U.S. patent application number 13/935117 was filed with the patent office on 2014-01-16 for modulators of pharmacokinetic properties of therapeutics.
The applicant listed for this patent is Gilead Sciences, Inc.. Invention is credited to Manoj C. Desai, Allen Yu Hong, Hon Chung Hui, Hongtao Liu, Randall W. Vivian, Lianhong Xu.
Application Number | 20140017199 13/935117 |
Document ID | / |
Family ID | 39522375 |
Filed Date | 2014-01-16 |
United States Patent
Application |
20140017199 |
Kind Code |
A1 |
Desai; Manoj C. ; et
al. |
January 16, 2014 |
MODULATORS OF PHARMACOKINETIC PROPERTIES OF THERAPEUTICS
Abstract
The present application provides for a compound of Formula IV,
##STR00001## or a pharmaceutically acceptable salt, solvate, and/or
ester thereof, compositions containing such compounds, therapeutic
methods that include the administration of such compounds, and
therapeutic methods and include the administration of such
compounds with at least one additional therapeutic agent.
Inventors: |
Desai; Manoj C.; (Pleasant
Hill, CA) ; Hong; Allen Yu; (Pasadena, CA) ;
Hui; Hon Chung; (San Mateo, CA) ; Liu; Hongtao;
(Cupertino, CA) ; Vivian; Randall W.; (San Mateo,
CA) ; Xu; Lianhong; (Palo Alto, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gilead Sciences, Inc. |
Foster City |
CA |
US |
|
|
Family ID: |
39522375 |
Appl. No.: |
13/935117 |
Filed: |
July 3, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13301642 |
Nov 21, 2011 |
8486942 |
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13935117 |
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12036124 |
Feb 22, 2008 |
8148374 |
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13301642 |
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60903228 |
Feb 23, 2007 |
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60958716 |
Jul 6, 2007 |
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Current U.S.
Class: |
424/85.6 ;
424/142.1; 424/85.4; 424/85.7; 514/171; 514/220; 514/230.5;
514/236.8; 514/253.09; 514/254.02; 514/255.02; 514/365; 514/86;
544/133; 544/369; 548/204 |
Current CPC
Class: |
A61P 31/12 20180101;
A61K 45/06 20130101; A61K 9/08 20130101; A61K 31/4178 20130101;
G01N 33/94 20130101; C07D 277/30 20130101; C07D 277/28 20130101;
A61K 31/427 20130101; A61P 43/00 20180101; A61P 31/00 20180101;
C07D 417/14 20130101; A61P 31/14 20180101; A61K 31/496 20130101;
A61K 31/426 20130101; C07B 2200/05 20130101; G01N 33/58 20130101;
A61K 31/5377 20130101; A61P 31/18 20180101; A61K 9/0053 20130101;
A61K 31/5377 20130101; A61K 2300/00 20130101; A61K 31/427 20130101;
A61K 2300/00 20130101; A61K 31/426 20130101; A61K 2300/00 20130101;
A61K 31/496 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/85.6 ;
548/204; 514/365; 544/133; 514/236.8; 544/369; 514/254.02;
424/142.1; 514/171; 514/255.02; 514/220; 514/230.5; 514/253.09;
514/86; 424/85.7; 424/85.4 |
International
Class: |
C07D 277/28 20060101
C07D277/28; A61K 45/06 20060101 A61K045/06; C07D 417/14 20060101
C07D417/14; A61K 31/496 20060101 A61K031/496; A61K 31/427 20060101
A61K031/427; A61K 31/5377 20060101 A61K031/5377 |
Claims
1. A compound of formula IV, ##STR00300## or a pharmaceutically
acceptable salt, solvate, and/or ester thereof, wherein, each
L.sup.3 is independently an alkylene or substituted alkylene; each
A is independently an aryl or substituted aryl; X is
heterocyclylalkyl; Y is heterocyclylalkyl or alkyl; G.sup.1 and
G.sup.2 are independently CH or N, with the proviso that G.sup.1
and G.sup.2 are different; G.sup.3 is --NR.sup.7-- or --O.sup.-;
R.sup.1, R.sup.3, R.sup.5, and R.sup.7 are each independently
selected from the group consisting of H, alkyl, substituted alkyl,
arylalkyl, and substituted arylalkyl; R.sup.2 is independently
selected from the group consisting of substituted alkyl,
alkoxyalkyl, hydroxyalkyl, trialkylsiloxyalkyl, heterocyclylalkyl,
substituted heterocyclylalkyl, aminoalkyl, substituted aminoalkyl,
-alkylene-N(R.sup.a)--C(O)-alkyl,
-alkylene-NR.sup.a--C(O)--N(R.sup.a).sub.2,
-alkylene-NR.sup.a--C(.dbd.N--R.sup.b)--N(R.sup.a).sub.2,
-alkylene-C(.dbd.N--R.sup.b)--N(R.sup.a).sub.2, -alkylene-C(O)--OH,
-alkylene-C(O)--Oalkyl, and -alkylene-C(O)--N(R.sup.c).sub.2;
R.sup.8 and R.sup.9 are each one or more substituents independently
selected from the group consisting of H, alkyl, substituted alkyl,
halogen, and --CN; each R.sup.a is independently selected from the
group consisting of H, alkyl, and substituted alkyl; R.sup.b is
selected from the group consisting of H, alkyl, substituted alkyl,
CN, and --S(O.sub.2)-alkyl; and each R.sup.c is independently
selected from the group consisting of H, alkyl, substituted alkyl,
heterocyclyl, substituted heterocyclyl, --S(O.sub.2)-alkyl,
--S(O.sub.2)-aryl, and substituted --S(O.sub.2)-aryl.
2. The compound of claim 1, having the following formula:
##STR00301## wherein R.sup.d is selected from the group consisting
of H, haloalkyl, --C(O)--N(R.sup.a).sub.2,
--C(.dbd.N--R.sup.b)--N(R.sup.a).sub.2, hydroxyalkyl,
--C(N(R.sup.a).sub.2).dbd.CHNO.sub.2, --C(O)-alkyl.
3. The compound of claim 1, having the following formula:
##STR00302##
4-5. (canceled)
6. The compound of claim 3, wherein said Heterocyclyl is a
substituted or unsubstituted heterocycloalkyl.
7. The compound of claim 6, wherein said heterocycloalkyl is
selected from the group consisting of pyrrolidinonyl,
pyrrolidine-dionyl, oxazolidinonyl, pyrrolidinyl, piperidinyl,
piperidinonyl, piperazinyl, thiomorpholinyl, and morpholinyl.
8. The compound of claim 7, wherein said heterocycloalkyl is
morpholinyl.
9-27. (canceled)
28. A method for treating an HIV infection comprising administering
to a patient in need thereof a therapeutically effective amount of
a compound of claim 1, or a pharmaceutically acceptable salt,
solvate, and/or ester thereof, in combination with a
therapeutically effective amount of one or more additional
therapeutic agents selected from the group consisting of HIV
protease inhibiting compounds, HIV non-nucleoside inhibitors of
reverse transcriptase, HIV nucleoside inhibitors of reverse
transcriptase, HIV nucleotide inhibitors of reverse transcriptase,
HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120
inhibitors, G6PD and NADH-oxidase inhibitors, CCR5 inhibitors,
other drugs for treating HIV, and mixtures thereof.
29. The method of claim 28, wherein: (1) said HIV protease
inhibitors are selected from the group consisting of amprenavir,
atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir,
nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126,
TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423,
RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100,
DG35, and AG 1859; (2) said HIV non-nucleoside inhibitors of
reverse transcriptase are selected from the group consisting of
capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+)
calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963,
MW-150, TMC-120, TMC-278 (rilpivirene), BILR 355 BS, VRX 840773,
UK-453061, and RDEA806; (3) said HIV nucleoside inhibitors of
reverse transcriptase are selected from the group consisting of
zidovudine, emtricitabine, didanosine, stavudine, zalcitabine,
lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210,
racivir (.+-.-FTC), D-d4FC, phosphazide, fozivudine tidoxil,
apricitibine (AVX754), amdoxovir, KP-1461, and fosalvudine tidoxil
(formerly HDP 99.0003); (4) said HIV nucleotide inhibitors of
reverse transcriptase are selected from the group consisting of
tenofovir disoproxil fumarate, GS-9131, and adefovir dipivoxil; (5)
said HIV integrase inhibitors are selected from the group
consisting of curcumin, derivatives of curcumin, derivatives of
curcumin, chicoric acid, derivatives of chicoric acid,
3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic
acid, aurintricarboxylic acid, derivatives of aurintricarboxylic
acid, caffeic acid phenethyl ester, derivatives of caffeic acid
phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin,
derivatives of quercetin, S-1360, zintevir (AR-177), L-870812,
L-870810, MK-0518 (raltegravir), elvitegravir, BMS-538158,
GSK364735C, BMS-707035, MK-2048, and BA 011; (6) said gp41
inhibitor are selected from the group consisting of enfuvirtide,
sifuvirtide, FB006M, and TRI-1144; (7) said CXCR4 inhibitor is
AMD-070; (8) said entry inhibitor is SP01A; (9) said gp120
inhibitor is BMS-488043 or BlockAide/CR; (10) said G6PD and
NADH-oxidase inhibitor is immunitin; (11) said CCR5 inhibitors are
selected from the group consisting of aplaviroc, vicriviroc,
maraviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5 mAb004;
(12) said other drugs for treating HIV are selected from the group
consisting of BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6,
ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), Ampligen, HRG214,
Cytolin, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025,
BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040
(PA-040).
30-31. (canceled)
32. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt, solvate, and/or ester
thereof, and a pharmaceutically acceptable carrier or
excipient.
33. The pharmaceutical composition of claim 32, further comprising
at least one additional therapeutic agent metabolized by cytochrome
P450.
34. The pharmaceutical composition of claim 33, wherein the at
least one additional therapeutic agent is selected from the group
consisting of HIV protease inhibiting compounds, HIV non-nucleoside
inhibitors of reverse transcriptase, HIV nucleoside inhibitors of
reverse transcriptase, HIV nucleotide inhibitors of reverse
transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4
inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid
polymerization inhibitors, interferons, ribavirin analogs, NS3
protease inhibitors, alpha-glucosidase 1 inhibitors,
hepatoprotectants, non-nucleoside inhibitors of HCV, other drugs
for treating HCV, and combinations thereof.
35. The pharmaceutical composition of claim 34, wherein: (1) said
HIV protease inhibitors are selected from the group consisting of
amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir,
ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir,
darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776),
L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17,
PPL-100, DG35, and AG 1859; (2) said HIV non-nucleoside inhibitors
of reverse transcriptase are selected from the group consisting of
capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+)
calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963,
MW-150, and TMC-120, TMC-278 (rilpivirene), efavirenz, BILR 355 BS,
VRX 840773, UK-453061, and RDEA806; (3) said HIV nucleoside
inhibitors of reverse transcriptase are selected from the group
consisting of zidovudine, emtricitabine, didanosine, stavudine,
zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine,
alovudine, MIV-210, racivir (.+-.-FTC), D-d4FC, emtricitabine,
phosphazide, fozivudine tidoxil, apricitibine (AVX754), amdoxovir,
KP-1461, and fosalvudine tidoxil (formerly HDP 99.0003); (4) said
HIV nucleotide inhibitors of reverse transcriptase are selected
from the group consisting of tenofovir disoproxil fumarate,
GS-9131, and adefovir dipivoxil; (5) said HIV integrase inhibitors
are selected from the group consisting of curcumin, derivatives of
curcumin, chicoric acid, derivatives of chicoric acid,
3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic
acid, aurintricarboxylic acid, derivatives of aurintricarboxylic
acid, caffeic acid phenethyl ester, derivatives of caffeic acid
phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin,
derivatives of quercetin, S-1360, zintevir (AR-177), L-870812, and
L-870810, MK-0518 (raltegravir), elvitegravir, BMS-538158,
GSK364735C, BMS-707035, MK-2048, and BA 011; (6) said gp41
inhibitor are selected from the group consisting of enfuvirtide,
sifuvirtide, FB006M, and TRI-1144; (7) said CXCR4 inhibitor is
AMD-070; (8) said entry inhibitor is SP01A; (9) said gp120
inhibitor is BMS-488043 or BlockAide/CR; (10) said G6PD and
NADH-oxidase inhibitor is immunitin; (11) said CCR5 inhibitors are
selected from the group consisting of aplaviroc, vicriviroc,
maraviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAb004;
(12) said other drugs for treating HIV are selected from the group
consisting of BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6,
ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), Ampligen, HRG214,
Cytolin, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025,
BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040
(PA-040); (13) said interferons are selected from the group
consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a,
rIFN-alpha 2b, rIFN-alpha 2a, consensus IFN alpha (infergen),
feron, reaferon, intermax alpha, r-IFN-beta, infergen+actimmune,
IFN-omega with DUROS, albuferon, locteron, Albuferon, Rebif, Oral
interferon alpha, IFNalpha-2b XL, AVI-005, PEG-Infergen, and
Pegylated IFN-beta; (14) said ribavirin analogs are selected from
the group consisting of rebetol, copegus, and viramidine
(taribavirin); (15) said NS5b polymerase inhibitors are selected
from the group consisting of NM-283, valopicitabine, R1626,
PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107,
R7128 (R4048), VCH-759, PF-868554, and GSK625433; (16) said NS3
protease inhibitor are selected from the group consisting of
SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339, and
ITMN-191; (17) said alpha-glucosidase 1 inhibitors are selected
from the group consisting of MX-3253 (celgosivir) and UT-231B; (18)
said hepatoprotectants are selected from the group consisting of
IDN-6556, ME 3738, LB-84451, and MitoQ; (19) said non-nucleoside
inhibitors of HCV are selected from the group consisting of
benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives,
phenylalanine derivatives, A-831, and A-689; and (20) said other
drugs for treating HCV are selected from the group consisting of
zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17
(altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir,
GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18,
NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab,
Oglufanide, and VX-497 (merimepodib).
36-41. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application Ser. No. 60/903,228, entitled "Modulators of
Pharmacokinetic Properties of Therapeutics", filed Feb. 23, 2007,
and U.S. Provisional Application Ser. No. 60/958,716, entitled
"Modulators of Pharmacokinetic Properties of Therapeutics", filed
Jul. 6, 2007. The contents of these provisional applications are
herein incorporated by reference in their entirety for all
purposes.
FIELD OF THE INVENTION
[0002] This application relates generally to compounds and
pharmaceutical compositions which modify, e.g., improve, the
pharmacokinetics of a co-administered drug, and methods of
modifying, e.g., improving, the pharmacokinetics of a drug by
co-administration of the compounds with the drug.
BACKGROUND OF THE INVENTION
[0003] Oxidative metabolism by cytochrome P450 enzymes is one of
the primary mechanisms of drug metabolism. It can be difficult to
maintain therapeutically effective blood plasma levels of drugs
which are rapidly metabolized by cytochrome P450 enzymes.
Accordingly, the blood plasma levels of drugs which are susceptible
to cytochrome P450 enzyme degradation can be maintained or enhanced
by co-administration of cytochrome P450 inhibitors, thereby
improving the pharmacokinetics of the drug.
[0004] While certain drugs are known to inhibit cytochrome P450
enzymes, more and/or improved inhibitors for cytochrome P450
monooxygenase are desirable. Particularly, it would be desirable to
have cytochrome P450 monooxygenase inhibitors which do not have
appreciable biological activity other than cytochrome P450
inhibition. Such inhibitors can be useful for minimizing
undesirable biological activity, e.g., side effects. In addition,
it would be desirable to have P450 monooxygenase inhibitors that
lack significant or have a reduced level of protease inhibitor
activity. Such inhibitors could be useful for enhancing the
effectiveness of antiretroviral drugs, while minimizing the
possibility of eliciting viral resistance, especially against
protease inhibitors.
SUMMARY OF THE INVENTION
[0005] One aspect of the present application is directed to
compounds and pharmaceutical compositions which modify, e.g.,
improve, the pharmacokinetics of a co-administered drug, e.g., by
inhibiting cytochrome P450 monooxygenase.
[0006] In one embodiment, the present application provides for
compounds having a structure according to Formula IV,
##STR00002##
or a pharmaceutically acceptable salt, solvate, and/or ester
thereof, wherein, [0007] each L.sup.3 is independently an alkylene
or substituted alkylene; [0008] each A is independently an aryl or
substituted aryl; [0009] X is heterocyclylalkyl; [0010] Y is
heterocyclylalkyl or alkyl; [0011] G.sup.1 and G.sup.2 are
independently CH or N, with the proviso that G.sup.1 and G.sup.2
are different; [0012] G.sup.3 is --NR.sup.7-- or --O--; [0013]
R.sup.1, R.sup.3, R.sup.5, and R.sup.7 are each independently
selected from the group consisting of H, alkyl, substituted alkyl,
arylalkyl, and substituted arylalkyl; [0014] R.sup.2 is
independently selected from the group consisting of substituted
alkyl, alkoxyalkyl, hydroxyalkyl, trialkylsiloxyalkyl,
heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl,
substituted aminoalkyl, -alkylene-N(R.sup.a)--C(O)-alkyl,
-alkylene-NR.sup.a--C(O)--N(R.sup.a).sub.2,
-alkylene-NR.sup.a--C(.dbd.N--R.sup.b)--N(R.sup.a).sub.2,
-alkylene-C(.dbd.N--R.sup.b)--N(R.sup.a).sub.2, -alkylene-C(O)--OH,
-alkylene-C(O)--Oalkyl, and -alkylene-C(O)--N(R.sup.c).sub.2;
[0015] R.sup.8 and R.sup.9 are each one or more substituents
independently selected from the group consisting of H, alkyl,
substituted alkyl, halogen, and --CN; [0016] each R.sup.a is
independently selected from the group consisting of H, alkyl, and
substituted alkyl; [0017] R.sup.b is selected from the group
consisting of H, alkyl, substituted alkyl, CN, and
--S(O.sub.2)-alkyl; and [0018] each R.sup.c is independently
selected from the group consisting of H, alkyl, substituted alkyl,
heterocyclyl, substituted heterocyclyl, --S(O.sub.2)-alkyl,
--S(O.sub.2)-aryl, and substituted --S(O.sub.2)-aryl.
[0019] In another embodiment, the present application provides for
a pharmaceutical composition comprising a compound of Formula I,
and a pharmaceutically acceptable carrier or excipient.
[0020] In another embodiment, the present application provides for
a pharmaceutical composition comprising a compound of Formula I, at
least one additional therapeutic agent, and a pharmaceutically
acceptable carrier or excipient.
[0021] In another embodiment, the present application provides for
a method for improving the pharmacokinetics of a drug, comprising
administering to a patient treated with said drug, a
therapeutically effective amount of a compound of Formula I, or a
pharmaceutically acceptable salt, solvate, and/or ester
thereof.
[0022] In another embodiment, the present application provides for
a method for inhibiting cytochrome P450 monooxygenase in a patient
comprising administering to a patient in need thereof an amount of
a compound of Formula I, or a pharmaceutically acceptable salt,
solvate, and/or ester thereof, effective to inhibit cytochrome P450
monooxygenase.
[0023] In another embodiment, the present application provides for
a method for treating a viral infection, e.g., HIV, comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of Formula I, or a pharmaceutically
acceptable salt, solvate, and/or ester thereof, in combination with
a therapeutically effective amount of one or more additional
therapeutic agents which are metabolized by cytochrome P450
monooxygenase, and are suitable for treating a viral infection,
e.g., HIV.
[0024] In another embodiment, the present application provides for
a combination pharmaceutical agent comprising:
[0025] a) a first pharmaceutical composition comprising a compound
of Formula I, or a pharmaceutically acceptable salt, solvate,
and/or ester thereof; and
[0026] b) a second pharmaceutical composition comprising at least
one additional active agent which is metabolized by cytochrome P450
monooxygenase.
DETAILED DESCRIPTION
[0027] 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.
[0028] All documents cited herein are each incorporated by
reference in their entirety for all purposes.
DEFINITIONS
[0029] Unless stated otherwise, the following terms and phrases as
used herein are intended to have the following meanings:
[0030] When trade names are used herein, applicants intend to
independently include the tradename product and the active
pharmaceutical ingredient(s) of the tradename product.
[0031] As used herein, "a compound of the invention" or "a compound
of formula (I)" means a compound of formula (I) or a
pharmaceutically acceptable salt, solvate, ester or stereoisomer
thereof, or a physiologically functional derivative thereof.
Similarly, with respect to isolatable intermediates, the phrase "a
compound of formula (number)" means a compound of that formula and
pharmaceutically acceptable salts, solvates and physiologically
functional derivatives thereof.
[0032] "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).
[0033] "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).
[0034] 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.
[0035] "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.
[0036] "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 or 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).
[0037] "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.
[0038] "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.
[0039] "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--).
[0040] "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.
[0041] 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--).
[0042] "Amino" means an --NH.sub.2 or a --NR.sub.2 group in which
the "R" groups are independently H, alkyl, haloalkyl,
hydroxylalkyl, carbocyclyl (substituted or unsubstituted, including
saturated or partially unsaturated cycloalkyl and aryl groups),
heterocyclyl (substituted or unsubstituted, including saturated or
unsaturated heterocycloalkyl and heteroaryl groups), arylalkyl
(substituted or unsubstituted) or arylalkyl (substituted or
unsubstituted) groups. Non-limiting examples of amino groups
include --NH.sub.2, --NH(alkyl), NH(haloalkyl), --NH(carbocyclyl),
--NH(heterocyclyl), --N(alkyl).sub.2, --N(carbocyclyl).sub.2,
--N(heterocyclyl).sub.2, --N(alkyl)(carbocyclyl),
--N(alkyl)(heterocyclyl), --N(carbocyclyl)(heterocyclyl), etc.,
wherein alkyl, carbocyclyl, and heterocyclyl can be substituted or
unsubstituted and as defined and described herein.
"Substituted" or "protected" amino means an aminoalkyl as described
and defined herein in which a H of the amino group is replaced with
e.g., acyl groups, for example conventional amine protecting groups
such as 9-Fluorenylmethyl carbamate ("Fmoc"), t-Butyl carbamate
("Boc"), Benzyl carbamate ("Cbz"), acetyl, trifluoracetyl,
--C(O)-amino, phthalimidyl, triphenylmethyl, p-Toluenesulfonyl
("Tosyl"), methylsulfonyl ("mesyl"), etc.
[0043] "Aminoalkyl" means an acyclic alkyl radical in which one of
the hydrogen atoms bonded to a carbon atom, typically a terminal or
spa carbon atom, is replaced with an amino radical as defined and
described herein. Non-limiting examples of aminoalkyl include
--CH.sub.2--NH.sub.2, --CH.sub.2CH.sub.2--NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2--NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--NH.sub.2,
--CH.sub.2CH(CH.sub.3)--NH.sub.2,
--CH.sub.2CH.sub.2CH(CH.sub.3)--NH.sub.2, --CH.sub.2--NH(CH.sub.3),
--CH.sub.2CH.sub.2--NH(CH.sub.3),
--CH.sub.2CH.sub.2CH.sub.2--NH(CH.sub.3),
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--NH(CH.sub.3),
--CH.sub.2CH(CH.sub.3)--NH(CH.sub.3),
--CH.sub.2CH.sub.2CH(CH.sub.3)--NH(CH.sub.3),
--CH.sub.2--N(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2--N(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.sub.2--N(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--N(CH.sub.3).sub.2,
--CH.sub.2CH(CH.sub.3)--N(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH(CH.sub.3)--N(CH.sub.3).sub.2,
--CH.sub.2--NH(CH.sub.2CH.sub.3),
--CH.sub.2CH.sub.2--NH(CH.sub.2CH.sub.3),
--CH.sub.2CH.sub.2CH.sub.2--NH(CH.sub.2CH.sub.3),
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--NH(CH.sub.2CH.sub.3),
--CH.sub.2CH(CH.sub.3)--NH(CH.sub.2CH.sub.3), --CH.sub.2CH.sub.2
CH(CH.sub.3)--NH(CH.sub.2CH.sub.3),
--CH.sub.2--N(CH.sub.2CH.sub.3).sub.2,
--CH.sub.2CH.sub.2--N(CH.sub.2CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.sub.2--N(CH.sub.2CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--N(CH.sub.2CH.sub.3).sub.2,
--CH.sub.2CH(CH.sub.3)--N(CH.sub.2CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH(CH.sub.3)--N(CH.sub.2CH.sub.3).sub.2, etc.
"Substituted" or "protected" aminoalkyl means an aminoalkyl as
described and defined herein in which the H of the amino group is
replaced with e.g., acyl groups, for example conventional amine
protecting groups such as 9-Fluorenylmethyl carbamate ("Fmoc"),
t-Butyl carbamate ("Boc"), Benzyl carbamate ("Cbz"), acetyl,
--C(O)-amino, trifluoracetyl, phthalimidyl, triphenylmethyl,
p-Toluenesulfonyl ("Tosyl"), methylsulfonyl ("mesyl"), etc.
[0044] "Aryl" means an 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 aryl 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.
[0045] "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.
[0046] "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.
[0047] "Arylalkynyl" refers to an acyclic alkynyl 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 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.
[0048] The term "substituted" in reference to alkyl, alkylene,
aryl, arylalkyl, heterocyclyl, heteroaryl, carbocyclyl, 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, --NHS(.dbd.O).sub.2R, --C(.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.sup.-), --C(.dbd.O)R, --C(.dbd.O)OR, --C(.dbd.O)X,
--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, alkenylene, and
alkynylene groups may also be similarly substituted. When the
number of carbon atoms is designated for a substituted group, the
number of carbon atoms refers to the group, not the substituent
(unless otherwise indicated). For example, a C.sub.1-4 substituted
alkyl refers to a C.sub.1-4 alkyl, which can be substituted with
groups having more the, e.g., 4 carbon atoms.
[0049] 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.
[0050] One skilled in the art will recognize that substituents and
other moieties of the compounds of Formula I 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 which have such stability are contemplated as falling within the
scope of the present invention.
[0051] "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(CH.sub.3).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) 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--CH.sub.3). 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.
[0052] "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 (i.e., heterocycloalkyls),
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:
##STR00003##
[0053] 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,
piperidirtyl, 4-piperidonyl, pyrrolidinyl, 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:
##STR00004##
[0054] 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.
[0055] 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.
[0056] "Heterocyclylalkyl" refers to an acyclic alkyl radical in
which one of the hydrogen atoms bonded to a carbon atom, typically
a terminal or spa 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--, heterocyclyl-CH(CH.sub.3)--,
heterocyclyl-CH.sub.2CH.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
heterocyclylalkyl group comprises 2 to 20 carbon atoms, e.g., the
alkyl portion of the heterocyclylalkyl group is 1 to 6 carbon atoms
and the heterocyclyl moiety is 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.
[0057] "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 heterocyclylalkenyl group comprises 3 to 20 carbon
atoms, e.g., the alkenyl portion of the heterocyclyl alkenyl group
is 2 to 6 carbon atoms and the heterocyclyl moiety is 1 to 14
carbon atoms.
[0058] "Heterocyclylalkynyl" refers to an acyclic alkynyl 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 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 heterocyclylalkynyl group comprises 3 to 20 carbon
atoms, e.g., the alkynyl portion of the heterocyclylalkynyl group
is 2 to 6 carbon atoms and the heterocyclyl moiety is 1 to 14
carbon atoms.
[0059] "Heteroaryl" refers to an 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.
[0060] "Carbocycle" or "carbocyclyl" refers to a saturated (i.e.,
cycloalkyl), partially unsaturated (e.g., cycloakenyl,
cycloalkadienyl, etc.) 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, or spiro-fused rings.
Non-limiting 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, and
phenyl. Non-limiting examples of bicyclo carbocycles includes
naphthyl.
[0061] "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-5-aryl,
-alkylene-5-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.
[0062] "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
[0063] 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, --C
H(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.
[0064] 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.
[0065] "Ac" means acetyl (--C(O)CH.sub.3).
[0066] "Ac.sub.2O" means acetic anhydride.
[0067] "DCM" means dichloromethane (CH.sub.2Cl.sub.2).
[0068] "DIBAL" means diisobutylaluminum hydride.
[0069] "DMAP" means dimethylaminopyridine.
[0070] "EDC" means
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide.
[0071] "Et" means ethyl.
[0072] "EtOAc" means ethylacetate.
[0073] "HOBt" means N-hydroxybenzotriazole.
[0074] "Me" means methyl (--CH.sub.3).
[0075] "MeOH" means methanol.
[0076] "MeCN" means acetonitrile.
[0077] "Pr" means propyl.
[0078] "i-Pr" means isopropyl (--CH(CH.sub.3).sub.2).
[0079] "i-PrOH" means isopropanol.
[0080] "rt" means room temperature.
[0081] "TFA" means trifluoroacetic acid.
[0082] "THF" means tetrahydrofuran.
[0083] 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.
[0084] 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.
[0085] "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.
[0086] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0087] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book 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 1 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
[0088] In the context of the present invention, protecting groups
include prodrug moieties and chemical protecting groups.
[0089] 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.
[0090] 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.
[0091] 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 0-471-16019-9) ("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
[0092] 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
[0093] 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
[0094] In one embodiment, the present application provides
compounds according to Formula I,
##STR00005##
or a pharmaceutically acceptable salt, solvate, and/or ester
thereof, wherein, [0095] L.sup.1 is selected from the group
consisting of --C(R.sup.6).sub.2--, --C(O)--, --S(O.sub.2)--,
--N(R.sup.7)--C(O)--, and --O--C(O)--; [0096] L.sup.2 is a covalent
bond, --C(R.sup.6).sub.2-- or --C(O)--; [0097] each L.sup.3 is
independently a covalent bond, an alkylene, or substituted
alkylene; [0098] each L.sup.4 is independently selected from the
group consisting of a covalent bond, alkylene, substituted
alkylene, --O--, --CH.sub.2--O--, and --NH--; [0099] each A is
independently selected from the group consisting of H, alkyl,
substituted alkyl, aryl, substituted aryl, heterocyclyl, and
substituted heterocyclyl, [0100] with the proviso that when A is H,
p is 0; [0101] Z.sup.1 and Z.sup.2 are each independently --O-- or
--N(R.sup.7)--; [0102] Y and X are independently selected from the
group consisting of heterocyclyl and heterocyclylalkyl; [0103] each
Ar is independently selected from the group consisting of aryl,
substituted aryl, heteroaryl, and substituted heteroaryl; [0104]
R.sup.1, R.sup.3, and R.sup.5 are each independently selected from
the group consisting of H, alkyl, substituted alkyl, arylalkyl, and
substituted arylalkyl; [0105] each R.sup.2 is independently
selected from the group consisting of H, alkyl, substituted alkyl,
alkoxyalkyl, hydroxyalkyl, arylheteroalkyl, substituted
arylheteroalkyl, arylalkyl, substituted arylalkyl,
heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl,
substituted aminoalkyl, -alkylene-C(O)--OH, -alkylene-C(O)--Oalkyl,
-alkylene-C(O)amino, -alkylene-C(O)-alkyl; [0106] R.sup.4 and
R.sup.6 are independently selected from the group consisting of H,
alkyl, substituted alkyl, and heteroalkyl; [0107] each R.sup.7 is
independently selected from the group consisting of H, alkyl,
substituted alkyl, heteroalkyl, carbocyclyl, substituted
carbocyclyl, heterocyclyl, and substituted heterocyclyl; [0108]
R.sup.8 and R.sup.9 are each one or more substituents independently
selected from the group consisting of H, alkyl, substituted alkyl,
halogen, aryl, substituted aryl, heterocyclyl, substituted
heterocyclyl, and --CN; [0109] m is 1 or 2; [0110] n is 0 or 1; and
[0111] each p is independently 0 or 1.
[0112] In another embodiment of the compounds of Formula I, n is
1.
[0113] In another embodiment of the compounds of Formula I, n is
0.
[0114] In another embodiment of the compounds of Formula I, n is 1
and L.sup.2 is --CH(R.sup.6)--, wherein R.sup.6 is selected from
the group consisting of H, alkyl, substituted alkyl, and
heteroalkyl.
[0115] In another embodiment of the compounds of Formula I, n is 1
and L.sup.2 is --CH.sub.2--.
[0116] In another embodiment of the compounds of Formula I, n is 1
and L.sup.2 is --C(O)--.
[0117] In another embodiment of the compounds of Formula I, n is 1
and Y is heterocyclylalkyl.
[0118] In another embodiment of the compounds of Formula I, n is 1
and Y--R.sup.8 is --CH.sub.2-(substituted heteroaryl).
[0119] In another embodiment of the compounds of Formula I, n is 1
and Y--R.sup.8 is
##STR00006##
[0120] In another embodiment of the compounds of Formula I, n is 1
and Y--R.sup.8 is
##STR00007##
wherein R.sup.8 is alkyl, for example 2-propyl.
[0121] In another embodiment of the compounds of Formula I, n is 1
and X is heterocyclylalkyl.
[0122] In another embodiment of the compounds of Formula I, n is 1
and X is --CH.sub.2-heteroaryl.
[0123] In another embodiment of the compounds of Formula I, n is 1
and X--R.sup.9 is
##STR00008##
[0124] In another embodiment of the compounds of Formula I, n is 1
and X--R.sup.9 is
##STR00009##
[0125] In another embodiment of the compounds of Formula I, n is 1
and Z.sup.1 is --N(R.sup.7)--.
[0126] In another embodiment of the compounds of Formula I, n is 1
and Z.sup.1 is --N(alkyl)- or --N(carbocyclyl)-.
[0127] In another embodiment of the compounds of Formula I, n is 1
and Z.sup.1 is --N(CH.sub.3)-- or --N(cyclopropyl)-.
[0128] In another embodiment of the compounds of Formula I, n is 1
and Z.sup.1 is --NH--.
[0129] In another embodiment of the compounds of Formula I, n is 1
and each A is independently aryl or substituted aryl.
[0130] In another embodiment of the compounds of Formula I, n is 1
and each A is phenyl.
[0131] In another embodiment of the compounds of Formula I, n is 1
and each A is phenyl and each p is 0.
[0132] In another embodiment of the compounds of Formula I, n is 1
and R.sup.2 is H, alkyl, substituted alkyl, or heteroalkyl.
[0133] In another embodiment of the compounds of Formula I, n is 1
and R.sup.2 is 2-propyl, methyl, --CH.sub.2--O-benzyl,
--CH(CH.sub.3)(O-t-Bu), or --CH(CH.sub.3)(OH).
[0134] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--; [0135] each A is independently aryl, substituted aryl,
alkyl, or substituted alkyl; [0136] R.sup.1 is H or alkyl; [0137]
each R.sup.2 is independently H, alkyl, substituted alkyl, or
heteroalkyl; [0138] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are each
H; [0139] each R.sup.7 is independently H, alkyl, or carbocyclyl;
[0140] R.sup.8 is H or alkyl; [0141] R.sup.9 is H; [0142] X and Y
are both heterocyclylalkyl; [0143] Z.sup.2 is --O--; and [0144] p
is 0.
[0145] In another embodiment of the compounds of Formula I, each A
is phenyl; [0146] R.sup.1 is H or --CH.sub.3; [0147] each R.sup.2
is H, methyl, ethyl, 2-propyl, --CH.sub.2--O-benzyl,
--CH(CH.sub.3)--OH, or --CH(CH.sub.3)(O-t-Bu); [0148] each R.sup.7
is H, methyl or cyclopropyl; [0149] R.sup.8 is H or 2-propyl;
[0150] X is
##STR00010##
[0150] and [0151] Y is
##STR00011##
[0152] In another embodiment, the compounds of Formula I have the
following general Formula IA:
##STR00012##
[0153] In another embodiment of the compounds of Formula IA,
Z.sup.1 is --N(R.sup.7)--. In a particular embodiment, R.sup.7 is
H. In another particular embodiment, R.sup.7 is alkyl, for example
any of the alkyl groups disclosed herein. In another particular
embodiment, R.sup.7 is heteroalkyl, for example any of the
heteroalkyl groups disclosed herein. In another particular
embodiment, R.sup.7 is substituted or unsubstituted carbocyclyl,
wherein for example, said carbocyclyl is any of the carbocyclyl
groups disclosed herein. In another particular embodiment, R.sup.7
is substituted or unsubstituted heterocyclyl, wherein for example,
said heterocyclyl is any of the heterocyclyl groups disclosed
herein.
[0154] In another embodiment of the compounds of Formula IA,
Z.sup.1 is --O--.
[0155] In another embodiment of the compounds of Formula IA,
L.sup.2 is --C(R.sup.6).sub.2--, wherein each R.sup.6 is H.
[0156] In another embodiment of the compounds of Formula IA,
L.sup.2 is --C(R.sup.6).sub.2--, wherein each R.sup.6 is
independently H or alkyl, and said alkyl includes any alkyl
disclosed herein.
[0157] In another embodiment of the compounds of Formula IA,
L.sup.2 is --C(R.sup.6).sub.2--, wherein one R.sup.6 is H and the
other R.sup.6 is alkyl, wherein said alkyl includes any alkyl
disclosed herein.
[0158] In another embodiment of the compounds of Formula IA, m is 1
and R.sup.2 is H.
[0159] In another embodiment of the compounds of Formula IA, m is 1
and R.sup.2 is alkyl, wherein said alkyl includes any alkyl
disclosed herein.
[0160] In another embodiment of the compounds of Formula IA, m is 1
and R.sup.2 is i-propyl.
[0161] In another embodiment of the compounds of Formula IA, m is 1
and R.sup.2 is i-butyl.
[0162] In another embodiment of the compounds of Formula IA, m is 1
and R.sup.2 is ethyl.
[0163] In another embodiment of the compounds of Formula IA, m is 1
and R.sup.2 is methyl.
[0164] In another embodiment of the compounds of Formula IA, m is 2
and each R.sup.2 is independently selected from H and alkyl.
[0165] In another embodiment of the compounds of Formula IA, m is 2
and each R.sup.2 is H.
[0166] In another embodiment, the compounds of Formula I have the
following general Formula IB:
##STR00013##
[0167] In another embodiment of the compounds of Formula IB,
Z.sup.1 is --N(R.sup.7)--. In a particular embodiment, R.sup.7 is
H. In another particular embodiment, R.sup.7 is alkyl, for example
any of the alkyl groups disclosed herein. In another particular
embodiment, R.sup.7 is heteroalkyl, for example any of the
heteroalkyl groups disclosed herein. In another particular
embodiment, R.sup.7 is substituted or unsubstituted carbocyclyl,
wherein for example, said carbocyclyl is any of the carbocyclyl
groups disclosed herein. In another particular embodiment, R.sup.7
is substituted or unsubstituted heterocyclyl, wherein for example,
said heterocyclyl is any of the heterocyclyl groups disclosed
herein.
[0168] In another embodiment of the compounds of Formula IB,
Z.sup.1 is --O--.
[0169] In another embodiment of the compounds of Formula IB,
L.sup.2 is --C(R.sup.6).sub.2--, wherein each R.sup.6 is H.
[0170] In another embodiment of the compounds of Formula IB,
L.sup.2 is --C(R.sup.6).sub.2--, wherein each R.sup.6 is
independently H or alkyl, and said alkyl includes any alkyl
disclosed herein.
[0171] In another embodiment of the compounds of Formula IB,
L.sup.2 is --C(R.sup.6).sub.2--, wherein one R.sup.6 is H and the
other R.sup.6 is alkyl, wherein said alkyl includes any alkyl
disclosed herein.
[0172] In another embodiment of the compounds of Formula IB,
R.sup.8 and R.sup.9 are both H.
[0173] In another embodiment of the compounds of Formula IB,
R.sup.8 and R.sup.9 are independently selected from H and alkyl,
wherein said alkyl includes any alkyl disclosed herein.
[0174] In another embodiment, the compounds of Formula I have one
of the following structures:
##STR00014## ##STR00015## ##STR00016## ##STR00017## ##STR00018##
##STR00019## ##STR00020## ##STR00021## ##STR00022## ##STR00023##
##STR00024## ##STR00025## ##STR00026##
including stereoisomers or mixtures of stereoisomers thereof. One
skilled in the art will recognize that stereoisomers or mixtures of
stereoisomers of the compounds of the present application include
enantiomers, diastereomers, and other stereoisomers. For example,
for:
##STR00027##
contemplated stereoisomers include at least:
##STR00028##
as well as mixtures of two or more of these stereoisomers.
[0175] In still another embodiment of the compounds of Formula I,
L.sup.1 is --C(R.sup.6).sub.2--, --C(O)--, --S(O.sub.2)--,
--N(R.sup.7)--C(O)--, or --O--C(O)--. When L.sup.1 is
--C(R.sup.6).sub.2--, each R.sup.6 is independently selected from
the group consisting of H, alkyl, substituted alkyl, and
heteroalkyl, wherein alkyl, substituted alkyl, and heteroalkyl are
as defined and exemplified herein. Non-limiting examples of
--C(R.sup.6).sub.2-- include --CH.sub.2--, --CH(alkyl)-,
--CH(substituted alkyl)-, --CH(heteroalkyl)-, --C(alkyl).sub.2-,
--C(substituted alkyl).sub.2-, --C(heteroalkyl).sub.2-,
--C(alkyl)(substituted alkyl)-, --C(heteroalkyl)(substituted
alkyl)-, and --C(alkyl)(heteroalkyl)-, wherein alkyl, substituted
alkyl, and heteroalkyl are as defined and exemplified herein. When
L.sup.1 is --N(R.sup.7)--C(O)--, R.sup.7 is H, alkyl, substituted
alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl,
heterocyclyl, or substituted heterocyclyl, wherein alkyl,
substituted alkyl, heteroalkyl, carbocyclyl, substituted
carbocyclyl, heterocyclyl, or substituted heterocyclyl are as
defined and exemplified herein.
[0176] In still another embodiment of the compounds of Formula I,
L.sup.2 is --C(R.sup.6).sub.2-- or --C(O)--. When L.sup.2 is
--C(R.sup.6).sub.2--, each R.sup.6 is independently selected from
H, alkyl, substituted alkyl or heteroalkyl, where each alkyl,
substituted alkyl, or heteroalkyl can include any of the alkyl,
substituted alkyl, or heteroalkyl groups defined or disclosed
herein. Non-limiting examples of --C(R.sup.6).sub.2-- include
--CH.sub.2--, --CH(CH.sub.3)--, --CH(--CH.sub.2CH.sub.3)--,
--CH(--CH.sub.2CH.sub.2CH.sub.3)--, --CH(--CH(CH.sub.3).sub.2)--,
--CH(--CH.sub.2CH.sub.2CH.sub.2CH.sub.3)--,
--CH(--CH.sub.2CH(CH.sub.3).sub.2)--,
--CH(--CH(CH.sub.3)CH.sub.2CH.sub.3)--,
--CH(--C(CH.sub.3).sub.3)--, --C(CH.sub.3).sub.2--,
--CH(OCH.sub.3)--, --CH(CH.sub.2OH)--, --CH(CH.sub.2CH.sub.2OH)--,
etc.
[0177] In still another embodiment of the compounds of Formula I,
each L.sup.3 is independently a covalent bond, an alkylene or
substituted alkylene. When any L.sup.3 is an alkylene, non-limiting
examples of alkylene includes any of the alkylenes defined or
disclosed herein. When any L.sup.3 is a substituted alkylene,
non-limiting examples of substituted alkylene includes any of the
substituted alkylenes defined or disclosed herein. For example,
substituted alkylenes include alkylenes substituted with one or
more --OH group, alkylenes substituted with one or more ether
group, e.g., a --O-Bn group, alkylenes substituted with one or more
halogen, or alkylenes substituted with combinations of two or more
substituents (e.g., --OH and halogen, halogen and ether, etc.).
[0178] In still another embodiment of the compounds of Formula I,
each L.sup.3 is the same, i.e., each L.sup.3 is the same alkylene
or substituted alkylene group.
[0179] In still another embodiment of the compounds of Formula I,
each L.sup.3 is different, i.e., one L.sup.3 is an alkylene and the
other L.sup.3 is a substituted alkylene, one L.sup.3 is an alkylene
and the other L.sup.3 is a different alkylene, or one L.sup.3 is a
substituted alkylene, and the other L.sup.3 is a different
substituted alkylene.
[0180] In still another embodiment of the compounds of Formula I,
each L.sup.4 is independently selected from the group consisting of
a covalent bond, alkylene, substituted alkylene, --O--,
--CH.sub.2--O--, and --NH--. When L.sup.4 is alkylene, said
alkylene includes any alkylene defined or exemplified herein. When
L.sup.4 is substituted alkylene, said substituent includes any
alkylene defined or exemplified herein, substituted by one or more
substituents as defined herein.
[0181] In still another embodiment of the compounds of Formula I,
both L.sup.4 groups are the same, i.e. both L.sup.4 groups are a
covalent bond, both are --O--, both are --CH.sub.2--O--, (wherein
the CH.sub.2 group is attached to either the "A" moiety or the "Ar"
moiety of Formula I), both are a substituted or unsubstituted
alkylene, or both are --NH--.
[0182] In still another embodiment of the compounds of Formula I,
each L.sup.4 is different. For example, one L.sup.4 is a covalent
bond and the other L.sup.4 is --O--, one L.sup.4 is a covalent bond
and the other L.sup.4 is --CH.sub.2--O-- (wherein the CH.sub.2
group is attached to either the "A" moiety or the "Ar" moiety of
Formula I), one L.sup.4 is a covalent bond and the other L.sup.4 is
--NH--, one L.sup.4 is a --O-- and the other L.sup.4 is
--CH.sub.2--O-- (wherein the CH.sub.2 group is attached to either
the "A" moiety or the "Ar" moiety of Formula I), one L.sup.4 is
--O-- and the other L.sup.4 is --NH--, one L.sup.4 is
--CH.sub.2--O-- (wherein the CH.sub.2 group is attached to either
the "A" moiety or the "Ar" moiety of Formula I) and the other
L.sup.4 is --NH--, one L.sup.4 is a covalent bond and the other
L.sup.4 is a substituted or unsubstituted alkylene, one L.sup.4 is
a substituted alkylene and the other L.sup.4 is a unsubstituted
alkylene, one L.sup.4 is a substituted or unsubstituted alkene and
the other L.sup.4 is --O--, one L.sup.4 is a substituted or
unsubstituted alkylene and the other L.sup.4 is --CH.sub.2--O--
(wherein the CH.sub.2 group is attached to either the "A" moiety or
the "Ar" moiety of Formula I), or one L.sup.4 is substituted or
unsubstituted alkylene and the other L.sup.4 is --NH--.
[0183] In still another embodiment of the compounds of Formula I,
each A is independently H, alkyl, substituted alkyl, aryl,
substituted aryl, heterocyclyl, or substituted heterocyclyl, with
the proviso that when A is H, p is 0. When any A is alkyl, said
alkyl includes any alkyl defined or exemplified herein. When any A
is substituted alkyl, said alkyl includes any alkyl defined or
exemplified herein substituted with one or more of any substituent
defined or exemplified herein. When any A is aryl, said aryl
includes any aryl defined or exemplified herein. When any A is
substituted aryl, said aryl includes any aryl defined or
exemplified herein substituted with one or more of any substituent
defined or exemplified herein. When any A is heterocyclyl, said
heterocyclyl includes any heterocyclyl defined or exemplified
herein. When any A is substituted heterocyclyl, said heterocyclyl
is any heterocyclyl defined or exemplified herein substituted with
one or more of any substituent defined or exemplified herein.
[0184] In still another embodiment of the compounds of Formula I,
each A is H and each p is 0.
[0185] In still another embodiment of the compounds of Formula I,
each A is substituted or unsubstituted alkyl, wherein alkyl is any
alkyl defined or exemplified herein, and, when present, the
substituents on said alkyl include one or more of any substituents
defined or exemplified herein.
[0186] In still another embodiment of the compounds of Formula I,
each A is substituted or unsubstituted aryl, wherein aryl is any
aryl defined or exemplified herein, and, when present, the
substituents on said aryl include one or more of any substituents
defined or exemplified herein. In a particular embodiment, A is
phenyl.
[0187] In still another embodiment of the compounds of Formula I,
each A is substituted or unsubstituted heterocyclyl, wherein
heterocyclyl is any heterocyclyl defined or exemplified herein,
and, when present, the substituents on said heterocyclyl include
one or more of any substituents defined or exemplified herein.
[0188] In still another embodiment of the compounds of Formula I,
one A is H and the other A is substituted or unsubstituted alkyl,
wherein alkyl is any alkyl defined or exemplified herein, and, when
present, the substituent on said alkyl includes one or more of any
substituent defined or exemplified herein.
[0189] In still another embodiment of the compounds of Formula I,
one A is H and the other A is substituted or unsubstituted aryl,
wherein aryl is any aryl defined or exemplified herein, and the
substituents on said aryl are any substituents defined and
exemplified herein. In a particular embodiment, one A is
phenyl.
[0190] In still another embodiment of the compounds of Formula I,
one A is H and the other A is substituted or unsubstituted
heterocyclyl, wherein heterocyclyl is any heterocyclyl defined or
exemplified herein, and, when present, the substituents on said
heterocyclyl include one or more of any substituent defined or
exemplified herein.
