U.S. patent application number 13/490696 was filed with the patent office on 2012-09-27 for modulators of toll-like receptor 7.
This patent application is currently assigned to Gilead Sciences, Inc.. Invention is credited to Michael Graupe, Randall L. Halcomb.
Application Number | 20120244121 13/490696 |
Document ID | / |
Family ID | 39789972 |
Filed Date | 2012-09-27 |
United States Patent
Application |
20120244121 |
Kind Code |
A1 |
Graupe; Michael ; et
al. |
September 27, 2012 |
MODULATORS OF TOLL-LIKE RECEPTOR 7
Abstract
The present invention includes therapeutic methods that include
the administration of a compound of Formula I or II: ##STR00001##
or a pharmaceutically acceptable salt, solvate, and/or ester
thereof, to a subject in need of such, and therapeutic methods that
include the administration of such compounds with at least one
additional active agent.
Inventors: |
Graupe; Michael; (Pacifica,
CA) ; Halcomb; Randall L.; (Foster City, CA) |
Assignee: |
Gilead Sciences, Inc.
Foster City
CA
|
Family ID: |
39789972 |
Appl. No.: |
13/490696 |
Filed: |
June 7, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13153340 |
Jun 3, 2011 |
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13490696 |
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12215598 |
Jun 26, 2008 |
7968544 |
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13153340 |
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60937726 |
Jun 29, 2007 |
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60959714 |
Jul 16, 2007 |
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Current U.S.
Class: |
424/85.6 ;
424/133.1; 424/85.4; 424/85.7; 435/375; 514/210.21; 514/217.06;
514/218; 514/234.2; 514/252.16; 514/263.2; 514/263.22; 514/263.37;
514/263.38; 514/43 |
Current CPC
Class: |
A61K 31/522 20130101;
A61P 31/00 20180101; A61K 31/55 20130101; A61P 31/14 20180101; C07D
473/18 20130101; A61K 31/551 20130101; A61K 31/5377 20130101; A61P
31/12 20180101; A61P 43/00 20180101; A61P 31/20 20180101; A61K
45/06 20130101 |
Class at
Publication: |
424/85.6 ;
514/263.2; 424/85.4; 514/43; 424/85.7; 435/375; 514/218;
514/252.16; 514/217.06; 514/210.21; 514/234.2; 514/263.37;
514/263.22; 514/263.38; 424/133.1 |
International
Class: |
A61K 31/52 20060101
A61K031/52; A61K 31/7056 20060101 A61K031/7056; C12N 5/07 20100101
C12N005/07; A61P 31/14 20060101 A61P031/14; A61K 31/55 20060101
A61K031/55; A61K 31/5377 20060101 A61K031/5377; A61P 31/12 20060101
A61P031/12; A61K 39/395 20060101 A61K039/395; A61K 38/21 20060101
A61K038/21; A61K 31/551 20060101 A61K031/551 |
Claims
1. A method for treating or preventing a viral infection
comprising: administering, to a patient in need thereof, a
therapeutically effective amount of at least one of a compound of
Formula I or II: ##STR00147## wherein: X.sup.1 is --NH--, --O--,
alkylene, substituted alkylene, alkenylene, substituted alkenylene,
alkynylene, substituted alkynylene, carbocyclylene, substituted
carbocyclylene, heterocyclylene, or substituted heterocyclylene; D
is carbocyclylene or heterocyclylene; each L.sup.1 is independently
alkylene or substituted alkylene; each R.sup.1 is independently
--NR.sup.4R.sup.5; m is 1 or 2; L.sup.2 is a covalent bond, --NH--,
--O--, or --S--; R.sup.2 is H, halo, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, carbocyclyl, substituted carbocyclyl,
carbocyclylalkyl, substituted carbocyclylalkyl, arylalkyl,
substituted arylalkyl, heterocyclylalkyl, substituted
heterocyclylalkyl, --C(O)R.sup.6, --C(O)OR.sup.6,
--C(O)NR.sup.7R.sup.8, --S(O)OR.sup.7, --S(O)NR.sup.7R.sup.8,
--S(O).sub.2R.sup.7, --S(O)R.sup.7, --S(O).sub.2OR.sup.7, or
--S(O).sub.2NR.sup.7R.sup.8; L.sup.3 is --NH--, --O--, --S--,
--N(R.sup.9)C(O)--, --S(O).sub.2--, --S(O)--, or a covalent bond;
R.sup.3 is alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; R.sup.4 and
R.sup.5 are each independently H, alkyl, substituted alkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, substituted heterocyclylalkyl, --C(O)H,
--C(O)R.sup.3, --S(O)R.sup.3, --S(O).sub.2R.sup.3, --C(O)OR.sup.3,
or --C(O)NR.sup.7R.sup.8; or R.sup.4 and R.sup.5, taken together
with the nitrogen to which they are both attached, form a
substituted or unsubstituted heterocycle; R.sup.6 is alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, heteroalkyl, substituted heteroalkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; R.sup.7 and
R.sup.8 are each independently H, alkyl, substituted alkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; or R.sup.7 and
R.sup.8, taken together with the nitrogen to which they are both
bonded, form a substituted or unsubstituted heterocycle; R.sup.9 is
H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl,
carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl,
substituted heterocyclyl, heterocyclylalkyl, or substituted
heterocyclylalkyl; R.sup.10 is halogen, cyano, azido, nitro, alkyl,
substituted alkyl, hydroxyl, amino, heteroalkyl, or substituted
heteroalkyl; n is an integer from 0 to 5; and with the following
provisos: (a) When X.sup.1 is --CH.sub.2--, D is 1,4-phenylene,
R.sup.3-L.sup.3- is CHSCH.sub.2CH.sub.2CH.sub.2O-- or
CH.sub.3--O--CH.sub.2CH.sub.2--O, n=0, m=1, then NR.sup.4R.sup.5 is
not: (1) a 4-substituted or 4,4-disubstituted piperidine or
piperazine (2) --NHCH.sub.3; (b) When X.sup.1 is --CH.sub.2--, D is
1,4-phenylene or 1,4-piperidinylene, R.sup.3-L.sup.3- is
CH.sub.3CH.sub.2CH.sub.2CH.sub.2O-- or
CH.sub.3--O--CH.sub.2CH.sub.2--O, n=0, m=1, then neither R.sup.4
nor R.sup.5 are substituted alkyl, substituted heterocycyl,
substituted benzyl; and (c) When X.sup.1 is --CH.sub.2--, D is
2,5-pyridylene, R.sup.3-L.sup.3- is
CH.sub.3CH.sub.2CH.sub.2CH.sub.2O-- or
CH.sub.3--O--CH.sub.2CH.sub.2--O, n=0, m=1, then NR.sup.4R.sup.5 is
not pyrrolyl, piperazyl, N(CH.sub.3).sub.2, or a pharmaceutically
acceptable salt, solvate, and/or ester thereof.
2. The method of claim 1, further comprising: co-administering at
least one additional active agent selected from the group
consisting of interferons, ribavirin or its analogs, HCV NS3
protease inhibitors, alpha-glucosidase 1 inhibitors,
hepatoprotectants, nucleoside or nucleotide inhibitors of HCV NS5B
polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV
NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES
inhibitors, pharmacokinetic enhancers, and other drugs for treating
HCV, or mixtures thereof.
3. The method of claim 2, wherein the at least one additional
active agent is selected from the group consisting of: (1)
interferons selected from the group consisting of pegylated
rIFN-alpha 2b (PEG-Intron), pegylated rIFN-alpha 2a (Pegasys),
rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A), interferon
alpha (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon,
subalin), interferon alfacon-1 (Infergen), interferon alpha-n1
(Wellferon), interferon alpha-n3 (Alferon), interferon-beta
(Avonex, DL-8234), interferon-omega (omega DUROS, Biomed 510),
albinterferon alpha-2b (Albuferon), IFN alpha-2b XL, BLX-883
(Locteron), DA-3021, glycosylated interferon alpha-2b (AVI-005),
PEG-Infergen, PEGylated interferon lambda-1 (PEGylated IL-29),
belerofon, and mixtures thereof; (2) ribavirin and its analogs
selected from the group consisting of ribavirin (Rebetol, Copegus),
taribavirin (Viramidine), and mixtures thereof; (3) HCV NS3
protease inhibitors selected from the group consisting of
boceprevir (SCH-503034, SCH-7), telaprevir (VX-950), TMC435350,
BI-1335, BI-1230, MK-7009, VBY-376, VX-500, BMS-790052, BMS-605339,
PHX-1766, AS-101, YH-5258, YH5530, YH5531, ITMN-191, and mixtures
thereof; (4) alpha-glucosidase 1 inhibitors selected from the group
consisting of celgosivir (MX-3253), Miglitol, UT-231B, and mixtures
thereof; (5) hepatoprotectants selected from the group consisting
of IDN-6556, ME 3738, LB-84451, silibilin, MitoQ, and mixtures
thereof; (6) nucleoside or nucleotide inhibitors of HCV NS5B
polymerase selected from the group consisting of R1626, R7128
(R4048), IDX184, IDX-102, BCX-4678, valopicitabine (NM-283),
MK-0608, and mixtures thereof; (7) non-nucleoside inhibitors of HCV
NS5B polymerase selected from the group consisting of PF-868554,
VCH-759, VCH-916, JTK-652, MK-3281, VBY-708, VCH-222, A848837,
ANA-598, GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329,
VCH-796 (nesbuvir), GSK625433, BILN-1941, XTL-2125, GS-9190, and
mixtures thereof; (8) HCV NS5A inhibitors selected from the group
consisting of AZD-2836 (A-831), A-689, and mixtures thereof; (9)
TLR-7 agonists selected from the group consisting of ANA-975,
SM-360320, and mixtures thereof; (10) cyclophillin inhibitors
selected from the group consisting of DEBIO-025, SCY-635, NIM811,
and mixtures thereof; (11) HCV IRES inhibitors selected from the
group consisting of MCI-067, (12) pharmacokinetic enhancers
selected from the group consisting of BAS-100, SPI-452, PF-4194477,
TMC-41629, roxythromycin, and mixtures thereof; and (13) other
drugs for treating HCV selected from the group consisting of
thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, NTZ), BIVN-401
(virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101),
KRN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-111, ITX2865,
TT-033i, ANA 971, NOV-205, tarvacin, EHC-18, VGX-410C, EMZ-702, AVI
4065, BMS-650032, BMS-791325, Bavituximab, MDX-1106 (ONO-4538),
Oglufanide, VX-497 (merimepodib), and mixtures thereof.
4. A method of agonizing toll-like receptor 7, comprising:
contacting a cell having a toll-like receptor 7 with an effective
amount of a compound of Formula I or II: ##STR00148## wherein:
X.sup.1 is --NH--, --O--, alkylene, substituted alkylene,
alkenylene, substituted alkenylene, alkynylene, substituted
alkynylene, carbocyclylene, substituted carbocyclylene,
heterocyclylene, or substituted heterocyclylene; D is
carbocyclylene or heterocyclylene; each L.sup.1 is independently
alkylene or substituted alkylene; each R.sup.1 is independently
--NR.sup.4R.sup.5; m is 1 or 2; L.sup.2 is a covalent bond, --NH--,
--O--, or --S--; R.sup.2 is H, halo, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, carbocyclyl, substituted carbocyclyl,
carbocyclylalkyl, substituted carbocyclylalkyl, arylalkyl,
substituted arylalkyl, heterocyclylalkyl, substituted
heterocyclylalkyl, --C(O)R.sup.6, --C(O)OR.sup.6,
--C(O)NR.sup.7R.sup.8, --S(O)OR.sup.7, --S(O)NR.sup.7R.sup.8,
--S(O).sub.2R.sup.7, --S(O)R.sup.7, --S(O).sub.2OR.sup.7, or
--S(O).sub.2NR.sup.7R.sup.8; L.sup.3 is --NH--, --O--, --S--,
--N(R.sup.9)C(O)--, --S(O).sub.2--, --S(O)--, or a covalent bond;
R.sup.3 is alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; R.sup.4 and
R.sup.5 are each independently H, alkyl, substituted alkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, substituted heterocyclylalkyl, --C(O)H,
--C(O)R.sup.3, --S(O)R.sup.3, --S(O).sub.2R.sup.3, --C(O)OR.sup.3,
or --C(O)NR.sup.7R.sup.8; or R.sup.4 and R.sup.5, taken together
with the nitrogen to which they are both attached, form a
substituted or unsubstituted heterocycle; R.sup.6 is alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, heteroalkyl, substituted heteroalkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; R.sup.7 and
R.sup.8 are each independently H, alkyl, substituted alkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; or R.sup.7 and
R.sup.8, taken together with the nitrogen to which they are both
bonded, form a substituted or unsubstituted heterocycle; R.sup.9 is
H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl,
carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl,
substituted heterocyclyl, heterocyclylalkyl, or substituted
heterocyclylalkyl; R.sup.10 is halogen, cyano, azido, nitro, alkyl,
substituted alkyl, hydroxyl, amino, heteroalkyl, or substituted
heteroalkyl; n is an integer from 0 to 5; and with the following
provisos: (a) When X.sup.1 is --CH.sub.2--, D is 1,4-phenylene,
R.sup.3-L.sup.3- is CH.sub.3CH.sub.2CH.sub.2CH.sub.2O-- or
CH.sub.3--O--CH.sub.2CH.sub.2--O, n=0, m=1, then NR.sup.4R.sup.5 is
not: (1) a 4-substituted or 4,4-disubstituted piperidine or
piperazine (2) --NHCH.sub.3; (b) When X.sup.1 is --CH.sub.2--, D is
1,4-phenylene or 1,4-piperidinylene, R.sup.3-L.sup.3- is
CH.sub.3CH.sub.2CH.sub.2CH.sub.2O-- or
CH.sub.3--O--CH.sub.2CH.sub.2--O, n=0, m=1, then neither R.sup.4
nor R.sup.5 are substituted alkyl, substituted heterocycyl,
substituted benzyl; and (c) When X.sup.1 is --CH.sub.2--, D is
2,5-pyridylene, R.sup.3-L.sup.3- is
CH.sub.3CH.sub.2CH.sub.2CH.sub.2O-- or
CH.sub.3--O--CH.sub.2CH.sub.2--O, n=0, m=1, then NR.sup.4R.sup.5 is
not pyrrolyl, piperazyl, N(CH.sub.3).sub.2, or a pharmaceutically
acceptable salt, solvate, and/or ester thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This is a continuation of U.S. Ser. No. 13/153,340, filed
Jun. 3, 2011, which claims the benefit of U.S. Ser. No. 12/215,598,
filed Jun. 26, 2008, which claims the benefit of U.S. Provisional
Application No. 60/937,726, filed Jun. 29, 2007, and U.S.
Provisional Application No. 60/959,714, filed Jul. 16, 2007, each
of which is herein incorporated by reference in its entirety for
all purposes.
FIELD OF THE INVENTION
[0002] This application relates generally to compounds and
pharmaceutical compositions which selectively activates toll-like
receptor 7 (TLR7), and methods of making and using them.
BACKGROUND OF THE INVENTION
[0003] The innate immune system provides the body with a first line
defense against invading pathogens. In an innate immune response,
an invading pathogen is recognized by a germline-encoded receptor,
the activation of which initiates a signaling cascade that leads to
the induction of cytokine expression. Innate immune system
receptors have broad specificity, recognizing molecular structures
that are highly conserved among different pathogens. One family of
these receptors is known as Toll-like receptors (TLRs), due to
their homology with receptors that were first identified and named
in Drosophila, and are present in cells such as macrophages,
dendritic cells, and epithelial cells.
[0004] There are at least ten different TLRs in mammals. Ligands
and corresponding signaling cascades have been identified for some
of these receptors. For example, TLR2 is activated by the
lipoprotein of bacteria (e.g., E. coli.), TLR3 is activated by
double-stranded RNA, TLR4 is activated by lipopolysaccharide (i.e.,
LPS or endotoxin) of Gram-negative bacteria (e.g., Salmonella and
E. coli O157:H7), TLR5 is activated by flagellin of motile bacteria
(e.g., Listeria), TLR7 recognizes and responds to imiquimod and
TLR9 is activated by unmethylated CpG sequences of pathogen DNA.
The stimulation of each of these receptors leads to activation of
the transcription factor NF-.kappa.B, and other signaling molecules
that are involved in regulating the expression of cytokine genes,
including those encoding tumor necrosis factor-alpha (TNF-.alpha.),
interleukin-1 (IL-1), and certain chemokines.
SUMMARY OF THE INVENTION
[0005] The present invention is based, in part, on the discovery by
the applicants that a number of small molecules can alter
TLR-mediated immunostimulatory signaling. Accordingly, the present
application is directed to compounds and pharmaceutical
compositions, and methods for use in preventing or treating
diseases or conditions associated with Toll-like receptor 7 (TLR7)
activity in patients. In one embodiment, the invention comprises a
compound of formula I or II:
##STR00002##
[0006] or a pharmaceutically acceptable salt thereof, wherein:
[0007] X.sup.1 is --NH--, --O--, alkylene, substituted alkylene,
alkenylene, substituted alkenylene, alkynylene, substituted
alkynylene, carbocyclylene, substituted carbocyclylene,
heterocyclylene, or substituted heterocyclylene; [0008] D is
carbocyclylene or heterocyclylene; [0009] each L' is independently
alkylene or substituted alkylene; [0010] each R.sup.1 is
independently --NR.sup.4R.sup.5; [0011] m is 1 or 2; [0012] L.sup.2
is a covalent bond, --NH--, --O--, or --S--; [0013] R.sup.2 is H,
halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, arylalkyl, substituted arylalkyl,
heterocyclylalkyl, substituted heterocyclylalkyl, [0014]
--C(O)R.sup.6, --C(O)OR.sup.6, --C(O)NR.sup.7R.sup.8,
--S(O)OR.sup.7, --S(O)NR.sup.7R.sup.8, --S(O).sub.2R.sup.7,
--S(O)R.sup.7, --S(O).sub.2OR.sup.7, or
--S(O).sub.2NR.sup.7R.sup.8; [0015] L.sup.3 is --NH--, --O--,
--S--, --N(R.sup.9)C(O)--, --S(O).sub.2--, --S(O)--, or a covalent
bond; [0016] R.sup.3 is alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl,
substituted heteroalkyl, carbocyclyl, substituted carbocyclyl,
carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl,
substituted heterocyclyl, heterocyclylalkyl, or substituted
heterocyclylalkyl; [0017] R.sup.4 and R.sup.5 are each
independently H, alkyl, substituted alkyl, carbocyclyl, substituted
carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl,
heterocyclyl, substituted heterocyclyl, heterocyclylalkyl,
substituted heterocyclylalkyl, --C(O)H, --C(O)R.sup.3,
--S(O)R.sup.3, --S(O).sub.2R.sup.3, --C(O)OR.sup.3, or
--C(O)NR.sup.7R.sup.8; or [0018] R.sup.4 and R.sup.5, taken
together with the nitrogen to which they are both attached, form a
substituted or unsubstituted heterocycle; [0019] R.sup.6 is alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, heteroalkyl, substituted heteroalkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; [0020] R.sup.7
and R.sup.8 are each independently H, alkyl, substituted alkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; or [0021]
R.sup.7 and R.sup.8, taken together with the nitrogen to which they
are both bonded, form a substituted or unsubstituted heterocycle;
[0022] R.sup.9 is H, alkyl, substituted alkyl, carbocyclyl,
substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; is halogen,
cyano, azido, nitro, alkyl, substituted alkyl, hydroxyl, amino,
heteroalkyl, or substituted heteroalkyl; and [0023] n is an integer
from 0 to 5; and [0024] with the following proviso: [0025] (a) When
X.sup.1 is --CH.sub.2--, D is 1,4-phenylene, R.sup.3-L.sup.3- is
CH.sub.3CH.sub.2CH.sub.2CH.sub.2O-- or
CH.sub.3--O--CH.sub.2CH.sub.2--O, n=0, m=1, then NR.sup.4R.sup.5 is
not: (1) a 4-substituted or 4,4-disubstituted piperidine or
piperazine (2) --NHCH.sub.3; [0026] (b) When X.sup.1 is
--CH.sub.2--, D is 1,4-phenylene or 1,4-piperidinylene,
R.sup.3-L.sup.3- is CH.sub.3CH.sub.2CH.sub.2CH.sub.2O-- or
CH.sub.3--O--CH.sub.2CH.sub.2--O, n=0, m=1, then neither R.sup.4
nor R.sup.5 are substituted alkyl, substituted heterocycyl, or
substituted benzyl; and [0027] (c) When X.sup.1 is --CH.sub.2--, D
is 2,5-pyridylene, R.sup.3-L.sup.3- is
CH.sub.3CH.sub.2CH.sub.2CH.sub.2O-- or
CH.sub.3--O--CH.sub.2CH.sub.2--O, n=0, m=1, then NR.sup.4R.sup.5 is
not pyrrolyl, piperazyl, or N(CH.sub.3).sub.2.
[0028] In another embodiment, Formula I can be represented by
Formula Ia:
##STR00003##
[0029] or a pharmaceutically acceptable salt thereof, wherein:
[0030] R.sup.1 is --NR.sup.4R.sup.5; [0031] R.sup.2 is H, alkyl,
substituted alkyl, carbocyclyl, substituted carbocyclyl,
carbocyclylalkyl, substituted carbocyclylalkyl, arylalkyl,
substituted arylalkyl, heterocyclylalkyl, substituted
heterocyclylalkyl, --C(O)R.sup.6, --C(O)OR.sup.6,
--C(O)NR.sup.7R.sup.8, --S(O).sub.2OR.sup.7, or
--S(O).sub.2NR.sup.7R.sup.8; [0032] L.sup.3 is --NH--, --O--,
--S--, --N(R.sup.9)C(O)--, --S(O).sub.2--, --S(O)--, or a covalent
bond; [0033] R.sup.3 is alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl,
substituted heteroalkyl, carbocyclyl, substituted carbocyclyl,
carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl,
substituted heterocyclyl, heterocyclylalkyl, or substituted
heterocyclylalkyl; [0034] R.sup.4 and R.sup.5 are each
independently H, alkyl, substituted alkyl, carbocyclyl, substituted
carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl,
heterocyclyl, substituted heterocyclyl, heterocyclylalkyl,
substituted heterocyclylalkyl, --C(O)H, --C(O)R.sup.3,
--S(O)R.sup.3, --S(O).sub.2R.sup.3, --C(O)OR.sup.3, or
--C(O)NR.sup.7R.sup.8; or [0035] R.sup.4 and R.sup.5, taken
together with the nitrogen to which they are both attached, form a
substituted or unsubstituted heterocycle; [0036] R.sup.6 is alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, heteroalkyl, substituted heteroalkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; [0037] R.sup.7
and R.sup.8 are each independently H, alkyl, substituted alkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; or [0038]
R.sup.7 and R.sup.8, taken together with the nitrogen to which they
are both bonded, form a substituted or unsubstituted heterocycle;
[0039] R.sup.9 is H, alkyl, substituted alkyl, carbocyclyl,
substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl, a protecting
group, or a prodrug moiety; [0040] R.sup.10 is halogen, cyano,
azido, nitro, alkyl, substituted alkyl, hydroxyl, amino,
heteroalkyl, or substituted heteroalkyl; and [0041] n is an integer
from 0 to 4.
[0042] In another embodiment, Formula II can be represented by
Formula IIa:
##STR00004##
[0043] or a pharmaceutically acceptable salt thereof, wherein:
[0044] R.sup.1 is --NR.sup.4R.sup.5; [0045] R.sup.2 is H, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, carbocyclyl,
substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, arylalkyl, substituted arylalkyl,
heterocyclylalkyl, substituted heterocyclylalkyl, --C(O)R.sup.6,
--C(O)OR.sup.6, --C(O)NR.sup.2R.sup.8, --S(O).sub.2OR.sup.7, or
--S(O).sub.2NR.sup.7R.sup.8; [0046] L.sup.3 is --NH--, --O--,
--S--, --N(R.sup.9)C(O)--, --S(O).sub.2--, --S(O)--, or a covalent
bond; [0047] R.sup.3 is alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl,
substituted heteroalkyl, carbocyclyl, substituted carbocyclyl,
carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl,
substituted heterocyclyl, heterocyclylalkyl, or substituted
heterocyclylalkyl; [0048] R.sup.4 and R.sup.5 are each
independently H, alkyl, substituted alkyl, carbocyclyl, substituted
carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl,
heterocyclyl, substituted heterocyclyl, heterocyclylalkyl,
substituted heterocyclylalkyl, --C(O)H, --C(O)R.sup.3,
--S(O)R.sup.3, --S(O).sub.2R.sup.3, --C(O)OR.sup.3, or
--C(O)NR.sup.7R.sup.8; or [0049] R.sup.4 and R.sup.5, taken
together with the nitrogen to which they are both attached, form a
substituted or unsubstituted heterocycle; [0050] R.sup.6 is alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, heteroalkyl, substituted heteroalkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; [0051] R.sup.7
and R.sup.8 are each independently H, alkyl, substituted alkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; or [0052]
R.sup.7 and R.sup.8, taken together with the nitrogen to which they
are both bonded, form a substituted or unsubstituted heterocycle;
[0053] R.sup.9 is H, alkyl, substituted alkyl, carbocyclyl,
substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl, a protecting
group, or a prodrug moiety; [0054] R.sup.10 is halogen, cyano,
azido, nitro, alkyl, substituted alkyl, hydroxyl, amino,
heteroalkyl, or substituted heteroalkyl; and [0055] n is 0, 1, 2,
or 3.
[0056] In another embodiment, the present application provides for
a pharmaceutical composition comprising at least one compound of
Formula I or II, or a pharmaceutically acceptable salt, solvate,
and/or ester thereof; and a pharmaceutically acceptable carrier or
excipient.
[0057] In another embodiment, the present application provides for
a pharmaceutical composition comprising at least one compound of
Formula I or II, or a pharmaceutically acceptable salt, solvate,
and/or ester thereof; at least one additional active agent; and a
pharmaceutically acceptable carrier or exipient.
[0058] In another embodiment, the present application provides for
a method for treating or preventing a viral infection comprising
administering, to a patient in need thereof, a therapeutically
effective amount of at least one compound of Formula I or II, or a
pharmaceutically acceptable salt, solvate, and/or ester
thereof.
[0059] In another embodiment, the present application provides for
a combination pharmaceutical agent comprising:
[0060] a) a first pharmaceutical composition comprising a compound
of Formula I or II, or a pharmaceutically acceptable salt, solvate,
and/or ester thereof; and
[0061] b) a second pharmaceutical composition comprising at least
one additional active agent selected from the group consisting of
interferons, ribavirin or its analogs, HCV NS3 protease inhibitors,
alpha-glucosidase 1 inhibitors, hepatoprotectants, nucleoside or
nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside
inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7
agonists, cyclophillin inhibitors, HCV IRES inhibitors,
pharmacokinetic enhancers, and other drugs for treating HCV, or
mixtures thereof.
DETAILED DESCRIPTION
[0062] Reference will now be made in detail to certain claims of
the invention, examples of which are illustrated in the
accompanying structures and formulas. While the invention will be
described in conjunction with the enumerated claims, it will be
understood that they are not intended to limit the invention to
those claims. On the contrary, the invention is intended to cover
all alternatives, modifications, and equivalents, which may be
included within the scope of the present invention as defined by
the claims.
[0063] All documents referenced herein are each incorporated by
reference in their entirety for all purposes.
DEFINITIONS
[0064] Unless stated otherwise, the following terms and phrases as
used herein are intended to have the following meanings:
[0065] When trade names are used herein, applicants intend to
independently include the tradename product and the active
pharmaceutical ingredient(s) of the tradename product.
[0066] As used herein, "a compound of the invention" or "a compound
of formula I or II" means a compound of formula I or II, or a
pharmaceutically acceptable salt, solvate, ester or physiologically
functional derivative thereof. Compounds of the invention also
include tautomeric forms thereof, e.g., tautomeric "enols" as
described herein. Similarly, with respect to isolatable
intermediates such as for example, compounds of formula (2), the
phrase "a compound of formula (number)" means a compound of that
formula and pharmaceutically acceptable salts, solvates and
physiologically functional derivatives thereof.
[0067] "Alkyl" is hydrocarbon containing normal, secondary,
tertiary or cyclic carbon atoms. For example, an alkyl group can
have 1 to 20 carbon atoms (i.e, C.sub.1-C.sub.20 alkyl), 1 to 10
carbon atoms (i.e., C.sub.1-C.sub.10 alkyl), or 1 to 6 carbon atoms
(i.e., C.sub.1-C.sub.6 alkyl). Examples of suitable alkyl groups
include, but are not limited to, methyl (Me, --CH.sub.3), ethyl
(Et, --CH.sub.2CH.sub.3), 1-propyl (n-Pr, n-propyl,
--CH.sub.2CH.sub.2CH.sub.3), 2-propyl (i-Pr, i-propyl,
--CH(CH.sub.3).sub.2), 1-butyl (n-Bu, n-butyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-methyl-1-propyl (i-Bu,
i-butyl, --CH.sub.2CH(CH.sub.3).sub.2), 2-butyl (s-Bu, s-butyl,
--CH(CH.sub.3)CH.sub.2CH.sub.3), 2-methyl-2-propyl (t-Bu, t-butyl,
--C(CH.sub.3).sub.3), 1-pentyl (n-pentyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.3), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 3-methyl-1-butyl
(--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-1-butyl
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), 1-hexyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-hexyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)),
2-methyl-2-pentyl (--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3),
3-methyl-2-pentyl (--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3),
4-methyl-2-pentyl (--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2),
3-methyl-3-pentyl (--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2),
2-methyl-3-pentyl (--CH(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2),
2,3-dimethyl-2-butyl (--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2),
3,3-dimethyl-2-butyl (--CH(CH.sub.3)C(CH.sub.3).sub.3, and octyl
(--(CH.sub.2).sub.7CH.sub.3).
[0068] "Alkoxy" means a group having the formula --O-alkyl, in
which an alkyl group, as defined above, is attached to the parent
molecule via an oxygen atom. The alkyl portion of an alkoxy group
can have 1 to 20 carbon atoms (i.e., C.sub.1-C.sub.20 alkoxy), 1 to
12 carbon atoms (i.e., C.sub.1-C.sub.12 alkoxy), or 1 to 6 carbon
atoms (i.e., C.sub.1-C.sub.6 alkoxy). Examples of suitable alkoxy
groups include, but are not limited to, methoxy (--O--CH.sub.3 or
--OMe), ethoxy (--OCH.sub.2CH.sub.3 or --OEt), t-butoxy
(--O--C(CH.sub.3).sub.3 or --OtBu) and the like.
[0069] "Haloalkyl" is an alkyl group, as defined above, in which
one or more hydrogen atoms of the alkyl group is replaced with a
halogen atom. The alkyl portion of a haloalkyl group can have 1 to
20 carbon atoms (i.e., C.sub.1-C.sub.20 haloalkyl), 1 to 12 carbon
atoms (i.e., C.sub.1-C.sub.12 haloalkyl), or 1 to 6 carbon atoms
(i.e., C.sub.1-C.sub.6 alkyl). Examples of suitable haloalkyl
groups include, but are not limited to, --CF.sub.3, --CHF.sub.2,
--CFH.sub.2, --CH.sub.2CF.sub.3, and the like.
[0070] "Alkenyl" is a hydrocarbon containing normal, secondary,
tertiary or cyclic carbon atoms with at least one site of
unsaturation, i.e. a carbon-carbon, sp.sup.2 double bond. For
example, an alkenyl group can have 2 to 20 carbon atoms (i.e.,
C.sub.2-C.sub.20 alkenyl), 2 to 12 carbon atoms (i.e.,
C.sub.2-C.sub.12 alkenyl), or 2 to 6 carbon atoms (i.e.,
C.sub.2-C.sub.6 alkenyl). Examples of suitable alkenyl groups
include, but are not limited to, ethylene, vinyl
(--CH.dbd.CH.sub.2), allyl (--CH.sub.2CH.dbd.CH.sub.2),
cyclopentenyl (--C.sub.5H.sub.7), and 5-hexenyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH.sub.2).
[0071] "Alkynyl" is a hydrocarbon containing normal, secondary,
tertiary or cyclic carbon atoms with at least one site of
unsaturation, i.e. a carbon-carbon, sp triple bond. For example, an
alkynyl group can have 2 to 20 carbon atoms (i.e., C.sub.2-C.sub.20
alkynyl), 2 to 12 carbon atoms (i.e., C.sub.2-C.sub.12 alkyne,), or
2 to 6 carbon atoms (i.e., C.sub.2-C.sub.6 alkynyl). Examples of
suitable alkynyl groups include, but are not limited to, acetylenic
(--C.ident.CH), propargyl (--CH.sub.2C.ident.CH), and the like.
[0072] "Alkylene" refers to a saturated, branched or straight chain
or cyclic hydrocarbon radical having two monovalent radical centers
derived by the removal of two hydrogen atoms from the same or two
different carbon atoms of a parent alkane. For example, an alkylene
group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to
6 carbon atoms. Typical alkylene radicals include, but are not
limited to, methylene (--CH.sub.2--), 1,1-ethyl (--CH(CH.sub.3)--),
1,2-ethyl (--CH.sub.2CH.sub.2--), 1,1-propyl
(--CH(CH.sub.2CH.sub.3)--), 1,2-propyl (--CH.sub.2CH(CH.sub.3)--),
1,3-propyl (--CH.sub.2CH.sub.2CH.sub.2--), 1,4-butyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), and the like.
