--NR.sup.B1C(.dbd.O)R.sup.B1.
6. The compound of claim 1, wherein R.sup.3 is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or
substituted or unsubstituted alkynyl.
7. The compound of claim 1, wherein R.sup.3 is a group of formula:
##STR00157## wherein each instance of R.sup.3a is hydrogen, halo,
or --ORF, wherein R.sup.F1 is substituted or unsubstituted alkyl;
and each instance of R.sup.3b and R.sup.3c is independently
hydrogen, halo, or substituted or unsubstituted alkyl, substituted
or unsubstituted carbocyclyl, or substituted or unsubstituted
heterocyclyl.
8. The compound of claim 1, wherein R.sup.3' is hydrogen.
9. The compound of claim 1, wherein R.sup.4 is hydrogen.
10. The compound of claim 1, wherein each of R.sup.6a and R.sup.6b
is independently hydrogen, halo, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, or substituted or
unsubstituted alkynyl, or R.sup.6a and R.sup.6b are joined to form
an oxo (.dbd.O) group.
11. The compound of claim 1, wherein both R.sup.6a and R.sup.6b are
hydrogen.
12. The compound of claim 1, wherein one of R.sup.6a and R.sup.6b
is a non-hydrogen group.
13. The compound of claim 1, wherein R.sup.6a is a non-hydrogen
alpha group.
14. The compound of claim 1, wherein R.sup.6a is a non-hydrogen
beta group.
15. The compound of claim 1, wherein R.sup.6a is halo or alkyl and
R.sup.6b is hydrogen.
16. The compound of claim 1, wherein R.sup.6a and R.sup.6b are both
halo.
17. The compound of claim 1, wherein R.sup.6a and R.sup.6b are both
alkyl.
18. The compound of claim 1, wherein R.sup.6a and R.sup.6b are
joined to form an oxo group.
19. The compound of claim 1, wherein each of R.sup.11a and
R.sup.11b is independently hydrogen, --OH, --OR.sup.D1,
--OC(.dbd.O)R.sup.D1, --NH.sub.2, --N(R.sup.D1).sub.2, or
--NR.sup.D1C(.dbd.O)R.sup.D1, or R.sup.11a and R.sup.11b are joined
to form an oxo (.dbd.O) group.
20. The compound of claim 1, wherein both R.sup.11a and R.sup.11b
are hydrogen.
21. The compound of claim 1, wherein one of R.sup.11a and R.sup.11b
is a non-hydrogen group.
22. The compound of claim 1, wherein R.sup.11a and R.sup.11b are
joined to form an oxo group
23. The compound of claim 1, wherein the compound of Formula (I) is
of the Formula (I-a1), (I-a2), or (I-a3): ##STR00158## or a
pharmaceutically acceptable salt thereof.
24. The compound of claim 2, wherein the compound of Formula (III)
is of the Formula (III-a1), (III-a2), or (III-a3): ##STR00159## or
a pharmaceutically acceptable salt thereof.
25. The compound of claim 1, wherein the compound is selected from
the group consisting of: ##STR00160## ##STR00161## ##STR00162##
##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167##
##STR00168## ##STR00169## ##STR00170## ##STR00171## ##STR00172##
##STR00173## ##STR00174## ##STR00175## ##STR00176## ##STR00177##
##STR00178## ##STR00179## ##STR00180## ##STR00181## ##STR00182##
##STR00183## ##STR00184## ##STR00185## ##STR00186## ##STR00187##
##STR00188## ##STR00189## ##STR00190## ##STR00191## and
pharmaceutically acceptable salts thereof.
26. The compound of claim 2, wherein the compound is selected from
the group consisting of: ##STR00192## ##STR00193## ##STR00194##
##STR00195## ##STR00196## ##STR00197## ##STR00198## ##STR00199##
##STR00200## ##STR00201## ##STR00202## ##STR00203## ##STR00204##
##STR00205## ##STR00206## ##STR00207## ##STR00208## ##STR00209##
##STR00210## ##STR00211## ##STR00212## ##STR00213## ##STR00214##
##STR00215## ##STR00216## ##STR00217## ##STR00218## ##STR00219##
##STR00220## ##STR00221## ##STR00222## ##STR00223## and
pharmaceutically acceptable salts thereof.
27. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound of claim 1, or a pharmaceutically
acceptable salt thereof.
Description
RELATED APPLICATIONS
[0001] This application is a division of U.S. Ser. No. 15/681,983
filed Aug. 21, 2017, which is a continuation of U.S. Ser. No.
14/351,449 filed Apr. 11, 2014, which is a national stage
application under 35 U.S.C. .sctn. 371 of International Application
No. PCT/US2012/060136 filed Oct. 12, 2012, published as
International Publication No. WO2013/056181 on Apr. 18, 2013, which
claims priority under 35 U.S.C. .sctn. 119(e) to U.S. provisional
patent applications, U.S. Ser. No. 61/547,291, filed Oct. 14, 2011
and U.S. Ser. No. 61/698,204, filed Sep. 7, 2012, each of which is
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Brain excitability is defined as the level of arousal of an
animal, a continuum that ranges from coma to convulsions, and is
regulated by various neurotransmitters. In general,
neurotransmitters are responsible for regulating the conductance of
ions across neuronal membranes. At rest, the neuronal membrane
possesses a potential (or membrane voltage) of approximately -70
mV, the cell interior being negative with respect to the cell
exterior. The potential (voltage) is the result of ion (K.sup.+,
Na.sup.+, Cl.sup.-, organic anions) balance across the neuronal
semipermeable membrane. Neurotransmitters are stored in presynaptic
vesicles and are released under the influence of neuronal action
potentials. When released into the synaptic cleft, an excitatory
chemical transmitter such as acetylcholine will cause membrane
depolarization (change of potential from -70 mV to -50 mV). This
effect is mediated by postsynaptic nicotinic receptors which are
stimulated by acetylcholine to increase membrane permeability to
Na.sup.+ ions. The reduced membrane potential stimulates neuronal
excitability in the form of a postsynaptic action potential.
[0003] In the case of the GABA receptor complex (GRC), the effect
on brain excitability is mediated by GABA, a neurotransmitter. GABA
has a profound influence on overall brain excitability because up
to 40% of the neurons in the brain utilize GABA as a
neurotransmitter. GABA regulates the excitability of individual
neurons by regulating the conductance of chloride ions across the
neuronal membrane. GABA interacts with its recognition site on the
GRC to facilitate the flow of chloride ions down an electrochemical
gradient of the GRC into the cell. An intracellular increase in the
levels of this anion causes hyperpolarization of the transmembrane
potential, rendering the neuron less susceptible to excitatory
inputs (i.e., reduced neuron excitability). In other words, the
higher the chloride ion concentration in the neuron, the lower the
brain excitability (the level of arousal).
[0004] It is well-documented that the GRC is responsible for the
mediation of anxiety, seizure activity, and sedation. Thus, GABA
and drugs that act like GABA or facilitate the effects of GABA
(e.g., the therapeutically useful barbiturates and benzodiazepines
(BZs), such as Valium.RTM.) produce their therapeutically useful
effects by interacting with specific regulatory sites on the GRC.
Accumulated evidence has now indicated that in addition to the
benzodiazepine and barbiturate binding site, the GRC contains a
distinct site for neuroactive steroids (Lan, N. C. et al.,
Neurochem. Res. 16:347-356 (1991)).
[0005] Neuroactive steroids can occur endogenously. The most potent
endogenous neuroactive steroids are 3.alpha.-hydroxy-5-reduced
pregnan-20-one and 3.alpha.-21-dihydroxy-5-reduced pregnan-20-one,
metabolites of hormonal steroids progesterone and
deoxycorticosterone, respectively. The ability of these steroid
metabolites to alter brain excitability was recognized in 1986
(Majewska, M. D. et al., Science 232:1004-1007 (1986); Harrison, N.
L. et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)).
[0006] The ovarian hormone progesterone and its metabolites have
been demonstrated to have profound effects on brain excitability
(Backstrom, T. et al., Acta Obstet. Gynecol. Scand. Suppl.
130:19-24 (1985); Pfaff, D. W and McEwen, B. S., Science
219:808-814 (1983); Gyermek et al., J Med Chem. 11: 117 (1968);
Lambert, J. et al., Trends Pharmacol. Sci. 8:224-227 (1987)). The
levels of progesterone and its metabolites vary with the phases of
the menstrual cycle. It has been well documented that the levels of
progesterone and its metabolites decrease prior to the onset of
menses. The monthly recurrence of certain physical symptoms prior
to the onset of menses has also been well documented. These
symptoms, which have become associated with premenstrual syndrome
(PMS), include stress, anxiety, and migraine headaches (Dalton, K.,
Premenstrual Syndrome and Progesterone Therapy, 2nd edition,
Chicago Yearbook, Chicago (1984)). Subjects with PMS have a monthly
recurrence of symptoms that are present in premenses and absent in
postmenses.
[0007] In a similar fashion, a reduction in progesterone has also
been temporally correlated with an increase in seizure frequency in
female epileptics, i.e., catamenial epilepsy (Laidlaw, J., Lancet,
1235-1237 (1956)). A more direct correlation has been observed with
a reduction in progesterone metabolites (Rosciszewska et al., J.
Neurol. Neurosurg. Psych. 49:47-51 (1986)). In addition, for
subjects with primary generalized petit mal epilepsy, the temporal
incidence of seizures has been correlated with the incidence of the
symptoms of premenstrual syndrome (Backstrom, T. et al., J
Psychosom. Obstet. Gynaecol. 2:8-20 (1983)). The steroid
deoxycorticosterone has been found to be effective in treating
subjects with epileptic spells correlated with their menstrual
cycles (Aird, R. B. and Gordan, G., J Amer. Med. Soc. 145:715-719
(1951)).
[0008] A syndrome also related to low progesterone levels is
postnatal depression (PND). Immediately after birth, progesterone
levels decrease dramatically leading to the onset of PND. The
symptoms of PND range from mild depression to psychosis requiring
hospitalization. PND is also associated with severe anxiety and
irritability. PND-associated depression is not amenable to
treatment by classic antidepressants, and women experiencing PND
show an increased incidence of PMS (Dalton, K., Premenstrual
Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook,
Chicago (1984)).
[0009] Collectively, these observations imply a crucial role for
progesterone and deoxycorticosterone and more specifically their
metabolites in the homeostatic regulation of brain excitability,
which is manifested as an increase in seizure activity or symptoms
associated with catamenial epilepsy, PMS, and PND. The correlation
between reduced levels of progesterone and the symptoms associated
with PMS, PND, and catamenial epilepsy (Backstrom, T. et al., J
Psychosom. Obstet. Gynaecol. 2:8-20 (1983)); Dalton, K.,
Premenstrual Syndrome and Progesterone Therapy, 2nd edition,
Chicago Yearbook, Chicago (1984)) has prompted the use of
progesterone in their treatment (Mattson et al.,
"Medroxyprogesterone therapy of catamenial epilepsy," in Advances
in Epileptology: XVth Epilepsy International Symposium, Raven
Press, New York (1984), pp. 279-282, and Dalton, K., Premenstrual
Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook,
Chicago (1984)). However, progesterone is not consistently
effective in the treatment of the aforementioned syndromes. For
example, no dose-response relationship exists for progesterone in
the treatment of PMS (Maddocks et al., Obstet. Gynecol. 154:573-581
(1986); Dennerstein et al., Brit. Med J 290:16-17 (1986)).
[0010] New and improved neuroactive steroids are needed that act as
modulating agents for brain excitability, as well as agents for the
prevention and treatment of CNS-related diseases. The compounds,
compositions, and methods described herein are directed toward this
end.
SUMMARY OF THE INVENTION
[0011] The present invention is based, in part, on the desire to
provide novel 19-nor compounds with good potency, pharmacokinetic
(PK) properties, oral bioavailability, formulatability, stability,
safety, clearance and/or metabolism. One key feature of the
compounds as described herein is disubstitution at the C3 position.
The inventors envision disubstitution at C-3 will eliminate the
potential for oxidation to the ketone, prevent further metabolism,
and reduce the potential for secondary elimination pathways, such
as glucuronidation. The inventors further envision the overall
effect of C3 disubstitution should be of improving the overall PK
parameters and reducing potential toxicities and side effects,
which may allow, in certain embodiments, administration orally
and/or chronically. Another key feature of the compounds as
described herein is the presence of a hydrogen at the C10 position
("19-nor") rather than a methyl group. The inventors envision
19-nor compounds, as compared to their C10-methyl counterparts,
will have improved physical properties, such as improved
solubility. The inventors envision further enhancement of
solubility, for example, when the AB ring system is in the cis
configuration.
[0012] Thus, in one aspect, provided herein are compounds according
to Formula (I) or (III):
##STR00002##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a
combination thereof wherein R.sup.2, R.sup.4, R.sup.6a, R.sup.6b,
R.sup.11a, R.sup.11b, are as defined herein,
[0013] R.sup.1 is hydrogen, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.A1, --SR.sup.A1, --N(R.sup.A1).sub.2,
--OC(.dbd.O)R.sup.A1, --OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A1).sub.2, --SC(.dbd.O)R.sup.A2,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1,
--NHC(.dbd.O)OR.sup.A1, --NHC(.dbd.O)SR.sup.A1,
--NHC(.dbd.O)N(R.sup.A1).sub.2, --OS(.dbd.O).sub.2R.sup.A2,
--OS(.dbd.O).sub.2OR.sup.A1, --S--S(.dbd.O).sub.2R.sup.A2,
--S--S(.dbd.O).sub.2OR.sup.A1, --S(.dbd.O)R.sup.A2,
--SO.sub.2R.sup.A2, or --S(.dbd.O).sub.2OR.sup.A1, wherein each
instance of R.sup.A1 is independently hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl, an
oxygen protecting group when attached to an oxygen atom, a sulfur
protecting group when attached to a sulfur atom, a nitrogen
protecting group when attached to a nitrogen atom, or two R.sup.A1
groups are joined to form an substituted or unsubstituted
heterocyclic or heteroaryl ring; and R.sup.A2 is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted
heteroaryl;
[0014] R.sup.3 is substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; and
[0015] R.sup.3' is hydrogen, --C(.dbd.O)R.sup.C1,
--C(.dbd.O)OR.sup.C1, --C(.dbd.O)SR.sup.C1,
--C(.dbd.O)N(R.sup.C1).sub.2, --S(.dbd.O).sub.2R.sup.C2,
--S(.dbd.O).sub.2OR.sup.C1, --P(.dbd.O).sub.2R.sup.C2,
--P(.dbd.O).sub.2OR.sup.C1, --P(.dbd.O)(OR.sup.C1),
--P(.dbd.O)(R.sup.C2).sub.2, or --P(.dbd.O)(R.sup.C2)(OR.sup.C1),
wherein R.sup.C1 is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, an oxygen protecting group
when attached to an oxygen atom, a sulfur protecting group when
attached to a sulfur atom, a nitrogen protecting group when
attached to a nitrogen atom, or two R.sup.C1 groups are joined to
form an substituted or unsubstituted heterocyclic ring; and
R.sup.C2 is substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl;
[0016] wherein independently represents a single or double bond,
provided if a double bond is present in Ring B, then one of
R.sup.6a or R.sup.6b is absent, and provided if a single bond is
present in Ring B, then the hydrogen at C5 is in the alpha or beta
position.
[0017] In another aspect, provided is a pharmaceutical composition
comprising a compound of Formula (I) or (III) and a
pharmaceutically acceptable carrier. In certain embodiments, the
compound of the present invention is provided in an effective
amount in the pharmaceutical composition. In certain embodiments,
the compound of the present invention is provided in a
therapeutically effective amount. In certain embodiments, the
compound of the present invention is provided in a prophylactically
effective amount.
[0018] Compounds as described herein, act, in certain embodiments,
as GABA modulators, e.g., effecting the GABA.sub.A receptor in
either a positive or negative manner. As modulators of the
excitability of the central nervous system (CNS), as mediated by
their ability to modulate GABA.sub.A receptor, such compounds are
expected to have CNS-activity.
[0019] Thus, in another aspect, provided are methods of treating a
CNS-related condition in a subject in need thereof, comprising
administering to the subject an effective amount of a compound of
Formula (I) or (III) to the subject. In certain embodiments, the
CNS-related condition is insomnia, depression, mood disorders,
convulsive disorders, memory disorders, attention disorders,
anxiety disorders, bipolar disorder, schizophrenia, depression,
bipolar disorder, schizoaffective disorder, mood disorders, anxiety
disorders, personality disorders, psychosis, compulsive disorders,
post-traumatic stress disorder, Autism spectrum disorder,
dysthymia, social anxiety disorder, obsessive compulsive disorder,
pain, sleep disorders, memory disorders, dementia, Alzheimer's
disease, a seizure disorder, traumatic brain injury, stroke,
addictive disorders, autism, Huntington's disease, Parkinson's
disease, Rett syndrome, withdrawal syndromes, or tinnitus.
[0020] Other objects and advantages will become apparent to those
skilled in the art from a consideration of the ensuing detailed
description, examples, and claims.
Definitions
Chemical Definitions
[0021] Definitions of specific functional groups and chemical terms
are described in more detail below. The chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75th Ed., inside
cover, and specific functional groups are generally defined as
described therein. Additionally, general principles of organic
chemistry, as well as specific functional moieties and reactivity,
are described in Thomas Sorrell, Organic Chemistry, University
Science Books, Sausalito, 1999; Smith and March, March's Advanced
Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New
York, 2001; Larock, Comprehensive Organic Transformations, VCH
Publishers, Inc., New York, 1989; and Carruthers, Some Modern
Methods of Organic Synthesis, 3rd Edition, Cambridge University
Press, Cambridge, 1987.
[0022] Compounds described herein can comprise one or more
asymmetric centers, and thus can exist in various isomeric forms,
e.g., enantiomers and/or diastereomers. For example, the compounds
described herein can be in the form of an individual enantiomer,
diastereomer or geometric isomer, or can be in the form of a
mixture of stereoisomers, including racemic mixtures and mixtures
enriched in one or more stereoisomer. Isomers can be isolated from
mixtures by methods known to those skilled in the art, including
chiral high pressure liquid chromatography (HPLC) and the formation
and crystallization of chiral salts; or preferred isomers can be
prepared by asymmetric syntheses. See, for example, Jacques et al.,
Enantiomers, Racemates and Resolutions (Wiley Interscience, New
York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel,
Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); and
Wilen, Tables of Resolving Agents and Optical Resolutions p. 268
(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind.
1972). The invention additionally encompasses compounds described
herein as individual isomers substantially free of other isomers,
and alternatively, as mixtures of various isomers.
[0023] As used herein a pure enantiomeric compound is substantially
free from other enantiomers or stereoisomers of the compound (i.e.,
in enantiomeric excess). In other words, an "S" form of the
compound is substantially free from the "R" form of the compound
and is, thus, in enantiomeric excess of the "R" form. The term
"enantiomerically pure" or "pure enantiomer" denotes that the
compound comprises more than 75% by weight, more than 80% by
weight, more than 85% by weight, more than 90% by weight, more than
91% by weight, more than 92% by weight, more than 93% by weight,
more than 94% by weight, more than 95% by weight, more than 96% by
weight, more than 97% by weight, more than 98% by weight, more than
98.5% by weight, more than 99% by weight, more than 99.2% by
weight, more than 99.5% by weight, more than 99.6% by weight, more
than 99.7% by weight, more than 99.8% by weight or more than 99.9%
by weight, of the enantiomer. In certain embodiments, the weights
are based upon total weight of all enantiomers or stereoisomers of
the compound.
[0024] As used herein and unless otherwise indicated, the term
"enantiomerically pure R-compound" refers to at least about 80% by
weight R-compound and at most about 20% by weight S-compound, at
least about 90% by weight R-compound and at most about 10% by
weight S-compound, at least about 95% by weight R-compound and at
most about 5% by weight S-compound, at least about 99% by weight
R-compound and at most about 1% by weight S-compound, at least
about 99.9% by weight R-compound or at most about 0.1% by weight
S-compound. In certain embodiments, the weights are based upon
total weight of compound.
[0025] As used herein and unless otherwise indicated, the term
"enantiomerically pure S-compound" or "S-compound" refers to at
least about 80% by weight S-compound and at most about 20% by
weight R-compound, at least about 90% by weight S-compound and at
most about 10% by weight R-compound, at least about 95% by weight
S-compound and at most about 5% by weight R-compound, at least
about 99% by weight S-compound and at most about 1% by weight
R-compound or at least about 99.9% by weight S-compound and at most
about 0.1% by weight R-compound. In certain embodiments, the
weights are based upon total weight of compound.
[0026] In the compositions provided herein, an enantiomerically
pure compound can be present with other active or inactive
ingredients. For example, a pharmaceutical composition comprising
enantiomerically pure R-compound can comprise, for example, about
90% excipient and about 10% enantiomerically pure R-compound. In
certain embodiments, the enantiomerically pure R-compound in such
compositions can, for example, comprise, at least about 95% by
weight R-compound and at most about 5% by weight S-compound, by
total weight of the compound. For example, a pharmaceutical
composition comprising enantiomerically pure S-compound can
comprise, for example, about 90% excipient and about 10%
enantiomerically pure S-compound. In certain embodiments, the
enantiomerically pure S-compound in such compositions can, for
example, comprise, at least about 95% by weight S-compound and at
most about 5% by weight R-compound, by total weight of the
compound. In certain embodiments, the active ingredient can be
formulated with little or no excipient or carrier.
[0027] The articles "a" and "an" may be used herein to refer to one
or to more than one (i.e. at least one) of the grammatical objects
of the article. By way of example "an analogue" means one analogue
or more than one analogue.
[0028] The following terms are intended to have the meanings
presented therewith below and are useful in understanding the
description and intended scope of the present invention.
[0029] When a range of values is listed, it is intended to
encompass each value and sub-range within the range. For example
"C.sub.1-6 alkyl" is intended to encompass, C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5,
C.sub.1-4, C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4,
C.sub.2-3, C.sub.3-6, C.sub.3-5, C.sub.3-4, C.sub.4-6, C.sub.4-5,
and C.sub.5-6 alkyl.
[0030] "Alkyl" refers to a radical of a straight-chain or branched
saturated hydrocarbon group having from 1 to 20 carbon atoms
("C.sub.1-20 alkyl"). In some embodiments, an alkyl group has 1 to
12 carbon atoms ("C.sub.1-12 alkyl"). In some embodiments, an alkyl
group has 1 to 10 carbon atoms ("C.sub.1-10 alkyl"). In some
embodiments, an alkyl group has 1 to 9 carbon atoms ("C.sub.1-9
alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon
atoms ("C.sub.1-8 alkyl"). In some embodiments, an alkyl group has
1 to 7 carbon atoms ("C.sub.1-7 alkyl"). In some embodiments, an
alkyl group has 1 to 6 carbon atoms ("C.sub.1-6 alkyl", also
referred to herein as "lower alkyl"). In some embodiments, an alkyl
group has 1 to 5 carbon atoms ("C.sub.1-5alkyl"). In some
embodiments, an alkyl group has 1 to 4 carbon atoms ("C.sub.1-4
alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon
atoms ("C.sub.3 alkyl"). In some embodiments, an alkyl group has 1
to 2 carbon atoms ("C.sub.1-2 alkyl"). In some embodiments, an
alkyl group has 1 carbon atom ("C.sub.1 alkyl"). In some
embodiments, an alkyl group has 2 to 6 carbon atoms ("C.sub.2-6
alkyl"). Examples of C.sub.1-6 alkyl groups include methyl
(C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), isopropyl
(C.sub.3), n-butyl (C.sub.4), tert-butyl (C.sub.4), sec-butyl
(C.sub.4), iso-butyl (C.sub.4), n-pentyl (C.sub.5), 3-pentanyl
(C.sub.5), amyl (C.sub.5), neopentyl (C.sub.5), 3-methyl-2-butanyl
(C.sub.5), tertiary amyl (C.sub.5), and n-hexyl (C.sub.6).
Additional examples of alkyl groups include n-heptyl (C.sub.7),
n-octyl (C.sub.8) and the like. Unless otherwise specified, each
instance of an alkyl group is independently optionally substituted,
i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a
"substituted alkyl") with one or more substituents; e.g., for
instance from 1 to 5 substituents, 1 to 3 substituents, or 1
substituent. In certain embodiments, the alkyl group is
unsubstituted C.sub.1-10 alkyl (e.g., --CH.sub.3). In certain
embodiments, the alkyl group is substituted C.sub.1-10 alkyl.
"Alkylene" refers to a substituted or unsubstituted alkyl group, as
defined above, wherein two hydrogens are removed to provide a
divalent radical. Exemplary divalent alkylene groups include, but
are not limited to, methylene (--CH.sub.2--), ethylene
(--CH.sub.2CH.sub.2--), the propylene isomers (e.g.,
--CH.sub.2CH.sub.2CH.sub.2-- and --CH(CH.sub.3)CH.sub.2--) and the
like.
[0031] "Alkenyl" refers to a radical of a straight-chain or
branched hydrocarbon group having from 2 to 20 carbon atoms, one or
more carbon-carbon double bonds, and no triple bonds ("C.sub.2-20
alkenyl"). In some embodiments, an alkenyl group has 2 to 10 carbon
atoms ("C.sub.2-10 alkenyl"). In some embodiments, an alkenyl group
has 2 to 9 carbon atoms ("C.sub.2-9 alkenyl"). In some embodiments,
an alkenyl group has 2 to 8 carbon atoms ("C.sub.2-8 alkenyl"). In
some embodiments, an alkenyl group has 2 to 7 carbon atoms
("C.sub.2-7 alkenyl"). In some embodiments, an alkenyl group has 2
to 6 carbon atoms ("C.sub.2-6 alkenyl"). In some embodiments, an
alkenyl group has 2 to 5 carbon atoms ("C.sub.2-5alkenyl"). In some
embodiments, an alkenyl group has 2 to 4 carbon atoms ("C.sub.2-4
alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon
atoms ("C.sub.2-3 alkenyl"). In some embodiments, an alkenyl group
has 2 carbon atoms ("C.sub.2 alkenyl"). The one or more
carbon-carbon double bonds can be internal (such as in 2-butenyl)
or terminal (such as in 1-butenyl). Examples of C.sub.2-4 alkenyl
groups include ethenyl (C.sub.2), 1-propenyl (C.sub.3), 2-propenyl
(C.sub.3), 1-butenyl (C.sub.4), 2-butenyl (C.sub.4), butadienyl
(C.sub.4), and the like. Examples of C.sub.2-6 alkenyl groups
include the aforementioned C.sub.2-4 alkenyl groups as well as
pentenyl (C.sub.5), pentadienyl (C.sub.5), hexenyl (C.sub.6), and
the like. Additional examples of alkenyl include heptenyl
(C.sub.7), octenyl (C.sub.8), octatrienyl (C.sub.8), and the like.
Unless otherwise specified, each instance of an alkenyl group is
independently optionally substituted, i.e., unsubstituted (an
"unsubstituted alkenyl") or substituted (a "substituted alkenyl")
with one or more substituents e.g., for instance from 1 to 5
substituents, 1 to 3 substituents, or 1 substituent. In certain
embodiments, the alkenyl group is unsubstituted C.sub.2-10 alkenyl.
In certain embodiments, the alkenyl group is substituted C.sub.2-10
alkenyl.
[0032] "Alkenylene" refers a substituted or unsubstituted alkenyl
group, as defined above, wherein two hydrogens are removed to
provide a divalent radical. Exemplary divalent alkenylene groups
include, but are not limited to, ethenylene (--CH.dbd.CH--),
propenylenes (e.g., --CH.dbd.CHCH.sub.2-- and
--C(CH.sub.3).dbd.CH-- and --CH.dbd.C(CH.sub.3)--), and the
like.
[0033] "Alkynyl" refers to a radical of a straight-chain or
branched hydrocarbon group having from 2 to 20 carbon atoms, one or
more carbon-carbon triple bonds, and optionally one or more double
bonds ("C.sub.2-20 alkynyl"). In some embodiments, an alkynyl group
has 2 to 10 carbon atoms ("C.sub.2-10 alkynyl"). In some
embodiments, an alkynyl group has 2 to 9 carbon atoms ("C.sub.2-9
alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon
atoms ("C.sub.2-8 alkynyl"). In some embodiments, an alkynyl group
has 2 to 7 carbon atoms ("C.sub.2-7 alkynyl"). In some embodiments,
an alkynyl group has 2 to 6 carbon atoms ("C.sub.2-6 alkynyl"). In
some embodiments, an alkynyl group has 2 to 5 carbon atoms
("C.sub.2-5 alkynyl"). In some embodiments, an alkynyl group has 2
to 4 carbon atoms ("C.sub.2-4 alkynyl"). In some embodiments, an
alkynyl group has 2 to 3 carbon atoms ("C.sub.2-3 alkynyl"). In
some embodiments, an alkynyl group has 2 carbon atoms ("C.sub.2
alkynyl"). The one or more carbon-carbon triple bonds can be
internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
Examples of C.sub.2-4 alkynyl groups include, without limitation,
ethynyl (C.sub.2), 1-propynyl (C.sub.3), 2-propynyl (C.sub.3),
1-butynyl (C.sub.4), 2-butynyl (C.sub.4), and the like. Examples of
C.sub.2-6 alkenyl groups include the aforementioned C.sub.2-4
alkynyl groups as well as pentynyl (C.sub.5), hexynyl (C.sub.5),
and the like. Additional examples of alkynyl include heptynyl
(C.sub.7), octynyl (C.sub.8), and the like. Unless otherwise
specified, each instance of an alkynyl group is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
alkynyl") or substituted (a "substituted alkynyl") with one or more
substituents; e.g., for instance from 1 to 5 substituents, 1 to 3
substituents, or 1 substituent. In certain embodiments, the alkynyl
group is unsubstituted C.sub.2-10 alkynyl. In certain embodiments,
the alkynyl group is substituted C.sub.2-10 alkynyl.
[0034] "Alkynylene" refers a substituted or unsubstituted alkynyl
group, as defined above, wherein two hydrogens are removed to
provide a divalent radical. Exemplary divalent alkynylene groups
include, but are not limited to, ethynylene, propynylene, and the
like.
[0035] "Aryl" refers to a radical of a monocyclic or polycyclic
(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g.,
having 6, 10, or 14 .pi. electrons shared in a cyclic array) having
6-14 ring carbon atoms and zero heteroatoms provided in the
aromatic ring system ("C.sub.6-14 aryl"). In some embodiments, an
aryl group has six ring carbon atoms ("C.sub.6 aryl"; e.g.,
phenyl). In some embodiments, an aryl group has ten ring carbon
atoms ("C.sub.10 aryl"; e.g., naphthyl such as 1-naphthyl and
2-naphthyl). In some embodiments, an aryl group has fourteen ring
carbon atoms ("C.sub.14 aryl"; e.g., anthracyl). "Aryl" also
includes ring systems wherein the aryl ring, as defined above, is
fused with one or more carbocyclyl or heterocyclyl groups wherein
the radical or point of attachment is on the aryl ring, and in such
instances, the number of carbon atoms continue to designate the
number of carbon atoms in the aryl ring system. Typical aryl groups
include, but are not limited to, groups derived from aceanthrylene,
acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,
chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,
hexalene, as-indacene, s-indacene, indane, indene, naphthalene,
octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,
pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,
pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and
trinaphthalene. Particularly aryl groups include phenyl, naphthyl,
indenyl, and tetrahydronaphthyl. Unless otherwise specified, each
instance of an aryl group is independently optionally substituted,
i.e., unsubstituted (an "unsubstituted aryl") or substituted (a
"substituted aryl") with one or more substituents. In certain
embodiments, the aryl group is unsubstituted C.sub.6-14 aryl. In
certain embodiments, the aryl group is substituted C.sub.6-14 aryl.
In certain embodiments, an aryl group substituted with one or more
of groups selected from halo, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 haloalkyl, cyano, hydroxy, C.sub.1-C.sub.8 alkoxy,
and amino.
[0036] Examples of representative substituted aryls include the
following:
##STR00003##
In these formulae one of R.sup.56 and R.sup.57 may be hydrogen, and
at least one of R.sup.56 and R.sup.57 is each independently
selected from C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 haloalkyl,
4-10 membered heterocyclyl, alkanoyl, C.sub.1-C.sub.8 alkoxy,
heteroaryloxy, alkylamino, arylamino, heteroarylamino,
--NR.sup.58COR.sup.59, --NR.sup.58SOR.sup.59,
--NR.sup.58SO.sub.2R.sup.59, --COOalkyl, --COOaryl,
--CONR.sup.58R.sup.59, --CONR.sup.58OR.sup.59, --NR.sup.58R.sup.59,
--SO.sub.2NR.sup.58R.sup.59, --S-alkyl, --SOalkyl, --SO.sub.2alkyl,
--Saryl, --SOaryl, --SO.sub.2aryl; or R.sup.56 and R.sup.57 may be
joined to form a cyclic ring (saturated or unsaturated) from 5 to 8
atoms, optionally containing one or more heteroatoms selected from
the group N, O, or S. R.sup.60 and R.sup.61 are independently
hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.3-C.sub.10 cycloalkyl, 4-10 membered heterocyclyl,
C.sub.6-C.sub.10 aryl, substituted C.sub.6-C.sub.10 aryl, 5-10
membered heteroaryl, or substituted 5-10 membered heteroaryl.
[0037] "Fused aryl" refers to an aryl having two of its ring carbon
in common with a second aryl ring or with an aliphatic ring.
[0038] "Aralkyl" is a subset of alkyl and aryl, as defined herein,
and refers to an optionally substituted alkyl group substituted by
an optionally substituted aryl group.
[0039] "Heteroaryl" refers to a radical of a 5-10 membered
monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or
10 .pi. electrons shared in a cyclic array) having ring carbon
atoms and 1-4 ring heteroatoms provided in the aromatic ring
system, wherein each heteroatom is independently selected from
nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In
heteroaryl groups that contain one or more nitrogen atoms, the
point of attachment can be a carbon or nitrogen atom, as valency
permits. Heteroaryl bicyclic ring systems can include one or more
heteroatoms in one or both rings. "Heteroaryl" includes ring
systems wherein the heteroaryl ring, as defined above, is fused
with one or more carbocyclyl or heterocyclyl groups wherein the
point of attachment is on the heteroaryl ring, and in such
instances, the number of ring members continue to designate the
number of ring members in the heteroaryl ring system. "Heteroaryl"
also includes ring systems wherein the heteroaryl ring, as defined
above, is fused with one or more aryl groups wherein the point of
attachment is either on the aryl or heteroaryl ring, and in such
instances, the number of ring members designates the number of ring
members in the fused (aryl/heteroaryl) ring system. Bicyclic
heteroaryl groups wherein one ring does not contain a heteroatom
(e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of
attachment can be on either ring, i.e., either the ring bearing a
heteroatom (e.g., 2-indolyl) or the ring that does not contain a
heteroatom (e.g., 5-indolyl).
[0040] In some embodiments, a heteroaryl group is a 5-10 membered
aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms provided in the aromatic ring system, wherein each
heteroatom is independently selected from nitrogen, oxygen, and
sulfur ("5-10 membered heteroaryl"). In some embodiments, a
heteroaryl group is a 5-8 membered aromatic ring system having ring
carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring
system, wherein each heteroatom is independently selected from
nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some
embodiments, a heteroaryl group is a 5-6 membered aromatic ring
system having ring carbon atoms and 1-4 ring heteroatoms provided
in the aromatic ring system, wherein each heteroatom is
independently selected from nitrogen, oxygen, and sulfur ("5-6
membered heteroaryl"). In some embodiments, the 5-6 membered
heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen,
and sulfur. In some embodiments, the 5-6 membered heteroaryl has
1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In
some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom
selected from nitrogen, oxygen, and sulfur. Unless otherwise
specified, each instance of a heteroaryl group is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
heteroaryl") or substituted (a "substituted heteroaryl") with one
or more substituents. In certain embodiments, the heteroaryl group
is unsubstituted 5-14 membered heteroaryl. In certain embodiments,
the heteroaryl group is substituted 5-14 membered heteroaryl.
[0041] Exemplary 5-membered heteroaryl groups containing one
heteroatom include, without limitation, pyrrolyl, furanyl and
thiophenyl. Exemplary 5-membered heteroaryl groups containing two
heteroatoms include, without limitation, imidazolyl, pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary
5-membered heteroaryl groups containing three heteroatoms include,
without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
[0042] Exemplary 5-membered heteroaryl groups containing four
heteroatoms include, without limitation, tetrazolyl. Exemplary
6-membered heteroaryl groups containing one heteroatom include,
without limitation, pyridinyl. Exemplary 6-membered heteroaryl
groups containing two heteroatoms include, without limitation,
pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered
heteroaryl groups containing three or four heteroatoms include,
without limitation, triazinyl and tetrazinyl, respectively.
Exemplary 7-membered heteroaryl groups containing one heteroatom
include, without limitation, azepinyl, oxepinyl, and thiepinyl.
Exemplary 5,6-bicyclic heteroaryl groups include, without
limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,
benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,
benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and
purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without
limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,
cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
[0043] Examples of representative heteroaryls include the
following:
##STR00004##
wherein each Y is selected from carbonyl, N, NR.sup.65, O, and S;
and R.sup.6 is independently hydrogen, C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.10 cycloalkyl, 4-10 membered heterocyclyl,
C.sub.6-C.sub.10 aryl, and 5-10 membered heteroaryl.
[0044] Examples of representative aryl having heteroatom-containing
substitutions include the following:
##STR00005##
wherein each W is selected from C(R.sup.66).sub.2, NR.sup.66, O,
and S; and each Y is selected from carbonyl, NR.sup.66, O, and S;
and R.sup.66 is independently hydrogen, C1-C alkyl, C.sub.3--C
cycloalkyl, 4-10-membered heterocyclyl, C.sub.6-C.sub.10 aryl, and
5-10-membered heteroaryl.
[0045] "Heteroaralkyl" is a subset of alkyl and heteroaryl, as
defined herein, and refers to an optionally substituted alkyl group
substituted by an optionally substituted heteroaryl group.