[0191] In still another embodiment of the compounds of Formula I,
one A is substituted or unsubstituted alkyl, and the other A is
substituted or unsubstituted aryl, wherein alkyl and aryl are any
alkyl or aryl defined or exemplified herein, and, when present, the
substituents on said alkyl or aryl include one or more of any
substituents defined or exemplified herein.
[0192] In still another embodiment of the compounds of Formula I,
one A is substituted or unsubstituted alkyl, and the other A is
substituted or unsubstituted heterocyclyl, wherein alkyl and
heterocyclyl are any alkyl or heterocyclyl defined or exemplified
herein, and, when present, the substituents on said alkyl or
heterocyclyl include one or more of any substituents defined or
exemplified herein.
[0193] In still another embodiment of the compounds of Formula I,
one A is substituted or unsubstituted aryl, and the other A is
substituted or unsubstituted heterocyclyl, wherein aryl and
heterocyclyl are any aryl or heterocyclyl defined or exemplified
herein, and, when present, the substituents on said aryl or
heterocyclyl include one or more of any substituents defined or
exemplified herein.
[0194] In still another embodiment of the compounds of Formula I,
Z.sup.1 is --O-- or --N(R.sup.7)--. When Z.sup.1 is --N(R.sup.7)--,
R.sup.7 is H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl,
substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl,
wherein alkyl, substituted alkyl, heteroalkyl, carbocyclyl,
substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl
are any alkyl, substituted alkyl, heteroalkyl, carbocyclyl,
substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl
defined or exemplified herein.
[0195] In still another embodiment of the compounds of Formula I,
Z.sup.2 is --O-- or --N(R.sup.7)--. When Z.sup.2 is --N(R.sup.7)--,
R.sup.7 is H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl,
substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl,
wherein alkyl, substituted alkyl, heteroalkyl, carbocyclyl,
substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl
are any alkyl, substituted alkyl, heteroalkyl, carbocyclyl,
substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl
defined or exemplified herein.
[0196] In still another embodiment of the compounds of Formula I,
Z.sup.1 and Z.sup.2 are the same, e.g., Z.sup.1 and Z.sup.2 are
both --O--, or Z.sup.1 and Z.sup.2 are both --N(R.sup.7)--, where
R.sup.7 is H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl,
substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl,
wherein alkyl, substituted alkyl, heteroalkyl, carbocyclyl,
substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl
are any alkyl, substituted alkyl, heteroalkyl, carbocyclyl,
substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl
defined or exemplified herein.
[0197] In still another embodiment of the compounds of Formula I,
Z.sup.1 and Z.sup.2 are different, e.g. Z.sup.1 is --O-- and
Z.sup.2 is --N(R.sup.7)--, Z.sup.1 is --N(R.sup.7)-- and Z.sup.2 is
--O--, or Z.sup.1 and Z.sup.2 are both --N(R.sup.7)-- but in
Z.sup.1 the R.sup.7 is different from the R.sup.7 in Z.sup.2. When
either Z.sup.1 of Z.sup.2 is --N(R.sup.7)--, R.sup.7 is H, alkyl,
substituted alkyl, heteroalkyl, carbocyclyl, substituted
carbocyclyl, heterocyclyl, or substituted heterocyclyl, wherein
alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted
carbocyclyl, heterocyclyl, or substituted heterocyclyl are any
alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted
carbocyclyl, heterocyclyl, or substituted heterocyclyl defined or
exemplified herein.
[0198] In still another embodiment of the compounds of Formula I, Y
is heterocyclyl or heterocyclylalkyl, wherein heterocyclyl and
heterocyclylalkyl are any heterocyclyl or heterocyclylalkyl defined
or exemplified herein. In a particular embodiment, Y is
heterocyclylalkyl, e.g. thiazolylmethyl (--CH.sub.2-thiazolyl).
[0199] In still another embodiment of the compounds of Formula I, X
is heterocyclyl or heterocyclylalkyl, wherein heterocyclyl and
heterocyclylalkyl are any heterocyclyl or heterocyclylalkyl defined
or exemplified herein. In a particular embodiment, X is
heterocyclylalkyl, e.g. thiazolylmethyl.
[0200] In still another embodiment of the compounds of Formula I, X
and Y are different, e.g., X and Y are different heterocyclyls, X
and Y are different heterocyclylalkyls, X is heterocyclyl and Y is
heterocyclylalkyl, or X is heterocyclylalkyl and Y is heterocyclyl,
wherein heterocyclyl and heterocyclylalkyl are any heterocyclyl or
heterocyclylalkyl defined or exemplified herein.
[0201] In still another embodiment of the compounds of Formula I, X
and Y are the same. In a particular embodiment both X and Y are
heterocyclylalkyls, e.g. thiazolylmethyl.
[0202] In still another embodiment of the compounds of Formula I,
each Ar is aryl, substituted aryl, heteroaryl, or substituted
heteroaryl, wherein the aryl or heteroaryl are any aryl or
heteroaryl defined or exemplified herein, and, when present, the
substituents on the aryl or heteroaryl include one or more of any
substituents defined or exemplified herein.
[0203] In still another embodiment of the compounds of Formula I,
each Ar is the same, e.g., each Ar is an aryl such as phenyl.
[0204] In still another embodiment of the compounds of Formula I,
each Ar is different, e.g. one Ar is a substituted or unsubstituted
aryl and the other Ar is a substituted or unsubstituted heteroaryl,
each Ar is a different substituted or unsubstituted aryl, or each
Ar is a different substituted or unsubstituted heteroaryl, wherein
aryl and heteroaryl are any aryl or heteroaryl defined or
exemplified herein, and, when present, the substituents on the aryl
or heteroaryl include one or more of any substituents defined or
exemplified herein.
[0205] In still another embodiment of the compounds of Formula I,
R.sup.1, R.sup.3, and R.sup.5 are each independently H, alkyl, or
substituted alkyl, wherein alkyl and substituted alkyl include any
of the alkyl or substituted alkyls defined or disclosed herein.
[0206] In still another embodiment of the compounds of Formula I,
R.sup.1, R.sup.3, and R.sup.5 are each the same. In a particular
embodiment R.sup.1, R.sup.3, and R.sup.5 are each H. in another
particular embodiment R.sup.1, R.sup.3, and R.sup.5 are each alkyl,
e.g. one of the alkyl groups defined or disclosed herein.
[0207] In still another embodiment of the compounds of Formula I,
R.sup.1, R.sup.3, and R.sup.5 are each different.
[0208] In still another embodiment of the compounds of Formula I,
one of R.sup.1, R.sup.3, and R.sup.5 is different from the other
two groups.
[0209] In still another embodiment of the compounds of Formula I, n
and m are both 1, and each R.sup.2 is independently H, alkyl,
substituted alkyl, arylheteroalkyl, arylalkyl, or
heterocyclylalkyl, wherein alkyl, substituted alkyl,
arylheteroalkyl, aryl alkyl, or heterocyclylalkyl is any alkyl,
substituted alkyl, arylheteroalkyl, aryl alkyl, or
heterocyclylalkyl defined or disclosed herein.
[0210] In still another embodiment of the compounds of Formula I, n
and m are both 1, and R.sup.2 is H.
[0211] In still another embodiment of the compounds of Formula I, n
is 1, m is 2, and R.sup.2 is H.
[0212] In still another embodiment of the compounds of Formula I, n
and m are both 1, and at least one R.sup.2 is alkyl. In a
particular embodiment at least one R.sup.2 is methyl. In another
particular embodiment at least one R.sup.2 is ethyl. In another
particular embodiment at least one R.sup.2 is i-propyl. In another
particular embodiment at least one R.sup.2 is t-butyl. In another
particular embodiment, one R.sup.2 is H, and the other R.sup.2 is
methyl. In another particular embodiment, one R.sup.2 is H, and the
other R.sup.2 is ethyl. In another particular embodiment, one
R.sup.2 is H, and the other R.sup.2 is i-propyl. In another
particular embodiment, one R.sup.2 is H, and the other R.sup.2 is
t-butyl.
[0213] In still another embodiment of the compounds of Formula I, n
and m are both 1, and R.sup.2 is substituted alkyl. In a particular
embodiment at least one R.sup.2 is --CH(CH.sub.3)OH or
--CH(CH.sub.3)O(t-Bu)
[0214] In still another embodiment of the compounds of Formula I, n
and m are both 1, and at least one R.sup.2 is arylheteroalkyl. In
particular embodiment n and m are both 1, and at least one R.sup.2
is selected from the group consisting of H, methyl, ethyl,
benzyl-O--CH.sub.2--, i-propyl, --CH(CH.sub.3)OBn,
--CH.sub.2CH(CH.sub.3)--O-tBu, --CH(CH.sub.3)OH, --CH.sub.2OH,
--CH.sub.2OtBu, --CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2NH--P
(where P is a protecting group such as Boc, Ac, methanesulfonyl,
etc.), --CH.sub.2CH.sub.2-morpholine, --CH.sub.2C(O)OH,
--CH.sub.2C(O)OtBu, and --CH.sub.2C(O)--NH.sub.2.
[0215] In still another embodiment of the compounds of Formula I, n
and m are both 1, and at least one R.sup.2 is arylheteroalkyl. In
particular embodiment n and m are both 1, one R.sup.2 is H and one
R.sup.2 is selected from the group consisting of H, methyl, ethyl,
benzyl-O--CH.sub.2--, i-propyl, --CH(CH.sub.3)OBn,
--CH.sub.2CH(CH.sub.3)--O-tBu, --CH(CH.sub.3)OH, --CH.sub.2OH,
--CH.sub.2OtBu, --CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2NH--P
(where P is a protecting group such as Boc, Ac, methanesulfonyl,
etc.), --CH.sub.2CH.sub.2-morpholine, --CH.sub.2C(O)OH,
--CH.sub.2C(O)OtBu, and --CH.sub.2C(O)--NH.sub.2.
[0216] In still another embodiment of the compounds of Formula I,
R.sup.4 is H, alkyl, substituted alkyl, and heteroalkyl, wherein
alkyl, substituted alkyl, and heteroalkyl are any alkyl,
substituted alkyl, or heteroalkyl defined or disclosed herein. A
particular embodiment, R.sup.4 is H.
[0217] In still another embodiment of the compounds of Formula I,
R.sup.6 is H, alkyl, substituted alkyl, and heteroalkyl, wherein
alkyl, substituted alkyl, and heteroalkyl are any alkyl,
substituted alkyl, or heteroalkyl defined or disclosed herein. A
particular embodiment, R.sup.6 is H.
[0218] In still another embodiment of the compounds of Formula I,
R.sup.8 and R.sup.9 are each one or more substituents independently
selected from the group consisting of H, alkyl, substituted alkyl,
halogen, aryl, substituted aryl, heterocyclyl, substituted
heterocyclyl, and --CN, wherein when R.sup.8 or R.sup.9 are alkyl,
substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl,
or substituted heterocyclyl, said alkyl, substituted alkyl,
halogen, aryl, substituted aryl, heterocyclyl, or substituted
heterocyclyl are any such groups defined or disclosed herein.
[0219] In still another embodiment of the compounds of Formula I,
R.sup.8 and R.sup.9 are the same. In a particular embodiment
R.sup.8 and R.sup.9 are both H.
[0220] In still another embodiment of the compounds of Formula I,
R.sup.8 and R.sup.9 are different. In a particular embodiment
R.sup.8 is alkyl and R.sup.9 is H. in another particular
embodiment, R.sup.8 is i-propyl and R.sup.9 is H.
[0221] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl group, wherein said alkylene and aryl moieties are
any alkylene and aryl moieties defined or exemplified herein,
optionally substituted on the alkylene and/or aryl with one or more
of any substituents defined or exemplified herein.
[0222] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl-alkylene-aryl group, wherein said alkylene and aryl
moieties are any alkylene and aryl moieties defined or exemplified
herein, optionally substituted on the alkylene and/or aryl with one
or more of any substituents defined or exemplified herein.
[0223] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl-alkylene-heteroaryl group, wherein said alkylene,
aryl, and heteroaryl moieties are any alkylene, aryl, and
heteroaryl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl, and/or heteroaryl with one
or more of any substituents defined or exemplified herein.
[0224] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heteroaryl-alkylene-heteroaryl group, wherein said
alkylene and heteroaryl moieties are any alkylene and heteroaryl
moieties defined or exemplified herein, optionally substituted on
the alkylene and/or heteroaryl with one or more of any substituents
defined or exemplified herein.
[0225] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heteroaryl-alkylene-aryl group, wherein said alkylene,
aryl, and heteroaryl moieties are any alkylene, aryl, and
heteroaryl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl, and/or heteroaryl with one
or more of any substituents defined or exemplified herein.
[0226] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl-aryl group, wherein said alkylene and aryl moieties
are any alkylene and aryl moieties defined or exemplified herein,
optionally substituted on the alkylene and/or aryl with one or more
of any substituents defined or exemplified herein.
[0227] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl-O-aryl group, wherein said alkylene and aryl
moieties are any alkylene and aryl moieties defined or exemplified
herein, optionally substituted on the alkylene and/or aryl with one
or more of any substituents defined or exemplified herein.
[0228] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl-CH.sub.2--O-aryl group, wherein said alkylene and
aryl moieties are any alkylene and aryl moieties defined or
exemplified herein, optionally substituted on the alkylene and/or
aryl with one or more of any substituents defined or exemplified
herein.
[0229] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl-OCH.sub.2-aryl group, wherein said alkylene and aryl
moieties are any alkylene and aryl moieties defined or exemplified
herein, optionally substituted on the alkylene and/or aryl with one
or more of any substituents defined or exemplified herein.
[0230] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl-NH-aryl group, wherein said alkylene and aryl
moieties are any alkylene and aryl moieties defined or exemplified
herein, optionally substituted on the alkylene and/or aryl with one
or more of any substituents defined or exemplified herein.
[0231] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl-heterocyclyl group, wherein said alkylene, aryl, and
heterocyclyl moieties are any alkylene, aryl, and heterocyclyl
moieties defined or exemplified herein, optionally substituted on
the alkylene and/or aryl and/or heterocyclyl with one or more of
any substituents defined or exemplified herein.
[0232] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl-O-heterocyclyl group, wherein said alkylene, aryl,
and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl
moieties defined or exemplified herein, optionally substituted on
the alkylene and/or aryl and/or heterocyclyl with one or more of
any substituents defined or exemplified herein.
[0233] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl-CH.sub.2--O-heterocyclyl group, wherein said
alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl,
and heterocyclyl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heterocyclyl with
one or more of any substituents defined or exemplified herein.
[0234] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl-OCH.sub.2-heterocyclyl group, wherein said alkylene,
aryl, and heterocyclyl moieties are any alkylene, aryl, and
heterocyclyl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heterocyclyl with
one or more of any substituents defined or exemplified herein.
[0235] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl-NH-heterocyclyl group, wherein said alkylene, aryl,
and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl
moieties defined or exemplified herein, optionally substituted on
the alkylene and/or aryl and/or heterocyclyl with one or more of
any substituents defined or exemplified herein.
[0236] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heterocyclyl-aryl group, wherein said alkylene, aryl, and
heterocyclyl moieties are any alkylene, aryl, and heterocyclyl
moieties defined or exemplified herein, optionally substituted on
the alkylene and/or aryl and/or heterocyclyl with one or more of
any substituents defined or exemplified herein.
[0237] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heterocyclyl-O-aryl group, wherein said alkylene, aryl,
and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl
moieties defined or exemplified herein, optionally substituted on
the alkylene and/or aryl and/or heterocyclyl with one or more of
any substituents defined or exemplified herein.
[0238] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heterocyclyl-CH.sub.2--O-aryl group, wherein said
alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl,
and heterocyclyl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heterocyclyl with
one or more of any substituents defined or exemplified herein.
[0239] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heterocyclyl-OCH.sub.2-aryl group, wherein said alkylene,
aryl, and heterocyclyl moieties are any alkylene, aryl, and
heterocyclyl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heterocyclyl with
one or more of any substituents defined or exemplified herein.
[0240] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heterocyclyl-NH-aryl group, wherein said alkylene, aryl,
and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl
moieties defined or exemplified herein, optionally substituted on
the alkylene and/or aryl and/or heterocyclyl with one or more of
any substituents defined or exemplified herein.
[0241] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heterocyclyl-heterocyclyl group, wherein said alkylene,
aryl, and heterocyclyl moieties are any alkylene, aryl, and
heterocyclyl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heterocyclyl with
one or more of any substituents defined or exemplified herein.
[0242] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heterocyclyl-O-heterocyclyl group, wherein said alkylene,
aryl, and heterocyclyl moieties are any alkylene, aryl, and
heterocyclyl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heterocyclyl with
one or more of any substituents defined or exemplified herein.
[0243] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heterocyclyl-CH.sub.2--O-heterocyclyl group, wherein said
alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl,
and heterocyclyl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heterocyclyl with
one or more of any substituents defined or exemplified herein.
[0244] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heterocyclyl-OCH.sub.2-heterocyclyl group, wherein said
alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl,
and heterocyclyl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heterocyclyl with
one or more of any substituents defined or exemplified herein.
[0245] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heterocyclyl-NH-heterocyclyl group, wherein said
alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl,
and heterocyclyl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heterocyclyl with
one or more of any substituents defined or exemplified herein.
[0246] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl-heteroaryl group, wherein said alkylene, aryl, and
heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties
defined or exemplified herein, optionally substituted on the
alkylene and/or aryl and/or heteroaryl with one or more of any
substituents defined or exemplified herein.
[0247] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl-O-heteroaryl group, wherein said alkylene, aryl, and
heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties
defined or exemplified herein, optionally substituted on the
alkylene and/or aryl and/or heteroaryl with one or more of any
substituents defined or exemplified herein.
[0248] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl-CH.sub.2--O-heteroaryl group, wherein said alkylene,
aryl, and heteroaryl moieties are any alkylene, aryl, and
heteroaryl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heteroaryl with one
or more of any substituents defined or exemplified herein.
[0249] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl-OCH.sub.2-heteroaryl group, wherein said alkylene,
aryl, and heteroaryl moieties are any alkylene, aryl, and
heteroaryl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heteroaryl with one
or more of any substituents defined or exemplified herein.
[0250] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-aryl-NH-heteroaryl group, wherein said alkylene, aryl,
and heteroaryl moieties are any alkylene, aryl, and heteroaryl
moieties defined or exemplified herein, optionally substituted on
the alkylene and/or aryl and/or heteroaryl with one or more of any
substituents defined or exemplified herein.
[0251] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heteroaryl-aryl group, wherein said alkylene, aryl, and
heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties
defined or exemplified herein, optionally substituted on the
alkylene and/or aryl and/or heteroaryl with one or more of any
substituents defined or exemplified herein.
[0252] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heteroaryl-O-aryl group, wherein said alkylene, aryl, and
heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties
defined or exemplified herein, optionally substituted on the
alkylene and/or aryl and/or heteroaryl with one or more of any
substituents defined or exemplified herein.
[0253] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heteroaryl-CH.sub.2--O-aryl group, wherein said alkylene,
aryl, and heteroaryl moieties are any alkylene, aryl, and
heteroaryl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heteroaryl with one
or more of any substituents defined or exemplified herein.
[0254] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heteroaryl-OCH.sub.2-aryl group, wherein said alkylene,
aryl, and heteroaryl moieties are any alkylene, aryl, and
heteroaryl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heteroaryl with one
or more of any substituents defined or exemplified herein.
[0255] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heteroaryl-NH-aryl group, wherein said alkylene, aryl,
and heteroaryl moieties are any alkylene, aryl, and heteroaryl
moieties defined or exemplified herein, optionally substituted on
the alkylene and/or aryl and/or heteroaryl with one or more of any
substituents defined or exemplified herein.
[0256] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heterocyclyl-heteroaryl group, wherein said alkylene,
aryl, and heteroaryl moieties are any alkylene, aryl, and
heteroaryl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heteroaryl with one
or more of any substituents defined or exemplified herein.
[0257] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heterocyclyl-O-heteroaryl group, wherein said alkylene,
aryl, and heteroaryl moieties are any alkylene, aryl, and
heteroaryl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heteroaryl with one
or more of any substituents defined or exemplified herein.
[0258] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heterocyclyl-CH.sub.2--O-heteroaryl group, wherein said
alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and
heteroaryl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heteroaryl with one
or more of any substituents defined or exemplified herein.
[0259] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heteroaryl-OCH.sub.2-heteroaryl group, wherein said
alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and
heteroaryl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heteroaryl with one
or more of any substituents defined or exemplified herein.
[0260] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an
-alkylene-heteroaryl-NH-heteroaryl group, wherein said alkylene,
aryl, and heteroaryl moieties are any alkylene, aryl, and
heteroaryl moieties defined or exemplified herein, optionally
substituted on the alkylene and/or aryl and/or heteroaryl with one
or more of any substituents defined or exemplified herein.
[0261] In yet another embodiment of the compounds of Formula I, at
least one of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties is an alkyl
group.
[0262] In yet another embodiment of the compounds of Formula I,
both of the -L.sup.3-A-(L.sup.4-Ar).sub.p moieties are alkyl
groups, wherein the alkyl groups are the same or different.
[0263] In yet another embodiment of the compounds of Formula I,
both -L.sup.3-A-(L.sup.4-Ar).sub.p moieties are --CH.sub.2-phenyl
and X and Y are both --CH.sub.2-heterocyclyl.
[0264] In yet another embodiment of the compounds of Formula I,
both -L.sup.3-A-(L.sup.4-Ar).sub.p moieties are --CH.sub.2-phenyl
and Y is --CH.sub.2-heterocyclyl.
[0265] In yet another embodiment of the compounds of Formula I,
both -L.sup.3-A-(L.sup.4-Ar).sub.p moieties are --CH.sub.2-phenyl
and X is --CH.sub.2-heterocyclyl.
[0266] In yet another embodiment of the compounds of Formula I,
both -L.sup.3-A-(L.sup.4-Ar).sub.p moieties are --CH.sub.2-phenyl
and Y is --CH.sub.2-thiazolyl.
[0267] In yet another embodiment of the compounds of Formula I,
both -L.sup.3-A-(L.sup.4-Ar).sub.p moieties are --CH.sub.2-phenyl
and X is --CH.sub.2-thiazolyl.
[0268] In yet another embodiment of the compounds of Formula I,
both -L.sup.3-A-(L.sup.4-Ar).sub.p moieties are --CH.sub.2-phenyl
and X and Y are both --CH.sub.2-thiazolyl.
[0269] In yet another embodiment of the compounds of Formula I,
both -L.sup.3-A-(L.sup.4-Ar).sub.p moieties are --CH.sub.2-phenyl,
X and Y are both --CH.sub.2-thiazolyl, and n and m are both 1.
[0270] In yet another embodiment of the compounds of Formula I,
both -L.sup.3-A-(L.sup.4-Ar).sub.p moieties are --CH.sub.2-phenyl,
X and Y are both --CH.sub.2-thiazolyl, n and m are both 1, and at
least one R.sup.2 is a C.sub.1-C.sub.6 alkyl.
[0271] In yet another embodiment of the compounds of Formula I,
both -L.sup.3-A-(L.sup.4-Ar).sub.p moieties are --CH.sub.2-phenyl,
X and Y are both --CH.sub.2-thiazolyl, n and m are both 1, and at
least one R.sup.2 is a C.sub.1-C.sub.6 hydroxyalkyl.
[0272] In yet another embodiment of the compounds of Formula I,
both -L.sup.3-A-(L.sup.4-Ar).sub.p moieties are --CH.sub.2-phenyl,
X and Y are both --CH.sub.2-thiazolyl, n and m are both 1, and at
least one R.sup.2 is a C.sub.2-C.sub.10 alkoxyalkyl.
[0273] In yet another embodiment of the compounds of Formula I,
both -L.sup.3-A-(L.sup.4-Ar).sub.p moieties are --CH.sub.2-phenyl,
X and Y are both --CH.sub.2-thiazolyl, n and m are both 1, and at
least one R.sup.2 is a C.sub.7-C.sub.14 arylalkyloxyalkyl.
[0274] In yet another embodiment of the compounds of Formula I,
both -L.sup.3-A-(L.sup.4-Ar).sub.p moieties are --CH.sub.2-phenyl,
X and Y are both --CH.sub.2-thiazolyl, n and m are both 1, and at
least one R.sup.2 is a C.sub.1-C.sub.6 aminoalkyl.
[0275] In yet another embodiment of the compounds of Formula I,
both -L.sup.3-A-(L.sup.4-Ar).sub.p moieties are --CH.sub.2-phenyl,
X and Y are both --CH.sub.2-thiazolyl, n and m are both 1, and at
least one R.sup.2 is a C.sub.1-C.sub.6 aminoalkyl substituted on
the nitrogen with an amine protecting group selected from acyl,
alkylsulfonyl, arylsulfonyl, heterocyclylacyl, and benzyl.
[0276] In yet another embodiment of the compounds of Formula I,
both -L.sup.3-A-(L.sup.4-Ar).sub.p moieties are --CH.sub.2-phenyl,
X and Y are both --CH.sub.2-thiazolyl, n and m are both 1, and at
least one R.sup.2 is a substituted or unsubstituted
heterocyclylalkyl.
[0277] In yet another embodiment of the compounds of Formula I,
both -L.sup.3-A-(L.sup.4-Ar).sub.p moieties are --CH.sub.2-phenyl,
X and Y are both --CH.sub.2-thiazolyl, n and m are both 1, and
L.sup.2 is --CH.sub.2--.
[0278] In yet another embodiment of the compounds of Formula I, at
least one -L.sup.3-A-(L.sup.4-Ar).sub.p moiety is
--CH.sub.2-phenyl-CH.sub.2-phenyl.
[0279] In yet another embodiment of the compounds of Formula I, at
least one -L.sup.3-A-(L.sup.4-Ar).sub.p moiety is --CH.sub.2--
heteroaryl-CH.sub.2-phenyl.
[0280] In yet another embodiment of the compounds of Formula I, at
least one -L.sup.3-A-(L.sup.4-Ar).sub.p moiety is
--CH.sub.2-phenyl-CH.sub.2-heteroaryl.
[0281] In yet another embodiment of the compounds of Formula I, at
least one -L.sup.3-A-(L.sup.4-Ar).sub.p moiety is --CH.sub.2--
heteroaryl-CH.sub.2-heteroaryl.
[0282] In yet another embodiment of the compounds of Formula I, X
and Y are both heterocyclylalkyl.
[0283] In yet another embodiment of the compounds of Formula I, X
and Y are both heteroarylalkyl.
[0284] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, and both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl.
[0285] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, and L.sup.2 is
--CH.sub.2--.
[0286] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, and m and n are both 1.
[0287] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, and R.sup.1 is H.
[0288] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, and Z.sup.1 is
--N(alkyl)-.
[0289] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, and Z.sup.1 is
--N(CH.sub.3)--.
[0290] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(alkyl)-, and Z.sup.2 is --O--.
[0291] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(CH.sub.3)--, and Z.sup.2 is --O--.
[0292] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(alkyl)-, Z.sup.2 is --O--, and Y is substituted or
unsubstituted --CH.sub.2-4-thiazole.
[0293] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(alkyl)-, Z.sup.2 is --O--, and R.sup.8--Y is
--CH.sub.2-(2-alkyl-4-thiazole).
[0294] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(H)--, Z.sup.2 is --O--, and R.sup.8--Y is
--CH.sub.2-(2-iPr-4-thiazole).
[0295] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(alkyl)-, Z.sup.2 is --O--, Y is substituted or unsubstituted
--CH.sub.2-4-thiazole, and X is substituted or unsubstituted
--CH.sub.2-5-thiazole.
[0296] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(alkyl)-, Z.sup.2 is --O--, Y is substituted or unsubstituted
--CH.sub.2-4-thiazole, and X is unsubstituted
--CH.sub.2-5-thiazole.
[0297] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(H)--, Z.sup.2 is --O--, R.sup.8--Y is
--CH.sub.2-(2-iPr-4-thiazole), and X is unsubstituted
--CH.sub.2-5-thiazole.
[0298] In another embodiment of the compounds of Formula I, each
R.sup.2 is independently H or hydroxyalkyl.
[0299] In another embodiment of the compounds of Formula I, each
R.sup.2 is independently H or heterocyclylalkyl.
[0300] In another embodiment of the compounds of Formula I, each
R.sup.2 is independently H or --CH.sub.2-heterocyclyl, wherein said
heterocyclyl is a 5- or 6-membered ring having at least one ring
nitrogen atom.
[0301] In another embodiment of the compounds of Formula I, each
R.sup.2 is independently H or --CH.sub.2-heterocyclyl, wherein said
heterocyclyl is a 6-membered ring having at least one ring nitrogen
atom.
[0302] In another embodiment of the compounds of Formula I, each
R.sup.2 is independently H or --CH.sub.2-heterocyclyl, wherein said
heterocyclyl is a 6-membered ring having at least one ring nitrogen
atom, where the --CH.sub.2-- moiety thereof is bonded to the ring
nitrogen atom.
[0303] In another embodiment of the compounds of Formula I, each
R.sup.2 is independently H or --CH.sub.2-heterocyclyl, wherein said
heterocyclyl is selected from the group consisting of piperadyl,
piperazyl, and morpholinyl.
[0304] In another embodiment of the compounds of Formula I, each
R.sup.2 is independently H or --CH.sub.2-heterocyclyl, wherein said
heterocyclyl is selected from the group consisting of piperadyl,
piperazyl, and morpholinyl, and the --CH.sub.2-- moiety thereof is
bonded to a ring nitrogen atom of the heterocyclyl.
[0305] In another embodiment of the compounds of Formula I, each
R.sup.2 is independently H or aminoalkyl.
[0306] In another embodiment of the compounds of Formula I, each
R.sup.2 is independently H or aminoalkyl substituted with an amine
protecting group selected from the group consisting of acetyl,
alkylsulfonyl, Boc, Cbz, and Fmoc.
[0307] In another embodiment of the compounds of Formula I, each
R.sup.2 is independently H or ethylacetamide
(--CH.sub.2CH.sub.2NHC(O)CH.sub.3).
[0308] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(H)--, Z.sup.2 is --O--, R.sup.8--Y is
--CH.sub.2-(2-iPr-4-thiazole), X is unsubstituted
--CH.sub.2-5-thiazole, and R.sup.2 is independently H or
hydroxyalkyl.
[0309] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(H)--, Z.sup.2 is --O--, R.sup.8--Y is
--CH.sub.2-(2-iPr-4-thiazole), X is unsubstituted
--CH.sub.2-5-thiazole, and one R.sup.2 is H and the other R.sup.2
is hydroxyalkyl.
[0310] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(H)--, Z.sup.2 is --O--, R.sup.8--Y is
--CH.sub.2-(2-iPr-4-thiazole), X is unsubstituted
--CH.sub.2-5-thiazole, and one R.sup.2 is H and the other R.sup.2
is hydroxymethyl.
[0311] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(H)--, Z.sup.2 is --O--, R.sup.8--Y is
--CH.sub.2-(2-iPr-4-thiazole), X is unsubstituted
--CH.sub.2-5-thiazole, and each R.sup.2 is independently H or
--CH.sub.2-heterocyclyl, wherein said heterocyclyl is a 5- or
6-membered ring having at least one ring nitrogen atom.
[0312] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(H)--, Z.sup.2 is --O--, R.sup.8--Y is
--CH.sub.2-(2-iPr-4-thiazole), X is unsubstituted
--CH.sub.2-5-thiazole, and each R.sup.2 is independently H or
--CH.sub.2-heterocyclyl, wherein said heterocyclyl is selected from
the group consisting of piperadyl, piperazyl, and morpholinyl, and
the --CH.sub.2-- moiety thereof is bonded to a ring nitrogen atom
of the heterocyclyl
[0313] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(H)--, Z.sup.2 is --O--, R.sup.8--Y is
--CH.sub.2-(2-iPr-4-thiazole), X is unsubstituted
--CH.sub.2-5-thiazole, and one R.sup.2 is H and the other R.sup.2
is --CH.sub.2-heterocyclyl, wherein said heterocyclyl is selected
from the group consisting of piperadyl, piperazyl, and morpholinyl,
and the --CH.sub.2-- moiety thereof is bonded to a ring nitrogen
atom of the heterocyclyl
[0314] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(H)--, Z.sup.2 is --O--, R.sup.8--Y is
--CH.sub.2-(2-iPr-4-thiazole), X is unsubstituted
--CH.sub.2-5-thiazole, and each R.sup.2 is independently H or
aminoalkyl substituted with an amine protecting group selected from
the group consisting of acetyl, alkylsulfonyl, Boc, Cbz, and
Fmoc.
[0315] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(H)--, Z.sup.2 is --O--, R.sup.8--Y is
--CH.sub.2-(2-iPr-4-thiazole), X is unsubstituted
--CH.sub.2-5-thiazole, and one R.sup.2 is H and the other R.sup.2
is aminoalkyl substituted with an amine protecting group selected
from the group consisting of acetyl, alkylsulfonyl, Boc, Cbz, and
Fmoc.
[0316] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(H)--, Z.sup.2 is --O--, R.sup.8--Y is
--CH.sub.2-(2-iPr-4-thiazole), X is unsubstituted
--CH.sub.2-5-thiazole, and one R.sup.2 is H and the other R.sup.2
is ethylacetamide (--CH.sub.2CH.sub.2NHC(O)CH.sub.3).
[0317] In another embodiment of the compounds of Formula I, L.sup.1
is --C(O)--, R.sup.4 is H, both -L.sup.3-A-(L.sup.4-Ar).sub.p
groups are substituted or unsubstituted benzyl, L.sup.2 is
--CH.sub.2--, m and n are both 1, R.sup.1 is H, Z.sup.1 is
--N(alkyl)-, Z.sup.2 is --O--, and Y is substituted or
unsubstituted --CH.sub.2-thiazole.
[0318] In still another embodiment, the compounds of Formula I, or
pharmaceutically acceptable salts, solvates, esters, or
stereoisomers thereof, have the structure shown in Formula IIA:
##STR00029##
wherein R.sup.11 and R.sup.16 are each independently heterocyclyl
or substituted heterocyclyl; and R.sup.12, R.sup.13, R.sup.14, and
R.sup.15 are each independently H, --C.sub.1-4 alkyl or --C.sub.1-4
substituted alkyl.
[0319] In still another embodiment of the compounds of Formula IIA,
R.sup.13 is H, --C.sub.1-4 alkyl,
--(CH.sub.2).sub.0-1CR.sup.17R.sup.18OR.sup.19,
--(CH.sub.2).sub.0-3CR.sup.17R.sup.18NR.sup.20R.sup.21,
--(CH.sub.2).sub.0-3CR.sup.17R.sup.18NR.sup.17C(O)--NR.sup.20R.sup.21,
--(CH.sub.2).sub.1-3C(O)R.sup.22,
--(CH.sub.2).sub.1-3S(O).sub.2R.sup.22 or
--(CH.sub.2).sub.1-3--R.sup.23; R.sup.14 and R.sup.15 are each
independently H, --C.sub.1-4 alkyl or arylalkyl; R.sup.17 and
R.sup.18 are each independently H or --C.sub.1-3 alkyl; R.sup.19 is
H, --C.sub.1-4 alkyl or arylalkyl; R.sup.20 and R.sup.21 are each
independently H, --C.sub.1-3 alkyl, --C(O)R.sup.17 or
--S(O).sub.2R.sup.17; or R.sup.20 and R.sup.21, taken together with
the nitrogen atom to which they are attached, form an unsubstituted
or substituted 5-6 membered heterocyclyl ring containing 1-2
heteroatoms selected from the group consisting of N and O; R.sup.22
is H, --C.sub.1-3 alkyl, --OR.sup.19 or --NR.sup.20R.sup.21; and
R.sup.23 is an unsubstituted or substituted 5-6 membered
heterocyclyl ring containing 1-2 heteroatoms selected from the
group consisting of N and O.
[0320] In still another embodiment of the compounds of Formula IIA,
R.sup.13 is --(CH.sub.2).sub.0-3CR.sup.17R.sup.18NR.sup.20R.sup.21,
--(CH.sub.2).sub.0-3CR.sup.17R.sup.18NR.sup.17C(O)--NR.sup.20R.sup.21,
or --(CH.sub.2).sub.1-3--R.sup.23 wherein R.sup.20 and R.sup.21
form a 5-6 membered heterocyclyl ring containing 1-2 heteroatoms
selected from the group consisting of N and O or R.sup.23 is an
unsubstituted or substituted 5-6 membered heterocyclyl ring
containing 1-2 heteroatoms selected from the group consisting of N
and O, and the 5-6 membered heterocyclyl ring is optionally
substituted with a C.sub.1-2 alkyl.
[0321] In still another embodiment of the compounds of Formula IIA,
R.sup.13 is --(CH.sub.2).sub.0-1CR.sup.17R.sup.18OR.sup.19. In a
particular embodiment, R.sup.13 is a C.sub.1-2 hydroxyalkyl or a
C.sub.1-6 alkoxyalkyl group.
[0322] In still another embodiment of the compounds of Formula IIA,
R.sup.13 is --(CH.sub.2).sub.0-3CR.sup.17R.sub.18NR.sup.20R.sup.21.
In a particular embodiment, R.sup.13 is a
C.sub.1-4alkylene-NH.sub.2 group, C.sub.1-4-alkylene-NHP (wherein P
is a protecting group such as Boc, Fmoc, Cbz, Ac, trifluoroacetyl,
toluenesulfony group, benzyl, etc.), or
C.sub.1-4alkylene-N(alkyl).sub.2 group.
[0323] In still another embodiment of the compounds of Formula IIA,
R.sup.13 is
--(CH.sub.2).sub.0-3CR.sup.17R.sup.18NR.sup.17C(O)--NR.sup.20R.sup.21.
In a particular embodiment, R.sup.13 is a
C.sub.1-4alkylene-C(O)NH.sub.2 group or
C.sub.1-4alkylene-C(O)N(alkyl).sub.2 group.
[0324] In still another embodiment of the compounds of Formula IIA,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, and R.sup.16 are
each independently selected from the groups shown in the Table,
below:
TABLE-US-00001 R.sup.11 R.sup.12 R.sup.13 ##STR00030## H
##STR00031## ##STR00032## ##STR00033## ##STR00034## Me Me
##STR00035## ##STR00036## ##STR00037## ##STR00038## H ##STR00039##
##STR00040## ##STR00041## Et ##STR00042## ##STR00043## ##STR00044##
##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049##
##STR00050## ##STR00051## ##STR00052## ##STR00053## ##STR00054##
##STR00055## ##STR00056## ##STR00057## R.sup.11 R.sup.14 R.sup.15
R.sup.16 ##STR00058## ##STR00059## ##STR00060## ##STR00061##
##STR00062## ##STR00063## ##STR00064## ##STR00065## Et Et
##STR00066## Me Me H H
[0325] In still another embodiment of the compounds of Formula IIA,
R.sup.11 is substituted or unsubstituted heterocyclyl, R.sup.12 is
alkyl, R.sup.11 is substituted or unsubstituted heterocyclylalkyl,
R.sup.14 and R.sup.15 are each independently substituted or
unsubstituted arylalkyl, and R.sup.16 is substituted or
unsubstituted heterocyclyl.
[0326] In still another embodiment of the compounds of Formula IIA,
R.sup.11 is substituted heterocyclyl, R.sup.12 is alkyl, R.sup.13
is unsubstituted heterocyclylalkyl, R.sup.14 and R.sup.15 are both
unsubstituted arylalkyl, and R.sup.16 is unsubstituted
heterocyclyl.
[0327] In still another embodiment of the compounds of Formula IIA,
R.sup.11 is substituted or unsubstituted heterocyclyl, R.sup.12 is
alkyl, R.sup.13 is hydroxyalkyl, R.sup.14 and R.sup.15 are each
independently substituted or unsubstituted arylalkyl, and R.sup.16
is substituted or unsubstituted heterocyclyl.
[0328] In still another embodiment of the compounds of Formula IIA,
R.sup.11 is substituted heterocyclyl, R.sup.12 is alkyl, R.sup.13
is hydroxyalkyl, R.sup.14 and R.sup.15 are both unsubstituted
arylalkyl, and R.sup.16 is unsubstituted heterocyclyl.
[0329] In still another embodiment of the compounds of Formula IIA,
R.sup.11 is substituted or unsubstituted heterocyclyl, R.sup.12 is
alkyl, R.sup.11 is protected or unprotected aminoalkyl, R.sup.14
and R.sup.15 are each independently substituted or unsubstituted
arylalkyl, and R.sup.16 is substituted or unsubstituted
heterocyclyl.
[0330] In still another embodiment of the compounds of Formula IIA,
R.sup.11 is substituted heterocyclyl, R.sup.12 is alkyl, R.sup.13
is protected aminoalkyl, R.sup.14 and R.sup.15 are both
unsubstituted arylalkyl, and R.sup.16 is unsubstituted
heterocyclyl.
[0331] In still another embodiment of the compounds of Formula IIA,
R.sup.11 is substituted heterocyclyl, R.sup.12 is alkyl, R.sup.13
is acylated aminoalkyl, R.sup.14 and R.sup.15 are both
unsubstituted arylalkyl, and R.sup.16 is unsubstituted
heterocyclyl.
[0332] In another embodiment, the compounds of Formula I, or
pharmaceutically acceptable salts, solvates, stereoisomers and/or
esters thereof, have the following structure IIB:
##STR00067##
R.sup.10a and R.sup.10b are each independently H or --C.sub.1-4
alkyl; R.sup.12 is H or --CH.sub.3; R.sup.13 is H, --C.sub.1-4
alkyl, --(CH.sub.2).sub.0-1CR.sup.17R.sup.18OR.sup.19,
--(CH.sub.2).sub.0-3CR.sup.17R.sup.18NR.sup.20R.sup.21,
--(CH.sub.2).sub.0-3CR.sup.17R.sup.18NR.sup.17C(O)NR.sup.20R.sup.21,
--(CH.sub.2).sub.1-3C(O)R.sup.22,
--(CH.sub.2).sub.1-3S(O).sub.2R.sup.22 or
--(CH.sub.2).sub.1-3--R.sup.23; R.sup.14 and R.sup.15 are each
independently H, --C.sub.1-4 alkyl or arylalkyl; R.sup.17 and
R.sup.18 are each independently H or --C.sub.1-3 alkyl; R.sup.19 is
H, --C.sub.1-4 alkyl or arylalkyl; R.sup.20 and R.sup.21 are each
independently H, --C.sub.1-3 alkyl, --C(O)R.sup.17 or
--S(O).sub.2R.sup.17; or R.sup.20 and R.sup.21, taken together with
the nitrogen atom to which they are attached, form an unsubstituted
or substituted 5-6 membered heterocyclyl ring containing 1-2
heteroatoms selected from the group consisting of N and O; R.sup.22
is H, --C.sub.1-3alkyl, --OR.sup.19 or --NR.sup.20R.sup.21; and
R.sup.23 is an unsubstituted or substituted 5-6 membered
heterocyclyl ring containing 1-2 heteroatoms selected from the
group consisting of N and O.
[0333] In still another embodiment of the compounds of Formula IIB,
R.sup.13 is --(CH.sub.2).sub.0-3CR.sup.17R.sup.18NR.sup.20R.sup.21,
--(CH.sub.2).sub.0-3CR.sup.17R.sup.18NR.sup.17C(O)--NR.sup.20R.sup.21,
or --(CH.sub.2).sub.1-3--R.sup.23 wherein R.sup.20 and R.sup.21
form a 5-6 membered heterocyclyl ring containing 1-2 heteroatoms
selected from the group consisting of N and O or R.sup.23 is an
unsubstituted or substituted 5-6 membered heterocyclyl ring
containing 1-2 heteroatoms selected from the group consisting of N
and O, and the 5-6 membered heterocyclyl ring is optionally
substituted with a C.sub.1-2 alkyl.
[0334] In another embodiment, the compounds of Formula I, or
pharmaceutically acceptable salts, solvates, stereoisomers and/or
esters thereof, have the following structure IIC:
##STR00068##
wherein: R.sup.13 is H, --C.sub.1-4 alkyl,
--(CH.sub.2).sub.0-1CR.sup.17R.sup.18OR.sup.19,
--(CH.sub.2).sub.0-3CR.sup.17R.sup.18NR.sup.20R.sup.21,
--(CH.sub.2).sub.0-3CR.sup.17R.sup.18NR.sup.17C(O)NR.sup.20R.sup.21,
--(CH.sub.2).sub.1-3C(O)R.sup.22 or --(CH.sub.2).sub.1-3--R.sup.23;
R.sup.17 and R.sup.18 are each independently H or C.sub.1-3 alkyl;
R.sup.19 is H, --C.sub.1-4 alkyl or arylalkyl; R.sup.20 and
R.sup.21 are each independently H, --C.sub.1-3 alkyl,
--C(O)R.sup.17 or --S(O).sub.2R.sup.17; or R.sup.20 and R.sup.21,
taken together with the nitrogen atom to which they are attached,
form a 5-6 membered heterocyclyl ring containing 1-2 heteroatoms
selected from the group consisting of N and O; R.sup.22 is H,
--C.sub.1-3alkyl, --OR.sup.19 or --NR.sup.20R.sup.21; and R.sup.23
is a 5-6 membered heterocyclyl ring containing 1-2 heteroatoms
selected from the group consisting of N and O.
[0335] In still another embodiment of the compounds of Formula IIC,
R.sup.13 is --(CH.sub.2).sub.0-3CR.sup.17R.sup.18NR.sup.20R.sup.21,
--(CH.sub.2).sub.0-3CR.sup.17R.sup.18NR.sup.17C(O)--NR.sup.20R.sup.21,
or --(CH.sub.2).sub.1-3--R.sup.23 wherein R.sup.20 and R.sup.21
form a 5-6 membered heterocyclyl ring containing 1-2 heteroatoms
selected from the group consisting of N and O or R.sup.23 is an
unsubstituted or substituted 5-6 membered heterocyclyl ring
containing 1-2 heteroatoms selected from the group consisting of N
and O, and the 5-6 membered heterocyclyl ring is optionally
substituted with a C.sub.1-2 alkyl.
[0336] In still another embodiment of the compounds of Formula IIC,
R.sup.13 is --(CH.sub.2).sub.0-3CR.sup.17R.sup.18NR.sup.20R.sup.21.
In a particular embodiment, R.sup.13 is a
C.sub.1-4alkylene-NH.sub.2 group, C.sub.1-4-alkylene-NHP (wherein P
is a protecting group such as Boc, Fmoc, Cbz, Ac, trifluoroacetyl,
toluenesulfony group, benzyl, etc.), or
C.sub.1-4alkylene-N(alkyl).sub.2 group.
[0337] In still another embodiment of the compounds of Formula IIC,
R.sup.13 is
--(CH.sub.2).sub.0-3CR.sup.17R.sup.18NR.sup.17C(O)--NR.sup.20R.sup.21.
In a particular embodiment, R.sup.13 is a
C.sub.1-4alkylene-C(O)NH.sub.2 group or
C.sub.1-4alkylene-C(O)N(alkyl).sub.2 group.
[0338] In still another embodiment of the compounds of Formula IIC,
R.sup.13 is --CH.sub.2OH, --CH.sub.2CH.sub.2NHC(O)CH.sub.3 or
##STR00069##
[0339] In another embodiment, the compounds of the present
invention, or pharmaceutically acceptable salts, solvates,
stereoisomers and/or esters thereof, have the following structure
IID:
##STR00070##
wherein, [0340] L.sup.1 is selected from the group consisting of
--C(R.sup.6).sub.2--, --C(O)--, --S(O.sub.2)--,
--N(R.sup.7)--C(O)--, and --O--C(O)--; [0341] each L.sup.3 is
independently a covalent bond, an alkylene, or substituted
alkylene; [0342] each L.sup.4 is independently selected from the
group consisting of a covalent bond, alkylene, substituted
alkylene, --O--, --CH.sub.2--O--, and --NH--; [0343] each A is
independently selected from the group consisting of H, alkyl,
substituted alkyl, aryl, substituted aryl, heterocyclyl, and
substituted heterocyclyl, [0344] with the proviso that when A is H,
p is 0; [0345] Z.sup.1 and Z.sup.2 are each independently --O-- or
--N(R.sup.7)--; [0346] Y and X are independently selected from the
group consisting of heterocyclyl and heterocyclylalkyl; [0347] each
Ar is independently selected from the group consisting of aryl,
substituted aryl, heteroaryl, and substituted heteroaryl; [0348]
R.sup.1, R.sup.3, and R.sup.5 are each independently selected from
the group consisting of H, alkyl, substituted alkyl, arylalkyl, and
substituted arylalkyl; [0349] R.sup.2 is independently selected
from the group consisting of H, alkyl, substituted alkyl,
alkoxyalkyl, hydroxyalkyl, arylheteroalkyl, substituted
arylheteroalkyl, arylalkyl, substituted arylalkyl,
heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl,
substituted aminoalkyl, -alkylene-C(O)--OH, -alkylene-C(O)--Oalkyl,
-alkylene-C(O)amino, -alkylene-C(O)-alkyl; [0350] R.sup.4 and
R.sup.6 are independently selected from the group consisting of H,
alkyl, substituted alkyl, and heteroalkyl; [0351] each R.sup.7 is
independently selected from the group consisting of H, alkyl,
substituted alkyl, heteroalkyl, carbocyclyl, substituted
carbocyclyl, heterocyclyl, and substituted heterocyclyl; [0352]
R.sup.8 and R.sup.9 are each one or more substituents independently
selected from the group consisting of H, alkyl, substituted alkyl,
halogen, aryl, substituted aryl, heterocyclyl, substituted
heterocyclyl, and --CN; and [0353] each p is independently 0 or
1.