[0073] "Alkenylene" refers to an unsaturated, branched or straight
chain or cyclic hydrocarbon radical having two monovalent radical
centers derived by the removal of two hydrogen atoms from the same
or two different carbon atoms of a parent alkene. For example, and
alkenylene group can have 1 to 20 carbon atoms, 1 to 10 carbon
atoms, or 1 to 6 carbon atoms. Typical alkenylene radicals include,
but are not limited to, 1,2-ethylene (--CH.dbd.CH--).
[0074] "Alkynylene" refers to an unsaturated, branched or straight
chain or cyclic hydrocarbon radical having two monovalent radical
centers derived by the removal of two hydrogen atoms from the same
or two different carbon atoms of a parent alkyne. For example, an
alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon
atoms, or 1 to 6 carbon atoms. Typical alkynylene radicals include,
but are not limited to, acetylene (--C.ident.C--), propargyl
(--CH.sub.2C.ident.C--), and 4-pentynyl
(--CH.sub.2CH.sub.2CH.sub.2C.ident.CH--).
[0075] "Aminoalkyl" refers to an acyclic alkyl radical in which one
of the hydrogen atoms bonded to a carbon atom, typically a terminal
or sp.sup.3 carbon atom, is replaced with an amino radical.
[0076] "Amidoalkyl" refers to an acyclic alkyl radical in which one
of the hydrogen atoms bonded to a carbon atom, typically a terminal
or sp.sup.3 carbon atom, is replaced with a --NR.sup.aCOR.sup.b
group where R.sup.a is hydrogen or alkyl and R.sup.b is alkyl,
substituted alkyl, aryl, or substituted aryl as defined herein,
e.g., --(CH.sub.2).sub.2--NHC(O)CH.sub.3,
--(CH.sub.2).sub.3--NH--C(O)--CH.sub.3, and the like.
[0077] "Aryl" means a monovalent aromatic hydrocarbon radical
derived by the removal of one hydrogen atom from a single carbon
atom of a parent aromatic ring system. For example, an awl group
can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12
carbon atoms. Typical aryl groups include, but are not limited to,
radicals derived from benzene (e.g., phenyl), substituted benzene,
naphthalene, anthracene, biphenyl, and the like.
[0078] "Arylene" refers to an aryl as defined above having two
monovalent radical centers derived by the removal of two hydrogen
atoms from the same or two different carbon atoms of a parent aryl.
Typical arylene radicals include, but are not limited to,
phenylene.
[0079] "Arylalkyl" refers to an acyclic alkyl radical in which one
of the hydrogen atoms bonded to a carbon atom, typically a terminal
or sp.sup.3 carbon atom, is replaced with an aryl radical. Typical
arylalkyl groups include, but are not limited to, benzyl,
2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,
naphthobenzyl, 2-naphthophenylethan-1-yl and the like. The
arylalkyl group can comprise 6 to 20 carbon atoms, e.g., the alkyl
moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon
atoms.
[0080] "Arylalkenyl" refers to an acyclic alkenyl radical in which
one of the hydrogen atoms bonded to a carbon atom, typically a
terminal or sp.sup.3 carbon atom, but also an sp.sup.2 carbon atom,
is replaced with an aryl radical. The aryl portion of the
arylalkenyl can include, for example, any of the aryl groups
disclosed herein, and the alkenyl portion of the arylalkenyl can
include, for example, any of the alkenyl groups disclosed herein.
The arylalkenyl group can comprise 6 to 20 carbon atoms, e.g., the
alkenyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to
14 carbon atoms.
[0081] "Arylalkynyl" refers to an acyclic alkynyl radical in which
one of the hydrogen atoms bonded to a carbon atom, typically a
terminal or spa carbon atom, but also an sp carbon atom, is
replaced with an aryl radical. The aryl portion of the arylalkynyl
can include, for example, any of the aryl groups disclosed herein,
and the alkynyl portion of the arylalkynyl can include, for
example, any of the alkynyl groups disclosed herein. The
arylalkynyl group can comprise 6 to 20 carbon atoms, e.g., the
alkynyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to
14 carbon atoms.
[0082] The term "substituted" in reference to alkyl, alkylene,
aryl, arylalkyl, heterocyclyl, etc., for example, "substituted
alkyl", "substituted alkylene", "substituted aryl", "substituted
arylalkyl", "substituted heterocyclyl", and "substituted
carbocyclyl" means alkyl, alkylene, aryl, arylalkyl, heterocyclyl,
carbocyclyl respectively, in which one or more hydrogen atoms are
each independently replaced with a non-hydrogen substituent.
Typical substituents include, but are not limited to, --X, --R,
--O.sup.-, .dbd.O, --OR, --SR, --S.sup.-, --NR.sub.2,
--N.sup.+R.sub.3, .dbd.NR, --CX.sub.3, --CN, --OCN, --SCN,
--N.dbd.C.dbd.O, --NCS, --NO, --NO.sub.2, .dbd.N.sub.2, --N.sub.3,
--NHC(.dbd.O)R, --C(.dbd.O)NRR--S(.dbd.O).sub.2O.sup.-,
--S(.dbd.O).sub.2OH, --S(.dbd.O).sub.2R, --OS(.dbd.O).sub.2OR,
--S(.dbd.O).sub.2NR, --S(.dbd.O)R, --OP(.dbd.O)(OR).sub.2,
--P(.dbd.O)(OR).sub.2, --P(.dbd.O)(O.sup.-).sub.2,
--P(.dbd.O)(OH).sub.2, --P(O)(OR)(O), --C(.dbd.O)R, --C(S)R,
--C(O)OR, --C(O)O.sup.-, --C(S)OR, --C(O)SR, --C(S)SR, --C(O)NRR,
--C(S)NRR, --C(.dbd.NR)NRR, where each X is independently a
halogen: F, Cl, Br, or I; and each R is independently H, alkyl,
aryl, arylalkyl, a heterocycle, or a protecting group or prodrug
moiety. Alkylene, alkynylene, and alkynylene groups may also be
similarly substituted.
[0083] Those skilled in the art will recognize that when moieties
such as "alkyl", "aryl", "heterocyclyl", etc. are substituted with
one or more substituents, they could alternatively be referred to
as "alkylene", "arylene", "heterocyclylene", etc. moieties (i.e.,
indicating that at least one of the hydrogen atoms of the parent
"alkyl", "aryl", "heterocyclyl" moieties has been replaced with the
indicated substituent(s)). When moieties such as "alkyl", "aryl",
"heterocyclyl", etc. are referred to herein as "substituted" or are
shown diagrammatically to be substituted (or optionally
substituted, e.g., when the number of substituents ranges from zero
to a positive integer), then the terms "alkyl", "aryl",
"heterocyclyl", etc. are understood to be interchangeable with
"alkylene", "arylene", "heterocyclylene", etc.
[0084] The term "prodrug" as used herein refers to any compound
that when administered to a biological system generates the drug
substance, i.e., active ingredient, as a result of spontaneous
chemical reaction(s), enzyme catalyzed chemical reaction(s),
photolysis, and/or metabolic chemical reaction(s). A prodrug is
thus a covalently modified analog or latent form of a
therapeutically active compound.
[0085] One skilled in the art will recognize that substituents and
other moieties of the compounds of Formula I or II should be
selected in order to provide a compound which is sufficiently
stable to provide a pharmaceutically useful compound which can be
formulated into an acceptably stable pharmaceutical composition.
Compounds of Formula I or II which have such stability are
contemplated as falling within the scope of the present
invention.
[0086] "Heteroalkyl" refers to an alkyl group where one or more
carbon atoms have been replaced with a heteroatom, such as, O, N,
or S. For example, if the carbon atom of the alkyl group which is
attached to the parent molecule is replaced with a heteroatom
(e.g., O, N, or S) the resulting heteroalkyl groups are,
respectively, an alkoxy group (e.g., --OCH.sub.3, etc.), an amine
(e.g., --NHCH.sub.3, --N(CHL).sub.2, etc.), or a thioalkyl group
(e.g., --SCH.sub.3). If a non-terminal carbon atom of the alkyl
group which is not attached to the parent molecule is replaced with
a heteroatom (e.g., O, N, or S) and the resulting heteroalkyl
groups are, respectively, an alkyl ether (e.g.,
--CH.sub.2CH.sub.2--O--CH.sub.3, etc.), an alkyl amine (e.g.,
--CH.sub.2NHCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2, etc.), or a
thioalkyl ether (e.g., --CH.sub.2--S--CHL). If a terminal carbon
atom of the alkyl group is replaced with a heteroatom (e.g., O, N,
or S), the resulting heteroalkyl groups are, respectively, a
hydroxyalkyl group (e.g., --CH.sub.2CH.sub.2--OH), an aminoalkyl
group (e.g., --CH.sub.2NH.sub.2), or an alkyl thiol group (e.g.,
--CH.sub.2CH.sub.2--SH). A heteroalkyl group can have, for example,
1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
A C.sub.1-C.sub.6 heteroalkyl group means a heteroalkyl group
having 1 to 6 carbon atoms.
[0087] "Heterocycle" or "heterocyclyl" as used herein includes by
way of example and not limitation those heterocycles described in
Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W.A.
Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and
9; The Chemistry of Heterocyclic Compounds, A Series of Monographs"
(John Wiley & Sons, New York, 1950 to present), in particular
Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960)
82:5566. In one specific embodiment of the invention "heterocycle"
includes a "carbocycle" as defined herein, wherein one or more
(e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a
heteroatom (e.g. O, N, or S). The terms "heterocycle" or
"heterocyclyl" includes saturated rings, partially unsaturated
rings, and aromatic rings (i.e., heteroaromatic rings). Substituted
heterocyclyls include, for example, heterocyclic rings substituted
with any of the substituents disclosed herein including carbonyl
groups. A non-limiting example of a carbonyl substituted
heterocyclyl is:
##STR00005##
[0088] Examples of heterocycles include by way of example and not
limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl),
thiazolyl, tetrahydrothiophenyl, sulfur oxidized
tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl,
pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl,
indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,
piperidinyl, 4-piperidonyl, pyrrolidinyl, azetidinyl,
2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,
octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl,
2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl,
isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl,
isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl,
isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl,
phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,
cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,
.beta.-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl,
phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl,
imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl,
isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl,
benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,
isatinoyl, and bis-tetrahydrofuranyl:
##STR00006##
[0089] By way of example and not limitation, carbon bonded
heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine,
position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a
pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4,
or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or
tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or
thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or
isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4
of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or
position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more
typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl,
4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl,
5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,
5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or
5-thiazolyl.
[0090] By way of example and not limitation, nitrogen bonded
heterocycles are bonded at position 1 of an aziridine, azetidine,
pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,
imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,
2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole,
indoline, 1H-indazole, position 2 of a isoindole, or isoindoline,
position 4 of a morpholine, and position 9 of a carbazole, or
.beta.-carboline. Still more typically, nitrogen bonded
heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl,
1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
[0091] "Heterocyclylene" refers to a heterocyclyl, as defined
herein, derived by replacing a hydrogen atom from a carbon atom or
heteroatom of a heterocyclyl, with an open valence. Similarly,
"heteroarylene" refers to an aromatic heterocyclylene.
[0092] "Heterocyclylalkyl" refers to an acyclic alkyl radical in
which one of the hydrogen atoms bonded to a carbon atom, typically
a terminal or sp.sup.3 carbon atom, is replaced with a heterocyclyl
radical (i.e., a heterocyclyl-alkylene-moiety). Typical
heterocyclyl alkyl groups include, but are not limited to
heterocyclyl-CH.sub.2--, 2-(heterocyclyl)ethan-1-yl, and the like,
wherein the "heterocyclyl" portion includes any of the heterocyclyl
groups described above, including those described in Principles of
Modern Heterocyclic Chemistry. One skilled in the art will also
understand that the heterocyclyl group can be attached to the alkyl
portion of the heterocyclyl alkyl by means of a carbon-carbon bond
or a carbon-heteroatom bond, with the proviso that the resulting
group is chemically stable. The heterocyclyl alkyl group comprises
2 to 20 carbon atoms, e.g., the alkyl portion of the arylalkyl
group comprises 1 to 6 carbon atoms and the heterocyclyl moiety
comprises 1 to 14 carbon atoms. Examples of heterocyclylalkyls
include by way of example and not limitation 5-membered sulfur,
oxygen, and/or nitrogen containing heterocycles such as
thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl,
oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur,
oxygen, and/or nitrogen containing heterocycles such as
piperidinylmethyl, piperazinylmethyl, morpholinylmethyl,
pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl,
etc.
[0093] "Heterocyclylalkenyl" refers to an acyclic alkenyl radical
in which one of the hydrogen atoms bonded to a carbon atom,
typically a terminal or sp.sup.3 carbon atom, but also a sp.sup.2
carbon atom, is replaced with a heterocyclyl radical (i.e., a
heterocyclyl-alkenylene-moiety). The heterocyclyl portion of the
heterocyclyl alkenyl group includes any of the heterocyclyl groups
described herein, including those described in Principles of Modern
Heterocyclic Chemistry, and the alkenyl portion of the heterocyclyl
alkenyl group includes any of the alkenyl groups disclosed herein.
One skilled in the art will also understand that the heterocyclyl
group can be attached to the alkenyl portion of the heterocyclyl
alkenyl by means of a carbon-carbon bond or a carbon-heteroatom
bond, with the proviso that the resulting group is chemically
stable. The heterocyclyl alkenyl group comprises 2 to 20 carbon
atoms, e.g., the alkenyl portion of the heterocyclyl alkenyl group
comprises 1 to 6 carbon atoms and the heterocyclyl moiety comprises
1 to 14 carbon atoms.
[0094] "Heterocyclylalkynyl" refers to an acyclic alkynyl radical
in which one of the hydrogen atoms bonded to a carbon atom,
typically a terminal or spa carbon atom, but also an sp carbon
atom, is replaced with a heterocyclyl radical (i.e., a
heterocyclyl-alkynylene-moiety). The heterocyclyl portion of the
heterocyclyl alkynyl group includes any of the heterocyclyl groups
described herein, including those described in Principles of Modern
Heterocyclic Chemistry, and the alkynyl portion of the heterocyclyl
alkynyl group includes any of the alkynyl groups disclosed herein.
One skilled in the art will also understand that the heterocyclyl
group can be attached to the alkynyl portion of the heterocyclyl
alkynyl by means of a carbon-carbon bond or a carbon-heteroatom
bond, with the proviso that the resulting group is chemically
stable. The heterocyclyl alkynyl group comprises 2 to 20 carbon
atoms, e.g., the alkynyl portion of the heterocyclyl alkynyl group
comprises 1 to 6 carbon atoms and the heterocyclyl moiety comprises
1 to 14 carbon atoms.
[0095] "Heteroaryl" refers to a monovalent aromatic heterocyclyl
having at least one heteroatom in the ring. Non-limiting examples
of suitable heteroatoms which can be included in the aromatic ring
include oxygen, sulfur, and nitrogen. Non-limiting examples of
heteroaryl rings include all of those listed in the definition of
"heterocyclyl", including pyridinyl, pyrrolyl, oxazolyl, indolyl,
isoindolyl, purinyl, furanyl, thienyl, benzofuranyl,
benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl,
pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl,
pyrimidyl, pyrazyl, etc.
[0096] "Carbocycle" or "carbocyclyl" refers to a saturated,
partially unsaturated or aromatic ring having 3 to 7 carbon atoms
as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about
20 carbon atoms as a polycycle. Monocyclic carbocycles have 3 to 6
ring atoms, still more typically 5 or 6 ring atoms. Bicyclic
carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo
(4,5), (5,5), (5,6) or (6,6) system, or 9 or 10 ring atoms arranged
as a bicyclo (5,6) or (6,6) system. Examples of monocyclic
carbocycles include cyclopropyl, cyclobutyl, cyclopentyl,
1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl,
cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,
1-cyclohex-3-enyl, phenyl, etc.
[0097] "Carbocyclylene" refers to a carbocyclyl or carbocycle as
defined above having two monovalent radical centers derived by the
removal of two hydrogen atoms from the same or two different carbon
atoms of a parent carbocyclyl. Typical carbocyclylene radicals
include, but are not limited to, phenylene.
[0098] "Arylheteroalkyl" refers to a heteroalkyl as defined herein,
in which a hydrogen atom (which may be attached either to a carbon
atom or a heteroatom) has been replaced with an aryl group as
defined herein. The aryl groups may be bonded to a carbon atom of
the heteroalkyl group, or to a heteroatom of the heteroalkyl group,
provided that the resulting arylheteroalkyl group provides a
chemically stable moiety. For example, an arylheteroalkyl group can
have the general formulae -alkylene-O-aryl,
-alkylene-O-alkylene-aryl, -alkylene-NH-aryl,
-alkylene-NH-alkylene-aryl, -alkylene-S-aryl,
-alkylene-S-alkylene-aryl, etc. In addition, any of the alkylene
moieties in the general formulae above can be further substituted
with any of the substituents defined or exemplified herein.
[0099] "Heteroarylalkyl" refers to an alkyl group, as defined
herein, in which a hydrogen atom has been replaced with a
heteroaryl group as defined herein. Non-limiting examples of
heteroaryl alkyl include --CH.sub.2-pyridinyl, --CH.sub.2-pyrrolyl,
--CH.sub.2-oxazolyl, --CH.sub.2-indolyl, --CH.sub.2-isoindolyl,
--CH.sub.2-purinyl, --CH.sub.2-furanyl, --CH.sub.2-thienyl,
--CH.sub.2-benzofuranyl, --CH.sub.2-benzothiophenyl,
--CH.sub.2-carbazolyl, --CH.sub.2-imidazolyl, --CH.sub.2-thiazolyl,
--CH.sub.2-isoxazolyl, --CH.sub.2-pyrazolyl,
--CH.sub.2-isothiazolyl, --CH.sub.2-quinolyl,
--CH.sub.2-isoquinolyl, --CH.sub.2-pyridazyl, --CH.sub.2-pyrimidyl,
--CH.sub.2-pyrazyl, --CH(CH.sub.3)-pyridinyl,
--CH(CH.sub.3)-pyrrolyl, --CH(CH.sub.3)-oxazolyl,
--CH(CH.sub.3)-indolyl, --CH(CH.sub.3)-isoindolyl,
--CH(CH.sub.3)-purinyl, --CH(CH.sub.3)-furanyl,
--CH(CH.sub.3)-thienyl, --CH(CH.sub.3)-benzofuranyl,
--CH(CH.sub.3)-benzothiophenyl, --CH(CH.sub.3)-carbazolyl,
--CH(CH.sub.3)-imidazolyl, --CH(CH.sub.3)--thiazolyl,
--CH(CH.sub.3)-isoxazolyl, --CH(CH.sub.3)-pyrazolyl,
--CH(CH.sub.3)-isothiazolyl, --CH(CH.sub.3)-quinolyl,
--CH(CH.sub.3)-isoquinolyl, --CH(CH.sub.3)-pyridazyl,
--CH(CH.sub.3)--pyrimidyl, --CH(CH.sub.3)-pyrazyl, etc.
[0100] The term "optionally substituted" in reference to a
particular moiety of the compound of Formula I (e.g., an optionally
substituted aryl group) refers to a moiety having 0, 1, 2, or more
substituents.
[0101] "Ester thereof" means any ester of a compound in which any
of the --COOH functions of the molecule is replaced by a --C(O)OR
function, or in which any of the --OH functions of the molecule are
replaced with a --OC(O)R function, in which the R moiety of the
ester is any carbon-containing group which forms a stable ester
moiety, including but not limited to alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl,
heterocyclylalkyl and substituted derivatives thereof. Esters can
also include esters--as described above--of "tautomeric enols",
e.g. as shown below:
##STR00007##
[0102] The term "ester thereof" includes but is not limited to
pharmaceutically acceptable esters thereof.
[0103] The term "chiral" refers to molecules which have the
property of non-superimposability of the mirror image partner,
while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
[0104] The term "stereoisomers" refers to compounds which have
identical chemical constitution, but differ with regard to the
arrangement of the atoms or groups in space.
[0105] "Diastereomer" refers to a stereoisomer with two or more
centers of chirality and whose molecules are not mirror images of
one another. Diastereomers have different physical properties,
e.g., melting points, boiling points, spectral properties, and
reactivities. Mixtures of diastereomers may separate under high
resolution analytical procedures such as electrophoresis and
chromatography.
[0106] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0107] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book
[0108] Company, New York; and Eliel, E. and Wilen, S.,
Stereochemistry of Organic Compounds (1994) John Wiley & Sons,
Inc., New York. Many organic compounds exist in optically active
forms, i.e., they have the ability to rotate the plane of
plane-polarized light. In describing an optically active compound,
the prefixes D and L or R and S are used to denote the absolute
configuration of the molecule about its chiral center(s). The
prefixes d and l or (+) and (-) are employed to designate the sign
of rotation of plane-polarized light by the compound, with (-) or l
meaning that the compound is levorotatory. A compound prefixed with
(+) or d is dextrorotatory. For a given chemical structure, these
stereoisomers are identical except that they are mirror images of
one another. A specific stereoisomer may also be referred to as an
enantiomer, and a mixture of such isomers is often called an
enantiomeric mixture. A 50:50 mixture of enantiomers is referred to
as a racemic mixture or a racemate, which may occur where there has
been no stereoselection or stereospecificity in a chemical reaction
or process. The terms "racemic mixture" and "racemate" refer to an
equimolar mixture of two enantiomeric species, devoid of optical
activity.
Protecting Groups
[0109] In the context of the present invention, protecting groups
include prodrug moieties and chemical protecting groups.
[0110] Protecting groups are available, commonly known and used,
and are optionally used to prevent side reactions with the
protected group during synthetic procedures, i.e. routes or methods
to prepare the compounds of the invention. For the most part the
decision as to which groups to protect, when to do so, and the
nature of the chemical protecting group "PG" will be dependent upon
the chemistry of the reaction to be protected against (e.g.,
acidic, basic, oxidative, reductive or other conditions) and the
intended direction of the synthesis. The PG groups do not need to
be, and generally are not, the same if the compound is substituted
with multiple PG. In general, PG will be used to protect functional
groups such as carboxyl, hydroxyl, thio, or amino groups and to
thus prevent side reactions or to otherwise facilitate the
synthetic efficiency. The order of deprotection to yield free,
deprotected groups is dependent upon the intended direction of the
synthesis and the reaction conditions to be encountered, and may
occur in any order as determined by the artisan.
[0111] Various functional groups of the compounds of the invention
may be protected. For example, protecting groups for --OH groups
(whether hydroxyl, carboxylic acid, phosphonic acid, or other
functions) include "ether- or ester-forming groups". Ether- or
ester-forming groups are capable of functioning as chemical
protecting groups in the synthetic schemes set forth herein.
However, some hydroxyl and thio protecting groups are neither
ether- nor ester-forming groups, as will be understood by those
skilled in the art, and are included with amides, discussed
below.
[0112] A very large number of hydroxyl protecting groups and
amide-forming groups and corresponding chemical cleavage reactions
are described in Protective Groups in Organic Synthesis, Theodora
W. Greene and Peter G. M. Wuts (John Wiley & Sons, Inc., New
York, 1999, ISBN 0-47146019-9) ("Greene"). See also Kocienski,
Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New
York, 1994), which is incorporated by reference in its entirety
herein. In particular Chapter 1, Protecting Groups: An Overview,
pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94,
Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4,
Carboxyl Protecting Groups, pages 118-154, Chapter 5, Carbonyl
Protecting Groups, pages 155-184. For protecting groups for
carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and
other protecting groups for acids see Greene as set forth below.
Such groups include by way of example and not limitation, esters,
amides, hydrazides, and the like.
Ether- and Ester-Forming Protecting Groups
[0113] Ester-forming groups include: (1) phosphonate ester-forming
groups, such as phosphonamidate esters, phosphorothioate esters,
phosphonate esters, and phosphon-bis-amidates; (2) carboxyl
ester-forming groups, and (3) sulphur ester-forming groups, such as
sulphonate, sulfate, and sulfinate.
Metabolites of the Compounds of the Invention
[0114] Also falling within the scope of this invention are the in
vivo metabolic products of the compounds described herein. Such
products may result for example from the oxidation, reduction,
hydrolysis, amidation, esterification and the like of the
administered compound, primarily due to enzymatic processes.
Accordingly, the invention includes compounds produced by a process
comprising contacting a compound of this invention with a mammal
for a period of time sufficient to yield a metabolic product
thereof. Such products typically are identified by preparing a
radiolabelled (e.g., C.sup.14 or H.sup.3) compound of the
invention, administering it parenterally in a detectable dose
(e.g., greater than about 0.5 mg/kg) to an animal such as rat,
mouse, guinea pig, monkey, or to man, allowing sufficient time for
metabolism to occur (typically about 30 seconds to 30 hours) and
isolating its conversion products from the urine, blood or other
biological samples. These products are easily isolated since they
are labeled (others are isolated by the use of antibodies capable
of binding epitopes surviving in the metabolite). The metabolite
structures are determined in conventional fashion, e.g., by MS or
NMR analysis. In general, analysis of metabolites is done in the
same way as conventional drug metabolism studies well-known to
those skilled in the art. The conversion products, so long as they
are not otherwise found in vivo, are useful in diagnostic assays
for therapeutic dosing of the compounds of the invention even if
they possess no anti-infective activity of their own.
Compounds of Formula I or II
[0115] In one embodiment, the present application provides
compounds according to Formula I or II, as described herein.
[0116] In each of the embodiments herein, the following provisos
apply when applicable: [0117] (a) When X.sup.1 is --CH.sub.2--, D
is 1,4-phenylene, R.sup.3-L.sup.3- is
CH.sub.3CH.sub.2CH.sub.2CH.sub.2O-- or
CH.sub.3--O--CH.sub.2CH.sub.2--O, n=0, m=1, then NR.sup.4R.sup.5 is
not: (1) a 4-substituted or 4,4-disubstituted piperidine or
piperazine (2) --NHCH.sub.3; [0118] (b) When X.sup.1 is
--CH.sub.2--, D is 1,4-phenylene or 1,4-piperidinylene,
R.sup.3-L.sup.3- is CH.sub.3CH.sub.2CH.sub.2CH.sub.2O-- or
CH.sub.3--O--CH.sub.2CH.sub.2--O, n=0, m=1, then neither R.sup.4
nor R.sup.5 are substituted alkyl, substituted heterocycyl, or
substituted benzyl; and [0119] (c) When X.sup.1 is --CH.sub.2--, D
is 2,5-pyridylene, R.sup.3-L.sup.3- is
CH.sub.3CH.sub.2CH.sub.2CH.sub.2O-- or
CH.sub.3--O--CH.sub.2CH.sub.2--O, n=0, m=1, then NR.sup.4R.sup.5 is
not pyrrolyl, piperazyl, or N(CH.sub.3).sub.2.
[0120] The compounds of the present invention do not include any of
the compounds disclosed in WO 07/034,817, WO 07/034,917, U.S.
Patent Application Publication 2006/0052403, JP 2005/089334, or
U.S. Pat. No. 6,329,381, each of which is incorporated by reference
in its entirety.
[0121] The definitions and substituents for various genus and
subgenus of the present compounds are described and illustrated
herein. It should be understood by one skilled in the art that any
combination of the definitions and substituents described above
should not result in an inoperable species or compound. "Inoperable
species or compounds" means compound structures that violates
relevant scientific principles (such as, for example, a carbon atom
connecting to more than four covalent bonds) or compounds too
unstable to permit isolation and formulation into pharmaceutically
acceptable dosage forms. For example, it is understood to one
skilled in the art that the definition of L.sup.2 as a covalent
bond only applies to Formula I, and not to Formula II.
[0122] Similarly, the skilled artisan will understand that when
L.sup.2 is --NH--, --O--, or --S--, in Formula II, L.sup.2 defines
a .dbd.NH (imine), .dbd.O (carbonyl), or .dbd.S (thiocarbonyl)
group.
[0123] In one embodiment of Formula I or H, X.sup.1 is alkylene or
substituted alkylene; wherein the substituted alkylene comprises an
alkylene substituted with one or more substituents selected from
the group consisting of halo, hydroxyl, amino, heteroalkyl,
substituted heteroalkyl, cyano, azido, nitro, alkyl, substituted
alkyl, and combinations thereof.
[0124] In another embodiment of Formula I or II, m is 1.
[0125] In another embodiment of Formula I or II, L.sup.1 is
--CH.sub.2-- or --CH.sub.2CH.sub.2--.
[0126] In another embodiment of Formula I or II, R.sup.1 is
independently --NR.sup.4R.sup.5; and R.sup.4 and R.sup.5, taken
together with the nitrogen to which they are both attached, form a
substituted or unsubstituted heterocycle.
[0127] In another embodiment of Formula I or II, R.sup.1 is
independently --NR.sup.4R.sup.5; and R.sup.4 and R.sup.5, taken
together with the nitrogen to which they are both attached, form a
substituted or unsubstituted heterocycle; wherein the heterocycle
is a 4- to 8-membered monocyclic fully saturated or partially
unsaturated ring containing at least one hetero atom selected from
N, O, and S; or a 8- to 12-membered fused bicyclic fully saturated
or partially unsaturated ring containing at least one hetero atom
selected from N, O, and S.
[0128] In another embodiment of Formula I or II, R.sup.1 is
independently --NR.sup.4R.sup.5; and R.sup.4 and R.sup.5, taken
together with the nitrogen to which they are both attached, form a
substituted or unsubstituted heteroaryl.
[0129] In another embodiment of Formula I or II, R.sup.1 is
independently --NR.sup.4R.sup.5; and R.sup.4 is H, alkyl,
substituted alkyl, carbocyclylalkyl, substituted carbocyclylalkyl;
and R.sup.5 is aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heterocyclylalkyl, substituted heterocyclylalkyl,
--C(O)H, --C(O)R.sup.3, --C(O)OR.sup.3, or
--C(O)NR.sup.7R.sup.8.
[0130] In another embodiment of Formula I or II, R.sup.1 is
independently --NR.sup.4R.sup.5; R.sup.4 is H or carbocyclylalkyl;
and R.sup.5 is alkyl, substituted alkyl, carbocyclylalkyl, or
substituted carbocyclylalkyl.
[0131] In another embodiment of Formula I or II, D is arylene or
heteroarylene.
[0132] In another embodiment of Formula I or II, L.sup.2 is
--O--.
[0133] In one embodiment of Formula I, -L.sup.2-R.sup.2 is
--OH.
[0134] In another embodiment of Formula I or II, L.sup.2 is --O--;
and R.sup.2 is --C(O)R.sup.6, --C(O)OR.sup.6,
--C(O)NR.sup.7R.sup.8, --S(O)OR.sup.7, --S(O)NR.sup.7R.sup.8,
--S(O).sub.2OR.sup.7, or --S(O).sub.2NR.sup.7R.sup.8.
[0135] In another embodiment of Formula I or II, R.sup.2 is
--C(O)OCH.sub.3, --C(O)OCH.sub.2CH.sub.3, --C(O)OCH(CHs).sub.2,
--C(O)NHCH.sub.3, --C(O)NHCH.sub.2CH.sub.3,
--C(O)NHCH(CH.sub.3).sub.2.
[0136] In another embodiment of Formula I or II, L.sup.2 is --O--;
and R.sup.2 is alkyl, substituted alkyl, cyclylalkyl, substituted
cyclylalkyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, heterocyclylalkyl, or substituted heterocyclylalkyl.
[0137] In another embodiment of Formula I or II, R.sup.2 is methyl,
ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl,
methylcyclopropyl, cyclopropylmethylene, benzyl, or
methoxybezyl.
[0138] In another embodiment of Formula I or II, L.sup.3 is
--O--.
[0139] In another embodiment of Formula I or II, R.sup.3 is alkyl,
substituted alkyl, heteroalkyl, or substituted heteroalkyl.
[0140] In another embodiment of Formula I or II, -L.sup.3-R.sup.3
is --O-alkyl or --O-alkylene-O-alkyl.
[0141] In another embodiment of Formula I or II, -L.sup.3-R.sup.3
is --OCH.sub.2CH.sub.2OCH.sub.3 or
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0142] In another embodiment of Formula I, R.sup.4 and R.sup.5 are
not each simultaneously H or alkyl.
[0143] In another embodiment of the present invention, Formula I is
represented by Formula Ia:
##STR00008##
[0144] or a pharmaceutically acceptable salt thereof, wherein:
[0145] R.sup.1 is --NR.sup.4R.sup.5; [0146] R.sup.2 is H, alkyl,
substituted alkyl, carbocyclyl, substituted carbocyclyl,
carbocyclylalkyl, substituted carbocyclylalkyl, arylalkyl,
substituted arylalkyl, heterocyclylalkyl, substituted
heterocyclylalkyl, --C(O)R.sup.6, --C(O)OR.sup.6,
--C(O)NR.sup.7R.sup.8, --S(O).sub.2OR.sup.7, or
--S(O).sub.2NR.sup.7R.sup.8; [0147] L.sup.3 is --NH--, --O--,
--S--, --N(R.sup.9)C(O)--, --S(O).sub.2--, --S(O)--, or a covalent
bond; [0148] R.sup.3 is alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl,
substituted heteroalkyl, carbocyclyl, substituted carbocyclyl,
carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl,
substituted heterocyclyl, heterocyclylalkyl, or substituted
heterocyclylalkyl; [0149] R.sup.4 and R.sup.5 are each
independently H, alkyl, substituted alkyl, carbocyclyl, substituted
carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl,
heterocyclyl, substituted heterocyclyl, heterocyclylalkyl,
substituted heterocyclylalkyl, --C(O)H, --C(O)R.sup.3,
--S(O)R.sup.3, --S(O).sub.2R.sup.3, --C(O)OR.sup.3, or
--C(O)NR.sup.7R.sup.8; or [0150] R.sup.4 and R.sup.5, taken
together with the nitrogen to which they are both attached, form a
substituted or unsubstituted heterocycle; [0151] R.sup.6 is alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, heteroalkyl, substituted heteroalkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; [0152] R.sup.7
and R.sup.8 are each independently H, alkyl, substituted alkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; or [0153]
R.sup.7 and R.sup.8, taken together with the nitrogen to which they
are both bonded, form a substituted or unsubstituted heterocycle;
[0154] R.sup.9 is H, alkyl, substituted alkyl, carbocyclyl,
substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl, a protecting
group, or a prodrug moiety; [0155] R.sup.10 is halogen, cyano,
azido, nitro, alkyl, substituted alkyl, hydroxyl, amino,
heteroalkyl, or substituted heteroalkyl; and [0156] n is an integer
from 0 to 4.