[0046] "Carbocyclyl" or "carbocyclic" refers to a radical of a
non-aromatic cyclic hydrocarbon group having from 3 to 10 ring
carbon atoms ("C.sub.3-10 carbocyclyl") and zero heteroatoms in the
non-aromatic ring system. In some embodiments, a carbocyclyl group
has 3 to 8 ring carbon atoms ("C.sub.3-8 carbocyclyl"). In some
embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms
("C.sub.3-7 carbocyclyl"). In some embodiments, a carbocyclyl group
has 3 to 6 ring carbon atoms ("C.sub.3-6 carbocyclyl"). In some
embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms
("C.sub.5-10 carbocyclyl"). Exemplary C.sub.3-6 carbocyclyl groups
include, without limitation, cyclopropyl (C.sub.3), cyclopropenyl
(C.sub.3), cyclobutyl (C.sub.4), cyclobutenyl (C.sub.4),
cyclopentyl (C.sub.5), cyclopentenyl (C.sub.5), cyclohexyl
(C.sub.6), cyclohexenyl (C.sub.6), cyclohexadienyl (C.sub.6), and
the like. Exemplary C.sub.3-8 carbocyclyl groups include, without
limitation, the aforementioned C.sub.3-6 carbocyclyl groups as well
as cycloheptyl (C.sub.7), cycloheptenyl (C.sub.7), cycloheptadienyl
(C.sub.7), cycloheptatrienyl (C.sub.7), cyclooctyl (C.sub.8),
cyclooctenyl (C.sub.8), bicyclo[2.2.1]heptanyl (C.sub.7),
bicyclo[2.2.2]octanyl (C.sub.8), and the like. Exemplary C.sub.3-10
carbocyclyl groups include, without limitation, the aforementioned
C.sub.3-8 carbocyclyl groups as well as cyclononyl (C.sub.9),
cyclononenyl (C.sub.9), cyclodecyl (C.sub.10), cyclodecenyl
(C.sub.10), octahydro-1H-indenyl (C.sub.9), decahydronaphthalenyl
(C.sub.10), spiro[4.5]decanyl (C.sub.10), and the like. As the
foregoing examples illustrate, in certain embodiments, the
carbocyclyl group is either monocyclic ("monocyclic carbocyclyl")
or contain a fused, bridged or spiro ring system such as a bicyclic
system ("bicyclic carbocyclyl") and can be saturated or can be
partially unsaturated. "Carbocyclyl" also includes ring systems
wherein the carbocyclyl ring, as defined above, is fused with one
or more aryl or heteroaryl groups wherein the point of attachment
is on the carbocyclyl ring, and in such instances, the number of
carbons continue to designate the number of carbons in the
carbocyclic ring system. Unless otherwise specified, each instance
of a carbocyclyl group is independently optionally substituted,
i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted
(a "substituted carbocyclyl") with one or more substituents. In
certain embodiments, the carbocyclyl group is unsubstituted
C.sub.3-10 carbocyclyl. In certain embodiments, the carbocyclyl
group is a substituted C.sub.3-10 carbocyclyl.
[0047] In some embodiments, "carbocyclyl" is a monocyclic,
saturated carbocyclyl group having from 3 to 10 ring carbon atoms
("C.sub.3-10 cycloalkyl"). In some embodiments, a cycloalkyl group
has 3 to 8 ring carbon atoms ("C.sub.3-8 cycloalkyl"). In some
embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms
("C.sub.3-6 cycloalkyl"). In some embodiments, a cycloalkyl group
has 5 to 6 ring carbon atoms ("C.sub.5-6 cycloalkyl"). In some
embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms
("C.sub.5-10 cycloalkyl"). Examples of C.sub.5-6 cycloalkyl groups
include cyclopentyl (C.sub.5) and cyclohexyl (C.sub.5). Examples of
C.sub.3-6 cycloalkyl groups include the aforementioned C.sub.5-6
cycloalkyl groups as well as cyclopropyl (C.sub.3) and cyclobutyl
(C.sub.4). Examples of C.sub.3-8 cycloalkyl groups include the
aforementioned C.sub.3-6 cycloalkyl groups as well as cycloheptyl
(C.sub.7) and cyclooctyl (C.sub.8). Unless otherwise specified,
each instance of a cycloalkyl group is independently unsubstituted
(an "unsubstituted cycloalkyl") or substituted (a "substituted
cycloalkyl") with one or more substituents. In certain embodiments,
the cycloalkyl group is unsubstituted C.sub.3-10 cycloalkyl. In
certain embodiments, the cycloalkyl group is substituted C.sub.3-10
cycloalkyl.
[0048] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3-
to 10-membered non-aromatic ring system having ring carbon atoms
and 1 to 4 ring heteroatoms, wherein each heteroatom is
independently selected from nitrogen, oxygen, sulfur, boron,
phosphorus, and silicon ("3-10 membered heterocyclyl"). In
heterocyclyl groups that contain one or more nitrogen atoms, the
point of attachment can be a carbon or nitrogen atom, as valency
permits. A heterocyclyl group can either be monocyclic ("monocyclic
heterocyclyl") or a fused, bridged or spiro ring system such as a
bicyclic system ("bicyclic heterocyclyl"), and can be saturated or
can be partially unsaturated. Heterocyclyl bicyclic ring systems
can include one or more heteroatoms in one or both rings.
"Heterocyclyl" also includes ring systems wherein the heterocyclyl
ring, as defined above, is fused with one or more carbocyclyl
groups wherein the point of attachment is either on the carbocyclyl
or heterocyclyl ring, or ring systems wherein the heterocyclyl
ring, as defined above, is fused with one or more aryl or
heteroaryl groups, wherein the point of attachment is on the
heterocyclyl ring, and in such instances, the number of ring
members continue to designate the number of ring members in the
heterocyclyl ring system. Unless otherwise specified, each instance
of heterocyclyl is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted heterocyclyl") or substituted (a
"substituted heterocyclyl") with one or more substituents. In
certain embodiments, the heterocyclyl group is unsubstituted 3-10
membered heterocyclyl. In certain embodiments, the heterocyclyl
group is substituted 3-10 membered heterocyclyl.
[0049] In some embodiments, a heterocyclyl group is a 5-10 membered
non-aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms, wherein each heteroatom is independently selected from
nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10
membered heterocyclyl"). In some embodiments, a heterocyclyl group
is a 5-8 membered non-aromatic ring system having ring carbon atoms
and 1-4 ring heteroatoms, wherein each heteroatom is independently
selected from nitrogen, oxygen, and sulfur ("5-8 membered
heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6
membered non-aromatic ring system having ring carbon atoms and 1-4
ring heteroatoms, wherein each heteroatom is independently selected
from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In
some embodiments, the 5-6 membered heterocyclyl has 1-3 ring
heteroatoms selected from nitrogen, oxygen, and sulfur. In some
embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms
selected from nitrogen, oxygen, and sulfur. In some embodiments,
the 5-6 membered heterocyclyl has one ring heteroatom selected from
nitrogen, oxygen, and sulfur.
[0050] Exemplary 3-membered heterocyclyl groups containing one
heteroatom include, without limitation, azirdinyl, oxiranyl,
thiorenyl. Exemplary 4-membered heterocyclyl groups containing one
heteroatom include, without limitation, azetidinyl, oxetanyl and
thietanyl.
[0051] Exemplary 5-membered heterocyclyl groups containing one
heteroatom include, without limitation, tetrahydrofuranyl,
dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl,
pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary
5-membered heterocyclyl groups containing two heteroatoms include,
without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and
oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups
containing three heteroatoms include, without limitation,
triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary
6-membered heterocyclyl groups containing one heteroatom include,
without limitation, piperidinyl, tetrahydropyranyl,
dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl
groups containing two heteroatoms include, without limitation,
piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered
heterocyclyl groups containing two heteroatoms include, without
limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups
containing one heteroatom include, without limitation, azepanyl,
oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups
containing one heteroatom include, without limitation, azocanyl,
oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups
fused to a C.sub.6 aryl ring (also referred to herein as a
5,6-bicyclic heterocyclic ring) include, without limitation,
indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,
benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl
groups fused to an aryl ring (also referred to herein as a
6,6-bicyclic heterocyclic ring) include, without limitation,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
[0052] Particular examples of heterocyclyl groups are shown in the
following illustrative examples:
##STR00006##
wherein each W is selected from CR.sup.67, C(R.sup.67).sub.2,
NR.sup.67, O, and S; and each Y is selected from NR.sup.67, O, and
S; and R.sup.67 is independently hydrogen, C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.10 cycloalkyl, 4-10 membered heterocyclyl,
C.sub.6-C.sub.10 aryl, 5-10 membered heteroaryl. These heterocyclyl
rings may be optionally substituted with one or more substituents
selected from the group consisting of the group consisting of acyl,
acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino,
amino, substituted amino, aminocarbonyl (carbamoyl or amido),
aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy,
azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro,
thiol, --S-alkyl, --S-aryl, --S(O)-alkyl, --S(O)-aryl,
--S(O).sub.2-alkyl, and --S(O).sub.2-aryl. Substituting groups
include carbonyl or thiocarbonyl which provide, for example, lactam
and urea derivatives.
[0053] "Hetero" when used to describe a compound or a group present
on a compound means that one or more carbon atoms in the compound
or group have been replaced by a nitrogen, oxygen, or sulfur
heteroatom. Hetero may be applied to any of the hydrocarbyl groups
described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g.,
heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g.,
cycloheteroalkenyl, and the like having from 1 to 5, and
particularly from 1 to 3 heteroatoms.
[0054] "Acyl" refers to a radical --C(O)R.sup.20, where R.sup.20 is
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, as defined herein.
"Alkanoyl" is an acyl group wherein R.sup.20 is a group other than
hydrogen. Representative acyl groups include, but are not limited
to, formyl (--CHO), acetyl (--C(.dbd.O)CH.sub.3),
cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl
(--C(.dbd.O)Ph), benzylcarbonyl (--C(.dbd.O)CH.sub.2Ph),
--C(O)--C.sub.1-C.sub.5 alkyl,
--C(O)--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--C(O)--(CH.sub.2).sub.t(5-10 membered heteroaryl),
--C(O)--(CH.sub.2).sub.t(C.sub.3-C.sub.1 cycloalkyl), and
--C(O)--(CH.sub.2).sub.t(4-10 membered heterocyclyl), wherein t is
an integer from 0 to 4. In certain embodiments, R.sup.21 is
C.sub.1-C.sub.8 alkyl, substituted with halo or hydroxy; or
C.sub.3-C.sub.1 cycloalkyl, 4-10 membered heterocyclyl,
C.sub.6-C.sub.10 aryl, arylalkyl, 5-10 membered heteroaryl or
heteroarylalkyl, each of which is substituted with unsubstituted
C.sub.1-C.sub.4 alkyl, halo, unsubstituted C.sub.1-C.sub.4 alkoxy,
unsubstituted C.sub.1-C.sub.4 haloalkyl, unsubstituted
C.sub.1-C.sub.4 hydroxyalkyl, or unsubstituted C.sub.1-C.sub.4
haloalkoxy or hydroxy.
[0055] "Acylamino" refers to a radical --NR.sup.22C(O)R.sup.23,
where each instance of R.sup.22 and R23 is independently hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl, as defined herein, or R.sup.22 is an
amino protecting group. Exemplary "acylamino" groups include, but
are not limited to, formylamino, acetylamino,
cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino,
benzoylamino and benzylcarbonylamino. Particular exemplary
"acylamino" groups are --NR.sup.24C(O)--C.sub.1-C.sub.8 alkyl,
--NR.sup.24C(O)--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--NR.sup.24C(O)--(CH.sub.2).sub.t(5-10 membered heteroaryl),
--NR.sup.24C(O)--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl), and
--NR.sup.24C(O)--(CH.sub.2).sub.t(4-10 membered heterocyclyl),
wherein t is an integer from 0 to 4, and each R.sup.24
independently represents H or C.sub.1-C.sub.8 alkyl. In certain
embodiments, R.sup.25 is H, C.sub.1-C.sub.8 alkyl, substituted with
halo or hydroxy; C.sub.3-C.sub.10 cycloalkyl, 4-10 membered
heterocyclyl, C.sub.6-C.sub.10 aryl, arylalkyl, 5-10 membered
heteroaryl or heteroarylalkyl, each of which is substituted with
unsubstituted C.sub.1-C.sub.4 alkyl, halo, unsubstituted
C.sub.1-C.sub.4 alkoxy, unsubstituted C.sub.1-C.sub.4 haloalkyl,
unsubstituted C.sub.1-C.sub.4 hydroxyalkyl, or unsubstituted
C.sub.1-C.sub.4 haloalkoxy or hydroxy; and R.sup.26 is H,
C.sub.1-C.sub.8 alkyl, substituted with halo or hydroxy;
C.sub.3-C.sub.1 cycloalkyl, 4-10 membered heterocyclyl,
C.sub.6-C.sub.10 aryl, arylalkyl, 5-10 membered heteroaryl or
heteroarylalkyl, each of which is substituted with unsubstituted
C.sub.1-C.sub.4 alkyl, halo, unsubstituted C.sub.1-C.sub.4 alkoxy,
unsubstituted C.sub.1-C.sub.4 haloalkyl, unsubstituted
C.sub.1-C.sub.4 hydroxyalkyl, or unsubstituted C.sub.1-C.sub.4
haloalkoxy or hydroxyl; provided at least one of R.sup.25 and
R.sup.26 is other than H.
[0056] "Acyloxy" refers to a radical --OC(O)R.sup.27, where
R.sup.27 is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, as defined herein.
Representative examples include, but are not limited to, formyl,
acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and
benzylcarbonyl. In certain embodiments, R.sup.28 is C.sub.1-C.sub.8
alkyl, substituted with halo or hydroxy; C.sub.3-C.sub.10
cycloalkyl, 4-10 membered heterocyclyl, C.sub.6-C.sub.10 aryl,
arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of
which is substituted with unsubstituted C.sub.1-C.sub.4 alkyl,
halo, unsubstituted C.sub.1-C.sub.4 alkoxy, unsubstituted
C.sub.1-C.sub.4 haloalkyl, unsubstituted C.sub.1-C.sub.4
hydroxyalkyl, or unsubstituted C.sub.1-C.sub.4 haloalkoxy or
hydroxy.
[0057] "Alkoxy" refers to the group --OR.sup.29 where R.sup.29 is
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl. Particular alkoxy groups are methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy,
n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy
groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms.
Further particular alkoxy groups have between 1 and 4 carbon
atoms.
[0058] In certain embodiments, R.sup.29 is a group that has 1 or
more substituents, for instance from 1 to 5 substituents, and
particularly from 1 to 3 substituents, in particular 1 substituent,
selected from the group consisting of amino, substituted amino,
C.sub.6-C.sub.10 aryl, aryloxy, carboxyl, cyano, C.sub.3-C.sub.10
cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered
heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol,
alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2-- and
aryl-S(O).sub.2--. Exemplary `substituted alkoxy` groups include,
but are not limited to, --O--(CH.sub.2).sub.t(C.sub.6-C.sub.10
aryl), --O--(CH.sub.2).sub.t(5-10 membered heteroaryl),
--O--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl), and
--O--(CH.sub.2).sub.t(4-10 membered heterocyclyl), wherein t is an
integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or
heterocyclyl groups present, may themselves be substituted by
unsubstituted C.sub.1-C.sub.4 alkyl, halo, unsubstituted
C.sub.1-C.sub.4 alkoxy, unsubstituted C.sub.1-C.sub.4 haloalkyl,
unsubstituted C.sub.1-C.sub.4 hydroxyalkyl, or unsubstituted
C.sub.1-C.sub.4 haloalkoxy or hydroxy. Particular exemplary
`substituted alkoxy` groups are --OCF.sub.3, --OCH.sub.2CF.sub.3,
--OCH.sub.2Ph, --OCH.sub.2-cyclopropyl, --OCH.sub.2CH.sub.2OH, and
--OCH.sub.2CH.sub.2NMe.sub.2.
[0059] "Amino" refers to the radical --NH.sub.2.
[0060] "Substituted amino" refers to an amino group of Formula
--N(R.sup.38).sub.2 wherein R.sup.38 is hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl, or
an amino protecting group, wherein at least one of R.sup.38 is not
a hydrogen. In certain embodiments, each R.sup.38 is independently
selected from: hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8
alkenyl, C.sub.3-C.sub.5 alkynyl, C.sub.6-C.sub.10 aryl, 5-10
membered heteroaryl, 4-10 membered heterocyclyl, or
C.sub.3-C.sub.10 cycloalkyl; or C.sub.1-C.sub.8 alkyl, substituted
with halo or hydroxy; C.sub.3-C.sub.8 alkenyl, substituted with
halo or hydroxy; C.sub.3-C.sub.5 alkynyl, substituted with halo or
hydroxy, or --(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--(CH.sub.2).sub.t(5-10 membered heteroaryl),
--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl), or
--(CH.sub.2).sub.t(4-10 membered heterocyclyl), wherein t is an
integer between 0 and 8, each of which is substituted by
unsubstituted C.sub.1-C.sub.4 alkyl, halo, unsubstituted
C.sub.1-C.sub.4 alkoxy, unsubstituted C.sub.1-C.sub.4 haloalkyl,
unsubstituted C.sub.1-C.sub.4 hydroxyalkyl, or unsubstituted
C.sub.1-C.sub.4 haloalkoxy or hydroxy; or both R.sup.38 groups are
joined to form an alkylene group.
[0061] Exemplary `substituted amino` groups are
--NR.sup.39--C.sub.1-C.sub.8 alkyl,
--NR.sup.39--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--NR.sup.39--(CH.sub.2).sub.t(5-10 membered heteroaryl),
--NR.sup.39--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl), and
--NR.sup.39--(CH.sub.2).sub.t(4-10 membered heterocyclyl), wherein
t is an integer from 0 to 4, for instance 1 or 2, each R.sup.39
independently represents H or C.sub.1-C.sub.8 alkyl; and any alkyl
groups present, may themselves be substituted by halo, substituted
or unsubstituted amino, or hydroxy; and any aryl, heteroaryl,
cycloalkyl, or heterocyclyl groups present, may themselves be
substituted by unsubstituted C.sub.1-C.sub.4 alkyl, halo,
unsubstituted C.sub.1-C.sub.4 alkoxy, unsubstituted C.sub.1-C.sub.4
haloalkyl, unsubstituted C.sub.1-C.sub.4 hydroxyalkyl, or
unsubstituted C.sub.1-C.sub.4 haloalkoxy or hydroxy. For the
avoidance of doubt the term `substituted amino` includes the groups
alkylamino, substituted alkylamino, alkylarylamino, substituted
alkylarylamino, arylamino, substituted arylamino, dialkylamino, and
substituted dialkylamino as defined below. Substituted amino
encompasses both monosubstituted amino and disubstituted amino
groups.
[0062] "Azido" refers to the radical --N.sub.3.
[0063] "Carbamoyl" or "amido" refers to the radical
--C(O)NH.sub.2.
[0064] "Substituted carbamoyl" or "substituted amido" refers to the
radical --C(O)N(R.sup.62).sub.2 wherein each R.sup.62 is
independently hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, or an amino protecting
group, wherein at least one of R.sup.62 is not a hydrogen. In
certain embodiments, R.sup.62 is selected from H, C.sub.1-C.sub.8
alkyl, C.sub.3-C.sub.10 cycloalkyl, 4-10 membered heterocyclyl,
C.sub.6-C.sub.10 aryl, aralkyl, 5-10 membered heteroaryl, and
heteroaralkyl; or C.sub.1-C.sub.8 alkyl substituted with halo or
hydroxy; or C.sub.3-C.sub.10 cycloalkyl, 4-10 membered
heterocyclyl, C.sub.6-C.sub.10 aryl, aralkyl, 5-10 membered
heteroaryl, or heteroaralkyl, each of which is substituted by
unsubstituted C.sub.1-C.sub.4 alkyl, halo, unsubstituted
C.sub.1-C.sub.4 alkoxy, unsubstituted C.sub.1-C.sub.4 haloalkyl,
unsubstituted C.sub.1-C.sub.4 hydroxyalkyl, or unsubstituted
C.sub.1-C.sub.4 haloalkoxy or hydroxy; provided that at least one
R.sup.62 is other than H. Exemplary `substituted carbamoyl` groups
include, but are not limited to, --C(O) NR.sup.64--C.sub.1-C.sub.8
alkyl, --C(O)NR.sup.64--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--C(O)NR.sup.64--(CH.sub.2).sub.t(5-10 membered heteroaryl),
--C(O)NR.sup.64--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl), and
--C(O)NR.sup.64--(CH.sub.2).sub.t(4-10 membered heterocyclyl),
wherein t is an integer from 0 to 4, each R.sup.64 independently
represents H or C.sub.1-C.sub.8 alkyl and any aryl, heteroaryl,
cycloalkyl or heterocyclyl groups present, may themselves be
substituted by unsubstituted C.sub.1-C.sub.4 alkyl, halo,
unsubstituted C.sub.1-C.sub.4 alkoxy, unsubstituted C.sub.1-C.sub.4
haloalkyl, unsubstituted C.sub.1-C.sub.4 hydroxyalkyl, or
unsubstituted C.sub.1-C.sub.4 haloalkoxy or hydroxy.
[0065] "Carboxy" refers to the radical --C(O)OH.
[0066] "Cyano" refers to the radical --CN.
[0067] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo
(Br), and iodo (I). In certain embodiments, the halo group is
either fluoro or chloro.
[0068] "Hydroxy" refers to the radical --OH.
[0069] "Nitro" refers to the radical --NO.sub.2.
[0070] "Cycloalkylalkyl" refers to an alkyl radical in which the
alkyl group is substituted with a cycloalkyl group. Typical
cycloalkylalkyl groups include, but are not limited to,
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl,
cyclopropylethyl, cyclobutylethyl, cyclopentylethyl,
cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the
like.
[0071] "Heterocyclylalkyl" refers to an alkyl radical in which the
alkyl group is substituted with a heterocyclyl group. Typical
heterocyclylalkyl groups include, but are not limited to,
pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl,
morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl,
piperazinylethyl, morpholinylethyl, and the like.
[0072] "Cycloalkenyl" refers to substituted or unsubstituted
carbocyclyl group having from 3 to 10 carbon atoms and having a
single cyclic ring or multiple condensed rings, including fused and
bridged ring systems and having at least one and particularly from
1 to 2 sites of olefinic unsaturation. Such cycloalkenyl groups
include, by way of example, single ring structures such as
cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.
[0073] "Fused cycloalkenyl" refers to a cycloalkenyl having two of
its ring carbon atoms in common with a second aliphatic or aromatic
ring and having its olefinic unsaturation located to impart
aromaticity to the cycloalkenyl ring.
[0074] "Ethenyl" refers to substituted or unsubstituted
--(CH.dbd.CH)--.
[0075] "Ethylene" refers to substituted or unsubstituted
--(CH.sub.2--CH.sub.2)--.
[0076] "Ethynyl" refers to --(C.ident.C)--.
[0077] "Nitrogen-containing heterocyclyl" group means a 4- to
7-membered non-aromatic cyclic group containing at least one
nitrogen atom, for example, but without limitation, morpholine,
piperidine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl),
pyrrolidine (e.g. 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine,
pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline,
pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl
piperazine. Particular examples include azetidine, piperidone and
piperazone.
[0078] "Thioketo" refers to the group .dbd.S.
[0079] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,
and heteroaryl groups, as defined herein, are optionally
substituted (e.g., "substituted" or "unsubstituted" alkyl,
"substituted" or "unsubstituted" alkenyl, "substituted" or
"unsubstituted" alkynyl, "substituted" or "unsubstituted"
carbocyclyl, "substituted" or "unsubstituted" heterocyclyl,
"substituted" or "unsubstituted" aryl or "substituted" or
"unsubstituted" heteroaryl group). In general, the term
"substituted", whether preceded by the term "optionally" or not,
means that at least one hydrogen present on a group (e.g., a carbon
or nitrogen atom) is replaced with a permissible substituent, e.g.,
a substituent which upon substitution results in a stable compound,
e.g., a compound which does not spontaneously undergo
transformation such as by rearrangement, cyclization, elimination,
or other reaction. Unless otherwise indicated, a "substituted"
group has a substituent at one or more substitutable positions of
the group, and when more than one position in any given structure
is substituted, the substituent is either the same or different at
each position. The term "substituted" is contemplated to include
substitution with all permissible substituents of organic
compounds, any of the substituents described herein that results in
the formation of a stable compound. The present invention
contemplates any and all such combinations in order to arrive at a
stable compound. For purposes of this invention, heteroatoms such
as nitrogen may have hydrogen substituents and/or any suitable
substituent as described herein which satisfy the valencies of the
heteroatoms and results in the formation of a stable moiety.
[0080] Exemplary carbon atom substituents include, but are not
limited to, halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H,
--SO.sub.3H, --OH, --OR.sup.aa, --ON(R.sup.bb).sub.2,
--N(R.sup.bb).sub.2, --N(R.sup.bb).sub.3.sup.+X.sup.-,
--N(OR.sup.cc)R.sup.bb, --SH, --SR.sup.aa, --SSR.sup.cc,
--C(.dbd.O)R.sup.aa, --CO.sub.2H, --CHO, --C(OR.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --OC(.dbd.O)R.sup.aa, --OCO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --OC(.dbd.O)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.O)R.sup.aa, --NR.sup.bbCO.sub.2R.sup.aa,
--NR.sup.bbC(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --OC(.dbd.NR.sup.bb)R.sup.aa,
--OC(.dbd.NR.sup.bb)OR.sup.aa,
--C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--OC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa, --NR.sup.bbSO.sub.2R.sup.aa,
--SO.sub.2N(R.sup.bb).sub.2, --SO.sub.2R.sup.aa,
--SO.sub.2OR.sup.aa, --OSO.sub.2R.sup.aa, --S(.dbd.O)R.sup.aa,
--OS(.dbd.O)R.sup.aa, --Si(R.sup.aa).sub.3,
--OSi(R.sup.aa).sub.3--C(.dbd.S)N(R.sup.bb).sub.2,
--C(.dbd.O)SR.sup.aa, --C(.dbd.S)SR.sup.aa, --SC(.dbd.S)SR.sup.aa,
--SC(.dbd.O)SR.sup.aa, --OC(.dbd.O)SR.sup.aa,
--SC(.dbd.O)OR.sup.aa, --SC(.dbd.O)R.sup.aa,
--P(.dbd.O).sub.2R.sup.aa, --OP(.dbd.O).sub.2R.sup.aa,
--P(.dbd.O)(R.sup.aa).sub.2--OP(.dbd.O)(R.sup.aa).sub.2--OP(.dbd.O)(OR.su-
p.cc).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2,
--OP(.dbd.O).sub.2N(R.sup.bb).sub.2, --P(.dbd.O)(NR.sup.bb).sub.2,
--OP(.dbd.O)(NR.sup.bb).sub.2,
--NR.sup.bbP(.dbd.O)(OR.sup.cc).sub.2,
--NR.sup.bbP(.dbd.O)(NR.sup.bb).sub.2, --P(R.sup.cc).sub.2,
--P(R.sup.cc).sub.3, --OP(R.sup.cc).sub.2, --OP(R.sup.cc).sub.3,
--B(R.sup.aa).sub.2, --B(OR.sup.cc).sub.2, --BR.sup.aa(OR.sup.cc),
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, and heteroaryl is independently substituted with 0, 1, 2, 3,
4, or 5 R.sup.dd groups; or two geminal hydrogens on a carbon atom
are replaced with the group .dbd.O, .dbd.S,
.dbd.NN(R.sup.bb).sub.2, .dbd.NNR.sup.bbC(.dbd.O)R.sup.aa,
.dbd.NNR.sup.bbC(.dbd.O)OR.sup.aa,
.dbd.NNR.sup.bbS(.dbd.O).sub.2R.sup.aa, .dbd.NR.sup.bb, or
.dbd.NOR.sup.cc;
[0081] each instance of R.sup.aa is, independently, selected from
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.aa groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0082] each instance of R.sup.bb is, independently, selected from
hydrogen, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2, --CN,
--C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O).sub.2N(R.sup.cc).sub.2, --P(.dbd.O)(NR.sup.cc).sub.2,
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.bb groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0083] each instance of R.sup.cc is, independently, selected from
hydrogen, C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.cc groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0084] each instance of R.sup.dd is, independently, selected from
halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H,
--OH, --OR.sup.ee, --ON(R.sup.ff).sub.2, --N(R.sup.ff).sub.2,
--N(R.sup.ff).sub.3.sup.+X.sup.-, --N(OR.sup.ee)R.sup.ff, --SH,
--SR.sup.ee, --SSR.sup.ee, --C(.dbd.O)R.sup.ee, --CO.sub.2H,
--CO.sub.2R.sup.ee, --OC(.dbd.O)R.sup.ee, --OCO.sub.2R.sup.ee,
--C(.dbd.O)N(R.sup.ff).sub.2, --OC(.dbd.O)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.O)R.sup.ee, --NR.sup.ffCO.sub.2R.sup.ee,
--NR.sup.ffC(.dbd.O)N(R.sup.ff).sub.2,
--C(.dbd.NR.sup.ff)OR.sup.ee, --OC(.dbd.NR.sup.ff)R.sup.ee,
--OC(.dbd.NR.sup.ff)OR.sup.ee,
--C(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--OC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffSO.sub.2R.sup.ee, --SO.sub.2N(R.sup.ff).sub.2,
--SO.sub.2R.sup.ee, --SO.sub.2OR.sup.ee, --OSO.sub.2R.sup.ee,
--S(.dbd.O)R.sup.ee, --Si(R.sup.ee).sub.3, --OSi(R.sup.ee).sub.3,
--C(.dbd.S)N(R.sup.ff).sub.2, --C(.dbd.O)SR.sup.ee,
--C(.dbd.S)SR.sup.ee, --SC(.dbd.S)SR.sup.ee,
--P(.dbd.O).sub.2R.sup.ee, --P(.dbd.O)(R.sup.ee).sub.2,
--OP(.dbd.O)(R.sup.ee).sub.2, --OP(.dbd.O)(OR.sup.ee).sub.2,
C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered
heterocyclyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, wherein
each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5
R.sup.gg groups, or two geminal Rad substituents can be joined to
form .dbd.O or .dbd.S;
[0085] each instance of R.sup.ee is, independently, selected from
C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10
membered heterocyclyl, and 3-10 membered heteroaryl, wherein each
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5
R.sup.gg groups;
[0086] each instance of R.sup.ff is, independently, selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered
heterocyclyl, C.sub.6-10 aryl and 5-10 membered heteroaryl, or two
R.sup.ff groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups;
and
[0087] each instance of R.sup.gg is, independently, halogen, --CN,
--NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H, --OH, --OC.sub.1-6
alkyl, --ON(C.sub.1-6 alkyl).sub.2, --N(C.sub.1-6 alkyl).sub.2,
--N(C.sub.1-6 alkyl).sub.3.sup.+X.sup.-, --NH(C.sub.1-6
alkyl).sub.2.sup.+X.sup.-, --NH.sub.2(C.sub.1-6
alkyl).sup.+X.sup.-, --NH.sub.3.sup.+X.sup.-, --N(OC.sub.1-6
alkyl)(C.sub.1-6 alkyl), --N(OH)(C.sub.1-6 alkyl), --NH(OH), --SH,
--SC.sub.1-6 alkyl, --SS(C.sub.1-6 alkyl), --C(.dbd.O)(C.sub.1-6
alkyl), --C.sub.2H, --C.sub.2(C.sub.1-6 alkyl),
--OC(.dbd.O)(C.sub.1-6 alkyl), --OCO.sub.2(C.sub.1-6 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)N(C.sub.1-6 alkyl).sub.2,
--OC(.dbd.O)NH(C.sub.1-6 alkyl), --NHC(.dbd.O)(C.sub.1-6 alkyl),
--N(C.sub.1-6 alkyl)C(.dbd.O)(C.sub.1-6 alkyl),
--NHCO.sub.2(C.sub.1-6 alkyl), --NHC(.dbd.O)N(C.sub.1-6
alkyl).sub.2, --NHC(.dbd.O)NH(C.sub.1-6 alkyl),
--NHC(.dbd.O)NH.sub.2, --C(.dbd.NH)O(C.sub.1-6 alkyl),
--OC(.dbd.NH)(C.sub.1-6 alkyl), --OC(.dbd.NH)OC.sub.1-6 alkyl,
--C(.dbd.NH)N(C.sub.1-6 alkyl).sub.2, --C(.dbd.NH)NH(C.sub.1-6
alkyl), --C(.dbd.NH)NH.sub.2, --OC(.dbd.NH)N(C.sub.1-6
alkyl).sub.2, --OC(NH)NH(C.sub.1-6 alkyl), --OC(NH)NH.sub.2,
--NHC(NH)N(C.sub.1-6 alkyl).sub.2, --NHC(.dbd.NH)NH.sub.2,
--NHSO.sub.2(C.sub.1-6 alkyl), --SO.sub.2N(C.sub.1-6 alkyl).sub.2,
--SO.sub.2NH(C.sub.1-6 alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2C.sub.1-6 alkyl, --SO.sub.2OC.sub.1-6 alkyl,
--OSO.sub.2C.sub.1-6 alkyl, --SOC.sub.1-6 alkyl, --Si(C.sub.1-6
alkyl).sub.3, --OSi(C.sub.1-6 alkyl).sub.3--C(.dbd.S)N(C.sub.1-6
alkyl).sub.2, C(.dbd.S)NH(C.sub.1-6 alkyl), C(.dbd.S)NH.sub.2,
--C(.dbd.O)S(C.sub.1-6 alkyl), --C(.dbd.S)SC.sub.1-6 alkyl,
--SC(.dbd.S)SC.sub.1-6 alkyl, --P(.dbd.O).sub.2(C.sub.1-6 alkyl),
--P(.dbd.O)(C.sub.1-6 alkyl).sub.2, --OP(.dbd.O)(C.sub.1-6
alkyl).sub.2, --OP(.dbd.O)(OC.sub.1-6 alkyl).sub.2, C.sub.1-6
alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10 membered
heterocyclyl, 5-10 membered heteroaryl; or two geminal R.sup.gg
substituents can be joined to form .dbd.O or .dbd.S; wherein X is a
counterion.
[0088] A "counterion" or "anionic counterion" is a negatively
charged group associated with a cationic quaternary amino group in
order to maintain electronic neutrality. Exemplary counterions
include halide ions (e.g., F.sup.-, Cl.sup.-, Br.sup.-, I.sup.-),
NO.sub.3.sup.-, ClO.sub.4.sup.-, OH.sup.-, H.sub.2PO.sub.4.sup.-,
HSO.sub.4.sup.-, sulfonate ions (e.g., methansulfonate,
trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate,
10-camphor sulfonate, naphthalene-2-sulfonate,
naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic
acid-2-sulfonate, and the like), and carboxylate ions (e.g.,
acetate, ethanoate, propanoate, benzoate, glycerate, lactate,
tartrate, glycolate, and the like).
[0089] Nitrogen atoms can be substituted or unsubstituted as
valency permits, and include primary, secondary, tertiary, and
quarternary nitrogen atoms. Exemplary nitrogen atom substitutents
include, but are not limited to, hydrogen, --OH, --OR.sup.aa,
--N(R.sup.cc).sub.2, --CN, --C(.dbd.O)R.sup.aa,
--C(.dbd.O)N(R.sup.cc).sub.2, --CO.sub.2R.sup.aa,
--SO.sub.2R.sup.aa, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O).sub.2N(R.sup.cc).sub.2, --P(.dbd.O)(NR.sup.cc).sub.2,
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R groups attached to a nitrogen atom are joined to form a 3-14
membered heterocyclyl or 5-14 membered heteroaryl ring, wherein
each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Ra
groups, and wherein R.sup.aa, R.sup.bb, R.sup.cc and R.sup.dd are
as defined above.
[0090] In certain embodiments, the substituent present on a
nitrogen atom is a nitrogen protecting group (also referred to as
an amino protecting group). Nitrogen protecting groups include, but
are not limited to, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2,
--C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa,
--C(.dbd.NR.sup.cc)R.sup.aa, --C(.dbd.NR.sup.cc)OR.sup.aa,
--C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2, --SO.sub.2N(R.sup.cc).sub.2,
--SO.sub.2R.sup.cc, --SO.sub.2OR.sup.cc, --SOR.sup.aa,
--C(.dbd.S)N(R.sup.cc).sub.2, --C(.dbd.O)SR.sup.cc,
--C(.dbd.S)SR.sup.cc, C.sub.1-10 alkyl (e.g., aralkyl,
heteroaralkyl), C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10
carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14
membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 Ra groups, and
wherein R.sup.aa, R.sup.bb, R.sup.cc and R.sup.dd are as defined
herein. Nitrogen protecting groups are well known in the art and
include those described in detail in Protecting Groups in Organic
Synthesis, T. W. Greene and P. G. M. Wuts, 3.sup.rd edition, John
Wiley & Sons, 1999, incorporated herein by reference.
[0091] For example, nitrogen protecting groups such as amide groups
(e.g., --C(.dbd.O)R.sup.aa) include, but are not limited to,
formamide, acetamide, chloroacetamide, trichloroacetamide,
trifluoroacetamide, phenylacetamide, 3-phenylpropanamide,
picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl
derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide,
o-nitrophenoxyacetamide, acetoacetamide,
(N'-dithiobenzyloxyacylamino)acetamide,
3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,
2-methyl-2-(o-nitrophenoxy)propanamide,
2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,
3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine
derivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.