[0354] In another embodiment of the compounds of Formula IID,
L.sup.1 is --C(R.sup.6).sub.2--.
[0355] In another embodiment of the compounds of Formula IID,
L.sup.1 is --CH.sub.2--.
[0356] In another embodiment of the compounds of Formula IID, each
L.sup.3 is alkylene.
[0357] In another embodiment of the compounds of Formula IID, each
L.sup.3 is --CH.sub.2--.
[0358] In another embodiment of the compounds of Formula IID, each
A is aryl or substituted aryl.
[0359] In another embodiment of the compounds of Formula IID, each
A is phenyl or substituted phenyl.
[0360] In another embodiment of the compounds of Formula IID, X is
heterocyclylalkyl.
[0361] In another embodiment of the compounds of Formula IID, X is
thiazolylmethyl.
[0362] In another embodiment of the compounds of Formula IID, Y is
heterocyclylalkyl.
[0363] In another embodiment of the compounds of Formula IID, Y is
thiazolylmethyl.
[0364] In another embodiment of the compounds of Formula IID,
Z.sup.1 is --N(R.sup.7)--.
[0365] In another embodiment of the compounds of Formula IID,
Z.sup.1 is --NH--.
[0366] In another embodiment of the compounds of Formula IID,
Z.sup.1 is --N(alkyl)-.
[0367] In another embodiment of the compounds of Formula IID,
Z.sup.1 is --N(CH.sub.3)--.
[0368] In another embodiment of the compounds of Formula IID,
Z.sup.2 is --O--.
[0369] In another embodiment of the compounds of Formula IID,
L.sup.1 is --C(R.sup.6).sub.2-- and X and Y are
heterocyclylalkyl.
[0370] In another embodiment of the compounds of Formula IID,
L.sup.1 is --CH.sub.2-- and X and Y are heterocyclylalkyl.
[0371] In another embodiment of the compounds of Formula IID,
L.sup.1 is --CH.sub.2-- and X and Y are thiazolylmethyl.
[0372] In another embodiment of the compounds of Formula IID,
L.sup.1 is --C(R.sup.6).sub.2-- and Z.sup.1 is --N(R.sup.7)--.
[0373] In another embodiment of the compounds of Formula IID,
L.sup.1 is --CH.sub.2-- and Z.sup.1 is --N(R.sup.7)--.
[0374] In another embodiment of the compounds of Formula IID,
L.sup.1 is --CH.sub.2-- and Z.sup.1 is --NH--.
[0375] In another embodiment of the compounds of Formula IID,
L.sup.1 is --CH.sub.2-- and Z.sup.1 is --N(alkyl)-.
[0376] In another embodiment of the compounds of Formula IID,
L.sup.1 is --CH.sub.2-- and Z.sup.1 is --N(CH.sub.3)--.
[0377] In another embodiment of the compounds of Formula IID,
L.sup.1 is --C(R.sup.6).sub.2-- and Z.sup.2 is --O--.
[0378] In another embodiment of the compounds of Formula IID, each
L.sup.3 is alkylene and each A is aryl or substituted aryl.
[0379] In another embodiment of the compounds of Formula IID, each
L.sup.3 is --CH.sub.2-- and each A is aryl or substituted aryl.
[0380] In another embodiment of the compounds of Formula IID, each
L.sup.3-A is benzyl or substituted benzyl.
[0381] In another embodiment of the compounds of Formula IID, X and
Y are heterocyclylalkyl and Z.sup.1 is --N(R.sup.7)--.
[0382] In another embodiment of the compounds of Formula IID, X and
Y are thiazolylmethyl and Z.sup.1 is --N(R.sup.7)--.
[0383] In another embodiment of the compounds of Formula IID, X and
Y are thiazolylmethyl and Z.sup.1 is --N(alkyl)-.
[0384] In another embodiment of the compounds of Formula IID, X and
Y are thiazolylmethyl and Z.sup.1 is --N(CH.sub.3)--.
[0385] In another embodiment of the compounds of Formula IID, X and
Y are thiazolylmethyl and Z.sup.1 is --NH--.
[0386] In another embodiment of the compounds of Formula IID, X and
Y are heterocyclylalkyl and Z.sup.2 is --O--.
[0387] In another embodiment of the compounds of Formula IID, X and
Y are thiazolylmethyl and Z.sup.2 is --O--.
[0388] In another embodiment of the compounds of Formula IID,
Z.sup.1 is --N(R.sup.7)-- and Z.sup.2 is --O--.
[0389] In another embodiment of the compounds of Formula IID,
Z.sup.1 is --N(alkyl)- and Z.sup.2 is --O--.
[0390] In another embodiment of the compounds of Formula IID,
Z.sup.1 is --N(CH.sub.3)-- and Z.sup.2 is --O--.
[0391] In another embodiment of the compounds of Formula IID,
Z.sup.1 is --NH-- and Z.sup.2 is --O--.
[0392] In another embodiment of the compounds of Formula IID,
L.sup.1 is --C(R.sup.6).sub.2--, X and Y are heterocyclylalkyl, and
Z.sup.1 is --N(R.sup.7)--.
[0393] In another embodiment of the compounds of Formula IID,
L.sup.1 is --CH.sub.2--, X and Y are heterocyclylalkyl, and Z.sup.1
is --N(R.sup.7)--.
[0394] In another embodiment of the compounds of Formula IID,
L.sup.1 is --CH.sub.2--, X and Y are thiazolylmethyl, and Z.sup.1
is --N(R.sup.7)--.
[0395] In another embodiment of the compounds of Formula IID,
L.sup.1 is --CH.sub.2--, X and Y are thiazolylmethyl, and Z.sup.1
is --N(alkyl)-.
[0396] In another embodiment of the compounds of Formula IID,
L.sup.1 is --CH.sub.2--, X and Y are thiazolylmethyl, and Z.sup.1
is --N(CH.sub.3)--.
[0397] In another embodiment of the compounds of Formula IID,
L.sup.1 is --CH.sub.2--, X and Y are thiazolylmethyl, and Z.sup.1
is --NH--.
[0398] In another embodiment of the compounds of Formula IID,
L.sup.1 is --C(R.sup.6).sub.2--; X and Y are heterocyclylalkyl; and
Z.sup.2 is --O--.
[0399] In another embodiment of the compounds of Formula IID,
L.sup.1 is --CH.sub.2--; X and Y are heterocyclylalkyl; and Z.sup.2
is --O--.
[0400] In another embodiment of the compounds of Formula IID,
L.sup.1 is --CH.sub.2--; X and Y are thiazolylmethyl; and Z.sup.2
is --O--.
[0401] In another embodiment of the compounds of Formula IID,
L.sup.1 is --C(R.sup.6).sub.2--; each L.sup.3 is alkylene; each A
is aryl or substituted aryl; X and Y are heterocyclylalkyl; Z.sup.1
is --N(R.sub.7)--; and Z.sup.2 is --O--.
[0402] In another embodiment of the compounds of Formula IID,
L.sup.1 is --CH.sub.2--; each L.sup.3-A is benzyl or substituted
benzyl; X and Y are thiazolylmethyl; Z.sup.1 is --N(CH.sub.3)--;
and Z.sup.2 is --O--.
[0403] In another embodiment of the compounds of Formula IID,
L.sup.1 is --CH.sub.2--; each L.sup.3-A is benzyl or substituted
benzyl; Z.sup.1 is --N(CH.sub.3)--; Z.sup.2 is --O--; X is
##STR00071##
and
[0404] Y is
##STR00072##
[0405] In another embodiment, the compounds of the present
invention, or pharmaceutically acceptable salts, solvates,
stereoisomers and/or esters thereof, have the following structure
IV:
##STR00073##
wherein, [0406] each L.sup.3 is independently an alkylene or
substituted alkylene; [0407] each A is independently an aryl or
substituted aryl; [0408] X is heterocyclylalkyl; [0409] Y is
heterocyclylalkyl or alkyl; [0410] G.sup.1 and G.sup.2 are
independently CH or N, with the proviso that G.sup.1 and G.sup.2
are different; [0411] G.sup.3 is --NR.sup.7-- or --O--; [0412]
R.sup.1, R.sup.3, R.sup.5, and R.sup.7 are each independently
selected from the group consisting of H, alkyl, substituted alkyl,
arylalkyl, and substituted arylalkyl; [0413] R.sup.2 is
independently selected from the group consisting of substituted
alkyl, alkoxyalkyl, hydroxyalkyl, trialkylsiloxyalkyl,
heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl,
substituted aminoalkyl, -alkylene-N(R.sup.a)--C(O)-alkyl,
-alkylene-NR.sup.a--C(O)--N(R.sup.a).sub.2,
-alkylene-NR.sup.a--C(.dbd.N--R.sup.b)--N(R.sup.a).sub.2,
-alkylene-C(.dbd.N--R.sup.b)--N(R.sup.a).sub.2, -alkylene-C(O)--OH,
-alkylene-C(O)--Oalkyl, and -alkylene-C(O)--N(R.sup.c).sub.2;
[0414] R.sup.8 and R.sup.9 are each one or more substituents
independently selected from the group consisting of H, alkyl,
substituted alkyl, halogen, and --CN; [0415] each R.sup.a is
independently selected from the group consisting of H, alkyl, and
substituted alkyl; [0416] R.sup.b is selected from the group
consisting of H, alkyl, substituted alkyl, CN, and
--S(O.sub.2)-alkyl; and
[0417] each R.sup.c is independently selected from the group
consisting of H, alkyl, substituted alkyl, heterocyclyl, and
--S(O.sub.2)-alkyl.
[0418] In some embodiments of the compounds of Formula IV, each
L.sup.3 is alkylene, for example any of those described herein,
e.g. --CH.sub.2-- and each A is phenyl. In a particular embodiment,
both -L.sup.3-A moieties are benzyl.
[0419] In some embodiments of the compounds of Formula IV, X and Y
are both heteroaryl (for example, any heteroaryl described herein).
In a particular embodiment, both X and Y are thiazolyl.
[0420] In some embodiments of the compounds of Formula IV, G.sup.1
is CH, and G.sup.2 is N. In a particular embodiment, G.sup.2 is N
and R.sup.1 is H. In another particular embodiment, G.sup.2 is N,
R.sup.1 is H, and G.sup.3 is NR.sup.7. In yet another particular
embodiment, G.sup.2 is N, R.sup.1 is H, and G.sup.1 is
NCH.sub.3.
[0421] In some embodiments of the compounds of Formula IV, R.sup.2
is substituted or unsubstituted aminoalkyl. In a particular
embodiment, R.sup.2 is substituted or unsubstituted aminoalkyl,
G.sup.2 is N and R.sup.1 is H, and both X and Y are thiazolyl. In
another particular embodiment, R.sup.2 is
--CH.sub.2CH.sub.2--NHR.sup.d, wherein R.sup.d is selected from the
group consisting of H, haloalkyl, --C(O)--N(R.sup.a).sub.2,
--C(.dbd.N--R.sup.b)--N(R.sup.a).sub.2, hydroxyalkyl,
--C(N(R.sup.a).sub.2).dbd.CHNO.sub.2, --C(O)-alkyl, G.sup.2 is N
and R.sup.1 is H, and both X and Y are thiazolyl. In still another
particular embodiment, R.sup.2 is
--CH.sub.2CH.sub.2--NH--C(O)-alkyl.
[0422] In specific embodiments, the compounds of Formula IV have
the following structures:
##STR00074## ##STR00075##
[0423] In other embodiments, the compounds of Formula IV have the
following general formula:
##STR00076##
wherein said "Heterocyclyl" is substituted or unsubstituted. In a
particular embodiment, said "Heterocyclyl" is a substituted or
unsubstituted heteroaryl, for example, and of the heteroaryls
described herein. In other embodiments, said "Heterocyclyl" is a
substituted or unsubstituted heterocycloalkyl, including any
heterocycloalkyl described herein. In a particular embodiment, the
heterocyclyl is unsubstituted morpholinyl. In a more specific
particular embodiment, the heterocyclyl is unsubstituted
morpholinyl and R.sup.8 is alkyl.
[0424] In other embodiments, the compounds of Formula IV have the
following general formula:
##STR00077##
In a particular embodiment of the compounds of the above general
formula, X and Y are both heteroarylalkyl.
[0425] In other specific embodiments, the compounds of Formula IV
have the following structures:
##STR00078## ##STR00079## ##STR00080## ##STR00081## ##STR00082##
##STR00083## ##STR00084##
[0426] In other embodiments, the compounds of Formula IV have the
following general formula:
##STR00085##
[0427] wherein Q is --OH or --N(R.sup.a).sub.2. In a particular
embodiment, Q is --OH. In another particular embodiment, Q is
--N(R.sup.a).sub.2. In yet another particular embodiment, Q is
--NH-pyridyl, --NH-pyrrolyl, or --NH--S(O.sub.2)-alkyl. In other
specific embodiments, the compounds of the above general formula
have the following structures:
##STR00086## ##STR00087##
[0428] In other embodiments, the compounds of Formula IV have the
following general formula:
##STR00088##
[0429] wherein M is substituted or unsubstituted alkyl. In
particular embodiments,
[0430] M is a substituted alkyl, for example hydroxyalkyl,
substituted hydroxyalkyl, cyanoalkyl, substituted cyanoalkyl, and
trialkylsiloxyalkyl. In other particular embodiments, the compounds
of the above general formula have the following structures:
##STR00089##
[0431] In still other embodiments, the compounds of Formula IV have
the following general formula:
##STR00090##
In particular embodiments, a compound of the above general formula
has the following structure:
##STR00091##
[0432] In still other embodiments of the compounds of Formula IV, Y
is alkyl. In particular embodiments, such compounds have the
following general formula:
##STR00092##
In specific embodiments, R.sup.8--Y-- is alkyl, for example any
alkyl described herein. In a particular embodiment, R.sup.8--Y-- is
methyl. Specific particular embodiments of the above general
structure include the following structures:
##STR00093##
[0433] In still yet another embodiment, the compounds of Formula I
are named below in tabular format (Table 6) as compounds of general
Formula II:
##STR00094##
[0434] Compounds of general formula II are depicted as a "core"
structure (Z) substituted with four moieties T1, T2, X1 and X2. The
core structures Z are depicted in Table 1. The points of attachment
of T1, T2, X1 and X2 are indicated on each of the core structures
depicted in Table 1. Tables 2-5, respectively, show the structures
of the T1, T2, X1 and X2 moieties. The point of attachment of the
core structure Z is indicated in each of the structures of T1, T2,
X1 and X2. Each core structure Z in Table 1, and each substituent
T1, T2, X1 and X2 and Tables 2-5 is represented by a "code"
comprising a letter and a number. Each structure of a compound of
Formula II can be designated in tabular form by combining the
"code" representing each structural moiety using the following
syntax: Z.T1.T2.X1.X2. Thus, for example, Z1.T1A.T2B.X1A.X2A
represents the following structure:
##STR00095##
[0435] In the structures depicted in Tables 1-5, the term "Alk"
means a substituted or unsubstituted alkyl, cycloalkyl, or alkylene
group, wherein the terms "alkyl", "cycloalkyl", and "alkylene" are
as defined herein. "Alk" means an alkyl or cycloalkyl group when
depicted as monovalent, and an alkylene group when depicted as
divalent. "Het" is a substituted or unsubstituted heterocyclyl or
heterocyclylene group, wherein the term "heterocyclyl" is as
defined herein, and the term "heterocyclylene" means a heterocyclyl
group as defined herein, in which a hydrogen atom has been replaced
by an open valence (in analogy to alkylene), thereby defining a
divalent heterocyclyl. "Het" is a heterocyclyl when depicted as
monovalent, and heterocyclylene when depicted as divalent. "Ar" is
a substitute or unsubstituted aryl or arylene group, wherein the
term "aryl" is as defined herein, and the term "arylene" means an
aryl group as defined herein, in which a hydrogen atom has been
replaced by an open valence (in analogy to alkylene), thereby
defining a divalent aryl. "Ar" is aryl when depicted as monovalent,
and arylene when depicted as divalent. When substituted, "Alk",
"Het", and "Ar" can be substituted with any of the substituents
defined or exemplified herein. For example, substituents of "Alk"
can include ether, halogen, --OH, amide, amine, etc., substituents
of "Het" can include alkyl, aryl, carbonyl, --OH, halogen, and
substituents of "Ar" can include alkyl, aryl, --OH, halogen, etc.,
with the proviso that the resulting structure is chemically
reasonable, and would provide compounds which are sufficiently
stable for formulation in a pharmaceutically acceptable
composition. When a structure or substructure shown in the tables
below contains more than one "Alk", "Het" or "Ar" group, these
groups are independently selected and can be the same or different.
So, for example, each of the "Alk" groups of substructure T1A are
independently selected and may be the same or different.
TABLE-US-00002 TABLE 1 Core Structures Core Core Structure Z1
##STR00096## Z2 ##STR00097## Z3 ##STR00098## Z4 ##STR00099## Z5
##STR00100## Z6 ##STR00101##
TABLE-US-00003 TABLE 2 T1 Structures Code T1 Structure T1A
##STR00102## T1B ##STR00103## T1C ##STR00104## T1D ##STR00105##
TABLE-US-00004 TABLE 3 T2 Structures Code T2 Structure T2A
--O-Alk-Het T2B --NH-Alk-Het T2C --N(Alk)-Alk-Het T2D
--N(Alk)-Het
TABLE-US-00005 TABLE 4 X1 Structures Code X1 Structure X1A -Alk X1B
-Alk-Ar X1C -Alk-Het X1D -Alk-Ar--O-Alk-Ar X1E -Alk-Ar--O-Alk-
Het
TABLE-US-00006 TABLE 5 X2 Structures Code X2 Structure X2A -Alk X2B
-Alk-Ar X2C -Alk-Het X2D -Alk-Ar--O-Alk-Ar X2E -Alk-Ar--O-Alk-
Het
TABLE-US-00007 TABLE 6 List of Compound Structures of Formula II
Z1.T1A.T2A.X1A.X2A, Z2.T1A.T2A.X1A.X2A, Z3.T1A.T2A.X1A.X2A,
Z4.T1A.T2A.X1A.X2A, Z5.T1A.T2A.X1A.X2A, Z6.T1A.T2A.X1A.X2A,
Z1.T1B.T2A.X1A.X2A, Z2.T1B.T2A.X1A.X2A, Z3.T1B.T2A.X1A.X2A,
Z4.T1B.T2A.X1A.X2A, Z5.T1B.T2A.X1A.X2A, Z6.T1B.T2A.X1A.X2A,
Z1.T1C.T2A.X1A.X2A, Z2.T1C.T2A.X1A.X2A, Z3.T1C.T2A.X1A.X2A,
Z4.T1C.T2A.X1A.X2A, Z5.T1C.T2A.X1A.X2A, Z6.T1C.T2A.X1A.X2A,
Z1.T1D.T2A.X1A.X2A, Z2.T1D.T2A.X1A.X2A, Z3.T1D.T2A.X1A.X2A,
Z4.T1D.T2A.X1A.X2A, Z5.T1D.T2A.X1A.X2A, Z6.T1D.T2A.X1A.X2A,
Z1.T1A.T2B.X1A.X2A, Z2.T1A.T2B.X1A.X2A, Z3.T1A.T2B.X1A.X2A,
Z4.T1A.T2B.X1A.X2A, Z5.T1A.T2B.X1A.X2A, Z6.T1A.T2B.X1A.X2A,
Z1.T1B.T2B.X1A.X2A, Z2.T1B.T2B.X1A.X2A, Z3.T1B.T2B.X1A.X2A,
Z4.T1B.T2B.X1A.X2A, Z5.T1B.T2B.X1A.X2A, Z6.T1B.T2B.X1A.X2A,
Z1.T1C.T2B.X1A.X2A, Z2.T1C.T2B.X1A.X2A, Z3.T1C.T2B.X1A.X2A,
Z4.T1C.T2B.X1A.X2A, Z5.T1C.T2B.X1A.X2A, Z6.T1C.T2B.X1A.X2A,
Z1.T1D.T2B.X1A.X2A, Z2.T1D.T2B.X1A.X2A, Z3.T1D.T2B.X1A.X2A,
Z4.T1D.T2B.X1A.X2A, Z5.T1D.T2B.X1A.X2A, Z6.T1D.T2B.X1A.X2A,
Z1.T1A.T2C.X1A.X2A, Z2.T1A.T2C.X1A.X2A, Z3.T1A.T2C.X1A.X2A,
Z4.T1A.T2C.X1A.X2A, Z5.T1A.T2C.X1A.X2A, Z6.T1A.T2C.X1A.X2A,
Z1.T1B.T2C.X1A.X2A, Z2.T1B.T2C.X1A.X2A, Z3.T1B.T2C.X1A.X2A,
Z4.T1B.T2C.X1A.X2A, Z5.T1B.T2C.X1A.X2A, Z6.T1B.T2C.X1A.X2A,
Z1.T1C.T2C.X1A.X2A, Z2.T1C.T2C.X1A.X2A, Z3.T1C.T2C.X1A.X2A,
Z4.T1C.T2C.X1A.X2A, Z5.T1C.T2C.X1A.X2A, Z6.T1C.T2C.X1A.X2A,
Z1.T1D.T2C.X1A.X2A, Z2.T1D.T2C.X1A.X2A, Z3.T1D.T2C.X1A.X2A,
Z4.T1D.T2C.X1A.X2A, Z5.T1D.T2C.X1A.X2A, Z6.T1D.T2C.X1A.X2A,
Z1.T1A.T2D.X1A.X2A, Z2.T1A.T2D.X1A.X2A, Z3.T1A.T2D.X1A.X2A,
Z4.T1A.T2D.X1A.X2A, Z5.T1A.T2D.X1A.X2A, Z6.T1A.T2D.X1A.X2A,
Z1.T1B.T2D.X1A.X2A, Z2.T1B.T2D.X1A.X2A, Z3.T1B.T2D.X1A.X2A,
Z4.T1B.T2D.X1A.X2A, Z5.T1B.T2D.X1A.X2A, Z6.T1B.T2D.X1A.X2A,
Z1.T1C.T2D.X1A.X2A, Z2.T1C.T2D.X1A.X2A, Z3.T1C.T2D.X1A.X2A,
Z4.T1C.T2D.X1A.X2A, Z5.T1C.T2D.X1A.X2A, Z6.T1C.T2D.X1A.X2A,
Z1.T1D.T2D.X1A.X2A, Z2.T1D.T2D.X1A.X2A, Z3.T1D.T2D.X1A.X2A,
Z4.T1D.T2D.X1A.X2A, Z5.T1D.T2D.X1A.X2A, Z6.T1D.T2D.X1A.X2A,
Z1.T1A.T2A.X1B.X2A, Z2.T1A.T2A.X1B.X2A, Z3.T1A.T2A.X1B.X2A,
Z4.T1A.T2A.X1B.X2A, Z5.T1A.T2A.X1B.X2A, Z6.T1A.T2A.X1B.X2A,
Z1.T1B.T2A.X1B.X2A, Z2.T1B.T2A.X1B.X2A, Z3.T1B.T2A.X1B.X2A,
Z4.T1B.T2A.X1B.X2A, Z5.T1B.T2A.X1B.X2A, Z6.T1B.T2A.X1B.X2A,
Z1.T1C.T2A.X1B.X2A, Z2.T1C.T2A.X1B.X2A, Z3.T1C.T2A.X1B.X2A,
Z4.T1C.T2A.X1B.X2A, Z5.T1C.T2A.X1B.X2A, Z6.T1C.T2A.X1B.X2A,
Z1.T1D.T2A.X1B.X2A, Z2.T1D.T2A.X1B.X2A, Z3.T1D.T2A.X1B.X2A,
Z4.T1D.T2A.X1B.X2A, Z5.T1D.T2A.X1B.X2A, Z6.T1D.T2A.X1B.X2A,
Z1.T1A.T2B.X1B.X2A, Z2.T1A.T2B.X1B.X2A, Z3.T1A.T2B.X1B.X2A,
Z4.T1A.T2B.X1B.X2A, Z5.T1A.T2B.X1B.X2A, Z6.T1A.T2B.X1B.X2A,
Z1.T1B.T2B.X1B.X2A, Z2.T1B.T2B.X1B.X2A, Z3.T1B.T2B.X1B.X2A,
Z4.T1B.T2B.X1B.X2A, Z5.T1B.T2B.X1B.X2A, Z6.T1B.T2B.X1B.X2A,
Z1.T1C.T2B.X1B.X2A, Z2.T1C.T2B.X1B.X2A, Z3.T1C.T2B.X1B.X2A,
Z4.T1C.T2B.X1B.X2A, Z5.T1C.T2B.X1B.X2A, Z6.T1C.T2B.X1B.X2A,
Z1.T1D.T2B.X1B.X2A, Z2.T1D.T2B.X1B.X2A, Z3.T1D.T2B.X1B.X2A,
Z4.T1D.T2B.X1B.X2A, Z5.T1D.T2B.X1B.X2A, Z6.T1D.T2B.X1B.X2A,
Z1.T1A.T2C.X1B.X2A, Z2.T1A.T2C.X1B.X2A, Z3.T1A.T2C.X1B.X2A,
Z4.T1A.T2C.X1B.X2A, Z5.T1A.T2C.X1B.X2A, Z6.T1A.T2C.X1B.X2A,
Z1.T1B.T2C.X1B.X2A, Z2.T1B.T2C.X1B.X2A, Z3.T1B.T2C.X1B.X2A,
Z4.T1B.T2C.X1B.X2A, Z5.T1B.T2C.X1B.X2A, Z6.T1B.T2C.X1B.X2A,
Z1.T1C.T2C.X1B.X2A, Z2.T1C.T2C.X1B.X2A, Z3.T1C.T2C.X1B.X2A,
Z4.T1C.T2C.X1B.X2A, Z5.T1C.T2C.X1B.X2A, Z6.T1C.T2C.X1B.X2A,
Z1.T1D.T2C.X1B.X2A, Z2.T1D.T2C.X1B.X2A, Z3.T1D.T2C.X1B.X2A,
Z4.T1D.T2C.X1B.X2A, Z5.T1D.T2C.X1B.X2A, Z6.T1D.T2C.X1B.X2A,
Z1.T1A.T2D.X1B.X2A, Z2.T1A.T2D.X1B.X2A, Z3.T1A.T2D.X1B.X2A,
Z4.T1A.T2D.X1B.X2A, Z5.T1A.T2D.X1B.X2A, Z6.T1A.T2D.X1B.X2A,
Z1.T1B.T2D.X1B.X2A, Z2.T1B.T2D.X1B.X2A, Z3.T1B.T2D.X1B.X2A,
Z4.T1B.T2D.X1B.X2A, Z5.T1B.T2D.X1B.X2A, Z6.T1B.T2D.X1B.X2A,
Z1.T1C.T2D.X1B.X2A, Z2.T1C.T2D.X1B.X2A, Z3.T1C.T2D.X1B.X2A,
Z4.T1C.T2D.X1B.X2A, Z5.T1C.T2D.X1B.X2A, Z6.T1C.T2D.X1B.X2A,
Z1.T1D.T2D.X1B.X2A, Z2.T1D.T2D.X1B.X2A, Z3.T1D.T2D.X1B.X2A,
Z4.T1D.T2D.X1B.X2A, Z5.T1D.T2D.X1B.X2A, Z6.T1D.T2D.X1B.X2A,
Z1.T1A.T2A.X1C.X2A, Z2.T1A.T2A.X1C.X2A, Z3.T1A.T2A.X1C.X2A,
Z4.T1A.T2A.X1C.X2A, Z5.T1A.T2A.X1C.X2A, Z6.T1A.T2A.X1C.X2A,
Z1.T1B.T2A.X1C.X2A, Z2.T1B.T2A.X1C.X2A, Z3.T1B.T2A.X1C.X2A,
Z4.T1B.T2A.X1C.X2A, Z5.T1B.T2A.X1C.X2A, Z6.T1B.T2A.X1C.X2A,
Z1.T1C.T2A.X1C.X2A, Z2.T1C.T2A.X1C.X2A, Z3.T1C.T2A.X1C.X2A,
Z4.T1C.T2A.X1C.X2A, Z5.T1C.T2A.X1C.X2A, Z6.T1C.T2A.X1C.X2A,
Z1.T1D.T2A.X1C.X2A, Z2.T1D.T2A.X1C.X2A, Z3.T1D.T2A.X1C.X2A,
Z4.T1D.T2A.X1C.X2A, Z5.T1D.T2A.X1C.X2A, Z6.T1D.T2A.X1C.X2A,
Z1.T1A.T2B.X1C.X2A, Z2.T1A.T2B.X1C.X2A, Z3.T1A.T2B.X1C.X2A,
Z4.T1A.T2B.X1C.X2A, Z5.T1A.T2B.X1C.X2A, Z6.T1A.T2B.X1C.X2A,
Z1.T1B.T2B.X1C.X2A, Z2.T1B.T2B.X1C.X2A, Z3.T1B.T2B.X1C.X2A,
Z4.T1B.T2B.X1C.X2A, Z5.T1B.T2B.X1C.X2A, Z6.T1B.T2B.X1C.X2A,
Z1.T1C.T2B.X1C.X2A, Z2.T1C.T2B.X1C.X2A, Z3.T1C.T2B.X1C.X2A,
Z4.T1C.T2B.X1C.X2A, Z5.T1C.T2B.X1C.X2A, Z6.T1C.T2B.X1C.X2A,
Z1.T1D.T2B.X1C.X2A, Z2.T1D.T2B.X1C.X2A, Z3.T1D.T2B.X1C.X2A,
Z4.T1D.T2B.X1C.X2A, Z5.T1D.T2B.X1C.X2A, Z6.T1D.T2B.X1C.X2A,
Z1.T1A.T2C.X1C.X2A, Z2.T1A.T2C.X1C.X2A, Z3.T1A.T2C.X1C.X2A,
Z4.T1A.T2C.X1C.X2A, Z5.T1A.T2C.X1C.X2A, Z6.T1A.T2C.X1C.X2A,
Z1.T1B.T2C.X1C.X2A, Z2.T1B.T2C.X1C.X2A, Z3.T1B.T2C.X1C.X2A,
Z4.T1B.T2C.X1C.X2A, Z5.T1B.T2C.X1C.X2A, Z6.T1B.T2C.X1C.X2A,
Z1.T1C.T2C.X1C.X2A, Z2.T1C.T2C.X1C.X2A, Z3.T1C.T2C.X1C.X2A,
Z4.T1C.T2C.X1C.X2A, Z5.T1C.T2C.X1C.X2A, Z6.T1C.T2C.X1C.X2A,
Z1.T1D.T2C.X1C.X2A, Z2.T1D.T2C.X1C.X2A, Z3.T1D.T2C.X1C.X2A,
Z4.T1D.T2C.X1C.X2A, Z5.T1D.T2C.X1C.X2A, Z6.T1D.T2C.X1C.X2A,
Z1.T1A.T2D.X1C.X2A, Z2.T1A.T2D.X1C.X2A, Z3.T1A.T2D.X1C.X2A,
Z4.T1A.T2D.X1C.X2A, Z5.T1A.T2D.X1C.X2A, Z6.T1A.T2D.X1C.X2A,
Z1.T1B.T2D.X1C.X2A, Z2.T1B.T2D.X1C.X2A, Z3.T1B.T2D.X1C.X2A,
Z4.T1B.T2D.X1C.X2A, Z5.T1B.T2D.X1C.X2A, Z6.T1B.T2D.X1C.X2A,
Z1.T1C.T2D.X1C.X2A, Z2.T1C.T2D.X1C.X2A, Z3.T1C.T2D.X1C.X2A,
Z4.T1C.T2D.X1C.X2A, Z5.T1C.T2D.X1C.X2A, Z6.T1C.T2D.X1C.X2A,
Z1.T1D.T2D.X1C.X2A, Z2.T1D.T2D.X1C.X2A, Z3.T1D.T2D.X1C.X2A,
Z4.T1D.T2D.X1C.X2A, Z5.T1D.T2D.X1C.X2A, Z6.T1D.T2D.X1C.X2A,
Z1.T1A.T2A.X1D.X2A, Z2.T1A.T2A.X1D.X2A, Z3.T1A.T2A.X1D.X2A,
Z4.T1A.T2A.X1D.X2A, Z5.T1A.T2A.X1D.X2A, Z6.T1A.T2A.X1D.X2A,
Z1.T1B.T2A.X1D.X2A, Z2.T1B.T2A.X1D.X2A, Z3.T1B.T2A.X1D.X2A,
Z4.T1B.T2A.X1D.X2A, Z5.T1B.T2A.X1D.X2A, Z6.T1B.T2A.X1D.X2A,
Z1.T1C.T2A.X1D.X2A, Z2.T1C.T2A.X1D.X2A, Z3.T1C.T2A.X1D.X2A,
Z4.T1C.T2A.X1D.X2A, Z5.T1C.T2A.X1D.X2A, Z6.T1C.T2A.X1D.X2A,
Z1.T1D.T2A.X1D.X2A, Z2.T1D.T2A.X1D.X2A, Z3.T1D.T2A.X1D.X2A,
Z4.T1D.T2A.X1D.X2A, Z5.T1D.T2A.X1D.X2A, Z6.T1D.T2A.X1D.X2A,
Z1.T1A.T2B.X1D.X2A, Z2.T1A.T2B.X1D.X2A, Z3.T1A.T2B.X1D.X2A,
Z4.T1A.T2B.X1D.X2A, Z5.T1A.T2B.X1D.X2A, Z6.T1A.T2B.X1D.X2A,
Z1.T1B.T2B.X1D.X2A, Z2.T1B.T2B.X1D.X2A, Z3.T1B.T2B.X1D.X2A,
Z4.T1B.T2B.X1D.X2A, Z5.T1B.T2B.X1D.X2A, Z6.T1B.T2B.X1D.X2A,
Z1.T1C.T2B.X1D.X2A, Z2.T1C.T2B.X1D.X2A, Z3.T1C.T2B.X1D.X2A,
Z4.T1C.T2B.X1D.X2A, Z5.T1C.T2B.X1D.X2A, Z6.T1C.T2B.X1D.X2A,
Z1.T1D.T2B.X1D.X2A, Z2.T1D.T2B.X1D.X2A, Z3.T1D.T2B.X1D.X2A,
Z4.T1D.T2B.X1D.X2A, Z5.T1D.T2B.X1D.X2A, Z6.T1D.T2B.X1D.X2A,
Z1.T1A.T2C.X1D.X2A, Z2.T1A.T2C.X1D.X2A, Z3.T1A.T2C.X1D.X2A,
Z4.T1A.T2C.X1D.X2A, Z5.T1A.T2C.X1D.X2A, Z6.T1A.T2C.X1D.X2A,
Z1.T1B.T2C.X1D.X2A, Z2.T1B.T2C.X1D.X2A, Z3.T1B.T2C.X1D.X2A,