[0157] In one embodiment of Formula Ia, R.sup.1 is NR.sup.4R.sup.5;
and R.sup.4 and R.sup.5, taken together with the nitrogen to which
they are both attached, form a substituted or unsubstituted
heterocycle.
[0158] In another embodiment of Formula Ia, R.sup.1 is
NR.sup.4R.sup.5; and R.sup.4 and R.sup.5, taken together with the
nitrogen to which they are both attached, form a substituted or
unsubstituted heterocycle; wherein the heterocycle is a 4- to
8-membered monocyclic fully saturated, partially unsaturated, or
heteroaryl ring containing at least one hetero atom selected from
N, O, and S; or a 8- to 12-membered fused bicyclic fully saturated
or partially unsaturated ring containing at least one hetero atom
selected from N, O, and S. [0159] In another embodiment of Formula
Ia, the heterocycle is selected from the group consisting of:
##STR00009##
[0160] In another embodiment of Formula Ia, R.sup.1 is
NR.sup.4R.sup.5; R.sup.4 is H, alkyl, substituted alkyl,
carbocyclylalkyl, substituted carbocyclylalkyl; and R.sup.5 is
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heterocyclylalkyl, substituted heterocyclylalkyl,
--C(O)H, --C(O)R.sup.3, --C(O)OR.sup.3, or
--C(O)NR.sup.7R.sup.8.
[0161] In another embodiment of Formula Ia, R.sup.4 is H, methyl,
ethyl, n-propyl, iso-propyl, n-butyl, cyclopropyl, or
cyclopropylmethylenyl, R.sup.5 is phenyl, pyridinyl,
--C(O)CH.sub.3, --C(O)OCH.sub.3, --C(O)CH.sub.2CH.sub.3, or
--C(O)OCH.sub.2CH.sub.3.
[0162] In another embodiment of Formula Ia, R.sup.1 is
NR.sup.4R.sup.5; R.sup.4 is H; and R.sup.5 is alkyl, substituted
alkyl, carbocyclylalkyl, substituted carbocyclylalkyl.
[0163] In another embodiment of Formula Ia, R.sup.1 is
independently --NR.sup.4R.sup.5; R.sup.4 is H; and R.sup.5 is
alkyl, substituted alkyl, carbocyclylalkyl, or substituted
carbocyclylalkyl.
[0164] In another embodiment of Formula Ia, R.sup.1 is
independently --NR.sup.4R.sup.5; R.sup.4 is H; and R.sup.5 is
selected from the group consisting of
##STR00010##
[0165] In another embodiment of Formula Ia, R.sup.2 is H.
[0166] In another embodiment of Formula Ia, R.sup.2 is
--C(O)R.sup.6, --C(O)OR.sup.6, --C(O)NR.sup.7R.sup.8,
--S(O)OR.sup.7, --S(O)NR.sup.7R.sup.8, --S(O).sub.2OR.sup.7, or
--S(O).sub.2NR.sup.7R.sup.8.
[0167] In another embodiment of Formula Ia, R.sup.2 is
--C(O)OCH.sub.3, --C(O)OCH.sub.2CH.sub.3,
--C(O)OCH(CH.sub.3).sub.2, --C(O)NHCH.sub.3,
--C(O)NHCH.sub.2CH.sub.3, --C(O)NHCH(CH.sub.3).sub.2.
[0168] In another embodiment of Formula Ia, R.sup.2 is alkyl,
substituted alkyl, cyclylalkyl, substituted cyclylalkyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl,
heterocyclylalkyl, or substituted heterocyclylalkyl.
[0169] In another embodiment of Formula Ia, R.sup.2 is methyl,
ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl,
methylcyclopropyl, cyclopropylmethylene, benzyl, or
methoxybezyl.
[0170] In another embodiment of Formula Ia, L.sup.3 is --O--.
[0171] In another embodiment of Formula Ia, -L.sup.3-R.sup.3 is
--O-alkyl, --O-(substituted alkyl), --O-carbocyclyl,
--O-heterocyclyl, --O-carbocyclylalkyl, --O-heterocyclylalkyl, or
--O-alkylene-O-alkyl. In this embodiment, it is preferred that
R.sup.2 is H. It is further preferred that R.sup.1 is
NR.sup.4R.sup.5 and R.sup.4 and R.sup.5, taken together with the
nitrogen to which they are both attached, form a heterocycle
selected from the group consisting of:
##STR00011##
[0172] In another embodiment of Formula Ia, -L.sup.3-R.sup.3 is
--OCH.sub.2CH.sub.2OCH.sub.3, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CF.sub.3, --OCH.sub.2CF.sub.2CF.sub.3,
--OCH.sub.2CH(CH.sub.3).sub.2, --OCH.sub.2CF.sub.3,
##STR00012##
In this embodiment, it is preferred that R.sup.2 is H. It is
further preferred that R.sup.1 is NR.sup.4R.sup.5 and R.sup.4 and
R.sup.5, taken together with the nitrogen to which they are both
attached, form a heterocycle selected from the group consisting
of:
##STR00013##
[0173] In another embodiment of Formula Ia, R.sup.1 is
--NR.sup.4R.sup.5; R.sup.2 is H, --C(O)R.sup.6, --C(O)OR.sup.6,
--C(O)NR.sup.7R.sup.8, --S(O).sub.2OR.sup.7, or
--S(O).sub.2NR.sup.7R.sup.8; L.sup.3 is --O--; R.sup.3 is alkyl,
substituted alkyl, heteroalkyl, substituted heteroalkyl,
carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl; and
R.sup.4 and R.sup.5 are each independently H, alkyl, substituted
alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl,
substituted carbocyclylalkyl, heterocyclyl, substituted
heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl,
--C(O)H, --C(O)R.sup.3, --S(O)R.sup.3, --S(O).sub.2R.sup.3,
--C(O)OR.sup.3, or --C(O)NR.sup.7R.sup.8; or R.sup.4 and R.sup.5,
taken together with the nitrogen to which they are both attached,
form a substituted or unsubstituted heterocycle.
[0174] In another embodiment of Formula Ia, R.sup.4 and R.sup.5 are
not each simultaneously H or alkyl.
[0175] In another embodiment of Formula Ia, -L.sup.3-R.sup.3 is
--OCH.sub.2CH.sub.2OCH.sub.3, --OCH.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.3, --Oi-butyl, --Oc-butyl,
--Oc-pentyl, --OCH.sub.2c-propyl, --OCH.sub.2c-butyl,
--OCH.sub.2CH.sub.2c-propyl, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OH,
--OCH.sub.2CF.sub.3, --OCH.sub.2CH.sub.2CF.sub.3,
--OCH.sub.2CH.sub.2CH.sub.2CF.sub.3, or
(tetrahydrofuran-2-yl)methoxy.
[0176] In another embodiment of Formula Ia, -L.sup.3-R.sup.3 is
--OCH.sub.2CH.sub.2OCH.sub.3, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CF.sub.3, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OH,
--Oi-butyl, --OCH.sub.2CH.sub.2c-propyl, or --OCH.sub.2c-propyl. In
still another embodiment, -L.sup.3-R.sup.3 is as defined
immediately previously, R.sup.2 is H, and R.sup.1 is
NR.sup.4R.sup.5 and R.sup.4 and R.sup.5, taken together with the
nitrogen to which they are both attached, form a heterocycle
selected from the group consisting of:
##STR00014##
[0177] In another embodiment of Formula Ia, -L.sup.3-R.sup.3 is
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.3, --OCH.sub.2CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.2CF.sub.3, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OH,
or --OCH.sub.2c-propyl. In still another embodiment,
-L.sup.3-R.sup.3 is as defined immediately previously, R.sup.2 is
H, and R.sup.1 is NR.sup.4R.sup.5 and R.sup.4 and R.sup.5, taken
together with the nitrogen to which they are both attached, form a
heterocycle selected from the group consisting of:
##STR00015##
In a further embodiment -L.sup.3-R.sup.3 is
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0178] In one embodiment of the present invention, Formula II is
represented by Formula IIa:
##STR00016##
[0179] or a pharmaceutically acceptable salt thereof, wherein:
[0180] R.sup.1 is --NR.sup.4R.sup.5; [0181] R.sup.2 is H, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, carbocyclyl,
substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, arylalkyl, substituted arylalkyl,
heterocyclylalkyl, substituted heterocyclylalkyl, --C(O)R.sup.6,
--C(O)OR.sup.6, --C(O)NR.sup.7R.sup.8, --S(O).sub.2OR.sup.7, or
--S(O).sub.2NR.sup.7R.sup.8; [0182] L.sup.3 is --NH--, --O--,
--S--, --N(R.sup.9)C(O)--, --S(O).sub.2--, --S(O)--, or a covalent
bond; [0183] R.sup.3 is alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl,
substituted heteroalkyl, carbocyclyl, substituted carbocyclyl,
carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl,
substituted heterocyclyl, heterocyclylalkyl, or substituted
heterocyclylalkyl; [0184] R.sup.4 and R.sup.5 are each
independently H, alkyl, substituted alkyl, carbocyclyl, substituted
carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl,
heterocyclyl, substituted heterocyclyl, heterocyclylalkyl,
substituted heterocyclylalkyl, --C(O)H, --C(O)R.sup.3,
--S(O)R.sup.3, --S(O).sub.2R.sup.3, --C(O)OR.sup.3, or
--C(O)NR.sup.7R.sup.8; or [0185] R.sup.4 and R.sup.5, taken
together with the nitrogen to which they are both attached, form a
substituted or unsubstituted heterocycle; [0186] R.sup.6 is alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, heteroalkyl, substituted heteroalkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; [0187] R.sup.7
and R.sup.8 are each independently H, alkyl, substituted alkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; or [0188]
R.sup.7 and R.sup.8, taken together with the nitrogen to which they
are both bonded, form a substituted or unsubstituted heterocycle;
[0189] R.sup.9 is H, alkyl, substituted alkyl, carbocyclyl,
substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl, a protecting
group, or a prodrug moiety; [0190] R.sup.10 is halogen, cyano,
azido, nitro, alkyl, substituted alkyl, hydroxyl, amino,
heteroalkyl, or substituted heteroalkyl; and [0191] n is 0, 1, 2,
or 3.
[0192] In one embodiment of Formula IIa, R.sup.1 is
NR.sup.4R.sup.5; and R.sup.4 and R.sup.5, taken together with the
nitrogen to which they are both attached, form a substituted or
unsubstituted heterocycle.
[0193] In another embodiment of Formula IIa, R.sup.1 is
NR.sup.4R.sup.5; and R.sup.4 and R.sup.5, taken together with the
nitrogen to which they are both attached, form a substituted or
unsubstituted heterocycle; wherein the heterocycle is a 4- to
6-membered monocyclic fully saturated or partially unsaturated ring
containing at least one hetero atom selected from N, O, and S; or a
10- to 12-membered fused bicyclic fully saturated or partially
unsaturated ring containing at least one hetero atom selected from
N, O, and S.
[0194] In another embodiment of Formula IIa, the heterocycle is
selected from the group consisting of:
##STR00017##
[0195] In another embodiment of Formula IIa, R.sup.1 is
NR.sup.4R.sup.5; R.sup.4 is H, alkyl, substituted alkyl,
carbocyclylalkyl, substituted carbocyclylalkyl; and R.sup.5 is
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heterocyclylalkyl, substituted heterocyclylalkyl,
--C(O)H, --C(O)R.sup.3, --C(O)OR.sup.3, or
--C(O)NR.sup.7R.sup.8.
[0196] In another embodiment of Formula IIa, R.sup.2 is
--C(O)R.sup.6, --C(O)OR.sup.6, --C(O)NR.sup.7R.sup.8,
--S(O)OR.sup.7, --S(O)NR.sup.7R.sup.8, --S(O).sub.2OR.sup.7, or
--S(O).sub.2NR.sup.7R.sup.8.
[0197] In another embodiment of Formula IIa, R.sup.4 is H, methyl,
ethyl, n-propyl, iso-propyl, n-butyl, cyclopropyl, or
cyclopropylmethylenyl, R.sup.5 is phenyl, pyridinyl,
--C(O)CH.sub.3, --C(O)OCH.sub.3, --C(O)CH.sub.2CH.sub.3, or
--C(O)OCH.sub.2CH.sub.3.
[0198] In another embodiment of Formula IIa, R.sup.2 is alkyl,
substituted alkyl, alkenyl, substituted alkenyl, carbocyclyl,
substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, heterocyclylalkyl, or substituted heterocyclylalkyl.
[0199] In another embodiment of Formula IIa, R.sup.2 is methyl,
ethyl, n-propyl, isopropyl, n-butyl, allyl, cyclopropyl,
methylcyclopropyl, cyclopropylmethylene, benzyl, or
methoxybezyl.
[0200] In another embodiment of Formula IIa, L.sup.3 is --O--.
[0201] In another embodiment of Formula IIa, -L.sup.3-R.sup.3 is
--O-alkyl or --O-alkylene-O-alkyl.
[0202] In another embodiment of Formula IIa, -L.sup.3-R.sup.3 is
--OCH.sub.2CH.sub.2OCH.sub.3 or
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0203] In another embodiment of Formula IIa, R.sup.1 is
--NR.sup.4R.sup.5; R.sup.2 is alkyl, substituted alkyl, alkenyl,
substituted alkenyl, cyclylalkyl, substituted cyclylalkyl,
cyclylalkylalkyl, substituted cyclylalkylalkyl, aryl, substituted
aryl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, or
substituted heterocyclylalkyl; L.sup.3 is --O--; R.sup.3 is alkyl,
substituted alkyl, heteroalkyl, substituted heteroalkyl; and
R.sup.4 and R.sup.5, taken together with the nitrogen to which they
are both attached, form a substituted or unsubstituted
heterocycle.
[0204] In one embodiment of Formula I, L.sup.2 is a covalent bond,
and R.sup.2 is hydrogen or halogen. That is, Formula I is
represented by Formula Ib:
##STR00018##
[0205] wherein: [0206] R.sup.1 is --NR.sup.4R.sup.5; [0207] R.sup.2
is H or halo; [0208] L.sup.3 is --NH--, --O--, --S--,
--N(R.sup.9)C(O)--, --S(O).sub.2--, --S(O)--, or a covalent bond;
[0209] R.sup.3 is alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted
heteroalkyl, carbocyclyl, substituted carbocyclyl,
carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl,
substituted heterocyclyl, heterocyclylalkyl, or substituted
heterocyclylalkyl; [0210] R.sup.4 and R.sup.5 are each
independently H, alkyl, substituted alkyl, carbocyclyl, substituted
carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl,
heterocyclyl, substituted heterocyclyl, heterocyclylalkyl,
substituted heterocyclylalkyl, --C(O)H, --C(O)R.sup.3,
--S(O)R.sup.3, --S(O).sub.2R.sup.3, --C(O)OR.sup.3, or
--C(O)NR.sup.7R.sup.8; or [0211] R.sup.4 and R.sup.5, taken
together with the nitrogen to which they are both attached, form a
substituted or unsubstituted heterocycle; [0212] R.sup.6 is alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, heteroalkyl, substituted heteroalkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; [0213] R.sup.7
and R.sup.8 are each independently H, alkyl, substituted alkyl,
carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; or [0214]
R.sup.7 and R.sup.8, taken together with the nitrogen to which they
are both bonded, form a substituted or unsubstituted heterocycle;
[0215] R.sup.9 is H, alkyl, substituted alkyl, carbocyclyl,
substituted carbocyclyl, carbocyclylalkyl, substituted
carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl, a protecting
group, or a prodrug moiety; [0216] R.sup.10 is halogen, cyano,
azido, nitro, alkyl, substituted alkyl, hydroxyl, amino,
heteroalkyl, or substituted heteroalkyl; and [0217] n is an integer
from 0 to 4; and
[0218] In one embodiment of Formula Ib, R.sup.1 is NR.sup.4R.sup.5;
and R.sup.4 and R.sup.5, taken together with the nitrogen to which
they are both attached, form a substituted or unsubstituted
heterocycle; wherein the heterocycle is a 4- to 6-membered
monocyclic fully saturated or partially unsaturated ring containing
at least one hetero atom selected from N, O, and S. In this
embodiment, the heterocycle can be selected from the group
consisting of:
##STR00019##
[0219] In one embodiment of Formula Ib, -L.sup.3-R.sup.3 is
--O-alkyl or --O-alkylene-O-alkyl. It is preferred that
-L.sup.3-R.sup.3 is --OCH.sub.2CH.sub.2OCH.sub.3 or
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0220] In one embodiment of Formula Ib, R.sup.1 is NR.sup.4R.sup.5;
-L.sup.3-R.sup.3 is --O-alkyl or --O-alkylene-O-alkyl; and R.sup.4
and R.sup.5, taken together with the nitrogen to which they are
both attached, form a substituted or unsubstituted heterocycle;
wherein the heterocycle is a 4- to 6-membered monocyclic fully
saturated or partially unsaturated ring containing at least one
hetero atom selected from N, O, and S.
[0221] In another embodiment of formula (I) or (II), the compound
is selected from the group consisting of:
##STR00020## ##STR00021## ##STR00022## ##STR00023## ##STR00024##
##STR00025## ##STR00026## ##STR00027## ##STR00028## ##STR00029##
##STR00030## ##STR00031## ##STR00032## ##STR00033## ##STR00034##
##STR00035## ##STR00036## ##STR00037##
or pharmaceutically acceptable salts, solvates, and/or esters
thereof.
[0222] In one embodiment, the present application provides
compounds according to formula Ia:
##STR00038##
or a pharmaceutically acceptable salt, solvate, and/or ester
thereof, wherein: [0223] -L.sup.3-R.sup.3 is
--OCH.sub.2CH.sub.2OCH.sub.3, --OCH.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.3, --Oi-butyl, --Oc-butyl,
--Oc-pentyl, --OCH.sub.2c-propyl, --OCH.sub.2c-butyl,
--OCH.sub.2CH.sub.2c-propyl, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OH,
--OCH.sub.2CF.sub.3, --OCH.sub.2CH.sub.2CF.sub.3,
--OCH.sub.2CH.sub.2CH.sub.2CF.sub.3, or
(tetrahydrofuran-2-yl)methoxy; [0224] R.sup.2 is H; [0225] n is 0;
[0226] R.sup.1 is --NR.sup.4R.sup.5; and R.sup.4 and R.sup.5, taken
together with the nitrogen to which they are both attached, form a
heterocycle selected from the group consisting of:
##STR00039##
[0227] In one embodiment of Formula Ia, -L.sup.3-R.sup.3 is
--OCH.sub.2CH.sub.2OCH.sub.3, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CF.sub.3, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OH,
--Oi-butyl, --OCH.sub.2CH.sub.2c-propyl, or
--OCH.sub.2c-propyl.
[0228] In one embodiment of Formula Ia, -L.sup.3-R.sup.3 is
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.3, --OCH.sub.2CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.2CF.sub.3, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OH,
or --OCH.sub.2c-propyl.
[0229] In one embodiment of Formula Ia, -L.sup.3-R.sup.3 is
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0230] In one embodiment of Formula Ia, R.sup.4 and R.sup.5, taken
together with the nitrogen to which they are both attached form a
heterocycle selected from the group consisting of:
##STR00040##
[0231] In still yet another embodiment, the compounds of Formula I
and II are named below in tabular format (Table 5) as compounds of
general Formula III:
##STR00041##
[0232] Compounds of general Formula III are depicted as four
moieties T1, T2, T3 and T4 attached in the manner shown above.
Tables A-D show, respectively, the structures of the T1, T2, T3 and
T4 moieties, with the point(s) of attachment to neighboring
moieties. Each moiety T1, T2, T3 and T4 in Tables A-D is
represented by a "code" comprising letters and numbers. Each
structure of a compound of Formula III can be designated in tabular
form by combining the "code" representing each structural moiety
using the following syntax: T1.T2.T3.T4. Thus, for example,
T1A.T2A.T3A.T4A represents the following structure:
##STR00042##
wherein the terms "alkylene", "arylene", "alkyl",
"cycloalkylalkyl", "heteroarylene", "carboxcyclylene",
"carbocyclyl", "heterocyclyl", etc. are as defined herein.
TABLE-US-00001 TABLE 1 T1 Structures Label T1 Structure T1A
--O-alkyl T1B --O-alkylene-O-alkyl T1C --S-alkyl T1D --NH-alkyl
(alkyl is substituted or unsubstituted) T1E alkyl T1F
(cycloalkyl)alkyl-O-- T1G Cycloalkyl-O--
TABLE-US-00002 TABLE 2 T2 Structures Label T2 Structure T2A
##STR00043## T2B ##STR00044## T2C ##STR00045## T2D ##STR00046##
TABLE-US-00003 TABLE 3 T3 Structures Label T3 Structure T3A
-alkylene-arylene-alkylene-T4 (substituted or unsubstituted) T3B
-alkylene-carbocyclylene-alkylene-T4 (substituted or unsubstituted)
T3C -alkylene-heteroarylene-alkylene-T4 (substituted or
unsubstituted) T3D -alkylene-heterocyclene-alkylene-T4 (substituted
or unsubstituted)
TABLE-US-00004 TABLE 4 T4 Structures Label T4 Structure T4A
--N(alkyl)S(O).sub.2-alkyl T4B --N(cycloalkylalkyl)C(O)O-alkyl T4C
--N(cycloalkylalkyl)C(O)N(alkyl).sub.2 T4D
--N(cycloalkylalkyl).sub.2 T4E --NH(cycloalkylalkyl) T4F
--NH(carbocyclyl) T4G --NH(heterocyclyl) T4H Nitrogen containing
heterocycle attached at nitrogen
TABLE-US-00005 TABLE 5 List of Compound Structures of Formula III
T1A.T2A.T3A.T4A, T1A.T2A.T3A.T4B, T1A.T2A.T3A.T4C, T1A.T2A.T3A.T4D,
T1A.T2A.T3A.T4E, T1A.T2A.T3A.T4F, T1A.T2A.T3A.T4G, T1A.T2A.T3A.T4H,
T1A.T2A.T3B.T4A, T1A.T2A.T3B.T4B, T1A.T2A.T3B.T4C, T1A.T2A.T3B.T4D,
T1A.T2A.T3B.T4E, T1A.T2A.T3B.T4F, T1A.T2A.T3B.T4G, T1A.T2A.T3B.T4H,
T1A.T2A.T3C.T4A, T1A.T2A.T3C.T4B, T1A.T2A.T3C.T4C, T1A.T2A.T3C.T4D,
T1A.T2A.T3C.T4E, T1A.T2A.T3C.T4F, T1A.T2A.T3C.T4G, T1A.T2A.T3C.T4H,
T1A.T2A.T3D.T4A, T1A.T2A.T3D.T4B, T1A.T2A.T3D.T4C, T1A.T2A.T3D.T4D,
T1A.T2A.T3D.T4E, T1A.T2A.T3D.T4F, T1A.T2A.T3D.T4G, T1A.T2A.T3D.T4H,
T1A.T2B.T3A.T4A, T1A.T2B.T3A.T4B, T1A.T2B.T3A.T4C, T1A.T2B.T3A.T4D,
T1A.T2B.T3A.T4E, T1A.T2B.T3A.T4F, T1A.T2B.T3A.T4G, T1A.T2B.T3A.T4H,
T1A.T2B.T3B.T4A, T1A.T2B.T3B.T4B, T1A.T2B.T3B.T4C, T1A.T2B.T3B.T4D,
T1A.T2B.T3B.T4E, T1A.T2B.T3B.T4F, T1A.T2B.T3B.T4G, T1A.T2B.T3B.T4H,
T1A.T2B.T3C.T4A, T1A.T2B.T3C.T4B, T1A.T2B.T3C.T4C, T1A.T2B.T3C.T4D,
T1A.T2B.T3C.T4E, T1A.T2B.T3C.T4F, T1A.T2B.T3C.T4G, T1A.T2B.T3C.T4H,
T1A.T2B.T3D.T4A, T1A.T2B.T3D.T4B, T1A.T2B.T3D.T4C, T1A.T2B.T3D.T4D,
T1A.T2B.T3D.T4E, T1A.T2B.T3D.T4F, T1A.T2B.T3D.T4G, T1A.T2B.T3D.T4H,
T1A.T2C.T3A.T4A, T1A.T2C.T3A.T4B, T1A.T2C.T3A.T4C, T1A.T2C.T3A.T4D,
T1A.T2C.T3A.T4E, T1A.T2C.T3A.T4F, T1A.T2C.T3A.T4G, T1A.T2C.T3A.T4H,
T1A.T2C.T3B.T4A, T1A.T2C.T3B.T4B, T1A.T2C.T3B.T4C, T1A.T2C.T3B.T4D,
T1A.T2C.T3B.T4E, T1A.T2C.T3B.T4F, T1A.T2C.T3B.T4G, T1A.T2C.T3B.T4H,
T1A.T2C.T3C.T4A, T1A.T2C.T3C.T4B, T1A.T2C.T3C.T4C, T1A.T2C.T3C.T4D,
T1A.T2C.T3C.T4E, T1A.T2C.T3C.T4F, T1A.T2C.T3C.T4G, T1A.T2C.T3C.T4H,
T1A.T2C.T3D.T4A, T1A.T2C.T3D.T4B, T1A.T2C.T3D.T4C, T1A.T2C.T3D.T4D,
T1A.T2C.T3D.T4E, T1A.T2C.T3D.T4F, T1A.T2C.T3D.T4G, T1A.T2C.T3D.T4H,
T1A.T2D.T3A.T4A, T1A.T2D.T3A.T4B, T1A.T2D.T3A.T4C, T1A.T2D.T3A.T4D,
T1A.T2D.T3A.T4E, T1A.T2D.T3A.T4F, T1A.T2D.T3A.T4G, T1A.T2D.T3A.T4H,
T1A.T2D.T3B.T4A, T1A.T2D.T3B.T4B, T1A.T2D.T3B.T4C, T1A.T2D.T3B.T4D,
T1A.T2D.T3B.T4E, T1A.T2D.T3B.T4F, T1A.T2D.T3B.T4G, T1A.T2D.T3B.T4H,
T1A.T2D.T3C.T4A, T1A.T2D.T3C.T4B, T1A.T2D.T3C.T4C, T1A.T2D.T3C.T4D,
T1A.T2D.T3C.T4E, T1A.T2D.T3C.T4F, T1A.T2D.T3C.T4G, T1A.T2D.T3C.T4H,
T1A.T2D.T3D.T4A, T1A.T2D.T3D.T4B, T1A.T2D.T3D.T4C, T1A.T2D.T3D.T4D,
T1A.T2D.T3D.T4E, T1A.T2D.T3D.T4F, T1A.T2D.T3D.T4G, T1A.T2D.T3D.T4H,
T1B.T2A.T3A.T4A, T1B.T2A.T3A.T4B, T1B.T2A.T3A.T4C, T1B.T2A.T3A.T4D,
T1B.T2A.T3A.T4E, T1B.T2A.T3A.T4F, T1B.T2A.T3A.T4G, T1B.T2A.T3A.T4H,
T1B.T2A.T3B.T4A, T1B.T2A.T3B.T4B, T1B.T2A.T3B.T4C, T1B.T2A.T3B.T4D,
T1B.T2A.T3B.T4E, T1B.T2A.T3B.T4F, T1B.T2A.T3B.T4G, T1B.T2A.T3B.T4H,
T1B.T2A.T3C.T4A, T1B.T2A.T3C.T4B, T1B.T2A.T3C.T4C, T1B.T2A.T3C.T4D,
T1B.T2A.T3C.T4E, T1B.T2A.T3C.T4F, T1B.T2A.T3C.T4G, T1B.T2A.T3C.T4H,
T1B.T2A.T3D.T4A, T1B.T2A.T3D.T4B, T1B.T2A.T3D.T4C, T1B.T2A.T3D.T4D,
T1B.T2A.T3D.T4E, T1B.T2A.T3D.T4F, T1B.T2A.T3D.T4G, T1B.T2A.T3D.T4H,
T1B.T2B.T3A.T4A, T1B.T2B.T3A.T4B, T1B.T2B.T3A.T4C, T1B.T2B.T3A.T4D,
T1B.T2B.T3A.T4E, T1B.T2B.T3A.T4F, T1B.T2B.T3A.T4G, T1B.T2B.T3A.T4H,
T1B.T2B.T3B.T4A, T1B.T2B.T3B.T4B, T1B.T2B.T3B.T4C, T1B.T2B.T3B.T4D,