[0092] Nitrogen protecting groups such as carbamate groups (e.g.,
--C(.dbd.O)OR.sup.aa) include, but are not limited to, methyl
carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc),
9-(2-sulfo)fluorenylmethyl carbamate,
9-(2,7-dibromo)fluoroenylmethyl carbamate,
2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl
carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),
2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl
carbamate (Teoc), 2-phenylethyl carbamate (hZ),
1-(1-adamantyl)-1-methylethyl carbamate (Adpoc),
1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl
carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate
(TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),
1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'-
and 4'-pyridyl)ethyl carbamate (Pyoc),
2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate
(BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl
carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl
carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl
carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate,
benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),
p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl
carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl
carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl
carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl
carbamate, 2-(p-toluenesulfonyl)ethyl carbamate,
[2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl
carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc),
2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl
carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate,
m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl
carbamate, 5-benzisoxazolylmethyl carbamate,
2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc),
m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate,
o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate,
phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl
thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate,
cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl
carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl
carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate,
1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,
1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,
2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl
carbamate, isobutyl carbamate, isonicotinyl carbamate,
p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl
carbamate, 1-methylcyclohexyl carbamate,
1-methyl-1-cyclopropylmethyl carbamate,
1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,
1-methyl-1-(p-phenylazophenyl)ethyl carbamate,
1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl
carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate,
2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl
carbamate, and 2,4,6-trimethylbenzyl carbamate.
[0093] Nitrogen protecting groups such as sulfonamide groups (e.g.,
--S(.dbd.O).sub.2R.sup.aa) include, but are not limited to,
p-toluenesulfonamide (Ts), benzenesulfonamide,
2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr),
2,4,6-trimethoxybenzenesulfonamide (Mtb),
2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),
2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),
4-methoxybenzenesulfonamide (Mbs),
2,4,6-trimethylbenzenesulfonamide (Mts),
2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),
2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc),
methanesulfonamide (Ms), 3-trimethylsilylethanesulfonamide (SES),
9-anthracenesulfonamide,
4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),
benzylsulfonamide, trifluoromethylsulfonamide, and
phenacylsulfonamide.
[0094] Other nitrogen protecting groups include, but are not
limited to, phenothiazinyl-(10)-acyl derivative,
N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl
derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine
derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,
N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide,
N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane
adduct (STABASE), 5-substituted
1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted
1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted
3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,
N-[2-(trimethylsilyl)ethoxy]methylamine (SEM),
N-3-acetoxypropylamine,
N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary
ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,
N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),
N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),
N-9-phenylfluorenylamine (PhF),
N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino
(Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine,
N-benzylideneamine, N-p-methoxybenzylideneamine,
N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,
N--(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine,
N-p-nitrobenzylideneamine, N-salicylideneamine,
N-5-chlorosalicylideneamine,
N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,
N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,
N-borane derivative, N-diphenylborinic acid derivative,
N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper
chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine
N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide
(Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates,
dibenzyl phosphoramidate, diphenyl phosphoramidate,
benzenesulfenamide, o-nitrobenzenesulfenamide (Nps),
2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide,
2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide,
and 3-nitropyridinesulfenamide (Npys).
[0095] In certain embodiments, the substituent present on an oxygen
atom is an oxygen protecting group (also referred to as a hydroxyl
protecting group). Oxygen protecting groups include, but are not
limited to, --R.sup.aa, --N(R.sup.bb).sub.2, --C(.dbd.O)SR.sup.aa,
--C(.dbd.O)R.sup.aa, --CO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--S(.dbd.O)R.sup.aa, --SO.sub.2R.sup.aa, --Si(R.sup.aa).sub.3,
--P(R.sup.cc).sub.2, --P(R.sup.cc).sub.3,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O)(OR.sup.aa).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2,
and --P(.dbd.O)(NR.sup.bb).sub.2, wherein R.sup.aa, R.sup.bb, and
R.sup.cc are as defined herein. Oxygen protecting groups are well
known in the art and include those described in detail in
Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, incorporated
herein by reference.
[0096] Exemplary oxygen protecting groups include, but are not
limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM),
t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM),
benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM),
(4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM),
t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl,
2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,
bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),
tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,
tetrahydrothiopyranyl, 1-methoxycyclohexyl,
4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl,
4-methoxytetrahydrothiopyranyl S,S-dioxide,
1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP),
1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,
2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,
1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,
1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl,
2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl,
p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl,
3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,
2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl,
4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl,
pp'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,
.alpha.-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,
di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl,
4-(4'-bromophenacyloxyphenyl)diphenylmethyl,
4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl,
4,4',4''-tris(levulinoyloxyphenyl)methyl,
4,4',4''-tris(benzoyloxyphenyl)methyl,
3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl,
1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl,
9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,
1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido,
trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl
(TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl
(DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS),
t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl,
triphenylsilyl, diphenylmethylsilyl (DPMS),
t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate,
acetate, chloroacetate, dichloroacetate, trichloroacetate,
trifluoroacetate, methoxyacetate, triphenylmethoxyacetate,
phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate,
4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate
(levulinoyldithioacetal), pivaloate, adamantoate, crotonate,
4-methoxycrotonate, benzoate, p-phenylbenzoate,
2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,
9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl
2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl
carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),
2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl
carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl
p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl
p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate,
alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl
S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl
dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate,
4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,
2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,
4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,
2,6-dichloro-4-methylphenoxyacetate,
2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,
2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,
isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,
o-(methoxyacyl)benzoate, .alpha.-naphthoate, nitrate, alkyl
N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,
borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,
sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate
(Ts).
[0097] In certain embodiments, the substituent present on a sulfur
atom is a sulfur protecting group (also referred to as a thiol
protecting group). Sulfur protecting groups include, but are not
limited to, --R.sup.aa, --N(R.sup.bb).sub.2, --C(.dbd.O)SR.sup.aa,
--C(.dbd.O)R.sup.aa, --CO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--S(.dbd.O)R.sup.aa, --SO.sub.2R.sup.aa, --Si(R.sup.aa).sub.3,
--P(R.sup.cc).sub.2, --P(R.sup.cc).sub.3,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2,
and --P(.dbd.O)(NR.sup.bb).sub.2, wherein R.sup.aa, R.sup.bb, and
R.sup.cc are as defined herein. Sulfur protecting groups are well
known in the art and include those described in detail in
Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, incorporated
herein by reference.
[0098] "Compounds of the present invention", and equivalent
expressions, are meant to embrace the compounds as described
herein, in particular compounds according to any of Formulae
recited and/or described herein, which expression includes the
prodrugs, the pharmaceutically acceptable salts, and the solvates,
e.g., hydrates, where the context so permits. Similarly, reference
to intermediates, whether or not they themselves are claimed, is
meant to embrace their salts, and solvates, where the context so
permits. These and other exemplary substituents are described in
more detail in the Detailed Description, Examples, and claims. The
invention is not intended to be limited in any manner by the above
exemplary listing of substituents.
Other Definitions
[0099] "Pharmaceutically acceptable" means approved or approvable
by a regulatory agency of the Federal or a state government or the
corresponding agency in countries other than the United States, or
that is listed in the U.S. Pharmacopoeia or other generally
recognized pharmacopoeia for use in animals, and more particularly,
in humans.
[0100] "Pharmaceutically acceptable salt" refers to a salt of a
compound of the invention that is pharmaceutically acceptable and
that possesses the desired pharmacological activity of the parent
compound. In particular, such salts are non-toxic may be inorganic
or organic acid addition salts and base addition salts.
Specifically, such salts include: (1) acid addition salts, formed
with inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like; or
formed with organic acids such as acetic acid, propionic acid,
hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic
acid, lactic acid, malonic acid, succinic acid, malic acid, maleic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like; or (2) salts formed when an acidic proton
present in the parent compound either is replaced by a metal ion,
e.g., an alkali metal ion, an alkaline earth ion, or an aluminum
ion; or coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, N-methylglucamine and the like.
Salts further include, by way of example only, sodium, potassium,
calcium, magnesium, ammonium, tetraalkylammonium, and the like; and
when the compound contains a basic functionality, salts of
non-toxic organic or inorganic acids, such as hydrochloride,
hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the
like.
[0101] The term "pharmaceutically acceptable cation" refers to an
acceptable cationic counter-ion of an acidic functional group. Such
cations are exemplified by sodium, potassium, calcium, magnesium,
ammonium, tetraalkylammonium cations, and the like. See, e.g.,
Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.
[0102] "Solvate" refers to forms of the compound that are
associated with a solvent or water (also referred to as "hydrate"),
usually by a solvolysis reaction. This physical association
includes hydrogen bonding. Conventional solvents include water,
ethanol, acetic acid, and the like. The compounds of the invention
may be prepared e.g. in crystalline form and may be solvated or
hydrated. Suitable solvates include pharmaceutically acceptable
solvates, such as hydrates, and further include both stoichiometric
solvates and non-stoichiometric solvates. In certain instances the
solvate will be capable of isolation, for example when one or more
solvent molecules are incorporated in the crystal lattice of the
crystalline solid. "Solvate" encompasses both solution-phase and
isolable solvates. Representative solvates include hydrates,
ethanolates and methanolates.
[0103] A "subject" to which administration is contemplated
includes, but is not limited to, humans (i.e., a male or female of
any age group, e.g., a pediatric subject (e.g., infant, child,
adolescent) or adult subject (e.g., young adult, middle-aged adult
or senior adult)) and/or a non-human animal, e.g., a mammal such as
primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs,
horses, sheep, goats, rodents, cats, and/or dogs. In certain
embodiments, the subject is a human. In certain embodiments, the
subject is a non-human animal. The terms "human," "patient," and
"subject" are used interchangeably herein.
[0104] "Condition," "disease," and "disorder" are used
interchangeably herein.
[0105] An "effective amount" means the amount of a compound that,
when administered to a subject for treating or preventing a
disease, is sufficient to effect such treatment or prevention. The
"effective amount" can vary depending on the compound, the disease
and its severity, and the age, weight, etc., of the subject to be
treated. A "therapeutically effective amount" refers to the
effective amount for therapeutic treatment. A "prophylactically
effective amount" refers to the effective amount for prophylactic
treatment.
[0106] "Preventing" or "prevention" or "prophylactic treatment"
refers to a reduction in risk of acquiring or developing a disease
or disorder (i.e., causing at least one of the clinical symptoms of
the disease not to develop in a subject not yet exposed to a
disease-causing agent, or predisposed to the disease in advance of
disease onset). The term "prophylaxis" is related to "prevention,"
and refers to a measure or procedure the purpose of which is to
prevent, rather than to treat or cure a disease.
[0107] "Treating" or "treatment" or "therapeutic treatment" of any
disease or disorder refers to ameliorating the disease or disorder
(i.e., arresting the disease or reducing the manifestation, extent
or severity of at least one of the clinical symptoms thereof). In
another embodiment "treating" or "treatment" refers to ameliorating
at least one physical parameter, which may not be discernible by
the subject. In yet another embodiment, "treating" or "treatment"
refers to modulating the disease or disorder, either physically,
(e.g., stabilization of a discernible symptom), physiologically,
(e.g., stabilization of a physical parameter), or both. In a
further embodiment, "treating" or "treatment" relates to slowing
the progression of the disease.
[0108] As used herein, the term "isotopic variant" refers to a
compound that contains unnatural proportions of isotopes at one or
more of the atoms that constitute such compound. For example, an
"isotopic variant" of a compound can contain one or more
non-radioactive isotopes, such as for example, deuterium (.sup.2H
or D), carbon-13 (.sup.13C), nitrogen-15 (.sup.15N), or the like.
It will be understood that, in a compound where such isotopic
substitution is made, the following atoms, where present, may vary,
so that for example, any hydrogen may be .sup.2HD, any carbon may
be .sup.13C, or any nitrogen may be .sup.15N, and that the presence
and placement of such atoms may be determined within the skill of
the art. Likewise, the invention may include the preparation of
isotopic variants with radioisotopes, in the instance for example,
where the resulting compounds may be used for drug and/or substrate
tissue distribution studies. The radioactive isotopes tritium,
i.e., .sup.3H, and carbon-14, i.e., .sup.1C, are particularly
useful for this purpose in view of their ease of incorporation and
ready means of detection. Further, compounds may be prepared that
are substituted with positron emitting isotopes, such as .sup.11C,
.sup.18F, .sup.15O, and .sup.13N, and would be useful in Positron
Emission Topography (PET) studies for examining substrate receptor
occupancy. All isotopic variants of the compounds provided herein,
radioactive or not, are intended to be encompassed within the scope
of the invention.
[0109] "Stereoisomers": It is also to be understood that compounds
that have the same molecular formula but differ in the nature or
sequence of bonding of their atoms or the arrangement of their
atoms in space are termed "isomers." Isomers that differ in the
arrangement of their atoms in space are termed "stereoisomers."
Stereoisomers that are not mirror images of one another are termed
"diastereomers" and those that are non-superimposable mirror images
of each other are termed "enantiomers." When a compound has an
asymmetric center, for example, it is bonded to four different
groups, a pair of enantiomers is possible. An enantiomer can be
characterized by the absolute configuration of its asymmetric
center and is described by the R- and S-sequencing rules of Cahn
and Prelog, or by the manner in which the molecule rotates the
plane of polarized light and designated as dextrorotatory or
levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral
compound can exist as either individual enantiomer or as a mixture
thereof. A mixture containing equal proportions of the enantiomers
is called a "racemic mixture".
[0110] "Tautomers" refer to compounds that are interchangeable
forms of a particular compound structure, and that vary in the
displacement of hydrogen atoms and electrons. Thus, two structures
may be in equilibrium through the movement of .pi. electrons and an
atom (usually H). For example, enols and ketones are tautomers
because they are rapidly interconverted by treatment with either
acid or base. Another example of tautomerism is the aci- and
nitro-forms of phenylnitromethane, that are likewise formed by
treatment with acid or base. Tautomeric forms may be relevant to
the attainment of the optimal chemical reactivity and biological
activity of a compound of interest.
[0111] "Pharmaceutically acceptable metabolically cleavable group"
refers to a group which is cleaved in vivo to yield the parent
molecule of the structural Formula indicated herein. Examples of
metabolically cleavable groups include --COR, --COOR, --CONRR and
--CH.sub.2OR radicals, where R is selected independently at each
occurrence from alkyl, trialkylsilyl, carbocyclic aryl or
carbocyclic aryl substituted with one or more of alkyl, halogen,
hydroxy or alkoxy. Specific examples of representative
metabolically cleavable groups include acetyl, methoxycarbonyl,
benzoyl, methoxymethyl and trimethylsilyl groups.
[0112] "Prodrugs" refers to compounds, including derivatives of the
compounds of the invention, which have cleavable groups and become
by solvolysis or under physiological conditions the compounds of
the invention which are pharmaceutically active in vivo. Such
examples include, but are not limited to, choline ester derivatives
and the like, N-alkylmorpholine esters and the like. Other
derivatives of the compounds of this invention have activity in
both their acid and acid derivative forms, but in the acid
sensitive form often offers advantages of solubility, tissue
compatibility, or delayed release in the mammalian organism (see,
Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier,
Amsterdam 1985). Prodrugs include acid derivatives well know to
practitioners of the art, such as, for example, esters prepared by
reaction of the parent acid with a suitable alcohol, or amides
prepared by reaction of the parent acid compound with a substituted
or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
Simple aliphatic or aromatic esters, amides and anhydrides derived
from acidic groups pendant on the compounds of this invention are
particular prodrugs. In some cases it is desirable to prepare
double ester type prodrugs such as (acyloxy)alkyl esters or
((alkoxycarbonyl)oxy)alkylesters. Particularly the C.sub.1 to
C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
aryl, C.sub.7-C.sub.12 substituted aryl, and C.sub.7-C.sub.12
arylalkyl esters of the compounds of the invention.
[0113] "Compounds of the present invention", and equivalent
expressions, are meant to embrace the compounds as described
herein, in particular compounds according to any of Formulae
recited and/or described herein, which expression includes the
prodrugs, the pharmaceutically acceptable salts, and the solvates,
e.g., hydrates, where the context so permits. Similarly, reference
to intermediates, whether or not they themselves are claimed, is
meant to embrace their salts, and solvates, where the context so
permits.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
[0114] As described herein, the present invention is based, in
part, on the desire to provide novel 19-nor compounds with good
potency, pharmacokinetic (PK) properties, oral bioavailability,
formulatability, stability, safety, clearance and/or metabolism.
One key feature of the compounds as described herein is
disubstitution at the C3 position. The inventors envision
disubstitution at C-3 will eliminate the potential for oxidation to
the ketone, prevent further metabolism, and reduce the potential
for secondary elimination pathways, such as glucuronidation. The
inventors further envision the overall effect of C3 disubstitution
should be of improving the overall PK parameters and reducing
potential toxicities and side effects, which may allow, in certain
embodiments, administration orally and/or chronically. Another key
feature of the compounds as described herein is the presence of a
hydrogen at the C10 position ("19-nor") rather than a methyl group.
The inventors envision 19-nor compounds, as compared to their
C10-methyl counterparts, will have improved physical properties,
such as improved solubility. The inventors envision further
enhancement of solubility, for example, when the AB ring system is
in the cis configuration.
[0115] Thus, in one aspect, provided is a 3,3-disubstituted 19-nor
pregnane compound of Formula (I):
##STR00007##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a
combination thereof; wherein:
[0116] R.sup.1 is hydrogen, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.A1, --SR.sup.A1, --N(R.sup.A1).sub.2,
--OC(.dbd.O)R.sup.A1, --OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A1).sub.2, --SC(.dbd.O)R.sup.A2,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1,
--NHC(.dbd.O)OR.sup.A1, --NHC(.dbd.O)SR.sup.A1,
--NHC(.dbd.O)N(R.sup.A1).sub.2, --OS(.dbd.O).sub.2R.sup.A2,
--OS(.dbd.O).sub.2OR.sup.A1, --S--S(.dbd.O).sub.2R.sup.A2,
--S--S(.dbd.O).sub.2OR.sup.A1, --S(.dbd.O)R.sup.A2,
--SO.sub.2R.sup.A2, or --S(.dbd.O).sub.2OR.sup.A1, wherein each
instance of R.sup.A1 is independently hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl, an
oxygen protecting group when attached to an oxygen atom, a sulfur
protecting group when attached to a sulfur atom, a nitrogen
protecting group when attached to a nitrogen atom, or two R.sup.A1
groups are joined to form an substituted or unsubstituted
heterocyclic or heteroaryl ring; and R.sup.A2 is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted
heteroaryl;
[0117] R.sup.2 is hydrogen, halo, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, --OH,
--OR.sup.B1, --OC(.dbd.O)R.sup.B1--NH.sub.2, --N(R.sup.B1).sub.2,
or --NR.sup.B1C(.dbd.O)R.sup.B1 wherein each instance of R.sup.B1
is independently hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, an oxygen protecting group
when attached to an oxygen atom, a nitrogen protecting group when
attached to a nitrogen atom, or two R.sup.B1 groups are joined to
form an substituted or unsubstituted heterocyclic ring;
[0118] R.sup.3 is substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl;
[0119] R.sup.3' is hydrogen, --C(.dbd.O)R.sup.C1,
--C(.dbd.O)OR.sup.C1, --C(.dbd.O)SR.sup.C1,
--C(.dbd.O)N(R.sup.C1).sub.2, --S(.dbd.O).sub.2R.sup.C2,
--S(.dbd.O).sub.2OR.sup.C1, --P(.dbd.O).sub.2R.sup.C2,
--P(.dbd.O).sub.2OR.sup.C1, --P(.dbd.O)(OR.sup.C1).sub.2,
--P(.dbd.O)(R.sup.C2).sub.2, or --P(.dbd.O)(R.sup.C2)(OR.sup.C1),
wherein R.sup.C1 is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, an oxygen protecting group
when attached to an oxygen atom, a sulfur protecting group when
attached to a sulfur atom, a nitrogen protecting group when
attached to a nitrogen atom, or two R.sup.C1 groups are joined to
form an substituted or unsubstituted heterocyclic ring; and
R.sup.C2 is substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl;
[0120] R.sup.4 is selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl;
[0121] each of R.sup.6a and R.sup.6b is independently hydrogen,
halo, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or
R.sup.6a and R.sup.6b are joined to form an oxo (.dbd.O) group;
[0122] each of R.sup.11a and R.sup.11b is independently hydrogen,
halo, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, --OH,
--OR.sup.D1, --OC(.dbd.O)R.sup.D1, --NH.sub.2, --N(R.sup.D1).sub.2,
or --NR.sup.D1C(.dbd.O)R.sup.D1, wherein each instance of R.sup.D1
is independently hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, an oxygen protecting group
when attached to an oxygen atom, a nitrogen protecting group when
attached to a nitrogen atom, or two R.sup.D1 groups are joined to
form an substituted or unsubstituted heterocyclic ring; or
R.sup.11a and R.sup.11b are joined to form an oxo (.dbd.O)
group;
[0123] wherein represents a single or double bond, provided if a
double bond is present in Ring B, then one of R.sup.6a or R.sup.6b
is absent, and provided if a single bond is present in Ring B, then
the hydrogen at C5 is in the alpha or beta position;
[0124] provided that the following compounds, and pharmaceutically
acceptable salts thereof, are specifically excluded:
##STR00008## ##STR00009## ##STR00010##
[0125] In another aspect, provided is a 3,3-disubstituted 19-nor
pregnane compound of Formula (III):
##STR00011##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a
combination thereof; wherein R.sup.1, R.sup.2, R.sup.3, R.sup.3',
R.sup.4, R.sup.6a, R.sup.6b, R.sup.11a, and R.sup.11b are as
defined herein.
[0126] In certain embodiments, the compound is a pharmaceutically
acceptable salt, e.g., a sodium, potassium, ammonium, or calcium
salt. In certain embodiments, the compound is a sodium salt. In
certain embodiments, the compound is an acid addition salt, e.g.,
hydrochloride, hydrobromide, benzoate, mesylate, or besylate
salt.
[0127] Compounds of Formula (I) and (III) are contemplated, in
certain embodiments, to act as GABA modulators.
Group R.sup.1
[0128] As generally described herein, R.sup.1 is hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.A1, --SR.sup.A1,
--N(R.sup.A1).sub.2, --OC(.dbd.O)R.sup.A1, --OC(.dbd.O)OR.sup.A1,
--OC(.dbd.O)SR.sup.A1, --OC(.dbd.O)N(R.sup.A1).sub.2,
--SC(.dbd.O)R.sup.A2, --SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1,
--NHC(.dbd.O)OR.sup.A1, --NHC(.dbd.O)SR.sup.A1,
--NHC(.dbd.O)N(R.sup.A1).sub.2, --OS(.dbd.O).sub.2R.sup.A2,
--OS(.dbd.O).sub.2OR.sup.A1, --S--S(.dbd.O).sub.2R.sup.A2,
--S--S(.dbd.O).sub.2OR.sup.A1, --S(.dbd.O)R.sup.A2,
--SO.sub.2R.sup.A2, or --S(.dbd.O).sub.2OR.sup.A1, wherein each
instance of R.sup.A1 is independently hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl, an
oxygen protecting group when attached to an oxygen atom, a sulfur
protecting group when attached to a sulfur atom, a nitrogen
protecting group when attached to a nitrogen atom, or two R.sup.A1
groups are joined to form an substituted or unsubstituted
heterocyclic or heteroaryl ring; and R.sup.A2 is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted
heteroaryl.
[0129] In certain embodiments, R.sup.1 is hydrogen.
[0130] In certain embodiments, R.sup.1 is halogen, e.g., fluoro,
bromo, chloro, or iodo. In certain embodiments, R.sup.1 is
bromo.
[0131] In certain embodiments, R.sup.1 is substituted or
unsubstituted alkyl, e.g., substituted or unsubstituted
C.sub.1-6alkyl, C.sub.2-6alkyl, C.sub.3-6alkyl, C.sub.4-6alkyl,
C.sub.5-6alkyl, C.sub.1alkyl, C.sub.2alkyl, C.sub.3alkyl,
C.sub.4alkyl, C.sub.5alkyl, or C.sub.6alkyl. In certain
embodiments, R.sup.1 is a substituted alkyl (e.g., haloalkyl,
alkyoxyalkyl).
[0132] In certain embodiments, R.sup.1 is substituted or
unsubstituted alkenyl, e.g., substituted or unsubstituted
C.sub.2-6alkenyl, substituted or unsubstituted C.sub.3-6alkenyl,
substituted or unsubstituted C.sub.4-6alkenyl, substituted or
unsubstituted C.sub.5-6alkenyl, substituted or unsubstituted
C.sub.2alkenyl, substituted or unsubstituted C.sub.3alkenyl,
substituted or unsubstituted C.sub.4alkenyl, substituted or
unsubstituted C.sub.5alkenyl, or substituted or unsubstituted
C.sub.6alkenyl.
[0133] In certain embodiments, R.sup.1 is substituted or
unsubstituted alkynyl, e.g., substituted or unsubstituted
C.sub.2-6alkynyl, substituted or unsubstituted C.sub.3-6alkynyl,
substituted or unsubstituted C.sub.4-6alkynyl, substituted or
unsubstituted C.sub.5-6alkynyl, substituted or unsubstituted
C.sub.2alkynyl, substituted or unsubstituted C.sub.3alkynyl,
substituted or unsubstituted C.sub.4alkynyl, substituted or
unsubstituted C.sub.5alkynyl, or substituted or unsubstituted
C.sub.6alkynyl.
[0134] In certain embodiments, R.sup.1 is substituted or
unsubstituted carbocyclyl, e.g., substituted or unsubstituted
C.sub.3-6 cycloalkyl.
[0135] In certain embodiments, R.sup.1 is substituted or
unsubstituted heterocyclyl, e.g., substituted or unsubstituted 3-
to 6-membered heterocyclyl, e.g., substituted or unsubstituted
3-membered heterocyclyl, substituted or unsubstituted 4-membered
heterocyclyl, substituted or unsubstituted 5-membered heterocyclyl,
or substituted or unsubstituted 6-membered heterocyclyl. In certain
embodiments, R.sup.1 is substituted or unsubstituted 5-membered
heterocyclyl, e.g., pyrolidinyl. In certain embodiments, R.sup.1 is
substituted or unsubstituted 6-membered heterocyclyl, e.g.,
substituted or unsubstituted morpholinyl, substituted or
unsubstituted piperidinyl, or substituted or unsubstituted
piperizinyl.
[0136] In certain embodiments, R.sup.1 is substituted or
unsubstituted aryl, e.g., substituted or unsubstituted phenyl or
substituted or unsubstituted naphthyl.
[0137] In certain embodiments, R.sup.1 is substituted or
unsubstituted heteroaryl. In certain embodiments, R.sup.1 is
substituted or unsubstituted 5-membered heteroaryl. In certain
embodiments, R.sup.1 is substituted or unsubstituted 5-membered
heteroaryl, with 1 heteroatom. In certain embodiments, R.sup.1 is
substituted or unsubstituted 5-membered heteroaryl, with 2
heteroatoms. In certain embodiments, R.sup.1 is substituted or
unsubstituted 5-membered heteroaryl, with 3 heteroatoms. In certain
embodiments, R.sup.1 is substituted or unsubstituted 5-membered
heteroaryl, with 4 heteroatoms. In certain embodiments, R.sup.1 is
heteroaryl substituted with one or more substituents selected from
the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkylnyl, hydroxyl, alkoxy, alkoxyalkyl, amino,
acyl, acylamino, oxo, cyano, aryl, heteroaryl, --SO-alkyl,
--SO.sub.2-alkyl, --SO-aryl, --SO.sub.2-aryl, --SO-heteroaryl,
--SO.sub.2-heteroaryl. However, in certain embodiments, R.sup.1 is
an unsubstituted heteroaryl.
[0138] In certain embodiments, R.sup.1 is substituted or
unsubstituted heteroaryl selected from the group consisting of
substituted or unsubstituted imidazolyl, pyrazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl,
tetrazolyl, quinolonyl, isoquinolonyl, dihydroquinolonyl, and
dihydroisoquinolonyl. In certain embodiments, R.sup.1 is
imidazolyl. In certain embodiments, R.sup.1 is pyrazolyl. In
certain embodiments, R.sup.1 is 1,2,3-triazolyl. In certain
embodiments, R.sup.1 is 1,2,4-triazolyl. In certain embodiments,
R.sup.1 is tetrazolyl.
[0139] In certain embodiments, R.sup.1 is imidazolyl, pyrazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, or
tetrazolyl; each unsubstituted or substituted with one or two
substituents selected from the group consisting of --SMe, --SOMe,
--SO.sub.2Me, --CH.sub.3, F, Cl, --CN, --CH.sub.2F, --CHF.sub.2,
and --CF.sub.3. In certain embodiments, R.sup.1 is imidazol-1-yl,
1,2,3-triazol-1-yl, or 1,2,3-triazol-2-yl, each unsubstituted or
substituted with one or two substituents selected from the group
consisting of --SMe, --SOMe, --SO.sub.2Me, --CH.sub.3, F, Cl, --CN,
--CH.sub.2F, --CHF.sub.2, and --CF.sub.3.
[0140] In certain embodiments, R.sup.1 is imidazolyl, pyrazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, or
tetrazolyl; each unsubstituted or substituted with oxo.
[0141] In certain embodiments, R.sup.1 is quinolinyl,
isoquinolinyl, or purinyl; each unsubstituted or substituted with
one or two substituents selected from the group consisting of
--SMe, --SOMe, --SO.sub.2Me, --CH.sub.3, F, Cl, --CN, --CH.sub.2F,
--CHF.sub.2, and --CF.sub.3.
[0142] In certain embodiments, R.sup.1 is quinolonyl, or
isoquinolonyl; each unsubstituted or substituted with one or two
substituents selected from the group consisting of --SMe, --SOMe,
--SO.sub.2Me, --CH.sub.3, F, Cl, --CN, --CH.sub.2F, --CHF.sub.2,
and --CF.sub.3.
[0143] In certain embodiments, R.sup.1 is dihydroquinolonyl or
dihydroisoquinolonyl; each unsubstituted or substituted with one or
two substituents selected from the group consisting of --SMe,
--SOMe, --SO.sub.2Me, --CH.sub.3, F, Cl, --CN, --CH.sub.2F,
--CHF.sub.2, and --CF.sub.3.
[0144] In certain embodiments, R.sup.1 is --OR.sup.A1, e.g.,
R.sup.1 is --OH or --O-(heteroaryl).
[0145] In certain embodiments, R.sup.1 is --SR.sup.A1, e.g.,
R.sup.1 is --SH or --S-(heteroaryl).
[0146] In certain embodiments, R.sup.1 is --OC(.dbd.O)R.sup.A1,
e.g., --O--C(.dbd.O)CH.sub.2--CH.sub.2--CO.sub.2H.
[0147] In certain embodiments, R.sup.1 is
--OC(.dbd.O)OR.sup.A1.
[0148] In certain embodiments, R.sup.1 is
--OC(.dbd.O)SR.sup.A1.
[0149] In certain embodiments, R.sup.1 is
--OC(.dbd.O)N(R.sup.A1).sub.2.
[0150] In certain embodiments, R.sup.1 is --SC(.dbd.O)R.sup.A2.
[0151] In certain embodiments, R.sup.1 is
--SC(.dbd.O)OR.sup.A1.
[0152] In certain embodiments, R.sup.1 is
--SC(.dbd.O)SR.sup.A1.
[0153] In certain embodiments, R.sup.1 is
--SC(.dbd.O)N(R.sup.A1).sub.2.
[0154] In certain embodiments, R.sup.1 is
--OS(.dbd.O).sub.2R.sup.A2.
[0155] In certain embodiments, R.sup.1 is
--OS(.dbd.O).sub.2OR.sup.A1, e.g., --O--SO.sub.3H.
[0156] In certain embodiments, R.sup.1 is
--S--S(.dbd.O).sub.2R.sup.A2.
[0157] In certain embodiments, R.sup.1 is
--S--S(.dbd.O).sub.2OR.sup.A1, e.g., --S--SO.sub.3H.
[0158] In certain embodiments, R.sup.1 is --S(.dbd.O)R.sup.A2.
[0159] In certain embodiments, R.sup.1 is --SO.sub.2R.sup.A2.
[0160] In certain embodiments, R.sup.1 is
--S(.dbd.O).sub.2OR.sup.A1, e.g., --SO.sub.3H.
[0161] In certain embodiments, R.sup.1 is --N(R.sup.A1).sub.2,
--NHC(.dbd.O)R.sup.A1, --NHC(.dbd.O)OR.sup.A1,
--NHC(.dbd.O)SR.sup.A1, --NHC(.dbd.O)N(R.sup.A1).sub.2. In certain
embodiments, R.sup.1 is --N(R.sup.A1).sub.2. In certain
embodiments, R is --NHC(.dbd.O)R.sup.A. In certain embodiments,
R.sup.1 is --NHC(.dbd.O)OR.sup.A. In certain embodiments, R.sup.1
is --NHC(.dbd.O)SRA. In certain embodiments, R.sup.1 is
--NHC(.dbd.O)N(R.sup.A1).sub.2.
[0162] In certain embodiments, R.sup.1 is selected from --OH,
--O--CO--CH.sub.2--CH.sub.2--CO.sub.2H, --O--SO.sub.3H, --SH,
--S--SO.sub.3H, heteroaryl, --O-(heteroaryl), and --S-(heteroaryl),
wherein heteroaryl is imidazolyl, pyrazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, quinolinyl,
isoquinolinyl or purinyl; and each heteroaryl is unsubstituted or
substituted with one or two substituents selected from the group
consisting of oxo, --CH.sub.3, F, Cl, --CN, --SMe, --SOMe,
--SO.sub.2Me, and --CF.sub.3. In certain embodiments, R.sup.1 is
--O-quinolinyl, --O-isoquinolinyl, --O-purinyl, --S-quinolinyl,
--S-isoquinolinyl, or --S-purinyl; each unsubstituted or
substituted with one or two substituents selected from the group
consisting of --CH.sub.3, F, Cl, --CN, --SMe, --SOMe, --SO.sub.2Me,
--CH.sub.2F, --CHF.sub.2, and --CF.sub.3.
[0163] In certain embodiments, R.sup.1 is --OH,
--O--CH.sub.2--CH.sub.2--CO.sub.2H, --SO.sub.3H, --OSO.sub.3H,
--SSO.sub.3H, pyrazol-1-yl, imidazol-1-yl, 1,2,4-triazol-1-yl, or
1,2,3-triazol-1-yl. In certain embodiments, R.sup.1 is --OH. In
certain embodiments, R.sup.1 is --O--CH.sub.2--CH.sub.2--CO.sub.2H.
In certain embodiments, R.sup.1 is --SO.sub.3H. In certain
embodiments, R.sup.1 is --OSO.sub.3H. In certain embodiments,
R.sup.1 is --SSO.sub.3H. In certain embodiments, R.sup.1 is
pyrazol-1-yl. In certain embodiments, R.sup.1 is imidazol-1-yl. In
certain embodiments, R.sup.1 is 1,2,4-triazol-1-yl. In certain
embodiments, R.sup.1 is 1,2,3-triazol-1-yl.
[0164] In certain embodiments, R.sup.1 is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
alkoxy, substituted or unsubstituted heterocyclyl, substituted or
unsubstituted thioalkoxy (--S-- alkyl), --OH,
--O--CO--(CH.sub.2).sub.t--CO.sub.2H, --SO.sub.3H, --O--SO.sub.3H,
--SH, --S--SO.sub.3H, or substituted or unsubstituted
--Y-(heteroaryl); wherein Y is a bond, --O--, --S--,
C.sub.1-C.sub.4 alkylene, C.sub.2-C.sub.4 alkenylene, or
C.sub.2-C.sub.4 alkynylene; and the subscript t is an integer
between 2 and 5, inclusive.
[0165] In certain embodiments, R.sup.1 is Br, --OH, --OMe,
substituted or unsubstituted heterocyclyl,
--O--CO--CH.sub.2--CH.sub.2--CO.sub.2H, --SO.sub.3H,
--O--SO.sub.3H, --S--SO.sub.3H, O--P(.dbd.O)(OH).sub.2, pyrazolyl,
imidazolyl, or triazolyl; each R.sup.2, R.sup.3', R.sup.4,
R.sup.11a, and R.sup.11b is H; and each of the dotted bonds is a
single bond; then R.sup.3 is not Et, --CF.sub.3, ethynyl,
4-hydroxypropynyl, or (4-acyl)-phenylethynyl.
[0166] In any of the above embodiments, at least one R.sup.A1 is
heteroaryl unsubstituted or substituted with one or more
substituents selected from the group consisting of halogen, --CN,
--NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H, --OH, --OR.sup.aa,
--ON(R.sup.bb).sub.2, --N(R.sup.bb).sub.2,
--N(R.sup.bb).sub.3.sup.+X.sup.-, --N(OR.sup.cc)R.sup.bb, --SH,
--SR.sup.aa, --SSR.sup.cc, --C(.dbd.O)R.sup.aa, --CO.sub.2H, --CHO,
--C(OR.sup.cc).sub.2, --CO.sub.2R.sup.aa, --OC(.dbd.O)R.sup.aa,
--OCO.sub.2R.sup.aa, --C(.dbd.O)N(R.sup.bb).sub.2,
--OC(.dbd.O)N(R.sup.bb).sub.2, --NR.sup.bbC(.dbd.O)R.sup.aa,
--NR.sup.bbCO.sub.2R.sup.aa, --NR.sup.bbC(.dbd.O)N(R.sup.bb).sub.2,
--C(.dbd.NR.sup.bb)R.sup.aa, --C(.dbd.NR.sup.bb)OR.sup.aa,
--OC(.dbd.NR.sup.bb)R.sup.aa, --OC(.dbd.NR.sup.bb)OR.sup.aa,
--C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--OC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa, --NR.sup.bbSO.sub.2R.sup.aa,
--SO.sub.2N(R.sup.bb).sub.2, --S.sub.2R.sup.aa,
--SO.sub.2OR.sup.aa, OSO.sub.2R.sup.aa, --S(.dbd.O)R.sup.aa,
--OS(.dbd.O)R.sup.aa, --Si(R.sup.aa).sub.3,
--OSi(R.sup.aa).sub.3--C(.dbd.S)N(R.sup.bb).sub.2,
--C(.dbd.O)SR.sup.aa, --C(.dbd.S)SR.sup.aa, --SC(.dbd.S)SR.sup.aa,
--SC(.dbd.O)SR.sup.aa, --OC(.dbd.O)SR.sup.aa,
--SC(.dbd.O)OR.sup.aa, --SC(.dbd.O)R.sup.aa,
--P(.dbd.O).sub.2R.sup.aa, --OP(.dbd.O).sub.2R.sup.aa,
--P(.dbd.O)(R.sup.aa).sub.2, OP(.dbd.O)(R.sup.aa).sub.2,
--OP(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2,
--OP(.dbd.O).sub.2N(R.sup.bb).sub.2, --P(.dbd.O)(NR.sup.bb).sub.2,
--OP(.dbd.O)(NR.sup.bb).sub.2,
--NR.sup.bbP(.dbd.O)(OR.sup.cc).sub.2,
--NR.sup.bbP(.dbd.O)(NR.sup.bb).sub.2, --P(R.sup.cc).sub.2,
--P(R.sup.cc).sub.3, --OP(R.sup.cc).sub.2, --OP(R.sup.cc).sub.3,
--B(R.sup.aa).sub.2, --B(OR.sup.cc).sub.2, --BR.sup.aa(OR.sup.cc),
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, and heteroaryl is independently substituted with 0, 1, 2, 3,
4, or 5 R.sup.dd groups; or two geminal hydrogens on a carbon atom
are replaced with the group .dbd.O, .dbd.S,
.dbd.NN(R.sup.bb).sub.2, .dbd.NNR.sup.bbC(.dbd.O)R.sup.aa,
.dbd.NNR.sup.bbC(.dbd.O)OR.sup.aa,
.dbd.NNR.sup.bbS(.dbd.O).sub.2R.sup.aa, .dbd.NR.sup.bb, or
.dbd.NOR.sup.cc; and R.sup.aa, R.sup.bb, R.sup.cc, Rad, R.sup.ee,
and R.sup.ff, are as described herein.