Z4.T1B.T2C.X1D.X2A, Z5.T1B.T2C.X1D.X2A, Z6.T1B.T2C.X1D.X2A,
Z1.T1C.T2C.X1D.X2A, Z2.T1C.T2C.X1D.X2A, Z3.T1C.T2C.X1D.X2A,
Z4.T1C.T2C.X1D.X2A, Z5.T1C.T2C.X1D.X2A, Z6.T1C.T2C.X1D.X2A,
Z1.T1D.T2C.X1D.X2A, Z2.T1D.T2C.X1D.X2A, Z3.T1D.T2C.X1D.X2A,
Z4.T1D.T2C.X1D.X2A, Z5.T1D.T2C.X1D.X2A, Z6.T1D.T2C.X1D.X2A,
Z1.T1A.T2D.X1D.X2A, Z2.T1A.T2D.X1D.X2A, Z3.T1A.T2D.X1D.X2A,
Z4.T1A.T2D.X1D.X2A, Z5.T1A.T2D.X1D.X2A, Z6.T1A.T2D.X1D.X2A,
Z1.T1B.T2D.X1D.X2A, Z2.T1B.T2D.X1D.X2A, Z3.T1B.T2D.X1D.X2A,
Z4.T1B.T2D.X1D.X2A, Z5.T1B.T2D.X1D.X2A, Z6.T1B.T2D.X1D.X2A,
Z1.T1C.T2D.X1D.X2A, Z2.T1C.T2D.X1D.X2A, Z3.T1C.T2D.X1D.X2A,
Z4.T1C.T2D.X1D.X2A, Z5.T1C.T2D.X1D.X2A, Z6.T1C.T2D.X1D.X2A,
Z1.T1D.T2D.X1D.X2A, Z2.T1D.T2D.X1D.X2A, Z3.T1D.T2D.X1D.X2A,
Z4.T1D.T2D.X1D.X2A, Z5.T1D.T2D.X1D.X2A, Z6.T1D.T2D.X1D.X2A,
Z1.T1A.T2A.X1E.X2A, Z2.T1A.T2A.X1E.X2A, Z3.T1A.T2A.X1E.X2A,
Z4.T1A.T2A.X1E.X2A, Z5.T1A.T2A.X1E.X2A, Z6.T1A.T2A.X1E.X2A,
Z1.T1B.T2A.X1E.X2A, Z2.T1B.T2A.X1E.X2A, Z3.T1B.T2A.X1E.X2A,
Z4.T1B.T2A.X1E.X2A, Z5.T1B.T2A.X1E.X2A, Z6.T1B.T2A.X1E.X2A,
Z1.T1C.T2A.X1E.X2A, Z2.T1C.T2A.X1E.X2A, Z3.T1C.T2A.X1E.X2A,
Z4.T1C.T2A.X1E.X2A, Z5.T1C.T2A.X1E.X2A, Z6.T1C.T2A.X1E.X2A,
Z1.T1D.T2A.X1E.X2A, Z2.T1D.T2A.X1E.X2A, Z3.T1D.T2A.X1E.X2A,
Z4.T1D.T2A.X1E.X2A, Z5.T1D.T2A.X1E.X2A, Z6.T1D.T2A.X1E.X2A,
Z1.T1A.T2B.X1E.X2A, Z2.T1A.T2B.X1E.X2A, Z3.T1A.T2B.X1E.X2A,
Z4.T1A.T2B.X1E.X2A, Z5.T1A.T2B.X1E.X2A, Z6.T1A.T2B.X1E.X2A,
Z1.T1B.T2B.X1E.X2A, Z2.T1B.T2B.X1E.X2A, Z3.T1B.T2B.X1E.X2A,
Z4.T1B.T2B.X1E.X2A, Z5.T1B.T2B.X1E.X2A, Z6.T1B.T2B.X1E.X2A,
Z1.T1C.T2B.X1E.X2A, Z2.T1C.T2B.X1E.X2A, Z3.T1C.T2B.X1E.X2A,
Z4.T1C.T2B.X1E.X2A, Z5.T1C.T2B.X1E.X2A, Z6.T1C.T2B.X1E.X2A,
Z1.T1D.T2B.X1E.X2A, Z2.T1D.T2B.X1E.X2A, Z3.T1D.T2B.X1E.X2A,
Z4.T1D.T2B.X1E.X2A, Z5.T1D.T2B.X1E.X2A, Z6.T1D.T2B.X1E.X2A,
Z1.T1A.T2C.X1E.X2A, Z2.T1A.T2C.X1E.X2A, Z3.T1A.T2C.X1E.X2A,
Z4.T1A.T2C.X1E.X2A, Z5.T1A.T2C.X1E.X2A, Z6.T1A.T2C.X1E.X2A,
Z1.T1B.T2C.X1E.X2A, Z2.T1B.T2C.X1E.X2A, Z3.T1B.T2C.X1E.X2A,
Z4.T1B.T2C.X1E.X2A, Z5.T1B.T2C.X1E.X2A, Z6.T1B.T2C.X1E.X2A,
Z1.T1C.T2C.X1E.X2A, Z2.T1C.T2C.X1E.X2A, Z3.T1C.T2C.X1E.X2A,
Z4.T1C.T2C.X1E.X2A, Z5.T1C.T2C.X1E.X2A, Z6.T1C.T2C.X1E.X2A,
Z1.T1D.T2C.X1E.X2A, Z2.T1D.T2C.X1E.X2A, Z3.T1D.T2C.X1E.X2A,
Z4.T1D.T2C.X1E.X2A, Z5.T1D.T2C.X1E.X2A, Z6.T1D.T2C.X1E.X2A,
Z1.T1A.T2D.X1E.X2A, Z2.T1A.T2D.X1E.X2A, Z3.T1A.T2D.X1E.X2A,
Z4.T1A.T2D.X1E.X2A, Z5.T1A.T2D.X1E.X2A, Z6.T1A.T2D.X1E.X2A,
Z1.T1B.T2D.X1E.X2A, Z2.T1B.T2D.X1E.X2A, Z3.T1B.T2D.X1E.X2A,
Z4.T1B.T2D.X1E.X2A, Z5.T1B.T2D.X1E.X2A, Z6.T1B.T2D.X1E.X2A,
Z1.T1C.T2D.X1E.X2A, Z2.T1C.T2D.X1E.X2A, Z3.T1C.T2D.X1E.X2A,
Z4.T1C.T2D.X1E.X2A, Z5.T1C.T2D.X1E.X2A, Z6.T1C.T2D.X1E.X2A,
Z1.T1D.T2D.X1E.X2A, Z2.T1D.T2D.X1E.X2A, Z3.T1D.T2D.X1E.X2A,
Z4.T1D.T2D.X1E.X2A, Z5.T1D.T2D.X1E.X2A, Z6.T1D.T2D.X1E.X2A,
Z1.T1A.T2A.X1A.X2B, Z2.T1A.T2A.X1A.X2B, Z3.T1A.T2A.X1A.X2B,
Z4.T1A.T2A.X1A.X2B, Z5.T1A.T2A.X1A.X2B, Z6.T1A.T2A.X1A.X2B,
Z1.T1B.T2A.X1A.X2B, Z2.T1B.T2A.X1A.X2B, Z3.T1B.T2A.X1A.X2B,
Z4.T1B.T2A.X1A.X2B,
Z5.T1B.T2A.X1A.X2B, Z6.T1B.T2A.X1A.X2B, Z1.T1C.T2A.X1A.X2B,
Z2.T1C.T2A.X1A.X2B, Z3.T1C.T2A.X1A.X2B, Z4.T1C.T2A.X1A.X2B,
Z5.T1C.T2A.X1A.X2B, Z6.T1C.T2A.X1A.X2B, Z1.T1D.T2A.X1A.X2B,
Z2.T1D.T2A.X1A.X2B, Z3.T1D.T2A.X1A.X2B, Z4.T1D.T2A.X1A.X2B,
Z5.T1D.T2A.X1A.X2B, Z6.T1D.T2A.X1A.X2B, Z1.T1A.T2B.X1A.X2B,
Z2.T1A.T2B.X1A.X2B, Z3.T1A.T2B.X1A.X2B, Z4.T1A.T2B.X1A.X2B,
Z5.T1A.T2B.X1A.X2B, Z6.T1A.T2B.X1A.X2B, Z1.T1B.T2B.X1A.X2B,
Z2.T1B.T2B.X1A.X2B, Z3.T1B.T2B.X1A.X2B, Z4.T1B.T2B.X1A.X2B,
Z5.T1B.T2B.X1A.X2B, Z6.T1B.T2B.X1A.X2B, Z1.T1C.T2B.X1A.X2B,
Z2.T1C.T2B.X1A.X2B, Z3.T1C.T2B.X1A.X2B, Z4.T1C.T2B.X1A.X2B,
Z5.T1C.T2B.X1A.X2B, Z6.T1C.T2B.X1A.X2B, Z1.T1D.T2B.X1A.X2B,
Z2.T1D.T2B.X1A.X2B, Z3.T1D.T2B.X1A.X2B, Z4.T1D.T2B.X1A.X2B,
Z5.T1D.T2B.X1A.X2B, Z6.T1D.T2B.X1A.X2B, Z1.T1A.T2C.X1A.X2B,
Z2.T1A.T2C.X1A.X2B, Z3.T1A.T2C.X1A.X2B, Z4.T1A.T2C.X1A.X2B,
Z5.T1A.T2C.X1A.X2B, Z6.T1A.T2C.X1A.X2B, Z1.T1B.T2C.X1A.X2B,
Z2.T1B.T2C.X1A.X2B, Z3.T1B.T2C.X1A.X2B, Z4.T1B.T2C.X1A.X2B,
Z5.T1B.T2C.X1A.X2B, Z6.T1B.T2C.X1A.X2B, Z1.T1C.T2C.X1A.X2B,
Z2.T1C.T2C.X1A.X2B, Z3.T1C.T2C.X1A.X2B, Z4.T1C.T2C.X1A.X2B,
Z5.T1C.T2C.X1A.X2B, Z6.T1C.T2C.X1A.X2B, Z1.T1D.T2C.X1A.X2B,
Z2.T1D.T2C.X1A.X2B, Z3.T1D.T2C.X1A.X2B, Z4.T1D.T2C.X1A.X2B,
Z5.T1D.T2C.X1A.X2B, Z6.T1D.T2C.X1A.X2B, Z1.T1A.T2D.X1A.X2B,
Z2.T1A.T2D.X1A.X2B, Z3.T1A.T2D.X1A.X2B, Z4.T1A.T2D.X1A.X2B,
Z5.T1A.T2D.X1A.X2B, Z6.T1A.T2D.X1A.X2B, Z1.T1B.T2D.X1A.X2B,
Z2.T1B.T2D.X1A.X2B, Z3.T1B.T2D.X1A.X2B, Z4.T1B.T2D.X1A.X2B,
Z5.T1B.T2D.X1A.X2B, Z6.T1B.T2D.X1A.X2B, Z1.T1C.T2D.X1A.X2B,
Z2.T1C.T2D.X1A.X2B, Z3.T1C.T2D.X1A.X2B, Z4.T1C.T2D.X1A.X2B,
Z5.T1C.T2D.X1A.X2B, Z6.T1C.T2D.X1A.X2B, Z1.T1D.T2D.X1A.X2B,
Z2.T1D.T2D.X1A.X2B, Z3.T1D.T2D.X1A.X2B, Z4.T1D.T2D.X1A.X2B,
Z5.T1D.T2D.X1A.X2B, Z6.T1D.T2D.X1A.X2B, Z1.T1A.T2A.X1B.X2B,
Z2.T1A.T2A.X1B.X2B, Z3.T1A.T2A.X1B.X2B, Z4.T1A.T2A.X1B.X2B,
Z5.T1A.T2A.X1B.X2B, Z6.T1A.T2A.X1B.X2B, Z1.T1B.T2A.X1B.X2B,
Z2.T1B.T2A.X1B.X2B, Z3.T1B.T2A.X1B.X2B, Z4.T1B.T2A.X1B.X2B,
Z5.T1B.T2A.X1B.X2B, Z6.T1B.T2A.X1B.X2B, Z1.T1C.T2A.X1B.X2B,
Z2.T1C.T2A.X1B.X2B, Z3.T1C.T2A.X1B.X2B, Z4.T1C.T2A.X1B.X2B,
Z5.T1C.T2A.X1B.X2B, Z6.T1C.T2A.X1B.X2B, Z1.T1D.T2A.X1B.X2B,
Z2.T1D.T2A.X1B.X2B, Z3.T1D.T2A.X1B.X2B, Z4.T1D.T2A.X1B.X2B,
Z5.T1D.T2A.X1B.X2B, Z6.T1D.T2A.X1B.X2B, Z1.T1A.T2B.X1B.X2B,
Z2.T1A.T2B.X1B.X2B, Z3.T1A.T2B.X1B.X2B, Z4.T1A.T2B.X1B.X2B,
Z5.T1A.T2B.X1B.X2B, Z6.T1A.T2B.X1B.X2B, Z1.T1B.T2B.X1B.X2B,
Z2.T1B.T2B.X1B.X2B, Z3.T1B.T2B.X1B.X2B, Z4.T1B.T2B.X1B.X2B,
Z5.T1B.T2B.X1B.X2B, Z6.T1B.T2B.X1B.X2B, Z1.T1C.T2B.X1B.X2B,
Z2.T1C.T2B.X1B.X2B, Z3.T1C.T2B.X1B.X2B, Z4.T1C.T2B.X1B.X2B,
Z5.T1C.T2B.X1B.X2B, Z6.T1C.T2B.X1B.X2B, Z1.T1D.T2B.X1B.X2B,
Z2.T1D.T2B.X1B.X2B, Z3.T1D.T2B.X1B.X2B, Z4.T1D.T2B.X1B.X2B,
Z5.T1D.T2B.X1B.X2B, Z6.T1D.T2B.X1B.X2B, Z1.T1A.T2C.X1B.X2B,
Z2.T1A.T2C.X1B.X2B, Z3.T1A.T2C.X1B.X2B, Z4.T1A.T2C.X1B.X2B,
Z5.T1A.T2C.X1B.X2B, Z6.T1A.T2C.X1B.X2B, Z1.T1B.T2C.X1B.X2B,
Z2.T1B.T2C.X1B.X2B, Z3.T1B.T2C.X1B.X2B, Z4.T1B.T2C.X1B.X2B,
Z5.T1B.T2C.X1B.X2B, Z6.T1B.T2C.X1B.X2B, Z1.T1C.T2C.X1B.X2B,
Z2.T1C.T2C.X1B.X2B, Z3.T1C.T2C.X1B.X2B, Z4.T1C.T2C.X1B.X2B,
Z5.T1C.T2C.X1B.X2B, Z6.T1C.T2C.X1B.X2B, Z1.T1D.T2C.X1B.X2B,
Z2.T1D.T2C.X1B.X2B, Z3.T1D.T2C.X1B.X2B, Z4.T1D.T2C.X1B.X2B,
Z5.T1D.T2C.X1B.X2B, Z6.T1D.T2C.X1B.X2B, Z1.T1A.T2D.X1B.X2B,
Z2.T1A.T2D.X1B.X2B, Z3.T1A.T2D.X1B.X2B, Z4.T1A.T2D.X1B.X2B,
Z5.T1A.T2D.X1B.X2B, Z6.T1A.T2D.X1B.X2B, Z1.T1B.T2D.X1B.X2B,
Z2.T1B.T2D.X1B.X2B, Z3.T1B.T2D.X1B.X2B, Z4.T1B.T2D.X1B.X2B,
Z5.T1B.T2D.X1B.X2B, Z6.T1B.T2D.X1B.X2B, Z1.T1C.T2D.X1B.X2B,
Z2.T1C.T2D.X1B.X2B, Z3.T1C.T2D.X1B.X2B, Z4.T1C.T2D.X1B.X2B,
Z5.T1C.T2D.X1B.X2B, Z6.T1C.T2D.X1B.X2B, Z1.T1D.T2D.X1B.X2B,
Z2.T1D.T2D.X1B.X2B, Z3.T1D.T2D.X1B.X2B, Z4.T1D.T2D.X1B.X2B,
Z5.T1D.T2D.X1B.X2B, Z6.T1D.T2D.X1B.X2B, Z1.T1A.T2A.X1C.X2B,
Z2.T1A.T2A.X1C.X2B, Z3.T1A.T2A.X1C.X2B, Z4.T1A.T2A.X1C.X2B,
Z5.T1A.T2A.X1C.X2B, Z6.T1A.T2A.X1C.X2B, Z1.T1B.T2A.X1C.X2B,
Z2.T1B.T2A.X1C.X2B, Z3.T1B.T2A.X1C.X2B, Z4.T1B.T2A.X1C.X2B,
Z5.T1B.T2A.X1C.X2B, Z6.T1B.T2A.X1C.X2B, Z1.T1C.T2A.X1C.X2B,
Z2.T1C.T2A.X1C.X2B, Z3.T1C.T2A.X1C.X2B, Z4.T1C.T2A.X1C.X2B,
Z5.T1C.T2A.X1C.X2B, Z6.T1C.T2A.X1C.X2B, Z1.T1D.T2A.X1C.X2B,
Z2.T1D.T2A.X1C.X2B, Z3.T1D.T2A.X1C.X2B, Z4.T1D.T2A.X1C.X2B,
Z5.T1D.T2A.X1C.X2B, Z6.T1D.T2A.X1C.X2B, Z1.T1A.T2B.X1C.X2B,
Z2.T1A.T2B.X1C.X2B, Z3.T1A.T2B.X1C.X2B, Z4.T1A.T2B.X1C.X2B,
Z5.T1A.T2B.X1C.X2B, Z6.T1A.T2B.X1C.X2B, Z1.T1B.T2B.X1C.X2B,
Z2.T1B.T2B.X1C.X2B, Z3.T1B.T2B.X1C.X2B, Z4.T1B.T2B.X1C.X2B,
Z5.T1B.T2B.X1C.X2B, Z6.T1B.T2B.X1C.X2B, Z1.T1C.T2B.X1C.X2B,
Z2.T1C.T2B.X1C.X2B, Z3.T1C.T2B.X1C.X2B, Z4.T1C.T2B.X1C.X2B,
Z5.T1C.T2B.X1C.X2B, Z6.T1C.T2B.X1C.X2B, Z1.T1D.T2B.X1C.X2B,
Z2.T1D.T2B.X1C.X2B, Z3.T1D.T2B.X1C.X2B, Z4.T1D.T2B.X1C.X2B,
Z5.T1D.T2B.X1C.X2B, Z6.T1D.T2B.X1C.X2B, Z1.T1A.T2C.X1C.X2B,
Z2.T1A.T2C.X1C.X2B, Z3.T1A.T2C.X1C.X2B, Z4.T1A.T2C.X1C.X2B,
Z5.T1A.T2C.X1C.X2B, Z6.T1A.T2C.X1C.X2B, Z1.T1B.T2C.X1C.X2B,
Z2.T1B.T2C.X1C.X2B, Z3.T1B.T2C.X1C.X2B, Z4.T1B.T2C.X1C.X2B,
Z5.T1B.T2C.X1C.X2B, Z6.T1B.T2C.X1C.X2B, Z1.T1C.T2C.X1C.X2B,
Z2.T1C.T2C.X1C.X2B, Z3.T1C.T2C.X1C.X2B, Z4.T1C.T2C.X1C.X2B,
Z5.T1C.T2C.X1C.X2B, Z6.T1C.T2C.X1C.X2B, Z1.T1D.T2C.X1C.X2B,
Z2.T1D.T2C.X1C.X2B, Z3.T1D.T2C.X1C.X2B, Z4.T1D.T2C.X1C.X2B,
Z5.T1D.T2C.X1C.X2B, Z6.T1D.T2C.X1C.X2B, Z1.T1A.T2D.X1C.X2B,
Z2.T1A.T2D.X1C.X2B, Z3.T1A.T2D.X1C.X2B, Z4.T1A.T2D.X1C.X2B,
Z5.T1A.T2D.X1C.X2B, Z6.T1A.T2D.X1C.X2B, Z1.T1B.T2D.X1C.X2B,
Z2.T1B.T2D.X1C.X2B, Z3.T1B.T2D.X1C.X2B, Z4.T1B.T2D.X1C.X2B,
Z5.T1B.T2D.X1C.X2B, Z6.T1B.T2D.X1C.X2B, Z1.T1C.T2D.X1C.X2B,
Z2.T1C.T2D.X1C.X2B, Z3.T1C.T2D.X1C.X2B, Z4.T1C.T2D.X1C.X2B,
Z5.T1C.T2D.X1C.X2B, Z6.T1C.T2D.X1C.X2B, Z1.T1D.T2D.X1C.X2B,
Z2.T1D.T2D.X1C.X2B, Z3.T1D.T2D.X1C.X2B, Z4.T1D.T2D.X1C.X2B,
Z5.T1D.T2D.X1C.X2B, Z6.T1D.T2D.X1C.X2B, Z1.T1A.T2A.X1D.X2B,
Z2.T1A.T2A.X1D.X2B, Z3.T1A.T2A.X1D.X2B, Z4.T1A.T2A.X1D.X2B,
Z5.T1A.T2A.X1D.X2B, Z6.T1A.T2A.X1D.X2B, Z1.T1B.T2A.X1D.X2B,
Z2.T1B.T2A.X1D.X2B, Z3.T1B.T2A.X1D.X2B, Z4.T1B.T2A.X1D.X2B,
Z5.T1B.T2A.X1D.X2B, Z6.T1B.T2A.X1D.X2B, Z1.T1C.T2A.X1D.X2B,
Z2.T1C.T2A.X1D.X2B, Z3.T1C.T2A.X1D.X2B, Z4.T1C.T2A.X1D.X2B,
Z5.T1C.T2A.X1D.X2B, Z6.T1C.T2A.X1D.X2B, Z1.T1D.T2A.X1D.X2B,
Z2.T1D.T2A.X1D.X2B, Z3.T1D.T2A.X1D.X2B, Z4.T1D.T2A.X1D.X2B,
Z5.T1D.T2A.X1D.X2B, Z6.T1D.T2A.X1D.X2B, Z1.T1A.T2B.X1D.X2B,
Z2.T1A.T2B.X1D.X2B, Z3.T1A.T2B.X1D.X2B, Z4.T1A.T2B.X1D.X2B,
Z5.T1A.T2B.X1D.X2B, Z6.T1A.T2B.X1D.X2B, Z1.T1B.T2B.X1D.X2B,
Z2.T1B.T2B.X1D.X2B, Z3.T1B.T2B.X1D.X2B, Z4.T1B.T2B.X1D.X2B,
Z5.T1B.T2B.X1D.X2B, Z6.T1B.T2B.X1D.X2B, Z1.T1C.T2B.X1D.X2B,
Z2.T1C.T2B.X1D.X2B, Z3.T1C.T2B.X1D.X2B, Z4.T1C.T2B.X1D.X2B,
Z5.T1C.T2B.X1D.X2B, Z6.T1C.T2B.X1D.X2B, Z1.T1D.T2B.X1D.X2B,
Z2.T1D.T2B.X1D.X2B, Z3.T1D.T2B.X1D.X2B, Z4.T1D.T2B.X1D.X2B,
Z5.T1D.T2B.X1D.X2B, Z6.T1D.T2B.X1D.X2B, Z1.T1A.T2C.X1D.X2B,
Z2.T1A.T2C.X1D.X2B, Z3.T1A.T2C.X1D.X2B, Z4.T1A.T2C.X1D.X2B,
Z5.T1A.T2C.X1D.X2B, Z6.T1A.T2C.X1D.X2B, Z1.T1B.T2C.X1D.X2B,
Z2.T1B.T2C.X1D.X2B, Z3.T1B.T2C.X1D.X2B, Z4.T1B.T2C.X1D.X2B,
Z5.T1B.T2C.X1D.X2B, Z6.T1B.T2C.X1D.X2B, Z1.T1C.T2C.X1D.X2B,
Z2.T1C.T2C.X1D.X2B, Z3.T1C.T2C.X1D.X2B, Z4.T1C.T2C.X1D.X2B,
Z5.T1C.T2C.X1D.X2B, Z6.T1C.T2C.X1D.X2B, Z1.T1D.T2C.X1D.X2B,
Z2.T1D.T2C.X1D.X2B, Z3.T1D.T2C.X1D.X2B, Z4.T1D.T2C.X1D.X2B,
Z5.T1D.T2C.X1D.X2B, Z6.T1D.T2C.X1D.X2B, Z1.T1A.T2D.X1D.X2B,
Z2.T1A.T2D.X1D.X2B, Z3.T1A.T2D.X1D.X2B, Z4.T1A.T2D.X1D.X2B,
Z5.T1A.T2D.X1D.X2B, Z6.T1A.T2D.X1D.X2B, Z1.T1B.T2D.X1D.X2B,
Z2.T1B.T2D.X1D.X2B, Z3.T1B.T2D.X1D.X2B, Z4.T1B.T2D.X1D.X2B,
Z5.T1B.T2D.X1D.X2B, Z6.T1B.T2D.X1D.X2B, Z1.T1C.T2D.X1D.X2B,
Z2.T1C.T2D.X1D.X2B, Z3.T1C.T2D.X1D.X2B, Z4.T1C.T2D.X1D.X2B,
Z5.T1C.T2D.X1D.X2B, Z6.T1C.T2D.X1D.X2B, Z1.T1D.T2D.X1D.X2B,
Z2.T1D.T2D.X1D.X2B, Z3.T1D.T2D.X1D.X2B, Z4.T1D.T2D.X1D.X2B,
Z5.T1D.T2D.X1D.X2B, Z6.T1D.T2D.X1D.X2B, Z1.T1A.T2A.X1E.X2B,
Z2.T1A.T2A.X1E.X2B, Z3.T1A.T2A.X1E.X2B, Z4.T1A.T2A.X1E.X2B,
Z5.T1A.T2A.X1E.X2B, Z6.T1A.T2A.X1E.X2B, Z1.T1B.T2A.X1E.X2B,
Z2.T1B.T2A.X1E.X2B, Z3.T1B.T2A.X1E.X2B, Z4.T1B.T2A.X1E.X2B,
Z5.T1B.T2A.X1E.X2B, Z6.T1B.T2A.X1E.X2B, Z1.T1C.T2A.X1E.X2B,
Z2.T1C.T2A.X1E.X2B, Z3.T1C.T2A.X1E.X2B, Z4.T1C.T2A.X1E.X2B,
Z5.T1C.T2A.X1E.X2B, Z6.T1C.T2A.X1E.X2B, Z1.T1D.T2A.X1E.X2B,
Z2.T1D.T2A.X1E.X2B, Z3.T1D.T2A.X1E.X2B, Z4.T1D.T2A.X1E.X2B,
Z5.T1D.T2A.X1E.X2B, Z6.T1D.T2A.X1E.X2B, Z1.T1A.T2B.X1E.X2B,
Z2.T1A.T2B.X1E.X2B, Z3.T1A.T2B.X1E.X2B, Z4.T1A.T2B.X1E.X2B,
Z5.T1A.T2B.X1E.X2B, Z6.T1A.T2B.X1E.X2B, Z1.T1B.T2B.X1E.X2B,
Z2.T1B.T2B.X1E.X2B, Z3.T1B.T2B.X1E.X2B, Z4.T1B.T2B.X1E.X2B,
Z5.T1B.T2B.X1E.X2B, Z6.T1B.T2B.X1E.X2B, Z1.T1C.T2B.X1E.X2B,
Z2.T1C.T2B.X1E.X2B, Z3.T1C.T2B.X1E.X2B, Z4.T1C.T2B.X1E.X2B,
Z5.T1C.T2B.X1E.X2B, Z6.T1C.T2B.X1E.X2B, Z1.T1D.T2B.X1E.X2B,
Z2.T1D.T2B.X1E.X2B, Z3.T1D.T2B.X1E.X2B, Z4.T1D.T2B.X1E.X2B,
Z5.T1D.T2B.X1E.X2B, Z6.T1D.T2B.X1E.X2B, Z1.T1A.T2C.X1E.X2B,
Z2.T1A.T2C.X1E.X2B, Z3.T1A.T2C.X1E.X2B, Z4.T1A.T2C.X1E.X2B,
Z5.T1A.T2C.X1E.X2B, Z6.T1A.T2C.X1E.X2B, Z1.T1B.T2C.X1E.X2B,
Z2.T1B.T2C.X1E.X2B, Z3.T1B.T2C.X1E.X2B, Z4.T1B.T2C.X1E.X2B,
Z5.T1B.T2C.X1E.X2B, Z6.T1B.T2C.X1E.X2B, Z1.T1C.T2C.X1E.X2B,
Z2.T1C.T2C.X1E.X2B, Z3.T1C.T2C.X1E.X2B, Z4.T1C.T2C.X1E.X2B,
Z5.T1C.T2C.X1E.X2B, Z6.T1C.T2C.X1E.X2B, Z1.T1D.T2C.X1E.X2B,
Z2.T1D.T2C.X1E.X2B, Z3.T1D.T2C.X1E.X2B, Z4.T1D.T2C.X1E.X2B,
Z5.T1D.T2C.X1E.X2B, Z6.T1D.T2C.X1E.X2B, Z1.T1A.T2D.X1E.X2B,
Z2.T1A.T2D.X1E.X2B, Z3.T1A.T2D.X1E.X2B, Z4.T1A.T2D.X1E.X2B,
Z5.T1A.T2D.X1E.X2B, Z6.T1A.T2D.X1E.X2B, Z1.T1B.T2D.X1E.X2B,
Z2.T1B.T2D.X1E.X2B, Z3.T1B.T2D.X1E.X2B, Z4.T1B.T2D.X1E.X2B,
Z5.T1B.T2D.X1E.X2B, Z6.T1B.T2D.X1E.X2B, Z1.T1C.T2D.X1E.X2B,
Z2.T1C.T2D.X1E.X2B, Z3.T1C.T2D.X1E.X2B, Z4.T1C.T2D.X1E.X2B,
Z5.T1C.T2D.X1E.X2B, Z6.T1C.T2D.X1E.X2B, Z1.T1D.T2D.X1E.X2B,
Z2.T1D.T2D.X1E.X2B, Z3.T1D.T2D.X1E.X2B, Z4.T1D.T2D.X1E.X2B,
Z5.T1D.T2D.X1E.X2B, Z6.T1D.T2D.X1E.X2B, Z1.T1A.T2A.X1A.X2C,
Z2.T1A.T2A.X1A.X2C, Z3.T1A.T2A.X1A.X2C, Z4.T1A.T2A.X1A.X2C,
Z5.T1A.T2A.X1A.X2C, Z6.T1A.T2A.X1A.X2C, Z1.T1B.T2A.X1A.X2C,
Z2.T1B.T2A.X1A.X2C, Z3.T1B.T2A.X1A.X2C, Z4.T1B.T2A.X1A.X2C,
Z5.T1B.T2A.X1A.X2C, Z6.T1B.T2A.X1A.X2C, Z1.T1C.T2A.X1A.X2C,
Z2.T1C.T2A.X1A.X2C, Z3.T1C.T2A.X1A.X2C, Z4.T1C.T2A.X1A.X2C,
Z5.T1C.T2A.X1A.X2C, Z6.T1C.T2A.X1A.X2C, Z1.T1D.T2A.X1A.X2C,
Z2.T1D.T2A.X1A.X2C, Z3.T1D.T2A.X1A.X2C, Z4.T1D.T2A.X1A.X2C,
Z5.T1D.T2A.X1A.X2C, Z6.T1D.T2A.X1A.X2C, Z1.T1A.T2B.X1A.X2C,
Z2.T1A.T2B.X1A.X2C, Z3.T1A.T2B.X1A.X2C, Z4.T1A.T2B.X1A.X2C,
Z5.T1A.T2B.X1A.X2C, Z6.T1A.T2B.X1A.X2C, Z1.T1B.T2B.X1A.X2C,
Z2.T1B.T2B.X1A.X2C,
Z3.T1B.T2B.X1A.X2C, Z4.T1B.T2B.X1A.X2C, Z5.T1B.T2B.X1A.X2C,
Z6.T1B.T2B.X1A.X2C, Z1.T1C.T2B.X1A.X2C, Z2.T1C.T2B.X1A.X2C,
Z3.T1C.T2B.X1A.X2C, Z4.T1C.T2B.X1A.X2C, Z5.T1C.T2B.X1A.X2C,
Z6.T1C.T2B.X1A.X2C, Z1.T1D.T2B.X1A.X2C, Z2.T1D.T2B.X1A.X2C,
Z3.T1D.T2B.X1A.X2C, Z4.T1D.T2B.X1A.X2C, Z5.T1D.T2B.X1A.X2C,
Z6.T1D.T2B.X1A.X2C, Z1.T1A.T2C.X1A.X2C, Z2.T1A.T2C.X1A.X2C,
Z3.T1A.T2C.X1A.X2C, Z4.T1A.T2C.X1A.X2C, Z5.T1A.T2C.X1A.X2C,
Z6.T1A.T2C.X1A.X2C, Z1.T1B.T2C.X1A.X2C, Z2.T1B.T2C.X1A.X2C,
Z3.T1B.T2C.X1A.X2C, Z4.T1B.T2C.X1A.X2C, Z5.T1B.T2C.X1A.X2C,
Z6.T1B.T2C.X1A.X2C, Z1.T1C.T2C.X1A.X2C, Z2.T1C.T2C.X1A.X2C,
Z3.T1C.T2C.X1A.X2C, Z4.T1C.T2C.X1A.X2C, Z5.T1C.T2C.X1A.X2C,
Z6.T1C.T2C.X1A.X2C, Z1.T1D.T2C.X1A.X2C, Z2.T1D.T2C.X1A.X2C,
Z3.T1D.T2C.X1A.X2C, Z4.T1D.T2C.X1A.X2C, Z5.T1D.T2C.X1A.X2C,
Z6.T1D.T2C.X1A.X2C, Z1.T1A.T2D.X1A.X2C, Z2.T1A.T2D.X1A.X2C,
Z3.T1A.T2D.X1A.X2C, Z4.T1A.T2D.X1A.X2C, Z5.T1A.T2D.X1A.X2C,
Z6.T1A.T2D.X1A.X2C, Z1.T1B.T2D.X1A.X2C, Z2.T1B.T2D.X1A.X2C,
Z3.T1B.T2D.X1A.X2C, Z4.T1B.T2D.X1A.X2C, Z5.T1B.T2D.X1A.X2C,
Z6.T1B.T2D.X1A.X2C, Z1.T1C.T2D.X1A.X2C, Z2.T1C.T2D.X1A.X2C,
Z3.T1C.T2D.X1A.X2C, Z4.T1C.T2D.X1A.X2C, Z5.T1C.T2D.X1A.X2C,
Z6.T1C.T2D.X1A.X2C, Z1.T1D.T2D.X1A.X2C, Z2.T1D.T2D.X1A.X2C,
Z3.T1D.T2D.X1A.X2C, Z4.T1D.T2D.X1A.X2C, Z5.T1D.T2D.X1A.X2C,
Z6.T1D.T2D.X1A.X2C, Z1.T1A.T2A.X1B.X2C, Z2.T1A.T2A.X1B.X2C,
Z3.T1A.T2A.X1B.X2C, Z4.T1A.T2A.X1B.X2C, Z5.T1A.T2A.X1B.X2C,
Z6.T1A.T2A.X1B.X2C, Z1.T1B.T2A.X1B.X2C, Z2.T1B.T2A.X1B.X2C,
Z3.T1B.T2A.X1B.X2C, Z4.T1B.T2A.X1B.X2C, Z5.T1B.T2A.X1B.X2C,
Z6.T1B.T2A.X1B.X2C, Z1.T1C.T2A.X1B.X2C, Z2.T1C.T2A.X1B.X2C,
Z3.T1C.T2A.X1B.X2C, Z4.T1C.T2A.X1B.X2C, Z5.T1C.T2A.X1B.X2C,
Z6.T1C.T2A.X1B.X2C, Z1.T1D.T2A.X1B.X2C, Z2.T1D.T2A.X1B.X2C,
Z3.T1D.T2A.X1B.X2C, Z4.T1D.T2A.X1B.X2C, Z5.T1D.T2A.X1B.X2C,
Z6.T1D.T2A.X1B.X2C, Z1.T1A.T2B.X1B.X2C, Z2.T1A.T2B.X1B.X2C,
Z3.T1A.T2B.X1B.X2C, Z4.T1A.T2B.X1B.X2C, Z5.T1A.T2B.X1B.X2C,
Z6.T1A.T2B.X1B.X2C, Z1.T1B.T2B.X1B.X2C, Z2.T1B.T2B.X1B.X2C,
Z3.T1B.T2B.X1B.X2C, Z4.T1B.T2B.X1B.X2C, Z5.T1B.T2B.X1B.X2C,
Z6.T1B.T2B.X1B.X2C, Z1.T1C.T2B.X1B.X2C, Z2.T1C.T2B.X1B.X2C,
Z3.T1C.T2B.X1B.X2C, Z4.T1C.T2B.X1B.X2C, Z5.T1C.T2B.X1B.X2C,
Z6.T1C.T2B.X1B.X2C, Z1.T1D.T2B.X1B.X2C, Z2.T1D.T2B.X1B.X2C,
Z3.T1D.T2B.X1B.X2C, Z4.T1D.T2B.X1B.X2C, Z5.T1D.T2B.X1B.X2C,
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Z3.T1A.T2C.X1B.X2C, Z4.T1A.T2C.X1B.X2C, Z5.T1A.T2C.X1B.X2C,
Z6.T1A.T2C.X1B.X2C, Z1.T1B.T2C.X1B.X2C, Z2.T1B.T2C.X1B.X2C,
Z3.T1B.T2C.X1B.X2C, Z4.T1B.T2C.X1B.X2C, Z5.T1B.T2C.X1B.X2C,
Z6.T1B.T2C.X1B.X2C, Z1.T1C.T2C.X1B.X2C, Z2.T1C.T2C.X1B.X2C,
Z3.T1C.T2C.X1B.X2C, Z4.T1C.T2C.X1B.X2C, Z5.T1C.T2C.X1B.X2C,
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Z3.T1D.T2C.X1B.X2C, Z4.T1D.T2C.X1B.X2C, Z5.T1D.T2C.X1B.X2C,
Z6.T1D.T2C.X1B.X2C, Z1.T1A.T2D.X1B.X2C, Z2.T1A.T2D.X1B.X2C,
Z3.T1A.T2D.X1B.X2C, Z4.T1A.T2D.X1B.X2C, Z5.T1A.T2D.X1B.X2C,
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Z3.T1B.T2D.X1B.X2C, Z4.T1B.T2D.X1B.X2C, Z5.T1B.T2D.X1B.X2C,
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Z3.T1C.T2D.X1B.X2C, Z4.T1C.T2D.X1B.X2C, Z5.T1C.T2D.X1B.X2C,
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Z3.T1D.T2D.X1B.X2C, Z4.T1D.T2D.X1B.X2C, Z5.T1D.T2D.X1B.X2C,
Z6.T1D.T2D.X1B.X2C, Z1.T1A.T2A.X1C.X2C, Z2.T1A.T2A.X1C.X2C,
Z3.T1A.T2A.X1C.X2C, Z4.T1A.T2A.X1C.X2C, Z5.T1A.T2A.X1C.X2C,
Z6.T1A.T2A.X1C.X2C, Z1.T1B.T2A.X1C.X2C, Z2.T1B.T2A.X1C.X2C,
Z3.T1B.T2A.X1C.X2C, Z4.T1B.T2A.X1C.X2C, Z5.T1B.T2A.X1C.X2C,
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Z3.T1D.T2A.X1C.X2C, Z4.T1D.T2A.X1C.X2C, Z5.T1D.T2A.X1C.X2C,
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Z3.T1A.T2B.X1C.X2C, Z4.T1A.T2B.X1C.X2C, Z5.T1A.T2B.X1C.X2C,
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Z3.T1D.T2C.X1C.X2C, Z4.T1D.T2C.X1C.X2C, Z5.T1D.T2C.X1C.X2C,
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Z3.T1A.T2D.X1C.X2C, Z4.T1A.T2D.X1C.X2C, Z5.T1A.T2D.X1C.X2C,
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Z3.T1B.T2D.X1C.X2C, Z4.T1B.T2D.X1C.X2C, Z5.T1B.T2D.X1C.X2C,
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Z3.T1C.T2D.X1C.X2C, Z4.T1C.T2D.X1C.X2C, Z5.T1C.T2D.X1C.X2C,
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Z3.T1D.T2D.X1C.X2C, Z4.T1D.T2D.X1C.X2C, Z5.T1D.T2D.X1C.X2C,
Z6.T1D.T2D.X1C.X2C, Z1.T1A.T2A.X1D.X2C, Z2.T1A.T2A.X1D.X2C,
Z3.T1A.T2A.X1D.X2C, Z4.T1A.T2A.X1D.X2C, Z5.T1A.T2A.X1D.X2C,
Z6.T1A.T2A.X1D.X2C, Z1.T1B.T2A.X1D.X2C, Z2.T1B.T2A.X1D.X2C,
Z3.T1B.T2A.X1D.X2C, Z4.T1B.T2A.X1D.X2C, Z5.T1B.T2A.X1D.X2C,
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Z3.T1C.T2A.X1D.X2C, Z4.T1C.T2A.X1D.X2C, Z5.T1C.T2A.X1D.X2C,
Z6.T1C.T2A.X1D.X2C, Z1.T1D.T2A.X1D.X2C, Z2.T1D.T2A.X1D.X2C,
Z3.T1D.T2A.X1D.X2C, Z4.T1D.T2A.X1D.X2C, Z5.T1D.T2A.X1D.X2C,
Z6.T1D.T2A.X1D.X2C, Z1.T1A.T2B.X1D.X2C, Z2.T1A.T2B.X1D.X2C,
Z3.T1A.T2B.X1D.X2C, Z4.T1A.T2B.X1D.X2C, Z5.T1A.T2B.X1D.X2C,
Z6.T1A.T2B.X1D.X2C, Z1.T1B.T2B.X1D.X2C, Z2.T1B.T2B.X1D.X2C,
Z3.T1B.T2B.X1D.X2C, Z4.T1B.T2B.X1D.X2C, Z5.T1B.T2B.X1D.X2C,
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Z3.T1C.T2B.X1D.X2C, Z4.T1C.T2B.X1D.X2C, Z5.T1C.T2B.X1D.X2C,
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Z3.T1D.T2B.X1D.X2C, Z4.T1D.T2B.X1D.X2C, Z5.T1D.T2B.X1D.X2C,
Z6.T1D.T2B.X1D.X2C, Z1.T1A.T2C.X1D.X2C, Z2.T1A.T2C.X1D.X2C,
Z3.T1A.T2C.X1D.X2C, Z4.T1A.T2C.X1D.X2C, Z5.T1A.T2C.X1D.X2C,
Z6.T1A.T2C.X1D.X2C, Z1.T1B.T2C.X1D.X2C, Z2.T1B.T2C.X1D.X2C,
Z3.T1B.T2C.X1D.X2C, Z4.T1B.T2C.X1D.X2C, Z5.T1B.T2C.X1D.X2C,
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Z3.T1C.T2C.X1D.X2C, Z4.T1C.T2C.X1D.X2C, Z5.T1C.T2C.X1D.X2C,
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Z3.T1D.T2C.X1D.X2C, Z4.T1D.T2C.X1D.X2C, Z5.T1D.T2C.X1D.X2C,
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Z3.T1A.T2D.X1D.X2C, Z4.T1A.T2D.X1D.X2C, Z5.T1A.T2D.X1D.X2C,
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Z3.T1B.T2D.X1D.X2C, Z4.T1B.T2D.X1D.X2C, Z5.T1B.T2D.X1D.X2C,
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Z3.T1C.T2D.X1D.X2C, Z4.T1C.T2D.X1D.X2C, Z5.T1C.T2D.X1D.X2C,
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Z3.T1D.T2D.X1D.X2C, Z4.T1D.T2D.X1D.X2C, Z5.T1D.T2D.X1D.X2C,
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Z3.T1A.T2A.X1E.X2C, Z4.T1A.T2A.X1E.X2C, Z5.T1A.T2A.X1E.X2C,
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Z3.T1B.T2A.X1E.X2C, Z4.T1B.T2A.X1E.X2C, Z5.T1B.T2A.X1E.X2C,
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Z3.T1C.T2A.X1E.X2C, Z4.T1C.T2A.X1E.X2C, Z5.T1C.T2A.X1E.X2C,
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Z3.T1D.T2A.X1E.X2C, Z4.T1D.T2A.X1E.X2C, Z5.T1D.T2A.X1E.X2C,
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Z3.T1A.T2B.X1E.X2C, Z4.T1A.T2B.X1E.X2C, Z5.T1A.T2B.X1E.X2C,
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Z3.T1B.T2B.X1E.X2C, Z4.T1B.T2B.X1E.X2C, Z5.T1B.T2B.X1E.X2C,
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Z3.T1C.T2B.X1E.X2C, Z4.T1C.T2B.X1E.X2C, Z5.T1C.T2B.X1E.X2C,
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Z3.T1D.T2B.X1E.X2C, Z4.T1D.T2B.X1E.X2C, Z5.T1D.T2B.X1E.X2C,
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Z3.T1D.T2C.X1E.X2C, Z4.T1D.T2C.X1E.X2C, Z5.T1D.T2C.X1E.X2C,
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Z3.T1A.T2D.X1E.X2C, Z4.T1A.T2D.X1E.X2C, Z5.T1A.T2D.X1E.X2C,
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Z3.T1B.T2D.X1E.X2C, Z4.T1B.T2D.X1E.X2C, Z5.T1B.T2D.X1E.X2C,
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Z3.T1C.T2D.X1E.X2C, Z4.T1C.T2D.X1E.X2C, Z5.T1C.T2D.X1E.X2C,
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Z3.T1D.T2D.X1E.X2C, Z4.T1D.T2D.X1E.X2C, Z5.T1D.T2D.X1E.X2C,
Z6.T1D.T2D.X1E.X2C, Z1.T1A.T2A.X1A.X2D, Z2.T1A.T2A.X1A.X2D,
Z3.T1A.T2A.X1A.X2D, Z4.T1A.T2A.X1A.X2D, Z5.T1A.T2A.X1A.X2D,
Z6.T1A.T2A.X1A.X2D, Z1.T1B.T2A.X1A.X2D, Z2.T1B.T2A.X1A.X2D,
Z3.T1B.T2A.X1A.X2D, Z4.T1B.T2A.X1A.X2D, Z5.T1B.T2A.X1A.X2D,
Z6.T1B.T2A.X1A.X2D, Z1.T1C.T2A.X1A.X2D, Z2.T1C.T2A.X1A.X2D,
Z3.T1C.T2A.X1A.X2D, Z4.T1C.T2A.X1A.X2D, Z5.T1C.T2A.X1A.X2D,
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Z3.T1D.T2A.X1A.X2D, Z4.T1D.T2A.X1A.X2D, Z5.T1D.T2A.X1A.X2D,
Z6.T1D.T2A.X1A.X2D, Z1.T1A.T2B.X1A.X2D, Z2.T1A.T2B.X1A.X2D,
Z3.T1A.T2B.X1A.X2D, Z4.T1A.T2B.X1A.X2D, Z5.T1A.T2B.X1A.X2D,
Z6.T1A.T2B.X1A.X2D, Z1.T1B.T2B.X1A.X2D, Z2.T1B.T2B.X1A.X2D,
Z3.T1B.T2B.X1A.X2D, Z4.T1B.T2B.X1A.X2D, Z5.T1B.T2B.X1A.X2D,
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Z3.T1C.T2B.X1A.X2D, Z4.T1C.T2B.X1A.X2D, Z5.T1C.T2B.X1A.X2D,
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Z3.T1D.T2B.X1A.X2D, Z4.T1D.T2B.X1A.X2D, Z5.T1D.T2B.X1A.X2D,
Z6.T1D.T2B.X1A.X2D, Z1.T1A.T2C.X1A.X2D, Z2.T1A.T2C.X1A.X2D,
Z3.T1A.T2C.X1A.X2D, Z4.T1A.T2C.X1A.X2D, Z5.T1A.T2C.X1A.X2D,
Z6.T1A.T2C.X1A.X2D,
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Z4.T1B.T2C.X1A.X2D, Z5.T1B.T2C.X1A.X2D, Z6.T1B.T2C.X1A.X2D,
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Z4.T1C.T2C.X1A.X2D, Z5.T1C.T2C.X1A.X2D, Z6.T1C.T2C.X1A.X2D,
Z1.T1D.T2C.X1A.X2D, Z2.T1D.T2C.X1A.X2D, Z3.T1D.T2C.X1A.X2D,
Z4.T1D.T2C.X1A.X2D, Z5.T1D.T2C.X1A.X2D, Z6.T1D.T2C.X1A.X2D,
Z1.T1A.T2D.X1A.X2D, Z2.T1A.T2D.X1A.X2D, Z3.T1A.T2D.X1A.X2D,
Z4.T1A.T2D.X1A.X2D, Z5.T1A.T2D.X1A.X2D, Z6.T1A.T2D.X1A.X2D,
Z1.T1B.T2D.X1A.X2D, Z2.T1B.T2D.X1A.X2D, Z3.T1B.T2D.X1A.X2D,
Z4.T1B.T2D.X1A.X2D, Z5.T1B.T2D.X1A.X2D, Z6.T1B.T2D.X1A.X2D,
Z1.T1C.T2D.X1A.X2D, Z2.T1C.T2D.X1A.X2D, Z3.T1C.T2D.X1A.X2D,
Z4.T1C.T2D.X1A.X2D, Z5.T1C.T2D.X1A.X2D, Z6.T1C.T2D.X1A.X2D,
Z1.T1D.T2D.X1A.X2D, Z2.T1D.T2D.X1A.X2D, Z3.T1D.T2D.X1A.X2D,
Z4.T1D.T2D.X1A.X2D, Z5.T1D.T2D.X1A.X2D, Z6.T1D.T2D.X1A.X2D,
Z1.T1A.T2A.X1B.X2D, Z2.T1A.T2A.X1B.X2D, Z3.T1A.T2A.X1B.X2D,
Z4.T1A.T2A.X1B.X2D, Z5.T1A.T2A.X1B.X2D, Z6.T1A.T2A.X1B.X2D,
Z1.T1B.T2A.X1B.X2D, Z2.T1B.T2A.X1B.X2D, Z3.T1B.T2A.X1B.X2D,
Z4.T1B.T2A.X1B.X2D, Z5.T1B.T2A.X1B.X2D, Z6.T1B.T2A.X1B.X2D,
Z1.T1C.T2A.X1B.X2D, Z2.T1C.T2A.X1B.X2D, Z3.T1C.T2A.X1B.X2D,