T1B.T2B.T3B.T4E, T1B.T2B.T3B.T4F, T1B.T2B.T3B.T4G, T1B.T2B.T3B.T4H,
T1B.T2B.T3C.T4A, T1B.T2B.T3C.T4B, T1B.T2B.T3C.T4C, T1B.T2B.T3C.T4D,
T1B.T2B.T3C.T4E, T1B.T2B.T3C.T4F, T1B.T2B.T3C.T4G, T1B.T2B.T3C.T4H,
T1B.T2B.T3D.T4A, T1B.T2B.T3D.T4B, T1B.T2B.T3D.T4C, T1B.T2B.T3D.T4D,
T1B.T2B.T3D.T4E, T1B.T2B.T3D.T4F, T1B.T2B.T3D.T4G, T1B.T2B.T3D.T4H,
T1B.T2C.T3A.T4A, T1B.T2C.T3A.T4B, T1B.T2C.T3A.T4C, T1B.T2C.T3A.T4D,
T1B.T2C.T3A.T4E, T1B.T2C.T3A.T4F, T1B.T2C.T3A.T4G, T1B.T2C.T3A.T4H,
T1B.T2C.T3B.T4A, T1B.T2C.T3B.T4B, T1B.T2C.T3B.T4C, T1B.T2C.T3B.T4D,
T1B.T2C.T3B.T4E, T1B.T2C.T3B.T4F, T1B.T2C.T3B.T4G, T1B.T2C.T3B.T4H,
T1B.T2C.T3C.T4A, T1B.T2C.T3C.T4B, T1B.T2C.T3C.T4C, T1B.T2C.T3C.T4D,
T1B.T2C.T3C.T4E, T1B.T2C.T3C.T4F, T1B.T2C.T3C.T4G, T1B.T2C.T3C.T4H,
T1B.T2C.T3D.T4A, T1B.T2C.T3D.T4B, T1B.T2C.T3D.T4C, T1B.T2C.T3D.T4D,
T1B.T2C.T3D.T4E, T1B.T2C.T3D.T4F, T1B.T2C.T3D.T4G, T1B.T2C.T3D.T4H,
T1B.T2D.T3A.T4A, T1B.T2D.T3A.T4B, T1B.T2D.T3A.T4C, T1B.T2D.T3A.T4D,
T1B.T2D.T3A.T4E, T1B.T2D.T3A.T4F, T1B.T2D.T3A.T4G, T1B.T2D.T3A.T4H,
T1B.T2D.T3B.T4A, T1B.T2D.T3B.T4B, T1B.T2D.T3B.T4C, T1B.T2D.T3B.T4D,
T1B.T2D.T3B.T4E, T1B.T2D.T3B.T4F, T1B.T2D.T3B.T4G, T1B.T2D.T3B.T4H,
T1B.T2D.T3C.T4A, T1B.T2D.T3C.T4B, T1B.T2D.T3C.T4C, T1B.T2D.T3C.T4D,
T1B.T2D.T3C.T4E, T1B.T2D.T3C.T4F, T1B.T2D.T3C.T4G, T1B.T2D.T3C.T4H,
T1B.T2D.T3D.T4A, T1B.T2D.T3D.T4B, T1B.T2D.T3D.T4C, T1B.T2D.T3D.T4D,
T1B.T2D.T3D.T4E, T1B.T2D.T3D.T4F, T1B.T2D.T3D.T4G, T1B.T2D.T3D.T4H,
T1C.T2A.T3A.T4A, T1C.T2A.T3A.T4B, T1C.T2A.T3A.T4C, T1C.T2A.T3A.T4D,
T1C.T2A.T3A.T4E, T1C.T2A.T3A.T4F, T1C.T2A.T3A.T4G, T1C.T2A.T3A.T4H,
T1C.T2A.T3B.T4A, T1C.T2A.T3B.T4B, T1C.T2A.T3B.T4C, T1C.T2A.T3B.T4D,
T1C.T2A.T3B.T4E, T1C.T2A.T3B.T4F, T1C.T2A.T3B.T4G, T1C.T2A.T3B.T4H,
T1C.T2A.T3C.T4A, T1C.T2A.T3C.T4B, T1C.T2A.T3C.T4C, T1C.T2A.T3C.T4D,
T1C.T2A.T3C.T4E, T1C.T2A.T3C.T4F, T1C.T2A.T3C.T4G, T1C.T2A.T3C.T4H,
T1C.T2A.T3D.T4A, T1C.T2A.T3D.T4B, T1C.T2A.T3D.T4C, T1C.T2A.T3D.T4D,
T1C.T2A.T3D.T4E, T1C.T2A.T3D.T4F, T1C.T2A.T3D.T4G, T1C.T2A.T3D.T4H,
T1C.T2B.T3A.T4A, T1C.T2B.T3A.T4B, T1C.T2B.T3A.T4C, T1C.T2B.T3A.T4D,
T1C.T2B.T3A.T4E, T1C.T2B.T3A.T4F, T1C.T2B.T3A.T4G, T1C.T2B.T3A.T4H,
T1C.T2B.T3B.T4A, T1C.T2B.T3B.T4B, T1C.T2B.T3B.T4C, T1C.T2B.T3B.T4D,
T1C.T2B.T3B.T4E, T1C.T2B.T3B.T4F, T1C.T2B.T3B.T4G, T1C.T2B.T3B.T4H,
T1C.T2B.T3C.T4A, T1C.T2B.T3C.T4B, T1C.T2B.T3C.T4C, T1C.T2B.T3C.T4D,
T1C.T2B.T3C.T4E, T1C.T2B.T3C.T4F, T1C.T2B.T3C.T4G, T1C.T2B.T3C.T4H,
T1C.T2B.T3D.T4A, T1C.T2B.T3D.T4B, T1C.T2B.T3D.T4C, T1C.T2B.T3D.T4D,
T1C.T2B.T3D.T4E, T1C.T2B.T3D.T4F, T1C.T2B.T3D.T4G, T1C.T2B.T3D.T4H,
T1C.T2C.T3A.T4A, T1C.T2C.T3A.T4B, T1C.T2C.T3A.T4C, T1C.T2C.T3A.T4D,
T1C.T2C.T3A.T4E, T1C.T2C.T3A.T4F, T1C.T2C.T3A.T4G, T1C.T2C.T3A.T4H,
T1C.T2C.T3B.T4A, T1C.T2C.T3B.T4B, T1C.T2C.T3B.T4C, T1C.T2C.T3B.T4D,
T1C.T2C.T3B.T4E, T1C.T2C.T3B.T4F, T1C.T2C.T3B.T4G, T1C.T2C.T3B.T4H,
T1C.T2C.T3C.T4A, T1C.T2C.T3C.T4B, T1C.T2C.T3C.T4C, T1C.T2C.T3C.T4D,
T1C.T2C.T3C.T4E, T1C.T2C.T3C.T4F, T1C.T2C.T3C.T4G, T1C.T2C.T3C.T4H,
T1C.T2C.T3D.T4A, T1C.T2C.T3D.T4B, T1C.T2C.T3D.T4C, T1C.T2C.T3D.T4D,
T1C.T2C.T3D.T4E, T1C.T2C.T3D.T4F, T1C.T2C.T3D.T4G, T1C.T2C.T3D.T4H,
T1C.T2D.T3A.T4A, T1C.T2D.T3A.T4B, T1C.T2D.T3A.T4C, T1C.T2D.T3A.T4D,
T1C.T2D.T3A.T4E, T1C.T2D.T3A.T4F, T1C.T2D.T3A.T4G, T1C.T2D.T3A.T4H,
T1C.T2D.T3B.T4A, T1C.T2D.T3B.T4B, T1C.T2D.T3B.T4C, T1C.T2D.T3B.T4D,
T1C.T2D.T3B.T4E, T1C.T2D.T3B.T4F, T1C.T2D.T3B.T4G, T1C.T2D.T3B.T4H,
T1C.T2D.T3C.T4A, T1C.T2D.T3C.T4B, T1C.T2D.T3C.T4C, T1C.T2D.T3C.T4D,
T1C.T2D.T3C.T4E, T1C.T2D.T3C.T4F, T1C.T2D.T3C.T4G, T1C.T2D.T3C.T4H,
T1C.T2D.T3D.T4A, T1C.T2D.T3D.T4B, T1C.T2D.T3D.T4C, T1C.T2D.T3D.T4D,
T1C.T2D.T3D.T4E, T1C.T2D.T3D.T4F, T1C.T2D.T3D.T4G, T1C.T2D.T3D.T4H,
T1D.T2A.T3A.T4A, T1D.T2A.T3A.T4B, T1D.T2A.T3A.T4C, T1D.T2A.T3A.T4D,
T1D.T2A.T3A.T4E, T1D.T2A.T3A.T4F, T1D.T2A.T3A.T4G, T1D.T2A.T3A.T4H,
T1D.T2A.T3B.T4A, T1D.T2A.T3B.T4B, T1D.T2A.T3B.T4C, T1D.T2A.T3B.T4D,
T1D.T2A.T3B.T4E, T1D.T2A.T3B.T4F, T1D.T2A.T3B.T4G, T1D.T2A.T3B.T4H,
T1D.T2A.T3C.T4A, T1D.T2A.T3C.T4B, T1D.T2A.T3C.T4C, T1D.T2A.T3C.T4D,
T1D.T2A.T3C.T4E, T1D.T2A.T3C.T4F, T1D.T2A.T3C.T4G, T1D.T2A.T3C.T4H,
T1D.T2A.T3D.T4A, T1D.T2A.T3D.T4B, T1D.T2A.T3D.T4C, T1D.T2A.T3D.T4D,
T1D.T2A.T3D.T4E, T1D.T2A.T3D.T4F, T1D.T2A.T3D.T4G, T1D.T2A.T3D.T4H,
T1D.T2B.T3A.T4A, T1D.T2B.T3A.T4B, T1D.T2B.T3A.T4C, T1D.T2B.T3A.T4D,
T1D.T2B.T3A.T4E, T1D.T2B.T3A.T4F, T1D.T2B.T3A.T4G, T1D.T2B.T3A.T4H,
T1D.T2B.T3B.T4A, T1D.T2B.T3B.T4B, T1D.T2B.T3B.T4C, T1D.T2B.T3B.T4D,
T1D.T2B.T3B.T4E, T1D.T2B.T3B.T4F, T1D.T2B.T3B.T4G, T1D.T2B.T3B.T4H,
T1D.T2B.T3C.T4A, T1D.T2B.T3C.T4B, T1D.T2B.T3C.T4C, T1D.T2B.T3C.T4D,
T1D.T2B.T3C.T4E, T1D.T2B.T3C.T4F, T1D.T2B.T3C.T4G, T1D.T2B.T3C.T4H,
T1D.T2B.T3D.T4A, T1D.T2B.T3D.T4B, T1D.T2B.T3D.T4C, T1D.T2B.T3D.T4D,
T1D.T2B.T3D.T4E, T1D.T2B.T3D.T4F, T1D.T2B.T3D.T4G, T1D.T2B.T3D.T4H,
T1D.T2C.T3A.T4A, T1D.T2C.T3A.T4B, T1D.T2C.T3A.T4C, T1D.T2C.T3A.T4D,
T1D.T2C.T3A.T4E, T1D.T2C.T3A.T4F, T1D.T2C.T3A.T4G, T1D.T2C.T3A.T4H,
T1D.T2C.T3B.T4A, T1D.T2C.T3B.T4B, T1D.T2C.T3B.T4C, T1D.T2C.T3B.T4D,
T1D.T2C.T3B.T4E, T1D.T2C.T3B.T4F, T1D.T2C.T3B.T4G, T1D.T2C.T3B.T4H,
T1D.T2C.T3C.T4A, T1D.T2C.T3C.T4B, T1D.T2C.T3C.T4C, T1D.T2C.T3C.T4D,
T1D.T2C.T3C.T4E, T1D.T2C.T3C.T4F, T1D.T2C.T3C.T4G, T1D.T2C.T3C.T4H,
T1D.T2C.T3D.T4A, T1D.T2C.T3D.T4B, T1D.T2C.T3D.T4C, T1D.T2C.T3D.T4D,
T1D.T2C.T3D.T4E, T1D.T2C.T3D.T4F, T1D.T2C.T3D.T4G, T1D.T2C.T3D.T4H,
T1D.T2D.T3A.T4A, T1D.T2D.T3A.T4B, T1D.T2D.T3A.T4C, T1D.T2D.T3A.T4D,
T1D.T2D.T3A.T4E, T1D.T2D.T3A.T4F, T1D.T2D.T3A.T4G, T1D.T2D.T3A.T4H,
T1D.T2D.T3B.T4A, T1D.T2D.T3B.T4B, T1D.T2D.T3B.T4C, T1D.T2D.T3B.T4D,
T1D.T2D.T3B.T4E, T1D.T2D.T3B.T4F, T1D.T2D.T3B.T4G, T1D.T2D.T3B.T4H,
T1D.T2D.T3C.T4A, T1D.T2D.T3C.T4B, T1D.T2D.T3C.T4C, T1D.T2D.T3C.T4D,
T1D.T2D.T3C.T4E, T1D.T2D.T3C.T4F, T1D.T2D.T3C.T4G, T1D.T2D.T3C.T4H,
T1D.T2D.T3D.T4A, T1D.T2D.T3D.T4B, T1D.T2D.T3D.T4C, T1D.T2D.T3D.T4D,
T1D.T2D.T3D.T4E, T1D.T2D.T3D.T4F, T1D.T2D.T3D.T4G, T1D.T2D.T3D.T4H,
T1E.T2A.T3A.T4A, T1E.T2A.T3A.T4B, T1E.T2A.T3A.T4C, T1E.T2A.T3A.T4D,
T1E.T2A.T3A.T4E, T1E.T2A.T3A.T4F, T1E.T2A.T3A.T4G, T1E.T2A.T3A.T4H,
T1E.T2A.T3B.T4A, T1E.T2A.T3B.T4B, T1E.T2A.T3B.T4C, T1E.T2A.T3B.T4D,
T1E.T2A.T3B.T4E, T1E.T2A.T3B.T4F, T1E.T2A.T3B.T4G, T1E.T2A.T3B.T4H,
T1E.T2A.T3C.T4A, T1E.T2A.T3C.T4B, T1E.T2A.T3C.T4C, T1E.T2A.T3C.T4D,
T1E.T2A.T3C.T4E, T1E.T2A.T3C.T4F, T1E.T2A.T3C.T4G, T1E.T2A.T3C.T4H,
T1E.T2A.T3D.T4A, T1E.T2A.T3D.T4B, T1E.T2A.T3D.T4C, T1E.T2A.T3D.T4D,
T1E.T2A.T3D.T4E, T1E.T2A.T3D.T4F, T1E.T2A.T3D.T4G, T1E.T2A.T3D.T4H,
T1E.T2B.T3A.T4A, T1E.T2B.T3A.T4B, T1E.T2B.T3A.T4C, T1E.T2B.T3A.T4D,
T1E.T2B.T3A.T4E, T1E.T2B.T3A.T4F, T1E.T2B.T3A.T4G, T1E.T2B.T3A.T4H,
T1E.T2B.T3B.T4A, T1E.T2B.T3B.T4B, T1E.T2B.T3B.T4C, T1E.T2B.T3B.T4D,
T1E.T2B.T3B.T4E, T1E.T2B.T3B.T4F, T1E.T2B.T3B.T4G, T1E.T2B.T3B.T4H,
T1E.T2B.T3C.T4A, T1E.T2B.T3C.T4B, T1E.T2B.T3C.T4C, T1E.T2B.T3C.T4D,
T1E.T2B.T3C.T4E, T1E.T2B.T3C.T4F, T1E.T2B.T3C.T4G, T1E.T2B.T3C.T4H,
T1E.T2B.T3D.T4A, T1E.T2B.T3D.T4B, T1E.T2B.T3D.T4C, T1E.T2B.T3D.T4D,
T1E.T2B.T3D.T4E, T1E.T2B.T3D.T4F, T1E.T2B.T3D.T4G, T1E.T2B.T3D.T4H,
T1E.T2C.T3A.T4A, T1E.T2C.T3A.T4B, T1E.T2C.T3A.T4C, T1E.T2C.T3A.T4D,
T1E.T2C.T3A.T4E, T1E.T2C.T3A.T4F, T1E.T2C.T3A.T4G, T1E.T2C.T3A.T4H,
T1E.T2C.T3B.T4A, T1E.T2C.T3B.T4B, T1E.T2C.T3B.T4C, T1E.T2C.T3B.T4D,
T1E.T2C.T3B.T4E, T1E.T2C.T3B.T4F, T1E.T2C.T3B.T4G, T1E.T2C.T3B.T4H,
T1E.T2C.T3C.T4A, T1E.T2C.T3C.T4B, T1E.T2C.T3C.T4C, T1E.T2C.T3C.T4D,
T1E.T2C.T3C.T4E, T1E.T2C.T3C.T4F, T1E.T2C.T3C.T4G, T1E.T2C.T3C.T4H,
T1E.T2C.T3D.T4A, T1E.T2C.T3D.T4B, T1E.T2C.T3D.T4C, T1E.T2C.T3D.T4D,
T1E.T2C.T3D.T4E, T1E.T2C.T3D.T4F, T1E.T2C.T3D.T4G, T1E.T2C.T3D.T4H,
T1E.T2D.T3A.T4A, T1E.T2D.T3A.T4B, T1E.T2D.T3A.T4C, T1E.T2D.T3A.T4D,
T1E.T2D.T3A.T4E, T1E.T2D.T3A.T4F, T1E.T2D.T3A.T4G, T1E.T2D.T3A.T4H,
T1E.T2D.T3B.T4A, T1E.T2D.T3B.T4B, T1E.T2D.T3B.T4C, T1E.T2D.T3B.T4D,
T1E.T2D.T3B.T4E, T1E.T2D.T3B.T4F, T1E.T2D.T3B.T4G, T1E.T2D.T3B.T4H,
T1E.T2D.T3C.T4A, T1E.T2D.T3C.T4B, T1E.T2D.T3C.T4C, T1E.T2D.T3C.T4D,
T1E.T2D.T3C.T4E, T1E.T2D.T3C.T4F, T1E.T2D.T3C.T4G, T1E.T2D.T3C.T4H,
T1E.T2D.T3D.T4A, T1E.T2D.T3D.T4B, T1E.T2D.T3D.T4C, T1E.T2D.T3D.T4D,
T1E.T2D.T3D.T4E, T1E.T2D.T3D.T4F, T1E.T2D.T3D.T4G, T1E.T2D.T3D.T4H,
T1F.T2A.T3A.T4A, T1F.T2A.T3A.T4B, T1F.T2A.T3A.T4C, T1F.T2A.T3A.T4D,
T1F.T2A.T3A.T4E, T1F.T2A.T3A.T4F, T1F.T2A.T3A.T4G, T1F.T2A.T3A.T4H,
T1F.T2A.T3B.T4A, T1F.T2A.T3B.T4B, T1F.T2A.T3B.T4C, T1F.T2A.T3B.T4D,
T1F.T2A.T3B.T4E, T1F.T2A.T3B.T4F, T1F.T2A.T3B.T4G, T1F.T2A.T3B.T4H,
T1F.T2A.T3C.T4A, T1F.T2A.T3C.T4B, T1F.T2A.T3C.T4C, T1F.T2A.T3C.T4D,
T1F.T2A.T3C.T4E, T1F.T2A.T3C.T4F, T1F.T2A.T3C.T4G, T1F.T2A.T3C.T4H,
T1F.T2A.T3D.T4A, T1F.T2A.T3D.T4B, T1F.T2A.T3D.T4C, T1F.T2A.T3D.T4D,
T1F.T2A.T3D.T4E, T1F.T2A.T3D.T4F, T1F.T2A.T3D.T4G, T1F.T2A.T3D.T4H,
T1F.T2B.T3A.T4A, T1F.T2B.T3A.T4B, T1F.T2B.T3A.T4C, T1F.T2B.T3A.T4D,
T1F.T2B.T3A.T4E, T1F.T2B.T3A.T4F, T1F.T2B.T3A.T4G, T1F.T2B.T3A.T4H,
T1F.T2B.T3B.T4A, T1F.T2B.T3B.T4B, T1F.T2B.T3B.T4C, T1F.T2B.T3B.T4D,
T1F.T2B.T3B.T4E, T1F.T2B.T3B.T4F, T1F.T2B.T3B.T4G, T1F.T2B.T3B.T4H,
T1F.T2B.T3C.T4A, T1F.T2B.T3C.T4B, T1F.T2B.T3C.T4C, T1F.T2B.T3C.T4D,
T1F.T2B.T3C.T4E, T1F.T2B.T3C.T4F, T1F.T2B.T3C.T4G, T1F.T2B.T3C.T4H,
T1F.T2B.T3D.T4A, T1F.T2B.T3D.T4B, T1F.T2B.T3D.T4C, T1F.T2B.T3D.T4D,
T1F.T2B.T3D.T4E, T1F.T2B.T3D.T4F, T1F.T2B.T3D.T4G, T1F.T2B.T3D.T4H,
T1F.T2C.T3A.T4A, T1F.T2C.T3A.T4B, T1F.T2C.T3A.T4C, T1F.T2C.T3A.T4D,
T1F.T2C.T3A.T4E, T1F.T2C.T3A.T4F, T1F.T2C.T3A.T4G, T1F.T2C.T3A.T4H,
T1F.T2C.T3B.T4A, T1F.T2C.T3B.T4B, T1F.T2C.T3B.T4C, T1F.T2C.T3B.T4D,
T1F.T2C.T3B.T4E, T1F.T2C.T3B.T4F, T1F.T2C.T3B.T4G, T1F.T2C.T3B.T4H,
T1F.T2C.T3C.T4A, T1F.T2C.T3C.T4B, T1F.T2C.T3C.T4C, T1F.T2C.T3C.T4D,
T1F.T2C.T3C.T4E, T1F.T2C.T3C.T4F, T1F.T2C.T3C.T4G, T1F.T2C.T3C.T4H,
T1F.T2C.T3D.T4A, T1F.T2C.T3D.T4B, T1F.T2C.T3D.T4C, T1F.T2C.T3D.T4D,
T1F.T2C.T3D.T4E, T1F.T2C.T3D.T4F, T1F.T2C.T3D.T4G, T1F.T2C.T3D.T4H,
T1F.T2D.T3A.T4A, T1F.T2D.T3A.T4B, T1F.T2D.T3A.T4C, T1F.T2D.T3A.T4D,
T1F.T2D.T3A.T4E, T1F.T2D.T3A.T4F, T1F.T2D.T3A.T4G, T1F.T2D.T3A.T4H,
T1F.T2D.T3B.T4A, T1F.T2D.T3B.T4B, T1F.T2D.T3B.T4C, T1F.T2D.T3B.T4D,
T1F.T2D.T3B.T4E, T1F.T2D.T3B.T4F, T1F.T2D.T3B.T4G, T1F.T2D.T3B.T4H,
T1F.T2D.T3C.T4A, T1F.T2D.T3C.T4B, T1F.T2D.T3C.T4C, T1F.T2D.T3C.T4D,
T1F.T2D.T3C.T4E, T1F.T2D.T3C.T4F, T1F.T2D.T3C.T4G, T1F.T2D.T3C.T4H,
T1F.T2D.T3D.T4A, T1F.T2D.T3D.T4B, T1F.T2D.T3D.T4C, T1F.T2D.T3D.T4D,
T1F.T2D.T3D.T4E, T1F.T2D.T3D.T4F, T1F.T2D.T3D.T4G, T1F.T2D.T3D.T4H,
T1G.T2A.T3A.T4A, T1G.T2A.T3A.T4B, T1G.T2A.T3A.T4C, T1G.T2A.T3A.T4D,
T1G.T2A.T3A.T4E, T1G.T2A.T3A.T4F, T1G.T2A.T3A.T4G, T1G.T2A.T3A.T4H,
T1G.T2A.T3B.T4A, T1G.T2A.T3B.T4B, T1G.T2A.T3B.T4C, T1G.T2A.T3B.T4D,
T1G.T2A.T3B.T4E, T1G.T2A.T3B.T4F, T1G.T2A.T3B.T4G, T1G.T2A.T3B.T4H,
T1G.T2A.T3C.T4A, T1G.T2A.T3C.T4B, T1G.T2A.T3C.T4C, T1G.T2A.T3C.T4D,
T1G.T2A.T3C.T4E, T1G.T2A.T3C.T4F, T1G.T2A.T3C.T4G, T1G.T2A.T3C.T4H,
T1G.T2A.T3D.T4A, T1G.T2A.T3D.T4B, T1G.T2A.T3D.T4C, T1G.T2A.T3D.T4D,
T1G.T2A.T3D.T4E, T1G.T2A.T3D.T4F, T1G.T2A.T3D.T4G, T1G.T2A.T3D.T4H,
T1G.T2B.T3A.T4A, T1G.T2B.T3A.T4B, T1G.T2B.T3A.T4C, T1G.T2B.T3A.T4D,
T1G.T2B.T3A.T4E, T1G.T2B.T3A.T4F, T1G.T2B.T3A.T4G, T1G.T2B.T3A.T4H,
T1G.T2B.T3B.T4A, T1G.T2B.T3B.T4B, T1G.T2B.T3B.T4C, T1G.T2B.T3B.T4D,
T1G.T2B.T3B.T4E, T1G.T2B.T3B.T4F, T1G.T2B.T3B.T4G, T1G.T2B.T3B.T4H,
T1G.T2B.T3C.T4A, T1G.T2B.T3C.T4B, T1G.T2B.T3C.T4C, T1G.T2B.T3C.T4D,
T1G.T2B.T3C.T4E, T1G.T2B.T3C.T4F, T1G.T2B.T3C.T4G, T1G.T2B.T3C.T4H,
T1G.T2B.T3D.T4A, T1G.T2B.T3D.T4B, T1G.T2B.T3D.T4C, T1G.T2B.T3D.T4D,
T1G.T2B.T3D.T4E, T1G.T2B.T3D.T4F, T1G.T2B.T3D.T4G, T1G.T2B.T3D.T4H,
T1G.T2C.T3A.T4A, T1G.T2C.T3A.T4B, T1G.T2C.T3A.T4C, T1G.T2C.T3A.T4D,
T1G.T2C.T3A.T4E, T1G.T2C.T3A.T4F, T1G.T2C.T3A.T4G, T1G.T2C.T3A.T4H,
T1G.T2C.T3B.T4A, T1G.T2C.T3B.T4B, T1G.T2C.T3B.T4C, T1G.T2C.T3B.T4D,
T1G.T2C.T3B.T4E, T1G.T2C.T3B.T4F, T1G.T2C.T3B.T4G, T1G.T2C.T3B.T4H,
T1G.T2C.T3C.T4A, T1G.T2C.T3C.T4B, T1G.T2C.T3C.T4C, T1G.T2C.T3C.T4D,
T1G.T2C.T3C.T4E, T1G.T2C.T3C.T4F, T1G.T2C.T3C.T4G, T1G.T2C.T3C.T4H,
T1G.T2C.T3D.T4A, T1G.T2C.T3D.T4B, T1G.T2C.T3D.T4C, T1G.T2C.T3D.T4D,
T1G.T2C.T3D.T4E, T1G.T2C.T3D.T4F, T1G.T2C.T3D.T4G, T1G.T2C.T3D.T4H,
T1G.T2D.T3A.T4A, T1G.T2D.T3A.T4B, T1G.T2D.T3A.T4C, T1G.T2D.T3A.T4D,
T1G.T2D.T3A.T4E, T1G.T2D.T3A.T4F, T1G.T2D.T3A.T4G, T1G.T2D.T3A.T4H,
T1G.T2D.T3B.T4A, T1G.T2D.T3B.T4B, T1G.T2D.T3B.T4C, T1G.T2D.T3B.T4D,
T1G.T2D.T3B.T4E, T1G.T2D.T3B.T4F, T1G.T2D.T3B.T4G, T1G.T2D.T3B.T4H,
T1G.T2D.T3C.T4A, T1G.T2D.T3C.T4B, T1G.T2D.T3C.T4C, T1G.T2D.T3C.T4D,
T1G.T2D.T3C.T4E, T1G.T2D.T3C.T4F, T1G.T2D.T3C.T4G, T1G.T2D.T3C.T4H,
T1G.T2D.T3D.T4A, T1G.T2D.T3D.T4B, T1G.T2D.T3D.T4C, T1G.T2D.T3D.T4D,
T1G.T2D.T3D.T4E, T1G.T2D.T3D.T4F, T1G.T2D.T3D.T4G,
T1G.T2D.T3D.T4H,
[0233] In still another embodiment, selected compounds of Formula I
and II are named below in tabular format (Table 10) as compounds of
general Formula IV (below):
##STR00047##
where X, A, Y, and Z are defined in Tables 6-9, below. Each
compound is designated in tabular form by combining the "code"
representing each structural moiety using the following syntax:
X.A.Y.Z. Thus, for example, X1.A1.Y1.Z1 represents the following
structure:
##STR00048##
TABLE-US-00006 TABLE 6 "A" Structures Code "A" Structure A1
##STR00049## A2 ##STR00050## A3 ##STR00051## A4 ##STR00052##
TABLE-US-00007 TABLE 7 "X" Structures Code "X" Structure X1
##STR00053## X2 ##STR00054## X3 ##STR00055## X4 ##STR00056## X5
##STR00057## X6 ##STR00058##
TABLE-US-00008 TABLE 8 "Y" Structures Code "Y" Structure Y1
##STR00059## Y2 ##STR00060## Y3 ##STR00061## Y4 ##STR00062##
TABLE-US-00009 TABLE 9 "Z" Structures Code "Z" Structure Z1
##STR00063## Z2 ##STR00064## Z3 ##STR00065## Z4 ##STR00066## Z5
##STR00067## Z6 ##STR00068## Z7 ##STR00069## Z8 ##STR00070##
TABLE-US-00010 TABLE 10 List of Compound Structures of Formula III
X1.A1.Y1.Z1, X1.A1.Y1.Z2, X1.A1.Y1.Z3, X1.A1.Y1.Z4, X1.A1.Y1.Z5,
X1.A1.Y1.Z6, X1.A1.Y1.Z7, X1.A1.Y1.Z8, X1.A1.Y2.Z1, X1.A1.Y2.Z2,
X1.A1.Y2.Z3, X1.A1.Y2.Z4, X1.A1.Y2.Z5, X1.A1.Y2.Z6, X1.A1.Y2.Z7,
X1.A1.Y2.Z8, X1.A1.Y3.Z1, X1.A1.Y3.Z2, X1.A1.Y3.Z3, X1.A1.Y3.Z4,
X1.A1.Y3.Z5, X1.A1.Y3.Z6, X1.A1.Y3.Z7, X1.A1.Y3.Z8, X1.A1.Y4.Z1,
X1.A1.Y4.Z2, X1.A1.Y4.Z3, X1.A1.Y4.Z4, X1.A1.Y4.Z5, X1.A1.Y4.Z6,
X1.A1.Y4.Z7, X1.A1.Y4.Z8, X1.A2.Y1.Z1, X1.A2.Y1.Z2, X1.A2.Y1.Z3,
X1.A2.Y1.Z4, X1.A2.Y1.Z5, X1.A2.Y1.Z6, X1.A2.Y1.Z7, X1.A2.Y1.Z8,
X1.A2.Y2.Z1, X1.A2.Y2.Z2, X1.A2.Y2.Z3, X1.A2.Y2.Z4, X1.A2.Y2.Z5,
X1.A2.Y2.Z6, X1.A2.Y2.Z7, X1.A2.Y2.Z8, X1.A2.Y3.Z1, X1.A2.Y3.Z2,
X1.A2.Y3.Z3, X1.A2.Y3.Z4, X1.A2.Y3.Z5, X1.A2.Y3.Z6, X1.A2.Y3.Z7,
X1.A2.Y3.Z8, X1.A2.Y4.Z1, X1.A2.Y4.Z2, X1.A2.Y4.Z3, X1.A2.Y4.Z4,
X1.A2.Y4.Z5, X1.A2.Y4.Z6, X1.A2.Y4.Z7, X1.A2.Y4.Z8, X1.A3.Y1.Z1,
X1.A3.Y1.Z2, X1.A3.Y1.Z3, X1.A3.Y1.Z4, X1.A3.Y1.Z5, X1.A3.Y1.Z6,
X1.A3.Y1.Z7, X1.A3.Y1.Z8, X1.A3.Y2.Z1, X1.A3.Y2.Z2, X1.A3.Y2.Z3,
X1.A3.Y2.Z4, X1.A3.Y2.Z5, X1.A3.Y2.Z6, X1.A3.Y2.Z7, X1.A3.Y2.Z8,
X1.A3.Y3.Z1, X1.A3.Y3.Z2, X1.A3.Y3.Z3, X1.A3.Y3.Z4, X1.A3.Y3.Z5,
X1.A3.Y3.Z6, X1.A3.Y3.Z7, X1.A3.Y3.Z8, X1.A3.Y4.Z1, X1.A3.Y4.Z2,
X1.A3.Y4.Z3, X1.A3.Y4.Z4, X1.A3.Y4.Z5, X1.A3.Y4.Z6, X1.A3.Y4.Z7,
X1.A3.Y4.Z8, X1.A4.Y1.Z1, X1.A4.Y1.Z2, X1.A4.Y1.Z3, X1.A4.Y1.Z4,
X1.A4.Y1.Z5, X1.A4.Y1.Z6, X1.A4.Y1.Z7, X1.A4.Y1.Z8, X1.A4.Y2.Z1,
X1.A4.Y2.Z2, X1.A4.Y2.Z3, X1.A4.Y2.Z4, X1.A4.Y2.Z5, X1.A4.Y2.Z6,
X1.A4.Y2.Z7, X1.A4.Y2.Z8, X1.A4.Y3.Z1, X1.A4.Y3.Z2, X1.A4.Y3.Z3,
X1.A4.Y3.Z4, X1.A4.Y3.Z5, X1.A4.Y3.Z6, X1.A4.Y3.Z7, X1.A4.Y3.Z8,
X1.A4.Y4.Z1, X1.A4.Y4.Z2, X1.A4.Y4.Z3, X1.A4.Y4.Z4, X1.A4.Y4.Z5,
X1.A4.Y4.Z6, X1.A4.Y4.Z7, X1.A4.Y4.Z8, X2.A1.Y1.Z1, X2.A1.Y1.Z2,
X2.A1.Y1.Z3, X2.A1.Y1.Z4, X2.A1.Y1.Z5, X2.A1.Y1.Z6, X2.A1.Y1.Z7,
X2.A1.Y1.Z8, X2.A1.Y2.Z1, X2.A1.Y2.Z2, X2.A1.Y2.Z3, X2.A1.Y2.Z4,
X2.A1.Y2.Z5, X2.A1.Y2.Z6, X2.A1.Y2.Z7, X2.A1.Y2.Z8, X2.A1.Y3.Z1,
X2.A1.Y3.Z2, X2.A1.Y3.Z3, X2.A1.Y3.Z4, X2.A1.Y3.Z5, X2.A1.Y3.Z6,
X2.A1.Y3.Z7, X2.A1.Y3.Z8, X2.A1.Y4.Z1, X2.A1.Y4.Z2, X2.A1.Y4.Z3,
X2.A1.Y4.Z4, X2.A1.Y4.Z5, X2.A1.Y4.Z6, X2.A1.Y4.Z7, X2.A1.Y4.Z8,
X2.A2.Y1.Z1, X2.A2.Y1.Z2, X2.A2.Y1.Z3, X2.A2.Y1.Z4, X2.A2.Y1.Z5,
X2.A2.Y1.Z6, X2.A2.Y1.Z7, X2.A2.Y1.Z8, X2.A2.Y2.Z1, X2.A2.Y2.Z2,
X2.A2.Y2.Z3, X2.A2.Y2.Z4, X2.A2.Y2.Z5, X2.A2.Y2.Z6, X2.A2.Y2.Z7,
X2.A2.Y2.Z8, X2.A2.Y3.Z1, X2.A2.Y3.Z2, X2.A2.Y3.Z3, X2.A2.Y3.Z4,
X2.A2.Y3.Z5, X2.A2.Y3.Z6, X2.A2.Y3.Z7, X2.A2.Y3.Z8, X2.A2.Y4.Z1,
X2.A2.Y4.Z2, X2.A2.Y4.Z3, X2.A2.Y4.Z4, X2.A2.Y4.Z5, X2.A2.Y4.Z6,
X2.A2.Y4.Z7, X2.A2.Y4.Z8, X2.A3.Y1.Z1, X2.A3.Y1.Z2, X2.A3.Y1.Z3,
X2.A3.Y1.Z4, X2.A3.Y1.Z5, X2.A3.Y1.Z6, X2.A3.Y1.Z7, X2.A3.Y1.Z8,
X2.A3.Y2.Z1, X2.A3.Y2.Z2, X2.A3.Y2.Z3, X2.A3.Y2.Z4, X2.A3.Y2.Z5,
X2.A3.Y2.Z6, X2.A3.Y2.Z7, X2.A3.Y2.Z8, X2.A3.Y3.Z1, X2.A3.Y3.Z2,
X2.A3.Y3.Z3, X2.A3.Y3.Z4, X2.A3.Y3.Z5, X2.A3.Y3.Z6, X2.A3.Y3.Z7,
X2.A3.Y3.Z8, X2.A3.Y4.Z1, X2.A3.Y4.Z2, X2.A3.Y4.Z3, X2.A3.Y4.Z4,
X2.A3.Y4.Z5, X2.A3.Y4.Z6, X2.A3.Y4.Z7, X2.A3.Y4.Z8, X2.A4.Y1.Z1,
X2.A4.Y1.Z2, X2.A4.Y1.Z3, X2.A4.Y1.Z4, X2.A4.Y1.Z5, X2.A4.Y1.Z6,
X2.A4.Y1.Z7, X2.A4.Y1.Z8, X2.A4.Y2.Z1, X2.A4.Y2.Z2, X2.A4.Y2.Z3,
X2.A4.Y2.Z4, X2.A4.Y2.Z5, X2.A4.Y2.Z6, X2.A4.Y2.Z7, X2.A4.Y2.Z8,
X2.A4.Y3.Z1, X2.A4.Y3.Z2, X2.A4.Y3.Z3, X2.A4.Y3.Z4, X2.A4.Y3.Z5,
X2.A4.Y3.Z6, X2.A4.Y3.Z7, X2.A4.Y3.Z8, X2.A4.Y4.Z1, X2.A4.Y4.Z2,
X2.A4.Y4.Z3, X2.A4.Y4.Z4, X2.A4.Y4.Z5, X2.A4.Y4.Z6, X2.A4.Y4.Z7,
X2.A4.Y4.Z8, X3.A1.Y1.Z1, X3.A1.Y1.Z2, X3.A1.Y1.Z3, X3.A1.Y1.Z4,
X3.A1.Y1.Z5, X3.A1.Y1.Z6, X3.A1.Y1.Z7, X3.A1.Y1.Z8, X3.A1.Y2.Z1,
X3.A1.Y2.Z2, X3.A1.Y2.Z3, X3.A1.Y2.Z4, X3.A1.Y2.Z5, X3.A1.Y2.Z6,
X3.A1.Y2.Z7, X3.A1.Y2.Z8, X3.A1.Y3.Z1, X3.A1.Y3.Z2, X3.A1.Y3.Z3,
X3.A1.Y3.Z4, X3.A1.Y3.Z5, X3.A1.Y3.Z6, X3.A1.Y3.Z7, X3.A1.Y3.Z8,
X3.A1.Y4.Z1, X3.A1.Y4.Z2, X3.A1.Y4.Z3, X3.A1.Y4.Z4, X3.A1.Y4.Z5,
X3.A1.Y4.Z6, X3.A1.Y4.Z7, X3.A1.Y4.Z8, X3.A2.Y1.Z1, X3.A2.Y1.Z2,
X3.A2.Y1.Z3, X3.A2.Y1.Z4, X3.A2.Y1.Z5, X3.A2.Y1.Z6, X3.A2.Y1.Z7,
X3.A2.Y1.Z8, X3.A2.Y2.Z1, X3.A2.Y2.Z2, X3.A2.Y2.Z3, X3.A2.Y2.Z4,
X3.A2.Y2.Z5, X3.A2.Y2.Z6, X3.A2.Y2.Z7, X3.A2.Y2.Z8, X3.A2.Y3.Z1,
X3.A2.Y3.Z2, X3.A2.Y3.Z3, X3.A2.Y3.Z4, X3.A2.Y3.Z5, X3.A2.Y3.Z6,
X3.A2.Y3.Z7, X3.A2.Y3.Z8, X3.A2.Y4.Z1, X3.A2.Y4.Z2, X3.A2.Y4.Z3,
X3.A2.Y4.Z4, X3.A2.Y4.Z5, X3.A2.Y4.Z6, X3.A2.Y4.Z7, X3.A2.Y4.Z8,
X3.A3.Y1.Z1, X3.A3.Y1.Z2, X3.A3.Y1.Z3, X3.A3.Y1.Z4, X3.A3.Y1.Z5,
X3.A3.Y1.Z6, X3.A3.Y1.Z7, X3.A3.Y1.Z8, X3.A3.Y2.Z1, X3.A3.Y2.Z2,
X3.A3.Y2.Z3, X3.A3.Y2.Z4, X3.A3.Y2.Z5, X3.A3.Y2.Z6, X3.A3.Y2.Z7,
X3.A3.Y2.Z8, X3.A3.Y3.Z1, X3.A3.Y3.Z2, X3.A3.Y3.Z3, X3.A3.Y3.Z4,
X3.A3.Y3.Z5, X3.A3.Y3.Z6, X3.A3.Y3.Z7, X3.A3.Y3.Z8, X3.A3.Y4.Z1,
X3.A3.Y4.Z2, X3.A3.Y4.Z3, X3.A3.Y4.Z4, X3.A3.Y4.Z5, X3.A3.Y4.Z6,
X3.A3.Y4.Z7, X3.A3.Y4.Z8, X3.A4.Y1.Z1, X3.A4.Y1.Z2, X3.A4.Y1.Z3,
X3.A4.Y1.Z4, X3.A4.Y1.Z5, X3.A4.Y1.Z6, X3.A4.Y1.Z7, X3.A4.Y1.Z8,
X3.A4.Y2.Z1, X3.A4.Y2.Z2, X3.A4.Y2.Z3, X3.A4.Y2.Z4, X3.A4.Y2.Z5,
X3.A4.Y2.Z6, X3.A4.Y2.Z7, X3.A4.Y2.Z8, X3.A4.Y3.Z1, X3.A4.Y3.Z2,
X3.A4.Y3.Z3, X3.A4.Y3.Z4, X3.A4.Y3.Z5, X3.A4.Y3.Z6, X3.A4.Y3.Z7,
X3.A4.Y3.Z8, X3.A4.Y4.Z1, X3.A4.Y4.Z2, X3.A4.Y4.Z3, X3.A4.Y4.Z4,
X3.A4.Y4.Z5, X3.A4.Y4.Z6, X3.A4.Y4.Z7, X3.A4.Y4.Z8, X4.A1.Y1.Z1,
X4.A1.Y1.Z2, X4.A1.Y1.Z3, X4.A1.Y1.Z4, X4.A1.Y1.Z5, X4.A1.Y1.Z6,
X4.A1.Y1.Z7, X4.A1.Y1.Z8, X4.A1.Y2.Z1, X4.A1.Y2.Z2, X4.A1.Y2.Z3,
X4.A1.Y2.Z4, X4.A1.Y2.Z5, X4.A1.Y2.Z6, X4.A1.Y2.Z7, X4.A1.Y2.Z8,
X4.A1.Y3.Z1, X4.A1.Y3.Z2, X4.A1.Y3.Z3, X4.A1.Y3.Z4, X4.A1.Y3.Z5,
X4.A1.Y3.Z6, X4.A1.Y3.Z7, X4.A1.Y3.Z8, X4.A1.Y4.Z1, X4.A1.Y4.Z2,
X4.A1.Y4.Z3, X4.A1.Y4.Z4, X4.A1.Y4.Z5, X4.A1.Y4.Z6, X4.A1.Y4.Z7,
X4.A1.Y4.Z8, X4.A2.Y1.Z1, X4.A2.Y1.Z2, X4.A2.Y1.Z3, X4.A2.Y1.Z4,
X4.A2.Y1.Z5, X4.A2.Y1.Z6, X4.A2.Y1.Z7, X4.A2.Y1.Z8, X4.A2.Y2.Z1,
X4.A2.Y2.Z2, X4.A2.Y2.Z3, X4.A2.Y2.Z4, X4.A2.Y2.Z5, X4.A2.Y2.Z6,
X4.A2.Y2.Z7, X4.A2.Y2.Z8, X4.A2.Y3.Z1, X4.A2.Y3.Z2, X4.A2.Y3.Z3,
X4.A2.Y3.Z4, X4.A2.Y3.Z5, X4.A2.Y3.Z6, X4.A2.Y3.Z7, X4.A2.Y3.Z8,
X4.A2.Y4.Z1, X4.A2.Y4.Z2, X4.A2.Y4.Z3, X4.A2.Y4.Z4, X4.A2.Y4.Z5,
X4.A2.Y4.Z6, X4.A2.Y4.Z7, X4.A2.Y4.Z8, X4.A3.Y1.Z1, X4.A3.Y1.Z2,
X4.A3.Y1.Z3, X4.A3.Y1.Z4, X4.A3.Y1.Z5, X4.A3.Y1.Z6, X4.A3.Y1.Z7,
X4.A3.Y1.Z8, X4.A3.Y2.Z1, X4.A3.Y2.Z2, X4.A3.Y2.Z3, X4.A3.Y2.Z4,
X4.A3.Y2.Z5, X4.A3.Y2.Z6, X4.A3.Y2.Z7, X4.A3.Y2.Z8, X4.A3.Y3.Z1,
X4.A3.Y3.Z2, X4.A3.Y3.Z3, X4.A3.Y3.Z4, X4.A3.Y3.Z5, X4.A3.Y3.Z6,
X4.A3.Y3.Z7, X4.A3.Y3.Z8, X4.A3.Y4.Z1, X4.A3.Y4.Z2, X4.A3.Y4.Z3,
X4.A3.Y4.Z4, X4.A3.Y4.Z5, X4.A3.Y4.Z6, X4.A3.Y4.Z7, X4.A3.Y4.Z8,
X4.A4.Y1.Z1, X4.A4.Y1.Z2, X4.A4.Y1.Z3, X4.A4.Y1.Z4, X4.A4.Y1.Z5,
X4.A4.Y1.Z6, X4.A4.Y1.Z7, X4.A4.Y1.Z8, X4.A4.Y2.Z1, X4.A4.Y2.Z2,
X4.A4.Y2.Z3, X4.A4.Y2.Z4, X4.A4.Y2.Z5, X4.A4.Y2.Z6, X4.A4.Y2.Z7,
X4.A4.Y2.Z8, X4.A4.Y3.Z1, X4.A4.Y3.Z2, X4.A4.Y3.Z3, X4.A4.Y3.Z4,
X4.A4.Y3.Z5, X4.A4.Y3.Z6, X4.A4.Y3.Z7, X4.A4.Y3.Z8, X4.A4.Y4.Z1,
X4.A4.Y4.Z2, X4.A4.Y4.Z3, X4.A4.Y4.Z4, X4.A4.Y4.Z5, X4.A4.Y4.Z6,
X4.A4.Y4.Z7, X4.A4.Y4.Z8, X5.A1.Y1.Z1, X5.A1.Y1.Z2, X5.A1.Y1.Z3,
X5.A1.Y1.Z4, X5.A1.Y1.Z5, X5.A1.Y1.Z6, X5.A1.Y1.Z7, X5.A1.Y1.Z8,
X5.A1.Y2.Z1, X5.A1.Y2.Z2, X5.A1.Y2.Z3, X5.A1.Y2.Z4, X5.A1.Y2.Z5,
X5.A1.Y2.Z6, X5.A1.Y2.Z7, X5.A1.Y2.Z8, X5.A1.Y3.Z1, X5.A1.Y3.Z2,
X5.A1.Y3.Z3, X5.A1.Y3.Z4, X5.A1.Y3.Z5, X5.A1.Y3.Z6, X5.A1.Y3.Z7,
X5.A1.Y3.Z8, X5.A1.Y4.Z1, X5.A1.Y4.Z2, X5.A1.Y4.Z3, X5.A1.Y4.Z4,
X5.A1.Y4.Z5, X5.A1.Y4.Z6, X5.A1.Y4.Z7, X5.A1.Y4.Z8, X5.A2.Y1.Z1,
X5.A2.Y1.Z2, X5.A2.Y1.Z3, X5.A2.Y1.Z4, X5.A2.Y1.Z5, X5.A2.Y1.Z6,
X5.A2.Y1.Z7, X5.A2.Y1.Z8, X5.A2.Y2.Z1, X5.A2.Y2.Z2, X5.A2.Y2.Z3,
X5.A2.Y2.Z4, X5.A2.Y2.Z5, X5.A2.Y2.Z6, X5.A2.Y2.Z7, X5.A2.Y2.Z8,
X5.A2.Y3.Z1, X5.A2.Y3.Z2, X5.A2.Y3.Z3, X5.A2.Y3.Z4, X5.A2.Y3.Z5,
X5.A2.Y3.Z6, X5.A2.Y3.Z7, X5.A2.Y3.Z8, X5.A2.Y4.Z1, X5.A2.Y4.Z2,
X5.A2.Y4.Z3, X5.A2.Y4.Z4, X5.A2.Y4.Z5, X5.A2.Y4.Z6, X5.A2.Y4.Z7,
X5.A2.Y4.Z8, X5.A3.Y1.Z1, X5.A3.Y1.Z2, X5.A3.Y1.Z3, X5.A3.Y1.Z4,
X5.A3.Y1.Z5, X5.A3.Y1.Z6, X5.A3.Y1.Z7, X5.A3.Y1.Z8, X5.A3.Y2.Z1,
X5.A3.Y2.Z2, X5.A3.Y2.Z3, X5.A3.Y2.Z4, X5.A3.Y2.Z5, X5.A3.Y2.Z6,
X5.A3.Y2.Z7, X5.A3.Y2.Z8, X5.A3.Y3.Z1, X5.A3.Y3.Z2, X5.A3.Y3.Z3,
X5.A3.Y3.Z4, X5.A3.Y3.Z5, X5.A3.Y3.Z6, X5.A3.Y3.Z7, X5.A3.Y3.Z8,
X5.A3.Y4.Z1, X5.A3.Y4.Z2, X5.A3.Y4.Z3, X5.A3.Y4.Z4, X5.A3.Y4.Z5,
X5.A3.Y4.Z6, X5.A3.Y4.Z7, X5.A3.Y4.Z8, X5.A4.Y1.Z1, X5.A4.Y1.Z2,
X5.A4.Y1.Z3, X5.A4.Y1.Z4, X5.A4.Y1.Z5, X5.A4.Y1.Z6, X5.A4.Y1.Z7,
X5.A4.Y1.Z8, X5.A4.Y2.Z1, X5.A4.Y2.Z2, X5.A4.Y2.Z3, X5.A4.Y2.Z4,
X5.A4.Y2.Z5, X5.A4.Y2.Z6, X5.A4.Y2.Z7, X5.A4.Y2.Z8, X5.A4.Y3.Z1,
X5.A4.Y3.Z2, X5.A4.Y3.Z3, X5.A4.Y3.Z4, X5.A4.Y3.Z5, X5.A4.Y3.Z6,
X5.A4.Y3.Z7, X5.A4.Y3.Z8, X5.A4.Y4.Z1, X5.A4.Y4.Z2, X5.A4.Y4.Z3,
X5.A4.Y4.Z4, X5.A4.Y4.Z5, X5.A4.Y4.Z6, X5.A4.Y4.Z7, X5.A4.Y4.Z8,