[0167] In any of the above embodiments, at least one R.sup.A1 is
heteroaryl unsubstituted or substituted with one or more
substituents selected from the group consisting of alkyl, alkenyl,
alkynyl, halo, haloalkyl, haloalkenyl, haloalkylnyl, hydroxyl,
alkoxy, alkoxyalkyl, amino, acyl, acylamino, oxo, cyano, aryl,
heteroaryl, --SO-alkyl, --SO.sub.2-alkyl, --SO-aryl,
--SO.sub.2-aryl, --SO-heteroaryl, and --SO.sub.2-heteroaryl.
[0168] In any of the above embodiments, at least one R.sup.A1 is
heteroaryl selected from the group consisting of unsubstituted
pyrrolyl, imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl,
1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl,
tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl,
isoquinolinyl, quinazolinyl, quinoxilinyl, naphthyridinyl, indolyl,
indazolyl, benzimidazloyl, pyrrolopyridinyl, pyrrolopyrimidinyl,
pyridopyrimidinyl, and purinyl.
[0169] In any of the above embodiments, at least one R.sup.A1 is
heteroaryl is selected from the group consisting of pyrrolyl,
imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl,
1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl,
tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl,
isoquinolinyl, quinazolinyl, quinoxilinyl, naphthyridinyl, indolyl,
indazolyl, benzimidazloyl, pyrrolopyridinyl, pyrrolopyrimidinyl,
pyridopyrimidinyl, and purinyl, each substituted with one or more
substituents selected from the group consisting of alkyl,
haloalkyl, alkenyl, alkynyl, oxo, hydroxy, halo, alkoxy, --S-alkyl,
aryl, heteroaryl, --SO-- alkyl, --SO.sub.2-alkyl, --SO-aryl,
--SO.sub.2-aryl, --SO-heteroaryl, --SO.sub.2-heteroaryl, amino,
cyano, and acyl.
Group R.sup.2
[0170] As generally defined above, R.sup.2 is hydrogen, halo,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OH, --OR.sup.B1, --OC(.dbd.O)R.sup.B1,
--NH.sub.2, --N(R.sup.B1).sub.2, or --NR.sup.B1C(.dbd.O)R.sup.B1,
wherein each instance of R.sup.B1 is independently hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl, an oxygen protecting group when attached
to an oxygen atom, a nitrogen protecting group when attached to a
nitrogen atom, or two R.sup.B1 groups are joined to form an
substituted or unsubstituted heterocyclic ring.
[0171] In certain embodiments, R.sup.2 is hydrogen.
[0172] In certain embodiments, R.sup.2 is halo, e.g., --F, --Br,
--I, or --Cl. In certain embodiments, R.sup.2 is --F. In certain
embodiments, R.sup.2 is --Cl. In certain embodiments, R.sup.2 is
--Br.
[0173] In certain embodiments, R.sup.2 is substituted or
unsubstituted alkyl, e.g., substituted or unsubstituted
C.sub.1-6alkyl, substituted or unsubstituted C.sub.1-2alkyl,
substituted or unsubstituted C.sub.2-3alkyl, substituted or
unsubstituted C.sub.3-4alkyl, substituted or unsubstituted
C.sub.4-5alkyl, or substituted or unsubstituted C.sub.5-6alkyl.
Exemplary R.sup.2 C.sub.1-6alkyl groups include, but are not
limited to, substituted or unsubstituted methyl (C.sub.1),
substituted or unsubstituted ethyl (C.sub.2), substituted or
unsubstituted n-propyl (C.sub.3), substituted or unsubstituted
isopropyl (C.sub.3), substituted or unsubstituted n-butyl
(C.sub.4), substituted or unsubstituted tert-butyl (C.sub.4),
substituted or unsubstituted sec-butyl (C.sub.4), substituted or
unsubstituted iso-butyl (C.sub.4), substituted or unsubstituted
n-pentyl (C.sub.5), substituted or unsubstituted 3-pentanyl
(C.sub.5), substituted or unsubstituted amyl (C.sub.5), substituted
or unsubstituted neopentyl (C.sub.5), substituted or unsubstituted
3-methyl-2-butanyl (C.sub.5), substituted or unsubstituted tertiary
amyl (C.sub.5), or substituted or unsubstituted n-hexyl (C.sub.6).
Exemplary substituted alkyl groups include, but are not limited to,
alkyl substituted with halogen groups ("haloalkyl") and alkyl
substituted with alkoxy groups ("alkoxyalkyl"). Exemplary haloalkyl
groups include, but are not limited to, --CF.sub.3, --CH.sub.2F,
--CHF.sub.2, difluoroethyl, 2,2,2-trifluoro-1,1-dimethyl-ethyl,
--CH.sub.2Cl, and --CHCl.sub.2. Exemplary alkoxyalkyl groups
include, but are not limited to, --CH.sub.2OCH.sub.3 and
--CH.sub.2OCH.sub.2CH.sub.3.
[0174] In certain embodiments, R.sup.2 is substituted or
unsubstituted alkenyl, e.g., substituted or unsubstituted
C.sub.2-6alkenyl, substituted or unsubstituted C.sub.2-3alkenyl,
substituted or unsubstituted C.sub.3-4alkenyl, substituted or
unsubstituted C.sub.4-5alkenyl, or substituted or unsubstituted
C.sub.5-6alkenyl. Exemplary substituted alkenyl groups include, but
are not limited to, alkenyl substituted with halogen groups
("haloalkenyl") and alkenyl substituted with alkoxy groups
("alkoxyalkenyl").
[0175] In certain embodiments, R.sup.2 is substituted or
unsubstituted alkynyl, e.g., substituted or unsubstituted
C.sub.2-6alkynyl, substituted or unsubstituted C.sub.2-3alkynyl,
substituted or unsubstituted C.sub.3-4alkynyl, substituted or
unsubstituted C.sub.4-5alkynyl, or substituted or unsubstituted
C.sub.5-6alkynyl. Exemplary substituted alkynyl groups include, but
are not limited to, alkynyl substituted with halogen groups
("haloalkynyl") and alkynyl substituted with alkoxy groups
("alkoxyalkynyl").
[0176] In certain embodiments, R.sup.2 is substituted or
unsubstituted carbocyclyl, e.g., substituted or unsubstituted
C.sub.3-6carbocyclyl, substituted or unsubstituted
C.sub.3-4carbocyclyl, substituted or unsubstituted C.sub.4-5
carbocyclyl, or substituted or unsubstituted C.sub.5-6
carbocyclyl.
[0177] In certain embodiments, R.sup.2 is substituted or
unsubstituted heterocyclyl, e.g., substituted or unsubstituted
C.sub.3-6 heterocyclyl, substituted or unsubstituted C.sub.3-4
heterocyclyl, substituted or unsubstituted C.sub.4-5 heterocyclyl,
or substituted or unsubstituted C.sub.5-6 heterocyclyl. For
example, in certain embodiments, R.sup.2 is a substituted or
unsubstituted piperidinyl, substituted or unsubstituted
piperazinyl, or substituted or unsubstituted morpholinyl ring. In
certain embodiments, R.sup.2 is a substituted or unsubstituted
morpholinyl ring.
[0178] In certain embodiments, R.sup.2 is substituted or
unsubstituted aryl, e.g., substituted or unsubstituted phenyl.
[0179] In certain embodiments, R.sup.2 is substituted or
unsubstituted heteroaryl, e.g., optionally substituted 5- to
6-membered heteroaryl.
[0180] In certain embodiments, R.sup.2 is --OH, --ORB, or
--OC(.dbd.O)R.sup.B1. In certain embodiments, R.sup.B1 is
substituted or unsubstituted alkyl, e.g., substituted or
unsubstituted C.sub.1-6alkyl, substituted or unsubstituted
C.sub.1-2alkyl, substituted or unsubstituted C.sub.2-3alkyl,
substituted or unsubstituted C.sub.3-4alkyl, substituted or
unsubstituted C.sub.4-5alkyl, or substituted or unsubstituted
C.sub.5-6alkyl. Exemplary R.sup.B1 C.sub.1-6alkyl groups include,
but are not limited to, substituted or unsubstituted methyl
(C.sub.1), substituted or unsubstituted ethyl (C.sub.2),
substituted or unsubstituted n-propyl (C.sub.3), substituted or
unsubstituted isopropyl (C.sub.3), substituted or unsubstituted
n-butyl (C.sub.4), substituted or unsubstituted tert-butyl
(C.sub.4), substituted or unsubstituted sec-butyl (C.sub.4),
substituted or unsubstituted iso-butyl (C.sub.4), substituted or
unsubstituted n-pentyl (C.sub.5), substituted or unsubstituted
3-pentanyl (C.sub.5), substituted or unsubstituted amyl (C.sub.5),
substituted or unsubstituted neopentyl (C.sub.5), substituted or
unsubstituted 3-methyl-2-butanyl (C.sub.5), substituted or
unsubstituted tertiary amyl (C.sub.5), or substituted or
unsubstituted n-hexyl (C.sub.6).
[0181] In certain embodiments, R.sup.2 is --NH.sub.2,
--N(R.sup.B1).sub.2, or --NR.sup.BC(.dbd.O)R.sup.B1. In certain
embodiments, R.sup.B1 is hydrogen or substituted or unsubstituted
alkyl, e.g., substituted or unsubstituted C.sub.1-6alkyl,
substituted or unsubstituted C.sub.1-2alkyl, substituted or
unsubstituted C.sub.2-3alkyl, substituted or unsubstituted
C.sub.3-4alkyl, substituted or unsubstituted C.sub.4-5alkyl, or
substituted or unsubstituted C.sub.5-6alkyl. Exemplary R.sup.B1
C.sub.1-6alkyl groups include, but are not limited to, substituted
or unsubstituted methyl (C.sub.1), ethyl (C.sub.2), n-propyl
(C.sub.3), isopropyl (C.sub.3), n-butyl (C.sub.4), tert-butyl
(C.sub.4), sec-butyl (C.sub.4), iso-butyl (C.sub.4), n-pentyl
(C.sub.5), 3-pentanyl (C.sub.5), amyl (C.sub.5), neopentyl
(C.sub.5), 3-methyl-2-butanyl (C.sub.5), tertiary amyl (C.sub.5),
or n-hexyl (C.sub.6).
[0182] In certain embodiments, R.sup.2 is halo, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, --OR.sup.B1, or
--OC(.dbd.O)R.sup.B1. In certain embodiments, R.sup.2 is hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,
alkoxyalkyl, --OH, --OR.sup.B1, --OC(.dbd.O)R.sup.B1, --NH.sub.2,
--N(R.sup.B1).sub.2, or --NR.sup.B1C(.dbd.O)R.sup.B1.
[0183] In certain embodiments, R.sup.2 is substituted alkyl (e.g.,
haloalkyl, alkoxyalkyl).
[0184] In certain embodiments, R.sup.2 is --F, --Cl, methyl, ethyl,
n-propyl, methoxy, ethoxy, propoxy, butoxy, ethynyl,
hydroxybutynyl, methoxypropynyl, chloroethynyl, or
cyclopropynyl.
[0185] In certain embodiments, R.sup.2 is a non-hydrogen group in
the alpha position. In certain embodiments, R.sup.2 is a
non-hydrogen group in the beta position.
Group R.sup.3
[0186] As generally defined above, R.sup.3 is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted
heteroaryl.
[0187] In certain embodiments, R.sup.3 is substituted or
unsubstituted alkyl, e.g., substituted or unsubstituted
C.sub.1-6alkyl, substituted or unsubstituted C.sub.1-2alkyl,
substituted or unsubstituted C.sub.2-3alkyl, substituted or
unsubstituted C.sub.3-4alkyl, substituted or unsubstituted
C.sub.4-5alkyl, or substituted or unsubstituted C.sub.5-6alkyl.
Exemplary R.sup.3 C.sub.1-6alkyl groups include, but are not
limited to, substituted or unsubstituted methyl (C.sub.1), ethyl
(C.sub.2), n-propyl (C.sub.3), isopropyl (C.sub.3), n-butyl
(C.sub.4), tert-butyl (C.sub.4), sec-butyl (C.sub.4), iso-butyl
(C.sub.4), n-pentyl (C.sub.5), 3-pentanyl (C.sub.5), amyl
(C.sub.5), neopentyl (C.sub.5), 3-methyl-2-butanyl (C.sub.5),
tertiary amyl (C.sub.5), n-hexyl (C.sub.6), C.sub.1-6 alkyl
substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluoro
groups (e.g., --CF.sub.3, --CH.sub.2F, --CHF.sub.2, difluoroethyl,
and 2,2,2-trifluoro-1,1-dimethyl-ethyl), C.sub.1-6 alkyl
substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more chloro
groups (e.g., --CH.sub.2Cl, --CHCl.sub.2), and C.sub.1-6 alkyl
substituted with alkoxy groups (e.g., --CH.sub.2OCH.sub.3 and
--CH.sub.2OCH.sub.2CH.sub.3). In certain embodiments, R.sup.3 is
substituted alkyl, e.g., R.sup.3 is haloalkyl, alkoxyalkyl, or
aminoalkyl. In certain embodiments, R.sup.3 is Me, Et, n-Pr, n-Bu,
i-Bu, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl,
trifluoroethyl, difluoroethyl, 2,2,2-trifluoro-1,1-dimethyl-ethyl,
methoxymethyl, methoxyethyl, or ethoxymethyl. In certain
embodiments, R.sup.3a is Me, Et, n-Pr, n-Bu, or i-Bu. In certain
embodiments, R.sup.3 is methoxymethyl, ethoxymethyl, propoxymethyl,
methoxyethyl, or ethoxyethyl. In certain embodiments, R.sup.3 is
trifluoromethoxymethyl. In certain embodiments, R.sup.3 is
fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl,
difluoroethyl, trifluoroethyl, or
2,2,2-trifluoro-1,1-dimethyl-ethyl. In certain embodiments, R.sup.3
is trifluoromethyl.
[0188] In certain embodiments, R.sup.3 is substituted or
unsubstituted alkenyl, e.g., substituted or unsubstituted
C.sub.2-6alkenyl, substituted or unsubstituted C.sub.2-3alkenyl,
substituted or unsubstituted C.sub.3-4alkenyl, substituted or
unsubstituted C.sub.4-5alkenyl, or substituted or unsubstituted
C.sub.5-6alkenyl. In certain embodiments, R.sup.3 is ethenyl
(C.sub.2), propenyl (C.sub.3), or butenyl (C.sub.4), unsubstituted
or substituted with one or more substituents selected from the
group consisting of alkyl, halo, haloalkyl, alkoxyalkyl, or
hydroxyl. In certain embodiments, R.sup.3 is ethenyl, propenyl, or
butenyl, unsubstituted or substituted with alkyl, halo, haloalkyl,
alkoxyalkyl, or hydroxy. In certain embodiments, R.sup.3 is
ethenyl.
[0189] In certain embodiments, R.sup.3 is substituted or
unsubstituted alkynyl, e.g., substituted or unsubstituted
C.sub.2-6alkynyl, substituted or unsubstituted C.sub.2-3alkynyl,
substituted or unsubstituted C.sub.3-4alkynyl, substituted or
unsubstituted C.sub.4-5alkynyl, or substituted or unsubstituted
C.sub.5-6alkynyl. Exemplary substituted or unsubstituted R.sup.3
alkynyl groups include, but are not limited to, ethynyl, propynyl,
or butynyl, unsubstituted or substituted with alkyl, halo,
haloalkyl (e.g., CF.sub.3), alkoxyalkyl, cycloalkyl (e.g.,
cyclopropyl or cyclobutyl), or hydroxyl. In certain embodiments,
R.sup.3 is selected from the group consisting of trifluoroethynyl,
cyclopropylethynyl, cyclobutylethynyl, and propynyl,
fluoropropynyl, and chloroethynyl. In certain embodiments, R.sup.3
is ethynyl (C.sub.2), propynyl (C.sub.3), or butynyl (C.sub.4),
unsubstituted or substituted with one or more substituents selected
from the group consisting of substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted carbocyclyl, and substituted or unsubstituted
heterocyclyl. In certain embodiments, R.sup.3 is ethynyl (C.sub.2),
propynyl (C.sub.3), or butynyl (C.sub.4) substituted with
substituted phenyl. In certain embodiment, the phenyl substitutent
is further substituted with one or more substituents selected from
the group consisting of halo, alkyl, trifluoroalkyl, alkoxy, acyl,
amino or amido. In certain embodiments, R.sup.3 is ethynyl
(C.sub.2), propynyl (C.sub.3), or butynyl (C.sub.4) substituted
with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl,
oxazoyl, thiazolyl, isoxazoyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
oxadiazolyl, thiadiazolyl, or tetrazolyl.
[0190] In certain embodiments, R.sup.3 is ethynyl, propynyl, or
butynyl, unsubstituted or substituted with alkyl, halo, haloalkyl,
alkoxyalkyl, or hydroxyl. In certain embodiments, R.sup.3a is
ethynyl or propynyl, substituted with substituted or unsubstituted
aryl. In certain embodiments, R.sup.3 is ethynyl or propynyl,
substituted with phenyl unsubstituted or substituted with halo,
alkyl, alkoxy, haloalkyl, trihaloalkyl, or acyl. In certain
embodiments, R.sup.3 is ethynyl or propynyl, substituted with
substituted or unsubstituted carbocyclyl. In certain embodiments,
R.sup.3 is ethynyl or propynyl, substituted with substituted or
unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
In certain embodiments, R.sup.3 is ethynyl or propynyl, substituted
with substituted or unsubstituted heteroaryl. In certain
embodiments, R.sup.3 is ethynyl or propynyl, substituted with
substituted or unsubstituted pyridinyl, or pyrimidinyl. In certain
embodiments, R.sup.3 is ethynyl or propynyl, substituted with
substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl,
oxazoyl, thiazolyl, isoxazoyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
oxadiazolyl, thiadiazolyl, tetrazolyl. In certain embodiments,
R.sup.3 is ethynyl or propynyl, substituted with substituted or
unsubstituted heterocyclyl. In certain embodiments, R.sup.3a is
ethynyl or propynyl, substituted with substituted or unsubstituted
pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. In certain
embodiments, R.sup.3 is propynyl or butynyl, substituted with
hydroxyl or alkoxy. In certain embodiments, R.sup.3 is propynyl or
butynyl, substituted with methoxy or ethoxy. In certain
embodiments, R.sup.3 is ethynyl or propynyl, substituted with Cl.
In certain embodiments, R.sup.3 is ethynyl or propynyl, substituted
with trifluoromethyl.
[0191] In certain embodiments, R.sup.3 is substituted or
unsubstituted carbocyclyl, e.g., substituted or unsubstituted
C.sub.3-6carbocyclyl, substituted or unsubstituted
C.sub.3-4carbocyclyl, substituted or unsubstituted C.sub.4-5
carbocyclyl, or substituted or unsubstituted C.sub.5-6
carbocyclyl.
[0192] In certain embodiments, R.sup.3 is substituted or
unsubstituted heterocyclyl, e.g., substituted or unsubstituted 3-6
membered heterocyclyl, substituted or unsubstituted 3-4 membered
heterocyclyl, substituted or unsubstituted 4-5 membered
heterocyclyl, or substituted or unsubstituted 5-6 membered
heterocyclyl.
[0193] In certain embodiments, R.sup.3 is substituted or
unsubstituted aryl. In certain embodiments, R.sup.3 is substituted
or unsubstituted phenyl.
[0194] In certain embodiments, R.sup.3 is substituted or
unsubstituted heteroaryl, e.g., optionally substituted 5- to
6-membered heteroaryl.
[0195] Further embodiments of R.sup.3, as a substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, and
substituted or unsubstituted alkynyl groups, are depicted
below:
##STR00012##
wherein each instance of R.sup.3a is hydrogen, halo, or
--OR.sup.F1, wherein R.sup.F1 is substituted or unsubstituted
alkyl; and each instance of R.sup.3b and R.sup.3c is independently
hydrogen, halo, or substituted or unsubstituted alkyl, substituted
or unsubstituted carbocyclyl, or substituted or unsubstituted
heterocyclyl.
[0196] In certain embodiments, at least one R.sup.3a is hydrogen.
In certain embodiments, at least two R.sup.3c is hydrogen. In
certain embodiments, each R.sup.3a is hydrogen. In certain
embodiments, at least one R.sup.3a is halogen (e.g., fluoro,
chloro, bromo, iodo). In certain embodiments, at least two R.sup.3a
are halogen (e.g., fluoro, chloro, bromo, iodo). In certain
embodiments, each R.sup.3a is halogen (e.g., fluoro, to provide the
group --CF.sub.3). In certain embodiments, at least one R.sup.3a is
--OR.sup.F1 (e.g., OMe or OEt). In certain embodiments, at least
two R.sup.3a is --OR.sup.F1 (e.g., OMe or OEt). In certain
embodiments, at least one R.sup.3a is hydrogen, F, --OMe, or --OEt.
In certain embodiments, one of R.sup.3a is a non-hydrogen group
(e.g., --F, --OMe, or OEt); and the rest are H, such as provided in
the below formula:
##STR00013##
[0197] In certain embodiments, R.sup.3b is hydrogen. In certain
embodiments, R.sup.3b is halogen (e.g., fluoro, chloro, bromo,
iodo). In certain embodiments, R.sup.3b is alkyl, e.g., --CH.sub.3,
--CF.sub.3, --CH.sub.2CH.sub.2Cl. In certain embodiments, R.sup.3b
is substituted or unsubstituted carbocyclyl, e.g., cyclopropyl or
cyclobutyl. In certain embodiments, R.sup.3b is hydrogen, --F,
--Br, --Cl, --I, --CH.sub.3, --CF.sub.3, cyclopropyl, or
cyclobutyl. In certain embodiments, R.sup.3b is substituted or
unsubstituted cyclopropyl. In certain embodiments, R.sup.3b is
hydrogen, --F, --Br, --Cl, --I, --CH.sub.3, --CF.sub.3,
--CH.sub.2CH.sub.2Cl, cyclopropyl, or cyclobutyl. In certain
embodiments, R.sup.3b is Me or Cl. In certain embodiments, R.sup.3b
is substituted or unsubstituted heterocyclyl.
[0198] In certain embodiments, at least one R.sup.3c is hydrogen.
In certain embodiments, each R.sup.3c is hydrogen. In certain
embodiments, at least one R.sup.3c is halogen (e.g., fluoro,
chloro, bromo, iodo). In certain embodiments, each R.sup.3c is
halogen (e.g., fluoro, chloro, bromo, iodo). In certain
embodiments, each of R.sup.3c is alkyl, e.g., each of R.sup.2c is
Me. In certain embodiments, one of R.sup.3 is alkyl; and the other
is hydrogen, e.g., one of R.sup.3c is Me; and the other is
hydrogen. In certain embodiments, one of R.sup.3c is substituted or
unsubstituted carbocyclyl, e.g., cyclopropyl or cyclobutyl, and the
other is hydrogen. In certain embodiments, at least one R.sup.3 is
hydrogen, --F, --Br, --Cl, --I, --CH.sub.3, --CF.sub.3,
cyclopropyl, or cyclobutyl. In certain embodiments, each instance
of R.sup.3c is H. In certain embodiments, each instance of R.sup.3c
is halogen (e.g., fluoro, chloro, bromo, iodo). In certain
embodiments, each instance of R.sup.3c is alkyl, e.g., --CH.sub.3,
--CF.sub.3, --CH.sub.2CH.sub.2Cl. In certain embodiments, each
instance of R.sup.3c is substituted or unsubstituted carbocyclyl,
e.g., cyclopropyl or cyclobutyl. In certain embodiments, R.sup.3c
is substituted or unsubstituted cyclopropyl. In certain
embodiments, each instance of R.sup.3 is hydrogen, --F, --Br, --Cl,
--I, --CH.sub.3, --CF.sub.3, --CH.sub.2CH.sub.2Cl, cyclopropyl, or
cyclobutyl. In certain embodiments, R.sup.3c is Me or Cl. In
certain embodiments, R.sup.3c is substituted or unsubstituted
heterocyclyl.
Group R.sup.3'
[0199] As generally defined above, R.sup.3' is H,
--C(.dbd.O)R.sup.C1, --C(.dbd.O)OR.sup.C1, --C(.dbd.O)SR.sup.C1,
--C(.dbd.O)N(R.sup.C1).sub.2, --S(.dbd.O).sub.2R.sup.C2,
--S(.dbd.O).sub.2OR.sup.C1, --P(.dbd.O).sub.2R.sup.C2,
P(.dbd.O).sub.2OR.sup.C1, --P(.dbd.O)(OR.sup.C1),
--P(.dbd.O)(R.sup.C2).sub.2, or --P(.dbd.O)(R.sup.C2)(OR.sup.C1),
wherein R.sup.C1 is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, an oxygen protecting group
when attached to an oxygen atom, a sulfur protecting group when
attached to a sulfur atom, a nitrogen protecting group when
attached to a nitrogen atom, or two R.sup.C1 groups are joined to
form an substituted or unsubstituted heterocyclic ring; and
R.sup.C2 is substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl.
[0200] In certain embodiments, R.sup.3' is H (hydrogen).
[0201] In certain embodiments, R.sup.3' is --C(.dbd.O)R.sup.C1,
--C(.dbd.O)OR.sup.C1, --C(.dbd.O)SR.sup.C1,
--C(.dbd.O)N(R.sup.C1).sub.2, S(.dbd.O).sub.2R.sup.C1,
--S(.dbd.O).sub.2OR.sup.C1, --P(.dbd.O).sub.2R.sup.C1,
--P(.dbd.O).sub.2OR.sup.C1, --P(.dbd.O)(OR.sup.C1).sub.2,
--P(.dbd.O)(R.sup.C1).sub.2, or
--P(.dbd.O)(R.sup.C1)(OR.sup.C1).
[0202] In certain embodiments, at least one instance of R.sup.C1 is
hydrogen or a protecting group, i.e., an oxygen protecting group
when attached to an oxygen atom, sulfur protecting group when
attached to an sulfur atom, or a nitrogen protecting group when
attached to a nitrogen atom. In certain embodiments, at least one
instance of R.sup.C1 is hydrogen.
[0203] In certain embodiments, at least one instance of R.sup.C1 is
substituted or unsubstituted alkyl, e.g., substituted or
unsubstituted C.sub.1-6alkyl, substituted or unsubstituted
C.sub.1-2alkyl, substituted or unsubstituted C.sub.2-3alkyl,
substituted or unsubstituted C.sub.3-4alkyl, substituted or
unsubstituted C.sub.4-5alkyl, or substituted or unsubstituted
C.sub.5-6alkyl. Exemplary R.sup.C1 C.sub.1-alkyl groups include,
but are not limited to, substituted or unsubstituted methyl
(C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), isopropyl
(C.sub.3), n-butyl (C.sub.4), tert-butyl (C.sub.4), sec-butyl
(C.sub.4), iso-butyl (C.sub.4), n-pentyl (C.sub.5), 3-pentanyl
(C.sub.5), amyl (C.sub.5), neopentyl (C.sub.5), 3-methyl-2-butanyl
(C.sub.5), tertiary amyl (C.sub.5), n-hexyl (C.sub.6), C.sub.1-6
alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more
fluoro groups (e.g., --CF.sub.3, --CH.sub.2F, --CHF.sub.2,
difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl), C.sub.1-6
alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more
chloro groups (e.g., --CH.sub.2Cl, --CHCl.sub.2), and C.sub.1-6
alkyl substituted with alkoxy groups (e.g., --CH.sub.2OCH.sub.3 and
--CH.sub.2OCH.sub.2CH.sub.3).
[0204] In certain embodiments, at least one instance of R.sup.C1 is
substituted or unsubstituted alkenyl, e.g., substituted or
unsubstituted C.sub.2-6alkenyl, substituted or unsubstituted
C.sub.2-3alkenyl, substituted or unsubstituted C.sub.3-4alkenyl,
substituted or unsubstituted C.sub.4-5alkenyl, or substituted or
unsubstituted C.sub.5-6alkenyl.
[0205] In certain embodiments, at least one instance of R.sup.C1 is
substituted or unsubstituted alkynyl, e.g., substituted or
unsubstituted C.sub.2-6alkynyl, substituted or unsubstituted
C.sub.2-3alkynyl, substituted or unsubstituted C.sub.3-4alkynyl,
substituted or unsubstituted C.sub.4-5alkynyl, or substituted or
unsubstituted C.sub.5-6alkynyl.
[0206] In certain embodiments, at least one instance of R.sup.C1 is
substituted or unsubstituted carbocyclyl, e.g., substituted or
unsubstituted C.sub.3-6carbocyclyl, substituted or unsubstituted
C.sub.3-4carbocyclyl, substituted or unsubstituted C.sub.4-5
carbocyclyl, or substituted or unsubstituted C.sub.5-6
carbocyclyl.
[0207] In certain embodiments, at least one instance of R.sup.C1 is
substituted or unsubstituted heterocyclyl, e.g., substituted or
unsubstituted 3-6 membered heterocyclyl, substituted or
unsubstituted 3-4 membered heterocyclyl, substituted or
unsubstituted 4-5 membered heterocyclyl, or substituted or
unsubstituted 5-6 membered heterocyclyl.
[0208] In certain embodiments, at least one instance of R.sup.C1 is
substituted or unsubstituted aryl, e.g., substituted or
unsubstituted phenyl.
[0209] In certain embodiments, at least one instance of R.sup.C1 is
substituted or unsubstituted heteroaryl, e.g., optionally
substituted 5- to 6-membered heteroaryl.
[0210] In certain embodiments, two R.sup.C1 groups are joined to
form a substituted or unsubstituted heterocyclic ring, e.g., a
substituted or unsubstituted piperidinyl, substituted or
unsubstituted piperazinyl, or substituted or unsubstituted
morpholinyl ring.
[0211] In certain embodiments, R.sup.3' is --C(.dbd.O)R.sup.C1,
--C(.dbd.O)OR.sup.C1, --C(.dbd.O)N(R.sup.C1).sub.2 or
--C(.dbd.O)N(OR.sup.C1)(R.sup.C1), wherein R.sup.C1 is as defined
herein.
[0212] In certain embodiments, R.sup.3' is --C(.dbd.O)R.sup.C1,
e.g., for example, wherein R.sup.C1 is, for example, substituted or
unsubstituted methyl (C.sub.1), ethyl (C.sub.2), n-propyl
(C.sub.3), isopropyl (C.sub.3), n-butyl (C.sub.4), tert-butyl
(C.sub.4), sec-butyl (C.sub.4), iso-butyl (C.sub.4), n-pentyl
(C.sub.5), 3-pentanyl (C.sub.5), amyl (C.sub.5), neopentyl
(C.sub.5), 3-methyl-2-butanyl (C.sub.5), tertiary amyl (C.sub.5),
or n-hexyl (C.sub.6). In certain embodiments, R.sup.3' is
--C(.dbd.O)CH.sub.3. In certain embodiments, R.sup.3' is
--C(.dbd.O)(CH.sub.2).sub.mCO.sub.2H, wherein m is an integer
between 2 and 5, inclusive. In certain embodiments, m is 2. In
certain embodiments, m is 3. In certain embodiments, m is 4. In
certain embodiments, m is 5. In certain embodiments, R.sup.3' is
--C(.dbd.O)CH.sub.2CH.sub.2C(.dbd.O)OH.
[0213] In certain embodiments, R.sup.3' is --C(.dbd.O)OR.sup.C1,
e.g., for example, wherein R.sup.C1 is, for example, substituted or
unsubstituted methyl (C.sub.1), ethyl (C.sub.2), n-propyl
(C.sub.3), isopropyl (C.sub.3), n-butyl (C.sub.4), tert-butyl
(C.sub.4), sec-butyl (C.sub.4), iso-butyl (C.sub.4), n-pentyl
(C.sub.5), 3-pentanyl (C.sub.5), amyl (C.sub.5), neopentyl
(C.sub.5), 3-methyl-2-butanyl (C.sub.5), tertiary amyl (C.sub.5),
or n-hexyl (C.sub.6).
[0214] In certain embodiments, R.sup.3' is --C(.dbd.O)SR.sup.C1,
e.g., for example, wherein R.sup.C1 is, for example, substituted or
unsubstituted methyl (C.sub.1), ethyl (C.sub.2), n-propyl
(C.sub.3), isopropyl (C.sub.3), n-butyl (C.sub.4), tert-butyl
(C.sub.4), sec-butyl (C.sub.4), iso-butyl (C.sub.4), n-pentyl
(C.sub.5), 3-pentanyl (C.sub.5), amyl (C.sub.5), neopentyl
(C.sub.5), 3-methyl-2-butanyl (C.sub.5), tertiary amyl (C.sub.5),
or n-hexyl (C.sub.6).
[0215] In certain embodiments, R.sup.3' is --C(.dbd.O)N(RC).sub.2,
e.g., --C(.dbd.O)NH.sub.2 or --C(.dbd.O)NHR.sup.C1, wherein
R.sup.C1 is, for example, substituted or unsubstituted methyl
(C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), isopropyl
(C.sub.3), n-butyl (C.sub.4), tert-butyl (C.sub.4), sec-butyl
(C.sub.4), iso-butyl (C.sub.4), n-pentyl (C.sub.5), 3-pentanyl
(C.sub.5), amyl (C.sub.5), neopentyl (C.sub.5), 3-methyl-2-butanyl
(C.sub.5), tertiary amyl (C.sub.5), or n-hexyl (C.sub.6), or
R.sup.3' is --C(.dbd.O)N(R.sup.C1).sub.2 wherein the two R.sup.C1
groups are joined to form a substituted or unsubstituted
heterocyclic ring, e.g., substituted or unsubstituted piperidinyl,
substituted or unsubstituted piperazinyl, or substituted or
unsubstituted morpholinyl ring.
[0216] In certain embodiments, R.sup.3' is
--S(.dbd.O).sub.2R.sup.C1 or --S(.dbd.O).sub.2OR.sup.C1, wherein
R.sup.C1 is, for example, hydrogen, or substituted or unsubstituted
methyl (C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), isopropyl
(C.sub.3), n-butyl (C.sub.4), tert-butyl (C.sub.4), sec-butyl
(C.sub.4), iso-butyl (C.sub.4), n-pentyl (C.sub.5), 3-pentanyl
(C.sub.5), amyl (C.sub.5), neopentyl (C.sub.5), 3-methyl-2-butanyl
(C.sub.5), tertiary amyl (C.sub.5), or n-hexyl (C.sub.6), or
substituted or unsubstituted phenyl. In certain embodiments,
R.sup.3' is --S(.dbd.O).sub.2R.sup.C1. In certain embodiments,
R.sup.3' is --S(.dbd.O).sub.2OR.sup.C1, e.g., --SO.sub.3H.
[0217] In certain embodiments, R.sup.3' is
--P(.dbd.O).sub.2R.sup.C1, --P(.dbd.O).sub.2OR.sup.C1,
--P(.dbd.O)(OR.sup.C1).sub.2, --P(.dbd.O)(R.sup.C1).sub.2, or
--P(.dbd.O)(R.sup.C1)(OR.sup.C1), wherein each R.sup.C1 is, for
example, independently hydrogen, substituted or unsubstituted
methyl (C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), isopropyl
(C.sub.3), n-butyl (C.sub.4), tert-butyl (C.sub.4), sec-butyl
(C.sub.4), iso-butyl (C.sub.4), n-pentyl (C.sub.5), 3-pentanyl
(C.sub.5), amyl (C.sub.5), neopentyl (C.sub.5), 3-methyl-2-butanyl
(C.sub.5), tertiary amyl (C.sub.5), or n-hexyl (C.sub.6), or
substituted or unsubstituted phenyl. In certain embodiments,
R.sup.3' is --P(.dbd.O).sub.2R.sup.C1. In certain embodiments,
R.sup.3' is --P(.dbd.O).sub.2OR.sup.C1. In certain embodiments,
R.sup.3' is --P(.dbd.O)(OR.sup.C1).sub.2. In certain embodiments,
R.sup.3' is --P(.dbd.O)(R.sup.C1).sub.2. In certain embodiments,
R.sup.3' is --P(.dbd.O)(R.sup.C1)(OR.sup.C1)
Groups R.sup.4, R.sup.6a, R.sup.6b, R.sup.11a and R.sup.11b
[0218] As generally defined above, R.sup.4 is H, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted
heteroaryl.
[0219] In certain embodiments, R.sup.4 is H, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or
substituted or unsubstituted alkynyl.