Z4.T1C.T2A.X1B.X2D, Z5.T1C.T2A.X1B.X2D, Z6.T1C.T2A.X1B.X2D,
Z1.T1D.T2A.X1B.X2D, Z2.T1D.T2A.X1B.X2D, Z3.T1D.T2A.X1B.X2D,
Z4.T1D.T2A.X1B.X2D, Z5.T1D.T2A.X1B.X2D, Z6.T1D.T2A.X1B.X2D,
Z1.T1A.T2B.X1B.X2D, Z2.T1A.T2B.X1B.X2D, Z3.T1A.T2B.X1B.X2D,
Z4.T1A.T2B.X1B.X2D, Z5.T1A.T2B.X1B.X2D, Z6.T1A.T2B.X1B.X2D,
Z1.T1B.T2B.X1B.X2D, Z2.T1B.T2B.X1B.X2D, Z3.T1B.T2B.X1B.X2D,
Z4.T1B.T2B.X1B.X2D, Z5.T1B.T2B.X1B.X2D, Z6.T1B.T2B.X1B.X2D,
Z1.T1C.T2B.X1B.X2D, Z2.T1C.T2B.X1B.X2D, Z3.T1C.T2B.X1B.X2D,
Z4.T1C.T2B.X1B.X2D, Z5.T1C.T2B.X1B.X2D, Z6.T1C.T2B.X1B.X2D,
Z1.T1D.T2B.X1B.X2D, Z2.T1D.T2B.X1B.X2D, Z3.T1D.T2B.X1B.X2D,
Z4.T1D.T2B.X1B.X2D, Z5.T1D.T2B.X1B.X2D, Z6.T1D.T2B.X1B.X2D,
Z1.T1A.T2C.X1B.X2D, Z2.T1A.T2C.X1B.X2D, Z3.T1A.T2C.X1B.X2D,
Z4.T1A.T2C.X1B.X2D, Z5.T1A.T2C.X1B.X2D, Z6.T1A.T2C.X1B.X2D,
Z1.T1B.T2C.X1B.X2D, Z2.T1B.T2C.X1B.X2D, Z3.T1B.T2C.X1B.X2D,
Z4.T1B.T2C.X1B.X2D, Z5.T1B.T2C.X1B.X2D, Z6.T1B.T2C.X1B.X2D,
Z1.T1C.T2C.X1B.X2D, Z2.T1C.T2C.X1B.X2D, Z3.T1C.T2C.X1B.X2D,
Z4.T1C.T2C.X1B.X2D, Z5.T1C.T2C.X1B.X2D, Z6.T1C.T2C.X1B.X2D,
Z1.T1D.T2C.X1B.X2D, Z2.T1D.T2C.X1B.X2D, Z3.T1D.T2C.X1B.X2D,
Z4.T1D.T2C.X1B.X2D, Z5.T1D.T2C.X1B.X2D, Z6.T1D.T2C.X1B.X2D,
Z1.T1A.T2D.X1B.X2D, Z2.T1A.T2D.X1B.X2D, Z3.T1A.T2D.X1B.X2D,
Z4.T1A.T2D.X1B.X2D, Z5.T1A.T2D.X1B.X2D, Z6.T1A.T2D.X1B.X2D,
Z1.T1B.T2D.X1B.X2D, Z2.T1B.T2D.X1B.X2D, Z3.T1B.T2D.X1B.X2D,
Z4.T1B.T2D.X1B.X2D, Z5.T1B.T2D.X1B.X2D, Z6.T1B.T2D.X1B.X2D,
Z1.T1C.T2D.X1B.X2D, Z2.T1C.T2D.X1B.X2D, Z3.T1C.T2D.X1B.X2D,
Z4.T1C.T2D.X1B.X2D, Z5.T1C.T2D.X1B.X2D, Z6.T1C.T2D.X1B.X2D,
Z1.T1D.T2D.X1B.X2D, Z2.T1D.T2D.X1B.X2D, Z3.T1D.T2D.X1B.X2D,
Z4.T1D.T2D.X1B.X2D, Z5.T1D.T2D.X1B.X2D, Z6.T1D.T2D.X1B.X2D,
Z1.T1A.T2A.X1C.X2D, Z2.T1A.T2A.X1C.X2D, Z3.T1A.T2A.X1C.X2D,
Z4.T1A.T2A.X1C.X2D, Z5.T1A.T2A.X1C.X2D, Z6.T1A.T2A.X1C.X2D,
Z1.T1B.T2A.X1C.X2D, Z2.T1B.T2A.X1C.X2D, Z3.T1B.T2A.X1C.X2D,
Z4.T1B.T2A.X1C.X2D, Z5.T1B.T2A.X1C.X2D, Z6.T1B.T2A.X1C.X2D,
Z1.T1C.T2A.X1C.X2D, Z2.T1C.T2A.X1C.X2D, Z3.T1C.T2A.X1C.X2D,
Z4.T1C.T2A.X1C.X2D, Z5.T1C.T2A.X1C.X2D, Z6.T1C.T2A.X1C.X2D,
Z1.T1D.T2A.X1C.X2D, Z2.T1D.T2A.X1C.X2D, Z3.T1D.T2A.X1C.X2D,
Z4.T1D.T2A.X1C.X2D, Z5.T1D.T2A.X1C.X2D, Z6.T1D.T2A.X1C.X2D,
Z1.T1A.T2B.X1C.X2D, Z2.T1A.T2B.X1C.X2D, Z3.T1A.T2B.X1C.X2D,
Z4.T1A.T2B.X1C.X2D, Z5.T1A.T2B.X1C.X2D, Z6.T1A.T2B.X1C.X2D,
Z1.T1B.T2B.X1C.X2D, Z2.T1B.T2B.X1C.X2D, Z3.T1B.T2B.X1C.X2D,
Z4.T1B.T2B.X1C.X2D, Z5.T1B.T2B.X1C.X2D, Z6.T1B.T2B.X1C.X2D,
Z1.T1C.T2B.X1C.X2D, Z2.T1C.T2B.X1C.X2D, Z3.T1C.T2B.X1C.X2D,
Z4.T1C.T2B.X1C.X2D, Z5.T1C.T2B.X1C.X2D, Z6.T1C.T2B.X1C.X2D,
Z1.T1D.T2B.X1C.X2D, Z2.T1D.T2B.X1C.X2D, Z3.T1D.T2B.X1C.X2D,
Z4.T1D.T2B.X1C.X2D, Z5.T1D.T2B.X1C.X2D, Z6.T1D.T2B.X1C.X2D,
Z1.T1A.T2C.X1C.X2D, Z2.T1A.T2C.X1C.X2D, Z3.T1A.T2C.X1C.X2D,
Z4.T1A.T2C.X1C.X2D, Z5.T1A.T2C.X1C.X2D, Z6.T1A.T2C.X1C.X2D,
Z1.T1B.T2C.X1C.X2D, Z2.T1B.T2C.X1C.X2D, Z3.T1B.T2C.X1C.X2D,
Z4.T1B.T2C.X1C.X2D, Z5.T1B.T2C.X1C.X2D, Z6.T1B.T2C.X1C.X2D,
Z1.T1C.T2C.X1C.X2D, Z2.T1C.T2C.X1C.X2D, Z3.T1C.T2C.X1C.X2D,
Z4.T1C.T2C.X1C.X2D, Z5.T1C.T2C.X1C.X2D, Z6.T1C.T2C.X1C.X2D,
Z1.T1D.T2C.X1C.X2D, Z2.T1D.T2C.X1C.X2D, Z3.T1D.T2C.X1C.X2D,
Z4.T1D.T2C.X1C.X2D, Z5.T1D.T2C.X1C.X2D, Z6.T1D.T2C.X1C.X2D,
Z1.T1A.T2D.X1C.X2D, Z2.T1A.T2D.X1C.X2D, Z3.T1A.T2D.X1C.X2D,
Z4.T1A.T2D.X1C.X2D, Z5.T1A.T2D.X1C.X2D, Z6.T1A.T2D.X1C.X2D,
Z1.T1B.T2D.X1C.X2D, Z2.T1B.T2D.X1C.X2D, Z3.T1B.T2D.X1C.X2D,
Z4.T1B.T2D.X1C.X2D, Z5.T1B.T2D.X1C.X2D, Z6.T1B.T2D.X1C.X2D,
Z1.T1C.T2D.X1C.X2D, Z2.T1C.T2D.X1C.X2D, Z3.T1C.T2D.X1C.X2D,
Z4.T1C.T2D.X1C.X2D, Z5.T1C.T2D.X1C.X2D, Z6.T1C.T2D.X1C.X2D,
Z1.T1D.T2D.X1C.X2D, Z2.T1D.T2D.X1C.X2D, Z3.T1D.T2D.X1C.X2D,
Z4.T1D.T2D.X1C.X2D, Z5.T1D.T2D.X1C.X2D, Z6.T1D.T2D.X1C.X2D,
Z1.T1A.T2A.X1D.X2D, Z2.T1A.T2A.X1D.X2D, Z3.T1A.T2A.X1D.X2D,
Z4.T1A.T2A.X1D.X2D, Z5.T1A.T2A.X1D.X2D, Z6.T1A.T2A.X1D.X2D,
Z1.T1B.T2A.X1D.X2D, Z2.T1B.T2A.X1D.X2D, Z3.T1B.T2A.X1D.X2D,
Z4.T1B.T2A.X1D.X2D, Z5.T1B.T2A.X1D.X2D, Z6.T1B.T2A.X1D.X2D,
Z1.T1C.T2A.X1D.X2D, Z2.T1C.T2A.X1D.X2D, Z3.T1C.T2A.X1D.X2D,
Z4.T1C.T2A.X1D.X2D, Z5.T1C.T2A.X1D.X2D, Z6.T1C.T2A.X1D.X2D,
Z1.T1D.T2A.X1D.X2D, Z2.T1D.T2A.X1D.X2D, Z3.T1D.T2A.X1D.X2D,
Z4.T1D.T2A.X1D.X2D, Z5.T1D.T2A.X1D.X2D, Z6.T1D.T2A.X1D.X2D,
Z1.T1A.T2B.X1D.X2D, Z2.T1A.T2B.X1D.X2D, Z3.T1A.T2B.X1D.X2D,
Z4.T1A.T2B.X1D.X2D, Z5.T1A.T2B.X1D.X2D, Z6.T1A.T2B.X1D.X2D,
Z1.T1B.T2B.X1D.X2D, Z2.T1B.T2B.X1D.X2D, Z3.T1B.T2B.X1D.X2D,
Z4.T1B.T2B.X1D.X2D, Z5.T1B.T2B.X1D.X2D, Z6.T1B.T2B.X1D.X2D,
Z1.T1C.T2B.X1D.X2D, Z2.T1C.T2B.X1D.X2D, Z3.T1C.T2B.X1D.X2D,
Z4.T1C.T2B.X1D.X2D, Z5.T1C.T2B.X1D.X2D, Z6.T1C.T2B.X1D.X2D,
Z1.T1D.T2B.X1D.X2D, Z2.T1D.T2B.X1D.X2D, Z3.T1D.T2B.X1D.X2D,
Z4.T1D.T2B.X1D.X2D, Z5.T1D.T2B.X1D.X2D, Z6.T1D.T2B.X1D.X2D,
Z1.T1A.T2C.X1D.X2D, Z2.T1A.T2C.X1D.X2D, Z3.T1A.T2C.X1D.X2D,
Z4.T1A.T2C.X1D.X2D, Z5.T1A.T2C.X1D.X2D, Z6.T1A.T2C.X1D.X2D,
Z1.T1B.T2C.X1D.X2D, Z2.T1B.T2C.X1D.X2D, Z3.T1B.T2C.X1D.X2D,
Z4.T1B.T2C.X1D.X2D, Z5.T1B.T2C.X1D.X2D, Z6.T1B.T2C.X1D.X2D,
Z1.T1C.T2C.X1D.X2D, Z2.T1C.T2C.X1D.X2D, Z3.T1C.T2C.X1D.X2D,
Z4.T1C.T2C.X1D.X2D, Z5.T1C.T2C.X1D.X2D, Z6.T1C.T2C.X1D.X2D,
Z1.T1D.T2C.X1D.X2D, Z2.T1D.T2C.X1D.X2D, Z3.T1D.T2C.X1D.X2D,
Z4.T1D.T2C.X1D.X2D, Z5.T1D.T2C.X1D.X2D, Z6.T1D.T2C.X1D.X2D,
Z1.T1A.T2D.X1D.X2D, Z2.T1A.T2D.X1D.X2D, Z3.T1A.T2D.X1D.X2D,
Z4.T1A.T2D.X1D.X2D, Z5.T1A.T2D.X1D.X2D, Z6.T1A.T2D.X1D.X2D,
Z1.T1B.T2D.X1D.X2D, Z2.T1B.T2D.X1D.X2D, Z3.T1B.T2D.X1D.X2D,
Z4.T1B.T2D.X1D.X2D, Z5.T1B.T2D.X1D.X2D, Z6.T1B.T2D.X1D.X2D,
Z1.T1C.T2D.X1D.X2D, Z2.T1C.T2D.X1D.X2D, Z3.T1C.T2D.X1D.X2D,
Z4.T1C.T2D.X1D.X2D, Z5.T1C.T2D.X1D.X2D, Z6.T1C.T2D.X1D.X2D,
Z1.T1D.T2D.X1D.X2D, Z2.T1D.T2D.X1D.X2D, Z3.T1D.T2D.X1D.X2D,
Z4.T1D.T2D.X1D.X2D, Z5.T1D.T2D.X1D.X2D, Z6.T1D.T2D.X1D.X2D,
Z1.T1A.T2A.X1E.X2D, Z2.T1A.T2A.X1E.X2D, Z3.T1A.T2A.X1E.X2D,
Z4.T1A.T2A.X1E.X2D, Z5.T1A.T2A.X1E.X2D, Z6.T1A.T2A.X1E.X2D,
Z1.T1B.T2A.X1E.X2D, Z2.T1B.T2A.X1E.X2D, Z3.T1B.T2A.X1E.X2D,
Z4.T1B.T2A.X1E.X2D, Z5.T1B.T2A.X1E.X2D, Z6.T1B.T2A.X1E.X2D,
Z1.T1C.T2A.X1E.X2D, Z2.T1C.T2A.X1E.X2D, Z3.T1C.T2A.X1E.X2D,
Z4.T1C.T2A.X1E.X2D, Z5.T1C.T2A.X1E.X2D, Z6.T1C.T2A.X1E.X2D,
Z1.T1D.T2A.X1E.X2D, Z2.T1D.T2A.X1E.X2D, Z3.T1D.T2A.X1E.X2D,
Z4.T1D.T2A.X1E.X2D, Z5.T1D.T2A.X1E.X2D, Z6.T1D.T2A.X1E.X2D,
Z1.T1A.T2B.X1E.X2D, Z2.T1A.T2B.X1E.X2D, Z3.T1A.T2B.X1E.X2D,
Z4.T1A.T2B.X1E.X2D, Z5.T1A.T2B.X1E.X2D, Z6.T1A.T2B.X1E.X2D,
Z1.T1B.T2B.X1E.X2D, Z2.T1B.T2B.X1E.X2D, Z3.T1B.T2B.X1E.X2D,
Z4.T1B.T2B.X1E.X2D, Z5.T1B.T2B.X1E.X2D, Z6.T1B.T2B.X1E.X2D,
Z1.T1C.T2B.X1E.X2D, Z2.T1C.T2B.X1E.X2D, Z3.T1C.T2B.X1E.X2D,
Z4.T1C.T2B.X1E.X2D, Z5.T1C.T2B.X1E.X2D, Z6.T1C.T2B.X1E.X2D,
Z1.T1D.T2B.X1E.X2D, Z2.T1D.T2B.X1E.X2D, Z3.T1D.T2B.X1E.X2D,
Z4.T1D.T2B.X1E.X2D, Z5.T1D.T2B.X1E.X2D, Z6.T1D.T2B.X1E.X2D,
Z1.T1A.T2C.X1E.X2D, Z2.T1A.T2C.X1E.X2D, Z3.T1A.T2C.X1E.X2D,
Z4.T1A.T2C.X1E.X2D, Z5.T1A.T2C.X1E.X2D, Z6.T1A.T2C.X1E.X2D,
Z1.T1B.T2C.X1E.X2D, Z2.T1B.T2C.X1E.X2D, Z3.T1B.T2C.X1E.X2D,
Z4.T1B.T2C.X1E.X2D, Z5.T1B.T2C.X1E.X2D, Z6.T1B.T2C.X1E.X2D,
Z1.T1C.T2C.X1E.X2D, Z2.T1C.T2C.X1E.X2D, Z3.T1C.T2C.X1E.X2D,
Z4.T1C.T2C.X1E.X2D, Z5.T1C.T2C.X1E.X2D, Z6.T1C.T2C.X1E.X2D,
Z1.T1D.T2C.X1E.X2D, Z2.T1D.T2C.X1E.X2D, Z3.T1D.T2C.X1E.X2D,
Z4.T1D.T2C.X1E.X2D, Z5.T1D.T2C.X1E.X2D, Z6.T1D.T2C.X1E.X2D,
Z1.T1A.T2D.X1E.X2D, Z2.T1A.T2D.X1E.X2D, Z3.T1A.T2D.X1E.X2D,
Z4.T1A.T2D.X1E.X2D, Z5.T1A.T2D.X1E.X2D, Z6.T1A.T2D.X1E.X2D,
Z1.T1B.T2D.X1E.X2D, Z2.T1B.T2D.X1E.X2D, Z3.T1B.T2D.X1E.X2D,
Z4.T1B.T2D.X1E.X2D, Z5.T1B.T2D.X1E.X2D, Z6.T1B.T2D.X1E.X2D,
Z1.T1C.T2D.X1E.X2D, Z2.T1C.T2D.X1E.X2D, Z3.T1C.T2D.X1E.X2D,
Z4.T1C.T2D.X1E.X2D, Z5.T1C.T2D.X1E.X2D, Z6.T1C.T2D.X1E.X2D,
Z1.T1D.T2D.X1E.X2D, Z2.T1D.T2D.X1E.X2D, Z3.T1D.T2D.X1E.X2D,
Z4.T1D.T2D.X1E.X2D, Z5.T1D.T2D.X1E.X2D, Z6.T1D.T2D.X1E.X2D,
Z1.T1A.T2A.X1A.X2E, Z2.T1A.T2A.X1A.X2E, Z3.T1A.T2A.X1A.X2E,
Z4.T1A.T2A.X1A.X2E, Z5.T1A.T2A.X1A.X2E, Z6.T1A.T2A.X1A.X2E,
Z1.T1B.T2A.X1A.X2E, Z2.T1B.T2A.X1A.X2E, Z3.T1B.T2A.X1A.X2E,
Z4.T1B.T2A.X1A.X2E, Z5.T1B.T2A.X1A.X2E, Z6.T1B.T2A.X1A.X2E,
Z1.T1C.T2A.X1A.X2E, Z2.T1C.T2A.X1A.X2E, Z3.T1C.T2A.X1A.X2E,
Z4.T1C.T2A.X1A.X2E, Z5.T1C.T2A.X1A.X2E, Z6.T1C.T2A.X1A.X2E,
Z1.T1D.T2A.X1A.X2E, Z2.T1D.T2A.X1A.X2E, Z3.T1D.T2A.X1A.X2E,
Z4.T1D.T2A.X1A.X2E, Z5.T1D.T2A.X1A.X2E, Z6.T1D.T2A.X1A.X2E,
Z1.T1A.T2B.X1A.X2E, Z2.T1A.T2B.X1A.X2E, Z3.T1A.T2B.X1A.X2E,
Z4.T1A.T2B.X1A.X2E, Z5.T1A.T2B.X1A.X2E, Z6.T1A.T2B.X1A.X2E,
Z1.T1B.T2B.X1A.X2E, Z2.T1B.T2B.X1A.X2E, Z3.T1B.T2B.X1A.X2E,
Z4.T1B.T2B.X1A.X2E, Z5.T1B.T2B.X1A.X2E, Z6.T1B.T2B.X1A.X2E,
Z1.T1C.T2B.X1A.X2E, Z2.T1C.T2B.X1A.X2E, Z3.T1C.T2B.X1A.X2E,
Z4.T1C.T2B.X1A.X2E, Z5.T1C.T2B.X1A.X2E, Z6.T1C.T2B.X1A.X2E,
Z1.T1D.T2B.X1A.X2E, Z2.T1D.T2B.X1A.X2E, Z3.T1D.T2B.X1A.X2E,
Z4.T1D.T2B.X1A.X2E, Z5.T1D.T2B.X1A.X2E, Z6.T1D.T2B.X1A.X2E,
Z1.T1A.T2C.X1A.X2E, Z2.T1A.T2C.X1A.X2E, Z3.T1A.T2C.X1A.X2E,
Z4.T1A.T2C.X1A.X2E, Z5.T1A.T2C.X1A.X2E, Z6.T1A.T2C.X1A.X2E,
Z1.T1B.T2C.X1A.X2E, Z2.T1B.T2C.X1A.X2E, Z3.T1B.T2C.X1A.X2E,
Z4.T1B.T2C.X1A.X2E, Z5.T1B.T2C.X1A.X2E, Z6.T1B.T2C.X1A.X2E,
Z1.T1C.T2C.X1A.X2E, Z2.T1C.T2C.X1A.X2E, Z3.T1C.T2C.X1A.X2E,
Z4.T1C.T2C.X1A.X2E, Z5.T1C.T2C.X1A.X2E, Z6.T1C.T2C.X1A.X2E,
Z1.T1D.T2C.X1A.X2E, Z2.T1D.T2C.X1A.X2E, Z3.T1D.T2C.X1A.X2E,
Z4.T1D.T2C.X1A.X2E, Z5.T1D.T2C.X1A.X2E, Z6.T1D.T2C.X1A.X2E,
Z1.T1A.T2D.X1A.X2E, Z2.T1A.T2D.X1A.X2E, Z3.T1A.T2D.X1A.X2E,
Z4.T1A.T2D.X1A.X2E,
Z5.T1A.T2D.X1A.X2E, Z6.T1A.T2D.X1A.X2E, Z1.T1B.T2D.X1A.X2E,
Z2.T1B.T2D.X1A.X2E, Z3.T1B.T2D.X1A.X2E, Z4.T1B.T2D.X1A.X2E,
Z5.T1B.T2D.X1A.X2E, Z6.T1B.T2D.X1A.X2E, Z1.T1C.T2D.X1A.X2E,
Z2.T1C.T2D.X1A.X2E, Z3.T1C.T2D.X1A.X2E, Z4.T1C.T2D.X1A.X2E,
Z5.T1C.T2D.X1A.X2E, Z6.T1C.T2D.X1A.X2E, Z1.T1D.T2D.X1A.X2E,
Z2.T1D.T2D.X1A.X2E, Z3.T1D.T2D.X1A.X2E, Z4.T1D.T2D.X1A.X2E,
Z5.T1D.T2D.X1A.X2E, Z6.T1D.T2D.X1A.X2E, Z1.T1A.T2A.X1B.X2E,
Z2.T1A.T2A.X1B.X2E, Z3.T1A.T2A.X1B.X2E, Z4.T1A.T2A.X1B.X2E,
Z5.T1A.T2A.X1B.X2E, Z6.T1A.T2A.X1B.X2E, Z1.T1B.T2A.X1B.X2E,
Z2.T1B.T2A.X1B.X2E, Z3.T1B.T2A.X1B.X2E, Z4.T1B.T2A.X1B.X2E,
Z5.T1B.T2A.X1B.X2E, Z6.T1B.T2A.X1B.X2E, Z1.T1C.T2A.X1B.X2E,
Z2.T1C.T2A.X1B.X2E, Z3.T1C.T2A.X1B.X2E, Z4.T1C.T2A.X1B.X2E,
Z5.T1C.T2A.X1B.X2E, Z6.T1C.T2A.X1B.X2E, Z1.T1D.T2A.X1B.X2E,
Z2.T1D.T2A.X1B.X2E, Z3.T1D.T2A.X1B.X2E, Z4.T1D.T2A.X1B.X2E,
Z5.T1D.T2A.X1B.X2E, Z6.T1D.T2A.X1B.X2E, Z1.T1A.T2B.X1B.X2E,
Z2.T1A.T2B.X1B.X2E, Z3.T1A.T2B.X1B.X2E, Z4.T1A.T2B.X1B.X2E,
Z5.T1A.T2B.X1B.X2E, Z6.T1A.T2B.X1B.X2E, Z1.T1B.T2B.X1B.X2E,
Z2.T1B.T2B.X1B.X2E, Z3.T1B.T2B.X1B.X2E, Z4.T1B.T2B.X1B.X2E,
Z5.T1B.T2B.X1B.X2E, Z6.T1B.T2B.X1B.X2E, Z1.T1C.T2B.X1B.X2E,
Z2.T1C.T2B.X1B.X2E, Z3.T1C.T2B.X1B.X2E, Z4.T1C.T2B.X1B.X2E,
Z5.T1C.T2B.X1B.X2E, Z6.T1C.T2B.X1B.X2E, Z1.T1D.T2B.X1B.X2E,
Z2.T1D.T2B.X1B.X2E, Z3.T1D.T2B.X1B.X2E, Z4.T1D.T2B.X1B.X2E,
Z5.T1D.T2B.X1B.X2E, Z6.T1D.T2B.X1B.X2E, Z1.T1A.T2C.X1B.X2E,
Z2.T1A.T2C.X1B.X2E, Z3.T1A.T2C.X1B.X2E, Z4.T1A.T2C.X1B.X2E,
Z5.T1A.T2C.X1B.X2E, Z6.T1A.T2C.X1B.X2E, Z1.T1B.T2C.X1B.X2E,
Z2.T1B.T2C.X1B.X2E, Z3.T1B.T2C.X1B.X2E, Z4.T1B.T2C.X1B.X2E,
Z5.T1B.T2C.X1B.X2E, Z6.T1B.T2C.X1B.X2E, Z1.T1C.T2C.X1B.X2E,
Z2.T1C.T2C.X1B.X2E, Z3.T1C.T2C.X1B.X2E, Z4.T1C.T2C.X1B.X2E,
Z5.T1C.T2C.X1B.X2E, Z6.T1C.T2C.X1B.X2E, Z1.T1D.T2C.X1B.X2E,
Z2.T1D.T2C.X1B.X2E, Z3.T1D.T2C.X1B.X2E, Z4.T1D.T2C.X1B.X2E,
Z5.T1D.T2C.X1B.X2E, Z6.T1D.T2C.X1B.X2E, Z1.T1A.T2D.X1B.X2E,
Z2.T1A.T2D.X1B.X2E, Z3.T1A.T2D.X1B.X2E, Z4.T1A.T2D.X1B.X2E,
Z5.T1A.T2D.X1B.X2E, Z6.T1A.T2D.X1B.X2E, Z1.T1B.T2D.X1B.X2E,
Z2.T1B.T2D.X1B.X2E, Z3.T1B.T2D.X1B.X2E, Z4.T1B.T2D.X1B.X2E,
Z5.T1B.T2D.X1B.X2E, Z6.T1B.T2D.X1B.X2E, Z1.T1C.T2D.X1B.X2E,
Z2.T1C.T2D.X1B.X2E, Z3.T1C.T2D.X1B.X2E, Z4.T1C.T2D.X1B.X2E,
Z5.T1C.T2D.X1B.X2E, Z6.T1C.T2D.X1B.X2E, Z1.T1D.T2D.X1B.X2E,
Z2.T1D.T2D.X1B.X2E, Z3.T1D.T2D.X1B.X2E, Z4.T1D.T2D.X1B.X2E,
Z5.T1D.T2D.X1B.X2E, Z6.T1D.T2D.X1B.X2E, Z1.T1A.T2A.X1C.X2E,
Z2.T1A.T2A.X1C.X2E, Z3.T1A.T2A.X1C.X2E, Z4.T1A.T2A.X1C.X2E,
Z5.T1A.T2A.X1C.X2E, Z6.T1A.T2A.X1C.X2E, Z1.T1B.T2A.X1C.X2E,
Z2.T1B.T2A.X1C.X2E, Z3.T1B.T2A.X1C.X2E, Z4.T1B.T2A.X1C.X2E,
Z5.T1B.T2A.X1C.X2E, Z6.T1B.T2A.X1C.X2E, Z1.T1C.T2A.X1C.X2E,
Z2.T1C.T2A.X1C.X2E, Z3.T1C.T2A.X1C.X2E, Z4.T1C.T2A.X1C.X2E,
Z5.T1C.T2A.X1C.X2E, Z6.T1C.T2A.X1C.X2E, Z1.T1D.T2A.X1C.X2E,
Z2.T1D.T2A.X1C.X2E, Z3.T1D.T2A.X1C.X2E, Z4.T1D.T2A.X1C.X2E,
Z5.T1D.T2A.X1C.X2E, Z6.T1D.T2A.X1C.X2E, Z1.T1A.T2B.X1C.X2E,
Z2.T1A.T2B.X1C.X2E, Z3.T1A.T2B.X1C.X2E, Z4.T1A.T2B.X1C.X2E,
Z5.T1A.T2B.X1C.X2E, Z6.T1A.T2B.X1C.X2E, Z1.T1B.T2B.X1C.X2E,
Z2.T1B.T2B.X1C.X2E, Z3.T1B.T2B.X1C.X2E, Z4.T1B.T2B.X1C.X2E,
Z5.T1B.T2B.X1C.X2E, Z6.T1B.T2B.X1C.X2E, Z1.T1C.T2B.X1C.X2E,
Z2.T1C.T2B.X1C.X2E, Z3.T1C.T2B.X1C.X2E, Z4.T1C.T2B.X1C.X2E,
Z5.T1C.T2B.X1C.X2E, Z6.T1C.T2B.X1C.X2E, Z1.T1D.T2B.X1C.X2E,
Z2.T1D.T2B.X1C.X2E, Z3.T1D.T2B.X1C.X2E, Z4.T1D.T2B.X1C.X2E,
Z5.T1D.T2B.X1C.X2E, Z6.T1D.T2B.X1C.X2E, Z1.T1A.T2C.X1C.X2E,
Z2.T1A.T2C.X1C.X2E, Z3.T1A.T2C.X1C.X2E, Z4.T1A.T2C.X1C.X2E,
Z5.T1A.T2C.X1C.X2E, Z6.T1A.T2C.X1C.X2E, Z1.T1B.T2C.X1C.X2E,
Z2.T1B.T2C.X1C.X2E, Z3.T1B.T2C.X1C.X2E, Z4.T1B.T2C.X1C.X2E,
Z5.T1B.T2C.X1C.X2E, Z6.T1B.T2C.X1C.X2E, Z1.T1C.T2C.X1C.X2E,
Z2.T1C.T2C.X1C.X2E, Z3.T1C.T2C.X1C.X2E, Z4.T1C.T2C.X1C.X2E,
Z5.T1C.T2C.X1C.X2E, Z6.T1C.T2C.X1C.X2E, Z1.T1D.T2C.X1C.X2E,
Z2.T1D.T2C.X1C.X2E, Z3.T1D.T2C.X1C.X2E, Z4.T1D.T2C.X1C.X2E,
Z5.T1D.T2C.X1C.X2E, Z6.T1D.T2C.X1C.X2E, Z1.T1A.T2D.X1C.X2E,
Z2.T1A.T2D.X1C.X2E, Z3.T1A.T2D.X1C.X2E, Z4.T1A.T2D.X1C.X2E,
Z5.T1A.T2D.X1C.X2E, Z6.T1A.T2D.X1C.X2E, Z1.T1B.T2D.X1C.X2E,
Z2.T1B.T2D.X1C.X2E, Z3.T1B.T2D.X1C.X2E, Z4.T1B.T2D.X1C.X2E,
Z5.T1B.T2D.X1C.X2E, Z6.T1B.T2D.X1C.X2E, Z1.T1C.T2D.X1C.X2E,
Z2.T1C.T2D.X1C.X2E, Z3.T1C.T2D.X1C.X2E, Z4.T1C.T2D.X1C.X2E,
Z5.T1C.T2D.X1C.X2E, Z6.T1C.T2D.X1C.X2E, Z1.T1D.T2D.X1C.X2E,
Z2.T1D.T2D.X1C.X2E, Z3.T1D.T2D.X1C.X2E, Z4.T1D.T2D.X1C.X2E,
Z5.T1D.T2D.X1C.X2E, Z6.T1D.T2D.X1C.X2E, Z1.T1A.T2A.X1D.X2E,
Z2.T1A.T2A.X1D.X2E, Z3.T1A.T2A.X1D.X2E, Z4.T1A.T2A.X1D.X2E,
Z5.T1A.T2A.X1D.X2E, Z6.T1A.T2A.X1D.X2E, Z1.T1B.T2A.X1D.X2E,
Z2.T1B.T2A.X1D.X2E, Z3.T1B.T2A.X1D.X2E, Z4.T1B.T2A.X1D.X2E,
Z5.T1B.T2A.X1D.X2E, Z6.T1B.T2A.X1D.X2E, Z1.T1C.T2A.X1D.X2E,
Z2.T1C.T2A.X1D.X2E, Z3.T1C.T2A.X1D.X2E, Z4.T1C.T2A.X1D.X2E,
Z5.T1C.T2A.X1D.X2E, Z6.T1C.T2A.X1D.X2E, Z1.T1D.T2A.X1D.X2E,
Z2.T1D.T2A.X1D.X2E, Z3.T1D.T2A.X1D.X2E, Z4.T1D.T2A.X1D.X2E,
Z5.T1D.T2A.X1D.X2E, Z6.T1D.T2A.X1D.X2E, Z1.T1A.T2B.X1D.X2E,
Z2.T1A.T2B.X1D.X2E, Z3.T1A.T2B.X1D.X2E, Z4.T1A.T2B.X1D.X2E,
Z5.T1A.T2B.X1D.X2E, Z6.T1A.T2B.X1D.X2E, Z1.T1B.T2B.X1D.X2E,
Z2.T1B.T2B.X1D.X2E, Z3.T1B.T2B.X1D.X2E, Z4.T1B.T2B.X1D.X2E,
Z5.T1B.T2B.X1D.X2E, Z6.T1B.T2B.X1D.X2E, Z1.T1C.T2B.X1D.X2E,
Z2.T1C.T2B.X1D.X2E, Z3.T1C.T2B.X1D.X2E, Z4.T1C.T2B.X1D.X2E,
Z5.T1C.T2B.X1D.X2E, Z6.T1C.T2B.X1D.X2E, Z1.T1D.T2B.X1D.X2E,
Z2.T1D.T2B.X1D.X2E, Z3.T1D.T2B.X1D.X2E, Z4.T1D.T2B.X1D.X2E,
Z5.T1D.T2B.X1D.X2E, Z6.T1D.T2B.X1D.X2E, Z1.T1A.T2C.X1D.X2E,
Z2.T1A.T2C.X1D.X2E, Z3.T1A.T2C.X1D.X2E, Z4.T1A.T2C.X1D.X2E,
Z5.T1A.T2C.X1D.X2E, Z6.T1A.T2C.X1D.X2E, Z1.T1B.T2C.X1D.X2E,
Z2.T1B.T2C.X1D.X2E, Z3.T1B.T2C.X1D.X2E, Z4.T1B.T2C.X1D.X2E,
Z5.T1B.T2C.X1D.X2E, Z6.T1B.T2C.X1D.X2E, Z1.T1C.T2C.X1D.X2E,
Z2.T1C.T2C.X1D.X2E, Z3.T1C.T2C.X1D.X2E, Z4.T1C.T2C.X1D.X2E,
Z5.T1C.T2C.X1D.X2E, Z6.T1C.T2C.X1D.X2E, Z1.T1D.T2C.X1D.X2E,
Z2.T1D.T2C.X1D.X2E, Z3.T1D.T2C.X1D.X2E, Z4.T1D.T2C.X1D.X2E,
Z5.T1D.T2C.X1D.X2E, Z6.T1D.T2C.X1D.X2E, Z1.T1A.T2D.X1D.X2E,
Z2.T1A.T2D.X1D.X2E, Z3.T1A.T2D.X1D.X2E, Z4.T1A.T2D.X1D.X2E,
Z5.T1A.T2D.X1D.X2E, Z6.T1A.T2D.X1D.X2E, Z1.T1B.T2D.X1D.X2E,
Z2.T1B.T2D.X1D.X2E, Z3.T1B.T2D.X1D.X2E, Z4.T1B.T2D.X1D.X2E,
Z5.T1B.T2D.X1D.X2E, Z6.T1B.T2D.X1D.X2E, Z1.T1C.T2D.X1D.X2E,
Z2.T1C.T2D.X1D.X2E, Z3.T1C.T2D.X1D.X2E, Z4.T1C.T2D.X1D.X2E,
Z5.T1C.T2D.X1D.X2E, Z6.T1C.T2D.X1D.X2E, Z1.T1D.T2D.X1D.X2E,
Z2.T1D.T2D.X1D.X2E, Z3.T1D.T2D.X1D.X2E, Z4.T1D.T2D.X1D.X2E,
Z5.T1D.T2D.X1D.X2E, Z6.T1D.T2D.X1D.X2E, Z1.T1A.T2A.X1E.X2E,
Z2.T1A.T2A.X1E.X2E, Z3.T1A.T2A.X1E.X2E, Z4.T1A.T2A.X1E.X2E,
Z5.T1A.T2A.X1E.X2E, Z6.T1A.T2A.X1E.X2E, Z1.T1B.T2A.X1E.X2E,
Z2.T1B.T2A.X1E.X2E, Z3.T1B.T2A.X1E.X2E, Z4.T1B.T2A.X1E.X2E,
Z5.T1B.T2A.X1E.X2E, Z6.T1B.T2A.X1E.X2E, Z1.T1C.T2A.X1E.X2E,
Z2.T1C.T2A.X1E.X2E, Z3.T1C.T2A.X1E.X2E, Z4.T1C.T2A.X1E.X2E,
Z5.T1C.T2A.X1E.X2E, Z6.T1C.T2A.X1E.X2E, Z1.T1D.T2A.X1E.X2E,
Z2.T1D.T2A.X1E.X2E, Z3.T1D.T2A.X1E.X2E, Z4.T1D.T2A.X1E.X2E,
Z5.T1D.T2A.X1E.X2E, Z6.T1D.T2A.X1E.X2E, Z1.T1A.T2B.X1E.X2E,
Z2.T1A.T2B.X1E.X2E, Z3.T1A.T2B.X1E.X2E, Z4.T1A.T2B.X1E.X2E,
Z5.T1A.T2B.X1E.X2E, Z6.T1A.T2B.X1E.X2E, Z1.T1B.T2B.X1E.X2E,
Z2.T1B.T2B.X1E.X2E, Z3.T1B.T2B.X1E.X2E, Z4.T1B.T2B.X1E.X2E,
Z5.T1B.T2B.X1E.X2E, Z6.T1B.T2B.X1E.X2E, Z1.T1C.T2B.X1E.X2E,
Z2.T1C.T2B.X1E.X2E, Z3.T1C.T2B.X1E.X2E, Z4.T1C.T2B.X1E.X2E,
Z5.T1C.T2B.X1E.X2E, Z6.T1C.T2B.X1E.X2E, Z1.T1D.T2B.X1E.X2E,
Z2.T1D.T2B.X1E.X2E, Z3.T1D.T2B.X1E.X2E, Z4.T1D.T2B.X1E.X2E,
Z5.T1D.T2B.X1E.X2E, Z6.T1D.T2B.X1E.X2E, Z1.T1A.T2C.X1E.X2E,
Z2.T1A.T2C.X1E.X2E, Z3.T1A.T2C.X1E.X2E, Z4.T1A.T2C.X1E.X2E,
Z5.T1A.T2C.X1E.X2E, Z6.T1A.T2C.X1E.X2E, Z1.T1B.T2C.X1E.X2E,
Z2.T1B.T2C.X1E.X2E, Z3.T1B.T2C.X1E.X2E, Z4.T1B.T2C.X1E.X2E,
Z5.T1B.T2C.X1E.X2E, Z6.T1B.T2C.X1E.X2E, Z1.T1C.T2C.X1E.X2E,
Z2.T1C.T2C.X1E.X2E, Z3.T1C.T2C.X1E.X2E, Z4.T1C.T2C.X1E.X2E,
Z5.T1C.T2C.X1E.X2E, Z6.T1C.T2C.X1E.X2E, Z1.T1D.T2C.X1E.X2E,
Z2.T1D.T2C.X1E.X2E, Z3.T1D.T2C.X1E.X2E, Z4.T1D.T2C.X1E.X2E,
Z5.T1D.T2C.X1E.X2E, Z6.T1D.T2C.X1E.X2E, Z1.T1A.T2D.X1E.X2E,
Z2.T1A.T2D.X1E.X2E, Z3.T1A.T2D.X1E.X2E, Z4.T1A.T2D.X1E.X2E,
Z5.T1A.T2D.X1E.X2E, Z6.T1A.T2D.X1E.X2E, Z1.T1B.T2D.X1E.X2E,
Z2.T1B.T2D.X1E.X2E, Z3.T1B.T2D.X1E.X2E, Z4.T1B.T2D.X1E.X2E,
Z5.T1B.T2D.X1E.X2E, Z6.T1B.T2D.X1E.X2E, Z1.T1C.T2D.X1E.X2E,
Z2.T1C.T2D.X1E.X2E, Z3.T1C.T2D.X1E.X2E, Z4.T1C.T2D.X1E.X2E,
Z5.T1C.T2D.X1E.X2E, Z6.T1C.T2D.X1E.X2E, Z1.T1D.T2D.X1E.X2E,
Z2.T1D.T2D.X1E.X2E, Z3.T1D.T2D.X1E.X2E, Z4.T1D.T2D.X1E.X2E,
Z5.T1D.T2D.X1E.X2E, and Z6.T1D.T2D.X1E.X2E.
[0436] In still another embodiment, selected compounds of Formula I
are named below in tabular format (Table 12) as compounds of
general Formula III (below):
##STR00106##
where 1, 2, 3, 4 and 5 are defined in Tables 7-11, below. Each
compound is designated in tabular form by combining the "code"
representing each structural moiety using the following syntax:
1.2.3.4.5. Thus, for example, 1a.2a.3a.4a.5a represents the
following structure:
##STR00107##
TABLE-US-00008 TABLE 7 "1" Structures Code "1" Structure 1a
##STR00108## 1b ##STR00109## 1c ##STR00110## 1d ##STR00111## 1e
##STR00112## 1f ##STR00113## 1g ##STR00114## 1h ##STR00115## 1i
##STR00116## 1j ##STR00117## 1k ##STR00118## 1l ##STR00119## 1m
##STR00120## 1n ##STR00121## 1o ##STR00122## 1p ##STR00123## 1q
##STR00124## 1r ##STR00125## 1s ##STR00126## 1t ##STR00127## 1u
##STR00128##
TABLE-US-00009 TABLE 8 "2" Structures Code "2" Structure 2a
##STR00129## 2b ##STR00130## 2c ##STR00131## 2d ##STR00132## 2e
##STR00133## 2f ##STR00134## 2g ##STR00135## 2h ##STR00136## 2i
##STR00137## 2j ##STR00138## 2k ##STR00139## 2l ##STR00140## 2m
##STR00141## 2n ##STR00142## 2o ##STR00143## 2p ##STR00144## 2q
##STR00145## 2r ##STR00146## 2s ##STR00147## 2t ##STR00148## 2u
##STR00149## 2v ##STR00150## 2w ##STR00151## 2x ##STR00152## 2y
##STR00153##
TABLE-US-00010 TABLE 9 "3" Structures Code "3" Structure 3a
--O--CH2-(5-thiazolyl) 3b --O--CH2-(3-pyridyl) 3c
--NH--CH2-(5-thiazolyl) 3d --NH--CH2-(3-pyridyl) 3e
--N(CH3)--CH2-(5-thiazolyl) 3f --N(CH3)--CH2-(3-pyridyl) 3g
--N(CH3)-(5-thiazolyl) 3h --N(CH3)-(3-pyridyl)
TABLE-US-00011 TABLE 10 "4" Structures Code "4" Structure 4a
n-propyl 4b i-butyl 4c --CH.sub.2-cyclohexyl 4d --CH.sub.2-phenyl
4e --CH.sub.2-(4-methoxyphenyl) 4f --CH.sub.2-(3-fluorophenyl) 4g
--CH.sub.2-(4-pyridyl) 4h --CH.sub.2-(3-pyridyl) 4i
--CH.sub.2-(2-pyridyl) 4j --CH.sub.2CH.sub.2-(4-morpholinyl) 4k
##STR00154## 4l ##STR00155## 4m ##STR00156## 4n ##STR00157## 4o
##STR00158## 4p ##STR00159##
TABLE-US-00012 TABLE 11 "5" Structures Code "5" Structure 5a
n-propyl 5b i-butyl 5c --CH.sub.2-cyclohexyl 5d --CH.sub.2-phenyl
5e --CH.sub.2-(4-methoxyphenyl) 5f --CH.sub.2-(3-fluorophenyl) 5g
--CH.sub.2-(4-pyridyl) 5h --CH.sub.2-(3-pyridyl) 5i
--CH.sub.2-(2-pyridyl) 5j --CH.sub.2CH.sub.2-(4-morpholinyl) 5k
##STR00160## 5l ##STR00161## 5m ##STR00162## 5n ##STR00163## 5o
##STR00164##
TABLE-US-00013 TABLE 12 List of Compound Structures of Formula II
1a.2a.3a.4a.5a., 1b.2a.3a.4a.5a., 1f.2a.3a.4a.5a., 1h.2a.3a.4a.5a.,
1j.2a.3a.4a.5a., 1p.2a.3a.4a.5a., 1a.2b.3a.4a.5a., 1b.2b.3a.4a.5a.,
1f.2b.3a.4a.5a., 1h.2b.3a.4a.5a., 1j.2b.3a.4a.5a., 1p.2b.3a.4a.5a.,
1a.2e.3a.4a.5a., 1b.2e.3a.4a.5a., 1f.2e.3a.4a.5a., 1h.2e.3a.4a.5a.,
1j.2e.3a.4a.5a., 1p.2e.3a.4a.5a., 1a.2f.3a.4a.5a., 1b.2f.3a.4a.5a.,
1f.2f.3a.4a.5a., 1h.2f.3a.4a.5a., 1j.2f.3a.4a.5a., 1p.2f.3a.4a.5a.,
1a.2i.3a.4a.5a., 1b.2i.3a.4a.5a., 1f.2i.3a.4a.5a., 1h.2i.3a.4a.5a.,
1j.2i.3a.4a.5a., 1p.2i.3a.4a.5a., 1a.2m.3a.4a.5a., 1b.2m.3a.4a.5a.,
1f.2m.3a.4a.5a., 1h.2m.3a.4a.5a., 1j.2m.3a.4a.5a., 1p.2m.3a.4a.5a.,
1a.2o.3a.4a.5a., 1b.2o.3a.4a.5a., 1f.2o.3a.4a.5a., 1h.2o.3a.4a.5a.,
1j.2o.3a.4a.5a., 1p.2o.3a.4a.5a., 1a.2u.3a.4a.5a., 1b.2u.3a.4a.5a.,
1f.2u.3a.4a.5a., 1h.2u.3a.4a.5a., 1j.2u.3a.4a.5a., 1p.2u.3a.4a.5a.,
1a.2y.3a.4a.5a., 1b.2y.3a.4a.5a., 1f.2y.3a.4a.5a., 1h.2y.3a.4a.5a.,
1j.2y.3a.4a.5a., 1p.2y.3a.4a.5a., 1a.2a.3b.4a.5a., 1b.2a.3b.4a.5a.,
1f.2a.3b.4a.5a., 1h.2a.3b.4a.5a., 1j.2a.3b.4a.5a., 1p.2a.3b.4a.5a.,
1a.2b.3b.4a.5a., 1b.2b.3b.4a.5a., 1f.2b.3b.4a.5a., 1h.2b.3b.4a.5a.,
1j.2b.3b.4a.5a., 1p.2b.3b.4a.5a., 1a.2e.3b.4a.5a., 1b.2e.3b.4a.5a.,
1f.2e.3b.4a.5a., 1h.2e.3b.4a.5a., 1j.2e.3b.4a.5a., 1p.2e.3b.4a.5a.,
1a.2f.3b.4a.5a., 1b.2f.3b.4a.5a., 1f.2f.3b.4a.5a., 1h.2f.3b.4a.5a.,
1j.2f.3b.4a.5a., 1p.2f.3b.4a.5a., 1a.2i.3b.4a.5a., 1b.2i.3b.4a.5a.,
1f.2i.3b.4a.5a., 1h.2i.3b.4a.5a., 1j.2i.3b.4a.5a., 1p.2i.3b.4a.5a.,
1a.2m.3b.4a.5a., 1b.2m.3b.4a.5a., 1f.2m.3b.4a.5a., 1h.2m.3b.4a.5a.,
1j.2m.3b.4a.5a., 1p.2m.3b.4a.5a., 1a.2o.3b.4a.5a., 1b.2o.3b.4a.5a.,
1f.2o.3b.4a.5a., 1h.2o.3b.4a.5a., 1j.2o.3b.4a.5a., 1p.2o.3b.4a.5a.,
1a.2u.3b.4a.5a., 1b.2u.3b.4a.5a., 1f.2u.3b.4a.5a., 1h.2u.3b.4a.5a.,
1j.2u.3b.4a.5a., 1p.2u.3b.4a.5a., 1a.2y.3b.4a.5a., 1b.2y.3b.4a.5a.,
1f.2y.3b.4a.5a., 1h.2y.3b.4a.5a., 1j.2y.3b.4a.5a., 1p.2y.3b.4a.5a.,
1a.2a.3e.4a.5a., 1b.2a.3e.4a.5a., 1f.2a.3e.4a.5a., 1h.2a.3e.4a.5a.,
1j.2a.3e.4a.5a., 1p.2a.3e.4a.5a., 1a.2b.3e.4a.5a., 1b.2b.3e.4a.5a.,
1f.2b.3e.4a.5a., 1h.2b.3e.4a.5a., 1j.2b.3e.4a.5a., 1p.2b.3e.4a.5a.,
1a.2e.3e.4a.5a., 1b.2e.3e.4a.5a., 1f.2e.3e.4a.5a., 1h.2e.3e.4a.5a.,
1j.2e.3e.4a.5a., 1p.2e.3e.4a.5a., 1a.2f.3e.4a.5a., 1b.2f.3e.4a.5a.,
1f.2f.3e.4a.5a., 1h.2f.3e.4a.5a., 1j.2f.3e.4a.5a., 1p.2f.3e.4a.5a.,
1a.2i.3e.4a.5a., 1b.2i.3e.4a.5a., 1f.2i.3e.4a.5a., 1h.2i.3e.4a.5a.,
1j.2i.3e.4a.5a., 1p.2i.3e.4a.5a., 1a.2m.3e.4a.5a., 1b.2m.3e.4a.5a.,
1f.2m.3e.4a.5a., 1h.2m.3e.4a.5a., 1j.2m.3e.4a.5a., 1p.2m.3e.4a.5a.,
1a.2o.3e.4a.5a., 1b.2o.3e.4a.5a., 1f.2o.3e.4a.5a., 1h.2o.3e.4a.5a.,
1j.2o.3e.4a.5a., 1p.2o.3e.4a.5a., 1a.2u.3e.4a.5a., 1b.2u.3e.4a.5a.,
1f.2u.3e.4a.5a., 1h.2u.3e.4a.5a., 1j.2u.3e.4a.5a., 1p.2u.3e.4a.5a.,
1a.2y.3e.4a.5a., 1b.2y.3e.4a.5a., 1f.2y.3e.4a.5a., 1h.2y.3e.4a.5a.,
1j.2y.3e.4a.5a., 1p.2y.3e.4a.5a., 1a.2a.3g.4a.5a., 1b.2a.3g.4a.5a.,
1f.2a.3g.4a.5a., 1h.2a.3g.4a.5a., 1j.2a.3g.4a.5a., 1p.2a.3g.4a.5a.,
1a.2b.3g.4a.5a., 1b.2b.3g.4a.5a., 1f.2b.3g.4a.5a., 1h.2b.3g.4a.5a.,
1j.2b.3g.4a.5a., 1p.2b.3g.4a.5a., 1a.2e.3g.4a.5a., 1b.2e.3g.4a.5a.,
1f.2e.3g.4a.5a., 1h.2e.3g.4a.5a., 1j.2e.3g.4a.5a., 1p.2e.3g.4a.5a.,
1a.2f.3g.4a.5a., 1b.2f.3g.4a.5a., 1f.2f.3g.4a.5a., 1h.2f.3g.4a.5a.,
1j.2f.3g.4a.5a., 1p.2f.3g.4a.5a., 1a.2i.3g.4a.5a., 1b.2i.3g.4a.5a.,
1f.2i.3g.4a.5a., 1h.2i.3g.4a.5a., 1j.2i.3g.4a.5a., 1p.2i.3g.4a.5a.,