X6.A1.Y1.Z1, X6.A1.Y1.Z2, X6.A1.Y1.Z3, X6.A1.Y1.Z4, X6.A1.Y1.Z5,
X6.A1.Y1.Z6, X6.A1.Y1.Z7, X6.A1.Y1.Z8, X6.A1.Y2.Z1, X6.A1.Y2.Z2,
X6.A1.Y2.Z3, X6.A1.Y2.Z4, X6.A1.Y2.Z5, X6.A1.Y2.Z6, X6.A1.Y2.Z7,
X6.A1.Y2.Z8, X6.A1.Y3.Z1, X6.A1.Y3.Z2, X6.A1.Y3.Z3, X6.A1.Y3.Z4,
X6.A1.Y3.Z5, X6.A1.Y3.Z6, X6.A1.Y3.Z7, X6.A1.Y3.Z8, X6.A1.Y4.Z1,
X6.A1.Y4.Z2, X6.A1.Y4.Z3, X6.A1.Y4.Z4, X6.A1.Y4.Z5, X6.A1.Y4.Z6,
X6.A1.Y4.Z7, X6.A1.Y4.Z8, X6.A2.Y1.Z1, X6.A2.Y1.Z2, X6.A2.Y1.Z3,
X6.A2.Y1.Z4, X6.A2.Y1.Z5, X6.A2.Y1.Z6, X6.A2.Y1.Z7, X6.A2.Y1.Z8,
X6.A2.Y2.Z1, X6.A2.Y2.Z2, X6.A2.Y2.Z3, X6.A2.Y2.Z4, X6.A2.Y2.Z5,
X6.A2.Y2.Z6, X6.A2.Y2.Z7, X6.A2.Y2.Z8, X6.A2.Y3.Z1, X6.A2.Y3.Z2,
X6.A2.Y3.Z3, X6.A2.Y3.Z4, X6.A2.Y3.Z5, X6.A2.Y3.Z6, X6.A2.Y3.Z7,
X6.A2.Y3.Z8, X6.A2.Y4.Z1, X6.A2.Y4.Z2, X6.A2.Y4.Z3, X6.A2.Y4.Z4,
X6.A2.Y4.Z5, X6.A2.Y4.Z6, X6.A2.Y4.Z7, X6.A2.Y4.Z8, X6.A3.Y1.Z1,
X6.A3.Y1.Z2, X6.A3.Y1.Z3, X6.A3.Y1.Z4, X6.A3.Y1.Z5, X6.A3.Y1.Z6,
X6.A3.Y1.Z7, X6.A3.Y1.Z8, X6.A3.Y2.Z1, X6.A3.Y2.Z2, X6.A3.Y2.Z3,
X6.A3.Y2.Z4, X6.A3.Y2.Z5, X6.A3.Y2.Z6, X6.A3.Y2.Z7, X6.A3.Y2.Z8,
X6.A3.Y3.Z1, X6.A3.Y3.Z2, X6.A3.Y3.Z3, X6.A3.Y3.Z4, X6.A3.Y3.Z5,
X6.A3.Y3.Z6, X6.A3.Y3.Z7, X6.A3.Y3.Z8, X6.A3.Y4.Z1, X6.A3.Y4.Z2,
X6.A3.Y4.Z3, X6.A3.Y4.Z4, X6.A3.Y4.Z5, X6.A3.Y4.Z6, X6.A3.Y4.Z7,
X6.A3.Y4.Z8, X6.A4.Y1.Z1,
X6.A4.Y1.Z2, X6.A4.Y1.Z3, X6.A4.Y1.Z4, X6.A4.Y1.Z5, X6.A4.Y1.Z6,
X6.A4.Y1.Z7, X6.A4.Y1.Z8, X6.A4.Y2.Z1, X6.A4.Y2.Z2, X6.A4.Y2.Z3,
X6.A4.Y2.Z4, X6.A4.Y2.Z5, X6.A4.Y2.Z6, X6.A4.Y2.Z7, X6.A4.Y2.Z8,
X6.A4.Y3.Z1, X6.A4.Y3.Z2, X6.A4.Y3.Z3, X6.A4.Y3.Z4, X6.A4.Y3.Z5,
X6.A4.Y3.Z6, X6.A4.Y3.Z7, X6.A4.Y3.Z8, X6.A4.Y4.Z1, X6.A4.Y4.Z2,
X6.A4.Y4.Z3, X6.A4.Y4.Z4, X6.A4.Y4.Z5, X6.A4.Y4.Z6, X6.A4.Y4.Z7,
X6.A4.Y4.Z8,
Pharmaceutical Formulations
[0234] The compounds of this invention are formulated with
conventional carriers and excipients, which will be selected in
accord with ordinary practice. Tablets will contain excipients,
glidants, fillers, binders and the like. Aqueous formulations are
prepared in sterile form, and when intended for delivery by other
than oral administration generally will be isotonic. All
formulations will optionally contain excipients such as those set
forth in the Handbook of Pharmaceutical Excipients (1986), herein
incorporated by reference in its entirety. Excipients include
ascorbic acid and other antioxidants, chelating agents such as
EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose,
hydroxyalkylmethylcellulose, stearic acid and the like. The pH of
the formulations ranges from about 3 to about 11, but is ordinarily
about 7 to 10.
[0235] While it is possible for the active ingredients to be
administered alone it may be preferable to present them as
pharmaceutical formulations. The formulations of the invention,
both for veterinary and for human use, comprise at least one active
ingredient, together with one or more acceptable carriers and
optionally other therapeutic ingredients. The carrier(s) must be
"acceptable" in the sense of being compatible with the other
ingredients of the formulation and physiologically innocuous to the
recipient thereof.
[0236] The formulations include those suitable for the foregoing
administration routes. The formulations may conveniently be
presented in unit dosage form and may be prepared by any of the
methods well known in the art of pharmacy. Techniques and
formulations generally are found in Remington's Pharmaceutical
Sciences (Mack Publishing Co., Easton, Pa.), herein incorporated by
reference in its entirety. Such methods include the step of
bringing into association the active ingredient with the carrier
which constitutes one or more accessory ingredients. In general the
formulations are prepared by uniformly and intimately bringing into
association the active ingredient with liquid carriers or finely
divided solid carriers or both, and then, if necessary, shaping the
product.
[0237] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
cachets or tablets each containing a predetermined amount of the
active ingredient; as a powder or granules; as a solution or a
suspension in an aqueous or non-aqueous liquid; or as an
oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The
active ingredient may also be administered as a bolus, electuary or
paste.
[0238] A tablet is made by compression or molding, optionally with
one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with a binder, lubricant, inert diluent, preservative,
surface active or dispersing agent. Molded tablets may be made by
molding in a suitable machine a mixture of the powdered active
ingredient moistened with an inert liquid diluent. The tablets may
optionally be coated or scored and optionally are formulated so as
to provide slow or controlled release of the active ingredient.
[0239] For administration to the eye or other external tissues
e.g., mouth and skin, the formulations are preferably applied as a
topical ointment or cream containing the active ingredient(s) in an
amount of, for example, 0.075 to 20% w/w (including active
ingredient(s) in a range between 0.1% and 20% in increments of 0.1%
w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w
and most preferably 0.5 to 10% w/w. When formulated in an ointment,
the active ingredients may be employed with either a paraffinic or
a water-miscible ointment base. Alternatively, the active
ingredients may be formulated in a cream with an oil-in-water cream
base.
[0240] If desired, the aqueous phase of the cream base may include,
for example, at least 30% w/w of a polyhydric alcohol, i.e. an
alcohol having two or more hydroxyl groups such as propylene
glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and
polyethylene glycol (including PEG 400) and mixtures thereof. The
topical formulations may desirably include a compound which
enhances absorption or penetration of the active ingredient through
the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethyl sulphoxide and related
analogs.
[0241] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier (otherwise known as an
emulgent), it desirably comprises a mixture of at least one
emulsifier with a fat or an oil or with both a fat and an oil.
Preferably, a hydrophilic emulsifier is included together with a
lipophilic emulsifier which acts as a stabilizer. It is also
preferred to include both an oil and a fat. Together, the
emulsifier(s) with or without stabilizer(s) make up the so-called
emulsifying wax, and the wax together with the oil and fat make up
the so-called emulsifying ointment base which forms the oily
dispersed phase of the cream formulations.
[0242] Emulgents and emulsion stabilizers suitable for use in the
formulation of the invention include Tween.RTM. 60, Span.RTM. 80,
cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl
mono-stearate and sodium lauryl sulfate.
[0243] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties. The cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as di-isoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate, decyl
oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters known as Crodamol CAP may be
used, the last three being preferred esters. These may be used
alone or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils are used.
[0244] Pharmaceutical formulations according to the present
invention comprise one or more compounds of the invention together
with one or more pharmaceutically acceptable carriers or excipients
and optionally other therapeutic agents. Pharmaceutical
formulations containing the active ingredient may be in any form
suitable for the intended method of administration. When used for
oral use for example, tablets, troches, lozenges, aqueous or oil
suspensions, dispersible powders or granules, emulsions, hard or
soft capsules, syrups or elixirs may be prepared. Compositions
intended for oral use may be prepared according to any method known
to the art for the manufacture of pharmaceutical compositions and
such compositions may contain one or more agents including
sweetening agents, flavoring agents, coloring agents and preserving
agents, in order to provide a palatable preparation. Tablets
containing the active ingredient in admixture with non-toxic
pharmaceutically acceptable excipient which are suitable for
manufacture of tablets are acceptable. These excipients may be, for
example, inert diluents, such as calcium or sodium carbonate,
lactose, lactose monohydrate, croscarmellose sodium, povidone,
calcium or sodium phosphate; granulating and disintegrating agents,
such as maize starch, or alginic acid; binding agents, such as
cellulose, microcrystalline cellulose, starch, gelatin or acacia;
and lubricating agents, such as magnesium stearate, stearic acid or
talc. Tablets may be uncoated or may be coated by known techniques
including microencapsulation to delay disintegration and adsorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monostearate or glyceryl distearate alone or with
a wax may be employed.
[0245] Formulations for oral use may be also presented as hard
gelatin capsules where the active ingredient is mixed with an inert
solid diluent, for example calcium phosphate or kaolin, or as soft
gelatin capsules wherein the active ingredient is mixed with water
or an oil medium, such as peanut oil, liquid paraffin or olive
oil.
[0246] Aqueous suspensions of the invention contain the active
materials in admixture with excipients suitable for the manufacture
of aqueous suspensions. Such excipients include a suspending agent,
such as sodium carboxymethylcellulose, methylcellulose,
hydroxypropyl methylcelluose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethyleneoxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous
suspension may also contain one or more preservatives such as ethyl
or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or
more flavoring agents and one or more sweetening agents, such as
sucrose or saccharin.
[0247] Oil suspensions may be formulated by suspending the active
ingredient in a vegetable oil, such as arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oral suspensions may contain a thickening agent, such
as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such
as those set forth herein, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an antioxidant such as ascorbic
acid.
[0248] Dispersible powders and granules of the invention suitable
for preparation of an aqueous suspension by the addition of water
provide the active ingredient in admixture with a dispersing or
wetting agent, a suspending agent, and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are
exemplified by those disclosed above. Additional excipients, for
example sweetening, flavoring and coloring agents, may also be
present.
[0249] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, such as olive oil or arachis oil, a mineral oil,
such as liquid paraffin, or a mixture of these. Suitable
emulsifying agents include naturally-occurring gums, such as gum
acacia and gum tragacanth, naturally occurring phosphatides, such
as soybean lecithin, esters or partial esters derived from fatty
acids and hexitol anhydrides, such as sorbitan monooleate, and
condensation products of these partial esters with ethylene oxide,
such as polyoxyethylene sorbitan monooleate. The emulsion may also
contain sweetening and flavoring agents. Syrups and elixirs may be
formulated with sweetening agents, such as glycerol, sorbitol or
sucrose. Such formulations may also contain a demulcent, a
preservative, a flavoring or a coloring agent.
[0250] The pharmaceutical compositions of the invention may be in
the form of a sterile injectable preparation, such as a sterile
injectable aqueous or oleaginous suspension. This suspension may be
formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents which have been
mentioned herein. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent, such as a solution in
1,3-butane-diol or prepared as a lyophilized powder. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile fixed oils may conventionally be employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid may likewise be used in
the preparation of injectables.
[0251] The amount of active ingredient that may be combined with
the carrier material to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a time-release formulation intended
for oral administration to humans may contain approximately 1 to
1000 mg of active material compounded with an appropriate and
convenient amount of carrier material which may vary from about 5
to about 95% of the total compositions (weight:weight). The
pharmaceutical composition can be prepared to provide easily
measurable amounts for administration. For example, an aqueous
solution intended for intravenous infusion may contain from about 3
to 500 .mu.g of the active ingredient per milliliter of solution in
order that infusion of a suitable volume at a rate of about 30
mL/hr can occur.
[0252] Formulations suitable for administration to the eye include
eye drops wherein the active ingredient is dissolved or suspended
in a suitable carrier, especially an aqueous solvent for the active
ingredient. The active ingredient is preferably present in such
formulations in a concentration of 0.5 to 20%, advantageously 0.5
to 10% particularly about 1.5% w/w.
[0253] Formulations suitable for topical administration in the
mouth include lozenges comprising the active ingredient in a
flavored basis, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0254] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
[0255] Formulations suitable for intrapulmonary or nasal
administration have a particle size for example in the range of 0.1
to 500 .mu.m (including particle sizes in a range between 0.1 and
500 .mu.m in increments such as 0.5 .mu.m, 1 .mu.m, 30 .mu.m, 35
.mu.m, etc.), which is administered by rapid inhalation through the
nasal passage or by inhalation through the mouth so as to reach the
alveolar sacs. Suitable formulations include aqueous or oily
solutions of the active ingredient. Formulations suitable for
aerosol or dry powder administration may be prepared according to
conventional methods and may be delivered with other therapeutic
agents such as compounds heretofore used in the treatment or
prophylaxis of infections as described herein.
[0256] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0257] Formulations suitable for parenteral administration include
aqueous and non-aqueous sterile injection solutions which may
contain anti-oxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents.
[0258] The formulations are presented in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and may be
stored in a freeze-dried (lyophilized) condition requiring only the
addition of the sterile liquid carrier, for example water for
injection, immediately prior to use. Extemporaneous injection
solutions and suspensions are prepared from sterile powders,
granules and tablets of the kind previously described. Preferred
unit dosage formulations are those containing a daily dose or unit
daily sub-dose, as herein above recited, or an appropriate fraction
thereof, of the active ingredient.
[0259] It should be understood that in addition to the ingredients
particularly mentioned above the formulations of this invention may
include other agents conventional in the art having regard to the
type of formulation in question, for example those suitable for
oral administration may include flavoring agents.
[0260] The invention further provides veterinary compositions
comprising at least one active ingredient as above defined together
with a veterinary carrier.
[0261] Veterinary carriers are materials useful for the purpose of
administering the composition and may be solid, liquid or gaseous
materials which are otherwise inert or acceptable in the veterinary
art and are compatible with the active ingredient. These veterinary
compositions may be administered orally, parenterally or by any
other desired route.
[0262] Compounds of the invention can also be formulated to provide
controlled release of the active ingredient to allow less frequent
dosing or to improve the pharmacokinetic or toxicity profile of the
active ingredient. Accordingly, the invention also provided
compositions comprising one or more compounds of the invention
formulated for sustained or controlled release.
[0263] The effective dose of an active ingredient depends at least
on the nature of the condition being treated, toxicity, whether the
compound is being used prophylactically (lower doses) or against an
active disease or condition, the method of delivery, and the
pharmaceutical formulation, and will be determined by the clinician
using conventional dose escalation studies. The effective dose can
be expected to be from about 0.0001 to about 10 mg/kg body weight
per day, typically from about 0.001 to about 1 mg/kg body weight
per day, more typically from about 0.01 to about 1 mg/kg body
weight per day, even more typically from about 0.05 to about 0.5
mg/kg body weight per day. For example, the daily candidate dose
for an adult human of approximately 70 kg body weight will range
from about 0.05 mg to about 100 mg, or between about 0.1 mg and
about 25 mg, or between about 0.4 mg and about 4 mg, and may take
the form of single or multiple doses.
[0264] In yet another embodiment, the present application discloses
pharmaceutical compositions comprising a compound of Formula I, Ia,
Ib, II, IIa, III, or IV, or a pharmaceutically acceptable salt,
solvate, and/or ester thereof, and a pharmaceutically acceptable
carrier or exipient.
[0265] In yet another embodiment, the present application discloses
pharmaceutical compositions comprising a compound of Formula I, Ia,
Ib, II, IIa, III, or IV, or a pharmaceutically acceptable salt,
solvate, and/or ester thereof, in combination with at least one
additional active agent, and a pharmaceutically acceptable carrier
or exipient.
[0266] In yet another embodiment, the present application discloses
pharmaceutical compositions comprising a compound of Formula I, Ia,
Ib, II, IIa, III, or IV, or a pharmaceutically acceptable salt,
solvate, and/or ester thereof, in combination with at least one
additional active agent, and a pharmaceutically acceptable carrier
or exipient. Examples of the additional active agent also include,
but are not limited to interferons, ribavirin or its analogs, HCV
NS3 protease inhibitors, alpha-glucosidase 1 inhibitors,
hepatoprotectants, nucleoside or nucleotide inhibitors of HCV NS5B
polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV
NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES
inhibitors, pharmacokinetic enhancers, and other drugs for treating
HCV, or mixtures thereof.
[0267] More specifically, one or more compounds of the present
invention may be combined with one or more compounds selected from
the group consisting of:
[0268] (1) interferons selected from the group consisting of
pegylated rIFN-alpha 2b (PEG-Intron), pegylated rIFN-alpha 2a
(Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A),
interferon alpha (MOR-22, OPC-18, Alfaferone, Alfanative,
Multiferon, subalin), interferon alfacon-1 (Infergen), interferon
alpha-n1 (Wellferon), interferon alpha-n3 (Alferon),
interferon-beta (Avonex, DL-8234), interferon-omega (omega DUROS,
Biomed 510), albinterferon alpha-2b (Albuferon), IFN alpha-2b XL,
BLX-883 (Locteron), DA-3021, glycosylated interferon alpha-2b
(AVI-005), PEG-Infergen, PEGylated interferon lambda-1 (PEGylated
IL-29), belerofon, and mixtures thereof;
[0269] (2) ribavirin and its analogs selected from the group
consisting of ribavirin (Rebetol, Copegus), taribavirin
(Viramidine), and mixtures thereof;
[0270] (3) HCV NS3 protease inhibitors selected from the group
consisting of boceprevir (SCH-503034 SCH-7), telaprevir (VX-950),
TMC435350, BI-1335, BI-1230, MK-7009, VBY-376, VX-500, BMS-790052,
BMS-605339, PHX-1766, AS-101, YH-5258, YH5530, YH5531, ITMN-191,
and mixtures thereof;
[0271] (4) alpha-glucosidase 1 inhibitors selected from the group
consisting of celgosivir (MX-3253), Miglitol, UT-231B, and mixtures
thereof;
[0272] (5) hepatoprotectants selected from the group consisting of
IDN-6556, ME 3738, LB-84451, silibilin, MitoQ, and mixtures
thereof;
[0273] (6) nucleoside or nucleotide inhibitors of HCV NS5B
polymerase selected from the group consisting of R1626, R7128
(R4048), IDX184, IDX-102, BCX-4678, valopicitabine (NM-283),
MK-0608, and mixtures thereof;
[0274] (7) non-nucleoside inhibitors of HCV NS5B polymerase
selected from the group consisting of PF-868554, VCH-759, VCH-916,
JTK-652, MK-3281, VBY-708, VCH-222, A848837, ANA-598, GL60667,
GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (nesbuvir),
GSK625433, BILN-1941, XTL-2125, GS-9190, and mixtures thereof;
[0275] (8) HCV NS5A inhibitors selected from the group consisting
of AZD-2836 (A-831), A-689, and mixtures thereof;
[0276] (9) TLR-7 agonists selected from the group consisting of
ANA-975, SM-360320, and mixtures thereof;
[0277] (10) cyclophillin inhibitors selected from the group
consisting of DEBIO-025, SCY-635, NIM811, and mixtures thereof;
[0278] (11) HCV IRES inhibitors selected from the group consisting
of MCI-067,
[0279] (12) pharmacokinetic enhancers selected from the group
consisting of BAS-100, SPI-452, PF-4194477, TMC-41629,
roxythromycin, and mixtures thereof; and
[0280] (13) other drugs for treating HCV selected from the group
consisting of thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea,
NTZ), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, action
(CPG-10101), KRN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-111,
ITX2865, TT-033i, ANA 971, NOV-205, tarvacin, EHC-18, VGX-410C,
EMZ-702, AVI 4065, BMS-650032, BMS-791325, Bavituximab, MDX-1106
(ONO-4538), Oglufanide, VX-497 (merimepodib), and mixtures
thereof.