[0220] In certain embodiments, R.sup.4 is H, --CH.sub.3, or
ethynyl.
[0221] In certain embodiments, R.sup.4 is H.
[0222] As generally defined above, each of R.sup.6a and R.sup.6b is
independently hydrogen, halo (e.g., fluoro), substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or
substituted or unsubstituted alkynyl, or R.sup.6a and R.sup.6b are
joined to form an oxo (.dbd.O) group, and represents a single or
double bond, provided if a double bond is present in Ring B, then
one of R.sup.6a or R.sup.6b is absent, and provided if a single
bond is present in Ring B, then the hydrogen at C5 is in the alpha
or beta position.
[0223] As generally defined above, wherein independently represents
a single or double bond, provided if a double bond is present in
Ring B, then one of R.sup.6a or R.sup.6b is absent, and provided if
a single bond is present in Ring B, then the hydrogen at C5 is in
the alpha or beta position. In certain embodiments, the dashed line
between C5 and C6 represents a single bond, and the hydrogen at the
5-position is in the 5.alpha.-conformation. In certain embodiments,
the dashed line between C5 and C6 represents a single bond, and the
hydrogen at the 5-position is in the 5.beta.-conformation. In
certain embodiments, the dashed line between C5 and C6 represents a
double bond.
[0224] In certain embodiments, wherein represents a single bond,
both R.sup.6a and R.sup.6b are hydrogen.
[0225] In certain embodiments, wherein represents a single bond,
and one of R.sup.6a and R.sup.6b is a non-hydrogen group, R.sup.6a
is alpha (down) and R.sup.6b is beta (up). In certain embodiments,
R.sup.6b is alpha (down) and R.sup.6a is beta (up).
[0226] In certain embodiments, wherein represents a single bond,
R.sup.6a is hydrogen, and R.sup.6b is halo, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or
substituted or unsubstituted alkynyl. In certain embodiments,
R.sup.6a is hydrogen, and R.sup.6b is halo (e.g., fluoro). In
certain embodiments, R.sup.6a is hydrogen, and R.sup.6b is
substituted or unsubstituted alkyl, e.g., substituted or
unsubstituted C.sub.1-6alkyl, substituted or unsubstituted
C.sub.1-2alkyl, substituted or unsubstituted C.sub.2-3alkyl,
substituted or unsubstituted C.sub.3-4alkyl, substituted or
unsubstituted C.sub.4-5alkyl, or substituted or unsubstituted
C.sub.5-6alkyl, e.g., methyl, ethyl, propyl, or isopropyl. In
certain embodiments, R.sup.6a is hydrogen, and R.sup.6b is
substituted or unsubstituted alkenyl. In certain embodiments,
R.sup.6a is hydrogen, and R.sup.6b is substituted or unsubstituted
alkynyl.
[0227] In certain embodiments, wherein represents a single bond,
R.sup.6b is hydrogen, and R.sup.6a is halo, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or
substituted or unsubstituted alkynyl. In certain embodiments,
R.sup.6b is hydrogen, and R.sup.6a is halo (e.g., fluoro). In
certain embodiments, R.sup.6b is hydrogen, and R.sup.6a is
substituted or unsubstituted alkyl, e.g., substituted or
unsubstituted C.sub.1-6alkyl, substituted or unsubstituted
C.sub.1-2alkyl, substituted or unsubstituted C.sub.2-3alkyl,
substituted or unsubstituted C.sub.3-4alkyl, substituted or
unsubstituted C.sub.4-5alkyl, or substituted or unsubstituted
C.sub.5-6alkyl, e.g., methyl, ethyl, propyl, or isopropyl. In
certain embodiments, R.sup.6b is hydrogen, and R.sup.6a is
substituted or unsubstituted alkenyl. In certain embodiments,
R.sup.6b is hydrogen, and R.sup.6a is substituted or unsubstituted
alkynyl.
[0228] Alternatively, in certain embodiments, wherein represents a
single bond, R.sup.6a and R.sup.6b are joined to form an oxo
(.dbd.O) group.
[0229] In certain embodiments, wherein represents a double bond,
R.sup.6a is hydrogen. In certain embodiments, wherein represents a
double bond, R.sup.6a is halo, e.g., fluoro. In certain
embodiments, wherein represents a double bond, R.sup.6a is
substituted or unsubstituted alkyl, e.g., substituted or
unsubstituted C.sub.1-6alkyl, substituted or unsubstituted
C.sub.1-2alkyl, substituted or unsubstituted C.sub.2-3alkyl,
substituted or unsubstituted C.sub.3-4alkyl, substituted or
unsubstituted C.sub.4-5alkyl, or substituted or unsubstituted
C.sub.5-6alkyl, e.g., methyl, ethyl, propyl, or isopropyl. In
certain embodiments, wherein represents a double bond, R.sup.6a is
substituted or unsubstituted alkenyl. In certain embodiments,
wherein represents a double bond, R.sup.6a is substituted or
unsubstituted alkynyl.
[0230] As generally defined above, each of R.sup.11a and R.sup.11b
is independently hydrogen, halo, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, --OH, --OR.sup.D1, --OC(.dbd.O)R.sup.D1,
--NH.sub.2, --N(R.sup.D1).sub.2, or --NR.sup.D1C(.dbd.O)R.sup.D1
wherein each instance of R.sup.D1 is independently hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, an oxygen protecting group when attached
to an oxygen atom, a nitrogen protecting group when attached to a
nitrogen atom, or two R.sup.D1 groups are joined to form an
substituted or unsubstituted heterocyclic ring; or R.sup.11a and
R.sup.11b are joined to form an oxo (.dbd.O) group.
[0231] In certain embodiments, R.sup.11a is alpha (down) and
R.sup.11b is beta (up). In certain embodiments, R.sup.11b is alpha
(down) and R.sup.11a is beta (up).
[0232] In certain embodiments, at least one of R.sup.11a and
R.sup.11b is hydrogen. In certain embodiments, each of R.sup.11a
and R.sup.11b is H.
[0233] In certain embodiments, at least one of R.sup.11a and
R.sup.11b is halo, e.g., --F, --Br, --I, or --Cl. In certain
embodiments, R.sup.11a is halo and R.sup.11b is hydrogen. In
certain embodiments, R.sup.11b is halo and R.sup.11a is
hydrogen.
[0234] In certain embodiments, at least one of R.sup.11a and
R.sup.11b is substituted or unsubstituted alkyl, e.g., substituted
or unsubstituted C.sub.1-6alkyl, substituted or unsubstituted
C.sub.1-2alkyl, substituted or unsubstituted C.sub.2-3alkyl,
substituted or unsubstituted C.sub.3-4alkyl, substituted or
unsubstituted C.sub.4-5alkyl, or substituted or unsubstituted
C.sub.5-6alkyl. Exemplary R.sup.11a C.sub.1-6alkyl groups include,
but are not limited to, substituted or unsubstituted methyl
(C.sub.1), substituted or unsubstituted ethyl (C.sub.2),
substituted or unsubstituted n-propyl (C.sub.3), substituted or
unsubstituted iso-propyl (C.sub.3), substituted or unsubstituted
n-butyl (C.sub.4), substituted or unsubstituted tert-butyl
(C.sub.4), substituted or unsubstituted sec-butyl (C.sub.4),
substituted or unsubstituted iso-butyl (C.sub.4), substituted or
unsubstituted n-pentyl (C.sub.5), substituted or unsubstituted
3-pentanyl (C.sub.5), substituted or unsubstituted amyl (C.sub.5),
substituted or unsubstituted neopentyl (C.sub.5), substituted or
unsubstituted 3-methyl-2-butanyl (C.sub.5), substituted or
unsubstituted tertiary amyl (C.sub.5), or substituted or
unsubstituted n-hexyl (C.sub.6). Exemplary substituted alkyl groups
include, but are not limited to, alkyl substituted with halogen
groups ("haloalkyl") and alkyl substituted with alkoxy groups
("alkoxyalkyl"). Exemplary haloalkyl groups include, but are not
limited to, --CF.sub.3, --CH.sub.2F, --CHF.sub.2, difluoroethyl,
2,2,2-trifluoro-1,1-dimethyl-ethyl, --CH.sub.2Cl, and --CHCl.sub.2.
Exemplary alkoxyalkyl groups include, but are not limited to,
--CH.sub.2OCH.sub.3 and --CH.sub.2OCH.sub.2CH.sub.3. In certain
embodiments, at least one of R.sup.11a and R.sup.11b is substituted
alkyl (e.g., haloalkyl, alkoxyalkyl). In certain embodiments,
R.sup.11a is alkyl and R.sup.11b is hydrogen. In certain
embodiments, R.sup.11b is alkyl and R.sup.11a is hydrogen.
[0235] In certain embodiments, at least one of R.sup.11a and
R.sup.11b is substituted or unsubstituted alkenyl, e.g.,
substituted or unsubstituted C.sub.2-alkenyl, substituted or
unsubstituted C.sub.2-3alkenyl, substituted or unsubstituted
C.sub.3-4alkenyl, substituted or unsubstituted C.sub.4-5alkenyl, or
substituted or unsubstituted C.sub.5-6alkenyl. Exemplary
substituted alkenyl groups include, but are not limited to, alkenyl
substituted with halogen groups ("haloalkenyl") and alkenyl
substituted with alkoxy groups ("alkoxyalkenyl"). In certain
embodiments, R.sup.11a is alkenyl and R.sup.11b is hydrogen. In
certain embodiments, R.sup.11b is alkenyl and R.sup.11a is
hydrogen.
[0236] In certain embodiments, at least one of R.sup.11a and
R.sup.11b is substituted or unsubstituted alkynyl, e.g.,
substituted or unsubstituted C.sub.2-6alkynyl, substituted or
unsubstituted C.sub.2-3alkynyl, substituted or unsubstituted
C.sub.3-4alkynyl, substituted or unsubstituted C.sub.4-5alkynyl, or
substituted or unsubstituted C.sub.5-6alkynyl. Exemplary
substituted alkynyl groups include, but are not limited to, alkynyl
substituted with halogen groups ("haloalkynyl") and alkynyl
substituted with alkoxy groups ("alkoxyalkynyl"). In certain
embodiments, R.sup.11a is alkynyl and R.sup.11b is hydrogen. In
certain embodiments, R.sup.11b is alkynyl and R.sup.11a is
hydrogen.
[0237] In certain embodiments, at least one of R.sup.11a and
R.sup.11b is substituted or unsubstituted carbocyclyl, e.g.,
substituted or unsubstituted C.sub.3-6carbocyclyl, substituted or
unsubstituted C.sub.3-4carbocyclyl, substituted or unsubstituted
C.sub.4-5 carbocyclyl, or substituted or unsubstituted C.sub.5-6
carbocyclyl. In certain embodiments, R.sup.11a is carbocyclyl and
R.sup.11b is hydrogen. In certain embodiments, R.sup.11b is
carbocyclyl and R.sup.11a is hydrogen.
[0238] In certain embodiments, at least one of R.sup.11a and
R.sup.11b is substituted or unsubstituted heterocyclyl, e.g.,
substituted or unsubstituted C.sub.3-6 heterocyclyl, substituted or
unsubstituted C.sub.3-4 heterocyclyl, substituted or unsubstituted
C.sub.4-5 heterocyclyl, or substituted or unsubstituted
C.sub.5-6heterocyclyl. For example, in certain embodiments, at
least one of R.sup.11a and R.sup.11b is a substituted or
unsubstituted piperidinyl, substituted or unsubstituted
piperazinyl, or substituted or unsubstituted morpholinyl ring. In
certain embodiments, at least one of R.sup.11a and R.sup.11b is a
substituted or unsubstituted morpholinyl ring. In certain
embodiments, R.sup.11a is heterocyclyl and R.sup.11b is hydrogen.
In certain embodiments, R.sup.11b is heterocyclyl and R.sup.11a is
hydrogen.
[0239] In certain embodiments, at least one of R.sup.11a and
R.sup.11b is substituted or unsubstituted aryl, e.g., substituted
or unsubstituted phenyl. In certain embodiments, R.sup.11a is aryl
and R.sup.11b is hydrogen. In certain embodiments, R.sup.11b is
aryl and R.sup.11a is hydrogen.
[0240] In certain embodiments, at least one of R.sup.11a and
R.sup.11b is substituted or unsubstituted heteroaryl, e.g.,
optionally substituted 5- to 6-membered heteroaryl. In certain
embodiments, R.sup.11a is heteroaryl and R.sup.11b is hydrogen. In
certain embodiments, R.sup.11b is heteroaryl and R.sup.11a is
hydrogen.
[0241] In certain embodiments, at least one of R.sup.11a and
R.sup.11b is --OH, --OR.sup.D1 or --OC(.dbd.O)R.sup.D1. In certain
embodiments, R.sup.D1 is substituted or unsubstituted alkyl, e.g.,
substituted or unsubstituted C.sub.1-6alkyl, substituted or
unsubstituted C.sub.1-2alkyl, substituted or unsubstituted
C.sub.2-3alkyl, substituted or unsubstituted C.sub.3-4alkyl,
substituted or unsubstituted C.sub.4-5alkyl, or substituted or
unsubstituted C.sub.5-6alkyl. Exemplary R.sup.D1 C.sub.1-6alkyl
groups include, but are not limited to, substituted or
unsubstituted methyl (C.sub.1), substituted or unsubstituted ethyl
(C.sub.2), substituted or unsubstituted n-propyl (C.sub.3),
substituted or unsubstituted isopropyl (C.sub.3), substituted or
unsubstituted n-butyl (C.sub.4), substituted or unsubstituted
tert-butyl (C.sub.4), substituted or unsubstituted sec-butyl
(C.sub.4), substituted or unsubstituted iso-butyl (C.sub.4),
substituted or unsubstituted n-pentyl (C.sub.5), substituted or
unsubstituted 3-pentanyl (C.sub.5), substituted or unsubstituted
amyl (C.sub.5), substituted or unsubstituted neopentyl (C.sub.5),
substituted or unsubstituted 3-methyl-2-butanyl (C.sub.5),
substituted or unsubstituted tertiary amyl (C.sub.5), or
substituted or unsubstituted n-hexyl (C.sub.6). In certain
embodiments, at least one of R.sup.11a and R.sup.11b is --OH. In
certain embodiments, R.sup.11a is --OH, --OR.sup.D1, or
--OC(.dbd.O)R.sup.D1 and R.sup.11b is hydrogen. In certain
embodiments, R.sup.11b is --OH, --OR.sup.D1, or
--OC(.dbd.O)R.sup.D1 and R.sup.11a is hydrogen.
[0242] In certain embodiments, at least one of R.sup.11a and
R.sup.11b is --NH.sub.2, --N(R.sup.D1).sub.2, or
--NR.sup.D1C(.dbd.O)R.sup.D1. In certain embodiments, R.sup.D1 is
hydrogen or substituted or unsubstituted alkyl, e.g., substituted
or unsubstituted C.sub.1-6alkyl, substituted or unsubstituted
C.sub.1-2alkyl, substituted or unsubstituted C.sub.2-3alkyl,
substituted or unsubstituted C.sub.3-4alkyl, substituted or
unsubstituted C.sub.4-5alkyl, or substituted or unsubstituted
C.sub.5-6alkyl. Exemplary R.sup.D1 C.sub.1-6alkyl groups include,
but are not limited to, substituted or unsubstituted methyl
(C.sub.1), substituted or unsubstituted ethyl (C.sub.2),
substituted or unsubstituted n-propyl (C.sub.3), substituted or
unsubstituted isopropyl (C.sub.3), substituted or unsubstituted
n-butyl (C.sub.4), substituted or unsubstituted tert-butyl
(C.sub.4), substituted or unsubstituted sec-butyl (C.sub.4),
substituted or unsubstituted iso-butyl (C.sub.4), substituted or
unsubstituted n-pentyl (C.sub.5), substituted or unsubstituted
3-pentanyl (C.sub.5), substituted or unsubstituted amyl (C.sub.5),
substituted or unsubstituted neopentyl (C.sub.5), substituted or
unsubstituted 3-methyl-2-butanyl (C.sub.5), substituted or
unsubstituted tertiary amyl (C.sub.5), or substituted or
unsubstituted n-hexyl (C.sub.6). In certain embodiments, at least
one of R.sup.11a and R.sup.11b is --N(R.sup.D1).sub.2, e.g.,
--NH.sub.2, --N(CH.sub.3).sub.2. In certain embodiments, R.sup.11a
is --NH.sub.2, --N(R.sup.D1).sub.2, or --NR.sup.D1C(.dbd.O)R.sup.D1
and R.sup.11b is hydrogen. In certain embodiments, R.sup.11b is
--NH.sub.2, --N(R.sup.D1).sub.2, or --NR.sup.D1C(.dbd.O)R.sup.D1
and R.sup.11a is hydrogen.
[0243] In certain embodiments, R.sup.11a and R.sup.11b are joined
to form an oxo (.dbd.O) group.
Additional Embodiments of Formula (I) and (III)
[0244] Various combinations of the above embodiments are further
contemplated herein. For example, in certain embodiments, the
compound of Formula (I) is of Formula (I-a1), (I-a2), or
(I-a3):
##STR00014##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a
combination thereof. In certain embodiments, R.sup.1 is hydrogen,
halogen (e.g., bromine), --OR.sup.A1 (e.g., --OH),
--N(R.sup.A1).sub.2, --S--S(.dbd.O).sub.2R.sup.A2, substituted or
unsubstituted heterocyclyl, or substituted or unsubstituted
heteroaryl. In certain embodiments, R.sup.1 is hydrogen, bromine,
or --OH. In certain embodiments, R.sup.2 is hydrogen, substituted
or unsubstituted heterocyclyl, --OH, --ORB, --OC(.dbd.O)RB,
--NH.sub.2, --N(R.sup.B1).sub.2, or --NR.sup.B1C(.dbd.O)R.sup.B1.
In certain embodiments, R.sup.3 is substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, or substituted or
unsubstituted alkynyl. In certain embodiments, R.sup.3' is
hydrogen. In certain embodiments, R.sup.4 is hydrogen. In certain
embodiments, both R.sup.6a and R.sup.6b are hydrogen. In certain
embodiments, one of R.sup.6a and R.sup.6b is a non-hydrogen group.
In certain embodiments, R.sup.6a is a non-hydrogen alpha group. In
certain embodiments, R.sup.6a is a non-hydrogen beta group. In
certain embodiments, R.sup.6a is halo, e.g., fluoro, or alkyl. In
certain embodiments, R.sup.6a is halo, e.g., fluoro, or alkyl, and
R.sup.6b is hydrogen. In certain embodiments, R.sup.6a and R.sup.6b
are both halo, e.g., fluoro. In certain embodiments, R.sup.6a and
R.sup.6b are both alkyl, e.g., methyl. In certain embodiments,
R.sup.6a and R.sup.6b are joined to form an oxo group. In certain
embodiments, both R.sup.11a and R.sup.11b are hydrogen. In certain
embodiments, one of R.sup.11a and R.sup.11b is a non-hydrogen
group. In certain embodiments, R.sup.11a and R.sup.11b are joined
to form an oxo group.
[0245] In certain embodiments, the compound of Formula (III) is of
Formula (III-a1), (III-a2), or (III-a3):
##STR00015##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a
combination thereof. In certain embodiments, R.sup.1 is hydrogen,
halogen (e.g., bromine), --OR.sup.A1 (e.g., --OH),
--N(R.sup.A1).sub.2, --S--S(.dbd.O).sub.2R.sup.A2, substituted or
unsubstituted heterocyclyl, or substituted or unsubstituted
heteroaryl. In certain embodiments, R.sup.1 is hydrogen, bromine,
or --OH. In certain embodiments, R.sup.2 is hydrogen, substituted
or unsubstituted heterocyclyl, --OH, --OR.sup.B1,
--OC(.dbd.O)R.sup.B1, --NH.sub.2, --N(R.sup.B1).sub.2, or
--NR.sup.B1C(.dbd.O)R.sup.B1. In certain embodiments, R.sup.3 is
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, or substituted or unsubstituted alkynyl. In certain
embodiments, R.sup.3' is hydrogen. In certain embodiments, R.sup.4
is hydrogen. In certain embodiments, both R.sup.6a and R.sup.6b are
hydrogen. In certain embodiments, one of R.sup.6a and R.sup.6b is a
non-hydrogen group. In certain embodiments, R.sup.6a is a
non-hydrogen alpha group. In certain embodiments, R.sup.6a is a
non-hydrogen beta group. In certain embodiments, R.sup.6a is halo,
e.g., fluoro, or alkyl. In certain embodiments, R.sup.6a is halo,
e.g., fluoro, or alkyl, and R.sup.6b is hydrogen. In certain
embodiments, R.sup.6a and R.sup.6b are both halo, e.g., fluoro. In
certain embodiments, R.sup.6a and R.sup.6b are both alkyl, e.g.,
methyl. In certain embodiments, R.sup.6a and R.sup.6b are joined to
form an oxo group. In certain embodiments, both R.sup.11a and
R.sup.11b are hydrogen. In certain embodiments, one of R.sup.11a
and R.sup.11b is a non-hydrogen group. In certain embodiments,
R.sup.11a and R.sup.11b are joined to form an oxo group.
[0246] In certain embodiments, wherein R.sup.2 and R.sup.4 are
hydrogen, the compound of Formula (I) is of Formula (I-b1), (I-b2),
or (I-b3):
##STR00016##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a
combination thereof. In certain embodiments, R.sup.1 is hydrogen,
halogen (e.g., bromine), --OR.sup.A1 (e.g., --OH),
--N(R.sup.A1).sub.2, --S--S(.dbd.O).sub.2R.sup.A2, substituted or
unsubstituted heterocyclyl, or substituted or unsubstituted
heteroaryl. In certain embodiments, R.sup.1 is hydrogen, bromine,
or --OH. In certain embodiments, R.sup.3 is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or
substituted or unsubstituted alkynyl. In certain embodiments,
R.sup.3' is hydrogen. In certain embodiments, both R.sup.6a and
R.sup.6b are hydrogen. In certain embodiments, one of R.sup.6a and
R.sup.6b is a non-hydrogen group. In certain embodiments, R.sup.6a
is a non-hydrogen alpha group. In certain embodiments, R.sup.6a is
a non-hydrogen beta group. In certain embodiments, R.sup.6a is
halo, e.g., fluoro, or alkyl. In certain embodiments, R.sup.6a is
halo, e.g., fluoro, or alkyl, and R.sup.6b is hydrogen. In certain
embodiments, R.sup.6a and R.sup.6b are both halo, e.g., fluoro. In
certain embodiments, R.sup.6a and R.sup.6b are both alkyl, e.g.,
methyl. In certain embodiments, R.sup.6a and R.sup.6b are joined to
form an oxo group. In certain embodiments, both R.sup.11a and
R.sup.11b are hydrogen. In certain embodiments, one of R.sup.11a
and R.sup.11b is a non-hydrogen group. In certain embodiments,
R.sup.11a and R.sup.11b are joined to form an oxo group.
[0247] In certain embodiments, wherein R.sup.2 and R.sup.4 are
hydrogen, the compound of Formula (III) is of Formula (III-b1),
(III-b2), or (III-b3):
##STR00017##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a
combination thereof. In certain embodiments, R.sup.1 is hydrogen,
halogen (e.g., bromine), --OR.sup.A1 (e.g., --OH),
--N(R.sup.A1).sub.2, --S--S(.dbd.O).sub.2R.sup.A2, substituted or
unsubstituted hetercyclyl, or substituted or unsubstituted
heteroaryl. In certain embodiments, R.sup.1 is hydrogen, bromine,
or --OH. In certain embodiments, R.sup.3 is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or
substituted or unsubstituted alkynyl. In certain embodiments,
R.sup.3' is hydrogen. In certain embodiments, both R.sup.6a and
R.sup.6b are hydrogen. In certain embodiments, one of R.sup.6a and
R.sup.6b is a non-hydrogen group. In certain embodiments, R.sup.6a
is a non-hydrogen alpha group. In certain embodiments, R.sup.6a is
a non-hydrogen beta group. In certain embodiments, R.sup.6a is
halo, e.g., fluoro, or alkyl. In certain embodiments, R.sup.6a is
halo, e.g., fluoro, or alkyl, and R.sup.6b is hydrogen. In certain
embodiments, R.sup.6a and R.sup.6b are both halo, e.g., fluoro. In
certain embodiments, R.sup.6a and R.sup.6b are both alkyl, e.g.,
methyl. In certain embodiments, R.sup.6a and R.sup.6b are joined to
form an oxo group. In certain embodiments, both R.sup.11a and
R.sup.11b are hydrogen. In certain embodiments, one of R.sup.11a
and R.sup.11b is a non-hydrogen group. In certain embodiments,
R.sup.11a and R.sup.11b are joined to form an oxo group.
[0248] In certain embodiments, wherein R.sup.2, R.sup.4, R.sup.11a
and R.sup.11b are hydrogen, the compound of Formula (I) is of
Formula (I-c1), (I-c2), or (I-c3):
##STR00018##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a
combination thereof. In certain embodiments, R.sup.1 is hydrogen,
halogen (e.g., bromine), --OR.sup.A1 (e.g., --OH),
--N(R.sup.A1).sub.2, --S--S(.dbd.O).sub.2R.sup.A2, substituted or
unsubstituted hetercyclyl, or substituted or unsubstituted
heteroaryl. In certain embodiments, R.sup.1 is hydrogen, bromine,
or --OH. In certain embodiments, R.sup.3 is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or
substituted or unsubstituted alkynyl. In certain embodiments,
R.sup.3' is hydrogen. In certain embodiments, both R.sup.6a and
R.sup.6b are hydrogen. In certain embodiments, one of R.sup.6a and
R.sup.6b is a non-hydrogen group. In certain embodiments, R.sup.6a
is a non-hydrogen alpha group. In certain embodiments, R.sup.6a is
a non-hydrogen beta group. In certain embodiments, R.sup.6a is
halo, e.g., fluoro, or alkyl. In certain embodiments, R.sup.6a is
halo, e.g., fluoro, or alkyl, and R.sup.6b is hydrogen. In certain
embodiments, R.sup.6a and R.sup.6b are both halo, e.g., fluoro. In
certain embodiments, R.sup.6a and R.sup.6b are both alkyl, e.g.,
methyl. In certain embodiments, R.sup.6a and R.sup.6b are joined to
form an oxo group.
[0249] In certain embodiments, wherein R.sup.2, R.sup.4, R.sup.11a
and R.sup.11b are hydrogen, the compound of Formula (III) is of
Formula (III-c1), (III-c2), or (III-c3):
##STR00019##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a
combination thereof. In certain embodiments, R.sup.1 is hydrogen,
halogen (e.g., bromine), --OR.sup.A1 (e.g., --OH),
--N(R.sup.A1).sub.2, --S--S(.dbd.O).sub.2R.sup.A2, substituted or
unsubstituted hetercyclyl, or substituted or unsubstituted
heteroaryl. In certain embodiments, R.sup.1 is hydrogen, bromine,
or --OH. In certain embodiments, R.sup.3 is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or
substituted or unsubstituted alkynyl. In certain embodiments,
R.sup.3' is hydrogen. In certain embodiments, both R.sup.6a and
R.sup.6b are hydrogen. In certain embodiments, one of R.sup.6a and
R.sup.6b is a non-hydrogen group. In certain embodiments, R.sup.6a
is a non-hydrogen alpha group. In certain embodiments, R.sup.6a is
a non-hydrogen beta group. In certain embodiments, R.sup.6a is
halo, e.g., fluoro, or alkyl. In certain embodiments, R.sup.6a is
halo, e.g., fluoro, or alkyl, and R.sup.6b is hydrogen. In certain
embodiments, R.sup.6a and R.sup.6b are both halo, e.g., fluoro. In
certain embodiments, R.sup.6a and R.sup.6b are both alkyl, e.g.,
methyl. In certain embodiments, R.sup.6a and R.sup.6b are joined to
form an oxo group.
[0250] In certain embodiments, wherein R.sup.2, R.sup.4, R.sup.11a,
R.sup.6b, R.sup.6, R.sup.6b are hydrogen, the compound of Formula
(I) is of Formula (I-d1), (I-d2), or (I-d3):
##STR00020##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a
combination thereof. In certain embodiments, R.sup.1 is hydrogen,
halogen (e.g., bromine), --OR.sup.A1 (e.g., --OH),
--N(R.sup.A1).sub.2, --S--S(.dbd.O).sub.2R.sup.A2, substituted or
unsubstituted hetercyclyl, or substituted or unsubstituted
heteroaryl. In certain embodiments, R.sup.1 is hydrogen, bromine,
or --OH. In certain embodiments, R.sup.3 is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or
substituted or unsubstituted alkynyl. In certain embodiments,
R.sup.3' is hydrogen.
[0251] In certain embodiments, wherein R.sup.2, R.sup.4, R.sup.11a,
R.sup.6b, R.sup.6a, R.sup.6b are hydrogen, the compound of Formula
(III) is of Formula (III-d1), (III-d2), or (III-d3):
##STR00021##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a
combination thereof. In certain embodiments, R.sup.1 is hydrogen,
halogen (e.g., bromine), --OR.sup.A1 (e.g., --OH),
--N(R.sup.A1).sub.2, --S--S(.dbd.O).sub.2R.sup.A2, substituted or
unsubstituted hetercyclyl, or substituted or unsubstituted
heteroaryl. In certain embodiments, R.sup.1 is hydrogen, bromine,
or --OH. In certain embodiments, R.sup.3 is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or
substituted or unsubstituted alkynyl. In certain embodiments,
R.sup.3' is hydrogen.
[0252] In certain further embodiments of Formula (I) and (III),
R.sup.1 is hydrogen, halogen, --OR.sup.A1, --SR.sup.A1,
--N(R.sup.A1).sub.2, --OC(.dbd.O)RA, --OC(.dbd.O)OR.sup.A1,
--OC(.dbd.O)SR.sup.A1, --OC(.dbd.O)N(R.sup.A1).sub.2,
--SC(.dbd.O)R.sup.A2, --SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A1).sub.2, --NHC(.dbd.O)R.sup.A1,
--NHC(.dbd.O)OR.sup.A1, --NHC(.dbd.O)SR.sup.A1,
--NHC(.dbd.O)N(R.sup.A1).sub.2, --OS(.dbd.O).sub.2R.sup.A2,
--OS(.dbd.O).sub.2OR.sup.A1, --S--S(.dbd.O).sub.2R.sup.A2,
--S--S(.dbd.O).sub.2OR.sup.A1, --S(.dbd.O)R.sup.A2,
--SO.sub.2R.sup.A2, or --S(.dbd.O).sub.2OR.sup.A1; R.sup.2 is
hydrogen, substituted or unsubstituted heterocyclyl, --OH,
--OR.sup.BI, --OC(.dbd.O)R.sup.B1, --NH.sub.2--N(R.sup.B1).sub.2,
or --NR.sup.B1C(.dbd.O)R.sup.B1; R.sup.3 is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R.sup.3' is hydrogen; R.sup.4 is hydrogen; each of R.sup.6a and
R.sup.6b is independently hydrogen, halo, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or
substituted or unsubstituted alkynyl, or R.sup.6a and R.sup.6b are
joined to form an oxo (.dbd.O) group; and each of R.sup.11a and
R.sup.11b is independently hydrogen, --OH, --OR.sup.D1,
--OC(.dbd.O)R.sup.D1, --NH.sub.2, --N(R.sup.D1).sub.2, or
--NR.sup.D1C(.dbd.O)R.sup.D1, or R.sup.11a and R.sup.11b are joined
to form an oxo (.dbd.O) group.
[0253] Additional embodiments of Formula (I) are further considered
herein. For example, in certain embodiments, the compound of
Formula (I) is selected from any one of the following Formula:
##STR00022## ##STR00023## ##STR00024## ##STR00025##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a
combination thereof.
[0254] In certain embodiments, the compound of Formula (I) is
selected from any one of the following Formula:
##STR00026## ##STR00027##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, or isotopic variant thereof, or a
combination thereof.
[0255] In certain embodiments, the compound of Formula (I) is
selected from any one of the following formulae:
##STR00028## ##STR00029##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, or isotopic variant thereof, or a
combination thereof.
[0256] In certain embodiments, the compound of Formula (I) is
selected from any one of the following formulae:
##STR00030## ##STR00031##
wherein m is 0, 1 or 2; and each R.sup.1c is independently
--CH.sub.3, F, Cl, --CN, --OMe, --SMe, --SOMe, --SO.sub.2Me,
--CH.sub.2F, --CHF.sub.2, or --CF.sub.3; or a pharmaceutically
acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer,
isotopic variant, or N-oxide thereof, or a combination thereof.
[0257] In certain embodiments, the compound of Formula (I) is
selected from any one of the following formulae:
##STR00032## ##STR00033##
wherein m is 0, 1 or 2; and each R.sup.1c is independently
--CH.sub.3, F, Cl, --CN, --OMe, --SMe, --SOMe, --SO.sub.2Me,
--CH.sub.2F, --CHF.sub.2, or --CF.sub.3; or a pharmaceutically
acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer,
isotopic variant, or N-oxide thereof, or a combination thereof.
[0258] In certain embodiments, the compound of Formula (I) is
selected from any one of the following formulae:
##STR00034## ##STR00035##
wherein m is 0, 1 or 2; and each R.sup.1 is independently
--CH.sub.3, Cl, F, --CN, --OMe, --SMe, --SOMe, --SO.sub.2Me,
--CH.sub.2F, --CHF.sub.2, or --CF.sub.3; or a pharmaceutically
acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer,
isotopic variant, or N-oxide thereof, or a combination thereof. In
certain embodiments, m is 0. In certain embodiments m is 1. In
certain embodiments m is 2. In certain embodiments, m is 1, and
each R.sup.1c is --CH.sub.3, Cl or --CN. In certain embodiments, m
is 2, and each R.sup.1c is --CH.sub.3, Cl or --CN.
[0259] In certain embodiments, the compound of Formula (I) is
selected from any one of the following formulae:
##STR00036## ##STR00037##
wherein R.sup.1c is H, --CH.sub.3, Cl, F, --CN, OMe, --SMe, --SOMe,
--SO.sub.2Me, --CH.sub.2F, --CHF.sub.2, or --CF.sub.3; or a
pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a
combination thereof.
[0260] In certain embodiments, the compound of Formula (I) is
selected from any one of the following formulae:
##STR00038## ##STR00039##
wherein X is --O-- or --S--; and R.sup.1c is independently H,
--CH.sub.3, F, Cl, --CN, OMe, --SMe, --SOMe, --SO.sub.2Me,
--CH.sub.2F, --CHF.sub.2, or --CF.sub.3; or a pharmaceutically
acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer,
isotopic variant, or N-oxide thereof, or a combination thereof.
[0261] In certain embodiments, the compound of Formula (I) is
selected from any one of the following formulae:
##STR00040##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, or isotopic variant thereof, or a
combination thereof.
[0262] In certain embodiments, the compound of Formula (I) is
selected from any one of the following formulae:
##STR00041##
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, or isotopic variant thereof, or a
combination thereof.
[0263] In certain embodiments, the compound of Formula (I) is
selected from any one of the following formulae:
##STR00042##
wherein m is 0, 1 or 2; and each R.sup.1c is independently
--CH.sub.3, F, Cl, --CN, --OMe, --SMe, --SOMe, --SO.sub.2Me,
--CH.sub.2F, --CHF.sub.2, or --CF.sub.3; or a pharmaceutically
acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer,
isotopic variant, or N-oxide thereof, or a combination thereof. In
certain embodiments, m is 0. In certain embodiments, m is 1. In
certain embodiments, m is 2. In certain embodiments, m is 2, and
each R.sup.1c is --CH.sub.3, Cl or --CN.
[0264] In certain embodiments, the compound of Formula (I) is
selected from any one of the following formulae:
##STR00043##
wherein m is 0, 1 or 2; and each R.sup.1c is independently
--CH.sub.3, F, Cl, --CN, --OMe, --SMe, --SOMe, --SO.sub.2Me,
--CH.sub.2F, --CHF.sub.2, or --CF.sub.3; or a pharmaceutically
acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer,
isotopic variant, or N-oxide thereof, or a combination thereof.
[0265] In certain embodiments, the compound of Formula (I) is
selected from any one of the following formulae:
##STR00044##
wherein m is 0, 1 or 2; and each R.sup.1c is independently
--CH.sub.3, F, Cl, --CN, --OMe, --SMe, --SOMe, --SO.sub.2Me,
--CH.sub.2F, --CHF.sub.2, or --CF.sub.3; or a pharmaceutically
acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer,
isotopic variant, or N-oxide thereof, or a combination thereof.
[0266] In certain embodiments, the compound of Formula (I) is
selected from any one of the following formulae:
##STR00045##
wherein R.sup.1c is H, --CH.sub.3, Cl, --CN, --OMe, --SMe, --F,
--SOMe, --SO.sub.2Me, --CH.sub.2F, --CHF.sub.2, or --CF.sub.3; or a
pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a
combination thereof.
[0267] In certain embodiments, the compound of Formula (I) is
selected from any one of the following formulae:
##STR00046##
wherein X is --O-- or --S--; and R.sup.1c is independently H,
--CH.sub.3, F, Cl, --CN, --OMe, --SMe, --SOMe, --SO.sub.2Me,
--CH.sub.2F, --CHF.sub.2, or --CF.sub.3; or a pharmaceutically
acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer,
isotopic variant, or N-oxide thereof, or a combination thereof. In
certain embodiments, each R.sup.1c is independently H, --CH.sub.3,
F, Cl, --CN, --OMe, --SMe, --SOMe, --SO.sub.2Me, --CH.sub.2F,
--CHF.sub.2, or --CF.sub.3. In certain embodiments, R.sup.1c is
--CH.sub.3, --CH.sub.2F, --CHF.sub.2, or --CF.sub.3. In certain
embodiments, R.sup.1c is F, Cl, or CN. In certain embodiments,
R.sup.1c is OMe. In certain embodiments, R.sup.1c is SMe, --SOMe,
or --SO.sub.2Me. In certain embodiments, X is --O--. In certain
embodiments, X is --S--.