1a.2m.3g.4a.5a., 1b.2m.3g.4a.5a., 1f.2m.3g.4a.5a., 1h.2m.3g.4a.5a.,
1j.2m.3g.4a.5a., 1p.2m.3g.4a.5a., 1a.2o.3g.4a.5a., 1b.2o.3g.4a.5a.,
1f.2o.3g.4a.5a., 1h.2o.3g.4a.5a., 1j.2o.3g.4a.5a., 1p.2o.3g.4a.5a.,
1a.2u.3g.4a.5a., 1b.2u.3g.4a.5a., 1f.2u.3g.4a.5a., 1h.2u.3g.4a.5a.,
1j.2u.3g.4a.5a., 1p.2u.3g.4a.5a., 1a.2y.3g.4a.5a., 1b.2y.3g.4a.5a.,
1f.2y.3g.4a.5a., 1h.2y.3g.4a.5a., 1j.2y.3g.4a.5a., 1p.2y.3g.4a.5a.,
1a.2a.3a.4d.5a., 1b.2a.3a.4d.5a., 1f.2a.3a.4d.5a., 1h.2a.3a.4d.5a.,
1j.2a.3a.4d.5a., 1p.2a.3a.4d.5a., 1a.2b.3a.4d.5a., 1b.2b.3a.4d.5a.,
1f.2b.3a.4d.5a., 1h.2b.3a.4d.5a., 1j.2b.3a.4d.5a., 1p.2b.3a.4d.5a.,
1a.2e.3a.4d.5a., 1b.2e.3a.4d.5a., 1f.2e.3a.4d.5a., 1h.2e.3a.4d.5a.,
1j.2e.3a.4d.5a., 1p.2e.3a.4d.5a., 1a.2f.3a.4d.5a., 1b.2f.3a.4d.5a.,
1f.2f.3a.4d.5a., 1h.2f.3a.4d.5a., 1j.2f.3a.4d.5a., 1p.2f.3a.4d.5a.,
1a.2i.3a.4d.5a., 1b.2i.3a.4d.5a., 1f.2i.3a.4d.5a., 1h.2i.3a.4d.5a.,
1j.2i.3a.4d.5a., 1p.2i.3a.4d.5a., 1a.2m.3a.4d.5a., 1b.2m.3a.4d.5a.,
1f.2m.3a.4d.5a., 1h.2m.3a.4d.5a., 1j.2m.3a.4d.5a., 1p.2m.3a.4d.5a.,
1a.2o.3a.4d.5a., 1b.2o.3a.4d.5a., 1f.2o.3a.4d.5a., 1h.2o.3a.4d.5a.,
1j.2o.3a.4d.5a., 1p.2o.3a.4d.5a., 1a.2u.3a.4d.5a., 1b.2u.3a.4d.5a.,
1f.2u.3a.4d.5a., 1h.2u.3a.4d.5a., 1j.2u.3a.4d.5a., 1p.2u.3a.4d.5a.,
1a.2y.3a.4d.5a., 1b.2y.3a.4d.5a., 1f.2y.3a.4d.5a., 1h.2y.3a.4d.5a.,
1j.2y.3a.4d.5a., 1p.2y.3a.4d.5a., 1a.2a.3b.4d.5a., 1b.2a.3b.4d.5a.,
1f.2a.3b.4d.5a., 1h.2a.3b.4d.5a., 1j.2a.3b.4d.5a., 1p.2a.3b.4d.5a.,
1a.2b.3b.4d.5a., 1b.2b.3b.4d.5a., 1f.2b.3b.4d.5a., 1h.2b.3b.4d.5a.,
1j.2b.3b.4d.5a., 1p.2b.3b.4d.5a., 1a.2e.3b.4d.5a., 1b.2e.3b.4d.5a.,
1f.2e.3b.4d.5a., 1h.2e.3b.4d.5a., 1j.2e.3b.4d.5a., 1p.2e.3b.4d.5a.,
1a.2f.3b.4d.5a., 1b.2f.3b.4d.5a., 1f.2f.3b.4d.5a., 1h.2f.3b.4d.5a.,
1j.2f.3b.4d.5a., 1p.2f.3b.4d.5a., 1a.2i.3b.4d.5a., 1b.2i.3b.4d.5a.,
1f.2i.3b.4d.5a., 1h.2i.3b.4d.5a., 1j.2i.3b.4d.5a., 1p.2i.3b.4d.5a.,
1a.2m.3b.4d.5a., 1b.2m.3b.4d.5a., 1f.2m.3b.4d.5a., 1h.2m.3b.4d.5a.,
1j.2m.3b.4d.5a., 1p.2m.3b.4d.5a., 1a.2o.3b.4d.5a., 1b.2o.3b.4d.5a.,
1f.2o.3b.4d.5a., 1h.2o.3b.4d.5a., 1j.2o.3b.4d.5a., 1p.2o.3b.4d.5a.,
1a.2u.3b.4d.5a., 1b.2u.3b.4d.5a., 1f.2u.3b.4d.5a., 1h.2u.3b.4d.5a.,
1j.2u.3b.4d.5a., 1p.2u.3b.4d.5a., 1a.2y.3b.4d.5a., 1b.2y.3b.4d.5a.,
1f.2y.3b.4d.5a., 1h.2y.3b.4d.5a., 1j.2y.3b.4d.5a., 1p.2y.3b.4d.5a.,
1a.2a.3e.4d.5a., 1b.2a.3e.4d.5a., 1f.2a.3e.4d.5a., 1h.2a.3e.4d.5a.,
1j.2a.3e.4d.5a., 1p.2a.3e.4d.5a., 1a.2b.3e.4d.5a., 1b.2b.3e.4d.5a.,
1f.2b.3e.4d.5a., 1h.2b.3e.4d.5a., 1j.2b.3e.4d.5a., 1p.2b.3e.4d.5a.,
1a.2e.3e.4d.5a., 1b.2e.3e.4d.5a., 1f.2e.3e.4d.5a., 1h.2e.3e.4d.5a.,
1j.2e.3e.4d.5a., 1p.2e.3e.4d.5a., 1a.2f.3e.4d.5a., 1b.2f.3e.4d.5a.,
1f.2f.3e.4d.5a., 1h.2f.3e.4d.5a., 1j.2f.3e.4d.5a., 1p.2f.3e.4d.5a.,
1a.2i.3e.4d.5a., 1b.2i.3e.4d.5a., 1f.2i.3e.4d.5a., 1h.2i.3e.4d.5a.,
1j.2i.3e.4d.5a., 1p.2i.3e.4d.5a., 1a.2m.3e.4d.5a., 1b.2m.3e.4d.5a.,
1f.2m.3e.4d.5a., 1h.2m.3e.4d.5a., 1j.2m.3e.4d.5a., 1p.2m.3e.4d.5a.,
1a.2o.3e.4d.5a., 1b.2o.3e.4d.5a., 1f.2o.3e.4d.5a., 1h.2o.3e.4d.5a.,
1j.2o.3e.4d.5a., 1p.2o.3e.4d.5a., 1a.2u.3e.4d.5a., 1b.2u.3e.4d.5a.,
1f.2u.3e.4d.5a., 1h.2u.3e.4d.5a., 1j.2u.3e.4d.5a., 1p.2u.3e.4d.5a.,
1a.2y.3e.4d.5a., 1b.2y.3e.4d.5a., 1f.2y.3e.4d.5a., 1h.2y.3e.4d.5a.,
1j.2y.3e.4d.5a., 1p.2y.3e.4d.5a., 1a.2a.3g.4d.5a., 1b.2a.3g.4d.5a.,
1f.2a.3g.4d.5a., 1h.2a.3g.4d.5a., 1j.2a.3g.4d.5a., 1p.2a.3g.4d.5a.,
1a.2b.3g.4d.5a., 1b.2b.3g.4d.5a., 1f.2b.3g.4d.5a., 1h.2b.3g.4d.5a.,
1j.2b.3g.4d.5a., 1p.2b.3g.4d.5a., 1a.2e.3g.4d.5a., 1b.2e.3g.4d.5a.,
1f.2e.3g.4d.5a., 1h.2e.3g.4d.5a., 1j.2e.3g.4d.5a., 1p.2e.3g.4d.5a.,
1a.2f.3g.4d.5a., 1b.2f.3g.4d.5a., 1f.2f.3g.4d.5a., 1h.2f.3g.4d.5a.,
1j.2f.3g.4d.5a., 1p.2f.3g.4d.5a., 1a.2i.3g.4d.5a., 1b.2i.3g.4d.5a.,
1f.2i.3g.4d.5a., 1h.2i.3g.4d.5a., 1j.2i.3g.4d.5a., 1p.2i.3g.4d.5a.,
1a.2m.3g.4d.5a., 1b.2m.3g.4d.5a., 1f.2m.3g.4d.5a., 1h.2m.3g.4d.5a.,
1j.2m.3g.4d.5a., 1p.2m.3g.4d.5a., 1a.2o.3g.4d.5a., 1b.2o.3g.4d.5a.,
1f.2o.3g.4d.5a., 1h.2o.3g.4d.5a., 1j.2o.3g.4d.5a., 1p.2o.3g.4d.5a.,
1a.2u.3g.4d.5a., 1b.2u.3g.4d.5a., 1f.2u.3g.4d.5a., 1h.2u.3g.4d.5a.,
1j.2u.3g.4d.5a., 1p.2u.3g.4d.5a., 1a.2y.3g.4d.5a., 1b.2y.3g.4d.5a.,
1f.2y.3g.4d.5a., 1h.2y.3g.4d.5a., 1j.2y.3g.4d.5a., 1p.2y.3g.4d.5a.,
1a.2a.3a.4f.5a., 1b.2a.3a.4f.5a., 1f.2a.3a.4f.5a., 1h.2a.3a.4f.5a.,
1j.2a.3a.4f.5a., 1p.2a.3a.4f.5a., 1a.2b.3a.4f.5a., 1b.2b.3a.4f.5a.,
1f.2b.3a.4f.5a., 1h.2b.3a.4f.5a., 1j.2b.3a.4f.5a., 1p.2b.3a.4f.5a.,
1a.2e.3a.4f.5a., 1b.2e.3a.4f.5a., 1f.2e.3a.4f.5a., 1h.2e.3a.4f.5a.,
1j.2e.3a.4f.5a., 1p.2e.3a.4f.5a., 1a.2f.3a.4f.5a., 1b.2f.3a.4f.5a.,
1f.2f.3a.4f.5a., 1h.2f.3a.4f.5a., 1j.2f.3a.4f.5a., 1p.2f.3a.4f.5a.,
1a.2i.3a.4f.5a., 1b.2i.3a.4f.5a., 1f.2i.3a.4f.5a., 1h.2i.3a.4f.5a.,
1j.2i.3a.4f.5a., 1p.2i.3a.4f.5a., 1a.2m.3a.4f.5a., 1b.2m.3a.4f.5a.,
1f.2m.3a.4f.5a., 1h.2m.3a.4f.5a., 1j.2m.3a.4f.5a., 1p.2m.3a.4f.5a.,
1a.2o.3a.4f.5a., 1b.2o.3a.4f.5a., 1f.2o.3a.4f.5a., 1h.2o.3a.4f.5a.,
1j.2o.3a.4f.5a., 1p.2o.3a.4f.5a., 1a.2u.3a.4f.5a., 1b.2u.3a.4f.5a.,
1f.2u.3a.4f.5a., 1h.2u.3a.4f.5a., 1j.2u.3a.4f.5a., 1p.2u.3a.4f.5a.,
1a.2y.3a.4f.5a., 1b.2y.3a.4f.5a., 1f.2y.3a.4f.5a., 1h.2y.3a.4f.5a.,
1j.2y.3a.4f.5a., 1p.2y.3a.4f.5a., 1a.2a.3b.4f.5a., 1b.2a.3b.4f.5a.,
1f.2a.3b.4f.5a., 1h.2a.3b.4f.5a., 1j.2a.3b.4f.5a., 1p.2a.3b.4f.5a.,
1a.2b.3b.4f.5a., 1b.2b.3b.4f.5a., 1f.2b.3b.4f.5a., 1h.2b.3b.4f.5a.,
1j.2b.3b.4f.5a., 1h.2b.3b.4f.5a., 1a.2e.3b.4f.5a., 1b.2e.3b.4f.5a.,
1f.2e.3b.4f.5a., 1h.2e.3b.4f.5a., 1j.2e.3b.4f.5a., 1p.2e.3b.4f.5a.,
1a.2f.3b.4f.5a., 1b.2f.3b.4f.5a., 1f.2f.3b.4f.5a., 1h.2f.3b.4f.5a.,
1j.2f.3b.4f.5a., 1p.2f.3b.4f.5a., 1a.2i.3b.4f.5a., 1b.2i.3b.4f.5a.,
1f.2i.3b.4f.5a., 1h.2i.3b.4f.5a., 1j.2i.3b.4f.5a., 1p.2i.3b.4f.5a.,
1a.2m.3b.4f.5a., 1b.2m.3b.4f.5a., 1f.2m.3b.4f.5a., 1h.2m.3b.4f.5a.,
1j.2m.3b.4f.5a., 1p.2m.3b.4f.5a., 1a.2o.3b.4f.5a., 1b.2o.3b.4f.5a.,
1f.2o.3b.4f.5a., 1h.2o.3b.4f.5a., 1j.2o.3b.4f.5a., 1p.2o.3b.4f.5a.,
1a.2u.3b.4f.5a., 1b.2u.3b.4f.5a., 1f.2u.3b.4f.5a., 1h.2u.3b.4f.5a.,
1j.2u.3b.4f.5a., 1p.2u.3b.4f.5a., 1a.2y.3b.4f.5a., 1b.2y.3b.4f.5a.,
1f.2y.3b.4f.5a., 1h.2y.3b.4f.5a., 1j.2y.3b.4f.5a., 1p.2y.3b.4f.5a.,
1a.2a.3e.4f.5a., 1b.2a.3e.4f.5a., 1f.2a.3e.4f.5a., 1h.2a.3e.4f.5a.,
1j.2a.3e.4f.5a., 1p.2a.3e.4f.5a., 1a.2b.3e.4f.5a., 1b.2b.3e.4f.5a.,
1f.2b.3e.4f.5a., 1h.2b.3e.4f.5a., 1j.2b.3e.4f.5a., 1p.2b.3e.4f.5a.,
1a.2e.3e.4f.5a., 1b.2e.3e.4f.5a., 1f.2e.3e.4f.5a., 1h.2e.3e.4f.5a.,
1j.2e.3e.4f.5a., 1p.2e.3e.4f.5a., 1a.2f.3e.4f.5a., 1b.2f.3e.4f.5a.,
1f.2f.3e.4f.5a., 1h.2f.3e.4f.5a., 1j.2f.3e.4f.5a., 1p.2f.3e.4f.5a.,
1a.2i.3e.4f.5a., 1b.2i.3e.4f.5a., 1f.2i.3e.4f.5a., 1h.2i.3e.4f.5a.,
1j.2i.3e.4f.5a., 1p.2i.3e.4f.5a., 1a.2m.3e.4f.5a., 1b.2m.3e.4f.5a.,
1f.2m.3e.4f.5a., 1h.2m.3e.4f.5a., 1j.2m.3e.4f.5a., 1p.2m.3e.4f.5a.,
1a.2o.3e.4f.5a., 1b.2o.3e.4f.5a., 1f.2o.3e.4f.5a., 1h.2o.3e.4f.5a.,
1j.2o.3e.4f.5a., 1p.2o.3e.4f.5a., 1a.2u.3e.4f.5a., 1b.2u.3e.4f.5a.,
1f.2u.3e.4f.5a., 1h.2u.3e.4f.5a., 1j.2u.3e.4f.5a., 1p.2u.3e.4f.5a.,
1a.2y.3e.4f.5a., 1b.2y.3e.4f.5a., 1f.2y.3e.4f.5a., 1h.2y.3e.4f.5a.,
1j.2y.3e.4f.5a., 1p.2y.3e.4f.5a., 1a.2a.3g.4f.5a., 1b.2a.3g.4f.5a.,
1f.2a.3g.4f.5a., 1h.2a.3g.4f.5a., 1j.2a.3g.4f.5a., 1p.2a.3g.4f.5a.,
1a.2b.3g.4f.5a., 1b.2b.3g.4f.5a., 1f.2b.3g.4f.5a., 1h.2b.3g.4f.5a.,
1j.2b.3g.4f.5a., 1p.2b.3g.4f.5a., 1a.2e.3g.4f.5a., 1b.2e.3g.4f.5a.,
1f.2e.3g.4f.5a., 1h.2e.3g.4f.5a., 1j.2e.3g.4f.5a., 1p.2e.3g.4f.5a.,
1a.2f.3g.4f.5a., 1b.2f.3g.4f.5a., 1f.2f.3g.4f.5a., 1h.2f.3g.4f.5a.,
1j.2f.3g.4f.5a., 1p.2f.3g.4f.5a., 1a.2i.3g.4f.5a., 1b.2i.3g.4f.5a.,
1f.2i.3g.4f.5a., 1h.2i.3g.4f.5a., 1j.2i.3g.4f.5a., 1p.2i.3g.4f.5a.,
1a.2m.3g.4f.5a., 1b.2m.3g.4f.5a., 1f.2m.3g.4f.5a., 1h.2m.3g.4f.5a.,
1j.2m.3g.4f.5a., 1p.2m.3g.4f.5a., 1a.2o.3g.4f.5a., 1b.2o.3g.4f.5a.,
1f.2o.3g.4f.5a., 1h.2o.3g.4f.5a., 1j.2o.3g.4f.5a., 1p.2o.3g.4f.5a.,
1a.2u.3g.4f.5a., 1b.2u.3g.4f.5a., 1f.2u.3g.4f.5a., 1h.2u.3g.4f.5a.,
1j.2u.3g.4f.5a., 1p.2u.3g.4f.5a., 1a.2y.3g.4f.5a., 1b.2y.3g.4f.5a.,
1f.2y.3g.4f.5a., 1h.2y.3g.4f.5a., 1j.2y.3g.4f.5a., 1p.2y.3g.4f.5a.,
1a.2a.3a.4g.5a., 1b.2a.3a.4g.5a., 1f.2a.3a.4g.5a., 1h.2a.3a.4g.5a.,
1j.2a.3a.4g.5a., 1p.2a.3a.4g.5a., 1a.2b.3a.4g.5a., 1b.2b.3a.4g.5a.,
1f.2b.3a.4g.5a., 1h.2b.3a.4g.5a., 1j.2b.3a.4g.5a., 1p.2b.3a.4g.5a.,
1a.2e.3a.4g.5a., 1b.2e.3a.4g.5a., 1f.2e.3a.4g.5a., 1h.2e.3a.4g.5a.,
1j.2e.3a.4g.5a., 1p.2e.3a.4g.5a., 1a.2f.3a.4g.5a., 1b.2f.3a.4g.5a.,
1f.2f.3a.4g.5a., 1h.2f.3a.4g.5a., 1j.2f.3a.4g.5a., 1p.2f.3a.4g.5a.,
1a.2i.3a.4g.5a., 1b.2i.3a.4g.5a., 1f.2i.3a.4g.5a., 1h.2i.3a.4g.5a.,
1j.2i.3a.4g.5a., 1p.2i.3a.4g.5a., 1a.2m.3a.4g.5a., 1b.2m.3a.4g.5a.,
1f.2m.3a.4g.5a., 1h.2m.3a.4g.5a., 1j.2m.3a.4g.5a., 1p.2m.3a.4g.5a.,
1a.2o.3a.4g.5a., 1b.2o.3a.4g.5a., 1f.2o.3a.4g.5a., 1h.2o.3a.4g.5a.,
1j.2o.3a.4g.5a., 1p.2o.3a.4g.5a., 1a.2u.3a.4g.5a., 1b.2u.3a.4g.5a.,
1f.2u.3a.4g.5a., 1h.2u.3a.4g.5a., 1j.2u.3a.4g.5a., 1p.2u.3a.4g.5a.,
1a.2y.3a.4g.5a., 1b.2y.3a.4g.5a., 1f.2y.3a.4g.5a., 1h.2y.3a.4g.5a.,
1j.2y.3a.4g.5a., 1p.2y.3a.4g.5a., 1a.2a.3b.4g.5a., 1b.2a.3b.4g.5a.,
1f.2a.3b.4g.5a., 1h.2a.3b.4g.5a., 1j.2a.3b.4g.5a., 1p.2a.3b.4g.5a.,
1a.2b.3b.4g.5a., 1b.2b.3b.4g.5a., 1f.2b.3b.4g.5a., 1h.2b.3b.4g.5a.,
1j.2b.3b.4g.5a., 1p.2b.3b.4g.5a., 1a.2e.3b.4g.5a., 1b.2e.3b.4g.5a.,
1f.2e.3b.4g.5a., 1h.2e.3b.4g.5a., 1j.2e.3b.4g.5a., 1p.2e.3b.4g.5a.,
1a.2f.3b.4g.5a., 1b.2f.3b.4g.5a., 1f.2f.3b.4g.5a., 1h.2f.3b.4g.5a.,
1j.2f.3b.4g.5a., 1p.2f.3b.4g.5a., 1a.2i.3b.4g.5a., 1b.2i.3b.4g.5a.,
1f.2i.3b.4g.5a., 1h.2i.3b.4g.5a., 1j.2i.3b.4g.5a., 1p.2i.3b.4g.5a.,
1a.2m.3b.4g.5a., 1b.2m.3b.4g.5a., 1f.2m.3b.4g.5a., 1h.2m.3b.4g.5a.,
1j.2m.3b.4g.5a., 1p.2m.3b.4g.5a., 1a.2o.3b.4g.5a., 1b.2o.3b.4g.5a.,
1f.2o.3b.4g.5a., 1h.2o.3b.4g.5a., 1j.2o.3b.4g.5a., 1p.2o.3b.4g.5a.,
1a.2u.3b.4g.5a., 1b.2u.3b.4g.5a., 1f.2u.3b.4g.5a., 1h.2u.3b.4g.5a.,
1j.2u.3b.4g.5a., 1p.2u.3b.4g.5a., 1a.2y.3b.4g.5a., 1b.2y.3b.4g.5a.,
1f.2y.3b.4g.5a., 1h.2y.3b.4g.5a., 1j.2y.3b.4g.5a., 1p.2y.3b.4g.5a.,
1a.2a.3e.4g.5a., 1b.2a.3e.4g.5a., 1f.2a.3e.4g.5a., 1h.2a.3e.4g.5a.,
1j.2a.3e.4g.5a., 1p.2a.3e.4g.5a., 1a.2b.3e.4g.5a., 1b.2b.3e.4g.5a.,
1f.2b.3e.4g.5a., 1h.2b.3e.4g.5a., 1j.2b.3e.4g.5a., 1p.2b.3e.4g.5a.,
1a.2e.3e.4g.5a., 1b.2e.3e.4g.5a., 1f.2e.3e.4g.5a., 1h.2e.3e.4g.5a.,
1j.2e.3e.4g.5a., 1p.2e.3e.4g.5a., 1a.2f.3e.4g.5a., 1b.2f.3e.4g.5a.,
1f.2f.3e.4g.5a., 1h.2f.3e.4g.5a., 1j.2f.3e.4g.5a., 1p.2f.3e.4g.5a.,
1a.2i.3e.4g.5a., 1b.2i.3e.4g.5a., 1f.2i.3e.4g.5a., 1h.2i.3e.4g.5a.,
1j.2i.3e.4g.5a., 1p.2i.3e.4g.5a., 1a.2m.3e.4g.5a., 1b.2m.3e.4g.5a.,
1f.2m.3e.4g.5a., 1h.2m.3e.4g.5a., 1j.2m.3e.4g.5a., 1p.2m.3e.4g.5a.,
1a.2o.3e.4g.5a., 1b.2o.3e.4g.5a., 1f.2o.3e.4g.5a., 1h.2o.3e.4g.5a.,
1j.2o.3e.4g.5a., 1p.2o.3e.4g.5a., 1a.2u.3e.4g.5a., 1b.2u.3e.4g.5a.,
1f.2u.3e.4g.5a., 1h.2u.3e.4g.5a., 1j.2u.3e.4g.5a., 1p.2u.3e.4g.5a.,
1a.2y.3e.4g.5a., 1b.2y.3e.4g.5a., 1f.2y.3e.4g.5a., 1h.2y.3e.4g.5a.,
1j.2y.3e.4g.5a., 1p.2y.3e.4g.5a., 1a.2a.3g.4g.5a., 1b.2a.3g.4g.5a.,
1f.2a.3g.4g.5a., 1h.2a.3g.4g.5a., 1j.2a.3g.4g.5a., 1p.2a.3g.4g.5a.,
1a.2b.3g.4g.5a., 1b.2b.3g.4g.5a., 1f.2b.3g.4g.5a., 1h.2b.3g.4g.5a.,
1j.2b.3g.4g.5a., 1p.2b.3g.4g.5a., 1a.2e.3g.4g.5a., 1b.2e.3g.4g.5a.,
1f.2e.3g.4g.5a., 1h.2e.3g.4g.5a., 1j.2e.3g.4g.5a., 1p.2e.3g.4g.5a.,
1a.2f.3g.4g.5a., 1b.2f.3g.4g.5a., 1f.2f.3g.4g.5a., 1h.2f.3g.4g.5a.,
1j.2f.3g.4g.5a., 1p.2f.3g.4g.5a., 1a.2i.3g.4g.5a., 1b.2i.3g.4g.5a.,
1f.2i.3g.4g.5a., 1h.2i.3g.4g.5a., 1j.2i.3g.4g.5a., 1p.2i.3g.4g.5a.,
1a.2m.3g.4g.5a., 1b.2m.3g.4g.5a., 1f.2m.3g.4g.5a., 1h.2m.3g.4g.5a.,
1j.2m.3g.4g.5a., 1p.2m.3g.4g.5a., 1a.2o.3g.4g.5a., 1b.2o.3g.4g.5a.,
1f.2o.3g.4g.5a., 1h.2o.3g.4g.5a., 1j.2o.3g.4g.5a., 1p.2o.3g.4g.5a.,
1a.2u.3g.4g.5a., 1b.2u.3g.4g.5a., 1f.2u.3g.4g.5a., 1h.2u.3g.4g.5a.,
1j.2u.3g.4g.5a., 1p.2u.3g.4g.5a., 1a.2y.3g.4g.5a., 1b.2y.3g.4g.5a.,
1f.2y.3g.4g.5a., 1h.2y.3g.4g.5a., 1j.2y.3g.4g.5a., 1p.2y.3g.4g.5a.,
1a.2a.3a.4h.5a., 1b.2a.3a.4h.5a., 1f.2a.3a.4h.5a., 1h.2a.3a.4h.5a.,
1j.2a.3a.4h.5a., 1p.2a.3a.4h.5a., 1a.2b.3a.4h.5a., 1b.2b.3a.4h.5a.,
1f.2b.3a.4h.5a., 1h.2b.3a.4h.5a., 1j.2b.3a.4h.5a., 1p.2b.3a.4h.5a.,
1a.2e.3a.4h.5a., 1b.2e.3a.4h.5a., 1f.2e.3a.4h.5a., 1h.2e.3a.4h.5a.,
1j.2e.3a.4h.5a., 1p.2e.3a.4h.5a., 1a.2f.3a.4h.5a., 1b.2f.3a.4h.5a.,
1f.2f.3a.4h.5a., 1h.2f.3a.4h.5a., 1j.2f.3a.4h.5a., 1p.2f.3a.4h.5a.,
1a.2i.3a.4h.5a., 1b.2i.3a.4h.5a., 1f.2i.3a.4h.5a., 1h.2i.3a.4h.5a.,
1j.2i.3a.4h.5a., 1p.2i.3a.4h.5a., 1a.2m.3a.4h.5a., 1b.2m.3a.4h.5a.,
1f.2m.3a.4h.5a., 1h.2m.3a.4h.5a., 1j.2m.3a.4h.5a., 1p.2m.3a.4h.5a.,
1a.2o.3a.4h.5a., 1b.2o.3a.4h.5a., 1f.2o.3a.4h.5a., 1h.2o.3a.4h.5a.,
1j.2o.3a.4h.5a., 1p.2o.3a.4h.5a., 1a.2u.3a.4h.5a., 1b.2u.3a.4h.5a.,
1f.2u.3a.4h.5a., 1h.2u.3a.4h.5a., 1j.2u.3a.4h.5a., 1p.2u.3a.4h.5a.,
1a.2y.3a.4h.5a., 1b.2y.3a.4h.5a., 1f.2y.3a.4h.5a., 1h.2y.3a.4h.5a.,
1j.2y.3a.4h.5a., 1p.2y.3a.4h.5a., 1a.2a.3b.4h.5a., 1b.2a.3b.4h.5a.,
1f.2a.3b.4h.5a., 1h.2a.3b.4h.5a., 1j.2a.3b.4h.5a., 1p.2a.3b.4h.5a.,
1a.2b.3b.4h.5a., 1b.2b.3b.4h.5a., 1f.2b.3b.4h.5a., 1h.2b.3b.4h.5a.,
1j.2b.3b.4h.5a., 1p.2b.3b.4h.5a., 1a.2e.3b.4h.5a., 1b.2e.3b.4h.5a.,
1f.2e.3b.4h.5a., 1h.2e.3b.4h.5a., 1j.2e.3b.4h.5a., 1p.2e.3b.4h.5a.,
1a.2f.3b.4h.5a., 1b.2f.3b.4h.5a., 1f.2f.3b.4h.5a., 1h.2f.3b.4h.5a.,
1j.2f.3b.4h.5a., 1p.2f.3b.4h.5a., 1a.2i.3b.4h.5a., 1b.2i.3b.4h.5a.,
1f.2i.3b.4h.5a., 1h.2i.3b.4h.5a., 1j.2i.3b.4h.5a., 1p.2i.3b.4h.5a.,
1a.2m.3b.4h.5a., 1b.2m.3b.4h.5a., 1f.2m.3b.4h.5a., 1h.2m.3b.4h.5a.,
1j.2m.3b.4h.5a., 1p.2m.3b.4h.5a., 1a.2o.3b.4h.5a., 1b.2o.3b.4h.5a.,
1f.2o.3b.4h.5a., 1h.2o.3b.4h.5a., 1j.2o.3b.4h.5a., 1p.2o.3b.4h.5a.,
1a.2u.3b.4h.5a., 1b.2u.3b.4h.5a., 1f.2u.3b.4h.5a., 1h.2u.3b.4h.5a.,
1j.2u.3b.4h.5a., 1p.2u.3b.4h.5a., 1a.2y.3b.4h.5a., 1b.2y.3b.4h.5a.,
1f.2y.3b.4h.5a., 1h.2y.3b.4h.5a., 1j.2y.3b.4h.5a., 1p.2y.3b.4h.5a.,
1a.2a.3e.4h.5a., 1b.2a.3e.4h.5a., 1f.2a.3e.4h.5a., 1h.2a.3e.4h.5a.,
1j.2a.3e.4h.5a., 1p.2a.3e.4h.5a., 1a.2b.3e.4h.5a.,
1b.2b.3e.4h.5a.,
1f.2b.3e.4h.5a., 1h.2b.3e.4h.5a., 1j.2b.3e.4h.5a., 1p.2b.3e.4h.5a.,
1a.2e.3e.4h.5a., 1b.2e.3e.4h.5a., 1f.2e.3e.4h.5a., 1h.2e.3e.4h.5a.,
1j.2e.3e.4h.5a., 1p.2e.3e.4h.5a., 1a.2f.3e.4h.5a., 1b.2f.3e.4h.5a.,
1f.2f.3e.4h.5a., 1h.2f.3e.4h.5a., 1j.2f.3e.4h.5a., 1p.2f.3e.4h.5a.,
1a.2i.3e.4h.5a., 1b.2i.3e.4h.5a., 1f.2i.3e.4h.5a., 1h.2i.3e.4h.5a.,
1j.2i.3e.4h.5a., 1p.2i.3e.4h.5a., 1a.2m.3e.4h.5a., 1b.2m.3e.4h.5a.,
1f.2m.3e.4h.5a., 1h.2m.3e.4h.5a., 1j.2m.3e.4h.5a., 1p.2m.3e.4h.5a.,
1a.2o.3e.4h.5a., 1b.2o.3e.4h.5a., 1f.2o.3e.4h.5a., 1h.2o.3e.4h.5a.,
1j.2o.3e.4h.5a., 1p.2o.3e.4h.5a., 1a.2u.3e.4h.5a., 1b.2u.3e.4h.5a.,
1f.2u.3e.4h.5a., 1h.2u.3e.4h.5a., 1j.2u.3e.4h.5a., 1p.2u.3e.4h.5a.,
1a.2y.3e.4h.5a., 1b.2y.3e.4h.5a., 1f.2y.3e.4h.5a., 1h.2y.3e.4h.5a.,
1j.2y.3e.4h.5a., 1p.2y.3e.4h.5a., 1a.2a.3g.4h.5a., 1b.2a.3g.4h.5a.,
1f.2a.3g.4h.5a., 1h.2a.3g.4h.5a., 1j.2a.3g.4h.5a., 1p.2a.3g.4h.5a.,
1a.2b.3g.4h.5a., 1b.2b.3g.4h.5a., 1f.2b.3g.4h.5a., 1h.2b.3g.4h.5a.,
1j.2b.3g.4h.5a., 1p.2b.3g.4h.5a., 1a.2e.3g.4h.5a., 1b.2e.3g.4h.5a.,
1f.2e.3g.4h.5a., 1h.2e.3g.4h.5a., 1j.2e.3g.4h.5a., 1p.2e.3g.4h.5a.,
1a.2f.3g.4h.5a., 1b.2f.3g.4h.5a., 1f.2f.3g.4h.5a., 1h.2f.3g.4h.5a.,
1j.2f.3g.4h.5a., 1p.2f.3g.4h.5a., 1a.2i.3g.4h.5a., 1b.2i.3g.4h.5a.,
1f.2i.3g.4h.5a., 1h.2i.3g.4h.5a., 1j.2i.3g.4h.5a., 1p.2i.3g.4h.5a.,
1a.2m.3g.4h.5a., 1b.2m.3g.4h.5a., 1f.2m.3g.4h.5a., 1h.2m.3g.4h.5a.,
1j.2m.3g.4h.5a., 1p.2m.3g.4h.5a., 1a.2o.3g.4h.5a., 1b.2o.3g.4h.5a.,
1f.2o.3g.4h.5a., 1h.2o.3g.4h.5a., 1j.2o.3g.4h.5a., 1p.2o.3g.4h.5a.,
1a.2u.3g.4h.5a., 1b.2u.3g.4h.5a., 1f.2u.3g.4h.5a., 1h.2u.3g.4h.5a.,
1j.2u.3g.4h.5a., 1p.2u.3g.4h.5a., 1a.2y.3g.4h.5a., 1b.2y.3g.4h.5a.,
1f.2y.3g.4h.5a., 1h.2y.3g.4h.5a., 1j.2y.3g.4h.5a., 1p.2y.3g.4h.5a.,
1a.2a.3a.4i.5a., 1b.2a.3a.4i.5a., 1f.2a.3a.4i.5a., 1h.2a.3a.4i.5a.,
1j.2a.3a.4i.5a., 1p.2a.3a.4i.5a., 1a.2b.3a.4i.5a., 1b.2b.3a.4i.5a.,
1f.2b.3a.4i.5a., 1h.2b.3a.4i.5a., 1j.2b.3a.4i.5a., 1p.2b.3a.4i.5a.,
1a.2e.3a.4i.5a., 1b.2e.3a.4i.5a., 1f.2e.3a.4i.5a., 1h.2e.3a.4i.5a.,
1j.2e.3a.4i.5a., 1p.2e.3a.4i.5a., 1a.2f.3a.4i.5a., 1b.2f.3a.4i.5a.,
1f.2f.3a.4i.5a., 1h.2f.3a.4i.5a., 1j.2f.3a.4i.5a., 1p.2f.3a.4i.5a.,
1a.2i.3a.4i.5a., 1b.2i.3a.4i.5a., 1f.2i.3a.4i.5a., 1h.2i.3a.4i.5a.,
1j.2i.3a.4i.5a., 1p.2i.3a.4i.5a., 1a.2m.3a.4i.5a., 1b.2m.3a.4i.5a.,
1f.2m.3a.4i.5a., 1h.2m.3a.4i.5a., 1j.2m.3a.4i.5a., 1p.2m.3a.4i.5a.,
1a.2o.3a.4i.5a., 1b.2o.3a.4i.5a., 1f.2o.3a.4i.5a., 1h.2o.3a.4i.5a.,
1j.2o.3a.4i.5a., 1p.2o.3a.4i.5a., 1a.2u.3a.4i.5a., 1b.2u.3a.4i.5a.,
1f.2u.3a.4i.5a., 1h.2u.3a.4i.5a., 1j.2u.3a.4i.5a., 1p.2u.3a.4i.5a.,
1a.2y.3a.4i.5a., 1b.2y.3a.4i.5a., 1f.2y.3a.4i.5a., 1h.2y.3a.4i.5a.,
1j.2y.3a.4i.5a., 1p.2y.3a.4i.5a., 1a.2a.3b.4i.5a., 1b.2a.3b.4i.5a.,
1f.2a.3b.4i.5a., 1h.2a.3b.4i.5a., 1j.2a.3b.4i.5a., 1p.2a.3b.4i.5a.,
1a.2b.3b.4i.5a., 1b.2b.3b.4i.5a., 1f.2b.3b.4i.5a., 1h.2b.3b.4i.5a.,
1j.2b.3b.4i.5a., 1p.2b.3b.4i.5a., 1a.2e.3b.4i.5a., 1b.2e.3b.4i.5a.,
1f.2e.3b.4i.5a., 1h.2e.3b.4i.5a., 1j.2e.3b.4i.5a., 1p.2e.3b.4i.5a.,
1a.2f.3b.4i.5a., 1b.2f.3b.4i.5a., 1f.2f.3b.4i.5a., 1h.2f.3b.4i.5a.,
1j.2f.3b.4i.5a., 1p.2f.3b.4i.5a., 1a.2i.3b.4i.5a., 1b.2i.3b.4i.5a.,
1f.2i.3b.4i.5a., 1h.2i.3b.4i.5a., 1j.2i.3b.4i.5a., 1p.2i.3b.4i.5a.,
1a.2m.3b.4i.5a., 1b.2m.3b.4i.5a., 1f.2m.3b.4i.5a., 1h.2m.3b.4i.5a.,
1j.2m.3b.4i.5a., 1p.2m.3b.4i.5a., 1a.2o.3b.4i.5a., 1b.2o.3b.4i.5a.,
1f.2o.3b.4i.5a., 1h.2o.3b.4i.5a., 1j.2o.3b.4i.5a., 1p.2o.3b.4i.5a.,
1a.2u.3b.4i.5a., 1b.2u.3b.4i.5a., 1f.2u.3b.4i.5a., 1h.2u.3b.4i.5a.,
1j.2u.3b.4i.5a., 1p.2u.3b.4i.5a., 1a.2y.3b.4i.5a., 1b.2y.3b.4i.5a.,
1f.2y.3b.4i.5a., 1h.2y.3b.4i.5a., 1j.2y.3b.4i.5a., 1p.2y.3b.4i.5a.,
1a.2a.3e.4i.5a., 1b.2a.3e.4i.5a., 1f.2a.3e.4i.5a., 1h.2a.3e.4i.5a.,
1j.2a.3e.4i.5a., 1p.2a.3e.4i.5a., 1a.2b.3e.4i.5a., 1b.2b.3e.4i.5a.,
1f.2b.3e.4i.5a., 1h.2b.3e.4i.5a., 1j.2b.3e.4i.5a., 1p.2b.3e.4i.5a.,
1a.2e.3e.4i.5a., 1b.2e.3e.4i.5a., 1f.2e.3e.4i.5a., 1h.2e.3e.4i.5a.,
1j.2e.3e.4i.5a., 1p.2e.3e.4i.5a., 1a.2f.3e.4i.5a., 1b.2f.3e.4i.5a.,
1f.2f.3e.4i.5a., 1h.2f.3e.4i.5a., 1j.2f.3e.4i.5a., 1p.2f.3e.4i.5a.,
1a.2i.3e.4i.5a., 1b.2i.3e.4i.5a., 1f.2i.3e.4i.5a., 1h.2i.3e.4i.5a.,
1j.2i.3e.4i.5a., 1p.2i.3e.4i.5a., 1a.2m.3e.4i.5a., 1b.2m.3e.4i.5a.,
1f.2m.3e.4i.5a., 1h.2m.3e.4i.5a., 1j.2m.3e.4i.5a., 1p.2m.3e.4i.5a.,
1a.2o.3e.4i.5a., 1b.2o.3e.4i.5a., 1f.2o.3e.4i.5a., 1h.2o.3e.4i.5a.,
1j.2o.3e.4i.5a., 1p.2o.3e.4i.5a., 1a.2u.3e.4i.5a., 1b.2u.3e.4i.5a.,
1f.2u.3e.4i.5a., 1h.2u.3e.4i.5a., 1j.2u.3e.4i.5a., 1p.2u.3e.4i.5a.,
1a.2y.3e.4i.5a., 1b.2y.3e.4i.5a., 1f.2y.3e.4i.5a., 1h.2y.3e.4i.5a.,
1j.2y.3e.4i.5a., 1p.2y.3e.4i.5a., 1a.2a.3g.4i.5a., 1b.2a.3g.4i.5a.,
1f.2a.3g.4i.5a., 1h.2a.3g.4i.5a., 1j.2a.3g.4i.5a., 1p.2a.3g.4i.5a.,
1a.2b.3g.4i.5a., 1b.2b.3g.4i.5a., 1f.2b.3g.4i.5a., 1h.2b.3g.4i.5a.,
1j.2b.3g.4i.5a., 1p.2b.3g.4i.5a., 1a.2e.3g.4i.5a., 1b.2e.3g.4i.5a.,
1f.2e.3g.4i.5a., 1h.2e.3g.4i.5a., 1j.2e.3g.4i.5a., 1p.2e.3g.4i.5a.,
1a.2f.3g.4i.5a., 1b.2f.3g.4i.5a., 1f.2f.3g.4i.5a., 1h.2f.3g.4i.5a.,
1j.2f.3g.4i.5a., 1p.2f.3g.4i.5a., 1a.2i.3g.4i.5a., 1b.2i.3g.4i.5a.,
1f.2i.3g.4i.5a., 1h.2i.3g.4i.5a., 1j.2i.3g.4i.5a., 1p.2i.3g.4i.5a.,
1a.2m.3g.4i.5a., 1b.2m.3g.4i.5a., 1f.2m.3g.4i.5a., 1h.2m.3g.4i.5a.,
1j.2m.3g.4i.5a., 1p.2m.3g.4i.5a., 1a.2o.3g.4i.5a., 1b.2o.3g.4i.5a.,
1f.2o.3g.4i.5a., 1h.2o.3g.4i.5a., 1j.2o.3g.4i.5a., 1p.2o.3g.4i.5a.,
1a.2u.3g.4i.5a., 1b.2u.3g.4i.5a., 1f.2u.3g.4i.5a., 1h.2u.3g.4i.5a.,
1j.2u.3g.4i.5a., 1p.2u.3g.4i.5a., 1a.2y.3g.4i.5a., 1b.2y.3g.4i.5a.,
1f.2y.3g.4i.5a., 1h.2y.3g.4i.5a., 1j.2y.3g.4i.5a., 1p.2y.3g.4i.5a.,
1a.2a.3a.4a.5d., 1b.2a.3a.4a.5d., 1f.2a.3a.4a.5d., 1h.2a.3a.4a.5d.,
1j.2a.3a.4a.5d., 1p.2a.3a.4a.5d., 1a.2b.3a.4a.5d., 1b.2b.3a.4a.5d.,
1f.2b.3a.4a.5d., 1h.2b.3a.4a.5d., 1j.2b.3a.4a.5d., 1p.2b.3a.4a.5d.,
1a.2e.3a.4a.5d., 1b.2e.3a.4a.5d., 1f.2e.3a.4a.5d., 1h.2e.3a.4a.5d.,
1j.2e.3a.4a.5d., 1p.2e.3a.4a.5d., 1a.2f.3a.4a.5d., 1b.2f.3a.4a.5d.,
1f.2f.3a.4a.5d., 1h.2f.3a.4a.5d., 1j.2f.3a.4a.5d., 1p.2f.3a.4a.5d.,
1a.2i.3a.4a.5d., 1b.2i.3a.4a.5d., 1f.2i.3a.4a.5d., 1h.2i.3a.4a.5d.,
1j.2i.3a.4a.5d., 1p.2i.3a.4a.5d., 1a.2m.3a.4a.5d., 1b.2m.3a.4a.5d.,
1f.2m.3a.4a.5d., 1h.2m.3a.4a.5d., 1j.2m.3a.4a.5d., 1p.2m.3a.4a.5d.,
1a.2o.3a.4a.5d., 1b.2o.3a.4a.5d., 1f.2o.3a.4a.5d., 1h.2o.3a.4a.5d.,
1j.2o.3a.4a.5d., 1p.2o.3a.4a.5d., 1a.2u.3a.4a.5d., 1b.2u.3a.4a.5d.,
1f.2u.3a.4a.5d., 1h.2u.3a.4a.5d., 1j.2u.3a.4a.5d., 1p.2u.3a.4a.5d.,
1a.2y.3a.4a.5d., 1b.2y.3a.4a.5d., 1f.2y.3a.4a.5d., 1h.2y.3a.4a.5d.,
1j.2y.3a.4a.5d., 1p.2y.3a.4a.5d., 1a.2a.3b.4a.5d., 1b.2a.3b.4a.5d.,
1f.2a.3b.4a.5d., 1h.2a.3b.4a.5d., 1j.2a.3b.4a.5d., 1p.2a.3b.4a.5d.,
1a.2b.3b.4a.5d., 1b.2b.3b.4a.5d., 1f.2b.3b.4a.5d., 1h.2b.3b.4a.5d.,
1j.2b.3b.4a.5d., 1p.2b.3b.4a.5d., 1a.2e.3b.4a.5d., 1b.2e.3b.4a.5d.,
1f.2e.3b.4a.5d., 1h.2e.3b.4a.5d., 1j.2e.3b.4a.5d., 1p.2e.3b.4a.5d.,
1a.2f.3b.4a.5d., 1b.2f.3b.4a.5d., 1f.2f.3b.4a.5d., 1h.2f.3b.4a.5d.,
1j.2f.3b.4a.5d., 1p.2f.3b.4a.5d., 1a.2i.3b.4a.5d., 1b.2i.3b.4a.5d.,
1f.2i.3b.4a.5d., 1h.2i.3b.4a.5d., 1j.2i.3b.4a.5d., 1p.2i.3b.4a.5d.,
1a.2m.3b.4a.5d., 1b.2m.3b.4a.5d., 1f.2m.3b.4a.5d., 1h.2m.3b.4a.5d.,
1j.2m.3b.4a.5d., 1p.2m.3b.4a.5d., 1a.2o.3b.4a.5d., 1b.2o.3b.4a.5d.,
1f.2o.3b.4a.5d., 1h.2o.3b.4a.5d., 1j.2o.3b.4a.5d., 1p.2o.3b.4a.5d.,
1a.2u.3b.4a.5d., 1b.2u.3b.4a.5d., 1f.2u.3b.4a.5d., 1h.2u.3b.4a.5d.,
1j.2u.3b.4a.5d., 1p.2u.3b.4a.5d., 1a.2y.3b.4a.5d., 1b.2y.3b.4a.5d.,
1f.2y.3b.4a.5d., 1h.2y.3b.4a.5d., 1j.2y.3b.4a.5d., 1p.2y.3b.4a.5d.,
1a.2a.3e.4a.5d., 1b.2a.3e.4a.5d., 1f.2a.3e.4a.5d., 1h.2a.3e.4a.5d.,
1j.2a.3e.4a.5d., 1p.2a.3e.4a.5d., 1a.2b.3e.4a.5d., 1b.2b.3e.4a.5d.,
1f.2b.3e.4a.5d., 1h.2b.3e.4a.5d., 1j.2b.3e.4a.5d., 1p.2b.3e.4a.5d.,
1a.2e.3e.4a.5d., 1b.2e.3e.4a.5d., 1f.2e.3e.4a.5d., 1h.2e.3e.4a.5d.,
1j.2e.3e.4a.5d., 1p.2e.3e.4a.5d., 1a.2f.3e.4a.5d., 1b.2f.3e.4a.5d.,
1f.2f.3e.4a.5d., 1h.2f.3e.4a.5d., 1j.2f.3e.4a.5d., 1p.2f.3e.4a.5d.,
1a.2i.3e.4a.5d., 1b.2i.3e.4a.5d., 1f.2i.3e.4a.5d., 1h.2i.3e.4a.5d.,
1j.2i.3e.4a.5d., 1p.2i.3e.4a.5d., 1a.2m.3e.4a.5d., 1b.2m.3e.4a.5d.,
1f.2m.3e.4a.5d., 1h.2m.3e.4a.5d., 1j.2m.3e.4a.5d., 1p.2m.3e.4a.5d.,
1a.2o.3e.4a.5d., 1b.2o.3e.4a.5d., 1f.2o.3e.4a.5d., 1h.2o.3e.4a.5d.,
1j.2o.3e.4a.5d., 1p.2o.3e.4a.5d., 1a.2u.3e.4a.5d., 1b.2u.3e.4a.5d.,
1f.2u.3e.4a.5d., 1h.2u.3e.4a.5d., 1j.2u.3e.4a.5d., 1p.2u.3e.4a.5d.,
1a.2y.3e.4a.5d., 1b.2y.3e.4a.5d., 1f.2y.3e.4a.5d., 1h.2y.3e.4a.5d.,
1j.2y.3e.4a.5d., 1p.2y.3e.4a.5d., 1a.2a.3g.4a.5d., 1b.2a.3g.4a.5d.,
1f.2a.3g.4a.5d., 1h.2a.3g.4a.5d., 1j.2a.3g.4a.5d., 1p.2a.3g.4a.5d.,
1a.2b.3g.4a.5d., 1b.2b.3g.4a.5d., 1f.2b.3g.4a.5d., 1h.2b.3g.4a.5d.,
1j.2b.3g.4a.5d., 1p.2b.3g.4a.5d., 1a.2e.3g.4a.5d., 1b.2e.3g.4a.5d.,
1f.2e.3g.4a.5d., 1h.2e.3g.4a.5d., 1j.2e.3g.4a.5d., 1p.2e.3g.4a.5d.,
1a.2f.3g.4a.5d., 1b.2f.3g.4a.5d., 1f.2f.3g.4a.5d., 1h.2f.3g.4a.5d.,
1j.2f.3g.4a.5d., 1p.2f.3g.4a.5d., 1a.2i.3g.4a.5d., 1b.2i.3g.4a.5d.,
1f.2i.3g.4a.5d., 1h.2i.3g.4a.5d., 1j.2i.3g.4a.5d., 1p.2i.3g.4a.5d.,
1a.2m.3g.4a.5d., 1b.2m.3g.4a.5d., 1f.2m.3g.4a.5d., 1h.2m.3g.4a.5d.,
1j.2m.3g.4a.5d., 1p.2m.3g.4a.5d., 1a.2o.3g.4a.5d., 1b.2o.3g.4a.5d.,
1f.2o.3g.4a.5d., 1h.2o.3g.4a.5d., 1j.2o.3g.4a.5d., 1p.2o.3g.4a.5d.,
1a.2u.3g.4a.5d., 1b.2u.3g.4a.5d., 1f.2u.3g.4a.5d., 1h.2u.3g.4a.5d.,
1j.2u.3g.4a.5d., 1p.2u.3g.4a.5d., 1a.2y.3g.4a.5d., 1b.2y.3g.4a.5d.,
1f.2y.3g.4a.5d., 1h.2y.3g.4a.5d., 1j.2y.3g.4a.5d., 1p.2y.3g.4a.5d.,
1a.2a.3a.4d.5d., 1b.2a.3a.4d.5d., 1f.2a.3a.4d.5d., 1h.2a.3a.4d.5d.,
1j.2a.3a.4d.5d., 1p.2a.3a.4d.5d., 1a.2b.3a.4d.5d., 1b.2b.3a.4d.5d.,
1f.2b.3a.4d.5d., 1h.2b.3a.4d.5d., 1j.2b.3a.4d.5d., 1p.2b.3a.4d.5d.,