[0281] In yet another embodiment, the present application provides
a combination pharmaceutical agent comprising:
[0282] a) a first pharmaceutical composition comprising a compound
of Formula I, Ia, Ib, II, IIa, III, or IV, or a pharmaceutically
acceptable salt, solvate, or ester thereof; and
[0283] b) a second pharmaceutical composition comprising at least
one additional active agent selected from the group consisting of
interferons, ribavirin or its analogs, HCV NS3 protease inhibitors,
alpha-glucosidase 1 inhibitors, hepatoprotectants, nucleoside or
nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside
inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7
agonists, cyclophillin inhibitors, HCV IRES inhibitors,
pharmacokinetic enhancers, and other drugs for treating HCV, or
mixtures thereof.
Routes of Administration
[0284] One or more compounds of the invention (herein referred to
as the active ingredients) are administered by any route
appropriate to the condition to be treated. Suitable routes include
oral, rectal, nasal, topical (including buccal and sublingual),
vaginal and parenteral (including subcutaneous, intramuscular,
intravenous, intradermal, intrathecal and epidural), and the like.
It will be appreciated that the preferred route may vary with for
example the condition of the recipient. An advantage of the
compounds of this invention is that they are orally bioavailable
and can be dosed orally.
Combination Therapy
[0285] In one embodiment, the compounds of the present invention
are used in combination with other active therapeutic ingredients
or agents. Combinations of the compounds of Formula I, Ia, Ib, II,
IIa, III, or IV, and additional active agents may be selected to
treat patients with a viral infection, e.g., HBV, HCV, or HIV
infection.
[0286] Preferably, the other active therapeutic ingredients or
agents are interferons, ribavirin or its analogs, HCV NS3 protease
inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants,
nucleoside or nucleotide inhibitors of HCV NS5B polymerase,
non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A
inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES
inhibitors, pharmacokinetic enhancers, and other drugs for treating
HCV, or mixtures thereof.
[0287] Combinations of the compounds of Formula I, Ia, Ib, II, IIa,
III, or IV, are typically selected based on the condition to be
treated, cross-reactivities of ingredients and pharmaco-properties
of the combination. For example, when treating an infection (e.g.,
HCV), the compositions of the invention are combined with other
active agents (such as those described herein).
[0288] Suitable active agents or ingredients which can be combined
with the compounds of Formula I, Ia, Ib, II, IIa, III, or IV, can
include one or more compounds selected from the group consisting
of:
[0289] (1) interferons selected from the group consisting of
pegylated rIFN-alpha 2b (PEG-Intron), pegylated rIFN-alpha 2a
(Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A),
interferon alpha (MOR-22, OPC-18, Alfaferone, Alfanative,
Multiferon, subalin), interferon alfacon-1 (Infergen), interferon
alpha-n1 (Wellferon), interferon alpha-n3 (Alferon),
interferon-beta (Avonex, DL-8234), interferon-omega (omega DUROS,
Biomed 510), albinterferon alpha-2b (Albuferon), IFN alpha-2b XL,
BLX-883 (Locteron), DA-3021, glycosylated interferon alpha-2b
(AVI-005), PEG-Infergen, PEGylated interferon lambda-1 (PEGylated
IL-29), belerofon, and mixtures thereof;
[0290] (2) ribavirin and its analogs selected from the group
consisting of ribavirin (Rebetol, Copegus), taribavirin
(Viramidine), and mixtures thereof;
[0291] (3) HCV NS3 protease inhibitors selected from the group
consisting of boceprevir (SCH-503034, SCH-7), telaprevir (VX-950),
TMC435350, BI-1335, BI-1230, MK-7009, VBY-376, VX-500, BMS-790052,
BMS-605339, PHX-1766, AS-101, YH-5258, YH5530, YH5531, ITMN-191,
and mixtures thereof;
[0292] (4) alpha-glucosidase 1 inhibitors selected from the group
consisting of celgosivir (MX-3253), Miglitol, UT-231B, and mixtures
thereof;
[0293] (5) hepatoprotectants selected from the group consisting of
IDN-6556, ME 3738, LB-84451, silibilin, MitoQ, and mixtures
thereof;
[0294] (6) nucleoside or nucleotide inhibitors of HCV NS5B
polymerase selected from the group consisting of 81626, R7128
(R4048), IDX184, IDX-102, BCX-4678, valopicitabine (NM-283),
MK-0608, and mixtures thereof;
[0295] (7) non-nucleoside inhibitors of HCV NS5B polymerase
selected from the group consisting of PF-868554, VCH-759, VCH-916,
JTK-652, MK-3281, VBY-708, VCH-222, A848837, ANA-598, GL60667,
GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (nesbuvir),
GSK625433, BILN-1941, XTL-2125, GS-9190, and mixtures thereof;
[0296] (8) HCV NS5A inhibitors selected from the group consisting
of AZD-2836 (A-831), A-689, and mixtures thereof;
[0297] (9) TLR-7 agonists selected from the group consisting of
ANA-975, SM-360320, and mixtures thereof;
[0298] (10) cyclophillin inhibitors selected from the group
consisting of DEBIO-025, SCY-635, NIM811, and mixtures thereof;
[0299] (11) HCV IRES inhibitors selected from the group consisting
of MCI-067,
[0300] (12) pharmacokinetic enhancers selected from the group
consisting of BAS-100, SPI-452, PF-4194477, TMC-41629,
roxythromycin, and mixtures thereof; and
[0301] (13) other drugs for treating HCV selected from the group
consisting of thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea,
NTZ), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon
(CPG-10101), KRN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-111,
ITX2865, TT-033i, ANA 971, NOV-205, tarvacin, EHC-18, VGX-410C,
EMZ-702, AVI 4065, BMS-650032, BMS-791325, Bavituximab, MDX-1106
(ONO-4538), Oglufanide, VX-497 (merimepodib), and mixtures
thereof.
[0302] In yet another embodiment, the present application discloses
pharmaceutical compositions comprising a compound of the present
invention, or a pharmaceutically acceptable salt, solvate, and/or
ester thereof, in combination with at least one additional active
agent, and a pharmaceutically acceptable carrier or exipient.
[0303] According to the present invention, the active agent used in
combination with the compound of the present invention can be any
agent having a therapeutic effect when used in combination with the
compound of the present invention. For example, the active agent
used in combination with the compound of the present invention can
be interferons, ribavirin or its analogs, HCV NS3 protease
inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants,
nucleoside or nucleotide inhibitors of HCV NS5B polymerase,
non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A
inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES
inhibitors, pharmacokinetic enhancers, and other drugs for treating
HCV, or mixtures thereof.
[0304] In another embodiment, the present application provides
pharmaceutical compositions comprising a compound of the present
invention, or a pharmaceutically acceptable salt, solvate, and/or
ester thereof, in combination with at least one additional active
agent selected from the group consisting of:
[0305] (1) interferons selected from the group consisting of
pegylated rIFN-alpha 2b (PEG-Intron), pegylated rIFN-alpha 2a
(Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A),
interferon alpha (MOR-22, OPC-18, Alfaferone, Alfanative,
Multiferon, subalin), interferon alfacon-1 (Infergen), interferon
alpha-n1 (Wellferon), interferon alpha-n3 (Alferon),
interferon-beta (Avonex, DL-8234), interferon-omega (omega DUROS,
Biomed 510), albinterferon alpha-2b (Albuferon), IFN alpha-2b XL,
BLX-883 (Locteron), DA-3021, glycosylated interferon alpha-2b
(AVI-005), PEG-Infergen, PEGylated interferon lambda-1 (PEGylated
IL-29), belerofon, and mixtures thereof;
[0306] (2) ribavirin and its analogs selected from the group
consisting of ribavirin (Rebetol, Copegus), taribavirin
(Viramidine), and mixtures thereof;
[0307] (3) HCV NS3 protease inhibitors selected from the group
consisting of boceprevir (SCH-503034 SCH-7), telaprevir (VX-950),
TMC435350, BI-1335, BI-1230, MK-7009, VBY-376, VX-500, BMS-790052,
BMS-605339, PHX-1766, AS-101, YH-5258, YH5530, YH5531, ITMN-191,
and mixtures thereof;
[0308] (4) alpha-glucosidase 1 inhibitors selected from the group
consisting of celgosivir (MX-3253), Miglitol, UT-231B, and mixtures
thereof;
[0309] (5) hepatoprotectants selected from the group consisting of
IDN-6556, ME 3738, LB-84451, silibilin, MitoQ, and mixtures
thereof;
[0310] (6) nucleoside or nucleotide inhibitors of HCV NS5B
polymerase selected from the group consisting of R1626, R7128
(R4048), IDX184, IDX-102, BCX-4678, valopicitabine (NM-283),
MK-0608, and mixtures thereof;
[0311] (7) non-nucleoside inhibitors of HCV NS5B polymerase
selected from the group consisting of PF-868554, VCH-759, VCH-916,
JTK-652, MK-3281, VBY-708, VCH-222, A848837, ANA-598, GL60667,
GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (nesbuvir),
GSK625433, BILN-1941, XTL-2125, GS-9190, and mixtures thereof;
[0312] (8) HCV NS5A inhibitors selected from the group consisting
of AZD-2836 (A-831), A-689, and mixtures thereof;
[0313] (9) TLR-7 agonists selected from the group consisting of
ANA-975, SM-360320, and mixtures thereof;
[0314] (10) cyclophillin inhibitors selected from the group
consisting of DEBIO-025, SCY-635, NIM811, and mixtures thereof;
[0315] (11) HCV IRES inhibitors selected from the group consisting
of MCI-067,
[0316] (12) pharmacokinetic enhancers selected from the group
consisting of BAS-100, SPI-452, PF-4194477, TMC-41629,
roxythromycin, and mixtures thereof; and
[0317] (13) other drugs for treating HCV selected from the group
consisting of thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea,
NTZ), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon
(CPG-10101), KRN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-111,
ITX2865, TT-033i, ANA 971, NOV-205, tarvacin, EHC-18, VGX-410C,
EMZ-702, AVI 4065, BMS-650032, BMS-791325, Bavituximab, MDX-1106
(ONO-4538), Oglufanide, VX-497 (merimepodib), and mixtures
thereof.
[0318] In yet another embodiment, the present application provides
a combination pharmaceutical agent comprising:
[0319] a) a first pharmaceutical composition comprising a compound
of the present invention, or a pharmaceutically acceptable salt,
solvate, or ester thereof; and
[0320] b) a second pharmaceutical composition comprising at least
one additional active agent selected from the group consisting of
interferons, ribavirin or its analogs, HCV NS3 protease inhibitors,
alpha-glucosidase 1 inhibitors, hepatoprotectants, nucleoside or
nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside
inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7
agonists, cyclophillin inhibitors, HCV IRES inhibitors,
pharmacokinetic enhancers, and other drugs for treating HCV, or
mixtures thereof.
[0321] It is also possible to combine any compound of the invention
with one or more other active agents in a unitary dosage form for
simultaneous or sequential administration to a patient. The
combination therapy may be administered as a simultaneous or
sequential regimen. When administered sequentially, the combination
may be administered in two or more administrations.
[0322] Co-administration of a compound of the invention with one or
more other active agents generally refers to simultaneous or
sequential administration of a compound of the invention and one or
more other active agents, such that therapeutically effective
amounts of the compound of the invention and one or more other
active agents are both present in the body of the patient.
[0323] Co-administration includes administration of unit dosages of
the compounds of the invention before or after administration of
unit dosages of one or more other active agents, for example,
administration of the compounds of the invention within seconds,
minutes, or hours of the administration of one or more other active
agents. For example, a unit dose of a compound of the invention can
be administered first, followed within seconds or minutes by
administration of a unit dose of one or more other active agents.
Alternatively, a unit dose of one or more other active agents can
be administered first, followed by administration of a unit dose of
a compound of the invention within seconds or minutes. In some
cases, it may be desirable to administer a unit dose of a compound
of the invention first, followed, after a period of hours (e.g.,
1-12 hours), by administration of a unit dose of one or more other
active agents. In other cases, it may be desirable to administer a
unit dose of one or more other active agents first, followed, after
a period of hours (e.g., 1-12 hours), by administration of a unit
dose of a compound of the invention.
[0324] The combination therapy may provide "synergy" and
"synergistic effect", i.e. the effect achieved when the active
ingredients used together is greater than the sum of the effects
that results from using the compounds separately. A synergistic
effect may be attained when the active ingredients are: (1)
co-formulated and administered or delivered simultaneously in a
combined formulation; (2) delivered by alternation or in parallel
as separate formulations; or (3) by some other regimen. When
delivered in alternation therapy, a synergistic effect may be
attained when the compounds are administered or delivered
sequentially, e.g., in separate tablets, pills or capsules, or by
different injections in separate syringes. In general, during
alternation therapy, an effective dosage of each active ingredient
is administered sequentially, i.e. serially, whereas in combination
therapy, effective dosages of two or more active ingredients are
administered together.
[0325] In still yet another embodiment, the present application
provides for methods of treating a viral infection in a patient,
comprising: administering to the patient a therapeutically
effective amount of a compound of Formula I, Ia, Ib, II, IIa, III,
or IV, or a pharmaceutically acceptable salt, solvate, and/or ester
thereof.
[0326] In still yet another embodiment, the present application
provides for methods of treating a viral infection in a patient,
comprising: administering to the patient a therapeutically
effective amount of a compound of Formula I, Ia, Ib, II, IIa, III,
or IV, or a pharmaceutically acceptable salt, solvate, and/or ester
thereof, and at least one additional active agent.
[0327] In still yet another embodiment, the present application
provides for methods of treating HCV in a patient, comprising:
administering to the patient a therapeutically effective amount of
a compound of Formula I, Ia, Ib, II, IIa, III, or IV, or a
pharmaceutically acceptable salt, solvate, and/or ester
thereof.
[0328] In still yet another embodiment, the present application
provides for methods of treating HCV in a patient, comprising:
administering to the patient a therapeutically effective amount of
a compound of Formula I, Ia, Ib, II, IIa, III, or IV, or a
pharmaceutically acceptable salt, solvate, and/or ester thereof,
and at least one additional active agent which inhibits HCV
polymerase.
[0329] In still yet another embodiment, the present application
provides for methods of treating HCV in a patient, comprising:
administering to the patient a therapeutically effective amount of
a compound of Formula I, Ia, Ib, II, IIa, III, or IV, or a
pharmaceutically acceptable salt, solvate, and/or ester thereof,
and at least one additional active agent selected from the group
consisting of interferons, ribavirin or its analogs, HCV NS3
protease inhibitors, alpha-glucosidase 1 inhibitors,
hepatoprotectants, nucleoside or nucleotide inhibitors of HCV NS5B
polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV
NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES
inhibitors, pharmacokinetic enhancers, and other drugs for treating
HCV, or mixtures thereof.
[0330] In still yet another embodiment, the present application
provides for the use of a compound of the present invention, or a
pharmaceutically acceptable salt, solvate, and/or ester thereof,
for the preparation of a medicament for treating a viral infection,
e.g., an HBV/HCV infection.
[0331] In yet another embodiment, the present application provides
a method for treating or preventing a viral infection comprising
co-administering, to a patient in need thereof, a therapeutically
effective amount of at least one compound of Formula I, Ia, Ib, II,
IIa, III, or IV, and at least one additional active agent selected
from the group consisting of:
[0332] (1) interferons selected from the group consisting of
pegylated rIFN-alpha 2b (PEG-Intron), pegylated rIFN-alpha 2a
(Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A),
interferon alpha (MOR-22, OPC-18, Alfaferone, Alfanative,
Multiferon, subalin), interferon alfacon-1 (Infergen), interferon
alpha-n1 (Wellferon), interferon alpha-n3 (Alferon),
interferon-beta (Avonex, DL-8234), interferon-omega (omega DUROS,
Biomed 510), albinterferon alpha-2b (Albuferon), IFN alpha-2b XL,
BLX-883 (Locteron), DA-3021, glycosylated interferon alpha-2b
(AVI-005), PEG-Infergen, PEGylated interferon lambda-1 (PEGylated
IL-29), belerofon, and mixtures thereof;
[0333] (2) ribavirin and its analogs selected from the group
consisting of ribavirin (Rebetol, Copegus), taribavirin
(Viramidine), and mixtures thereof;
[0334] (3) HCV NS3 protease inhibitors selected from the group
consisting of boceprevir (SCH-503034 SCH-7), telaprevir (VX-950),
TMC435350, BI-1335, BI-1230, MK-7009, VBY-376, VX-500, BMS-790052,
BMS-605339, PHX-1766, AS-101, YH-5258, YH5530, YH5531, ITMN-191,
and mixtures thereof;
[0335] (4) alpha-glucosidase 1 inhibitors selected from the group
consisting of celgosivir (MX-3253), Miglitol, UT-231B, and mixtures
thereof;
[0336] (5) hepatoprotectants selected from the group consisting of
IDN-6556, ME 3738, LB-84451, silibilin, MitoQ, and mixtures
thereof;
[0337] (6) nucleoside or nucleotide inhibitors of HCV NS5B
polymerase selected from the group consisting of R1626, R7128
(R4048), IDX184, IDX-102, BCX-4678, valopicitabine (NM-283),
MK-0608, and mixtures thereof;
[0338] (7) non-nucleoside inhibitors of HCV NS5B polymerase
selected from the group consisting of PF-868554, VCH-759, VCH-916,
JTK-652, MK-3281, VBY-708, VCH-222, A848837, ANA-598, GL60667,
GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (nesbuvir),
GSK625433, BILN-1941, XTL-2125, GS-9190, and mixtures thereof;
[0339] (8) HCV NS5A inhibitors selected from the group consisting
of AZD-2836 (A-831), A-689, and mixtures thereof;
[0340] (9) TLR-7 agonists selected from the group consisting of
ANA-975, SM-360320, and mixtures thereof;
[0341] (10) cyclophillin inhibitors selected from the group
consisting of DEBIO-025, SCY-635, NIM811, and mixtures thereof;
[0342] (11) HCV IRES inhibitors selected from the group consisting
of MCI-067,
[0343] (12) pharmacokinetic enhancers selected from the group
consisting of BAS-100, SPI-452, PF-4194477, TMC-41629,
roxythromycin, and mixtures thereof; and
[0344] (13) other drugs for treating HCV selected from the group
consisting of thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea,
NTZ), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon
(CPG-10101), KRN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-111,
ITX2865, TT-033i, ANA 971, NOV-205, tarvacin, EHC-18, VGX-410C,
EMZ-702, AVI 4065, BMS-650032, BMS-791325, Bavituximab, MDX-1106
(ONO-4538), Oglufanide, VX-497 (merimepodib), and mixtures
thereof.
[0345] In yet another embodiment, the present application provides
a method for modulating toll-like receptor 7, comprising contacting
a cell having a toll-like receptor 7 with an effective amount of a
compound of Formula I, Ia, Ib, II, IIa, III, or IV or a
pharmaceutically acceptable salt, solvate, and/or ester thereof.
The term "modulating" refers to contacting the toll-like receptor 7
with a compound of Formula I, Ia, Ib, II, III, or IV which is e.g.,
an agonist or partial agonist of toll-like receptor 7.
[0346] In yet another embodiment, the present application provides
a method for inducing interferon (or IFN-a) production in a patient
in need thereof, comprising administering to the patient, a
therapeutically effective amount of at least one compound of
Formula I, Ia, Ib, II, IIa, III, or IV, or a pharmaceutically
acceptable salt, solvate, and/or ester thereof.
EXAMPLES
Synthesis of Example A
##STR00071##
[0347] Compound 2
[0348] 2-(2-Methoxy-ethoxy)-9H-purin-6-ylamine (1 g, 4.78 mmol)
(1), .alpha.,.alpha.'-dibromo-m-xylene (2.52 g, 9.56 mmol) and
anhydrous potassium carbonate (1.32 g, 9.56 mmol) were combined in
DMF (10 mL) and stirred at ambient temperature for 5 hours. The
reaction mixture was diluted with ethyl acetate (120 mL), washed
with water (2.times.), brine, dried with Na.sub.2SO.sub.4, and
evaporated under vacuum. The crude product was purified by
chromatography on silica gel with 0-10% methanol in ethyl acetate
as eluent. Evaporation of the appropriate fractions gave
9-(3-Bromomethyl-benzyl)-2-(2-methoxy-ethoxy)-9H-purin-6-ylamine
(2) (1.1 g, 2.80 mmol, 59%). MS: 392/394 (MH.sup.+).
Compound 3
[0349]
9-(3-Bromomethyl-benzyl)-2-(2-methoxy-ethoxy)-9H-purin-6-ylamine
(2) (1 g, 2.54 mmol) was dissolved in acetonitrile (10 mL).
N-bromosuccinimide (1.5 g, 8.4 mmol) was added in portions over 5
min. The mixture was stirred at ambient temperature for 1 hour,
then diluted with ethyl acetate (100 mL), washed with 10% aqueous
Na.sub.2S.sub.2O.sub.3 solution, and brine, dried with
Na.sub.2SO.sub.4, and evaporated under vacuum. The crude
8-Bromo-9-(3-bromomethyl-benzyl)-2-(2-methoxy-ethoxy)-9H-purin-6-ylamine
(3) (.about.1 g) was used in the next step without further
purification.
Example A
[0350] Crude
8-Bromo-9-(3-bromomethyl-benzyl)-2-(2-methoxy-ethoxy)-9H-purin-6-ylamine
(3) (.about.1 g) was dissolved in dichloromethane (10 mL) and
pyrrolidine (1 mL) was added. The reaction mixture was stirred at
ambient temperature overnight and then evaporated under vacuum. The
residue (4) was dissolved in methanol (20 mL) and 50% aqueous KOH
(2 mL) was added. The mixture was heated under reflux until HPLC
analysis indicated complete disappearance of starting material
(.about.3 hours). Then the mixture was cooled to ambient
temperature and concentrated aq. HCl was added (5 mL). Heating
under reflux was continued for 1 hour after which the reaction
mixture was evaporated to dryness under vacuum. The solid residue
was extracted 3.times. with methanol to separate from salts. The
methanol solution was evaporated under vacuum and the crude product
was purified by reverse phase preparative HPLC (5-45%
acetonitrile/40 mM aqueous HCl) giving
6-Amino-2-(2-methoxy-ethoxy)-9-(3-pyrrolidin-1-ylmethyl-benzyl)-9H-purin--
8-ol (Example A) (450 mg, 1.13 mmol) as yellowish solid as the HCl
salt.
[0351] .sup.1H-NMR (DMSO) .delta.: 10.09 (s, 1H), 9.78 (br, 1H),
7.47-7.33 (m, 4H), 6.54 (br, 2H), 4.87 (s, 2H), 4.32 (d, J=5.1,
2H), 4.23 (t, J=4.5 Hz, 2H), 3.56 (t, J=4.5 Hz, 2H), 3.25 (s, 3H),
3.38-3.00 (m, 4H), 2.05-1.75 (m, 4H). MS: 399 (MH.sup.+).
[0352] Examples B, C, D, E, F, G, H, I, J, K, L, M, and N were
prepared using procedures similar to those used to prepare Example
A except that pyrrolidine was replaced with the appropriate amine
for each of these examples.
Example B
##STR00072##
[0353]
6-Amino-2-(2-methoxy-ethoxy)-9-(3-morpholin-4-ylmethyl-benzyl)-9H-p-
urin-8-ol
[0354] .sup.1H-NMR (DMSO) .delta.: 10.08 (s, 1H), 9.85 (br, 1H),
7.55-7.35 (m, 4H), 6.53 (br, 2H), 4.89 (s, 2H), 4.32 (s, 2H), 4.23
(t, J=4.5 Hz, 2H), 3.98-3.89 (m, 2H), 3.66-3.52 (m, 4H), 3.25 (s,
3H), 3.25-3.02 (m, 4H). MS: 415 (MH.sup.+).
Example C
##STR00073##
[0355]
6-Amino-2-(2-methoxy-ethoxy)-9-[3-(4-methyl-piperazin-1-ylmethyl)-b-
enzyl]-9H-purin-8-ol
[0356] .sup.1H-NMR (DMSO) .delta.: 11.6 (br, 2H), 10.75 (s, 1H),
7.59-7.33 (m, 4H), 4.89 (s, 2H), 4.37-4.28 (m, 4H), 3.60-3.27 (m,
10H), 3.26 (s, 3H), 2.80 (s, 3H). MS: 428 (MH.sup.+).
Example D
##STR00074##
[0357]
6-Amino-9-{3-[(cyclopropylmethyl-amino)-methyl]-benzyl}-2-(2-methox-
y-ethoxy)-9H-purin-8-ol
[0358] .sup.1H-NMR (DMSO) .delta.: 10.89 (s, 1H), 9.18 (br, 2H),
7.50-7.32 (m, 4H), 5.58 (br, 2H), 4.89 (s, 2H), 4.32 (t, J=4 Hz,
2H), 4.09 (t, J=4.5 Hz, 2H), 3.59 (t, J=4.5 Hz, 2H), 3.26 (s, 3H),
2.80-2.74 (m, 2H), 1.10-1.03 (m, 1H), 0.57-0.52 (m, 2H), 0.34-0.30
(m, 2H). MS: 399 (MH.sup.+).
Example E
##STR00075##
[0359]
6-Amino-9-(3-imidazol-1-ylmethyl-benzyl)-2-(2-methoxy-ethoxy)-9H-pu-
rin-8-ol
[0360] .sup.1H-NMR (DMSO) .delta.: 10.85 (s, 1H), 9.28 (s, 1H),
7.76 (s, 1H), 7.68 (s, 1H), 7.40-7.26 (m, 4H), 5.42 (s, 2H), 5.40
(br, 2H), 4.87 (s, 2H), 4.29 (t, J=4.5 Hz, 2H), 3.59 (t, J=4.5 Hz,
2H), 3.26 (s, 3H). MS: 396 (MH.sup.+).
##STR00076##
Example F
6-Amino-9-[3-(3,5-dimethyl-piperidin-1-ylmethyl)-benzyl]-2-(2-methoxy-etho-
xy)-9H-purin-8-ol (mixture of cis and trans); MS: 441
(MH.sup.+).
##STR00077##
[0361] Example G
6-Amino-9-[3-(2,6-dimethyl-morpholin-4-ylmethyl)-benzyl]-2-(2-methoxy-etho-
xy)-9H-purin-8-ol
[0362] .sup.1H-NMR (DMSO) .delta.: 11.31 (br, 1H), 10.90 (s, 1H),
7.60-7.36 (m, 4H), 5.10 (br, 2H), 4.91 (s, 2H), 4.33 (t, J=4.5 Hz,
2H), 4.26 (m, 2H), 3.98-3.89 (m, 2H), 3.59 (t, J=4.5 Hz, 2H), 3.26
(s, 3H), 3.18 (d, J=11.7 Hz, 2H), 2.65-2.50 (m, 2H), 1.07 (d, J=6.3
Hz, 6H). MS: 443 (MH.sup.+).
Example H
##STR00078##
[0363]
6-Amino-9-[3-(2,3-dihydro-indol-1-ylmethyl)-benzyl]-2-(2-methoxy-et-
hoxy)-9H-purin-8-ol
[0364] .sup.1H-NMR (DMSO) .delta.: 9.94 (s, 1H), 7.32-7.15 (m, 4H),
7.01 (d, J=6.9 Hz, 1H), 6.93 (t, J=7.2 Hz, 1H), 6.59-6.49 (m, 2H),
6.46 (s, 2H), 4.84 (s, 2H), 4.23 (t, J=4.5 Hz, 2H), 4.21 (s, 2H),
3.55 (t, J=4.5 Hz, 2H), 3.25 (s, 3H), 3.19 (t, J=8.4 Hz, 2H), 2.85
(t, J=8.4 Hz, 2H). MS: 447 (MH.sup.+).
Example I
##STR00079##
[0365]
6-Amino-9-[3-(1,3-dihydro-isoindol-2-ylmethyl)-benzyl]-2-(2-methoxy-
-ethoxy)-9H-purin-8-ol
[0366] .sup.1H-NMR (DMSO) .delta.: 11.31 (br, 1H), 10.42 (s, 1H),
7.63-7.34 (m, 8H), 6.77 (br, 2H), 4.91 (s, 2H), 4.60-4.52 (m, 6H),
4.26 (t, J=4.5 Hz, 2H), 3.56 (t, J=4.5 Hz, 2H), 3.24 (s, 3H). MS:
447 (MH.sup.+).
Example J
##STR00080##
[0367]
6-Amino-2-(2-methoxy-ethoxy)-9-(3-piperidin-1-ylmethyl-benzyl)-9H-p-
urin-8-ol
[0368] .sup.1H-NMR (DMSO) .delta.: 10.67 (s, 1H), 10.08 (br, 1H),
7.51-7.34 (m, 4H), 4.90 (s, 2H), 4.51 (br, 2H), 4.30-4.20 (m, 4H),
3.57 (t, J=4.5 Hz, 2H), 3.25 (s, 3H), 3.30-3.20 (m, 2H), 2.87-2.74
(m, 2H), 1.80-1.25 (m, 6H). MS: 413 (MH.sup.+).
Example K
##STR00081##
[0369] Example K
6-Amino-9-[3-(4-fluoro-piperidin-1-ylmethyl)-benzyl]-2-(2-methoxy-ethoxy)--
9H-purin-8-ol
[0370] .sup.1H-NMR (DMSO) .delta.: 10.90 (s, 1H), 10.85 (br, 1H),
7.58-7.34 (m, 4H), 4.91 (s, 2H), 4.30-4.20 (m, 4H), 3.59 (t, J=4.5
Hz, 2H), 3.26 (s, 3H), 3.30-2.90 (m, 5H), 2.25-1.95 (m, 4H). MS:
431 (MH.sup.+).
Example L
##STR00082##
[0371]
6-Amino-9-[3-(3,3-difluoro-piperidin-1-ylmethyl)-benzyl]-2-(2-metho-
xy-ethoxy)-9H-purin-8-ol
[0372] .sup.1H-NMR (DMSO) .delta.: 11.05 (br, 1H), 11.00 (s, 1H),
7.53-7.38 (m, 4H), 4.92 (s, 2H), 4.38-4.29 (m, 4H), 3.59 (t, J=4.5
Hz, 2H), 3.55-3.45 (m, 2H), 3.26 (s, 3H), 3.05-2.90 (m, 2H),
2.20-1.85 (m, 4H). MS: 449 (MH.sup.+).
Example M
##STR00083##
[0373]
9-(3-((pyridin-2-ylamino)methyl)benzyl)-6-amino-2-(2-methoxyethoxy)-
-9H-purin-8-ol
[0374] .sup.1H-NMR (DMSO) .delta.: 10.47 (s, 1H), 8.53 (br, 2H),
8.09 (d, J=6.3 Hz, 1H), 7.90 (t, J=7.5 Hz, 1H), 7.37 (t, J=8 Hz,
1H) 7.28 (d, J=7.5 Hz, 1H) 7.12-7.03 (m, 3H), 6.91 (t, J=7.5 Hz,
1H), 5.42 (s, 2H), 4.84 (s, 2H), 4.25 (t, J=4.5 Hz, 2H), 3.59 (t,
J=4.5 Hz, 2H), 3.27 (s, 3H). MS: 422 (MH.sup.+).
Example N
##STR00084##
[0375]
9-(3-(azetidin-1-ylmethyl)benzyl)-6-amino-2-(2-methoxyethoxy)-9H-pu-
rin-8-ol
[0376] .sup.1H NMR (DMSO) .delta.: 2.17-2.41 (m, 2H), 3.25 (s, 3H),
3.59 (t, 3H, J=4.5 Hz), 3.82-4.02 (m, 4H), 4.28 (d, 2H, J=6 Hz),
4.39 (t, 2H, J=4.5 Hz), 4.90 (s, 2H), 7.35-7.44 (m, 4H), 11.32 (s,
1H). LCMS: m/z for C.sub.19H.sub.24N.sub.6O.sub.3.sup.++H observed
385.2 at 1.61 minutes of a 3.5 minute run, gradient 5-95%
CH.sub.3CN in H.sub.2O.
Synthesis of Example O
##STR00085##
[0377] Compound 5
[0378] Crude
8-Bromo-9-(3-bromomethyl-benzyl)-2-(2-methoxy-ethoxy)-9H-purin-6-ylamine
(.about.70 mg) was dissolved in DMF (2 mL). 2-Hydroxypyridine (100
mg) and anhydrous potassium carbonate (100 mg) was added and the
reaction mixture was stirred overnight. After dilution with ethyl
acetate (100 mL), the solution was washed with water and brine,
dried with Na.sub.2SO.sub.4 and evaporated under vacuum. The crude
product (5) was converted to
1-((3-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenyl-
)methyl)pyridin-2(1H)-one (Example O, 41 mg) using procedures
similar to those used to convert Compound 4 to Example A.