[0268] In certain embodiments, the compound of Formula (I) is
selected from any one of the following formulae:
##STR00047##
wherein R.sup.1, R.sup.2, and R.sup.3 are as described herein; or a
pharmaceutically acceptable salt, solvate, hydrate, prodrug,
stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a
combination thereof.
[0269] In certain embodiments, the compound of Formula (I) is
selected from any one of the following compounds, or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomers,
tautomer, isotopic variant, N-oxide thereof, or a combination
thereof:
##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052##
##STR00053## ##STR00054## ##STR00055## ##STR00056## ##STR00057##
##STR00058##
[0270] In certain embodiments, the compound of Formula (I) is
selected from any one of the following compounds, or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomers,
tautomer, isotopic variant, N-oxide thereof, or a combination
thereof:
##STR00059## ##STR00060## ##STR00061## ##STR00062## ##STR00063##
##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068##
##STR00069##
[0271] In certain embodiments, the compound of Formula (I) is
selected from any one of the following compounds, or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomers,
tautomer, isotopic variant, N-oxide thereof, or a combination
thereof:
##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074##
##STR00075##
[0272] In certain embodiments, the compound of Formula (III) is
selected from any one of the following compounds, or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomers,
tautomer, isotopic variant, N-oxide thereof, or a combination
thereof:
##STR00076## ##STR00077## ##STR00078## ##STR00079## ##STR00080##
##STR00081## ##STR00082##
[0273] In certain embodiments, the compound of Formula (III) is
selected from any one of the following compounds, or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomers,
tautomer, isotopic variant, N-oxide thereof, or a combination
thereof:
##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087##
##STR00088##
[0274] In certain embodiments, the compound of Formula (III) is
selected from any one of the following compounds, or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomers,
tautomer, isotopic variant, N-oxide thereof, or a combination
thereof:
##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093##
##STR00094##
Pharmaceutical Compositions
[0275] In another aspect, the invention provides a pharmaceutical
composition comprising a compound of the present invention and a
pharmaceutically acceptable carrier. In certain embodiments, the
pharmaceutical composition comprises an effective amount of the
compound. In certain embodiments, the pharmaceutical composition
comprises a therapeutically effective amount of the compound. In
certain embodiments, the pharmaceutical composition comprises a
prophylactically effective amount of the compound.
[0276] When employed as pharmaceuticals, the compounds provided
herein are typically administered in the form of a pharmaceutical
composition. Such compositions can be prepared in a manner well
known in the pharmaceutical art and comprise at least one active
compound.
[0277] In one embodiment, with respect to the pharmaceutical
composition, the carrier is a parenteral carrier, oral carrier, or
topical carrier.
[0278] The present invention also relates to a compound of the
present invention or pharmaceutical composition thereof for use as
a pharmaceutical or a medicament.
[0279] Generally, the compounds provided herein are administered in
a therapeutically effective amount. The amount of the compound
actually administered will typically be determined by a physician,
in the light of the relevant circumstances, including the condition
to be treated, the chosen route of administration, the actual
compound administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms, and the
like.
[0280] The pharmaceutical compositions provided herein can be
administered by a variety of routes including oral, rectal,
transdermal, subcutaneous, intravenous, intramuscular, and
intranasal. Depending on the intended route of delivery, the
compounds provided herein are preferably formulated as either
injectable or oral compositions or as salves, as lotions or as
patches all for transdermal administration.
[0281] The pharmaceutical compositions provided herein can also be
administered chronically ("chronic administration"). Chronic
administration refers to administration of a compound or
pharmaceutical composition thereof over an extended period of time,
e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3
years, 5 years, etc., or may be continued indefinitely, for
example, for the rest of the subject's life. In certain
embodiments, the chronic administration is intended to provide a
constant level of the compound in the blood, e.g., within the
therapeutic window over the extended period of time.
[0282] The compositions for oral administration can take the form
of bulk liquid solutions or suspensions, or bulk powders. More
commonly, however, the compositions are presented in unit dosage
forms to facilitate accurate dosing. The term "unit dosage forms"
refers to physically discrete units suitable as unitary dosages for
human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect, in association with a suitable
pharmaceutical excipient. Typical unit dosage forms include
prefilled, premeasured ampules or syringes of the liquid
compositions or pills, tablets, capsules or the like in the case of
solid compositions. In such compositions, the compound is usually a
minor component (from about 0.1 to about 50% by weight or
preferably from about 1 to about 40% by weight) with the remainder
being various vehicles or carriers and processing aids helpful for
forming the desired dosing form.
[0283] Liquid forms suitable for oral administration may include a
suitable aqueous or nonaqueous vehicle with buffers, suspending and
dispensing agents, colorants, flavors and the like. Solid forms may
include, for example, any of the following ingredients, or
compounds of a similar nature: a binder such as microcrystalline
cellulose, gum tragacanth or gelatin; an excipient such as starch
or lactose, a disintegrating agent such as alginic acid, Primogel,
or corn starch; a lubricant such as magnesium stearate; a glidant
such as colloidal silicon dioxide; a sweetening agent such as
sucrose or saccharin; or a flavoring agent such as peppermint,
methyl salicylate, or orange flavoring.
[0284] Injectable compositions are typically based upon injectable
sterile saline or phosphate-buffered saline or other injectable
carriers known in the art. As before, the active compound in such
compositions is typically a minor component, often being from about
0.05 to 10% by weight with the remainder being the injectable
carrier and the like.
[0285] Transdermal compositions are typically formulated as a
topical ointment or cream containing the active ingredient(s),
generally in an amount ranging from about 0.01 to about 20% by
weight, preferably from about 0.1 to about 20% by weight,
preferably from about 0.1 to about 10% by weight, and more
preferably from about 0.5 to about 15% by weight. When formulated
as a ointment, the active ingredients will typically be combined
with either a paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream
with, for example an oil-in-water cream base. Such transdermal
formulations are well-known in the art and generally include
additional ingredients to enhance the dermal penetration of
stability of the active ingredients or Formulation. All such known
transdermal formulations and ingredients are included within the
scope provided herein.
[0286] The compounds provided herein can also be administered by a
transdermal device. Accordingly, transdermal administration can be
accomplished using a patch either of the reservoir or porous
membrane type, or of a solid matrix variety.
[0287] The above-described components for orally administrable,
injectable or topically administrable compositions are merely
representative. Other materials as well as processing techniques
and the like are set forth in Part 8 of Remington's Pharmaceutical
Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa.,
which is incorporated herein by reference.
[0288] The above-described components for orally administrable,
injectable, or topically administrable compositions are merely
representative. Other materials as well as processing techniques
and the like are set forth in Part 8 of Remington's The Science and
Practice of Pharmacy, 21st edition, 2005, Publisher: Lippincott
Williams & Wilkins, which is incorporated herein by
reference.
[0289] The compounds of this invention can also be administered in
sustained release forms or from sustained release drug delivery
systems. A description of representative sustained release
materials can be found in Remington's Pharmaceutical Sciences.
[0290] The present invention also relates to the pharmaceutically
acceptable formulations of a compound of the present invention. In
one embodiment, the formulation comprises water. In another
embodiment, the formulation comprises a cyclodextrin derivative.
The most common cyclodextrins are .alpha.-, .beta.- and
.gamma.-cyclodextrins consisting of 6, 7 and 8 .alpha.-1,4-linked
glucose units, respectively, optionally comprising one or more
substituents on the linked sugar moieties, which include, but are
not limited to, methylated, hydroxyalkylated, acylated, and
sulfoalkylether substitution. In certain embodiments, the
cyclodextrin is a sulfoalkyl ether .beta.-cyclodextrin, e.g., for
example, sulfobutyl ether .beta.-cyclodextrin, also known as
Captisol.RTM.. See, e.g., U.S. Pat. No. 5,376,645. In certain
embodiments, the formulation comprises
hexapropyl-.beta.-cyclodextrin (e.g., 10-50% in water).
[0291] The present invention also relates to the pharmaceutically
acceptable acid addition salt of a compound of the present
invention. The acid which may be used to prepare the
pharmaceutically acceptable salt is that which forms a non-toxic
acid addition salt, i.e., a salt containing pharmacologically
acceptable anions such as the hydrochloride, hydroiodide,
hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate,
lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate,
para-toluenesulfonate, and the like.
[0292] The following formulation examples illustrate representative
pharmaceutical compositions that may be prepared in accordance with
this invention. The present invention, however, is not limited to
the following pharmaceutical compositions.
[0293] Exemplary Formulation 1--Tablets: A compound of the present
invention may be admixed as a dry powder with a dry gelatin binder
in an approximate 1:2 weight ratio. A minor amount of magnesium
stearate is added as a lubricant. The mixture is formed into
240-270 mg tablets (80-90 mg of active compound per tablet) in a
tablet press. Exemplary Formulation 2--Capsules: A compound of the
present invention may be admixed as a dry powder with a starch
diluent in an approximate 1:1 weight ratio. The mixture is filled
into 250 mg capsules (125 mg of active compound per capsule).
[0294] Exemplary Formulation 3--Liquid: A compound of the present
invention (125 mg) may be admixed with sucrose (1.75 g) and xanthan
gum (4 mg) and the resultant mixture may be blended, passed through
a No. 10 mesh U.S. sieve, and then mixed with a previously made
solution of microcrystalline cellulose and sodium carboxymethyl
cellulose (11:89.50 mg) in water. Sodium benzoate (10 mg), flavor,
and color are diluted with water and added with stirring.
Sufficient water may then be added to produce a total volume of 5
mL.
[0295] Exemplary Formulation 4--Tablets: A compound of the present
invention may be admixed as a dry powder with a dry gelatin binder
in an approximate 1:2 weight ratio. A minor amount of magnesium
stearate is added as a lubricant. The mixture is formed into
450-900 mg tablets (150-300 mg of active compound) in a tablet
press.
[0296] Exemplary Formulation 5--Injection: A compound of the
present invention may be dissolved or suspended in a buffered
sterile saline injectable aqueous medium to a concentration of
approximately 5 mg/mL.
[0297] Exemplary Formulation 6--Tablets: A compound of the present
invention may be admixed as a dry powder with a dry gelatin binder
in an approximate 1:2 weight ratio. A minor amount of magnesium
stearate is added as a lubricant. The mixture is formed into 90-150
mg tablets (30-50 mg of active compound per tablet) in a tablet
press.
[0298] Exemplary Formulation 7--Tablets: A compound of the present
invention may be admixed as a dry powder with a dry gelatin binder
in an approximate 1:2 weight ratio. A minor amount of magnesium
stearate is added as a lubricant. The mixture is formed into 30-90
mg tablets (10-30 mg of active compound per tablet) in a tablet
press.
[0299] Exemplary Formulation 8--Tablets: A compound of the present
invention may be admixed as a dry powder with a dry gelatin binder
in an approximate 1:2 weight ratio. A minor amount of magnesium
stearate is added as a lubricant. The mixture is formed into 0.3-30
mg tablets (0.1-10 mg of active compound per tablet) in a tablet
press.
[0300] Exemplary Formulation 9--Tablets: A compound of the present
invention may be admixed as a dry powder with a dry gelatin binder
in an approximate 1:2 weight ratio. A minor amount of magnesium
stearate is added as a lubricant. The mixture is formed into
150-240 mg tablets (50-80 mg of active compound per tablet) in a
tablet press.
[0301] Exemplary Formulation 10--Tablets: A compound of the present
invention may be admixed as a dry powder with a dry gelatin binder
in an approximate 1:2 weight ratio. A minor amount of magnesium
stearate is added as a lubricant. The mixture is formed into
270-450 mg tablets (90-150 mg of active compound per tablet) in a
tablet press.
[0302] Injection dose levels range from about 0.1 mg/kg/hour to at
least 10 mg/kg/hour, all for from about 1 to about 120 hours and
especially 24 to 96 hours. A preloading bolus of from about 0.1
mg/kg to about 10 mg/kg or more may also be administered to achieve
adequate steady state levels. The maximum total dose is not
expected to exceed about 2 g/day for a 40 to 80 kg human
patient.
[0303] For the prevention and/or treatment of long-term conditions
the regimen for treatment usually stretches over many months or
years so oral dosing is preferred for patient convenience and
tolerance. With oral dosing, one to five and especially two to four
and typically three oral doses per day are representative regimens.
Using these dosing patterns, each dose provides from about 0.01 to
about 20 mg/kg of the compound provided herein, with preferred
doses each providing from about 0.1 to about 10 mg/kg, and
especially about 1 to about 5 mg/kg.
[0304] Transdermal doses are generally selected to provide similar
or lower blood levels than are achieved using injection doses.
[0305] When used to prevent the onset of a CNS-disorder, the
compounds provided herein will be administered to a subject at risk
for developing the condition, typically on the advice and under the
supervision of a physician, at the dosage levels described above.
Subjects at risk for developing a particular condition generally
include those that have a family history of the condition, or those
who have been identified by genetic testing or screening to be
particularly susceptible to developing the condition.
Methods of Use and Treatment
[0306] Earlier studies (see, e.g., Gee et al., European Journal of
Pharmacology, 136:419-423 (1987)) demonstrated that certain
3.alpha.-hydroxylated steroids are orders of magnitude more potent
as modulators of the GRC than others had reported (see, e.g.,
Majewska et al., Science 232:1004-1007 (1986); Harrison et al., J
Pharmacol. Exp. Ther. 241:346-353 (1987)). Majewska et al. and
Harrison et al. taught that 3.alpha.-hydroxylated-5-reduced
steroids are only capable of much lower levels of effectiveness. In
vitro and in vivo experimental data have now demonstrated that the
high potency of these steroids allows them to be therapeutically
useful in the modulation of brain excitability via the GRC (see,
e.g., Gee et al., European Journal of Pharmacology, 136:419-423
(1987); Wieland et al., Psychopharmacology 118(1):65-71
(1995)).
[0307] Various synthetic steroids have also been prepared as
neuroactive steroids. See, for example, U.S. Pat. No. 5,232,917,
which discloses neuroactive steroid compounds useful in treating
stress, anxiety, insomnia, seizure disorders, and mood disorders,
that are amenable to GRC-active agents, such as depression, in a
therapeutically beneficial manner. Furthermore, it has been
previously demonstrated that these steroids interact at a unique
site on the GRC which is distinct from other known sites of
interaction (e.g., barbiturates, benzodiazepines, and GABA) where
therapeutically beneficial effects on stress, anxiety, sleep, mood
disorders and seizure disorders have been previously elicited (see,
e.g., Gee, K. W. and Yamamura, H. I., "Benzodiazepines and
Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and
Seizure Disorders," in Central Nervous System Disorders, Horvell,
ed., Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, K. G. and
Morselli, P. L., "Psychopharmacology of GABAergic Drugs," in
Psychopharmacology: The Third Generation of Progress, H. Y.
Meltzer, ed., Raven Press, N.Y. (1987), pp. 183-195; and Gee et
al., European Journal of Pharmacology, 136:419-423 (1987). These
compounds are desirable for their duration, potency, and oral
activity (along with other forms of administration).
[0308] Accordingly, the compounds and pharmaceutical compositions
provided herein find use as therapeutics for preventing and/or
treating CNS conditions in mammals including humans and non-human
mammals. Thus, and as stated earlier, the present invention
includes within its scope, and extends to, the recited methods of
treatment, as well as to the compounds for such methods, and to the
use of such compounds for the preparation of medicaments useful for
such methods.
[0309] In one aspect, compounds of the present invention are
contemplated as therapeutic agents, e.g., for the treatment of CNS
conditions in mammals, such as for the treatment of insomnia,
depression, mood disorders, convulsive disorders, memory disorders,
attention disorders, anxiety disorders (e.g., stress), bipolar
disorder (e.g., I and/or II), schizophrenia, depression, bipolar
disorder, schizoaffective disorder, mood disorders, anxiety
disorders, personality disorders, psychosis, compulsive disorders,
post-traumatic stress disorder (PTSD), Autism spectrum disorder
(ASD), dysthymia (mild depression), social anxiety disorder,
obsessive compulsive disorder (OCD), pain (e.g., a painful syndrome
or disorder, e.g., acute pain, chronic pain, neuropathic pain),
sleep disorders, memory disorders, dementia, Alzheimer's disease, a
seizure disorder (e.g., epilepsy), traumatic brain injury, stroke,
addictive disorders (e.g., addiction to opiates, cocaine, and/or
alcohol), autism, Huntington's disease, Parkinson's disease, Rett
syndrome, withdrawal syndromes, or tinnitus. In certain
embodiments, the compounds of the present invention are useful in
the treatment of depression, anxiety, mood disorders, sleep
disorders, memory disorders, traumatic brain injury, stroke,
epilepsy, and schizophrenia.
[0310] In another aspect, provided is a method of treating a mammal
susceptible to or afflicted with a condition associated with brain
excitability, which method comprises administering an effective
amount of one or more of the pharmaceutical compositions described
herein.
[0311] In yet another aspect, provided is the use of a compound of
the present invention as a pharmaceutical, e.g., especially in the
treatment or prevention of the aforementioned conditions and
diseases.
[0312] In still yet another aspect, provided is a method of
manufacture of a medicament for the treatment or prevention of one
of the aforementioned conditions and diseases.
[0313] In still yet another aspect, the present invention provides
a method for preventing, treating, ameliorating, or managing a
disease or condition which comprises administering to a subject in
need of such prevention, treatment, amelioration or management, a
prophylactically or therapeutically effective amount of a compound
of the present invention, or the pharmaceutical composition
thereof.
[0314] In yet another aspect, the present invention provides a use
of a compound of the present invention for the manufacture of a
medicament to treat a disease or condition associated with brain
excitability. In one embodiment, the disease or condition is
selected from depression, anxiety, schizophrenia, sleep disorders,
memory disorders, and mood disorders.
[0315] In yet another aspect, the present invention provides a
method of treatment of a mammal, e.g., a human being, to treat a
disease associated with brain excitability, including treating said
mammal with an effective amount of a compound of the present
invention or composition thereof.
[0316] In yet another aspect, the present invention provides a
combination of a compound of the present invention and another
pharmacologically active agent. As generally understood herein, the
compounds provided herein can be administered as the sole active
agent or they can be administered in combination with other agents.
Administration in combination can proceed by any technique apparent
to those of skill in the art including, for example, separate,
sequential, concurrent, and alternating administration.
[0317] In yet another aspect, the present invention provides a use
of a compound of the present invention, or composition thereof, for
the manufacture of a medicament to treat a disease or condition
associated with CNS in a subject. In certain embodiments, the
disease or condition is selected from. sleep disorders, mood
disorders, insomnia, anxiety, depression, TBI, stress, and
epilepsy.
[0318] In yet another aspect, the present invention provides method
of in vitro modulation of GABA.sub.A receptor-chloride ionophore
complex in a subject through binding to the neurosteroid site on
said complex, comprising administering to the subject an amount
effective to modulate said complex of a compound of the present
invention.
[0319] In yet another aspect, the present invention provides method
of modulating the GABA.sub.A receptor-chloride ionophore complex in
a subject through binding to the neurosteroid site on said complex,
comprising administering to the subject an amount effective to
modulate said complex of a compound of the present invention.
[0320] In yet another aspect, the present invention provides method
of treating or preventing stress or anxiety in a subject,
comprising administering to the subject in need of such treatment
an effective amount of a compound of the present invention, or a
composition thereof.
[0321] In yet another aspect, the present invention provides method
of alleviating or preventing seizure activity in a subject,
comprising administering to the subject in need of such treatment
an effective amount of a compound of the present invention, or a
composition thereof.
[0322] In yet another aspect, the present invention provides method
of alleviating or preventing insomnia in a subject, comprising
administering to the subject in need of such treatment an effective
amount of a compound of the present invention, or a composition
thereof.
[0323] In yet another aspect, the present invention provides method
of inducing sleep and maintaining substantially the level of REM
sleep that is found in normal sleep, wherein substantial rebound
insomnia is not induced, comprising administering an effective
amount of a compound of the present invention, or a composition
thereof.
[0324] In yet another aspect, the present invention provides method
of alleviating or preventing PMS or PND in a subject, comprising
administering to the subject in need of such treatment an effective
amount of a compound of the present invention, or a composition
thereof.
[0325] In yet another aspect, the present invention provides method
of treating or preventing mood disorders in a subject, comprising
administering to the subject in need of such treatment an effective
amount of a compound of the present invention, or a composition
thereof.
[0326] In certain embodiments the mood disorder is depression.
[0327] In yet another aspect, the present invention provides a
method of inducing anesthesia in a subject, comprising
administering to the subject an effective amount of a compound of
the present invention. In certain embodiments, the subject is a
human. In certain embodiments, the compound is a pharmaceutically
acceptable 3-ester or 3-diester of an acid selected from the group
consisting of acetic, propionic, maleic, fumaric, ascorbic,
pimelic, succinic, glutaric, bismethylenesalicylic,
methanesulfonic, ethane-di-sulfonic, oxalic, tartaric, salicylic,
citric, gluconic, itaconic, glycolic, .gamma.-aminobenzoic,
aspartic, glutamic, .gamma.-amino-butyric,
.alpha.-(2-hydroxyethylamino)-propionic, glycine and other
.alpha.-amino acids, phosphoric, sulfuric, glucuronic, and
1-methyl-1,4-dihydronicotinic.
[0328] In yet another aspect, the present invention provides a
method of cognition enhancement or treating memory disorder by
administering to the subject a therapeutically effective amount of
a compound of the present invention. In certain embodiments, the
disorder is Alzheimer's disease. In certain embodiments, the
disorder is Rett syndrome.
[0329] In yet another aspect, the present invention provides a
method of of treating attention disorders by administering to the
subject a therapeutically effective amount of a compound of the
present invention. In certain embodiments, the attention disorder
is ADHD.
[0330] In certain embodiments, the compound is administered to the
subject chronically. In certain embodiments, the compound is
administered to the subject orally.
Exemplification
[0331] In order that the invention described herein may be more
fully understood, the following examples are set forth. The
synthetic and biological examples described in this application are
offered to illustrate the compounds, pharmaceutical compositions,
and methods provided herein and are not to be construed in any way
as limiting their scope.
Materials and Methods
[0332] The compounds provided herein can be prepared from readily
available starting materials using the following general methods
and procedures. See, e.g., Synthetic Schemes below. It will be
appreciated that where typical or preferred process conditions
(i.e., reaction temperatures, times, mole ratios of reactants,
solvents, pressures, etc.) are given, other process conditions can
also be used unless otherwise stated. Optimum reaction conditions
may vary with the particular reactants or solvent used, but such
conditions can be determined by one skilled in the art by routine
optimization procedures.
[0333] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions. The
choice of a suitable protecting group for a particular functional
group as well as suitable conditions for protection and
deprotection are well known in the art. For example, numerous
protecting groups, and their introduction and removal, are
described in T. W. Greene and P. G. M. Wuts, Protecting Groups in
Organic Synthesis, Second Edition, Wiley, New York, 1991, and
references cited therein.
[0334] The compounds provided herein may be isolated and purified
by known standard procedures. Such procedures include (but are not
limited to) recrystallization, column chromatography, or HPLC. The
following schemes are presented with details as to the preparation
of representative substituted biarylamides that have been listed
herein. The compounds provided herein may be prepared from known or
commercially available starting materials and reagents by one
skilled in the art of organic synthesis.
[0335] The enantiomerically pure compounds provided herein may be
prepared according to any techniques known to those of skill in the
art. For instance, they may be prepared by chiral or asymmetric
synthesis from a suitable optically pure precursor or obtained from
a racemate by any conventional technique, for example, by
chromatographic resolution using a chiral column, TLC or by the
preparation of diastereoisomers, separation thereof and
regeneration of the desired enantiomer. See, e.g., Enantiomers,
Racemates and Resolutions, by J. Jacques, A. Collet, and S. H.
Wilen, (Wiley-Interscience, New York, 1981); S. H. Wilen, A.
Collet, and J. Jacques, Tetrahedron, 2725 (1977); E. L. Eliel,
Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); and
S. H. Wilen Tables of Resolving Agents and Optical Resolutions 268
(E. L. Eliel ed., Univ. of Notre Dame Press, Notre Dame, Ind.,
1972, Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel
H. Wilen and Lewis N. Manda (1994 John Wiley & Sons, Inc.), and
Stereoselective Synthesis A Practical Approach, Mihaly Nogradi
(1995 VCH Publishers, Inc., NY, NY).
[0336] In certain embodiments, an enantiomerically pure compound of
Formula (I) may be obtained by reaction of the racemate with a
suitable optically active acid or base. Suitable acids or bases
include those described in Bighley et al., 1995, Salt Forms of
Drugs and Adsorption, in Encyclopedia of Pharmaceutical Technology,
vol. 13, Swarbrick & Boylan, eds., Marcel Dekker, New York; ten
Hoeve & H. Wynberg, 1985, Journal of Organic Chemistry
50:4508-4514; Dale & Mosher, 1973, J Am. Chem. Soc. 95:512; and
CRC Handbook of Optical Resolution via Diastereomeric Salt
Formation, the contents of which are hereby incorporated by
reference in their entireties.
[0337] Enantiomerically pure compounds can also be recovered either
from the crystallized diastereomer or from the mother liquor,
depending on the solubility properties of the particular acid
resolving agent employed and the particular acid enantiomer used.
The identity and optical purity of the particular compound so
recovered can be determined by polarimetry or other analytical
methods known in the art. The diastereoisomers can then be
separated, for example, by chromatography or fractional
crystallization, and the desired enantiomer regenerated by
treatment with an appropriate base or acid. The other enantiomer
may be obtained from the racemate in a similar manner or worked up
from the liquors of the first separation.
[0338] In certain embodiments, enantiomerically pure compound can
be separated from racemic compound by chiral chromatography.
Various chiral columns and eluents for use in the separation of the
enantiomers are available and suitable conditions for the
separation can be empirically determined by methods known to one of
skill in the art. Exemplary chiral columns available for use in the
separation of the enantiomers provided herein include, but are not
limited to, CHIRALCEL.RTM. OB, CHIRALCEL.RTM. OB-H, CHIRALCEL.RTM.
OD, CHIRALCEL.RTM. OD-H, CHIRALCEL.RTM. OF, CHIRALCEL.RTM. OG,
CHIRALCEL.RTM. OJ, and CHIRALCEL.RTM. OK.
Synthetic Procedures
[0339] The compounds of the invention can be prepared in accordance
with methods described in the art (Upasani et al., J Med. Chem.
1997, 40:73-84; and Hogenkamp et al., J Med. Chem. 1997, 40:61-72)
and using the appropriate reagents, starting materials, and
purification methods known to those skilled in the art. A few
representative methods are depicted below. In any of the Schemes,
depicted below, the compounds may be either 5.alpha.- or
5.beta.-isomers.
##STR00095##
##STR00096##
##STR00097##
wherein Base may be K-O-t-Bu.
##STR00098##
##STR00099##
##STR00100##
##STR00101##
##STR00102##
##STR00103##
##STR00104##
##STR00105##
##STR00106##
wherein Cy is N-containing heteroaryl.
##STR00107##
wherein Cy is heteroaryl; and X is --O-- or --S--.
Example 1. Synthesis of Compounds 8a/b, 9a/b, and 10a/b
##STR00108## ##STR00109## ##STR00110##
[0341] Synthesis of compound 2. Compound 1(500 mg, 1.84 mmol) and
10% Pd/C (20 mg) in tetrahydrofuran (5 mL) and concentrated
hydrobromic acid (0.02 mL) was hydrogenated with a hydrogen
balloon. After stirring at room temperature for 24 h, the mixture
was filtered through a pad of celite and the filtrate was
concentrated in vacuo. Recrystallization from acetone to give
compound 2 (367 mg, 1.34 mmol, 73%). .sup.1H NMR (400 MHz,
CDCl.sub.3), .delta. (ppm), 2.61-2.54 (m, 1H), 0.98 (S, 3H).
[0342] Synthesis of compound 3. To a solution of compound 2 (274
mg. 1 mmol) in methanol (4 mL) was added iodine (0.1 mmol). After
stirring at 60.degree. C. for 12 h, TLC showed no SM and the
solvent was removed in vacuo. The crude product was dissolved in
dichloromethane (20 mL) and washed with saturated NaHCO.sub.3 (15
mL), brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified by chromatography on basic
alumina (petroleum ether/ethyl acetate=9:1) to give compound 3 (280
mg, 0.87 mmol, 87%). .sup.1H NMR (400 MHz, CDCl.sub.3), .delta.
(ppm), 3.19 (S, 3H), 3.13 (S, 3H), 3.18-3.13 (m, 1H), 0.83 (S,
3H).
[0343] Synthesis of compound 4. To a suspension of t-BuOK (300 mg,
2.68 mmol) in THF (30 mL) at 0.degree. C. was added
ethyltriphenylphosphonium bromide (995 mg, 2.69 mmol) slowly. After
stirring at 60.degree. C. for 3 h, compound 3 (86 mg, 0.268 mmol)
was added and the mixture was stirred at 60.degree. C. for another
2 h. The reaction mixture was poured into saturated ammonium
chloride and extracted with EtOAc (2.times.50 mL). The combined
organic layers were washed with brine, dried over sodium sulfate,
filtered and concentrate to afford the crude compound 4 (274 mg).
The crude product was used in the next step without further
purification.
[0344] Synthesis of compound 5. To a solution of crude compound 4
(274 mg) in THF (4 mL) was acidified to pH=3 by 1 N aqueous HCl.
After stirring at room temperature for 12 h, the reaction mixture
was extracted with ethyl acetate (15 mL.times.3). The combined
organic layers were washed with brine, dried over sodium sulfate,
filtered, and concentrated. The residue was purified by column
chromatography (petroleum ether/ethyl acetate=10:1 to 5:1) to
afford compound 5 (60 mg, 0.21 mmol, 78% for two steps). .sup.1H
NMR (400 MHz, CDCl3), .delta. (ppm), 5.13-5.08 (m, 3H), 0.73 (m,
3H).
[0345] Synthesis of compound 6a and 6b. To a solution of MeMgBr (5
mmol, 1M in THF) in THF (20 mL) at 0.degree. C. was added a
solution of compound 5 (858 mg, 3 mmol) in dry THF (5 mL) via
syringe pump over 30 min. After stirring at 0.degree. C. for 5 h,
the reaction mixture was allowed to warm up and stirred at room
temperature overnight. The reaction mixture was quenched with
iced-cold water and extracted with ethyl acetate (15 mL.times.3).
The combined organic layers were washed with brine, dried over
sodium sulfate, filtered, and concentrated. The white residue was
purified by flash column chromatography (petroleum ether/ethyl
acetate=20:1 to 10:1) to give compound 6a (450 mg, 1.49 mmol, 50%;
Rf=0.35, PE:EtOAc=10:1). .sup.1H NMR (400 MHz, CDCl.sub.3), .delta.
(ppm), 5.14-5.08 (m, 1H), 1.26 (s, 3H), 0.87 (s, 3H) and compound
6b (150 mg, 0.50 mmol, 17%; Rf=0.30, PE:EtOAc=10:1). .sup.1H NMR
(400 MHz, CDCl.sub.3), .delta. (ppm), 5.14-5.09 (m, 1H), 1.21 (s,
3H), 0.88 (s, 3H).
[0346] Synthesis of compound 7a. To a solution of compound 6a (200
mg, 0.66 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran
complex (2 mL of 1.0 M solution in THF). After stirring at room
temperature for 1 hour, the reaction mixture was cooled in an ice
bath then quenched slowly with 10% aqueous NaOH (1 mL) followed 30%
aqueous solution of H.sub.2O.sub.2 (1.2 mL). The mixture was
allowed to stir at room temperature for 1 hour then extracted with
EtOAc (3.times.10 mL). The combined organic layers were washed with
10% aqueous Na.sub.2S.sub.2O.sub.3 (10 mL), brine (10 mL), dried
over MgSO.sub.4, filtered, and concentrated to afford crude
compound 7a (260 mg). The crude product was used in the next step
without further purification.
[0347] Synthesis of compound 7b. To a solution of compound 6b (150
mg, 0.50 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran
complex (1.34 mL of 1.0 M solution in THF). After stirring at room
temperature for 1 hour, the reaction mixture was cooled in an ice
bath then quenched slowly with 10% aqueous NaOH (1 mL) followed 30%
aqueous solution of H.sub.2O.sub.2 (1.2 mL). The mixture was
allowed to stir at room temperature for 1 hour then extracted with
EtOAc (3.times.10 mL). The combined organic layers were washed with
10% aqueous Na.sub.2S.sub.2O.sub.3 (10 mL), brine (10 mL), dried
over MgSO.sub.4, filtered, and concentrated to afford crude
compound 7b (200 mg). The crude product was used in the next step
without further purification.
[0348] Synthesis of compound 8a. To a solution of crude compound 7a
(260 mg) was dissolved in 10 mL of H.sub.2O saturated
dichloromethane (dichloromethane had been shaken with several
milliliters of H.sub.2O then separated from the water layer) was
added Dess-Martin periodinate (449 mg, 1.06 mmol). After stirring
at room temperature for 24 h, the reaction mixture was extracted
with dichloromethane (3.times.10 mL). The combined organic layers
were washed with 10% aqueous Na.sub.2S.sub.2O.sub.3 (10 mL), brine
(10 mL), dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified by chromatography on silica gel (petroleum
ether/ethyl acetate=4:1 to 2:1) to afford title compound 8a (85 mg,
0.27 mmol, 40% for two steps) as a white solid. .sup.1H NMR (400
MHz, CDCl.sub.3), .delta. (ppm), 2.57-2.53 (m, 1H), 2.12 (S, 3H),
1.20 (S, 3H), 0.62 (S, 3H).
[0349] Synthesis of compound 8b. To a solution of crude compound 7b
(200 mg) was dissolved in 10 mL of H.sub.2O saturated
dichloromethane (dichloromethane had been shaken with several
milliliters of H.sub.2O then separated from the water layer) was
added Dess-Martin periodinate (400 mg, 0.94 mmol). After stirring
at room temperature for 24 h, the reaction mixture was extracted
with dichloromethane (3.times.10 mL). The combined organic layers
were washed with 10% aqueous Na.sub.2S.sub.2O.sub.3 (10 mL), brine
(10 mL), dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified by chromatography on silica gel (petroleum
ether/ethyl acetate=4:1 to 2:1) to afford title compound 8b (90 mg,
0.28 mmol, 57% for two steps) as a white solid. .sup.1H NMR (400
MHz, CDCl.sub.3), .delta. (ppm), 2.55-2.51 (m, 1H), 2.11 (S, 3H),
1.32 (S, 3H), 0.61(S, 3H).
[0350] Synthesis of compound 9a. To a solution of compound 8a (70
mg, 0.22 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%)
followed by bromine (100 mg, 0.63 mmol). After stirring at room
temperature for 1 h, the reaction mixture was poured into ice-water
then extracted with ethyl acetate (15 mL.times.3). The combined
organic layers were washed with brine (20 mL), dried over
MgSO.sub.4, filtered, and concentrated to give crude compound 9a
(90 mg). The crude product was used in the next step without
further purification.
[0351] Synthesis of compound 9b. To a solution of compound 8b (80
mg, 0.25 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%)
followed by bromine (100 mg, 0.63 mmol). After stirring at room
temperature for 1 h, the reaction mixture was poured into ice-water
then extracted with ethyl acetate (15 mL.times.3). The combined
organic layers were washed with brine (20 mL), dried over
MgSO.sub.4, filtered, and concentrated to give crude compound 9b
(95 mg). The crude product was used in the next step without
further purification.
[0352] Synthesis of compound 10a. To a solution of crude compound
9a (90 mg) in acetone (10 mL) was treated with CF.sub.3COOH (0.5
mL) and EtsN (0.7 mL). After heating at reflux for 30 min,
CF.sub.3COONa salt (540 mg, 397 mmol) was added and the mixture was
refluxed for overnight. The reaction was allowed to cool to room
temperature and the solvent was removed in vacuo. The residue was
extracted with ethyl acetate (10 mL.times.3). The combined organic
layers were washed with brine (15 mL), dried over MgSO.sub.4,
filtered, and concentrated. The residue was purified by
chromatography on silica gel (petroleum ether/ethyl acetate=3:1) to
afford compound 10a (25 mg, 0.075 mmol, 34% for two steps). .sup.1H
NMR (400 MHz, CDCl.sub.3), .delta. (ppm), 4.24-4.12 (m, 2H),
2.48-2.44 (m, 1H), 1.07 (S, 3H), 0.64 (S, 3H).
[0353] Synthesis of compound 10b. To a solution of crude compound
9b (95 mg) in acetone (10 mL) was treated with CF.sub.3COOH (0.5
mL) and Et.sub.3N (0.7 mL). After heating at reflux for 30 min,
CF.sub.3COONa salt (540 mg, 3.97 mmol) was added and the mixture
was refluxed for overnight. The reaction was allowed to cool to
room temperature and the solvent was removed in vacuo. The residue
was extracted with ethyl acetate (10 mL.times.3). The combined
organic layers were washed with brine (15 mL), dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified by
chromatography on silica gel (petroleumether/ethyl acetate=3:1) to
afford compound 10b (34 mg, 0.10 mmol, 41% for two steps). .sup.1H
NMR (400 MHz, CDCl.sub.3), .delta. (ppm), 4.25-4.12 (m, 2H),
2.48-2.44 (m, 1H), 1.32 (S, 3H), 0.64 (S, 3H).
Example 2. Synthesis of Compounds 14a/b, 15a/b, and 16a/b
##STR00111## ##STR00112## ##STR00113##
[0355] Synthesis of compound 11a and 11b. To a solution of compound
5 (800 mg, 2.79 mmol) and PhSO.sub.2CF.sub.2H (540 mg, 2.79 mmol)
in THF (25 mL) and HMPA (0.5 mL) at -78.degree. C. under N.sub.2
was added LHMDS (4 mL, 1M in THF) dropwise. After stirring at
-78.degree. C. for 2 h, the reaction mixture was quenched with
saturated aqueous NH.sub.4Cl solution (10 mL) and allowed to warm
to room temperature then extracted with Et.sub.2O (20 mL.times.3).