1a.2e.3a.4d.5d., 1b.2e.3a.4d.5d., 1f.2e.3a.4d.5d., 1h.2e.3a.4d.5d.,
1j.2e.3a.4d.5d., 1p.2e.3a.4d.5d., 1a.2f.3a.4d.5d., 1b.2f.3a.4d.5d.,
1f.2f.3a.4d.5d., 1h.2f.3a.4d.5d., 1j.2f.3a.4d.5d., 1p.2f.3a.4d.5d.,
1a.2i.3a.4d.5d., 1b.2i.3a.4d.5d., 1f.2i.3a.4d.5d., 1h.2i.3a.4d.5d.,
1j.2i.3a.4d.5d., 1p.2i.3a.4d.5d., 1a.2m.3a.4d.5d., 1b.2m.3a.4d.5d.,
1f.2m.3a.4d.5d., 1h.2m.3a.4d.5d., 1j.2m.3a.4d.5d., 1p.2m.3a.4d.5d.,
1a.2o.3a.4d.5d., 1b.2o.3a.4d.5d., 1f.2o.3a.4d.5d., 1h.2o.3a.4d.5d.,
1j.2o.3a.4d.5d., 1p.2o.3a.4d.5d., 1a.2u.3a.4d.5d., 1b.2u.3a.4d.5d.,
1f.2u.3a.4d.5d., 1h.2u.3a.4d.5d., 1j.2u.3a.4d.5d., 1p.2u.3a.4d.5d.,
1a.2y.3a.4d.5d., 1b.2y.3a.4d.5d., 1f.2y.3a.4d.5d., 1h.2y.3a.4d.5d.,
1j.2y.3a.4d.5d., 1p.2y.3a.4d.5d., 1a.2a.3b.4d.5d., 1b.2a.3b.4d.5d.,
1f.2a.3b.4d.5d., 1h.2a.3b.4d.5d., 1j.2a.3b.4d.5d., 1p.2a.3b.4d.5d.,
1a.2b.3b.4d.5d., 1b.2b.3b.4d.5d., 1f.2b.3b.4d.5d., 1h.2b.3b.4d.5d.,
1j.2b.3b.4d.5d., 1p.2b.3b.4d.5d., 1a.2e.3b.4d.5d., 1b.2e.3b.4d.5d.,
1f.2e.3b.4d.5d., 1h.2e.3b.4d.5d., 1j.2e.3b.4d.5d., 1p.2e.3b.4d.5d.,
1a.2f.3b.4d.5d., 1b.2f.3b.4d.5d., 1f.2f.3b.4d.5d., 1h.2f.3b.4d.5d.,
1j.2f.3b.4d.5d., 1p.2f.3b.4d.5d., 1a.2i.3b.4d.5d., 1b.2i.3b.4d.5d.,
1f.2i.3b.4d.5d., 1h.2i.3b.4d.5d., 1j.2i.3b.4d.5d., 1p.2i.3b.4d.5d.,
1a.2m.3b.4d.5d., 1b.2m.3b.4d.5d., 1f.2m.3b.4d.5d., 1h.2m.3b.4d.5d.,
1j.2m.3b.4d.5d., 1p.2m.3b.4d.5d., 1a.2o.3b.4d.5d., 1b.2o.3b.4d.5d.,
1f.2o.3b.4d.5d., 1h.2o.3b.4d.5d., 1j.2o.3b.4d.5d., 1p.2o.3b.4d.5d.,
1a.2u.3b.4d.5d., 1b.2u.3b.4d.5d., 1f.2u.3b.4d.5d., 1h.2u.3b.4d.5d.,
1j.2u.3b.4d.5d., 1p.2u.3b.4d.5d., 1a.2y.3b.4d.5d., 1b.2y.3b.4d.5d.,
1f.2y.3b.4d.5d., 1h.2y.3b.4d.5d., 1j.2y.3b.4d.5d., 1p.2y.3b.4d.5d.,
1a.2a.3e.4d.5d., 1b.2a.3e.4d.5d., 1f.2a.3e.4d.5d., 1h.2a.3e.4d.5d.,
1j.2a.3e.4d.5d., 1p.2a.3e.4d.5d., 1a.2b.3e.4d.5d., 1b.2b.3e.4d.5d.,
1f.2b.3e.4d.5d., 1h.2b.3e.4d.5d., 1j.2b.3e.4d.5d., 1p.2b.3e.4d.5d.,
1a.2e.3e.4d.5d., 1b.2e.3e.4d.5d., 1f.2e.3e.4d.5d., 1h.2e.3e.4d.5d.,
1j.2e.3e.4d.5d., 1p.2e.3e.4d.5d., 1a.2f.3e.4d.5d., 1b.2f.3e.4d.5d.,
1f.2f.3e.4d.5d., 1h.2f.3e.4d.5d., 1j.2f.3e.4d.5d., 1p.2f.3e.4d.5d.,
1a.2i.3e.4d.5d., 1b.2i.3e.4d.5d., 1f.2i.3e.4d.5d., 1h.2i.3e.4d.5d.,
1j.2i.3e.4d.5d., 1p.2i.3e.4d.5d., 1a.2m.3e.4d.5d., 1b.2m.3e.4d.5d.,
1f.2m.3e.4d.5d., 1h.2m.3e.4d.5d., 1j.2m.3e.4d.5d., 1p.2m.3e.4d.5d.,
1a.2o.3e.4d.5d., 1b.2o.3e.4d.5d., 1f.2o.3e.4d.5d., 1h.2o.3e.4d.5d.,
1j.2o.3e.4d.5d., 1p.2o.3e.4d.5d., 1a.2u.3e.4d.5d., 1b.2u.3e.4d.5d.,
1f.2u.3e.4d.5d., 1h.2u.3e.4d.5d., 1j.2u.3e.4d.5d., 1p.2u.3e.4d.5d.,
1a.2y.3e.4d.5d., 1b.2y.3e.4d.5d., 1f.2y.3e.4d.5d., 1h.2y.3e.4d.5d.,
1j.2y.3e.4d.5d., 1p.2y.3e.4d.5d., 1a.2a.3g.4d.5d., 1b.2a.3g.4d.5d.,
1f.2a.3g.4d.5d., 1h.2a.3g.4d.5d., 1j.2a.3g.4d.5d., 1p.2a.3g.4d.5d.,
1a.2b.3g.4d.5d., 1b.2b.3g.4d.5d., 1f.2b.3g.4d.5d., 1h.2b.3g.4d.5d.,
1j.2b.3g.4d.5d., 1p.2b.3g.4d.5d., 1a.2e.3g.4d.5d., 1b.2e.3g.4d.5d.,
1f.2e.3g.4d.5d., 1h.2e.3g.4d.5d., 1j.2e.3g.4d.5d., 1p.2e.3g.4d.5d.,
1a.2f.3g.4d.5d., 1b.2f.3g.4d.5d., 1f.2f.3g.4d.5d., 1h.2f.3g.4d.5d.,
1j.2f.3g.4d.5d., 1p.2f.3g.4d.5d., 1a.2i.3g.4d.5d., 1b.2i.3g.4d.5d.,
1f.2i.3g.4d.5d., 1h.2i.3g.4d.5d., 1j.2i.3g.4d.5d., 1p.2i.3g.4d.5d.,
1a.2m.3g.4d.5d., 1b.2m.3g.4d.5d., 1f.2m.3g.4d.5d., 1h.2m.3g.4d.5d.,
1j.2m.3g.4d.5d., 1p.2m.3g.4d.5d., 1a.2o.3g.4d.5d., 1b.2o.3g.4d.5d.,
1f.2o.3g.4d.5d., 1h.2o.3g.4d.5d., 1j.2o.3g.4d.5d., 1p.2o.3g.4d.5d.,
1a.2u.3g.4d.5d., 1b.2u.3g.4d.5d., 1f.2u.3g.4d.5d., 1h.2u.3g.4d.5d.,
1j.2u.3g.4d.5d., 1p.2u.3g.4d.5d., 1a.2y.3g.4d.5d., 1b.2y.3g.4d.5d.,
1f.2y.3g.4d.5d., 1h.2y.3g.4d.5d., 1j.2y.3g.4d.5d., 1p.2y.3g.4d.5d.,
1a.2a.3a.4f.5d., 1b.2a.3a.4f.5d., 1f.2a.3a.4f.5d., 1h.2a.3a.4f.5d.,
1j.2a.3a.4f.5d., 1p.2a.3a.4f.5d., 1a.2b.3a.4f.5d., 1b.2b.3a.4f.5d.,
1f.2b.3a.4f.5d., 1h.2b.3a.4f.5d., 1j.2b.3a.4f.5d., 1p.2b.3a.4f.5d.,
1a.2e.3a.4f.5d., 1b.2e.3a.4f.5d., 1f.2e.3a.4f.5d., 1h.2e.3a.4f.5d.,
1j.2e.3a.4f.5d., 1p.2e.3a.4f.5d., 1a.2f.3a.4f.5d., 1b.2f.3a.4f.5d.,
1f.2f.3a.4f.5d., 1h.2f.3a.4f.5d., 1j.2f.3a.4f.5d., 1p.2f.3a.4f.5d.,
1a.2i.3a.4f.5d., 1b.2i.3a.4f.5d., 1f.2i.3a.4f.5d., 1h.2i.3a.4f.5d.,
1j.2i.3a.4f.5d., 1p.2i.3a.4f.5d., 1a.2m.3a.4f.5d., 1b.2m.3a.4f.5d.,
1f.2m.3a.4f.5d., 1h.2m.3a.4f.5d., 1j.2m.3a.4f.5d., 1p.2m.3a.4f.5d.,
1a.2o.3a.4f.5d., 1b.2o.3a.4f.5d., 1f.2o.3a.4f.5d., 1h.2o.3a.4f.5d.,
1j.2o.3a.4f.5d., 1p.2o.3a.4f.5d., 1a.2u.3a.4f.5d., 1b.2u.3a.4f.5d.,
1f.2u.3a.4f.5d., 1h.2u.3a.4f.5d., 1j.2u.3a.4f.5d., 1p.2u.3a.4f.5d.,
1a.2y.3a.4f.5d., 1b.2y.3a.4f.5d., 1f.2y.3a.4f.5d., 1h.2y.3a.4f.5d.,
1j.2y.3a.4f.5d., 1p.2y.3a.4f.5d., 1a.2a.3b.4f.5d., 1b.2a.3b.4f.5d.,
1f.2a.3b.4f.5d., 1h.2a.3b.4f.5d., 1j.2a.3b.4f.5d., 1p.2a.3b.4f.5d.,
1a.2b.3b.4f.5d., 1b.2b.3b.4f.5d., 1f.2b.3b.4f.5d., 1h.2b.3b.4f.5d.,
1j.2b.3b.4f.5d., 1p.2b.3b.4f.5d., 1a.2e.3b.4f.5d., 1b.2e.3b.4f.5d.,
1f.2e.3b.4f.5d., 1h.2e.3b.4f.5d., 1j.2e.3b.4f.5d., 1p.2e.3b.4f.5d.,
1a.2f.3b.4f.5d., 1b.2f.3b.4f.5d., 1f.2f.3b.4f.5d., 1h.2f.3b.4f.5d.,
1j.2f.3b.4f.5d., 1p.2f.3b.4f.5d., 1a.2i.3b.4f.5d., 1b.2i.3b.4f.5d.,
1f.2i.3b.4f.5d., 1h.2i.3b.4f.5d., 1j.2i.3b.4f.5d., 1p.2i.3b.4f.5d.,
1a.2m.3b.4f.5d., 1b.2m.3b.4f.5d., 1f.2m.3b.4f.5d., 1h.2m.3b.4f.5d.,
1j.2m.3b.4f.5d., 1p.2m.3b.4f.5d., 1a.2o.3b.4f.5d., 1b.2o.3b.4f.5d.,
1f.2o.3b.4f.5d., 1h.2o.3b.4f.5d., 1j.2o.3b.4f.5d., 1p.2o.3b.4f.5d.,
1a.2u.3b.4f.5d., 1b.2u.3b.4f.5d., 1f.2u.3b.4f.5d., 1h.2u.3b.4f.5d.,
1j.2u.3b.4f.5d., 1p.2u.3b.4f.5d., 1a.2y.3b.4f.5d., 1b.2y.3b.4f.5d.,
1f.2y.3b.4f.5d., 1h.2y.3b.4f.5d., 1j.2y.3b.4f.5d., 1p.2y.3b.4f.5d.,
1a.2a.3e.4f.5d., 1b.2a.3e.4f.5d., 1f.2a.3e.4f.5d., 1h.2a.3e.4f.5d.,
1j.2a.3e.4f.5d., 1p.2a.3e.4f.5d., 1a.2b.3e.4f.5d., 1b.2b.3e.4f.5d.,
1f.2b.3e.4f.5d., 1h.2b.3e.4f.5d., 1j.2b.3e.4f.5d., 1p.2b.3e.4f.5d.,
1a.2e.3e.4f.5d., 1b.2e.3e.4f.5d., 1f.2e.3e.4f.5d., 1h.2e.3e.4f.5d.,
1j.2e.3e.4f.5d., 1p.2e.3e.4f.5d., 1a.2f.3e.4f.5d., 1b.2f.3e.4f.5d.,
1f.2f.3e.4f.5d., 1h.2f.3e.4f.5d., 1j.2f.3e.4f.5d., 1p.2f.3e.4f.5d.,
1a.2i.3e.4f.5d., 1b.2i.3e.4f.5d., 1f.2i.3e.4f.5d., 1h.2i.3e.4f.5d.,
1j.2i.3e.4f.5d., 1p.2i.3e.4f.5d., 1a.2m.3e.4f.5d., 1b.2m.3e.4f.5d.,
1f.2m.3e.4f.5d., 1h.2m.3e.4f.5d., 1j.2m.3e.4f.5d., 1p.2m.3e.4f.5d.,
1a.2o.3e.4f.5d., 1b.2o.3e.4f.5d., 1f.2o.3e.4f.5d., 1h.2o.3e.4f.5d.,
1j.2o.3e.4f.5d., 1p.2o.3e.4f.5d., 1a.2u.3e.4f.5d., 1b.2u.3e.4f.5d.,
1f.2u.3e.4f.5d., 1h.2u.3e.4f.5d., 1j.2u.3e.4f.5d., 1p.2u.3e.4f.5d.,
1a.2y.3e.4f.5d., 1b.2y.3e.4f.5d., 1f.2y.3e.4f.5d., 1h.2y.3e.4f.5d.,
1j.2y.3e.4f.5d., 1p.2y.3e.4f.5d., 1a.2a.3g.4f.5d., 1b.2a.3g.4f.5d.,
1f.2a.3g.4f.5d., 1h.2a.3g.4f.5d., 1j.2a.3g.4f.5d., 1p.2a.3g.4f.5d.,
1a.2b.3g.4f.5d., 1b.2b.3g.4f.5d., 1f.2b.3g.4f.5d., 1h.2b.3g.4f.5d.,
1j.2b.3g.4f.5d., 1p.2b.3g.4f.5d., 1a.2e.3g.4f.5d., 1b.2e.3g.4f.5d.,
1f.2e.3g.4f.5d., 1h.2e.3g.4f.5d., 1j.2e.3g.4f.5d., 1p.2e.3g.4f.5d.,
1a.2f.3g.4f.5d., 1b.2f.3g.4f.5d., 1f.2f.3g.4f.5d., 1h.2f.3g.4f.5d.,
1j.2f.3g.4f.5d., 1p.2f.3g.4f.5d., 1a.2i.3g.4f.5d., 1b.2i.3g.4f.5d.,
1f.2i.3g.4f.5d., 1h.2i.3g.4f.5d., 1j.2i.3g.4f.5d., 1p.2i.3g.4f.5d.,
1a.2m.3g.4f.5d., 1b.2m.3g.4f.5d., 1f.2m.3g.4f.5d., 1h.2m.3g.4f.5d.,
1j.2m.3g.4f.5d., 1p.2m.3g.4f.5d., 1a.2o.3g.4f.5d., 1b.2o.3g.4f.5d.,
1f.2o.3g.4f.5d., 1h.2o.3g.4f.5d., 1j.2o.3g.4f.5d., 1p.2o.3g.4f.5d.,
1a.2u.3g.4f.5d., 1b.2u.3g.4f.5d., 1f.2u.3g.4f.5d., 1h.2u.3g.4f.5d.,
1j.2u.3g.4f.5d., 1p.2u.3g.4f.5d., 1a.2y.3g.4f.5d., 1b.2y.3g.4f.5d.,
1f.2y.3g.4f.5d., 1h.2y.3g.4f.5d., 1j.2y.3g.4f.5d., 1p.2y.3g.4f.5d.,
1a.2a.3a.4g.5d., 1b.2a.3a.4g.5d., 1f.2a.3a.4g.5d., 1h.2a.3a.4g.5d.,
1j.2a.3a.4g.5d., 1p.2a.3a.4g.5d., 1a.2b.3a.4g.5d., 1b.2b.3a.4g.5d.,
1f.2b.3a.4g.5d., 1h.2b.3a.4g.5d., 1j.2b.3a.4g.5d., 1p.2b.3a.4g.5d.,
1a.2e.3a.4g.5d., 1b.2e.3a.4g.5d., 1f.2e.3a.4g.5d., 1h.2e.3a.4g.5d.,
1j.2e.3a.4g.5d., 1p.2e.3a.4g.5d., 1a.2f.3a.4g.5d., 1b.2f.3a.4g.5d.,
1f.2f.3a.4g.5d., 1h.2f.3a.4g.5d., 1j.2f.3a.4g.5d., 1p.2f.3a.4g.5d.,
1a.2i.3a.4g.5d., 1b.2i.3a.4g.5d., 1f.2i.3a.4g.5d., 1h.2i.3a.4g.5d.,
1j.2i.3a.4g.5d., 1p.2i.3a.4g.5d., 1a.2m.3a.4g.5d., 1b.2m.3a.4g.5d.,
1f.2m.3a.4g.5d., 1h.2m.3a.4g.5d., 1j.2m.3a.4g.5d., 1p.2m.3a.4g.5d.,
1a.2o.3a.4g.5d., 1b.2o.3a.4g.5d., 1f.2o.3a.4g.5d.,
1h.2o.3a.4g.5d.,
1j.2o.3a.4g.5d., 1p.2o.3a.4g.5d., 1a.2u.3a.4g.5d., 1b.2u.3a.4g.5d.,
1f.2u.3a.4g.5d., 1h.2u.3a.4g.5d., 1j.2u.3a.4g.5d., 1p.2u.3a.4g.5d.,
1a.2y.3a.4g.5d., 1b.2y.3a.4g.5d., 1f.2y.3a.4g.5d., 1h.2y.3a.4g.5d.,
1j.2y.3a.4g.5d., 1p.2y.3a.4g.5d., 1a.2a.3b.4g.5d., 1b.2a.3b.4g.5d.,
1f.2a.3b.4g.5d., 1h.2a.3b.4g.5d., 1j.2a.3b.4g.5d., 1p.2a.3b.4g.5d.,
1a.2b.3b.4g.5d., 1b.2b.3b.4g.5d., 1f.2b.3b.4g.5d., 1h.2b.3b.4g.5d.,
1j.2b.3b.4g.5d., 1p.2b.3b.4g.5d., 1a.2e.3b.4g.5d., 1b.2e.3b.4g.5d.,
1f.2e.3b.4g.5d., 1h.2e.3b.4g.5d., 1j.2e.3b.4g.5d., 1p.2e.3b.4g.5d.,
1a.2f.3b.4g.5d., 1b.2f.3b.4g.5d., 1f.2f.3b.4g.5d., 1h.2f.3b.4g.5d.,
1j.2f.3b.4g.5d., 1p.2f.3b.4g.5d., 1a.2i.3b.4g.5d., 1b.2i.3b.4g.5d.,
1f.2i.3b.4g.5d., 1h.2i.3b.4g.5d., 1j.2i.3b.4g.5d., 1p.2i.3b.4g.5d.,
1a.2m.3b.4g.5d., 1b.2m.3b.4g.5d., 1f.2m.3b.4g.5d., 1h.2m.3b.4g.5d.,
1j.2m.3b.4g.5d., 1p.2m.3b.4g.5d., 1a.2o.3b.4g.5d., 1b.2o.3b.4g.5d.,
1f.2o.3b.4g.5d., 1h.2o.3b.4g.5d., 1j.2o.3b.4g.5d., 1p.2o.3b.4g.5d.,
1a.2u.3b.4g.5d., 1b.2u.3b.4g.5d., 1f.2u.3b.4g.5d., 1h.2u.3b.4g.5d.,
1j.2u.3b.4g.5d., 1p.2u.3b.4g.5d., 1a.2y.3b.4g.5d., 1b.2y.3b.4g.5d.,
1f.2y.3b.4g.5d., 1h.2y.3b.4g.5d., 1j.2y.3b.4g.5d., 1p.2y.3b.4g.5d.,
1a.2a.3e.4g.5d., 1b.2a.3e.4g.5d., 1f.2a.3e.4g.5d., 1h.2a.3e.4g.5d.,
1j.2a.3e.4g.5d., 1p.2a.3e.4g.5d., 1a.2b.3e.4g.5d., 1b.2b.3e.4g.5d.,
1f.2b.3e.4g.5d., 1h.2b.3e.4g.5d., 1j.2b.3e.4g.5d., 1p.2b.3e.4g.5d.,
1a.2e.3e.4g.5d., 1b.2e.3e.4g.5d., 1f.2e.3e.4g.5d., 1h.2e.3e.4g.5d.,
1j.2e.3e.4g.5d., 1p.2e.3e.4g.5d., 1a.2f.3e.4g.5d., 1b.2f.3e.4g.5d.,
1f.2f.3e.4g.5d., 1h.2f.3e.4g.5d., 1j.2f.3e.4g.5d., 1p.2f.3e.4g.5d.,
1a.2i.3e.4g.5d., 1b.2i.3e.4g.5d., 1f.2i.3e.4g.5d., 1h.2i.3e.4g.5d.,
1j.2i.3e.4g.5d., 1p.2i.3e.4g.5d., 1a.2m.3e.4g.5d., 1b.2m.3e.4g.5d.,
1f.2m.3e.4g.5d., 1h.2m.3e.4g.5d., 1j.2m.3e.4g.5d., 1p.2m.3e.4g.5d.,
1a.2o.3e.4g.5d., 1b.2o.3e.4g.5d., 1f.2o.3e.4g.5d., 1h.2o.3e.4g.5d.,
1j.2o.3e.4g.5d., 1p.2o.3e.4g.5d., 1a.2u.3e.4g.5d., 1b.2u.3e.4g.5d.,
1f.2u.3e.4g.5d., 1h.2u.3e.4g.5d., 1j.2u.3e.4g.5d., 1p.2u.3e.4g.5d.,
1a.2y.3e.4g.5d., 1b.2y.3e.4g.5d., 1f.2y.3e.4g.5d., 1h.2y.3e.4g.5d.,
1j.2y.3e.4g.5d., 1p.2y.3e.4g.5d., 1a.2a.3g.4g.5d., 1b.2a.3g.4g.5d.,
1f.2a.3g.4g.5d., 1h.2a.3g.4g.5d., 1j.2a.3g.4g.5d., 1p.2a.3g.4g.5d.,
1a.2b.3g.4g.5d., 1b.2b.3g.4g.5d., 1f.2b.3g.4g.5d., 1h.2b.3g.4g.5d.,
1j.2b.3g.4g.5d., 1p.2b.3g.4g.5d., 1a.2e.3g.4g.5d., 1b.2e.3g.4g.5d.,
1f.2e.3g.4g.5d., 1h.2e.3g.4g.5d., 1j.2e.3g.4g.5d., 1p.2e.3g.4g.5d.,
1a.2f.3g.4g.5d., 1b.2f.3g.4g.5d., 1f.2f.3g.4g.5d., 1h.2f.3g.4g.5d.,
1j.2f.3g.4g.5d., 1p.2f.3g.4g.5d., 1a.2i.3g.4g.5d., 1b.2i.3g.4g.5d.,
1f.2i.3g.4g.5d., 1h.2i.3g.4g.5d., 1j.2i.3g.4g.5d., 1p.2i.3g.4g.5d.,
1a.2m.3g.4g.5d., 1b.2m.3g.4g.5d., 1f.2m.3g.4g.5d., 1h.2m.3g.4g.5d.,
1j.2m.3g.4g.5d., 1p.2m.3g.4g.5d., 1a.2o.3g.4g.5d., 1b.2o.3g.4g.5d.,
1f.2o.3g.4g.5d., 1h.2o.3g.4g.5d., 1j.2o.3g.4g.5d., 1p.2o.3g.4g.5d.,
1a.2u.3g.4g.5d., 1b.2u.3g.4g.5d., 1f.2u.3g.4g.5d., 1h.2u.3g.4g.5d.,
1j.2u.3g.4g.5d., 1p.2u.3g.4g.5d., 1a.2y.3g.4g.5d., 1b.2y.3g.4g.5d.,
1f.2y.3g.4g.5d., 1h.2y.3g.4g.5d., 1j.2y.3g.4g.5d., 1p.2y.3g.4g.5d.,
1a.2a.3a.4h.5d., 1b.2a.3a.4h.5d., 1f.2a.3a.4h.5d., 1h.2a.3a.4h.5d.,
1j.2a.3a.4h.5d., 1p.2a.3a.4h.5d., 1a.2b.3a.4h.5d., 1b.2b.3a.4h.5d.,
1f.2b.3a.4h.5d., 1h.2b.3a.4h.5d., 1j.2b.3a.4h.5d., 1p.2b.3a.4h.5d.,
1a.2e.3a.4h.5d., 1b.2e.3a.4h.5d., 1f.2e.3a.4h.5d., 1h.2e.3a.4h.5d.,
1j.2e.3a.4h.5d., 1p.2e.3a.4h.5d., 1a.2f.3a.4h.5d., 1b.2f.3a.4h.5d.,
1f.2f.3a.4h.5d., 1h.2f.3a.4h.5d., 1j.2f.3a.4h.5d., 1p.2f.3a.4h.5d.,
1a.2i.3a.4h.5d., 1b.2i.3a.4h.5d., 1f.2i.3a.4h.5d., 1h.2i.3a.4h.5d.,
1j.2i.3a.4h.5d., 1p.2i.3a.4h.5d., 1a.2m.3a.4h.5d., 1b.2m.3a.4h.5d.,
1f.2m.3a.4h.5d., 1h.2m.3a.4h.5d., 1j.2m.3a.4h.5d., 1p.2m.3a.4h.5d.,
1a.2o.3a.4h.5d., 1b.2o.3a.4h.5d., 1f.2o.3a.4h.5d., 1h.2o.3a.4h.5d.,
1j.2o.3a.4h.5d., 1p.2o.3a.4h.5d., 1a.2u.3a.4h.5d., 1b.2u.3a.4h.5d.,
1f.2u.3a.4h.5d., 1h.2u.3a.4h.5d., 1j.2u.3a.4h.5d., 1p.2u.3a.4h.5d.,
1a.2y.3a.4h.5d., 1b.2y.3a.4h.5d., 1f.2y.3a.4h.5d., 1h.2y.3a.4h.5d.,
1j.2y.3a.4h.5d., 1p.2y.3a.4h.5d., 1a.2a.3b.4h.5d., 1b.2a.3b.4h.5d.,
1f.2a.3b.4h.5d., 1h.2a.3b.4h.5d., 1j.2a.3b.4h.5d., 1p.2a.3b.4h.5d.,
1a.2b.3b.4h.5d., 1b.2b.3b.4h.5d., 1f.2b.3b.4h.5d., 1h.2b.3b.4h.5d.,
1j.2b.3b.4h.5d., 1p.2b.3b.4h.5d., 1a.2e.3b.4h.5d., 1b.2e.3b.4h.5d.,
1f.2e.3b.4h.5d., 1h.2e.3b.4h.5d., 1j.2e.3b.4h.5d., 1p.2e.3b.4h.5d.,
1a.2f.3b.4h.5d., 1b.2f.3b.4h.5d., 1f.2f.3b.4h.5d., 1h.2f.3b.4h.5d.,
1j.2f.3b.4h.5d., 1p.2f.3b.4h.5d., 1a.2i.3b.4h.5d., 1b.2i.3b.4h.5d.,
1f.2i.3b.4h.5d., 1h.2i.3b.4h.5d., 1j.2i.3b.4h.5d., 1p.2i.3b.4h.5d.,
1a.2m.3b.4h.5d., 1b.2m.3b.4h.5d., 1f.2m.3b.4h.5d., 1h.2m.3b.4h.5d.,
1j.2m.3b.4h.5d., 1p.2m.3b.4h.5d., 1a.2o.3b.4h.5d., 1b.2o.3b.4h.5d.,
1f.2o.3b.4h.5d., 1h.2o.3b.4h.5d., 1j.2o.3b.4h.5d., 1p.2o.3b.4h.5d.,
1a.2u.3b.4h.5d., 1b.2u.3b.4h.5d., 1f.2u.3b.4h.5d., 1h.2u.3b.4h.5d.,
1j.2u.3b.4h.5d., 1p.2u.3b.4h.5d., 1a.2y.3b.4h.5d., 1b.2y.3b.4h.5d.,
1f.2y.3b.4h.5d., 1h.2y.3b.4h.5d., 1j.2y.3b.4h.5d., 1p.2y.3b.4h.5d.,
1a.2a.3e.4h.5d., 1b.2a.3e.4h.5d., 1f.2a.3e.4h.5d., 1h.2a.3e.4h.5d.,
1j.2a.3e.4h.5d., 1p.2a.3e.4h.5d., 1a.2b.3e.4h.5d., 1b.2b.3e.4h.5d.,
1f.2b.3e.4h.5d., 1h.2b.3e.4h.5d., 1j.2b.3e.4h.5d., 1p.2b.3e.4h.5d.,
1a.2e.3e.4h.5d., 1b.2e.3e.4h.5d., 1f.2e.3e.4h.5d., 1h.2e.3e.4h.5d.,
1j.2e.3e.4h.5d., 1p.2e.3e.4h.5d., 1a.2f.3e.4h.5d., 1b.2f.3e.4h.5d.,
1f.2f.3e.4h.5d., 1h.2f.3e.4h.5d., 1j.2f.3e.4h.5d., 1p.2f.3e.4h.5d.,
1a.2i.3e.4h.5d., 1b.2i.3e.4h.5d., 1f.2i.3e.4h.5d., 1h.2i.3e.4h.5d.,
1j.2i.3e.4h.5d., 1p.2i.3e.4h.5d., 1a.2m.3e.4h.5d., 1b.2m.3e.4h.5d.,
1f.2m.3e.4h.5d., 1h.2m.3e.4h.5d., 1j.2m.3e.4h.5d., 1p.2m.3e.4h.5d.,
1a.2o.3e.4h.5d., 1b.2o.3e.4h.5d., 1f.2o.3e.4h.5d., 1h.2o.3e.4h.5d.,
1j.2o.3e.4h.5d., 1p.2o.3e.4h.5d., 1a.2u.3e.4h.5d., 1b.2u.3e.4h.5d.,
1f.2u.3e.4h.5d., 1h.2u.3e.4h.5d., 1j.2u.3e.4h.5d., 1p.2u.3e.4h.5d.,
1a.2y.3e.4h.5d., 1b.2y.3e.4h.5d., 1f.2y.3e.4h.5d., 1h.2y.3e.4h.5d.,
1j.2y.3e.4h.5d., 1p.2y.3e.4h.5d., 1a.2a.3g.4h.5d., 1b.2a.3g.4h.5d.,
1f.2a.3g.4h.5d., 1h.2a.3g.4h.5d., 1j.2a.3g.4h.5d., 1p.2a.3g.4h.5d.,
1a.2b.3g.4h.5d., 1b.2b.3g.4h.5d., 1f.2b.3g.4h.5d., 1h.2b.3g.4h.5d.,
1j.2b.3g.4h.5d., 1p.2b.3g.4h.5d., 1a.2e.3g.4h.5d., 1b.2e.3g.4h.5d.,
1f.2e.3g.4h.5d., 1h.2e.3g.4h.5d., 1j.2e.3g.4h.5d., 1p.2e.3g.4h.5d.,
1a.2f.3g.4h.5d., 1b.2f.3g.4h.5d., 1f.2f.3g.4h.5d., 1h.2f.3g.4h.5d.,
1j.2f.3g.4h.5d., 1p.2f.3g.4h.5d., 1a.2i.3g.4h.5d., 1b.2i.3g.4h.5d.,
1f.2i.3g.4h.5d., 1h.2i.3g.4h.5d., 1j.2i.3g.4h.5d., 1p.2i.3g.4h.5d.,
1a.2m.3g.4h.5d., 1b.2m.3g.4h.5d., 1f.2m.3g.4h.5d., 1h.2m.3g.4h.5d.,
1j.2m.3g.4h.5d., 1p.2m.3g.4h.5d., 1a.2o.3g.4h.5d., 1b.2o.3g.4h.5d.,
1f.2o.3g.4h.5d., 1h.2o.3g.4h.5d., 1j.2o.3g.4h.5d., 1p.2o.3g.4h.5d.,
1a.2u.3g.4h.5d., 1b.2u.3g.4h.5d., 1f.2u.3g.4h.5d., 1h.2u.3g.4h.5d.,
1j.2u.3g.4h.5d., 1p.2u.3g.4h.5d., 1a.2y.3g.4h.5d., 1b.2y.3g.4h.5d.,
1f.2y.3g.4h.5d., 1h.2y.3g.4h.5d., 1j.2y.3g.4h.5d., 1p.2y.3g.4h.5d.,
1a.2a.3a.4i.5d., 1b.2a.3a.4i.5d., 1f.2a.3a.4i.5d., 1h.2a.3a.4i.5d.,
1j.2a.3a.4i.5d., 1p.2a.3a.4i.5d., 1a.2b.3a.4i.5d., 1b.2b.3a.4i.5d.,
1f.2b.3a.4i.5d., 1h.2b.3a.4i.5d., 1j.2b.3a.4i.5d., 1p.2b.3a.4i.5d.,
1a.2e.3a.4i.5d., 1b.2e.3a.4i.5d., 1f.2e.3a.4i.5d., 1h.2e.3a.4i.5d.,
1j.2e.3a.4i.5d., 1p.2e.3a.4i.5d., 1a.2f.3a.4i.5d., 1b.2f.3a.4i.5d.,
1f.2f.3a.4i.5d., 1h.2f.3a.4i.5d., 1j.2f.3a.4i.5d., 1p.2f.3a.4i.5d.,
1a.2i.3a.4i.5d., 1b.2i.3a.4i.5d., 1f.2i.3a.4i.5d., 1h.2i.3a.4i.5d.,
1j.2i.3a.4i.5d., 1p.2i.3a.4i.5d., 1a.2m.3a.4i.5d., 1b.2m.3a.4i.5d.,
1f.2m.3a.4i.5d., 1h.2m.3a.4i.5d., 1j.2m.3a.4i.5d., 1p.2m.3a.4i.5d.,
1a.2o.3a.4i.5d., 1b.2o.3a.4i.5d., 1f.2o.3a.4i.5d., 1h.2o.3a.4i.5d.,
1j.2o.3a.4i.5d., 1p.2o.3a.4i.5d., 1a.2u.3a.4i.5d., 1b.2u.3a.4i.5d.,
1f.2u.3a.4i.5d., 1h.2u.3a.4i.5d., 1j.2u.3a.4i.5d., 1p.2u.3a.4i.5d.,
1a.2y.3a.4i.5d., 1b.2y.3a.4i.5d., 1f.2y.3a.4i.5d., 1h.2y.3a.4i.5d.,
1j.2y.3a.4i.5d., 1p.2y.3a.4i.5d., 1a.2a.3b.4i.5d., 1b.2a.3b.4i.5d.,
1f.2a.3b.4i.5d., 1h.2a.3b.4i.5d., 1j.2a.3b.4i.5d., 1p.2a.3b.4i.5d.,
1a.2b.3b.4i.5d., 1b.2b.3b.4i.5d., 1f.2b.3b.4i.5d., 1h.2b.3b.4i.5d.,
1j.2b.3b.4i.5d., 1p.2b.3b.4i.5d., 1a.2e.3b.4i.5d., 1b.2e.3b.4i.5d.,
1f.2e.3b.4i.5d., 1h.2e.3b.4i.5d., 1j.2e.3b.4i.5d., 1p.2e.3b.4i.5d.,
1a.2f.3b.4i.5d., 1b.2f.3b.4i.5d., 1f.2f.3b.4i.5d., 1h.2f.3b.4i.5d.,
1j.2f.3b.4i.5d., 1p.2f.3b.4i.5d., 1a.2i.3b.4i.5d., 1b.2i.3b.4i.5d.,
1f.2i.3b.4i.5d., 1h.2i.3b.4i.5d., 1j.2i.3b.4i.5d., 1p.2i.3b.4i.5d.,
1a.2m.3b.4i.5d., 1b.2m.3b.4i.5d., 1f.2m.3b.4i.5d., 1h.2m.3b.4i.5d.,
1j.2m.3b.4i.5d., 1p.2m.3b.4i.5d., 1a.2o.3b.4i.5d., 1b.2o.3b.4i.5d.,
1f.2o.3b.4i.5d., 1h.2o.3b.4i.5d., 1j.2o.3b.4i.5d., 1p.2o.3b.4i.5d.,
1a.2u.3b.4i.5d., 1b.2u.3b.4i.5d., 1f.2u.3b.4i.5d., 1h.2u.3b.4i.5d.,
1j.2u.3b.4i.5d., 1p.2u.3b.4i.5d., 1a.2y.3b.4i.5d., 1b.2y.3b.4i.5d.,
1f.2y.3b.4i.5d., 1h.2y.3b.4i.5d., 1j.2y.3b.4i.5d., 1p.2y.3b.4i.5d.,
1a.2a.3e.4i.5d., 1b.2a.3e.4i.5d., 1f.2a.3e.4i.5d., 1h.2a.3e.4i.5d.,
1j.2a.3e.4i.5d., 1p.2a.3e.4i.5d., 1a.2b.3e.4i.5d., 1b.2b.3e.4i.5d.,
1f.2b.3e.4i.5d., 1h.2b.3e.4i.5d., 1j.2b.3e.4i.5d., 1p.2b.3e.4i.5d.,
1a.2e.3e.4i.5d., 1b.2e.3e.4i.5d., 1f.2e.3e.4i.5d., 1h.2e.3e.4i.5d.,
1j.2e.3e.4i.5d., 1p.2e.3e.4i.5d., 1a.2f.3e.4i.5d., 1b.2f.3e.4i.5d.,
1f.2f.3e.4i.5d., 1h.2f.3e.4i.5d., 1j.2f.3e.4i.5d., 1p.2f.3e.4i.5d.,
1a.2i.3e.4i.5d., 1b.2i.3e.4i.5d., 1f.2i.3e.4i.5d., 1h.2i.3e.4i.5d.,
1j.2i.3e.4i.5d., 1p.2i.3e.4i.5d., 1a.2m.3e.4i.5d., 1b.2m.3e.4i.5d.,
1f.2m.3e.4i.5d., 1h.2m.3e.4i.5d., 1j.2m.3e.4i.5d., 1p.2m.3e.4i.5d.,
1a.2o.3e.4i.5d., 1b.2o.3e.4i.5d., 1f.2o.3e.4i.5d., 1h.2o.3e.4i.5d.,
1j.2o.3e.4i.5d., 1p.2o.3e.4i.5d., 1a.2u.3e.4i.5d., 1b.2u.3e.4i.5d.,
1f.2u.3e.4i.5d., 1h.2u.3e.4i.5d., 1j.2u.3e.4i.5d., 1p.2u.3e.4i.5d.,
1a.2y.3e.4i.5d., 1b.2y.3e.4i.5d., 1f.2y.3e.4i.5d., 1h.2y.3e.4i.5d.,
1j.2y.3e.4i.5d., 1p.2y.3e.4i.5d., 1a.2a.3g.4i.5d., 1b.2a.3g.4i.5d.,
1f.2a.3g.4i.5d., 1h.2a.3g.4i.5d., 1j.2a.3g.4i.5d., 1p.2a.3g.4i.5d.,
1a.2b.3g.4i.5d., 1b.2b.3g.4i.5d., 1f.2b.3g.4i.5d., 1h.2b.3g.4i.5d.,
1j.2b.3g.4i.5d., 1p.2b.3g.4i.5d., 1a.2e.3g.4i.5d., 1b.2e.3g.4i.5d.,
1f.2e.3g.4i.5d., 1h.2e.3g.4i.5d., 1j.2e.3g.4i.5d., 1p.2e.3g.4i.5d.,
1a.2f.3g.4i.5d., 1b.2f.3g.4i.5d., 1f.2f.3g.4i.5d., 1h.2f.3g.4i.5d.,
1j.2f.3g.4i.5d., 1p.2f.3g.4i.5d., 1a.2i.3g.4i.5d., 1b.2i.3g.4i.5d.,
1f.2i.3g.4i.5d., 1h.2i.3g.4i.5d., 1j.2i.3g.4i.5d., 1p.2i.3g.4i.5d.,
1a.2m.3g.4i.5d., 1b.2m.3g.4i.5d., 1f.2m.3g.4i.5d., 1h.2m.3g.4i.5d.,
1j.2m.3g.4i.5d., 1p.2m.3g.4i.5d., 1a.2o.3g.4i.5d., 1b.2o.3g.4i.5d.,
1f.2o.3g.4i.5d., 1h.2o.3g.4i.5d., 1j.2o.3g.4i.5d., 1p.2o.3g.4i.5d.,
1a.2u.3g.4i.5d., 1b.2u.3g.4i.5d., 1f.2u.3g.4i.5d., 1h.2u.3g.4i.5d.,
1j.2u.3g.4i.5d., 1p.2u.3g.4i.5d., 1a.2y.3g.4i.5d., 1b.2y.3g.4i.5d.,
1f.2y.3g.4i.5d., 1h.2y.3g.4i.5d., 1j.2y.3g.4i.5d., 1p.2y.3g.4i.5d.,
1a.2a.3a.4a.5f., 1b.2a.3a.4a.5f., 1f.2a.3a.4a.5f., 1h.2a.3a.4a.5f.,
1j.2a.3a.4a.5f., 1p.2a.3a.4a.5f., 1a.2b.3a.4a.5f., 1b.2b.3a.4a.5f.,
1f.2b.3a.4a.5f., 1h.2b.3a.4a.5f., 1j.2b.3a.4a.5f., 1p.2b.3a.4a.5f.,
1a.2e.3a.4a.5f., 1b.2e.3a.4a.5f., 1f.2e.3a.4a.5f., 1h.2e.3a.4a.5f.,
1j.2e.3a.4a.5f., 1p.2e.3a.4a.5f., 1a.2f.3a.4a.5f., 1b.2f.3a.4a.5f.,
1f.2f.3a.4a.5f., 1h.2f.3a.4a.5f., 1j.2f.3a.4a.5f., 1p.2f.3a.4a.5f.,
1a.2i.3a.4a.5f., 1b.2i.3a.4a.5f., 1f.2i.3a.4a.5f., 1h.2i.3a.4a.5f.,
1j.2i.3a.4a.5f., 1p.2i.3a.4a.5f., 1a.2m.3a.4a.5f., 1b.2m.3a.4a.5f.,
1f.2m.3a.4a.5f., 1h.2m.3a.4a.5f., 1j.2m.3a.4a.5f., 1p.2m.3a.4a.5f.,
1a.2o.3a.4a.5f., 1b.2o.3a.4a.5f., 1f.2o.3a.4a.5f., 1h.2o.3a.4a.5f.,
1j.2o.3a.4a.5f., 1p.2o.3a.4a.5f., 1a.2u.3a.4a.5f., 1b.2u.3a.4a.5f.,
1f.2u.3a.4a.5f., 1h.2u.3a.4a.5f., 1j.2u.3a.4a.5f., 1p.2u.3a.4a.5f.,
1a.2y.3a.4a.5f., 1b.2y.3a.4a.5f., 1f.2y.3a.4a.5f., 1h.2y.3a.4a.5f.,
1j.2y.3a.4a.5f., 1p.2y.3a.4a.5f., 1a.2a.3b.4a.5f., 1b.2a.3b.4a.5f.,
1f.2a.3b.4a.5f., 1h.2a.3b.4a.5f., 1j.2a.3b.4a.5f., 1p.2a.3b.4a.5f.,
1a.2b.3b.4a.5f., 1b.2b.3b.4a.5f., 1f.2b.3b.4a.5f., 1h.2b.3b.4a.5f.,
1j.2b.3b.4a.5f., 1p.2b.3b.4a.5f., 1a.2e.3b.4a.5f., 1b.2e.3b.4a.5f.,
1f.2e.3b.4a.5f., 1h.2e.3b.4a.5f., 1j.2e.3b.4a.5f., 1p.2e.3b.4a.5f.,
1a.2f.3b.4a.5f., 1b.2f.3b.4a.5f., 1f.2f.3b.4a.5f., 1h.2f.3b.4a.5f.,
1j.2f.3b.4a.5f., 1p.2f.3b.4a.5f., 1a.2i.3b.4a.5f., 1b.2i.3b.4a.5f.,
1f.2i.3b.4a.5f., 1h.2i.3b.4a.5f., 1j.2i.3b.4a.5f., 1p.2i.3b.4a.5f.,
1a.2m.3b.4a.5f., 1b.2m.3b.4a.5f., 1f.2m.3b.4a.5f., 1h.2m.3b.4a.5f.,
1j.2m.3b.4a.5f., 1p.2m.3b.4a.5f., 1a.2o.3b.4a.5f., 1b.2o.3b.4a.5f.,
1f.2o.3b.4a.5f., 1h.2o.3b.4a.5f., 1j.2o.3b.4a.5f., 1p.2o.3b.4a.5f.,
1a.2u.3b.4a.5f., 1b.2u.3b.4a.5f., 1f.2u.3b.4a.5f., 1h.2u.3b.4a.5f.,
1j.2u.3b.4a.5f., 1p.2u.3b.4a.5f., 1a.2y.3b.4a.5f., 1b.2y.3b.4a.5f.,
1f.2y.3b.4a.5f., 1h.2y.3b.4a.5f., 1j.2y.3b.4a.5f., 1p.2y.3b.4a.5f.,
1a.2a.3e.4a.5f., 1b.2a.3e.4a.5f., 1f.2a.3e.4a.5f., 1h.2a.3e.4a.5f.,
1j.2a.3e.4a.5f., 1p.2a.3e.4a.5f., 1a.2b.3e.4a.5f., 1b.2b.3e.4a.5f.,
1f.2b.3e.4a.5f., 1h.2b.3e.4a.5f., 1j.2b.3e.4a.5f., 1p.2b.3e.4a.5f.,
1a.2e.3e.4a.5f., 1b.2e.3e.4a.5f., 1f.2e.3e.4a.5f., 1h.2e.3e.4a.5f.,
1j.2e.3e.4a.5f., 1p.2e.3e.4a.5f., 1a.2f.3e.4a.5f., 1b.2f.3e.4a.5f.,
1f.2f.3e.4a.5f., 1h.2f.3e.4a.5f., 1j.2f.3e.4a.5f., 1p.2f.3e.4a.5f.,
1a.2i.3e.4a.5f., 1b.2i.3e.4a.5f., 1f.2i.3e.4a.5f., 1h.2i.3e.4a.5f.,
1j.2i.3e.4a.5f., 1p.2i.3e.4a.5f., 1a.2m.3e.4a.5f., 1b.2m.3e.4a.5f.,
1f.2m.3e.4a.5f., 1h.2m.3e.4a.5f., 1j.2m.3e.4a.5f., 1p.2m.3e.4a.5f.,
1a.2o.3e.4a.5f., 1b.2o.3e.4a.5f., 1f.2o.3e.4a.5f., 1h.2o.3e.4a.5f.,
1j.2o.3e.4a.5f., 1p.2o.3e.4a.5f., 1a.2u.3e.4a.5f., 1b.2u.3e.4a.5f.,
1f.2u.3e.4a.5f., 1h.2u.3e.4a.5f., 1j.2u.3e.4a.5f., 1p.2u.3e.4a.5f.,
1a.2y.3e.4a.5f., 1b.2y.3e.4a.5f., 1f.2y.3e.4a.5f., 1h.2y.3e.4a.5f.,
1j.2y.3e.4a.5f., 1p.2y.3e.4a.5f., 1a.2a.3g.4a.5f., 1b.2a.3g.4a.5f.,
1f.2a.3g.4a.5f., 1h.2a.3g.4a.5f., 1j.2a.3g.4a.5f., 1p.2a.3g.4a.5f.,
1a.2b.3g.4a.5f., 1b.2b.3g.4a.5f., 1f.2b.3g.4a.5f., 1h.2b.3g.4a.5f.,
1j.2b.3g.4a.5f., 1p.2b.3g.4a.5f., 1a.2e.3g.4a.5f., 1b.2e.3g.4a.5f.,
1f.2e.3g.4a.5f., 1h.2e.3g.4a.5f., 1j.2e.3g.4a.5f., 1p.2e.3g.4a.5f.,
1a.2f.3g.4a.5f., 1b.2f.3g.4a.5f., 1f.2f.3g.4a.5f., 1h.2f.3g.4a.5f.,
1j.2f.3g.4a.5f., 1p.2f.3g.4a.5f., 1a.2i.3g.4a.5f., 1b.2i.3g.4a.5f.,
1f.2i.3g.4a.5f., 1h.2i.3g.4a.5f., 1j.2i.3g.4a.5f., 1p.2i.3g.4a.5f.,
1a.2m.3g.4a.5f., 1b.2m.3g.4a.5f., 1f.2m.3g.4a.5f., 1h.2m.3g.4a.5f.,
1j.2m.3g.4a.5f., 1p.2m.3g.4a.5f., 1a.2o.3g.4a.5f., 1b.2o.3g.4a.5f.,
1f.2o.3g.4a.5f., 1h.2o.3g.4a.5f., 1j.2o.3g.4a.5f., 1p.2o.3g.4a.5f.,
1a.2u.3g.4a.5f., 1b.2u.3g.4a.5f., 1f.2u.3g.4a.5f., 1h.2u.3g.4a.5f.,
1j.2u.3g.4a.5f., 1p.2u.3g.4a.5f., 1a.2y.3g.4a.5f., 1b.2y.3g.4a.5f.,
1f.2y.3g.4a.5f., 1h.2y.3g.4a.5f., 1j.2y.3g.4a.5f., 1p.2y.3g.4a.5f.,
1a.2a.3a.4d.5f., 1b.2a.3a.4d.5f., 1f.2a.3a.4d.5f., 1h.2a.3a.4d.5f.,
1j.2a.3a.4d.5f., 1p.2a.3a.4d.5f., 1a.2b.3a.4d.5f., 1b.2b.3a.4d.5f.,
1f.2b.3a.4d.5f., 1h.2b.3a.4d.5f., 1j.2b.3a.4d.5f., 1p.2b.3a.4d.5f.,
1a.2e.3a.4d.5f., 1b.2e.3a.4d.5f., 1f.2e.3a.4d.5f., 1h.2e.3a.4d.5f.,
1j.2e.3a.4d.5f., 1p.2e.3a.4d.5f., 1a.2f.3a.4d.5f., 1b.2f.3a.4d.5f.,
1f.2f.3a.4d.5f., 1h.2f.3a.4d.5f., 1j.2f.3a.4d.5f., 1p.2f.3a.4d.5f.,
1a.2i.3a.4d.5f., 1b.2i.3a.4d.5f., 1f.2i.3a.4d.5f., 1h.2i.3a.4d.5f.,
1j.2i.3a.4d.5f., 1p.2i.3a.4d.5f., 1a.2m.3a.4d.5f., 1b.2m.3a.4d.5f.,
1f.2m.3a.4d.5f., 1h.2m.3a.4d.5f., 1j.2m.3a.4d.5f., 1p.2m.3a.4d.5f.,
1a.2o.3a.4d.5f., 1b.2o.3a.4d.5f., 1f.2o.3a.4d.5f., 1h.2o.3a.4d.5f.,
1j.2o.3a.4d.5f., 1p.2o.3a.4d.5f., 1a.2u.3a.4d.5f., 1b.2u.3a.4d.5f.,
1f.2u.3a.4d.5f., 1h.2u.3a.4d.5f., 1j.2u.3a.4d.5f., 1p.2u.3a.4d.5f.,