[0379] .sup.1H-NMR (DMSO) .delta.: 10.54 (s, 1H), 7.72 (d, J=7 Hz,
1H), 7.40 (t, J=7 Hz, 1H), 7.29 (t, J=7.2 Hz, 1H), 7.22-7.11 (m,
3H), 6.38 (d, J=9 Hz, 1H), 6.20 (t, J=6.6 Hz, 1H), 5.06 (s, 2H),
4.84 (s, 2H), 4.31 (t, J=4.5 Hz, 2H), 3.60 (t, J=4.5 Hz, 2H), 3.27
(s, 3H). MS: 423 (MH.sup.+).
Synthesis of Example P
##STR00086##
[0380] Example P
[0381]
6-Amino-2-(2-methoxy-ethoxy)-9-(3-pyrrolidin-1-ylmethyl-benzyl)-9H--
purin-8-ol (Example A) (31 mg, 0.078 mmol) was dissolved in DMF (2
mL). Anhydrous potassium carbonate (50 mg) was added followed by
p-methoxybenzyl chloride (13.7 .mu.L, 0.101 mmol). The mixture was
stirred at ambient temperature overnight. The reaction mixture was
diluted with dichloromethane, washed with water and brine, dried
with Na.sub.2SO.sub.4 and evaporated under vacuum. Purification by
preparative HPLC (5-60% acetonitrile/40 mM aqueous HCl) gave
6-amino-7-(4-methoxy-benzyl)-2-(2-methoxy-ethoxy)-9-(3-pyrrolidin-1-ylmet-
hyl-benzyl)-7,9-dihydro-purin-8-one (Example P) (6 mg) as the HCl
salt.
[0382] .sup.1H-NMR (CDCl.sub.3) .delta.: 12.54 (br, 1H), 7.85-6.88
(m, 10H), 5.24 (s, 2H), 5.14 (s, 2H), 4.66 (s, 2H), 4.20 (br, 2H),
3.81 (s, 3H), 3.72 (br, 2H), 3.58 (br, 2H), 3.36 (s, 3H), 2.85 (br,
2H), 2.25-2.00 (m, 4H). MS: 519 (MH.sup.+).
Synthesis of Example Q
##STR00087##
[0384]
6-Amino-2-(2-methoxy-ethoxy)-9-(3-pyrrolidin-1-ylmethyl-benzyl)-9H--
purin-8-01 (Example A) (60 mg, 0.15 mmol) was dissolved in
dichloromethane (2 mL). N,N-diisopropylethylamine (0.1 mL) was
added and the mixture was cooled to 0.degree. C. Ethylchloroformate
(0.04 mL, 0.42 mmol) was added. After stirring for 30 minutes, the
reaction was quenched with water and concentrated under vacuum.
Purification by preparative reverse phase HPLC (5-45%
acetonitrile/40 mM aqueous HCl) gave
9-(3-(pyrrolidin-1-ylmethyl)benzyl)-6-amino-2-(2-methoxyethoxy)-9H-purin--
8-yl ethyl carbonate (Example Q) (24 mg) as a white glassy solid,
HCl salt.
[0385] .sup.1H-NMR (DMSO) .delta.: 9.99 (br, 1H), 7.45-7.32 (m,
4H), 7.08 (br, 2H), 4.89 (s, 2H), 4.37 (q, J=6.9 Hz, 2H), 4.29 (t,
J=4.5 Hz, 2H), 4.20 (br, 2H), 3.58 (t, J=4.5 Hz, 2H), 3.26 (s, 3H),
3.15-2.85 (m, 4H), 1.92-1.78 (m, 4H), 1.31 (t, J=6.9 Hz, 3H). MS:
471 (MH.sup.+).
[0386] Examples R, S, T, U, and V were prepared using procedures
similar to those used to prepare Example Q except that ethyl
chloroformate was replaced with isopropyl chloroformate and the
appropriate starting material was utilized for each of these
examples.
Example R
##STR00088##
[0388]
9-(3-(pyrrolidin-1-ylmethyl)benzyl)-6-amino-2-(2-methoxyethoxy)-9H--
purin-8-yl isopropyl carbonate prepared from Example A.
[0389] .sup.1H-NMR (DMSO) .delta.: 10.65 (br, 1H), 7.55-7.37 (m,
4H), 7.10 (br, 2H), 5.11 (sept, J=6.3 Hz, 1H), 4.89 (s, 2H),
4.33-4.25 (m, 4H), 3.58 (t, J=4.5 Hz, 2H), 3.36-3.26 (m, 2H), 3.26
(s, 3H), 3.08-2.95 (m, 2H), 2.05-1.80 (m, 4H), 1.33 (d, J=6.3 Hz,
6H). MS: 485 (MH.sup.+).
Example S
##STR00089##
[0391]
9-(3-((4-fluoropiperidin-1-yl)methyl)benzyl)-6-amino-2-(2-methoxyet-
hoxy)-9H-purin-8-yl isopropyl carbonate prepared from Example
K.
[0392] .sup.1H-NMR (DMSO) .delta.: 10.95 (br, 1H), 7.59-7.38 (m,
4H), 7.10 (br, 2H), 5.10 (sept, J=6.3 Hz, 1H), 4.89 (s, 2H),
4.33-4.23 (m, 4H), 3.58 (t, J=4.5 Hz, 2H), 3.36-2.87 (m, 5H), 3.26
(s, 3H), 2.25-1.95 (m, 4H), 1.33 (d, J=6.3 Hz, 6H). MS: 517
(MH.sup.+).
Example T
##STR00090##
[0394]
9-(3-(piperidin-1-ylmethyl)benzyl)-6-amino-2-(2-methoxyethoxy)-9H-p-
urin-8-yl isopropyl carbonate prepared from Example J.
[0395] .sup.1H NMR (CD.sub.3OD) .delta.: 1.43 (d, 6H, J=6 Hz),
1.72-1.97 (m, 6H), 2.95 (t, 4H, J=9.3 Hz), 3.38 (s, 3H), 3.75 (t,
2H, J=4.5, 9 Hz), 4.28 (s, 2H), 4.62 (t, 2H, J=4.5, 9 Hz), 5.11 (s,
2H), 5.21-5.31 (m, 1H), 7.48 (d, 2H, J=4.2 Hz), 7.56 (d, 1H, J=3.6
Hz), 7.66 (s, 1H). LCMS: m/z for
C.sub.25H.sub.34N.sub.6O.sub.5.sup.++H observed 499.2 at 2.31
minutes of a 3.5 minute run, gradient 5-95% CH.sub.3CN in
H.sub.2O.
Example U
##STR00091##
[0397]
9-(3-((4-methylpiperazin-1-yl)methyl)benzyl)-6-amino-2-(2-methoxyet-
hoxy)-9H-purin-8-yl isopropyl carbonate prepared from Example
C.
[0398] .sup.1H NMR (CD.sub.3OD) .delta.: 1.43 (d, 6H, J=6 Hz), 3.0
(s, 4H), 3.39 (s, 3H), 3.64 (s, 2H), 3.77 (t, 2H, J=4.5 Hz), 4.49
(s, 2H), 4.63 (t, 2H, J=4.5 Hz), 5.11 (s, 2H), 5.23-5.31 (m, 1H),
7.46-7.62 (m, 3H), 7.72 (s, 1H). LCMS: m/z for
C.sub.25H.sub.35N.sub.7O.sub.5.sup.++H observed 514.2 at 2.09
minutes of a 3.5 minute run, gradient 5-95% CH.sub.3CN in
H.sub.2O.
Example V
##STR00092##
[0400]
9-(3-(pyrrolidin-1-ylmethyl)benzyl)-6-amino-2-butoxy-9H-purin-8-yl
isopropyl carbonate prepared from Example W.
[0401] .sup.1H NMR (DMSO) .delta.: 0.89 (t, 3H, J=7.2 Hz), 3.17 (d,
6H), 1.29-42 (m, 2H), 1.62 (q, 2H, J=7.5), 1.79-2.02 (m, 4H),
2.91-3.08 (m, 2H), 3.21-3.36 (m, 2H), 4.17 (t, 2H, J=6.6), 4.29 (d,
2H, J=6), 4.89 (s, 2H), 5.06-5.15 (m, 1H), 7.38-7.57 (m, 4H), 10.95
(s, 1H). LCMS: m/z for C.sub.25H.sub.34N.sub.6O.sub.4.sup.++H
observed 483.2 at 2.64 minutes of a 3.5 minute run, gradient 5-95%
CH.sub.3CN in H.sub.2O.
Synthesis of Example W
##STR00093##
[0402] Compound 6
[0403] 2-chloroadenine (1.53 g, 9.03 mmol) was divided among three
microwave vials (10-20 mL), each containing 1-butanol (10 mL) and
t-BuOK (5 mL, 1M in THF). Each vial was heated to 170.degree. C.
for 40 minutes. The three reaction mixtures were combined, the
solvent was removed by rotary evaporation and the product was
purified on flash column eluting 10% methanol in ethylacetate.
Evaporation of solvent gave 1.33 g (70%) of
2-butoxy-9H-purin-6-amine (6) as an off white solid. .sup.1H NMR
(DMSO) .delta.: 0.919 (t, 3H), 1.39 (m, 2H), 1.62 (m, 2H), 4.09 (t,
2H), 6.00 (s, 2H), 7.44 (s, 1H). LCMS: m/z for
C.sub.9H.sub.13N.sub.5O.sup.++H observed 208.1 at 1.34 minutes of a
3.5 minute run, gradient 5-95% CH.sub.3CN in H.sub.2O.
[0404] Example W was prepared from Compound 6 using procedures
similar to those used to prepare Example A.
[0405] .sup.1H NMR (DMSO) .delta.: 0.89 (t, 3H, J=7.2 Hz),
1.29-1.42 (m, 2H), 1.60 (q, 2H, J=7.2), 1.77-2.04 (m, 4H),
2.97-3.10 (m, 2H), 3.26-3.37 (m, 2H), 4.12 (t, 2H, J=7), 4.30 (d,
2H, J=6), 4.89 (s, 2H), 7.30-7.50 (m, 4H), 10.26 (s, 1H). LCMS: m/z
for C.sub.21H.sub.28N.sub.6O.sub.2.sup.++H observed 397.2 at 2.50
minutes of a 3.5 minute run, gradient 5-95% CH.sub.3CN in
H.sub.2O.
Synthesis of Example X
##STR00094##
[0406] Example X
[0407] Example D (40 mg, 0.100 mmol) was dissolved in
dichloromethane (2 mL) and cooled to 0.degree. C.
Diisopropylethylamine (0.1 mL) and then methanesulfonyl chloride
(0.012 mL, 0.154 mmol) was added sequentially. After stirring for 1
hour at 0.degree. C., the reaction mixture was quenched with water
(1 mL) and evaporated to dryness. Purification by reverse phase
preparative HPLC (5-60% acetonitrile/40 mM aqueous HCl) gave
Example X (23 mg).
[0408] .sup.1H-NMR (DMSO) .delta.: 9.96 (s, 1H), 7.34-7.18 (m, 4H),
6.45 (br, 2H), 4.85 (s, 2H), 4.37 (s, 2H), 4.24 (t, J=4.5 Hz, 2H),
3.57 (t, J=4.5 Hz, 2H), 3.26 (s, 3H), 2.94 (s, 3H), 2.91 (d, J=6.9
Hz, 2H), 0.88-0.78 (m, 1H), 0.35-0.29 (m, 2H), 0.04-0.00 (m, 2H).
MS: 477 (MH.sup.+).
Synthesis of Example Y
##STR00095##
[0409] Example Y
[0410] Example A (30 mg, 0.075 mmol) was dissolved in
dichloromethane (2 mL). Diisopropylethylamine (0.1 mL) and then
ethyl isocyanate (0.05 mL) was added. After stirring at ambient
temperature overnight, the reaction mixture was evaporated to
dryness under vacuum. Purification by reverse phase preparative
HPLC (5-60% acetonitrile/40 mM aqueous HCl) gave Example Y (23 mg)
as a white solid as the HCl salt.
[0411] .sup.1H-NMR (DMSO) .delta.: 10.96 (br, 1H), 8.87 (t, J=5.7
Hz, 1H), 7.57-7.36 (m, 4H), 4.95 (s, 2H), 4.32-4.25 (m, 4H), 3.58
(t, J=4.5 Hz, 2H), 3.25 (s, 3H), 3.36-3.25 (m, 4H), 3.05-2.92 (m,
2H), 2.02-1.80 (m, 4H), 1.13 (t, J=7.2 Hz, 3H). MS: 470
(MH.sup.+).
Synthesis of Example Z
##STR00096##
[0412] Example Z
[0413] Example D (40 mg, 0.10 mmol) was dissolved in
dichloromethane (2 mL). N,N-diisopropylethylamine (0.1 mL) was
added and the mixture was cooled to 0.degree. C. Ethylchloroformate
(0.021 mL, 0.22 mmol) was added. After stirring for 30 minutes, the
reaction was quenched with water and concentrated under vacuum.
Purification by preparative reverse phase HPLC (5-60%
acetonitrile/40 mM aqueous HCl) gave Example Z (17 mg) as a white
solid.
[0414] .sup.1H-NMR (DMSO) .delta.: 7.32-7.11 (m, 4H), 7.06 (br,
2H), 4.85 (s, 2H), 4.45 (s, 2H), 4.36 (q, J=7.5 Hz, 2H), 4.28 (t,
J=4.5 Hz, 2H), 4.02 (br, 2H), 3.58 (t, J=4.5 Hz, 2H), 3.26 (s, 3H),
3.06-2.97 (m, 2H), 1.30 (t, J=6.9 Hz, 3H), 1.22-1.02 (m, 3H),
0.93-0.81 (m, 1H), 0.38-0.29 (m, 2H), 0.12-0.05 (m, 2H). MS: 543
(MH.sup.+)
Synthesis of Example AA and Example AB
##STR00097##
[0415] Examples AA and AB
[0416] Example D (40 mg, 0.10 mmol) was dissolved in
dichloromethane (2 mL). N,N-diisopropylethylamine (0.1 mL) was
added and then ethyl isocyanate (0.05 mL). After stirring at
ambient temperature for 30 minutes, the reaction mixture was
evaporated to dryness under vacuum. Purification by reverse phase
preparative HPLC (5-60% acetonitrile/40 mM aqueous HCl) gave
Example AA (4 mg) and Example AB (6.5 mg) as white solids.
[0417] Example AA: .sup.1H-NMR (DMSO) .delta.: 9.93 (s, 1H),
7.30-7.09 (m, 4H), 6.44 (br, 2H), 6.30 (m, 1H), 4.82 (s, 2H), 4.46
(s, 2H), 4.24 (t, J=4.5 Hz, 2H), 3.57 (t, J=4.5 Hz, 2H), 3.26 (s,
3H), 3.10-2.94 (m, 4H), 0.96 (t, J=6.9 Hz, 3H), 0.93-0.81 (m, 1H),
0.34-0.25 (m, 2H), 0.08-0.01 (m, 2H). MS: 470 (MH.sup.+).
[0418] Example AB: .sup.1H-NMR (DMSO) .delta.: 8.88 (m, 1H),
7.30-7.05 (m, 4H), 6.29 (m, 1H), 4.90 (s, 2H), 4.46 (s, 2H), 4.29
(t, J=4.5 Hz, 2H), 3.59 (t, J=4.5 Hz, 2H), 3.30 (m, 2H), 3.26 (s,
3H), 3.08-2.94 (m, 4H), 1.13 (t, J=6.9 Hz, 3H), 0.95 (t, J=6.9 Hz,
3H), 0.90-0.80 (m, 1H), 0.34-0.25 (m, 2H), 0.08-0.01 (m, 2H). MS:
541 (MH.sup.+).
Synthesis of AC
##STR00098## ##STR00099##
[0419] Compound 7
[0420] 2-(2-Methoxyethoxy)-9H-purin-6-amine (1) (1.28 g, 6.12
mmol), b-bromo-m-tolunitrile (1.37 g, 7.0 mmol), and potassium
carbonate (0.97 g, 7.0 mmol) were combined in DMF (10 mL) and
stirred at ambient temperature for 4 hours. The mixture was diluted
with ethyl acetate (200 mL), washed with water and brine, dried
with Na.sub.2SO.sub.4 and evaporated under vacuum. The residue was
crystallized from ethyl acetate giving
3-((6-amino-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzonitrile
(7) (1.0 g) as a white solid.
Compound 9
[0421]
3-((6-amino-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzonitrile
(7) (1.0 g) was suspended in acetonitrile. N-Bromosuccinimide (1.0
g) was added in small portions over 10 minutes. After stirring for
1 hour, the mixture was diluted with ethyl acetate, washed with 10%
aqueous Na.sub.2S.sub.2O.sub.3 solution, saturated aqueous
NaHCO.sub.3 solution and brine, dried with Na.sub.2SO.sub.4 and
evaporated to dryness under vacuum. The crude
3-((6-amino-8-bromo-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzonitrile
(8) was dissolved in methanol (50 mL) and 50% aqueous KOH solution
(1 mL) was added. The mixture was heated under reflux for 3 hours
and then concentrated under vacuum. The product was extracted with
ethyl acetate, the combined organic layers were washed with water
and brine, dried with Na.sub.2SO.sub.4 and evaporated under vacuum.
Purification by flash chromatography on silica gel (eluent: 0-10%
MeOH in ethyl acetate) gave
3-((6-amino-8-methoxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzonitri-
le (9) (0.45 g) as a pinkish solid.
Compound 10
[0422]
3-((6-Amino-8-methoxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benz-
onitrile (9) (50 mg) was dissolved in acetonitrile (2 mL). A 6N
aqueous HCl solution (2 mL) was added and the mixture was stirred
at ambient temperature overnight. After evaporation to dryness, the
residue was dissolved in DMF (1 mL). Potassium carbonate (100 mg)
and ethyl iodide (0.02 mL) were added and the mixture was stirred
at ambient temperature for 5 hours. After dilution with water (20
mL) the product was extracted with dichloromethane. The combined
organic layers were washed with water and brine, dried with
Na.sub.2SO.sub.4 and evaporated under vacuum. Purification by flash
chromatography on silica gel (eluent: 0-10% MeOH in ethyl acetate)
gave
3-((6-amino-7-ethyl-2-(2-methoxyethoxy)-8-oxo-7,8-dihydropurin-9-yl)methy-
l)benzonitrile (10) (35 mg) as a colorless glass.
Example AC
[0423]
3-((6-Amino-7-ethyl-2-(2-methoxyethoxy)-8-oxo-7,8-dihydropurin-9-yl-
)methyl)benzonitrile (35 mg) was dissolved in dichloromethane (2
mL) and cooled to 0.degree. C. 1M DIBAL solution in toluene (0.5
mL) was added. After stirring for 1 hour, the reaction was quenched
with water and a saturated solution of Rochelle salt was added.
After vigorous stirring for 30 minutes, the mixture was extracted
with dichloromethane. The combined organic layers were washed with
water and brine, dried with Na.sub.2SO.sub.4 and evaporated under
vacuum. The crude product (11) was dissolved in methanol (1 mL) and
acetic acid (0.5 mL). Pyrrolidine (0.1 mL) was added followed by
sodium triacetoxy borohydride (100 mg). The mixture was stirred for
1 hour at ambient temperature and then evaporated to dryness. The
residue was dissolved in aqueous HCl/acetonitrile and purified by
preparative reverse phase HPLC (5-60% acetonitrile/40 mM aqueous
HCl) which gave Example AC (9 mg) as the HCl salt as a colorless
glass.
[0424] .sup.1H-NMR (DMSO) .delta.: 10.66 (br, 1H), 7.54-7.29 (m,
4H), 6.74 (br, 2H), 4.92 (s, 2H), 4.31-4.25 (m, 4H), 3.97 (m, 2H,
under the water peak), 3.58 (t, J=4.5 Hz, 2H), 3.26 (s, 3H),
3.35-3.25 (m, 2H), 3.07-2.95 (m, 2H), 2.05-1.80 (m, 4H), 1.12 (t,
J=6.9 Hz, 3H). MS: 427 (MH.sup.+).
Synthesis of Example AD
##STR00100##
[0425] Compound 12
[0426] To a suspension of 2-chloroadenine (1.7 g, 10.18 mmol) in
DMF (10 mL) was added K.sub.2CO.sub.3 (1.4 g, 10.18 mmol),
2-bromomethylbenzonitrile (2 g, 10.18 mmol). The reaction was
reacted at 80.degree. C. After the reaction was complete, the
reaction mixture was diluted with water, and then the precipitate
was collected. The solid was washed by water, then ether ester. The
product (12) was dried under high vacuum. MS: 285 (MH.sup.+).
Compound 13
[0427] To a flask with n-BuOH (10 ml), was added NaH (60%, 840 mg,
21 mmol) at room temperature. The reaction mixture was stirred at
ambient temperature for 5 min. Then compound 12 (2.4 g, 8.4 mmol)
was added. The mixture was allowed to react at 120.degree. C. for
about half an hour. Then the reaction mixture was cooled, washed
with saturated NH.sub.4Cl solution and extracted with DCM. The
organic layer was dried over Na.sub.2SO.sub.4 and filtered. The
filtrate was concentrated down, and the residue (13) was purified
by silica gel column, using DCM/MeOH as solvent. .sup.1H NMR
(d.sub.6-DMSO) .delta.: 0.90 (t, 3H), 1.33-1.41 (m, 2H), 1.58-1.67
(m, 2H), 4.19 (t, 2H), 5.32 (s, 2H), 7.22 (s, 2H), 7.52-7.84 (m,
4H), 8.06 (s, 1H); 323 (MH.sup.+).
[0428] Example AD was prepared from Compound 13 using procedures
similar to those used to prepare Example AC except that Compound 10
was replaced with Compound 13.
[0429] .sup.1H NMR (CD.sub.3OD) .delta.: 0.99 (t, 3H), 1.46-1.54
(m, 2H), 1.76-1.1.83 (m, 2H), 2.01-2.11 (m, 2H), 2.15-2.17 (m, 2H),
3.16-3.18 (m, 2H), 3.45-3.47 (m, 2H), 3.61 (s, 3H), 4.36 (s, 2H),
4.54 (t, 2H), 5.14 (s, 2H), 7.48-7.60 (m, 4H); MS: 411
(MH.sup.+).
[0430] Examples AE, AF, AG and AH were prepared using procedures
similar to those used to prepare Example AD except that the
appropriate iodide was used during the 7-N alkylation step to make
the corresponding compounds.
Example AE
##STR00101##
[0432] .sup.1H NMR (CD.sub.3OD) .delta.: 0.99 (t, 3H), 1.47-1.54
(m, 2H), 1.77-1.86 (m, 2H), 2.02-2.07 (m, 2H), 2.10-2.16 (m, 2H),
3.15-3.19 (m, 2H), 3.44-3.47 (m, 2H), 4.37 (s, 2H), 4.56 (t, 2H),
4.70 (s, 2H), 5.08-5.26 (m, 4H), 5.98-6.07 (m, 1H), 7.44-7.63 (m,
4H); MS: 437 (MH.sup.+).
Example AF
##STR00102##
[0434] .sup.1H NMR (CD.sub.3OD) .delta.: 0.41-0.42 (m, 2H),
0.53-0.56 (m, 2H), 0.99 (t, 3H), 1.53-1.57 (m, 1H), 1.47-1.55 (m,
2H), 1.78-1.84 (m, 2H), 2.01-2.04 (m, 2H), 2.14-2.17 (m, 2H),
3.15-3.19 (m, 2H), 3.44-3.47 (m, 2H), 3.97 (d, 2H), 4.38 (s, 2H),
4.55 (t, 2H), 5.16 (s, 2H), 7.50-7.61 (m, 4H); MS: 451
(MH.sup.+).
Example AG
##STR00103##
[0436] .sup.1H (CD.sub.3OD) .delta.: 0.90-1.01 (m, 6H), 1.46-1.54
(m, 2H), 1.69-1.84 (m, 4H), 2.00-2.04 (m, 2H), 2.15-2.17 (m, 2H),
3.16-3.19 (m, 2H), 3.44-3.47 (m, 2H), 4.04 (m, 2H), 4.37 (s, 2H),
4.56 (t, 2H), 5.16 (s, 2H), 7.46-7.61 (m, 2H); MS: 439
(MH.sup.+).
Example AH
##STR00104##
[0438] .sup.1H NMR (CD.sub.3OD) .delta.: 0.99 (t, 3H), 1.46-1.54
(m, 2H), 1.59 (d, 6H), 1.77-1.82 (m, 2H), 2.00-2.04 (m, 2H),
2.15-2.18 (m, 2H), 3.16-3.20 (m, 2H), 3.45-3.49 (m, 2H), 4.38 (s,
2H), 4.55 (t, 3H), 5.11 (s, 2H), 7.48-7.60 (m, 4H); MS: 439
(MH.sup.+).
Synthesis of Example AI
##STR00105## ##STR00106##
[0440] Compound 14 was prepared using the procedures similar to
those used to prepare Compound 13 except that cyclobutanol was used
instead of n-BuOH. .sup.1H NMR (CDCl.sub.3) .delta.: 1.61-1.95 (m,
2H), 2.14-2.44 (m, 4H), 5.13-5.18 (m, 1H), 5.30 (s, 2H), 5.94 (s,
2H), 7.44-7.64 (m, 5H); MS: 321 (MH.sup.+).
[0441] Example AI was prepared using the procedures shown in Scheme
12, and similar to those used to prepare Example AC. The spectral
data of the intermediates and Example AC are shown below.
[0442] Compound 15
[0443] .sup.1H NMR (CDCl.sub.3) .delta.: 1.62-1.88 (m, 2H),
2.11-2.45 (m, 4H), 5.14-5.16 (m, 1H), 5.30 (s, 2H), 6.23 (s, 2H),
7.44-7.65 (m, 4H); MS: 399 (MH.sup.+).
Compounds 16
[0444] .sup.1H NMR (CDCl.sub.3) .delta.: 1.52-1.77 (m, 2H),
1.96-2.17 (m, 2H), 2.29-2.38 (m, 2H), 4.02 (s, 3H), 5.01-5.08 (m,
3H), 5.91 (s, 2H), 7.32-7.56 (m, 4H); MS: 351 (MH.sup.+).
Compound 17
[0445] .sup.1H NMR (CDCl.sub.3) .delta.: 1.68-1.88 (m, 2H),
3.20-3.37 (m, 4H), 5.00-5.02 (m, 2H), 5.19-5.20 (m, 1H), 7.45-7.68
(m, 4H); MS: 337 (MH.sup.+).
Example AI
[0446] .sup.1H NMR (CD.sub.3OD) .delta.: 1.73-2.28 (m, 8H),
2.44-2.48 (m, 2H), 3.15-3.20 (m, 2H), 4.44-4.48 (m, 2H), 4.37 (s,
2H), 5.10 (s, 2H), 5.25-5.34 (m, 1H), 7.49-7.59 (m, 4H); MS: 395
(MH.sup.+).
Synthesis of Example AJ
##STR00107## ##STR00108##
[0448] Example AJ was prepared using the procedures shown in scheme
13, and similar to those used to prepare Example AC. The spectral
data of the intermediates and Example AJ are listed below.
Compound 18
[0449] .sup.1H NMR (DMSO) .delta.: 1.47-1.56 (m, 2H), 1.64-1.74 (m,
2H), 3.33-3.43 (m, 2H), 4.16 (t, 2H), 7.05 (s, 2H), 7.87 (s, 1H),
12.55 (bs, 1H); MS: 224 (MH.sup.+).
Compound 19
[0450] .sup.1H NMR (CDCl.sub.3) .delta.: 1.65-1.74 (m, 2H),
1.81-1.87 (m, 2H), 3.69 (t, 2H), 5.27 (s, 2H), 6.52 (s, 2H),
7.39-7.68 (m, 5H); MS: 339 (MH.sup.+).
Compound 20
[0451] .sup.1H NMR (CDCl.sub.3) .delta.: 1.70-1.76 (m, 2H),
1.82-1.87 (m, 2H), 3.69 (t, 2H), 4.32 (t, 2H), 5.28 (s, 2H), 6.57
(s, 2H), 7.39-7.63 (m, 4H); MS: 419 (MH.sup.+).
Compound 21
[0452] .sup.1H NMR (CDCl.sub.3) .delta.: 1.70-1.74 (m, 2H),
1.81-1.87 (m, 2H), 3.69 (t, 2H), 4.07 (s, 3H), 4.29 (t, 2H), 5.08
(s, 2H), 5.81 (s, 2H), 7.37-7.61 (m, 4H); MS: 369 (MH.sup.+).
Compound 22
[0453] .sup.1H NMR (CD.sub.3OD) .delta.: 1.69-1.70 (m, 2H),
1.87-1.91 (m, 2H), 3.63 (t, 2H), 4.56 (t, 2H), 5.11 (s, 2H),
7.56-7.82 (4H); MS: 355 (MH.sup.+).
Example AJ
[0454] .sup.1H NMR (CD.sub.3OD) .delta.: 1.66-1.72 (m, 2H),
1.87-1.93 (m, 2H), 2.01-2.04 (m, 2H), 2.15-2.18 (m, 2H), 3.15-3.19
(m, 2H), 3.45-3.49 (m, 2H), 3.62 (t, 2H), 4.38 (t, 2H), 4.58 (t,
2H), 5.12 (s, 2H), 7.47-7.61 (m, 4H); MS: 413 (MH.sup.+).
Synthesis of Example AK and Example AL
##STR00109##
[0456] Example AK and Example AL were prepared using the procedures
shown in Scheme 14, and similar to those used to prepare Example
AC. The bromide (23) used in the first step was made by treating
the corresponding benzenemethyl compound with NBS in acetonitrile
at room temperature or at 40.degree. C. The spectral data of
intermediates and Example AK and Example AL are listed below.
Compound 23
[0457] .sup.1H NMR (CDCl.sub.3) .delta.: 3.43 (s, 3H), 3.75 (t,
2H), 4.47 (s, 2H), 5.28 (s, 2H), 5.85 (s, 2H), 7.47-7.65 (m, 4H);
MS: 359 (MH.sup.+).
Compound 24
[0458] .sup.1H NMR (CD.sub.3OD) .delta.: 3.40 (s, 3H), 3.73 (s,
2H), 4.47 (s, 2H), 5.38 (s, 2H), 7.58-7.62 (m, 2H), 7.84 (s, 1H);
MS: 437 (MH.sup.+).
Compound 25
[0459] .sup.1H NMR (CDCl.sub.3) .delta.: 3.41 (s, 3H), 3.74 (t,
2H), 4.09 (s, 3H), 4.44 (t, 2H), 5.06 (s, 2H), 5.48 (s, 2H),
7.42-7.61 (m, 3H); MS: 389 (MH.sup.+).
Compound 26
[0460] .sup.1H NMR (CDCl.sub.3) .delta.: 3.41 (s, 3H), 3.72-3.76
(m, 2H), 3.89 (s, 3H), 4.09 (s, 3H), 3.42-3.47 (m, 2H), 5.00 (s,
2H), 5.48 (s, 2H), 7.45-7.62 (m, 3H); MS: 385 (MH.sup.+).
Example AK
[0461] .sup.1H NMR (CD.sub.3OD) .delta.: 2.02-2.06 (m, 2H),
2.20-2.23 (m, 2H), 3.10-3.16 (m, 2H), 3.40 (s, 3H), 3.54-3.58 (m,
2H), 3.76 (t, 2H), 4.63 (t, 2H), 5.10 (s, 2H), 7.52-7.59 (m, 2H),
7.74 (s, 1H); MS: 433 (MH.sup.+).
Example AL
[0462] .sup.1H NMR (CD.sub.3OD) .delta.: 2.01-2.03 (m, 2H),
2.15-2.19 (m, 2H), 3.18-3.23 (m, 2H), 3.41 (s, 3H), 4.44-3.49 (m,
2H), 3.77 (t, 2H), 3.93 (s, 3H), 4.36 (s, 2H), 4.66 (t, 2H), 5.03
(s, 2H), 7.11 (d, 1H), 7.52-7.58 (m, 2H); MS: 429 (MH.sup.+).
Synthesis of Example AM
##STR00110##
[0464] Example AM was prepared using the procedures shown in Scheme
15, and similar to the procedures used to prepare Example AC. The
spectral data of the intermediates and Example AM are listed
below.
Compound 27
[0465] .sup.1H NMR (CD.sub.3OD) .delta.: 3.39 (s, 3H), 3.73 (t,
2H), 4.45 (t, 2H), 5.44 (s, 2H), 7.36 (t, 1H), 7.78-7.87 (m, 2H),
8.01 (s, 1H); MS: 343 (MH.sup.+).
Compound 28
[0466] .sup.1H NMR (CD.sub.3OD) .delta.: 3.39 (s, 3H), 3.72 (t,
2H), 4.44 (t, 2H), 5.44 (s, 2H), 7.37 (t, 1H), 7.67-7.79 (m, 2H);
MS: 421 (MH.sup.+).
Compound 29
[0467] .sup.1H NMR (CDCl.sub.3) .delta.: 3.40 (s, 3H), 3.73 (t,
2H), 3.92 (s, 3H), 4.11 (s, 3H), 4.46 (t, 2H), 5.12 (s, 2H), 6.94
(d, 1H), 7.14 (s, 1H), 7.60 (dd, 1H); MS: 385 (MH.sup.+).