The combined organic layers were washed with brine, dried over
sodium sulfate, filtered, and concentrate. The residue was purified
by silica gel column chromatography (petroleum ether/ethyl
acetate=10/1) to give the mixture of compound 11a and 11b (700 mg).
The mixture was further purified by chiral-HPLC to afford compound
11a (200 mg, t=4.31 min). .sup.1H NMR (400 MHz, CDCl.sub.3),
.delta. (ppm), 7.99-7.97 (d, 2H, J=7.6 Hz), 7.77-7.75 (m, 1H),
7.64-7.60 (m, 2H), 5.14-5.08 (m, 1H), 0.88 (s, 3H); compound 11b
(260 mg, t=5.66 min). 1H NMR (400 MHz, CDCl.sub.3), .delta. (ppm),
8.00-7.98 (d, 2H, J=7.6 Hz), 7.77-7.75 (in, 1H), 7.64-7.60 (m, 2H),
5.14-5.09 (m, 1H), 0.88 (s, 3H). Chiral-HPLC separation conditions:
Co-solvent: MeOH (0.1% HNEt.sub.2), Column: OZ-H (4.6*250 mm 5
.mu.m), Column Temperature: 38.9, CO.sub.2 Flow Rate: 2.10,
Co-Solvent Flow Rate: 0.9, Co-Solvent %: 30, PDA Start Wavelength:
214 nm, PDA Start Wavelength: 359 nm, Peak 1: 11a RT=4.31 min, Peak
2: 11b RT=5.66 min
[0356] Synthesis of compound 12a. To a solution of compound 11a
(100 mg, 0.209 mmol) and anhydrous Na.sub.2HPO.sub.4 (100 mg) in
anhydrous methanol (5 mL) at -20.degree. C. under N.sub.2 was added
Na/Hg amalgam (500 mg). After stirring at -20.degree. C. to
0.degree. C. for 1 h, the methanol solution was decanted out and
the solid residue was washed with Et.sub.2O (5.times.3 mL). The
combined organic layers were washed with brine (20 mL), dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified by
silica gel chromatography (petroleum ether/ethyl acetate=10/1) to
give compound 12a (30 mg, 0.089 mmol, 42%). .sup.1H NMR (400 MHz,
CDCl3), .delta. (ppm), 5.60-5.45 (t, 1H, J=60 Hz), 5.17-5.15 (m,
1H), 0.88 (m, 3H).
[0357] Synthesis of compound 12b. To a solution of compound 11 b
(100 mg, 0.209 mmol) and anhydrous Na.sub.2HPO.sub.4 (100 mg) in
anhydrous methanol (5 mL) at -20.degree. C. under N.sub.2 was added
Na/Hg amalgam (500 mg). After stirring at -20.degree. C. to
0.degree. C. for 1 h, the methanol solution was decanted out and
the solid residue was washed with Et.sub.2O (5.times.3 mL). The
combined organic layers were washed with brine (20 mL), dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified by
silica gel chromatography (petroleum ether/ethyl acetate=10/1) to
give compound 12b (36 ng, 0.106 mmol, 51%). .sup.1H NMR (400 MHz,
CDCl.sub.3), .delta. (ppm), 6.02-5.88 (t, 1H, J=49.2 Hz), 5.17-5.15
(m, 1H), 0.88 (s, 3H).
[0358] Synthesis of compound 13a. To a solution of compound 12a
(150 mg, 0.443 mmol) in dry THF (5 mL) was added
borane-tetrahydrofuran complex (1.34 mL of 1.0 M solution in THF).
After stirring at room temperature for 1 hour, the reaction mixture
was cooled in an ice bath then quenched slowly with 10% aqueous
NaOH (1 mL) followed 30% aqueous solution of H.sub.2O.sub.2 (1.2
mL). The mixture was allowed to stir at room temperature for 1 hour
then extracted with EtOAc (3.times.10 mL). The combined organic
layers were washed with 10% aqueous Na.sub.2S.sub.2O.sub.3 (10 mL),
brine (10 m), dried over MgSO.sub.4, filtered, and concentrated to
afford crude compound 13a (200 mg). The crude product was used in
the next step without further purification.
[0359] Synthesis of compound 13b. To a solution of compound 12b
(150 mg, 0.443 mmol) in dry THF (5 mL) was added
borane-tetrahydrofuran complex (1.34 mL of 1.0 M solution in THF).
After stirring at room temperature for 1 hour, the reaction mixture
was cooled in an ice bath then quenched slowly with 10% aqueous
NaOH (1 ml) followed 30% aqueous solution of H.sub.2O.sub.2 (1.2
mL). The mixture was allowed to stir at room temperature for 1 hour
then extracted with EtOAc (3.times.10 mL). The combined organic
layers were washed with 10% aqueous Na.sub.2S.sub.2O.sub.3 (10 mL),
brine (10 mL), dried over MgSO.sub.4, filtered, and concentrated to
afford crude compound 13b (210 mg). The crude product was used in
the next step without further purification.
[0360] Synthesis of compound 14a. To a solution of crude compound
13a (200 mg) was dissolved in 10 mL of H.sub.2O saturated
dichloromethane (dichloromethane had been shaken with several
milliliters of H.sub.2O then separated from the water layer) was
added Dess-Martin periodinate (449 mg, 1.06 mmol). After stirring
at room temperature for 24 h, the reaction mixture was extracted
with dichloromethane (3.times.10 mL). The combined organic layers
were washed with 10% aqueous Na.sub.2S.sub.2O.sub.3 (10 mL), brine
(10 mL), dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified by chromatography on silica gel (petroleum
ether/ethyl acetate=5:1) to afford compound 14a (85 mg, 0.24 mmol,
54%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3), .delta.
(ppm), 5.60-5.71 (t, 1H, J=56.8 Hz), 2.57-2.51 (m, 1H), 0.62 (S,
3H).
[0361] Synthesis of compound 14b. To a solution of crude compound
13b (210 mg) was dissolved in 10 mL of H.sub.2O saturated
dichloromethane (dichloromethane had been shaken with several
milliliters of H.sub.2O then separated from the water layer) was
added Dess-Martin periodinate (380 mg, 0.896 mmol). After stirring
at room temperature for 24 h, the reaction mixture was extracted
with dichloromethane (3.times.10 mL). The combined organic layers
were washed with 10% aqueous Na.sub.2S.sub.2O.sub.3 (10 mL), brine
(10 mL), dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified by chromatography on silica gel (petroleum
ether/ethyl acetate=5:1) to afford compound 14b (90 mg, 0.254 mmol,
57%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3), .delta.
(ppm), 6.01-5.73 (t, 1H, J=56.4 Hz), 2.55-2.54 (m, 1H), 2.12 (S,
3H), 0.62 (S, 3H).
[0362] Synthesis of compound 15a. To a solution of compound 14a (70
mg, 0.197 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%)
followed by bromine (100 mg, 0.63 mmol). After stirring at room
temperature for 1 h, the reaction mixture was poured into ice-water
then extracted with ethyl acetate (15 mL.times.3), The combined
organic layers were washed with brine (20 mL), dried over
MgSO.sub.4, filtered, and concentrated to give crude compound 15a
(90 mg). The crude product was used in the next step without
further purification.
[0363] Synthesis of compound 15b. To a solution of compound 14b (80
mg, 0.226 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%)
followed by bromine (100 mg, 0.63 mmol). After stirring at room
temperature for 1 h, the reaction mixture was poured into ice-water
then extracted with ethyl acetate (15 mL.times.3), The combined
organic layers were washed with brine (20 mL), dried over
MgSO.sub.4, filtered, and concentrated to give crude compound 15b
(95 mg). The crude product was used in the next step without
further purification.
[0364] Synthesis of compound 16a. To a solution of crude compound
15a (90 mg) in acetone (10 mL) was treated with CF.sub.3COOH (0.5
mL) and Et.sub.3N (0.7 mL). After heating at reflux for 30 min,
CF.sub.3COONa salt (540 mg, 3.9 mmol) was added and the mixture was
refluxed for overnight. The reaction was allowed to cool to room
temperature and the solvent was removed in vacuo. The residue was
extracted with ethyl acetate (10 ml.times.3). The combined organic
layers were washed with brine (15 mL), dried over MgSO.sub.4,
filtered, and concentrated. The residue was purified by
chromatography on silica gel (petroleumether/ethyl acetate=3:1) to
afford compound 16a (25 mg, 0.067 mmol, 34% for two steps). .sup.1H
NMR (400 MHz, CDCl.sub.3), .delta. (ppm), 5.60-5.31 (t, 1H, J=56.8
Hz), 4.22-4.18 (m, 2H), 0.64 (S, 3H).
[0365] Synthesis of compound 16b. To a solution of crude compound
15b (95 mg) in acetone (10 mL) was treated with CF.sub.3COOH (0.5
mL) and Et.sub.3N (0.7 mL). After heating at reflux for 30 min,
CF.sub.3COONa salt (540 mg, 3.9 mmol) was added and the mixture was
refluxed for overnight. The reaction was allowed to cool to room
temperature and the solvent was removed in vacuo. The residue was
extracted with ethyl acetate (10 mL.times.3) The combined organic
layers were washed with brine (15 mL), dried over MgSO.sub.4,
filtered, and concentrated. The residue was purified by
chromatography on silica gel (petroleum:ether/ethyl acetate=3:1) to
afford compound 16b (38 mg, 0.102 mmol, 46% for two steps). .sup.1H
NMR (400 MHz, CDCl3), .delta. (ppm), 6.00-5.74 (t, 1H, J=51.2 Hz),
4.42-4.18 (m, 2H), 0.64 (S, 3H).
Example 3. Synthesis of Compounds 9, 9a/b/c and 11a/b
##STR00114## ##STR00115## ##STR00116##
[0367] Synthesis of compound 5. To a solution of 4 (5 g, 15 mmol)
in dry THF (20 mL) was added borane-tetrahydrofuran complex (30 ml
of 1.0 M solution in THF). After stirring at room temperature for 1
hour, the reaction mixture was cooled in an ice bath and quenched
slowly with 10% aqueous NaOH (56 mL) followed by 30% aqueous
solution of H.sub.2O.sub.2(67 mL). The reaction mixture was stirred
at room temperature for 1 hour then extracted with EtOAc
(3.times.100 mL). The combined organic layers were washed with 10%
aqueous Na.sub.2S.sub.2O.sub.3 (100 mL), brine (100 mL), dried over
MgSO.sub.4, filtered, and concentrated to afford the crude product
5 (3.2 g, 9.0 mmol). The crude product was used in the next step
without further purification.
[0368] Synthesis of compound 6. To a solution of compound 5 (3.2 g,
9 mmol) in THF (40 mL) was added hydrogen chloride (3 mL, 3 M
aqueous solution). After stirring at room temperature for 12 hours,
the solvent was removed under reduced pressure, and the residue was
purified by silica gel chromatography (petroleum ether/ethyl
acetate=10:1 to 5:1) to give compound 6 (2.2 g, 81%) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3), .delta. (ppm), 3.82-3.93
(m, 1H), 2.58-2.62 (m, 1H), 2.19-2.23 (m, 4H), 0.72 (s, 3H).
[0369] Synthesis of compound 7. To a solution of
trimethylsulfoxonium iodide (8.1 g, 36.9 mmol) in DMSO (100 mL) was
added NaH (60%; 1.26 g, 31.5 mmol). After stirring at room
temperature for 1 h, a suspension of compound 6 (2.2 g, 7.2 mmol)
in DMSO (20 mL) was added dropwise. After stirring at room
temperature for another 2.5 h, the reaction mixture was poured into
ice-cold water and extracted with ether (100 mL.times.3). The
combined organic layers were washed with brine (100 mL.times.3),
dried over (MgSO.sub.4), filtered, and concentrated to give
compound 7 (1.6 g, 70%) as a white solid. .sup.1H NMR (400 MHz,
CDCl3), .delta. (ppm), 3.69-3.71 (m, 1H), 2.56-2.61 (m, 2H),
2.21-2.28 (m, 1H), 0.68 (s, 3H).
[0370] Synthesis of compound 8. To a solution of compound 7 (1.6 g,
5.0 mmol) in 60 mL of H.sub.2O saturated dichloromethane
(CH.sub.2Cl.sub.2 had been shaken with several milliliters of
H.sub.2O then separated from the water layer) was added Dess-Martin
periodinane (4.2 g, 10 mmol). After stirring at room temperature
for 24 h, the reaction mixture was extracted with dichloromethane
(3.times.100 mL). The combined organic layers were washed with 10%
aqueous Na.sub.2S.sub.2O.sub.3 (100 mL), brine (100 mL), dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified by
chromatography on silica gel (petroleum ether/ethyl acetate=20:1 to
10:1) to afford compound 8 (1.2 g, 75%) as a white solid. .sup.1H
NMR (400 MHz, CDCl3), .delta. (ppm), 2.50-2.58 (m, 2H), 2.56-2.61
(m, 2H), 2.19 (s, 3H), 0.65 (s, 3H).
[0371] Synthesis of compound 9. To a solution of compound 8 (1.2 g,
3.8 mmol) in dry methanol (250 mL) was added Na (262 mg, 11.4
mmol). After heating at reflux for 16 h, the solvent was removed in
vacuo and the residue was dissolved in dichloromethane (100 mL)
then washed with H.sub.2O (3.times.50 mL) and brine (100 mL), dried
over MgSO.sub.4, filtered, and concentrated. The residue was
purified by silica gel chromatography (petroleum ether/ethyl
acetate=10:1 to 5:1) to afford compound 9a (300 mg, 25%), 9b (100
mg, 8%) and 9c (20 mg, 2%) as a white solid. Compound 9a: .sup.1H
NMR (400 MHz, CDCl3), .delta. (ppm), 3.38-3.43 (m, 5H), 2.52-2.56
(m, 1H), 2.16 (s, 3H), 0.60 (s, 3H). Compound 9b: .sup.1H NMR (400
MHz, CDCl3), .delta. (ppm), 3.39 (s, 3H), 3.20 (s, 2H), 2.48-2.54
(m, 1H), 2.70 (s, 3H), 0.61 (s, 3H). Compound 9c: .sup.1H NMR (400
MHz, CDCl3), .delta. (ppm), 3.39 (s, 3H), 3.18 (s, 2H), 2.81-2.83
(d, 1H), 2.65 (s, 3H), 0.61 (s, 3H).
[0372] Synthesis of compound 10a. To a solution of compound 9a (50
mg, 0.14 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%)
followed by bromine (6 drops). After stirring at room temperature
for 1 h, the reaction mixture was poured into ice-water then
extracted with ethyl acetate (15 mL.times.3). The combined organic
layers were washed with brine (50 mL), dried over MgSO.sub.4,
filtered, and concentrated to give compound 10a (46 mg. 0.11 mmol).
The crude product was used in the next step without further
purification. Synthesis of compound 11a. To a solution of compound
10a (46 mg, 0.11 mmol) in acetone (10 mL) was treated with
CF.sub.3COOH (0.5 mL) and Et.sub.3N (0.7 mL). After heating at
refluxed for 30 min, CF.sub.3COONa (300 mg, 2.2 mmol) was added in
parts over a period of 10 hr. The reaction mixture was allowed to
cool to room temperature and the solvent was removed in vacuo. The
residue was extracted with ethyl acetate (10 mL.times.3). The
combined organic layers were washed with brine (30 mL), dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified by
chromatography on silica gel (petroleum ether/ethyl acetate=10:1 to
3:1) to afford compound 11a (10 mg, 25%). Compound 11a: .sup.1H NMR
(400 MHz, CDCl3), .delta. (ppm), 4.17-4.98 (m, 2H), 3.39-3.40 (m,
5H), 2.44-2.52 (m, 1H), 2.18-2.24 (m, 1H), 0.63 (s, 3H).
[0373] Synthesis of compound 10b. To a solution of compound 9b (50
mg, 0.14 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%)
followed by bromine (6 drops). After stirring at room temperature
for 1 h, the reaction mixture was poured into ice-water then
extracted with ethyl acetate (15 mL.times.3). The combined organic
layers were washed with brine (50 mL), dried over MgSO.sub.4,
filtered, and concentrated to give compound 10b (46 mg, 0.11 mmol).
The crude product was used in the next step without further
purification.
[0374] Synthesis of compound 11b. To a solution of compound 10b (46
mg, 0.11 mmol) in acetone (10 mL) was treated with CF.sub.3COOH
(0.5 mL) and Et.sub.3N (0.7 mL). After heating at refluxed for 30
min, CF.sub.3COONa (300 mg, 2.2 mmol) was added in parts over a
period of 10 hr. The reaction mixture was allowed to cool to room
temperature and the solvent was removed in vacuo. The residue was
extracted with ethyl acetate (10 mL.times.3). The combined organic
layers were washed with brine (30 mL), dried over MgSO.sub.4,
filtered, and concentrated. The residue was purified by
chromatography on silica gel (petroleum ether/ethyl acetate=10:1 to
3:1) to afford compound 11b (10 mg, 25%). Compound 11b: .sup.1H NMR
(400 MHz, CDCl.sub.3), .delta. (ppm), 4.16-4.19 (m, 2H), 3.39 (s,
3H), 3.32 (s, 1H), 3.20 (s, 2H), 2.23-2.45 (m, 1H), 2.00-2.12 (m,
2H), 0.64 (s, 3H).
Example 3. Synthesis of 6-Difluoro Analogs
##STR00117## ##STR00118##
[0375] Example 4. Synthesis of 5,6-alkenyl-6-Monofluoro Analogs
##STR00119## ##STR00120##
[0376] Example 5. Synthesis of 6.beta.-Me Analogs
##STR00121## ##STR00122##
##STR00123##
[0377] Example 6
##STR00124## ##STR00125## ##STR00126##
[0379] Synthesis of compounds 39 and 40. Small pieces of lithium
(7.63 g, 1.1 mol) were added to 2.7 L of condensed ammonia in a
three neck flask at -70.degree. C. As soon as all lithium was
dissolved, the blue solution was warmed to -50.degree. C. A
solution of 19-norandrost-4-ene-3,17-dione 1(1, 30 g, 110 mmol) and
tert-BuOH (8.14 g, 110 mmol) in 800 ml of anhydrous tetrahydrofuran
was added dropwise and stirred for 90 min until the reaction
mixture turned light yellow. Ammonium chloride (70 g) was added and
excess ammonia was left to evaporate. The residue was extracted
with 0.5N HC (500 mL) and dichloromethane (500 mL.times.2). The
combined organic layers were washed with saturated
NaHCO.sub.3solution, dried over Na.sub.2SO.sub.4, filtered and
concentrated to give a mixture of 39 and 40 (21 g, 70% o) which was
directly used in the next step without further purification. A
solution of 39 and 40 (21 g, 76 mmol) in 50 mL of anhydrous
dichloromethane was added to a suspension of pyridinium
chlorochromate (PCC) (32.8 g, 152 mmol) in 450 mL of
dichloromethane. After stirring at room temperature for 2 h, 2N
NaOH solution (500 mL) was added to the dark brown reaction mixture
and stirred for another 10 min. The resulting solution was
extracted with dichloromethane, the combined organic layers were
washed with 2N HCl, brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated. The residue was purified by chromatography on
silica gel (petroleum ether/ethyl acetate=20:1 to 10:1) to afford
title compound 40 (16.8 g, 80%) as a white solid. .sup.1H NMR of 39
(400 MHz, CDCl.sub.3), .delta. (ppm), 3.65 (t, 1H, J=8 Hz, 1H),
0.77 (s, 3H). .sup.1H NMR of 40 (400 MHz, CDCl.sub.3), .delta.
(ppm), 0.88 (s, 3H).
[0380] Synthesis of compound 41. To a solution of compound 40 (16.8
g. 61.3 mmol) in methanol (250 mL) was added iodine (1.54 g, 6.1
mmol). After stirring at 60.degree. C. for 12 h, the solvent was
removed in vacuo. The crude product was dissolved in
dichloromethane (200 mL) and washed with saturated NaHCO.sub.3 (150
mL), brine, dried over Na.sub.2SO.sub.4, filtered and concentrated.
The residue was purified by chromatography on basic alumina
(petroleum ether/ethyl acetate=100:1) to give compound 41(14 g,
43.8 mmol, 71%). .sup.1H NMR (400 MHz, CDCl.sub.3), .delta. (ppm),
3.18 (s, 3H), 3.12 (s, 3H), 0.85 (s, 3H).
[0381] Synthesis of compound 42. To a suspension of t-BuOK (7.36 g,
65.7 mmol) in THF (100 mL) at 0.degree. C. was added
ethyltriphenylphosphonium bromide (26 g, 70 mmol) slowly. After
stirring at 60.degree. C. for 3 h, compound 41(7 g, 21.9 mmol) was
added and the mixture was stirred at 60.degree. C. for another 2 h.
After cooling to room temperature, the reaction mixture was poured
into saturated ammonium chloride and extracted with EtOAc
(2.times.500 mL). The combined organic layers were washed with
brine, dried over sodium sulfate, filtered and concentrate to
afford the crude compound 42 (7.36 g, 100%). The crude product was
used in the next step without further purification.
[0382] Synthesis of compound 43. A solution of crude compound 42
(7.36 g, 21.9 mmol) in THF (50 mL) was acidified to pH=3 by 1N
aqueous HCl. After stirring at room temperature for 12 h, the
reaction mixture was extracted with ethyl acetate (250 mL.times.3).
The combined organic layers were washed with brine, dried over
sodium sulfate, filtered and concentrated. The residue was purified
by column chromatography (petroleum ether/ethyl acetate=30:1 to
20:1) to afford compound 43 (4.8 g, 16.7 mmol, 76% for two steps).
.sup.1H NMR (400 MHz, CDCl.sub.3), .delta. (ppm), 5.12-5.10 (m,
1H), 1.64-1.63 (m, 3H), 0.77 (s, 3H).
[0383] Synthesis of compound 44a and 44b. To a solution of MeMgBr
(28 mmol, 1M in THF) in THF (50 mL) at 0.degree. C. was added a
solution of compound 43 (4.8 g, 16.8 mmol) in dry THF (10 mL) via
syringe pump over 30 min. After stirring at 0.degree. C. for 5 h,
the reaction mixture was allowed to warm up and stirred at room
temperature overnight. The reaction mixture was quenched with
iced-cold water and extracted with ethyl acetate (150 mL.times.3).
The combined organic layers were washed with brine, dried over
sodium sulfate, filtered and concentrated. The white residue was
purified by flash column chromatography (petroleum ether/ethyl
acetate=20:1 to 10:1) to give compound 44a (2.5 g, 8.28 mmol, 49%;
Rf=0.35, PE:EtOAc=10:1). .sup.1H NMR (400 MHz, CDCl.sub.3), .delta.
(ppm), 5.05-5.03 (m, 1H), 1.21 (s, 3H), 0.90 (s, 3H) and compound
44b (800 mg, 2.64 mmol, 16%; Rf=0.30, PE:EtOAc=10:1). .sup.1H NMR
(400 MHz, CDCl.sub.3), .delta. (ppm), 5.12-5.10 (m, 1H), 1.12 (s,
3H), 0.88 (s, 3H).
[0384] Synthesis of compound 45a. To a solution of compound 44a (2
g, 6.62 mmol) in dry THF (50 mL) was added borane-tetrahydrofuran
complex (20 mL; 1.0 M solution in THF). After stirring at room
temperature for 1 hour, the reaction mixture was cooled in an ice
bath then quenched slowly with 10% aqueous NaOH (10 mL) followed by
30% aqueous solution of H.sub.2O.sub.2 (12 mL). After stirring at
room temperature for one hour, the mixture was extracted with EtOAc
(3.times.100 mL). The combined organic layers were washed with 10%
aqueous Na.sub.2S.sub.2O.sub.3 (100 mL), brine (100 mL), dried over
MgSO.sub.4, filtered and concentrated to afford crude compound 45a
(2 g, 100%). The crude product was used in the next step without
further purification.
[0385] Synthesis of compound 46a. To a solution of crude compound
45a (2 g, 6.62 mmol) in 60 mL of wet dichloromethane
(dichloromethane had been shaken with several milliliters of
H.sub.2O then separated from the water layer) was added Dess-Martin
periodinate (5.5 g, 13 mmol). After stirring at room temperature
for 24 h, the reaction mixture was extracted with dichloromethane
(3.times.100 mL). The combined organic layers were washed with 10%
aqueous Na.sub.2S.sub.2O.sub.3 (100 mL), brine (100 mL), dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
chromatography on silica gel (petroleum ether/ethyl acetate=10:1 to
5:1) to afford compound 46a (1 g, 3.14 mmol, 47% for two steps) as
a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3), .delta. (ppm),
2.56-2.51 (m, 1H), 2.11 (s, 3H), 1.20 (s, 3H), 0.62 (s, 3H).
[0386] Synthesis of compound 47a. To a solution of compound 46a
(600 mg, 1.89 mmol) in MeOH (20 mL) was added 5 drops of HBr (48%)
followed by bromine (302 mg, 1.89 mmol). After stirring at room
temperature for 1 h, the reaction mixture was poured into ice-water
then extracted with ethyl acetate (100 mL.times.3). The combined
organic layers were washed with brine (200 mL), dried over
MgSO.sub.4, filtered and concentrated to give crude compound 47a
(600 mg). The crude product was used in the next step without
further purification.
[0387] Synthesis of compound 48a. A solution of compound 47a (600
mg, 1.5 mmol) in acetone 10 mL was treated with CF.sub.3COOH (6.8
mL) and Et.sub.3N (9.5 mL). After refluxed for 30 min,
CF.sub.3COONa salt (4.49 g, 33 mmol) was added in parts over a
period of 10 hr. The reaction mixture was allowed to cool to room
temperature and the solvent was removed in vacuo. The residue was
extracted with ethyl acetate, dried over MgSO.sub.4, filtered and
concentrated. The mixture was purified by chromatography on silica
gel (petroleum ether/ethyl acetate=10:1 to 3:1) to afford 48a (300
mg, yield: 50% for two steps). .sup.1H NMR (400 MHz, CDCl.sub.3),
.delta. (ppm), 4.23-4.13 (m, 2H), 2.48-2.44 (m, 1H), 2.24-2.17 (m,
1H), 1.20 (s, 3H), 0.64 (s, 3H).
[0388] Synthesis of compound 45b. To a solution of compound 44b
(500 mg, 1.66 mmol) in dry THF (13 mL) was added
borane-tetrahydrofuran complex (5 mL; 1.0 M solution in THF). After
stirring at room temperature for 1 hour, the reaction mixture was
cooled in an ice bath then quenched slowly with 10% aqueous NaOH
(2.5 mL) followed 30% aqueous solution of H.sub.2O.sub.2 (3 mL).
The mixture was allowed to warm to room temperature and stirred for
1 hour then extracted with EtOAc (3.times.25 mL). The combined
organic layers were washed with 10% aqueous Na.sub.2S.sub.2O.sub.3
(25 mL), brine (25 mL), dried over MgSO.sub.4, filtered and
concentrated to afford crude compound 45b (500 mg). The crude
product was used in the next step without further purification.
[0389] Synthesis of compound 46b. To a solution of crude compound
45b (500 mg, 1.66 mmol) in 15 mL wet dichloromethane
(dichloromethane had been shaken with several milliliters of
H.sub.2O then separated from the water layer) was added Dess-Martin
periodinate (1.38 g, 3.3 mmol). After stirring at room temperature
for 24 h, the reaction mixture was extracted with dichloromethane
(3.times.25 mL). The combined organic layers were washed with 10%
aqueous Na.sub.2S.sub.2O.sub.3 (25 mL), brine (25 mL), dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
chromatography on silica gel (petroleum ether/ethyl acetate=10:1 to
5:1) to afford title compound 46b (250 mg, 0.79 mmol, 47% for two
steps) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3), .delta.
(ppm), 2.54-2.50 (m, 1H), 2.11 (s, 3H), 1.23 (s, 3H), 0.62 (s,
3H).
[0390] Synthesis of compound 47b. To a solution of compound 46b
(250 mg, 0.79 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%)
followed by bromine (126 mg, 0.79 mmol). After stirring at room
temperature for 1 h, the reaction mixture was poured into ice-water
then extracted with ethyl acetate (10 mL.times.3). The combined
organic layers were washed with brine (20 mL), dried over
MgSO.sub.4, filtered and concentrated to give crude compound 47b
(250 mg). The crude product was used in the next step without
further purification.
[0391] Synthesis of compound 48b. A solution of compound 47b (60
mg, 0.15 mmol) in acetone (10 mL) was treated with CF.sub.3COOH
(0.7 mL) and Et.sub.3N (0.9 mL). After refluxed for 30 min,
CF.sub.3COONa salt (449 mg, 3.3 mmol) was added in parts over a
period of 10 hr. The reaction mixture was allowed to cool to room
temperature and the solvent was removed in vacuo. The residue was
extracted with ethyl acetate, dried over MgSO.sub.4, filtered and
concentrated. The residue was purified by chromatography on silica
gel (petroleum ether/ethyl acetate=10:1 to 3:1) to afford 48b (20
mg, yield: 33% for two steps). H NMR (400 MHz, CDCl.sub.3), .delta.
(ppm), 4.24-4.12 (m, 2H), 2.48-2.43 (m, 1H), 2.24-2.16 (m, 1H),
1.23 (s, 3H), 0.64 (s, 3H).
Example 7
##STR00127## ##STR00128## ##STR00129##
[0393] Synthesis of compound 49a and 49b. To a solution of compound
43 (800 mg, 2.79 mmol) and PhSO.sub.2CF.sub.2H (540 mg, 2.79 mmol)
in THF (25 mL) and HMPA (0.5 mL) at -78.degree. C. under N.sub.2
was added LHMDS (4 mL, 1M in THF) dropwise. After stirring at
-78.degree. C. for 2 h, the reaction mixture was quenched with
saturated aqueous NH.sub.4Cl solution (10 mL) and allowed to warm
to room temperature then extracted with Et.sub.2O (20 mL.times.3).
The combined organic layers were washed with brine, dried over
sodium sulfate, filtered and concentrate. The residue was purified
by silica gel column chromatography (petroleum ether/ethyl
acetate=10/1) to give the mixture of compound 49a and 49b (650 mg).
The mixture was further purified by chiral-HPLC to afford compound
49a (250 mg, t=3.29 min) and 49b (230 mg, t=3.89 min). Chiral-HPLC
conditions: Elutant=MeOH (0.1% DEA); Column=AS-H (4.6*250 mm, 5
um).
[0394] Synthesis of compound 50a. To a solution of compound 49a
(250 mg, 0.524 mmol) and anhydrous Na.sub.2HPO.sub.4 (150 mg) in
anhydrous methanol (5 mL) at -20.degree. C. under N.sub.2 was added
Na/Hg amalgam (800 mg). After stirring at -20.degree. C. to
0.degree. C. for 1 h, the methanol solution was decanted out and
the solid residue was washed with Et.sub.2O (5.times.3 mL). The
combined organic phase was removed under vacuum, and 20 ml brine
was added, followed by extracting with Et.sub.2O. The combined
ether phase was dried with MgSO.sub.4, filtered and concentrated.
The crude product was purified by silica gel chromatography
(PE/EA=10/1) to give compound 49a (130 mg, 73%). .sup.1H NMR (400
MHz, CDCl.sub.3), .delta. (ppm), 5.60-5.30 (t, 1H, J=63.6 Hz),
5.14-5.09 (m, 1H), 0.88 (m, 3H).
[0395] Synthesis of compound 50b. To a solution of compound 49b
(230 mg, 0.489 mmol) and anhydrous Na.sub.2HPO.sub.4 (150 mg) in
anhydrous methanol (5 mL) at -20.degree. C. under N.sub.2 was added
Na/Hg amalgam (700 mg). After stirring at -20.degree. C. to
0.degree. C. for 1 h, the methanol solution was decanted out and
the solid residue was washed with Et.sub.2O (5.times.3 mL). The
combined organic phase was removed under vacuum and 20 ml brine was
added, followed by extracting with Et.sub.2O. The combined ether
phase was dried with MgSO.sub.4, filtered and concentrated. The
crude product was purified by silica gel chromatography
(PE/EA=10/1) to give compound 50b (120 mg, 73%). .sup.1H NMR (400
MHz, CD.sub.3COCD.sub.3), .delta. (ppm), 6.02-5.88 (t, 1H, J=59.6
Hz), 5.13-5.08 (m, 1H), 0.92 (s, 3H).
[0396] Synthesis of compound 51a. To a solution of compound 50a
(130 mg, 0.384 mmol) in dry THF (5 mL) was added
borane-tetrahydrofuran complex (1.3 mL; 1.0 M solution in THF).
After stirring at room temperature for 1 hour, the reaction mixture
was cooled in an ice bath then quenched slowly with 10% aqueous
NaOH (1 mL) followed by 30% aqueous solution of H.sub.2O.sub.2 (1.2
mL). The mixture was allowed to stir at room temperature for 1 hour
then extracted with EtOAc (3.times.10 mL). The combined organic
layers were washed with 10% aqueous Na.sub.2S.sub.2O.sub.3 (10 mL),
brine (10 mL), dried over MgSO.sub.4, filtered and concentrated to
afford compound 51a (200 mg, crude). The crude product was used in
the next step without further purification.
[0397] Synthesis of compound 51b. To a solution of compound 50b
(120 mg, 0.355 mmol) in dry THF (5 mL) was added
borane-tetrahydrofuran complex (1.20 mL; 1.0 M solution in THF).
After stirring at room temperature for 1 hour, the reaction mixture
was cooled in an ice bath then quenched slowly with 10% aqueous
NaOH (1 mL) followed by 30% aqueous solution of H.sub.2O.sub.2 (1.2
mL). The mixture was allowed to stir at room temperature for 1 hour
then extracted with EtOAc (3.times.10 mL). The combined organic
layers were washed with 10% aqueous Na.sub.2S.sub.2O.sub.3 (10 mL),
brine (10 mL), dried over MgSO.sub.4, filtered and concentrated to
afford compound 51b (180 mg, crude). The crude product was used in
the next step without further purification.
[0398] Synthesis of compound 52a. To a solution of compound 51a
(200 mg, crude) in 10 mL of wet dichloromethane (dichloromethane
had been shaken with several milliliters of H.sub.2O then separated
from the water layer) was added Dess-Martin periodinate (400 mg,
0.94 mmol). After stirring at room temperature for 24 h, the
reaction mixture was extracted with dichloromethane (3.times.10
mL). The combined organic layers were washed with 10'% aqueous
Na.sub.2S.sub.2O.sub.3 (10 mL), brine (10 mL), dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
chromatography on silica gel (petroleum ether/ethyl acetate=1:5) to
afford compound 52a (75 mg, 55.1% for two steps) as a white solid.
.sup.1H NMR (400 MHz, CDCl3), .delta. (ppm), 5.58-5.32 (t, 1H,
J=52.0 Hz), 2.53-2.51 (m, 1H), 2.14 (s, 3H), 0.62 (s, 3H).
[0399] Synthesis of compound 52b. To a solution of compound 51b
(180 mg, crude) in 10 mL of wet dichloromethane (dichloromethane
had been shaken with several milliliters of H.sub.2O then separated
from the water layer) was added Dess-Martin periodinate (380 mg,
0.896 mmol). After stirring at room temperature for 24 h, the
reaction mixture was extracted with dichloromethane (3.times.10
mL). The combined organic layers were washed with 10% aqueous
Na.sub.2S.sub.2O.sub.3 (10 mL), brine (10 mL), dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
chromatography on silica gel (petroleum ether/ethyl acetate=1:5) to
afford compound 52b (70 mg, 55.7% for two steps) as a white solid.
.sup.1H NMR (400 MHz, CDCl3), .delta. (ppm), 5.90-5.61 (t, 1H, J=60
Hz), 2.48-2.43 (m, 1H), 2.10 (s, 3H), 0.55 (s, 3H).
[0400] Synthesis of compound 53a. To a solution of compound 52a (40
mg, 0.113 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%)
followed by bromine (100 mg, 0.62 mmol). After stirring at room
temperature for 1 h, the reaction mixture was poured into ice-water
then extracted with ethyl acetate (15 mL.times.3). The combined
organic layers were washed with brine (20 mL), dried over
MgSO.sub.4, filtered and concentrated to give compound 53a (84 mg,
crude). The crude product was used in the next step without further
purification.
[0401] Synthesis of compound 53b. To a solution of compound 52b (50
mg, 0.14 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%)
followed by bromine (100 mg, 0.62 mmol). After stirring at room
temperature for 1 h, the reaction mixture was poured into ice-water
then extracted with ethyl acetate (15 mL.times.3). The combined
organic layers were washed with brine (20 mL), dried over
MgSO.sub.4, filtered and concentrated to give compound 53b (72 mg,
crude). The crude product was used in the next step without further
purification.
[0402] Synthesis of compound 54a. To a solution of compound 53a (84
mg, crude) in acetone (6 mL) was treated with CF.sub.3COOH (0.3 mL)
and Et.sub.3N (0.5 mL). After heating at reflux for 30 min,
CF.sub.3COONa salt (432 mg, 3.12 mmol) was added and the mixture
was refluxed for overnight. The reaction was allowed to cool to
room temperature and the solvent was removed in vacuo. The residue
was extracted with ethyl acetate (10 mL.times.3). The combined
organic layers were washed with brine (15 mL), dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
chromatography on silica gel (petroleum ether/ethyl acetate=3:1) to
afford compound 54a (15 mg, 36% for two steps). .sup.1H NMR (500
MHz, CDCl3), .delta. (ppm), 5.56-5.33 (t, 1H, J=56.5 Hz), 4.22-4.13
(m, 2H), 3.25-3.23 (m, 1H), 0.64 (s, 3H).
[0403] Synthesis of compound 54b. To a solution of compound 53b (72
mg, crude) in acetone (5 mL) was treated with CF.sub.3COOH (0.3 mL)
and Et.sub.3N (0.45 mL). After heating at reflux for 30 min,
CF.sub.3COONa salt (270 mg, 1.95 mmol) was added and the mixture
was refluxed for overnight. The reaction was allowed to cool to
room temperature and the solvent was removed in vacuo. The residue
was extracted with ethyl acetate (10 mL.times.3). The combined
organic layers were washed with brine (10 ml), dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
chromatography on silica gel (petroleum ether/ethyl acetate=3:1) to
afford compound 54b (10 mg, 19.2% for two steps). .sup.1H NMR (400
MHz, CDCl3), .delta. (ppm), 5.96-5.68 (t, 1H, J=56 Hz), 4.24-4.10
(m, 2H), 3.2 (s, 1H), 0.64 (s, 3H).