Example AM
[0468] .sup.1H NMR (CD.sub.3OD) .delta.: 1.97-1.99 (m, 2H),
2.13-2.16 (m, 2H), 3.12-3.17 (m, 2H), 3.37 (s, 3H), 3.38-3.44 (m,
2H), 3.72 (t, 2H), 3.89 (s, 3H), 4.27 (s, 2H), 4.56 (t, 2H), 5.08
(s, 2H), 7.09 (d, 1H), 7.33 (s, 1H), 7.45 (dd, 1H); MS: 429
(MH.sup.+).
Synthesis of Example AN
[0469] Example AN was prepared using the procedures shown in Scheme
16, and similar to those used to prepare Example AC. The spectral
data of intermediates and Example AN are listed below.
##STR00111##
Compound 30
[0470] .sup.1H NMR (CD.sub.3OD) .delta.: 3.40 (s, 3H), 3.73 (t,
2H), 4.47 (t, 2H), 5.36 (s, 2H), 7.35 (t, 1H), 7.72-7.86 (m, 2H),
8.03 (s, 1H); MS: 343 (MH.sup.+).
Compound 31
[0471] .sup.1H NMR (CDCl.sub.3) .delta.: 3.44 (s, 3H), 3.77 (t,
2H), 4.53 (s, 2H), 5.30 (s, 2H), 6.11 (bs, 2H), 7.21-7.27 (m, 2H),
7.64-7.68 (m, 2H); MS: 421 (MH.sup.+).
Compound 32
[0472] .sup.1H NMR (CD.sub.3OD) .delta.: 2.00-2.12 (m, 2H),
2.13-2.17 (m, 2H), 3.19-3.22 (m, 2H), 3.40 (s, 3H), 3.42-3.54 (m,
2H), 3.74 (t, 2H), 4.45 (s, 2H), 4.54 (t, 2H), 5.39 (s, 2H), 7.29
(t, 1H), 7.52-7.56 (m, 2H); MS: 479 (MH.sup.+).
Example AN
[0473] .sup.1H NMR (CD.sub.3OD) .delta.: 2.01-2.06 (m, 2H),
2.18-2.20 (m, 2H), 3.18-3.24 (m, 2H), 3.40 (s, 3H), 3.51-3.55 (m,
2H), 3.76-3.79 (m, 2H), 4.46 (s, 2H), 4.66-4.69 (m, 2H), 5.10 (s,
2H), 7.27 (t, 1H), 7.61-7.63 (m, 1H), 7.68-7.72 (m, 1H); MS: 417
(MH.sup.+).
[0474] Example AO was prepared using procedures similar to those
used to prepare Example AM (Scheme 15), except that in the first
step, 1-bromo-(3-cyanophenyl)ethane was used to alkylate Compound
1. The product obtained from the first step was then taken through
the remaining steps described in Scheme 15 to give Example AO.
1-Bromo-(3-cyanophenyl)ethane was synthesized using a two-step
procedure by first reducing 3-acetylbenzonitrile to
1-(3-cyanophenyl)-ethanol, followed by conversion to
1-bromo-(3-cyanophenyl)ethane. Examples AP, AQ, AR, and AS were
prepared using procedures similar to those used to prepare Example
AN (Scheme 16) by using an appropriate bromide in the first
alkylation step. For compound AP, Na(CN).sub.3BH was used instead
of Na(OAc).sub.3BH during the reductive amination. The structure
and spectral data of these compounds are listed below.
Example AO
##STR00112##
[0476] .sup.1H NMR (CD.sub.3OD) .delta.: 2.00-2.20 (m, 7H),
3.12-3.20 (m, 2H), 3.38 (S, 3H), 3.44-3.50 (m, 2H), 3.74 (t, 2H),
4.39 (s, 2H), 4.56-4.64 (m, 2H), 5.78 (q, 1H), 7.48-7.69 (m, 4H);
MS: 413 (MH.sup.+).
Example AP
##STR00113##
[0478] .sup.1H NMR (CD.sub.3OD) .delta.: 1.72 (d, 3H), 1.92-2.18
(m, 4H), 2.92-3.04 (m, 2H), 3.19-3.29 (m, 2H), 3.39 (s, 3H),
3.75-3.84 (m, 3H), 4.40 (q, 1H), 4.64-4.67 (m, 2H), 5.10-5.13 (m,
2H), 7.47-7.64 (m, 4H); MS: 413 (MH.sup.+).
Example AQ
##STR00114##
[0480] .sup.1H NMR (CD.sub.3OD) .delta.: 2.00-2.05 (m, 2H),
2.08-2.19 (m, 2H), 3.16-3.21 (m, 2H), 3.38 (s, 3H), 3.47-3.52 (m,
2H), 3.74-3.77 (m, 2H), 4.49 (s, 2H), 4.65 (t, 2H), 5.20 (s, 2H),
7.90-7.92 (m, 3H); MS: 467 (MH.sup.+).
Example AR
##STR00115##
[0482] .sup.1H NMR (CD.sub.3OD) .delta.: 3.20-3.35 (m, 4H), 3.39
(s, 3H), 3.75-3.78 (m, 4H), 3.86-3.87 (m, 2H), 4.00-4.04 (m, 2H),
4.46 (s, 2H), 4.65-4.68 (m, 2H), 5.20 (s, 2H), 7.90-7.97 (m, 3H);
MS: 483 (MH.sup.+).
Example AS
##STR00116##
[0484] .sup.1H NMR (CD.sub.3OD) .delta.: 1.54-1.58 (m, 1H),
1.80-1.90 (m, 5H), 2.99 (t, 2H), 3.39 (s, 3H), 3.42 (s, 2H), 3.76
(m, 2H), 4.39 (s, 2H), 4.66 (t, 2H), 5.20 (2H), 7.87-7.93 (m, 3H);
MS: 481 (MH.sup.+).
[0485] Examples AT, AU, AV, and AW were prepared using procedures
similar to those used to prepare Example W except that NMP was used
as the solvent and different alcohols were used instead of butanol.
For Example AT, the first step was conducted at 200.degree. C.
Example AT
##STR00117##
[0487] .sup.1H NMR (DMSO) 8:1.84-1.97 (m, 4H), 2.98-3.00 (m, 2H),
3.27-3.29 (m, 2H), 4.30 (dd, 2H), 4.80-4.90 (m, 4H), 7.33-7.54 (m,
4H), 10.70 (s, 1H); MS: 423 (MH.sup.+).
Example AU
##STR00118##
[0489] .sup.1H NMR (DMSO) .delta.: 0.05-0.07 (m, 2H), 0.38-0.40 (m,
2H), 0.73-0.76 (m, 1H), 1.51-1.58 (m, 2H), 1.82-1.98 (m, 4H),
2.97-3.02 (m, 2H), 3.26-3.30 (m, 2H), 4.22-4.30 (m, 4H), 10.65 (s,
1H); MS: 409 (MH.sup.+).
Example AV
##STR00119##
[0491] .sup.1H NMR (CD.sub.3OD) .delta.: 1.92-2.20 (m, 11H),
3.15-3.21 (m, 2H), 3.43-3.52 (m, 2H), 4.38 (s, 2H), 4.50 (d, 2H),
5.12 (s, 2H), 7.49-7.60 (m, 4H); MS: 409 (MH.sup.+).
Example AW
##STR00120##
[0493] .sup.1H NMR (DMSO) .delta.: 0.27-0.31 (m, 2H), 0.49-0.61 (m,
2H), 1.64-1.84 (m, 1H), 1.84-1.98 (m, 4H), 2.98-3.01 (m, 2H),
3.27-3.29 (m, 2H), 4.29-4.31 (m, 4H), 5.01 (s, 2H), 7.34-7.55 (m,
4H), 10.65 (s, 1H); MS: 395 (MH.sup.+).
Example AX
##STR00121##
[0495] Example AX was prepared using procedures similar to those
used to prepare Example AC, except Compound 1 was replaced with
Compound 6. .sup.1H NMR (DMSO) .delta.: 0.89 (t, J=7.5 Hz, 3H),
1.13 (t, J=7.2 Hz, 3H), 1.35 (sext, J=7.2 Hz, 2H), 1.63 (quint,
J=7.5 Hz, 2H), 1.80-2.02 (m, 4H), 2.91-3.04 (m, 2H), 3.20-3.31 (m,
2H), 4.00 (q, J=7.2 Hz, 2H), 4.21-4.30 (m, 4H), 4.94 (s, 2H), 7.00
(br, 2H), 7.30-7.58 (m, 4H), 11.23 (s, 1H); MS: 425 (MH.sup.+).
[0496] Examples AY, AZ and BA were prepared using the procedures
similar to those used to prepare Example A, except that pyrrolidine
was replaced with an appropriate amine. For example, pyrrolidine
was replaced with cyclohexylmethanamine in Example AZ.
Example AY
##STR00122##
[0498] .sup.1H MNR (DMSO) .delta.: 1.13 (s, 6H), 2.68-2.74 (m, 2H),
3.25 (s, 3H), 3.57 (t, J=4.5 Hz, 2H), 4.05-4.15 (m, 2H), 4.29 (t,
J=4.5 Hz, 2H), 4.89 (s, 2H), 7.10 (br, 2H), 7.49-7.32 (m, 4H), 8.84
(br, 2H), 10.71 (s, 1H); MS: 417 (MH.sup.+).
Example AZ
##STR00123##
[0500] .sup.1H NMR (DMSO) .delta.: 0.94-0.81 (m, 2H), 1.08-1.26 (m,
2H), 1.55-1.77 (m, 6H), 2.66-2.74 (m, 2H), 3.25 (s, 3H), 3.57 (t,
J=4.5 Hz, 2H), 4.05-4.15 (m, 2H), 4.26 (t, J=4.5 Hz, 2H), 4.88 (s,
2H), 6.84 (br, 2H), 7.32-7.48 (m, 4H), 8.87 (br, 2H), 10.53 (s,
1H); MS: 441 (MH.sup.+).
Example BA
##STR00124##
[0502] .sup.1H NMR (DMSO) .delta.: 1.12-1.57 (m, 10H), 2.68-2.76
(m, 2H), 3.25 (s, 3H), 3.59 (t, J=4.5 Hz, 2H), 4.06-4.14 (m, 2H),
4.32 (t, J=4.5 Hz, 2H), 4.89 (s, 2H), 7.30 (br, 2H), 7.32-7.51 (m,
4H), 8.88 (br, 2H), 10.96 (s, 1H); MS: 457 (MH.sup.+).
[0503] Examples BB and BC were prepared using procedures similar to
those used to prepare Example W, except that the appropriate amine
was used for the different compounds.
Example BB
##STR00125##
[0505] .sup.1H NMR (DMSO) .delta.: 0.88 (t, J=7.2 Hz, 3H), 1.36
(sext, J=7.2 Hz, 2H), 1.64 (quint, J=6.6 Hz, 2H), 2.96-3.19 (m,
4H), 3.72-3.92 (m, 4H), 4.22-4.34 (m, 4H), 4.92 (s, 2H), 7.30 (br,
2H), 7.36-7.58 (m, 4H), 11.6 (s, 1H), 11.35 (br, 1H); MS: 314
(MH.sup.+).
Example BC
##STR00126##
[0507] .sup.1H NMR (DMSO) .delta.: 0.88 (t, J=7.2 Hz, 3H), 1.35
(sext, J=7.2 Hz, 2H), 1.62 (quint, J=6.6 Hz, 2H), 4.18 (t, J=6.6
Hz, 2H), 4.87 (s, 2H), 5.42 (s, 2H), 7.20 (br, 2H), 7.25-7.40 (m,
4H), 7.68 (s, 1H), 7.76 (s, H), 8.29 (s, 1H), 10.90 (s, 1H); MS:
394 (MH.sup.+).
Synthesis of Example BD
##STR00127##
[0508] Compound 33
[0509] A sample of the 2-butoxy-8-methoxy-9H-purin-6-amine TFA salt
(7.58 g) was dissolved in CH.sub.3CN (400 mL) and treated with
Cs.sub.2CO.sub.3 (21.1 g) at 23.degree. C. for 5 min.
3-(bromomethyl)-benzaldehyde (4.27 g) was then added. Once the
reaction was gauged complete using LCMS and HPLC, it was filtered
through a plug of Na.sub.2SO.sub.4 over a glass frit. The filtrate
was concentrated to an orange solid. A minimum of warm glacial AcOH
(30 mL) was used to dissolve the solid with stirring in an oil bath
at 80.degree. C. H.sub.2O (54 mL) was added slowly with mild
stirring. Clouding was persistent, so the reaction was allowed to
cool to 23.degree. C. in the oil bath. An orange oil began to
coagulate out of the mother liquor. More glacial AcOH (5 mL) was
added, but the oil failed to resorb into the mother liquor. The
mixture was cooled in a refrigerator overnight, and the orange oil
solidified. The mother liquor was decanted away, and almost
immediately, white crystals began to grow. These crystals proved to
be 95% pure compound 33 (.about.1.5 g), which was captured via
filtration. The orange solidified oil could be purified on silica
gel (DCM:MeOH, 98:2, isocratic gradient), affording 90% pure 33
(yield not determined). .sup.1H NMR (CDCl.sub.3) .delta.: 0.97 (t,
3H), 1.46-1.55 (m, 2H), 1.73-1.81 (m, 2H), 4.11 (s, 3H), 4.31 (t,
2H), 5.18 (d, 4H), 7.47-7.60 (m, 2H), 7.79-7.86 (m, 2H), 9.99 (s,
1H); MS: 356 (MH.sup.+).
Example BD
[0510] To a solution of aldehyde 33 (90 mg) in DMF (1.5 mL) was
added 4-fluoropiperidine hydrochloride (106 mg). Glacial AcOH (90
.mu.L) and NaBH(OAc).sub.3 (270 mg) were introduced, and the
reaction was stirred at 23.degree. C. for 1.5 h. Once the reaction
was gauged complete using LCMS and HPLC analysis, 12 M aq HCl (300
.mu.L) was added. The next day, 1.0 M aq HCl (1.0 mL) was added to
aid conversion. Once the reaction had reached completion, the
entire reaction was directly purified on a C-18 reversed-phase HPLC
column (eluent: 0.5% w/v aq HCl+CH.sub.3CN; 5/90 to 100:0), giving
amine BD (85.5 mg, 81% yield) as a yellow gum after lyophilization.
.sup.1H NMR (DMSO) .delta.: 0.89 (t, 3H), 1.32-1.38 (m, 2H),
1.57-1.63 (m, 2H), 1.90-2.12 (m, 5H), 3.07-3.21 (m, 4H), 4.12 (t,
2H), 4.28-4.32 (m, 2H), 4.89 (s, 2H), 7.36-7.44 (m, 4H), 10.04 (bs,
1H), 10.28 (s, 1H); MS: 429 (MH.sup.+).
[0511] Examples BE and BF were prepared using procedures similar to
those used to prepare Example BD, except that the appropriate amine
was used for different examples and that the reductive amination
step to make example BF was conducted at 80.degree. C.
Example BE
##STR00128##
[0513] .sup.1H NMR (DMSO) .delta.: 0.88 (t, 3H), 1.33-1.40 (m, 2H),
1.59-1.68 (m, 2H), 2.26-2.38 (m, 2H), 3.87-3.99 (m, 4H), 4.28 (t,
2H), 4.91 (s, 2H), 7.30-7.42 (m, 4H), 11.01 (bs, 1H), 11.13 (s,
1H); MS: 383 (MH.sup.+).
Example BF
##STR00129##
[0515] .sup.1H NMR (DMSO) .delta.: 0.89 (t, 3H), 1.35-1.42 (m, 2H),
1.58-1.62 (m, 2H), 4.13 (t, 2H), 4.29 (d, 2H), 4.86 (s, 2H),
6.49-7.97 (m, 7H), 10.02 (s, 1H); MS: 420 (MH.sup.+).
Synthesis of Example BG
##STR00130##
[0516] Compound 34
[0517] Sodium Hydride (170 mg) was added to an excess of isobutanol
(10 mL) until completely dissolved. Nitrile 12 (1.26 g) was added
and the mixture stirred at 83.degree. C. overnight. The mixture was
poured onto icy water with 2 mL of glacial HOAc and stirred for 5
minutes. Extract with EtOAc (3.times.100 mL), dry with
Na.sub.2SO.sub.4 and concentrate. Chromatography on silica gel
using ISCO combiflash on a 40G column using solid loading and a
DCM/20% MeOH in DCM eluent performed with a 4-40% gradient over 10
column volumes gave isobutyl ether 34 (333 mg). (The product was a
mixture with corresponding ester from reduction of nitrile which
was carried forward and removed later in the reaction sequence).
MS: 323 (MH.sup.+).
[0518] Example BG was prepared from Compound 34 using procedures
similar to those used to prepare Example AI.
[0519] .sup.1H NMR (300 MHz, d.sup.6 DMSO) .delta.: 0.91-0.93 (d
J=6.6 Hz, 6H); 1.81-2.04 (m, 5H); 3.00 (m, 2H); 3.28 (m, 2H);
3.98-4.01 (d J=6.6 Hz, 2H); 4.28-4.31 (d J=6.3 Hz, 2H); 4.91 (s,
2H); 7.34-7.45 (m, 3H); 7.51-7.53 (d J=7.2 Hz, 1H) 10.75, (bs, 1H);
10.92 (s, 1H). MS: 397 (MH.sup.+).
[0520] Example BH was prepared using procedures similar to those
used to prepare Example BG, except that 3,3,3-trifluoropropan-1-ol
was used in the first step and that the mixture reacted in a sealed
tube at 94.degree. C. for 2.5 h.
##STR00131##
[0521] .sup.1H NMR (300 MHz, d.sup.6 DMSO) .delta.: 1.82-1.98 (bd,
8H); 2.68-2.76 (m, 2H); 3.02 (bm, 2H); 3.29 (bm, 2H); 4.29-4.37
(ddd, 4H); 4.90 (s, 2H), 7.36-7.50 (m, 4H); 10.40 (bs, 1H); 10.53
(s, 1H); MS: 437 (MH.sup.+).
Synthesis of Example BI
##STR00132##
[0523] To a solution of aldehyde 33 (230 mg) in MeOH (.about.10 mL)
was added homopiperidine (aka hexamethyleneimine) (270 .mu.L).
Glacial AcOH (100 .mu.L) and NaHB(OAc).sub.3 (307 mg) were
introduced, and the reaction was stirred at 23.degree. C. for 12
hrs. Once the reaction was determined to be complete using LCMS and
HPLC analysis, the crude Schiff base was purified by PREP HPLC. All
product fractions were combined, neutralized with an excess of
K.sub.2CO.sub.3, concentrated to remove acetonitrile, and extracted
with EtOAc (3.times.30 mL). The combined organic extracts were
dried with Na.sub.2SO.sub.4 and concentrated to a solid in vacuo.
The resulting solid was dissolved in minimal CH.sub.3CN and conc.
HCl (900 .mu.L) was added and stirred at 23.degree. C. for 30
minutes, then the entire reaction was directly purified on a
Preparative C-18 reversed-phase HPLC column (eluent: 0.5% w/v aq
HCl+CH.sub.3CN; 1-40% CH.sub.3CN in water over 20 minutes), giving
amine Example BI (18 mg) as a lyophilized HCl salt.
[0524] .sup.1H NMR (300 MHz, d.sup.6 DMSO) .delta.: 0.89 (t, 3H),
1.32-1.40 (m, 2H), 1.54-1.64 (m, 6H), 1.75-1.77 (m, 4H), 2.98-3.03
(m, 2H), 3.21-3.26 (m, 2H), 4.18 (t, 2H), 4.27 (d, 2H), 7.35-7.54
(m, 4H), 10.22 (bs, 1H), 10.71 (S, 1H); MS: 425 (MH.sup.+).
[0525] Example BJ was prepared using procedures similar to those
used to prepare Example BG, except that tetrahydrofuran-3-ol was
used in the first step and the reaction mixture was reacted at
94.degree. C. for 2 hrs.
##STR00133##
[0526] .sup.1H NMR (300 MHz, d.sup.6 DMSO) .delta.: 1.81-1.98 (bd,
8H); 2.09-2.21 (m, 2H); 3.01 (bm, 2H); 3.31 (bm, 2H); 3.66-3.88 (m,
4H); 4.29-4.31 (d J=6.0 Hz, 2H); 4.89, (s, 2H); 5.27 (bm, 1H);
7.35-7.50 (m, 4H); 10.45 (bs, 1H); 10.59 (s, 1H); MS: 410
(MH.sup.+).
[0527] Example BK was prepared using procedures similar to those
used to prepare Example BG, except that
(tetrahydrofuran-2-yl)methanol was used in the first step and that
the reaction mixture reacted in a sealed tube at 94.degree. C. for
2 hrs.
##STR00134##
[0528] .sup.1H NMR (300 MHz, d.sup.6 DMSO) .delta.: 1.58-2.01 (m,
8H), 2.87-3.17 (m, 2H), 3.37-3.35 (m, 2H), 3.60-3.77 (m, 2H),
4.04-4.14 (m, 3H), 4.30 (d, 2H), 4.90 (s, 2H), 7.24-7.50 (m, 4H),
10.20 (bs, 1H), 10.39 (s, 1H); MS: 425 (MH.sup.+).
[0529] Example BL was prepared using procedures similar to those
used to prepare Example BG, except that
2,2,3,3,3-pentafluoropropanol was used in the first step and that
the reaction mixture reacted in a sealed tube at 95.degree. C. for
9 hrs.
##STR00135##
[0530] .sup.1H NMR (300 MHz, d.sup.6 DMSO) .delta.: 1.80-1.99 (m,
4H), 3.01-3.18 (m, 2H), 3.27-3.32 (m, 2H), 4.30 (d, 2H), 4.91-4.99
(m, 4H), 7.33-7.52 (m, 4H), 10.48 (bs, 1H), 10.69 (s, 1H); MS: 472
(MH.sup.+).
[0531] Example BM was prepared using procedures similar to those
used to prepare Example BG, except that cyclopentanol was used in
the first step.
##STR00136##
[0532] .sup.1H-NMR (300 MHz, DMSO) .delta.: 1.54-1.67 (m, 6H),
1.82-1.98 (m, 6H), 3.01 (m, 2H), 3.29 (m, 2H), 4.29-4.31 (d, 2H),
4.89 (s, 2H), 5.32 (m, 1H), 7.35-7.56 (m, 4H), 10.49 (bs, 1H),
10.63 (s, 1H); MS: 409 (MH.sup.+).
[0533] Example BN was prepared using procedures similar to those
used to prepare Example A, except that Compound 2 was reacted
directly with 1-methylpiperazine (i.e., bromination of the
8-position of the puring ring was not carried out).
##STR00137##
[0534] .sup.1H-NMR (DMSO) .delta.: 8.04 (s, 1H), 7.33-7.17 (m, 6H),
5.24 (s, 2H), 4.31 (t, J=4.5 Hz, 2H), 3.60 (t, J=4.5 Hz, 2H), 3.46
(s, 2H), 3.27 (s, 3H), 2.75-2.30 (m, 8H), 2.40 (s, 3H). MS: 412
(MH.sup.+)
[0535] Similarly, Example BO was prepared using procedures similar
to those used to prepare Example A, except that Compound 2 was
reacted directly with pyrrolidine (and bromination of the
8-position of the puring ring was not carried out).
##STR00138##
[0536] .sup.1H-NMR (DMSO) .delta.: 0.33-0.34 (m, 2H), 0.51-0.55 (m,
2H), 1.20-1.23 (m, 1H), 1.81-1.96 (m, 4H), 2.96-3.01 (m, 2H),
3.25-3.28 (m, 2H), 4.15-4.29 (m, 4H), 5.37 (s, 2H), 7.40-7.59 (m,
4H), 8.54 (s, 1H); MS: 379 (MH.sup.+).
[0537] Examples BP, BQ, BR, BS, and BT were prepared using
procedures similar to those used to prepare Example A except that
pyrrolidine was replaced with the appropriate amine for each of
these examples.
##STR00139##
[0538] .sup.1H-NMR (DMSO) .delta.: 11.23 (br, 1H), 10.69 (s, 1H),
7.54-7.36 (m, 4H), 7.10 (br, 2H), 4.87 (s, 2H), 4.32 (s, 2H), 4.27
(t, J=4.5 Hz, 2H), 3.56 (t, J=4.5 Hz, 2H), 3.40-3.30 (m, 2H), 3.23
(s, 3H), 3.12-3.01 (m, 2H), 2.50-2.22 (m, 4H). MS: 449
(MH.sup.+)
##STR00140##
[0539] .sup.1H-NMR (DMSO) .delta.: 10.63 (s, 1H), 9.94 (br, 2H),
7.49-7.34 (m, 4H), 6.94 (br, 2H), 4.89 (s, 2H), 4.27 (t, J=4.5 Hz,
2H), 4.19 (s, 2H), 3.99 (q, J=18.9 Hz, 2H), 3.57 (t, J=4.5 Hz, 2H),
3.25 (s, 3H). MS: 427 (MH.sup.+)
##STR00141##
[0540] .sup.1H-NMR (DMSO) .delta.: 10.80 (s, 1H), 9.79 (br, 2H),
7.56-7.43 (m, 4H), 7.05 (br, 2H), 4.92 (s, 2H), 4.68-4.58 (m, 2H),
4.28 (t, J=4.5 Hz, 2H), 3.83-3.45 (m, 8H), 3.27 (s, 3H), 3.22-3.13
(m, 2H), 2.99 (s, 3H), 2.20-2.12 (m, 2H). MS: 442 (MH.sup.+)
##STR00142##
[0541] .sup.1H-NMR (DMSO) .delta.: 11.41 (br, 1H), 10.75 (s, 1H),
9.58 (br, 1H), 9.42 (br, 1H), 7.60-7.34 (m, 4H), 7.10 (br, 2H),
4.89 (s, 2H), 4.35 (s, 2H), 4.30 (t, J=4.5 Hz, 2H), 3.58 (t, J=4.5
Hz, 2H), 3.68-3.10 (m, 8H), 3.26 (s, 3H), 2.18-2.10 (m, 2H). MS:
428 (MH.sup.+)
##STR00143##
[0542] .sup.1H-NMR (DMSO) .delta.: 11.95 (br, 1H), 10.88 (s, 1H),
9.69 (br, 2H), 7.60-7.35 (m, 4H), 7.20 (br, 2H), 4.90 (s, 2H), 4.38
(s, 2H), 4.32 (t, J=4.5 Hz, 2H), 3.59 (t, J=4.5 Hz, 2H), 3.55-3.10
(m, 8H), 3.26 (s, 3H). MS: 414 (MH.sup.+)
[0543] Examples BU and BV were prepared using procedures similar to
those used to prepare Example AC except that bis(cyclopropylmethyl)
amine or cyclopropylmethanamine was used instead of
pyrrolidine.
##STR00144##
[0544] .sup.1H-NMR (DMSO) .delta.: 10.46 (br, 1H), 7.60-7.33 (m,
4H), 6.80 (br, 2H), 4.93 (s, 2H), 4.39 (d, J=4.5 Hz, 2H), 4.29 (t,
J=4.8 Hz, 2H), 3.98 (q, J=6.6 Hz, 2H), 3.58 (t, J=4.5 Hz, 2H), 3.26
(s, 3H), 3.05-2.84 (m, 4H), 1.12 (t, J=6.9 Hz, 3H), 1.20-1.05 (m,
2H), 0.62-0.53 (m, 4H), 0.38-0.28 (m, 4H). MS: 481 (MH.sup.+)
##STR00145##
[0545] .sup.1H-NMR (DMSO) .delta.: 9.14 (br, 2H), 7.50-7.28 (m,
4H), 6.71 (br, 2H), 4.92 (s, 2H), 4.27 (t, J=4.5 Hz, 2H) 4.05-3.93
(m, 4H), 3.58 (t, J=4.5 Hz, 2H), 3.26 (s, 3H), 2.82-2.72 (m, 2H),
1.13 (t, J=6.9 Hz, 3H), 1.15-1.00 (m, 1H), 0.58-0.51 (m, 2H),
0.35-0.29 (m, 2H). MS: 427 (MH.sup.+)
[0546] Example BW was prepared using procedures similar to those
used to prepare Example AC except that 4-(bromomethyl)benzonitrile
is used to alkylate Compound 1 instead of
3-(bromomethyl)benzonitrile, and subsequently, the corresponding
analog of Compound 8 was hydrolyzed to
4-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzonitri-
le without reaction with ethyl iodide, and the corresponding
4-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzaldehy-
de was the reacted with pyrrolidine.
##STR00146##
[0547] .sup.1H-NMR (300 MHz, DMSO) .delta.: 1.82-1.99 (m, 4H),
3.01-3.03 (m, 2H), 3.24-3.28 (m, 5H), 3.59 (t, 2H), 4.28-4.31 (m,
4H), 4.90 (s, 2H), 7.34-7.55 (m, 4H), 10.59 (bs, 2H); MS: 399
(MH.sup.+).
TLR7 Reporter Assay protocol
A. HEK293 Assay
1. Cell Culture:
[0548] HEK293 cells stably transfected with the human TLR7 gene and
a pNiFty.TM. NF-.kappa.B inducible luciferase reporter plasmid were
obtained from Invivogen (San Diego, Calif.). DMEM/F12 medium, fetal
bovine serum (FBS), Penicillin-Streptomycin (Pen-Strep),
Blasticidin and Zeocine were from Invitrogen (Carlsbad, Calif.).
The HEK293/TLR7/Luciferase cell line was constructed by
transfecting stably the HEK293/TLR7 cells with the pNiFty plasmid.
Cells were grown in the DMEM/F12 medium with 10% heat-inactivated
FBS, supplemented with 1.times. Pen-Strep, 10 .mu.g/mL Blasticidin
and 5 .mu.g/mL Zeocin.
2. Assay Procedure:
[0549] For the determination of the EC50 and Emax values of TLR7
agonists in the reporter assay, 20 .mu.L of 2.times. test
concentration of serial diluted compound in cell culture medium was
added to each well of a white, clear-bottomed 384-well cell culture
plate from Corning (Corning, N.Y.). To this plate, 20 .mu.L of cell
culture medium containing 12,000 HEK293/TLR7/Luciferase cells was
dispensed to each well. The plate was then placed in incubator
(37.degree. C. and 5% CO.sub.2) and incubated for 2 days. After the
incubation, 40 .mu.L of the pre-mixed lysis buffer/luciferase
substrate solution was dispensed into each well. The lysis buffer
(5.times.) and luciferase substrate was obtained from Promega
(Madison, Wis.) and they were mixed at 2:3 (v/v) ratio immediately
prior to use. After 10 minutes of incubation at room temperature,
the luminescence signal was measured using a VictorLight plate
reader (Perkin Elmer, Wellesley, Mass.) with an integration time of
0.1 seconds per sample.
[0550] Data analysis was performed with Prism software from
GraphPad (San Diego, Calif.) using a single site binding algorithm.
The maximum signal for each test compound (E.sub.max) was
normalized with the maximum signal for the positive control,
Resiquimod, on each plate. The concentration of a compound that
corresponds to 50% of the maximum signal is defined as the
EC.sub.50.
[0551] The compounds of the present invention have HCV EC50 values
(.mu.M) in the range of about 0.01 to about 1000, or about 0.1 to
about 500, or about 0.1 to about 300, or about 0.1 to about 200, or
about 0.1 to about 100, or about 0.1 to about 50, or less than
about 500, or less than about 400, or less than about 300, or less
than about 200, or less than about 100, or less than about 50, or
less than about 20, or less than about 10.
B. PBMC Assay
[0552] Assays were conducted to determine cytokine stimulation at
24 hours from human Peripheral Blood Mononuclear Cell (PMBC) using
the compounds of the present invention. The assays were run in
duplicate, with 8-point, half-log dilution curves. The compounds of
the present invention were diluted from 10 .mu.M DMSO solution.
Cell supernatants are assayed directly for IFN.alpha. and 1:10
dilution for TNF.alpha.. The assays were performed in a similar
fashion as described in Bioorg. Med. Chem. Lett. 16, 4559, (2006).
Specifically, cryo-preserved PBMCs were thawed and seeded 96 well
plates with 750,000 cells/well in 190 .mu.L/well cell media. The
PBMCs were then incubated for 1 hour at 37.degree. C. at 5%
CO.sub.2. Then, the compounds of the present invention were added
in 10 .mu.L cell media at 8 point, half-log dilution titration. The
plates were incubated at 37.degree. C. and 5% CO.sub.2 for 24 hours
and then spinned at 1200 rpm for 10 min, which was followed by
collecting supernatant and storing the same at -80.degree. C.
Cytokine secretion was assayed with Luminex and Upstate multi-plex
kits, using a Luminex analysis instrument. IFN ECmax value for a
compound was the concentration at which the compound stimulated
maximum IFN .alpha. production as determined using the assay method
above.
[0553] The compounds of the present invention have IFN ECmax values
(nM) in the range of about 0.1 to about 10,000, or about 0.1 to
about 1,000, or about 0.1 to about 300, or about 0.1 to about 100,
or about 0.1 to about 10, or about 0.1 to about 5, or about 0.1 to
about 1, or less than about 5000, or less than about 3000, or less
than about 1000, or less than about 500, or less than about 400, or
less than about 300, or less than about 200, or less than about
100, or less than about 50, or less than about 20, or less than
about 10, or less than about 5, or less than about 1. Examples A,
C, D, F, J, N, R, W, Y, AI, AJ, AQ, AS, AU, AV, AW, AZ, BE, BG, BH,
and BM have IFN ECmax values (nM) of less than about 5.
* * * * *