Example 8
##STR00130## ##STR00131## ##STR00132##
[0405] Synthesis of compound 55a and 55b. To a solution of compound
5 (1.2 g, 4.2 mmol) and PhSO.sub.2CF.sub.2I (730 mg, 4.2 mmol) in
THF (25 mL) and HMPA (0.5 mL) at -78.degree. C. under N.sub.2 was
added LHMDS (5.5 mL, 1M in THE) dropwise. After stirring at
-78.degree. C. for 2 h, the reaction mixture was quenched with
saturated aqueous NH.sub.4Cl solution (10 mL). The mixture was
allowed to warm to room temperature and extracted with Et.sub.2O
(20 mL.times.3). The combined organic layers were washed with
brine, dried over sodium sulfate, filtered and concentrated. The
residue was purified by silica gel column chromatography (petroleum
ether/ethyl acetate=10/1) to give the mixture of compound 55a and
55b (1.4 g). The mixture was further purified by chiral-HPLC to
afford compound 55a1 (220 mg, t=362 min). .sup.1H NMR (500 MHz,
CDCl3), (ppm), 99-7.97 (d, 2H, J=7.6 Hz), 7.76-7.72 (m, 1H),
7.62-7.60 (m, 2H), 5.17-5.13 (m, 1H), 4.88-4.78 (d, 1H, J=46 Hz),
0.88 (s, 3H); 55a2 (200 mg, t=3.94 min) H NMR (500 MHz, CDCl3),
.delta. (ppm), 7.97-7.95 (d, 2H, J=7.6 Hz), 7.77-7.76 (m, 1H),
7.66-7.62 (m, 2H), 5.11-5.10 (m, 1H), 4.88-4.78 (d, 1H, J=46 Hz),
0.88 (s, 3H); 55b1 (235 mg, t=4.95 min). H NMR (500 MHz, CDCl3),
.delta. (ppm), 7.98-7.96 (d, 2H, J=7.5 Hz), 7.72-7.76 (m, 1H),
7.62-7.59 (m, 2H), 5.37-5.27 (d, 1H, J=46 Hz), 5.07-5.05 (m, 1H),
0.88 (s, 3H); 55b2 (220 mg, t=6.92 mi). .sup.1H NMR (500 MHz,
CDCl3), .delta. (ppm), 7.98-7.96 (d, 2H, J=7.5 Hz), 7.76-7.72 (m,
1H), 7.62-7.59 (m, 2H), 5.37-5.27 (d, 1H, J=46 Hz), 5.07-4.98 (m,
1H), 0.88 (s, 3H). Chiral-HPLC conditions: Elutant=MeOH (0.1% DEA);
Column=IC (4.6*250 mm, 5 um).
[0406] Synthesis of compound 56a. To a solution of compound 55a1
(200 mg, 0.434 mmol) and anhydrous Na.sub.2PO.sub.4 (100 mg) in
anhydrous methanol (15 mL) at -20.degree. C. under N.sub.2 was
added Na/Hg amalgam (400 mg). After stirring at -20.degree. C. to
0.degree. C. for 1 h, the methanol solution was decanted out and
the solid residue was washed with Et.sub.2O (5.times.3 mL). The
combined organic phase was removed under vacuum, and 20 mL brine
was added, followed by extracting with Et.sub.2O. The combined
ether phase was dried with MgSO.sub.4, filtered and concentrated.
The crude product was purified by silica gel chromatography
(PE/EA=10/1) to give compound 56a (90 mg, 65%). .sup.1H NMR (500
MHz, CDCl3), .delta. (ppm), 5.12-5.11 (m, 1H), 4.2-4.15 (d, 2H,
J=48 Hz), 0.62 (s, 3H).
[0407] Synthesis of compound 56b. To a solution of compound 55b2
(200 mg, 0.434 mmol) and anhydrous Na.sub.2HPO.sub.4 (100 mg) in
anhydrous methanol (5 mL) at -20.degree. C. under N.sub.2 was added
Na/Hg amalgam (500 mg). After stirring at -20.degree. C. to
0.degree. C. for 1 h, the methanol solution was decanted out and
the solid residue was washed with Et.sub.2O (5.times.3 mL). The
combined organic phase was removed under vacuum, and 20 mL brine
was added, followed by extracting with Et.sub.2O. The combined
ether phase was dried with MgSO.sub.4, filtered and concentrated.
The crude product was purified by silica gel chromatography
(PE/EA=10/1) to give compound 56b (95 mg, 68%). .sup.1H NMR (500
MHz, CDCl3), .delta. (ppm), 5.14-4.10 (m, 1H), 4.50-4.35 (m, 2H),
0.79 (s, 3H).
[0408] Synthesis of compound 57a. To a solution of compound 56a (90
mg, 0.281 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran
complex (1 mL; 1.0 M solution in THF). After stirring at room
temperature for 1 hour, the reaction mixture was cooled in an ice
bath then quenched slowly with 10% aqueous NaOH (1 mL) followed by
30% aqueous solution of H.sub.2O.sub.2 (1.2 mL). The mixture was
allowed to stir at room temperature for 1 hour then extracted with
EtOAc (3.times.10 mL). The combined organic layers were washed with
10% aqueous Na.sub.2S.sub.2O.sub.3 (10 mL), brine (10 mL), dried
over MgSO.sub.4, filtered and concentrated to afford compound 57a
(130 mg, crude). The crude product was used in the next step
without further purification.
[0409] Synthesis of compound 57b. To a solution of compound 56b (95
mg, 0.297 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran
complex (1.1 mL; 1.0 M solution in THF). After stirring at room
temperature for 1 hour, the reaction mixture was cooled in an ice
bath then quenched slowly with 10% aqueous NaOH (1 mL) followed by
30% aqueous solution of H.sub.2O.sub.2 (1.2 mL). The mixture was
allowed to stir at room temperature for 1 hour then extracted with
EtOAc (3.times.10 mL). The combined organic layers were washed with
10% aqueous Na.sub.2S.sub.2O.sub.3 (10 mL), brine (10 mL), dried
over MgSO.sub.4, filtered and concentrated to afford compound 57b
(135 mg crude). The crude product was used in the next step without
further purification.
[0410] Synthesis of compound 58a. To a solution of compound 57a
(130 mg crude) in 10 mL of wet dichloromethane (dichloromethane had
been shaken with several milliliters of H.sub.2O then separated
from the water layer) was added Dess-Martin periodinate (300 mg,
707 mmol). After stirring at room temperature for 24 h, the
reaction mixture was extracted with dichloromethane (3.times.10
mL). The combined organic layers were washed with 10% aqueous
Na.sub.2S.sub.2O.sub.3 (10 mL), brine (10 mL), dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
chromatography on silica gel (petroleum ether/ethyl acetate=1:5) to
afford compound 58a (60 mg, 64% for two steps) as a white solid.
.sup.1H NMR (500 MHz, CDCl3), .delta. (ppm), 4.23-4.11 (d, 2H, J=60
Hz), 2.55-2.51 (m, 1H), 2.09 (s, 3H), 0.62 (s, 3H).
[0411] Synthesis of compound 58b. To a solution of compound 57b
(135 mg crude) in 10 mL of wet dichloromethane (dichloromethane had
been shaken with several milliliters of H.sub.2O then separated
from the water layer) was added Dess-Martin periodinate (380 mg,
0.896 mmol). After stirring at room temperature for 24 h, the
reaction mixture was extracted with dichloromethane (3.times.10
mL). The combined organic layers were washed with 10% aqueous
Na.sub.2S.sub.2O.sub.3 (10 mL), brine (10 mL), dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
chromatography on silica gel (petroleum ether/ethyl acetate=1:5) to
afford compound 58b (68 mg, 69%) as a white solid. .sup.1H NMR (500
MHz, CDCl3), .delta. (ppm), 4.50-4.34 (m, 2H), 2.56-2.52 (m, 1H),
2.15 (s, 3H), 0.61 (s, 3H).
[0412] Synthesis of compound 59a. To a solution of compound 58a (40
mg, 0.119 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%)
followed by bromine (100 mg, 0.62 mmol). After stirring at room
temperature for 1 h, the reaction mixture was poured into ice-water
then extracted with ethyl acetate (15 mL.times.3). The combined
organic layers were washed with brine (20 mL), dried over
MgSO.sub.4, filtered and concentrated to give compound 59a (60 mg
crude). The crude product was used in the next step without further
purification.
[0413] Synthesis of compound 60a. To a solution of compound 59a (60
mg crude) in acetone (5 mL) was treated with CF.sub.3COOH (0.1 mL)
and Et.sub.3N (0.17 mL). After heating at reflux for 30 min,
CF.sub.3COONa salt (180 mg, 1.3 mmol) was added and the mixture was
refluxed for overnight. The reaction was allowed to cool to room
temperature and the solvent was removed in vacuo. The residue was
extracted with ethyl acetate (10 mL.times.3). The combined organic
layers were washed with brine (15 mL), dried over MgSO.sub.4,
filtered and concentrated. The residue was purified by
chromatography on silica gel (petroleum ether/ethyl acetate=3:1) to
afford compound 60a (15 mg, 36% for two steps). .sup.1H NMR (500
MHz, CDCl3), .delta. (ppm), 4.21-4.11 (m, 4H), 3.39-3.36 (m, 1H),
2.84 (s, 1H), 0.65 (s, 3H).
Example 9
##STR00133## ##STR00134##
[0415] Synthesis of compound 61. To a solution of compound 42 (5 g,
15 mmol) in dry THF (20 mL) was added borane-tetrahydrofuran
complex (30 mL; 1.0 M solution in THF). After stirring at room
temperature for 1 hour, the reaction mixture was cooled in an ice
bath then quenched slowly with 10% aqueous NaOH (56 mL) followed by
30% aqueous solution of H.sub.2O.sub.2 (67 mL). After stirring at
room temperature for one hour, the mixture was extracted with EtOAc
(3.times.100 mL). The combined organic layers were washed with 10%
aqueous Na.sub.2S.sub.2O.sub.3 (100 mL), brine (100 mL), dried over
MgSO.sub.4, filtered and concentrated to afford crude compound 61
(5 g). The crude product was used in the next step without further
purification.
[0416] Synthesis of compound 62. A solution of crude compound 61
(3.2 g, 9 mmol) in THF (50 mL) was acidified to pH=3 by 1N aqueous
HCl. After stirring at room temperature for 12 h, the reaction
mixture was extracted with ethyl acetate (150 mL.times.3). The
combined organic layers were washed with brine, dried over sodium
sulfate, filtered and concentrated. The residue was purified by
column chromatography (petroleum ether/ethyl acetate=30:1 to 20:1)
to afford compound 62 (2.2 g, 7 mmol, 81% for two steps). m/z
(ES+APCI).sup.+: [M+H].sup.+ 305.
[0417] Synthesis of compound 63. To a stirred solution of
trimethylsulfonium iodide (8.1 g, 36.9 mmol) in 100 mL of DMSO was
added NaH (60%; 1.26 g, 31.5 mmol). After stirring at room
temperature for 1 h, a suspension of compound 62 (2.2 g, 7.2 mmol)
in DMSO (20 mL) was added dropwise. The mixture was stirred for
another 2.5 h, then poured into ice-cold water and extracted with
ether (100 mL.times.3). The combined ether layers were then washed
with brine (100 mL.times.3), dried over MgSO.sub.4, filtered, and
concentrated to give the crude product 63 (2.2 g). The crude
product was used in the next step without further purification.
[0418] Synthesis of compound 64. To a solution of crude compound 63
(1.6 g, 5 mmol) in 60 mL of wet dichloromethane (dichloromethane
had been shaken with several milliliters of H.sub.2O then separated
from the water layer) was added Dess-Martin periodinate (4.2 g, 10
mmol). After stirring at room temperature for 24 h, the reaction
mixture was extracted with dichloromethane (3.times.100 mL). The
combined organic layers were washed with 10% aqueous
Na.sub.2S.sub.2O.sub.3 (100 mL), brine (100 mL), dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
chromatography on silica gel (petroleum ether/ethyl acetate=20:1 to
10:1) to afford compound 64 (1.2 g, 3.8 mmol, 75% for two steps) as
a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3), .delta. (ppm),
2.63-2.58 (m, 3H), 2.11 (s, 3H), 0.63 (s, 3H).
[0419] Synthesis of compound 65. To a solution of compound 64 (1.2
g, 3.8 mmol) in dry methanol (250 mL) was added Na (262 mg, 11.4
mmol). After reflux for 16 h, the solvent was evaporated and the
residue was dissolved in dichloromethane. The mixture was washed
with H.sub.2O (3.times.50 mL), brine (100 mL), dried over
MgSO.sub.4, filtered, and concentrated. The crude product was
purified by silica gel chromatography (petroleum ether/ethyl
acetate=10:1 to 5:1) to give compound 65a (300 mg, 25%) and
compound 65b (100 mg, 8%) as a white solid. 65a, 1H NMR (400 MHz,
CDCl.sub.3), .delta. (ppm), 3.38 (s, 3H), 3.18 (s, 2H), 2.56-2.51
(m, 1H), 2.11 (s, 3H), 0.61 (s, 3H). 65b, 1H NMR (400 MHz,
CDCl.sub.3), .delta. (ppm), 3.40 (s, 3H), 3.37 (s, 2H), 2.54-2.50
(m, 1H), 2.11 (s, 3H), 0.62 (s, 3H).
[0420] Synthesis of compound 66a. To a solution of compound 65a (50
mg, 0.14 mmol) in MeOH (10 mL) was added 2 drops of HBr (48%)
followed by bromine (23 mg, 0.14 mmol). After stirring at room
temperature for 1 h, the reaction mixture was poured into ice-water
then extracted with ethyl acetate (10 mL.times.3). The combined
organic layers were washed with brine (20 mL), dried over
MgSO.sub.4, filtered and concentrated to give crude compound 66a
(46 mg, 92%). The crude product was used in the next step without
further purification.
[0421] Synthesis of compound 67a. A solution of compound 66a (46
mg, 0.11 mmol) in acetone 10 mL was treated with CF.sub.3COOH (0.5
mL) and Et.sub.3N (0.7 mL). After refluxed for 30 min,
CF.sub.3COONa salt (300 mg, 2.2 mmol) was added in parts over a
period of 10 hr. The reaction mixture was allowed to cool to room
temperature and the solvent was removed in vacuo. The residue was
extracted with ethyl acetate, dried over MgSO.sub.4, filtered and
concentrated. The mixture was purified by chromatography on silica
gel (petroleum ether/ethyl acetate=10:1 to 3:1) to afford 67a (10
mg, yield: 25% for two steps). 67a, 1H NMR (400 MHz, CDCl.sub.3),
.delta. (ppm), 4.20-4.16 (m, 2H), 3.39 (s, 3H), 3.25 (m, 1H), 3.18
(s, 2H), 2.48-2.45 (m, 1H), 2.23-2.17 (m, 1H), 0.64 (s, 3H).
Example 10
##STR00135##
[0423] Synthesis of compound 68a. To a solution of compound 15a
(200 mg, 0.63 mmol) in acetic anhydride (10 mL) was added pyridine
(50 mg, 0.63 mmol). The reaction mixture was stirred at 80.degree.
C. for 10 hour. The reaction mixture was poured into ice-cold water
and extracted with ethyl acetate (20 mL.times.3). The combined
ether layers were then washed with brine (10 mL.times.3), dried
over MgSO.sub.4, filtered and concentrated to give crude product
68a (160 mg, 80%). The crude product was used in the next step
without further purification. .sup.1HNMR (400 MHz, CDCl.sub.3),
.delta. (ppm), 2.55-2.50 (t, J=9.2 Hz, 1H), 2.38-2.34 (m, 1H), 2.11
(s, 3H), 2.00 (s, 3H), 1.45 (s, 3H), 0.62 (s, 3H).
Example 11
##STR00136##
[0424] Synthesis of Compound 71
##STR00137##
[0426] To a suspension of K.sub.2CO.sub.3 (25 mg, 0.18 mmol) in THF
(5 mL) was added morpholine (16 mg, 0.18 mmol) and compound 16a (36
mg, 0.09 mmol). After stirring at room temperature for 15 h, the
reaction mixture was poured in to 5 mL H.sub.2O and extracted with
EtOAc (2.times.10 mL). The combined organic layers were washed with
brine, dried over sodium sulfate, filtered and concentrate. The
reaction mixture was purified with by reverse-phase prep-HPLC to
afford the title compound as a white solid (12 mg, 33%). 1HNMR (500
MHz, CDCl.sub.3), .delta. (ppm), 3.77-3.75 (m, 4H), 3.19-3.18 (m,
2H), 2.59-2.50 (m, 5H), 2.19-2.12 (m, 1H), 1.20 (s, 3H), 0.63 (s,
3H).
Synthesis of Compound 72
##STR00138##
[0428] To a suspension of K.sub.2CO.sub.3 (25 mg, 0.18 mmol) in THF
(5 mL) was added piperidine (16 mg, 0.18 mmol) and compound 16a (36
mg, 0.09 mmol). After stirring at room temperature for 15 h, the
reaction mixture was poured in to 5 mL H.sub.2O and extracted with
EtOAc (2.times.10 mL). The combined organic layers were washed with
brine, dried over sodium sulfate, filtered and concentrate. The
reaction mixture was purified with by reverse-phase prep-HPLC to
afford the title compound as a white solid (12 mg, 33%). 1HNMR (500
MHz, CDCl.sub.3), .delta. (ppm), 3.12-3.04 (m, 2H), 2.57-2.53 (t,
J=9 Hz, 1H), 2.59-2.50 (m, 5H), 2.19-2.12 (m, 1H), 1.20 (s, 3H),
0.63 (s, 3H).
Synthesis of Compound 73
##STR00139##
[0430] To a suspension of K.sub.2CO.sub.3 (25 mg, 0.18 mmol) in THF
(5 mL) was added pyrrolidine (13 mg, 0.18 mmol) and compound 16a
(36 mg, 0.09 mmol). After stirring at room temperature for 15 h,
the reaction mixture was poured in to 5 mL H.sub.2O and extracted
with EtOAc (2.times.10 mL). The combined organic layers were washed
with brine, dried over sodium sulfate, filtered and concentrate.
The reaction mixture was purified with by reverse-phase prep-HPLC
to afford the title compound as a white solid (15 mg, 42%). 1HNMR
(400 MHz, CDCl.sub.3), .delta. (ppm), 3.43-3.31 (m, 2H), 2.61-2.53
(m, 5H), 2.21-2.13 (m, 1H), 1.20 (s, 3H), 0.63 (s, 3H).
Synthesis of Compound 74
##STR00140##
[0432] To a suspension of K.sub.2CO.sub.3 (14 mg, 0.10 mmol) in THF
(5 mL) was added 1H-imidazole (7 mg, 0.10 mmol) and compound 16a
(20 mg, 0.05 mmol). After stirring at room temperature for 15 h,
the reaction mixture was poured in to 5 mL H.sub.2O and extracted
with EtOAc (2.times.10 mL). The combined organic layers were washed
with brine, dried over sodium sulfate, filtered and concentrate.
The reaction mixture was purified with by reverse-phase prep-HPLC
to afford the title compound as a white solid (7 mg, 35%). 1HNMR
(500 MHz, CDCl.sub.3), .delta. (ppm), 7.49 (s, 1H), 7.12 (s, 1H),
6.86 (s, 1H), 4.75-4.66 (m, 2H), 2.60-2.56 (t, J=8.5 Hz, 1H),
2.21-2.13 (m, 1H), 1.21 (s, 3H), 0.68 (s, 3H).
Example 12
##STR00141## ##STR00142##
[0434] Synthesis of compound 75a and 75b. To a solution of compound
43 (1.3 g, 4.5 mmol) and PhSO.sub.2CH.sub.2F (790 mg, 4.5 mmol) in
THF (25 ml) and HMPA (0.5 mL) at -78.degree. C. under N.sub.2 was
added LHMDS (5.5 mL, 1M in THF) drop-wise. After stirring at
-78.degree. C. for 2 h, the reaction mixture was quenched with
saturated aqueous NH.sub.4Cl solution (10 mL) and allowed to warm
to room temperature then extracted with Et.sub.2O (20 mL.times.3).
The combined organic layers were washed with brine, dried over
sodium sulfate, filtered and concentrate. The residue was purified
by silica gel column chromatography (petroleum ether/ethyl
acetate=10/1) to give the mixture of compound 75a and 75b (1.53 g).
The mixture was further purified by chiral-HPLC to afford compound
75a1 (220 mg, t=3.41 min). .sup.1H NMR (500 MHz, CDCl3), .delta.
(ppm), 7.99-7.97 (m, 2H), 7.75-7.74 (m, 1H), 7.62-7.55 (m, 2H),
5.13-5.09 (m, 1H), 4.86-4.78 (d, 1H, J=42 Hz), 0.88 (s, 3H); 75a2
(200 mg, t=3.66 min); .sup.1H NMR (500 MHz, CDCl3), .delta. (ppm),
7.96-7.95 (m, 1H), 7.71-7.69 (m, 1H), 7.62-7.58 (m, 2H), 5.13-5.09
(m, 1H), 4.87-4.77 (d, 1H, J=46.5 Hz), 0.88 (s, 3H); 75b1 (235 mg,
t=4.9 min), .sup.1H NMR (500 MHz, CDCl3), .delta. (ppm), 7.99-7.97
(m, 1H), 7.72-7.70 (m, 1H), 7.62-7.59 (m, 2H), 5.29-5.20 (d, 1H,
J=43 Hz), 4.88-4.78 (m, 1H), 0.88 (s, 3H); 75b2 (220 mg, t=5.2
min). .sup.1H NMR (500 MHz, CDCl3), .delta. (ppm), 7.99-7.97 (m,
2H), 7.72 (m, 1H), 7.62-7.59 (m, 2H), 5.30-5.20 (d, 1H, J=46.5 Hz),
5.09-5.08 (m, 1H), 0.88 (s, 3H). Chiral HPLC conditions:
Elutant=MeOH (0.1% DEA); Column=IC (4.6*250 mm, 5 um).
[0435] Synthesis of compound 76a. To a solution of compound 75a1
(200 mg, 0.434 mmol) and anhydrous Na.sub.2HPO.sub.4 (100 mg) in
anhydrous methanol (15 mL) at -20.degree. C. under N.sub.2 was
added Na/Hg amalgam (400 mg). After stirring at -20.degree. C. to
0.degree. C. for 1 h, the methanol solution was decanted out and
the solid residue was washed with Et.sub.2O (5.times.3 mL). The
solvent of combined organic phase was removed under vacuum, and 20
ml brine was added, followed by extracting with Et.sub.2O. The
combined ether phase was dried with MgSO.sub.4, and the ether was
removed to give the crude product, which was further purified by
silica gel chromatography (PE/EA=10/1) to give compound 76a (99 mg,
69%). .sup.1H NMR (500 MHz, CDCl3), .delta. (ppm), 5.12-5.10 (m,
1H,), 4.21-24.11 (d, 2H, J=47.5 Hz), 0.88 (s, 3H).
[0436] Synthesis of compound 77a. To a solution of compound 76a (95
mg, 0.296 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran
complex (1 mL of 1.0 M solution in THF). After stirring at room
temperature for 1 hour, the reaction mixture was cooled in an ice
bath then quenched slowly with 10% aqueous NaOH (1 mL) followed by
30% aqueous solution of H.sub.2O.sub.2 (1.2 mL). The mixture was
allowed to stir at room temperature for 1 hour then extracted with
EtOAc (3.times.10 mL). The combined organic layers were washed with
10% aqueous Na.sub.2S.sub.2O.sub.3 (10 mL), brine (10 mL), dried
over MgSO.sub.4, filtered and concentrated to afford compound 77a
(120 mg crude). The crude product was used in the next step without
further purification.
[0437] Synthesis of compound 78a. To a solution of compound 77a
(120 mg crude) was dissolved in 10 mL of wet dichloromethane
(dichloromethane had been shaken with several milliliters of
H.sub.2O then separated from the water layer) was added Dess-Martin
periodinate (300 mg, 707 mmol). After stirring at room temperature
for 24 h, the reaction mixture was extracted with dichloromethane
(3.times.10 mL). The combined organic layers were washed with 10%
aqueous Na.sub.2S.sub.2O.sub.3 (10 mL), brine (10 mL), dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
chromatography on silica gel (petroleum ether/ethyl acetate 1:5) to
afford compound 78a (70 mg, 70% for two steps) as a white solid.
.sup.1H NMR (500 MHz, CDCl3), .delta. (ppm), 4.21-4.11 (d, 2H, J=48
Hz), 2.19 (s, 3H), 0.62 (s, 3H).
Assay Methods
[0438] Compounds provided herein can be evaluated using various in
vitro and in vivo assays; examples of which are described
below.
Steroid Inhibition of TBPS Binding
[0439] TBPS binding assays using rat brain cortical membranes in
the presence of 5 .mu.M GABA has been described (Gee et al, J.
Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson et al, Mol.
Pharmacol. 1994, 46, 977-985).
[0440] Briefly, cortices are rapidly removed following decapitation
of carbon dioxide-anesthetized Sprague-Dawley rats (200-250 g). The
cortices are homogenized in 10 volumes of ice-cold 0.32 M sucrose
using a glass/teflon homogenizer and centrifuged at 1500.times.g
for 10 min at 4.degree. C. The resultant supernatants are
centrifuged at 10,000.times.g for 20 min at 4.degree. C. to obtain
the P2 pellets. The P2 pellets are resuspended in 200 mM NaCl/50 mM
Na--K phosphate pH 7.4 buffer and centrifuged at 10,000.times.g for
10 min at 4.degree. C. This ishing procedure is repeated twice and
the pellets are resuspended in 10 volumes of buffer. Aliquots (100
.mu.L) of the membrane suspensions are incubated with 2 nM
[.sup.35S]-TBPS and 5 .mu.L aliquots of test drug dissolved in
dimethyl sulfoxide (DMSO) (final 0.5%) in the presence of 5 .mu.M
GABA. The incubation is brought to a final volume of 1.0 mL with
buffer. Nonspecific binding is determined in the presence of 2 M
unlabeled TBPS and ranged from 15 to 25%. Following a 90 min
incubation at room temp, the assays are terminated by filtration
through glass fiber filters (Schleicher and Schuell No. 32) using a
cell harvester (Brandel) and rinsed three times with ice-cold
buffer. Filter bound radioactivity is measured by liquid
scintillation spectrometry. Non-linear curve fitting of the overall
data for each drug averaged for each concentration is done using
Prism (GraphPad). The data are fit to a partial instead of a full
inhibition model if the sum of squares is significantly lower by
F-test. Similarly, the data are fit to a two component instead of a
one component inhibition model if the sum of squares is
significantly lower by F-test. The concentration of test compound
producing 50% inhibition (IC.sub.50) of specific binding and the
maximal extent of inhibition (I.sub.max) are determined for the
individual experiments with the same model used for the overall
data and then the means.+-.SEM.s of the individual experiments are
calculated.
[0441] Various compounds are or can be screened to determine their
potential as modulators of [.sup.35S]-TBPS binding in vitro. These
assays are or can be performed in accordance with the above
discussed procedures.
In Vivo Pharmacology
[0442] Male NSA mice weighing between 15-20 g are obtained from
Harlan Sprague-Dawley (San Diego, Calif.). Upon arrival they are
housed in standard polycarbonate cages (4 per cage) containing a
sterilized bedding material in a room of constant temp
(23.0.degree..+-.2.5.degree. C.) with a 12 h (07.00-19.00 light)
light/dark cycle. Food (Teklad LM 485) and water are freely
available. Mice are acclimated a minimum of 4 days prior to
experimentation.
Pentylenetetrazol-Induced Seizures
[0443] Seizures are induced by administration of 85 mg/kg, s.c
pentylenetetrazol (30 min observation period). The dose used is
previously determined to be the CD.sub.97. A clonic seizure is
defined as forelimb clonus of .gtoreq.3 sec duration. Data are
treated quantally.
Maximal Electroshock-Induced Seizures
[0444] Seizures are induced by application of current (50 mA, 60
pulses/sec, 0.8 msec pulse width, 1 sec duration, D.C.) using a Ugo
Basile ECT device (Model 7801). Mice are restrained by gripping the
loose skin on their dorsal surface and saline-coated corneal
electrodes are held lightly against the two cornea. Current is
applied and mice are observed for a period of up to 30 sec for the
occurrence of a tonic hindlimb extensor response. Atonic seizure is
defined as a hindlimb extension in excess of 90 degrees from the
plane of the body. Results are treated in a quantal manner.
Hanging Wire
[0445] The hanging-wire test used a custom-built apparatus that
consisted of a metal wire (2 mm diameter) suspended horizontally
above a padded surface (25 cm). Mice are held by the base of the
tail, their forepaws placed in contact with the wire, and then
released. Animals are required to bring both hindpaws in contact
with the wire within 5 sec in order to be scored as a pass. Results
are treated quantally.
Drug Metabolism and Pharmacokinetics: HERG Assay.
[0446] HEK 293 cells which stably express the HERG potassium
channel are used for electrophysiological studies. The methodology
for stable transfection of this channel in HEK cells can be found
elsewhere (Zhou et al., Biophys. J. 74:230-41, 1998). Before the
day of experimentation, the cells are harvested from culture flasks
and plated onto glass coverslips in a standard Minimum Essential
Medium (MEM) medium with 10% Fetal Calf Serum (FCS). The plated
cells are stored in an incubator at 37.degree. C. maintained in an
atmosphere of 95% O.sub.2/5% CO.sub.2. Cells are studied between
15-28 hrs after harvest.
[0447] HERG currents are studied using standard patch clamp
techniques in the whole-cell mode. During the experiment the cells
are superfused with a standard external solution of the following
composition (mM); NaCl, 130; KCl, 4; CaCl.sub.2, 2; MgCl.sub.2, 1;
Glucose, 10; HEPES, 5; pH 7.4 with NaOH. Whole-cell recordings are
made using a patch clamp amplifier and patch pipettes which have a
resistance of 1-3 MOhm when filled with the standard internal
solution of the following composition (mM); KCl, 130; MgATP, 5;
MgCl.sub.2, 1.0; HEPES, 10; EGTA 5, pH 7.2 with KOH. Only those
cells with access resistances below 15 MOhm and seal resistances
>1GOhm are accepted for further experimentation. Series
resistance compensation was applied up to a maximum of 80%. No leak
subtraction is done. However, acceptable access resistance depended
on the size of the recorded currents and the level of series
resistance compensation that can safely be used. Following the
achievement of whole cell configuration and sufficient time for
cell dialysis with pipette solution (>5 min), a standard voltage
protocol is applied to the cell to evoke membrane currents. The
voltage protocol is as follows. The membrane is depolarized from a
holding potential of -80 mV to +40 mV for 1000 ms. This was
followed by a descending voltage ramp (rate 0.5 mV msec-1) back to
the holding potential. The voltage protocol is applied to a cell
continuously throughout the experiment every 4 seconds (0.25 Hz).
The amplitude of the peak current elicited around -40 mV during the
ramp is measured. Once stable evoked current responses are obtained
in the external solution, vehicle (0.5% DMSO in the standard
external solution) is applied for 10-20 min by a peristalic pump.
Provided there were minimal changes in the amplitude of the evoked
current response in the vehicle control condition, the test
compound of either 0.3, 1, 3, or 10 mM is applied for a 10 min
period. The 10 min period included the time which supplying
solution was passing through the tube from solution reservoir to
the recording chamber via the pump. Exposing time of cells to the
compound solution was more than 5 min after the drug concentration
in the chamber well reached the attempting concentration. There is
a subsequent wash period of a 10-20 min to assess reversibility.
Finally, the cells is exposed to high dose of dofetilide (5 mM), a
specific IKr blocker, to evaluate the insensitive endogenous
current.
[0448] All experiments are performed at room temperature
(23.+-.1.degree. C.). Evoked membrane currents were recorded
on-line on a computer, filtered at 500-1 KHz (Bessel -3 dB) and
sampled at 1-2 KHz using the patch clamp amplifier and a specific
data analyzing software. Peak current amplitude, which occurred at
around -40 mV, is measured off line on the computer.
[0449] The arithmetic mean of the ten values of amplitude is
calculated under vehicle control conditions and in the presence of
drug. Percent decrease of IN in each experiment was obtained by the
normalized current value using the following the formula:
IN=(1-ID/IC).times.100, where ID is the mean current value in the
presence of drug and IC is the mean current value under control
conditions. Separate experiments are performed for each drug
concentration or time-matched control, and arithmetic mean in each
experiment is defined as the result of the study.
Patch Clamp Electrophysiology of Recombinant
.alpha..sub.1.beta..sub.2.gamma..sub.2 GABA.sub.A Receptors
[0450] Cellular electrophysiology is used to measure in vitro
potency and efficacy of our GABA.sub.A receptor modulators in Ltk
cells. Each compound is tested for its ability to affect GABA
mediated currents at a submaximal agonist dose (GABA EC10=0.5
.mu.M) in a whole cell patch clamp technique using a EPC-10, HEKA
Electronics Amplifier and PatchMaster software. These experiments
measure potency, efficacy (Emax), direct gating properties and
acute desensitization. Test article is added at 0.1, 1.0 and 10
uM.
Drug Metabolism and Pharmacokinetics: Half-Life in Human Liver
Microsomes (HLM)
[0451] Test compounds (1 .mu.M) are incubated with 3.3 mM
MgCl.sub.2 and 0.78 mg/mL HLM (HL101) in 100 mM potassium phosphate
buffer (pH 7.4) at 37.degree. C. on the 96-deep well plate. The
reaction mixture is split into two groups, a non-P450 and a P450
group. NADPH is only added to the reaction mixture of the P450
group. An aliquot of samples of P450 group is collected at 0, 10,
30, and 60 min time point, where 0 min time point indicated the
time when NADPH was added into the reaction mixture of P450 group.
An aliquot of samples of non-P450 group is collected at -10 and 65
min time point. Collected aliquots are extracted with acetonitrile
solution containing an internal standard. The precipitated protein
is spun down in centrifuge (2000 rpm, 15 min). The compound
concentration in supernatant is measured by LC/MS/MS system. The
half-life value is obtained by plotting the natural logarithm of
the peak area ratio of compounds/internal standard versus time. The
slope of the line of best fit through the points yields the rate of
metabolism (k). This is converted to a half-life value using the
equation: Half-life=In 2/k.
TABLE-US-00001 TABLE 1 Patchclamp electrophysiology potentiation
and TBPS binding data TBPS % % % binding potentiation potentiation
potentiation IC50 Structure at 100 nM at 1000 nM at 10000 nM (nM)
##STR00143## 101 163 86 ##STR00144## 33 ##STR00145## 170
##STR00146## 41 ##STR00147## 80 157 270 93
TABLE-US-00002 TABLE 1 Patchclamp electrophysiology potentiation
and TBPS binding data TBPS % % % binding potentiation potentiation
potentiation IC50 Structure at 100 nM at 1000 nM at 10000 nM (nM)
##STR00148## 130 227 220 ##STR00149## 0 100 >10000 ##STR00150##
94 ##STR00151## 100
Other Embodiments
[0452] In the claims articles such as "a," "an," and "the" may mean
one or more than one unless indicated to the contrary or otherwise
evident from the context. Claims or descriptions that include "or"
between one or more members of a group are considered satisfied if
one, more than one, or all of the group members are present in,
employed in, or otherwise relevant to a given product or process
unless indicated to the contrary or otherwise evident from the
context. The invention includes embodiments in which exactly one
member of the group is present in, employed in, or otherwise
relevant to a given product or process. The invention includes
embodiments in which more than one, or all of the group members are
present in, employed in, or otherwise relevant to a given product
or process.
[0453] Furthermore, the invention encompasses all variations,
combinations, and permutations in which one or more limitations,
elements, clauses, and descriptive terms from one or more of the
listed claims is introduced into another claim. For example, any
claim that is dependent on another claim can be modified to include
one or more limitations found in any other claim that is dependent
on the same base claim. Where elements are presented as lists,
e.g., in Markush group format, each subgroup of the elements is
also disclosed, and any element(s) can be removed from the group.
It should it be understood that, in general, where the invention,
or aspects of the invention, is/are referred to as comprising
particular elements and/or features, certain embodiments of the
invention or aspects of the invention consist, or consist
essentially of, such elements and/or features. For purposes of
simplicity, those embodiments have not been specifically set forth
in haec verba herein. It is also noted that the terms "comprising"
and "containing" are intended to be open and permits the inclusion
of additional elements or steps. Where ranges are given, endpoints
are included. Furthermore, unless otherwise indicated or otherwise
evident from the context and understanding of one of ordinary skill
in the art, values that are expressed as ranges can assume any
specific value or sub-range within the stated ranges in different
embodiments of the invention, to the tenth of the unit of the lower
limit of the range, unless the context clearly dictates
otherwise.
[0454] This application refers to various issued patents, published
patent applications, journal articles, and other publications, all
of which are incorporated herein by reference. If there is a
conflict between any of the incorporated references and the instant
specification, the specification shall control. In addition, any
particular embodiment of the present invention that falls within
the prior art may be explicitly excluded from any one or more of
the claims. Because such embodiments are deemed to be known to one
of ordinary skill in the art, they may be excluded even if the
exclusion is not set forth explicitly herein. Any particular
embodiment of the invention can be excluded from any claim, for any
reason, whether or not related to the existence of prior art.
[0455] Those skilled in the art will recognize or be able to
ascertain using no more than routine experimentation many
equivalents to the specific embodiments described herein. The scope
of the present embodiments described herein is not intended to be
limited to the above Description, but rather is as set forth in the
appended claims. Those of ordinary skill in the art will appreciate
that various changes and modifications to this description may be
made without departing from the spirit or scope of the present
invention, as defined in the following claims.
* * * * *