1a.2y.3a.4d.5f., 1b.2y.3a.4d.5f., 1f.2y.3a.4d.5f., 1h.2y.3a.4d.5f.,
1j.2y.3a.4d.5f., 1p.2y.3a.4d.5f., 1a.2a.3b.4d.5f., 1b.2a.3b.4d.5f.,
1f.2a.3b.4d.5f., 1h.2a.3b.4d.5f., 1j.2a.3b.4d.5f., 1p.2a.3b.4d.5f.,
1a.2b.3b.4d.5f., 1b.2b.3b.4d.5f., 1f.2b.3b.4d.5f., 1h.2b.3b.4d.5f.,
1j.2b.3b.4d.5f., 1p.2b.3b.4d.5f., 1a.2e.3b.4d.5f., 1b.2e.3b.4d.5f.,
1f.2e.3b.4d.5f., 1h.2e.3b.4d.5f., 1j.2e.3b.4d.5f., 1p.2e.3b.4d.5f.,
1a.2f.3b.4d.5f., 1b.2f.3b.4d.5f., 1f.2f.3b.4d.5f., 1h.2f.3b.4d.5f.,
1j.2f.3b.4d.5f., 1p.2f.3b.4d.5f., 1a.2i.3b.4d.5f., 1b.2i.3b.4d.5f.,
1f.2i.3b.4d.5f., 1h.2i.3b.4d.5f., 1j.2i.3b.4d.5f., 1p.2i.3b.4d.5f.,
1a.2m.3b.4d.5f., 1b.2m.3b.4d.5f., 1f.2m.3b.4d.5f., 1h.2m.3b.4d.5f.,
1j.2m.3b.4d.5f., 1p.2m.3b.4d.5f., 1a.2o.3b.4d.5f., 1b.2o.3b.4d.5f.,
1f.2o.3b.4d.5f., 1h.2o.3b.4d.5f., 1j.2o.3b.4d.5f., 1p.2o.3b.4d.5f.,
1a.2u.3b.4d.5f., 1b.2u.3b.4d.5f., 1f.2u.3b.4d.5f., 1h.2u.3b.4d.5f.,
1j.2u.3b.4d.5f., 1p.2u.3b.4d.5f., 1a.2y.3b.4d.5f., 1b.2y.3b.4d.5f.,
1f.2y.3b.4d.5f., 1h.2y.3b.4d.5f., 1j.2y.3b.4d.5f., 1p.2y.3b.4d.5f.,
1a.2a.3e.4d.5f., 1b.2a.3e.4d.5f., 1f.2a.3e.4d.5f., 1h.2a.3e.4d.5f.,
1j.2a.3e.4d.5f., 1p.2a.3e.4d.5f., 1a.2b.3e.4d.5f., 1b.2b.3e.4d.5f.,
1f.2b.3e.4d.5f., 1h.2b.3e.4d.5f., 1j.2b.3e.4d.5f., 1p.2b.3e.4d.5f.,
1a.2e.3e.4d.5f., 1b.2e.3e.4d.5f., 1f.2e.3e.4d.5f., 1h.2e.3e.4d.5f.,
1j.2e.3e.4d.5f., 1p.2e.3e.4d.5f., 1a.2f.3e.4d.5f., 1b.2f.3e.4d.5f.,
1f.2f.3e.4d.5f., 1h.2f.3e.4d.5f., 1j.2f.3e.4d.5f., 1p.2f.3e.4d.5f.,
1a.2i.3e.4d.5f., 1b.2i.3e.4d.5f., 1f.2i.3e.4d.5f., 1h.2i.3e.4d.5f.,
1j.2i.3e.4d.5f., 1p.2i.3e.4d.5f., 1a.2m.3e.4d.5f., 1b.2m.3e.4d.5f.,
1f.2m.3e.4d.5f., 1h.2m.3e.4d.5f., 1j.2m.3e.4d.5f., 1p.2m.3e.4d.5f.,
1a.2o.3e.4d.5f., 1b.2o.3e.4d.5f., 1f.2o.3e.4d.5f., 1h.2o.3e.4d.5f.,
1j.2o.3e.4d.5f., 1p.2o.3e.4d.5f., 1a.2u.3e.4d.5f., 1b.2u.3e.4d.5f.,
1f.2u.3e.4d.5f., 1h.2u.3e.4d.5f., 1j.2u.3e.4d.5f., 1p.2u.3e.4d.5f.,
1a.2y.3e.4d.5f., 1b.2y.3e.4d.5f., 1f.2y.3e.4d.5f., 1h.2y.3e.4d.5f.,
1j.2y.3e.4d.5f., 1p.2y.3e.4d.5f., 1a.2a.3g.4d.5f., 1b.2a.3g.4d.5f.,
1f.2a.3g.4d.5f., 1h.2a.3g.4d.5f., 1j.2a.3g.4d.5f., 1p.2a.3g.4d.5f.,
1a.2b.3g.4d.5f., 1b.2b.3g.4d.5f., 1f.2b.3g.4d.5f., 1h.2b.3g.4d.5f.,
1j.2b.3g.4d.5f., 1p.2b.3g.4d.5f., 1a.2e.3g.4d.5f., 1b.2e.3g.4d.5f.,
1f.2e.3g.4d.5f., 1h.2e.3g.4d.5f., 1j.2e.3g.4d.5f.,
1p.2e.3g.4d.5f.,
1a.2f.3g.4d.5f., 1b.2f.3g.4d.5f., 1f.2f.3g.4d.5f., 1h.2f.3g.4d.5f.,
1j.2f.3g.4d.5f., 1p.2f.3g.4d.5f., 1a.2i.3g.4d.5f., 1b.2i.3g.4d.5f.,
1f.2i.3g.4d.5f., 1h.2i.3g.4d.5f., 1j.2i.3g.4d.5f., 1p.2i.3g.4d.5f.,
1a.2m.3g.4d.5f., 1b.2m.3g.4d.5f., 1f.2m.3g.4d.5f., 1h.2m.3g.4d.5f.,
1j.2m.3g.4d.5f., 1p.2m.3g.4d.5f., 1a.2o.3g.4d.5f., 1b.2o.3g.4d.5f.,
1f.2o.3g.4d.5f., 1h.2o.3g.4d.5f., 1j.2o.3g.4d.5f., 1p.2o.3g.4d.5f.,
1a.2u.3g.4d.5f., 1b.2u.3g.4d.5f., 1f.2u.3g.4d.5f., 1h.2u.3g.4d.5f.,
1j.2u.3g.4d.5f., 1p.2u.3g.4d.5f., 1a.2y.3g.4d.5f., 1b.2y.3g.4d.5f.,
1f.2y.3g.4d.5f., 1h.2y.3g.4d.5f., 1j.2y.3g.4d.5f., 1p.2y.3g.4d.5f.,
1a.2a.3a.4f.5f., 1b.2a.3a.4f.5f., 1f.2a.3a.4f.5f., 1h.2a.3a.4f.5f.,
1j.2a.3a.4f.5f., 1p.2a.3a.4f.5f., 1a.2b.3a.4f.5f., 1b.2b.3a.4f.5f.,
1f.2b.3a.4f.5f., 1h.2b.3a.4f.5f., 1j.2b.3a.4f.5f., 1p.2b.3a.4f.5f.,
1a.2e.3a.4f.5f., 1b.2e.3a.4f.5f., 1f.2e.3a.4f.5f., 1h.2e.3a.4f.5f.,
1j.2e.3a.4f.5f., 1p.2e.3a.4f.5f., 1a.2f.3a.4f.5f., 1b.2f.3a.4f.5f.,
1f.2f.3a.4f.5f., 1h.2f.3a.4f.5f., 1j.2f.3a.4f.5f., 1p.2f.3a.4f.5f.,
1a.2i.3a.4f.5f., 1b.2i.3a.4f.5f., 1f.2i.3a.4f.5f., 1h.2i.3a.4f.5f.,
1j.2i.3a.4f.5f., 1p.2i.3a.4f.5f., 1a.2m.3a.4f.5f., 1b.2m.3a.4f.5f.,
1f.2m.3a.4f.5f., 1h.2m.3a.4f.5f., 1j.2m.3a.4f.5f., 1p.2m.3a.4f.5f.,
1a.2o.3a.4f.5f., 1b.2o.3a.4f.5f., 1f.2o.3a.4f.5f., 1h.2o.3a.4f.5f.,
1j.2o.3a.4f.5f., 1p.2o.3a.4f.5f., 1a.2u.3a.4f.5f., 1b.2u.3a.4f.5f.,
1f.2u.3a.4f.5f., 1h.2u.3a.4f.5f., 1j.2u.3a.4f.5f., 1p.2u.3a.4f.5f.,
1a.2y.3a.4f.5f., 1b.2y.3a.4f.5f., 1f.2y.3a.4f.5f., 1h.2y.3a.4f.5f.,
1j.2y.3a.4f.5f., 1p.2y.3a.4f.5f., 1a.2a.3b.4f.5f., 1b.2a.3b.4f.5f.,
1f.2a.3b.4f.5f., 1h.2a.3b.4f.5f., 1j.2a.3b.4f.5f., 1p.2a.3b.4f.5f.,
1a.2b.3b.4f.5f., 1b.2b.3b.4f.5f., 1f.2b.3b.4f.5f., 1h.2b.3b.4f.5f.,
1j.2b.3b.4f.5f., 1p.2b.3b.4f.5f., 1a.2e.3b.4f.5f., 1b.2e.3b.4f.5f.,
1f.2e.3b.4f.5f., 1h.2e.3b.4f.5f., 1j.2e.3b.4f.5f., 1p.2e.3b.4f.5f.,
1a.2f.3b.4f.5f., 1b.2f.3b.4f.5f., 1f.2f.3b.4f.5f., 1h.2f.3b.4f.5f.,
1j.2f.3b.4f.5f., 1p.2f.3b.4f.5f., 1a.2i.3b.4f.5f., 1b.2i.3b.4f.5f.,
1f.2i.3b.4f.5f., 1h.2i.3b.4f.5f., 1j.2i.3b.4f.5f., 1p.2i.3b.4f.5f.,
1a.2m.3b.4f.5f., 1b.2m.3b.4f.5f., 1f.2m.3b.4f.5f., 1h.2m.3b.4f.5f.,
1j.2m.3b.4f.5f., 1p.2m.3b.4f.5f., 1a.2o.3b.4f.5f., 1b.2o.3b.4f.5f.,
1f.2o.3b.4f.5f., 1h.2o.3b.4f.5f., 1j.2o.3b.4f.5f., 1p.2o.3b.4f.5f.,
1a.2u.3b.4f.5f., 1b.2u.3b.4f.5f., 1f.2u.3b.4f.5f., 1h.2u.3b.4f.5f.,
1j.2u.3b.4f.5f., 1p.2u.3b.4f.5f., 1a.2y.3b.4f.5f., 1b.2y.3b.4f.5f.,
1f.2y.3b.4f.5f., 1h.2y.3b.4f.5f., 1j.2y.3b.4f.5f., 1p.2y.3b.4f.5f.,
1a.2a.3e.4f.5f., 1b.2a.3e.4f.5f., 1f.2a.3e.4f.5f., 1h.2a.3e.4f.5f.,
1j.2a.3e.4f.5f., 1p.2a.3e.4f.5f., 1a.2b.3e.4f.5f., 1b.2b.3e.4f.5f.,
1f.2b.3e.4f.5f., 1h.2b.3e.4f.5f., 1j.2b.3e.4f.5f., 1p.2b.3e.4f.5f.,
1a.2e.3e.4f.5f., 1b.2e.3e.4f.5f., 1f.2e.3e.4f.5f., 1h.2e.3e.4f.5f.,
1j.2e.3e.4f.5f., 1p.2e.3e.4f.5f., 1a.2f.3e.4f.5f., 1b.2f.3e.4f.5f.,
1f.2f.3e.4f.5f., 1h.2f.3e.4f.5f., 1j.2f.3e.4f.5f., 1p.2f.3e.4f.5f.,
1a.2i.3e.4f.5f., 1b.2i.3e.4f.5f., 1f.2i.3e.4f.5f., 1h.2i.3e.4f.5f.,
1j.2i.3e.4f.5f., 1p.2i.3e.4f.5f., 1a.2m.3e.4f.5f., 1b.2m.3e.4f.5f.,
1f.2m.3e.4f.5f., 1h.2m.3e.4f.5f., 1j.2m.3e.4f.5f., 1p.2m.3e.4f.5f.,
1a.2o.3e.4f.5f., 1b.2o.3e.4f.5f., 1f.2o.3e.4f.5f., 1h.2o.3e.4f.5f.,
1j.2o.3e.4f.5f., 1p.2o.3e.4f.5f., 1a.2u.3e.4f.5f., 1b.2u.3e.4f.5f.,
1f.2u.3e.4f.5f., 1h.2u.3e.4f.5f., 1j.2u.3e.4f.5f., 1p.2u.3e.4f.5f.,
1a.2y.3e.4f.5f., 1b.2y.3e.4f.5f., 1f.2y.3e.4f.5f., 1h.2y.3e.4f.5f.,
1j.2y.3e.4f.5f., 1p.2y.3e.4f.5f., 1a.2a.3g.4f.5f., 1b.2a.3g.4f.5f.,
1f.2a.3g.4f.5f., 1h.2a.3g.4f.5f., 1j.2a.3g.4f.5f., 1p.2a.3g.4f.5f.,
1a.2b.3g.4f.5f., 1b.2b.3g.4f.5f., 1f.2b.3g.4f.5f., 1h.2b.3g.4f.5f.,
1j.2b.3g.4f.5f., 1p.2b.3g.4f.5f., 1a.2e.3g.4f.5f., 1b.2e.3g.4f.5f.,
1f.2e.3g.4f.5f., 1h.2e.3g.4f.5f., 1j.2e.3g.4f.5f., 1p.2e.3g.4f.5f.,
1a.2f.3g.4f.5f., 1b.2f.3g.4f.5f., 1f.2f.3g.4f.5f., 1h.2f.3g.4f.5f.,
1j.2f.3g.4f.5f., 1p.2f.3g.4f.5f., 1a.2i.3g.4f.5f., 1b.2i.3g.4f.5f.,
1f.2i.3g.4f.5f., 1h.2i.3g.4f.5f., 1j.2i.3g.4f.5f., 1p.2i.3g.4f.5f.,
1a.2m.3g.4f.5f., 1b.2m.3g.4f.5f., 1f.2m.3g.4f.5f., 1h.2m.3g.4f.5f.,
1j.2m.3g.4f.5f., 1p.2m.3g.4f.5f., 1a.2o.3g.4f.5f., 1b.2o.3g.4f.5f.,
1f.2o.3g.4f.5f., 1h.2o.3g.4f.5f., 1j.2o.3g.4f.5f., 1p.2o.3g.4f.5f.,
1a.2u.3g.4f.5f., 1b.2u.3g.4f.5f., 1f.2u.3g.4f.5f., 1h.2u.3g.4f.5f.,
1j.2u.3g.4f.5f., 1p.2u.3g.4f.5f., 1a.2y.3g.4f.5f., 1b.2y.3g.4f.5f.,
1f.2y.3g.4f.5f., 1h.2y.3g.4f.5f., 1j.2y.3g.4f.5f., 1p.2y.3g.4f.5f.,
1a.2a.3a.4g.5f., 1b.2a.3a.4g.5f., 1f.2a.3a.4g.5f., 1h.2a.3a.4g.5f.,
1j.2a.3a.4g.5f., 1p.2a.3a.4g.5f., 1a.2b.3a.4g.5f., 1b.2b.3a.4g.5f.,
1f.2b.3a.4g.5f., 1h.2b.3a.4g.5f., 1j.2b.3a.4g.5f., 1p.2b.3a.4g.5f.,
1a.2e.3a.4g.5f., 1b.2e.3a.4g.5f., 1f.2e.3a.4g.5f., 1h.2e.3a.4g.5f.,
1j.2e.3a.4g.5f., 1p.2e.3a.4g.5f., 1a.2f.3a.4g.5f., 1b.2f.3a.4g.5f.,
1f.2f.3a.4g.5f., 1h.2f.3a.4g.5f., 1j.2f.3a.4g.5f., 1p.2f.3a.4g.5f.,
1a.2i.3a.4g.5f., 1b.2i.3a.4g.5f., 1f.2i.3a.4g.5f., 1h.2i.3a.4g.5f.,
1j.2i.3a.4g.5f., 1p.2i.3a.4g.5f., 1a.2m.3a.4g.5f., 1b.2m.3a.4g.5f.,
1f.2m.3a.4g.5f., 1h.2m.3a.4g.5f., 1j.2m.3a.4g.5f., 1p.2m.3a.4g.5f.,
1a.2o.3a.4g.5f., 1b.2o.3a.4g.5f., 1f.2o.3a.4g.5f., 1h.2o.3a.4g.5f.,
1j.2o.3a.4g.5f., 1p.2o.3a.4g.5f., 1a.2u.3a.4g.5f., 1b.2u.3a.4g.5f.,
1f.2u.3a.4g.5f., 1h.2u.3a.4g.5f., 1j.2u.3a.4g.5f., 1p.2u.3a.4g.5f.,
1a.2y.3a.4g.5f., 1b.2y.3a.4g.5f., 1f.2y.3a.4g.5f., 1h.2y.3a.4g.5f.,
1j.2y.3a.4g.5f., 1p.2y.3a.4g.5f., 1a.2a.3b.4g.5f., 1b.2a.3b.4g.5f.,
1f.2a.3b.4g.5f., 1h.2a.3b.4g.5f., 1j.2a.3b.4g.5f., 1p.2a.3b.4g.5f.,
1a.2b.3b.4g.5f., 1b.2b.3b.4g.5f., 1f.2b.3b.4g.5f., 1h.2b.3b.4g.5f.,
1j.2b.3b.4g.5f., 1p.2b.3b.4g.5f., 1a.2e.3b.4g.5f., 1b.2e.3b.4g.5f.,
1f.2e.3b.4g.5f., 1h.2e.3b.4g.5f., 1j.2e.3b.4g.5f., 1p.2e.3b.4g.5f.,
1a.2f.3b.4g.5f., 1b.2f.3b.4g.5f., 1f.2f.3b.4g.5f., 1h.2f.3b.4g.5f.,
1j.2f.3b.4g.5f., 1p.2f.3b.4g.5f., 1a.2i.3b.4g.5f., 1b.2i.3b.4g.5f.,
1f.2i.3b.4g.5f., 1h.2i.3b.4g.5f., 1j.2i.3b.4g.5f., 1p.2i.3b.4g.5f.,
1a.2m.3b.4g.5f., 1b.2m.3b.4g.5f., 1f.2m.3b.4g.5f., 1h.2m.3b.4g.5f.,
1j.2m.3b.4g.5f., 1p.2m.3b.4g.5f., 1a.2o.3b.4g.5f., 1b.2o.3b.4g.5f.,
1f.2o.3b.4g.5f., 1h.2o.3b.4g.5f., 1j.2o.3b.4g.5f., 1p.2o.3b.4g.5f.,
1a.2u.3b.4g.5f., 1b.2u.3b.4g.5f., 1f.2u.3b.4g.5f., 1h.2u.3b.4g.5f.,
1j.2u.3b.4g.5f., 1p.2u.3b.4g.5f., 1a.2y.3b.4g.5f., 1b.2y.3b.4g.5f.,
1f.2y.3b.4g.5f., 1h.2y.3b.4g.5f., 1j.2y.3b.4g.5f., 1p.2y.3b.4g.5f.,
1a.2a.3e.4g.5f., 1b.2a.3e.4g.5f., 1f.2a.3e.4g.5f., 1h.2a.3e.4g.5f.,
1j.2a.3e.4g.5f., 1p.2a.3e.4g.5f., 1a.2b.3e.4g.5f., 1b.2b.3e.4g.5f.,
1f.2b.3e.4g.5f., 1h.2b.3e.4g.5f., 1j.2b.3e.4g.5f., 1p.2b.3e.4g.5f.,
1a.2e.3e.4g.5f., 1b.2e.3e.4g.5f., 1f.2e.3e.4g.5f., 1h.2e.3e.4g.5f.,
1j.2e.3e.4g.5f., 1p.2e.3e.4g.5f., 1a.2f.3e.4g.5f., 1b.2f.3e.4g.5f.,
1f.2f.3e.4g.5f., 1h.2f.3e.4g.5f., 1j.2f.3e.4g.5f., 1p.2f.3e.4g.5f.,
1a.2i.3e.4g.5f., 1b.2i.3e.4g.5f., 1f.2i.3e.4g.5f., 1h.2i.3e.4g.5f.,
1j.2i.3e.4g.5f., 1p.2i.3e.4g.5f., 1a.2m.3e.4g.5f., 1b.2m.3e.4g.5f.,
1f.2m.3e.4g.5f., 1h.2m.3e.4g.5f., 1j.2m.3e.4g.5f., 1p.2m.3e.4g.5f.,
1a.2o.3e.4g.5f., 1b.2o.3e.4g.5f., 1f.2o.3e.4g.5f., 1h.2o.3e.4g.5f.,
1j.2o.3e.4g.5f., 1p.2o.3e.4g.5f., 1a.2u.3e.4g.5f., 1b.2u.3e.4g.5f.,
1f.2u.3e.4g.5f., 1h.2u.3e.4g.5f., 1j.2u.3e.4g.5f., 1p.2u.3e.4g.5f.,
1a.2y.3e.4g.5f., 1b.2y.3e.4g.5f., 1f.2y.3e.4g.5f., 1h.2y.3e.4g.5f.,
1j.2y.3e.4g.5f., 1p.2y.3e.4g.5f., 1a.2a.3g.4g.5f., 1b.2a.3g.4g.5f.,
1f.2a.3g.4g.5f., 1h.2a.3g.4g.5f., 1j.2a.3g.4g.5f., 1p.2a.3g.4g.5f.,
1a.2b.3g.4g.5f., 1b.2b.3g.4g.5f., 1f.2b.3g.4g.5f., 1h.2b.3g.4g.5f.,
1j.2b.3g.4g.5f., 1p.2b.3g.4g.5f., 1a.2e.3g.4g.5f., 1b.2e.3g.4g.5f.,
1f.2e.3g.4g.5f., 1h.2e.3g.4g.5f., 1j.2e.3g.4g.5f., 1p.2e.3g.4g.5f.,
1a.2f.3g.4g.5f., 1b.2f.3g.4g.5f., 1f.2f.3g.4g.5f., 1h.2f.3g.4g.5f.,
1j.2f.3g.4g.5f., 1p.2f.3g.4g.5f., 1a.2i.3g.4g.5f., 1b.2i.3g.4g.5f.,
1f.2i.3g.4g.5f., 1h.2i.3g.4g.5f., 1j.2i.3g.4g.5f., 1p.2i.3g.4g.5f.,
1a.2m.3g.4g.5f., 1b.2m.3g.4g.5f., 1f.2m.3g.4g.5f., 1h.2m.3g.4g.5f.,
1j.2m.3g.4g.5f., 1p.2m.3g.4g.5f., 1a.2o.3g.4g.5f., 1b.2o.3g.4g.5f.,
1f.2o.3g.4g.5f., 1h.2o.3g.4g.5f., 1j.2o.3g.4g.5f., 1p.2o.3g.4g.5f.,
1a.2u.3g.4g.5f., 1b.2u.3g.4g.5f., 1f.2u.3g.4g.5f., 1h.2u.3g.4g.5f.,
1j.2u.3g.4g.5f., 1p.2u.3g.4g.5f., 1a.2y.3g.4g.5f., 1b.2y.3g.4g.5f.,
1f.2y.3g.4g.5f., 1h.2y.3g.4g.5f., 1j.2y.3g.4g.5f., 1p.2y.3g.4g.5f.,
1a.2a.3a.4h.5f., 1b.2a.3a.4h.5f., 1f.2a.3a.4h.5f., 1h.2a.3a.4h.5f.,
1j.2a.3a.4h.5f., 1p.2a.3a.4h.5f., 1a.2b.3a.4h.5f., 1b.2b.3a.4h.5f.,
1f.2b.3a.4h.5f., 1h.2b.3a.4h.5f., 1j.2b.3a.4h.5f., 1p.2b.3a.4h.5f.,
1a.2e.3a.4h.5f., 1b.2e.3a.4h.5f., 1f.2e.3a.4h.5f., 1h.2e.3a.4h.5f.,
1j.2e.3a.4h.5f., 1p.2e.3a.4h.5f., 1a.2f.3a.4h.5f., 1b.2f.3a.4h.5f.,
1f.2f.3a.4h.5f., 1h.2f.3a.4h.5f., 1j.2f.3a.4h.5f., 1p.2f.3a.4h.5f.,
1a.2i.3a.4h.5f., 1b.2i.3a.4h.5f., 1f.2i.3a.4h.5f., 1h.2i.3a.4h.5f.,
1j.2i.3a.4h.5f., 1p.2i.3a.4h.5f., 1a.2m.3a.4h.5f., 1b.2m.3a.4h.5f.,
1f.2m.3a.4h.5f., 1h.2m.3a.4h.5f., 1j.2m.3a.4h.5f., 1p.2m.3a.4h.5f.,
1a.2o.3a.4h.5f., 1b.2o.3a.4h.5f., 1f.2o.3a.4h.5f., 1h.2o.3a.4h.5f.,
1j.2o.3a.4h.5f., 1p.2o.3a.4h.5f., 1a.2u.3a.4h.5f., 1b.2u.3a.4h.5f.,
1f.2u.3a.4h.5f., 1h.2u.3a.4h.5f., 1j.2u.3a.4h.5f., 1p.2u.3a.4h.5f.,
1a.2y.3a.4h.5f., 1b.2y.3a.4h.5f., 1f.2y.3a.4h.5f., 1h.2y.3a.4h.5f.,
1j.2y.3a.4h.5f., 1p.2y.3a.4h.5f., 1a.2a.3b.4h.5f., 1b.2a.3b.4h.5f.,
1f.2a.3b.4h.5f., 1h.2a.3b.4h.5f., 1j.2a.3b.4h.5f., 1p.2a.3b.4h.5f.,
1a.2b.3b.4h.5f., 1b.2b.3b.4h.5f., 1f.2b.3b.4h.5f., 1h.2b.3b.4h.5f.,
1j.2b.3b.4h.5f., 1p.2b.3b.4h.5f., 1a.2e.3b.4h.5f., 1b.2e.3b.4h.5f.,
1f.2e.3b.4h.5f., 1h.2e.3b.4h.5f., 1j.2e.3b.4h.5f., 1p.2e.3b.4h.5f.,
1a.2f.3b.4h.5f., 1b.2f.3b.4h.5f., 1f.2f.3b.4h.5f., 1h.2f.3b.4h.5f.,
1j.2f.3b.4h.5f., 1p.2f.3b.4h.5f., 1a.2i.3b.4h.5f., 1b.2i.3b.4h.5f.,
1f.2i.3b.4h.5f., 1h.2i.3b.4h.5f., 1j.2i.3b.4h.5f., 1p.2i.3b.4h.5f.,
1a.2m.3b.4h.5f., 1b.2m.3b.4h.5f., 1f.2m.3b.4h.5f., 1h.2m.3b.4h.5f.,
1j.2m.3b.4h.5f., 1p.2m.3b.4h.5f., 1a.2o.3b.4h.5f., 1b.2o.3b.4h.5f.,
1f.2o.3b.4h.5f., 1h.2o.3b.4h.5f., 1j.2o.3b.4h.5f., 1p.2o.3b.4h.5f.,
1a.2u.3b.4h.5f., 1b.2u.3b.4h.5f., 1f.2u.3b.4h.5f., 1h.2u.3b.4h.5f.,
1j.2u.3b.4h.5f., 1p.2u.3b.4h.5f., 1a.2y.3b.4h.5f., 1b.2y.3b.4h.5f.,
1f.2y.3b.4h.5f., 1h.2y.3b.4h.5f., 1j.2y.3b.4h.5f., 1p.2y.3b.4h.5f.,
1a.2a.3e.4h.5f., 1b.2a.3e.4h.5f., 1f.2a.3e.4h.5f., 1h.2a.3e.4h.5f.,
1j.2a.3e.4h.5f., 1p.2a.3e.4h.5f., 1a.2b.3e.4h.5f., 1b.2b.3e.4h.5f.,
1f.2b.3e.4h.5f., 1h.2b.3e.4h.5f., 1j.2b.3e.4h.5f., 1p.2b.3e.4h.5f.,
1a.2e.3e.4h.5f., 1b.2e.3e.4h.5f., 1f.2e.3e.4h.5f., 1h.2e.3e.4h.5f.,
1j.2e.3e.4h.5f., 1p.2e.3e.4h.5f., 1a.2f.3e.4h.5f., 1b.2f.3e.4h.5f.,
1f.2f.3e.4h.5f., 1h.2f.3e.4h.5f., 1j.2f.3e.4h.5f., 1p.2f.3e.4h.5f.,
1a.2i.3e.4h.5f., 1b.2i.3e.4h.5f., 1f.2i.3e.4h.5f., 1h.2i.3e.4h.5f.,
1j.2i.3e.4h.5f., 1p.2i.3e.4h.5f., 1a.2m.3e.4h.5f., 1b.2m.3e.4h.5f.,
1f.2m.3e.4h.5f., 1h.2m.3e.4h.5f., 1j.2m.3e.4h.5f., 1p.2m.3e.4h.5f.,
1a.2o.3e.4h.5f., 1b.2o.3e.4h.5f., 1f.2o.3e.4h.5f., 1h.2o.3e.4h.5f.,
1j.2o.3e.4h.5f., 1p.2o.3e.4h.5f., 1a.2u.3e.4h.5f., 1b.2u.3e.4h.5f.,
1f.2u.3e.4h.5f., 1h.2u.3e.4h.5f., 1j.2u.3e.4h.5f., 1p.2u.3e.4h.5f.,
1a.2y.3e.4h.5f., 1b.2y.3e.4h.5f., 1f.2y.3e.4h.5f., 1h.2y.3e.4h.5f.,
1j.2y.3e.4h.5f., 1p.2y.3e.4h.5f., 1a.2a.3g.4h.5f., 1b.2a.3g.4h.5f.,
1f.2a.3g.4h.5f., 1h.2a.3g.4h.5f., 1j.2a.3g.4h.5f., 1p.2a.3g.4h.5f.,
1a.2b.3g.4h.5f., 1b.2b.3g.4h.5f., 1f.2b.3g.4h.5f., 1h.2b.3g.4h.5f.,
1j.2b.3g.4h.5f., 1p.2b.3g.4h.5f., 1a.2e.3g.4h.5f., 1b.2e.3g.4h.5f.,
1f.2e.3g.4h.5f., 1h.2e.3g.4h.5f., 1j.2e.3g.4h.5f., 1p.2e.3g.4h.5f.,
1a.2f.3g.4h.5f., 1b.2f.3g.4h.5f., 1f.2f.3g.4h.5f., 1h.2f.3g.4h.5f.,
1j.2f.3g.4h.5f., 1p.2f.3g.4h.5f., 1a.2i.3g.4h.5f., 1b.2i.3g.4h.5f.,
1f.2i.3g.4h.5f., 1h.2i.3g.4h.5f., 1j.2i.3g.4h.5f., 1p.2i.3g.4h.5f.,
1a.2m.3g.4h.5f., 1b.2m.3g.4h.5f., 1f.2m.3g.4h.5f., 1h.2m.3g.4h.5f.,
1j.2m.3g.4h.5f., 1p.2m.3g.4h.5f., 1a.2o.3g.4h.5f., 1b.2o.3g.4h.5f.,
1f.2o.3g.4h.5f., 1h.2o.3g.4h.5f., 1j.2o.3g.4h.5f., 1p.2o.3g.4h.5f.,
1a.2u.3g.4h.5f., 1b.2u.3g.4h.5f., 1f.2u.3g.4h.5f., 1h.2u.3g.4h.5f.,
1j.2u.3g.4h.5f., 1p.2u.3g.4h.5f., 1a.2y.3g.4h.5f., 1b.2y.3g.4h.5f.,
1f.2y.3g.4h.5f., 1h.2y.3g.4h.5f., 1j.2y.3g.4h.5f., 1p.2y.3g.4h.5f.,
1a.2a.3a.4i.5f., 1b.2a.3a.4i.5f., 1f.2a.3a.4i.5f., 1h.2a.3a.4i.5f.,
1j.2a.3a.4i.5f., 1p.2a.3a.4i.5f., 1a.2b.3a.4i.5f., 1b.2b.3a.4i.5f.,
1f.2b.3a.4i.5f., 1h.2b.3a.4i.5f., 1j.2b.3a.4i.5f., 1p.2b.3a.4i.5f.,
1a.2e.3a.4i.5f., 1b.2e.3a.4i.5f., 1f.2e.3a.4i.5f., 1h.2e.3a.4i.5f.,
1j.2e.3a.4i.5f., 1p.2e.3a.4i.5f., 1a.2f.3a.4i.5f., 1b.2f.3a.4i.5f.,
1f.2f.3a.4i.5f., 1h.2f.3a.4i.5f., 1j.2f.3a.4i.5f., 1p.2f.3a.4i.5f.,
1a.2i.3a.4i.5f., 1b.2i.3a.4i.5f., 1f.2i.3a.4i.5f., 1h.2i.3a.4i.5f.,
1j.2i.3a.4i.5f., 1p.2i.3a.4i.5f., 1a.2m.3a.4i.5f., 1b.2m.3a.4i.5f.,
1f.2m.3a.4i.5f., 1h.2m.3a.4i.5f., 1j.2m.3a.4i.5f., 1p.2m.3a.4i.5f.,
1a.2o.3a.4i.5f., 1b.2o.3a.4i.5f., 1f.2o.3a.4i.5f., 1h.2o.3a.4i.5f.,
1j.2o.3a.4i.5f., 1p.2o.3a.4i.5f., 1a.2u.3a.4i.5f., 1b.2u.3a.4i.5f.,
1f.2u.3a.4i.5f., 1h.2u.3a.4i.5f., 1j.2u.3a.4i.5f., 1p.2u.3a.4i.5f.,
1a.2y.3a.4i.5f., 1b.2y.3a.4i.5f., 1f.2y.3a.4i.5f., 1h.2y.3a.4i.5f.,
1j.2y.3a.4i.5f., 1p.2y.3a.4i.5f., 1a.2a.3b.4i.5f., 1b.2a.3b.4i.5f.,
1f.2a.3b.4i.5f., 1h.2a.3b.4i.5f., 1j.2a.3b.4i.5f., 1p.2a.3b.4i.5f.,
1a.2b.3b.4i.5f., 1b.2b.3b.4i.5f., 1f.2b.3b.4i.5f., 1h.2b.3b.4i.5f.,
1j.2b.3b.4i.5f., 1p.2b.3b.4i.5f., 1a.2e.3b.4i.5f., 1b.2e.3b.4i.5f.,
1f.2e.3b.4i.5f., 1h.2e.3b.4i.5f., 1j.2e.3b.4i.5f., 1p.2e.3b.4i.5f.,
1a.2f.3b.4i.5f., 1b.2f.3b.4i.5f., 1f.2f.3b.4i.5f., 1h.2f.3b.4i.5f.,
1j.2f.3b.4i.5f., 1p.2f.3b.4i.5f., 1a.2i.3b.4i.5f., 1b.2i.3b.4i.5f.,
1f.2i.3b.4i.5f., 1h.2i.3b.4i.5f., 1j.2i.3b.4i.5f., 1p.2i.3b.4i.5f.,
1a.2m.3b.4i.5f., 1b.2m.3b.4i.5f., 1f.2m.3b.4i.5f., 1h.2m.3b.4i.5f.,
1j.2m.3b.4i.5f., 1p.2m.3b.4i.5f., 1a.2o.3b.4i.5f., 1b.2o.3b.4i.5f.,
1f.2o.3b.4i.5f., 1h.2o.3b.4i.5f., 1j.2o.3b.4i.5f., 1p.2o.3b.4i.5f.,
1a.2u.3b.4i.5f., 1b.2u.3b.4i.5f., 1f.2u.3b.4i.5f., 1h.2u.3b.4i.5f.,
1j.2u.3b.4i.5f., 1p.2u.3b.4i.5f., 1a.2y.3b.4i.5f., 1b.2y.3b.4i.5f.,
1f.2y.3b.4i.5f., 1h.2y.3b.4i.5f., 1j.2y.3b.4i.5f., 1p.2y.3b.4i.5f.,
1a.2a.3e.4i.5f., 1b.2a.3e.4i.5f., 1f.2a.3e.4i.5f., 1h.2a.3e.4i.5f.,
1j.2a.3e.4i.5f., 1p.2a.3e.4i.5f., 1a.2b.3e.4i.5f., 1b.2b.3e.4i.5f.,
1f.2b.3e.4i.5f., 1h.2b.3e.4i.5f., 1j.2b.3e.4i.5f., 1p.2b.3e.4i.5f.,
1a.2e.3e.4i.5f., 1b.2e.3e.4i.5f., 1f.2e.3e.4i.5f., 1h.2e.3e.4i.5f.,
1j.2e.3e.4i.5f., 1p.2e.3e.4i.5f., 1a.2f.3e.4i.5f., 1b.2f.3e.4i.5f.,
1f.2f.3e.4i.5f., 1h.2f.3e.4i.5f., 1j.2f.3e.4i.5f., 1p.2f.3e.4i.5f.,
1a.2i.3e.4i.5f., 1b.2i.3e.4i.5f., 1f.2i.3e.4i.5f., 1h.2i.3e.4i.5f.,
1j.2i.3e.4i.5f., 1p.2i.3e.4i.5f., 1a.2m.3e.4i.5f., 1b.2m.3e.4i.5f.,
1f.2m.3e.4i.5f., 1h.2m.3e.4i.5f., 1j.2m.3e.4i.5f., 1p.2m.3e.4i.5f.,
1a.2o.3e.4i.5f., 1b.2o.3e.4i.5f., 1f.2o.3e.4i.5f., 1h.2o.3e.4i.5f.,
1j.2o.3e.4i.5f., 1p.2o.3e.4i.5f., 1a.2u.3e.4i.5f., 1b.2u.3e.4i.5f.,
1f.2u.3e.4i.5f., 1h.2u.3e.4i.5f., 1j.2u.3e.4i.5f., 1p.2u.3e.4i.5f.,
1a.2y.3e.4i.5f., 1b.2y.3e.4i.5f., 1f.2y.3e.4i.5f., 1h.2y.3e.4i.5f.,
1j.2y.3e.4i.5f., 1p.2y.3e.4i.5f., 1a.2a.3g.4i.5f., 1b.2a.3g.4i.5f.,
1f.2a.3g.4i.5f., 1h.2a.3g.4i.5f., 1j.2a.3g.4i.5f., 1p.2a.3g.4i.5f.,
1a.2b.3g.4i.5f., 1b.2b.3g.4i.5f., 1f.2b.3g.4i.5f., 1h.2b.3g.4i.5f.,
1j.2b.3g.4i.5f., 1p.2b.3g.4i.5f., 1a.2e.3g.4i.5f., 1b.2e.3g.4i.5f.,
1f.2e.3g.4i.5f., 1h.2e.3g.4i.5f., 1j.2e.3g.4i.5f., 1p.2e.3g.4i.5f.,
1a.2f.3g.4i.5f., 1b.2f.3g.4i.5f., 1f.2f.3g.4i.5f., 1h.2f.3g.4i.5f.,
1j.2f.3g.4i.5f., 1p.2f.3g.4i.5f., 1a.2i.3g.4i.5f., 1b.2i.3g.4i.5f.,
1f.2i.3g.4i.5f., 1h.2i.3g.4i.5f., 1j.2i.3g.4i.5f., 1p.2i.3g.4i.5f.,
1a.2m.3g.4i.5f., 1b.2m.3g.4i.5f., 1f.2m.3g.4i.5f., 1h.2m.3g.4i.5f.,
1j.2m.3g.4i.5f., 1p.2m.3g.4i.5f., 1a.2o.3g.4i.5f., 1b.2o.3g.4i.5f.,
1f.2o.3g.4i.5f., 1h.2o.3g.4i.5f., 1j.2o.3g.4i.5f., 1p.2o.3g.4i.5f.,
1a.2u.3g.4i.5f., 1b.2u.3g.4i.5f., 1f.2u.3g.4i.5f., 1h.2u.3g.4i.5f.,
1j.2u.3g.4i.5f., 1p.2u.3g.4i.5f., 1a.2y.3g.4i.5f., 1b.2y.3g.4i.5f.,
1f.2y.3g.4i.5f., 1h.2y.3g.4i.5f., 1j.2y.3g.4i.5f., 1p.2y.3g.4i.5f.,
1a.2a.3a.4a.5g., 1b.2a.3a.4a.5g., 1f.2a.3a.4a.5g., 1h.2a.3a.4a.5g.,
1j.2a.3a.4a.5g., 1p.2a.3a.4a.5g., 1a.2b.3a.4a.5g., 1b.2b.3a.4a.5g.,
1f.2b.3a.4a.5g., 1h.2b.3a.4a.5g., 1j.2b.3a.4a.5g., 1p.2b.3a.4a.5g.,
1a.2e.3a.4a.5g., 1b.2e.3a.4a.5g., 1f.2e.3a.4a.5g., 1h.2e.3a.4a.5g.,
1j.2e.3a.4a.5g., 1p.2e.3a.4a.5g., 1a.2f.3a.4a.5g., 1b.2f.3a.4a.5g.,
1f.2f.3a.4a.5g., 1h.2f.3a.4a.5g., 1j.2f.3a.4a.5g., 1p.2f.3a.4a.5g.,
1a.2i.3a.4a.5g., 1b.2i.3a.4a.5g., 1f.2i.3a.4a.5g., 1h.2i.3a.4a.5g.,
1j.2i.3a.4a.5g., 1p.2i.3a.4a.5g., 1a.2m.3a.4a.5g., 1b.2m.3a.4a.5g.,
1f.2m.3a.4a.5g., 1h.2m.3a.4a.5g., 1j.2m.3a.4a.5g., 1p.2m.3a.4a.5g.,
1a.2o.3a.4a.5g., 1b.2o.3a.4a.5g., 1f.2o.3a.4a.5g., 1h.2o.3a.4a.5g.,
1j.2o.3a.4a.5g., 1p.2o.3a.4a.5g., 1a.2u.3a.4a.5g., 1b.2u.3a.4a.5g.,
1f.2u.3a.4a.5g., 1h.2u.3a.4a.5g., 1j.2u.3a.4a.5g., 1p.2u.3a.4a.5g.,
1a.2y.3a.4a.5g., 1b.2y.3a.4a.5g., 1f.2y.3a.4a.5g., 1h.2y.3a.4a.5g.,
1j.2y.3a.4a.5g., 1p.2y.3a.4a.5g., 1a.2a.3b.4a.5g., 1b.2a.3b.4a.5g.,
1f.2a.3b.4a.5g., 1h.2a.3b.4a.5g., 1j.2a.3b.4a.5g., 1p.2a.3b.4a.5g.,
1a.2b.3b.4a.5g., 1b.2b.3b.4a.5g., 1f.2b.3b.4a.5g., 1h.2b.3b.4a.5g.,
1j.2b.3b.4a.5g., 1p.2b.3b.4a.5g., 1a.2e.3b.4a.5g., 1b.2e.3b.4a.5g.,
1f.2e.3b.4a.5g., 1h.2e.3b.4a.5g., 1j.2e.3b.4a.5g., 1p.2e.3b.4a.5g.,
1a.2f.3b.4a.5g., 1b.2f.3b.4a.5g., 1f.2f.3b.4a.5g., 1h.2f.3b.4a.5g.,
1j.2f.3b.4a.5g., 1p.2f.3b.4a.5g., 1a.2i.3b.4a.5g., 1b.2i.3b.4a.5g.,
1f.2i.3b.4a.5g., 1h.2i.3b.4a.5g., 1j.2i.3b.4a.5g., 1p.2i.3b.4a.5g.,
1a.2m.3b.4a.5g., 1b.2m.3b.4a.5g., 1f.2m.3b.4a.5g., 1h.2m.3b.4a.5g.,
1j.2m.3b.4a.5g., 1p.2m.3b.4a.5g., 1a.2o.3b.4a.5g., 1b.2o.3b.4a.5g.,
1f.2o.3b.4a.5g., 1h.2o.3b.4a.5g., 1j.2o.3b.4a.5g., 1p.2o.3b.4a.5g.,
1a.2u.3b.4a.5g., 1b.2u.3b.4a.5g., 1f.2u.3b.4a.5g., 1h.2u.3b.4a.5g.,
1j.2u.3b.4a.5g., 1p.2u.3b.4a.5g., 1a.2y.3b.4a.5g.,
1b.2y.3b.4a.5g.,
1f.2y.3b.4a.5g., 1h.2y.3b.4a.5g., 1j.2y.3b.4a.5g., 1p.2y.3b.4a.5g.,
1a.2a.3e.4a.5g., 1b.2a.3e.4a.5g., 1f.2a.3e.4a.5g., 1h.2a.3e.4a.5g.,
1j.2a.3e.4a.5g., 1p.2a.3e.4a.5g., 1a.2b.3e.4a.5g., 1b.2b.3e.4a.5g.,
1f.2b.3e.4a.5g., 1h.2b.3e.4a.5g., 1j.2b.3e.4a.5g., 1p.2b.3e.4a.5g.,
1a.2e.3e.4a.5g., 1b.2e.3e.4a.5g., 1f.2e.3e.4a.5g., 1h.2e.3e.4a.5g.,
1j.2e.3e.4a.5g., 1p.2e.3e.4a.5g., 1a.2f.3e.4a.5g., 1b.2f.3e.4a.5g.,
1f.2f.3e.4a.5g., 1h.2f.3e.4a.5g., 1j.2f.3e.4a.5g., 1p.2f.3e.4a.5g.,
1a.2i.3e.4a.5g., 1b.2i.3e.4a.5g., 1f.2i.3e.4a.5g., 1h.2i.3e.4a.5g.,
1j.2i.3e.4a.5g., 1p.2i.3e.4a.5g., 1a.2m.3e.4a.5g., 1b.2m.3e.4a.5g.,
1f.2m.3e.4a.5g., 1h.2m.3e.4a.5g., 1j.2m.3e.4a.5g., 1p.2m.3e.4a.5g.,
1a.2o.3e.4a.5g., 1b.2o.3e.4a.5g., 1f.2o.3e.4a.5g., 1h.2o.3e.4a.5g.,
1j.2o.3e.4a.5g., 1p.2o.3e.4a.5g., 1a.2u.3e.4a.5g., 1b.2u.3e.4a.5g.,
1f.2u.3e.4a.5g., 1h.2u.3e.4a.5g., 1j.2u.3e.4a.5g., 1p.2u.3e.4a.5g.,
1a.2y.3e.4a.5g., 1b.2y.3e.4a.5g., 1f.2y.3e.4a.5g., 1h.2y.3e.4a.5g.,
1j.2y.3e.4a.5g., 1p.2y.3e.4a.5g., 1a.2a.3g.4a.5g., 1b.2a.3g.4a.5g.,
1f.2a.3g.4a.5g., 1h.2a.3g.4a.5g., 1j.2a.3g.4a.5g., 1p.2a.3g.4a.5g.,
1a.2b.3g.4a.5g., 1b.2b.3g.4a.5g., 1f.2b.3g.4a.5g., 1h.2b.3g.4a.5g.,
1j.2b.3g.4a.5g., 1p.2b.3g.4a.5g., 1a.2e.3g.4a.5g., 1b.2e.3g.4a.5g.,
1f.2e.3g.4a.5g., 1h.2e.3g.4a.5g., 1j.2e.3g.4a.5g., 1p.2e.3g.4a.5g.,
1a.2f.3g.4a.5g., 1b.2f.3g.4a.5g., 1f.2f.3g.4a.5g., 1h.2f.3g.4a.5g.,
1j.2f.3g.4a.5g., 1p.2f.3g.4a.5g., 1a.2i.3g.4a.5g., 1b.2i.3g.4a.5g.,
1f.2i.3g.4a.5g., 1h.2i.3g.4a.5g., 1j.2i.3g.4a.5g., 1p.2i.3g.4a.5g.,
1a.2m.3g.4a.5g., 1b.2m.3g.4a.5g., 1f.2m.3g.4a.5g., 1h.2m.3g.4a.5g.,
1j.2m.3g.4a.5g., 1p.2m.3g.4a.5g., 1a.2o.3g.4a.5g., 1b.2o.3g.4a.5g.,
1f.2o.3g.4a.5g., 1h.2o.3g.4a.5g., 1j.2o.3g.4a.5g., 1p.2o.3g.4a.5g.,
1a.2u.3g.4a.5g., 1b.2u.3g.4a.5g., 1f.2u.3g.4a.5g., 1h.2u.3g.4a.5g.,
1j.2u.3g.4a.5g., 1p.2u.3g.4a.5g., 1a.2y.3g.4a.5g., 1b.2y.3g.4a.5g.,
1f.2y.3g.4a.5g., 1h.2y.3g.4a.5g., 1j.2y.3g.4a.5g., 1p.2y.3g.4a.5g.,
1a.2a.3a.4d.5g., 1b.2a.3a.4d.5g., 1f.2a.3a.4d.5g., 1h.2a.3a.4d.5g.,
1j.2a.3a.4d.5g., 1p.2a.3a.4d.5g., 1a.2b.3a.4d.5g., 1b.2b.3a.4d.5g.,
1f.2b.3a.4d.5g., 1h.2b.3a.4d.5g., 1j.2b.3a.4d.5g., 1p.2b.3a.4d.5g.,
1a.2e.3a.4d.5g., 1b.2e.3a.4d.5g., 1f.2e.3a.4d.5g., 1h.2e.3a.4d.5g.,
1j.2e.3a.4d.5g., 1p.2e.3a.4d.5g., 1a.2f.3a.4d.5g., 1b.2f.3a.4d.5g.,
1f.2f.3a.4d.5g., 1h.2f.3a.4d.5g., 1j.2f.3a.4d.5g., 1p.2f.3a.4d.5g.,
1a.2i.3a.4d.5g., 1b.2i.3a.4d.5g., 1f.2i.3a.4d.5g., 1h.2i.3a.4d.5g.,
1j.2i.3a.4d.5g., 1p.2i.3a.4d.5g., 1a.2m.3a.4d.5g., 1b.2m.3a.4d.5g.,
1f.2m.3a.4d.5g., 1h.2m.3a.4d.5g., 1j.2m.3a.4d.5g., 1p.2m.3a.4d.5g.,
1a.2o.3a.4d.5g., 1b.2o.3a.4d.5g., 1f.2o.3a.4d.5g., 1h.2o.3a.4d.5g.,
1j.2o.3a.4d.5g., 1p.2o.3a.4d.5g., 1a.2u.3a.4d.5g., 1b.2u.3a.4d.5g.,
1f.2u.3a.4d.5g., 1h.2u.3a.4d.5g., 1j.2u.3a.4d.5g., 1p.2u.3a.4d.5g.,
1a.2y.3a.4d.5g., 1b.2y.3a.4d.5g., 1f.2y.3a.4d.5g., 1h.2y.3a.4d.5g.,
1j.2y.3a.4d.5g., 1p.2y.3a.4d.5g., 1a.2a.3b.4d.5g., 1b.2a.3b.4d.5g.,
1f.2a.3b.4d.5g., 1h.2a.3b.4d.5g., 1j.2a.3b.4d.5g., 1p.2a.3b.4d.5g.,
1a.2b.3b.4d.5g., 1b.2b.3b.4d.5g., 1f.2b.3b.4d.5g., 1h.2b.3b.4d.5g.,
1j.2b.3b.4d.5g., 1p.2b.3b.4d.5g., 1a.2e.3b.4d.5g., 1b.2e.3b.4d.5g.,
1f.2e.3b.4d.5g., 1h.2e.3b.4d.5g., 1j.2e.3b.4d.5g., 1p.2e.3b.4d.5g.,
1a.2f.3b.4d.5g., 1b.2f.3b.4d.5g., 1f.2f.3b.4d.5g., 1h.2f.3b.4d.5g.,
1j.2f.3b.4d.5g., 1p.2f.3b.4d.5g., 1a.2i.3b.4d.5g., 1b.2i.3b.4d.5g.,
1f.2i.3b.4d.5g., 1h.2i.3b.4d.5g., 1j.2i.3b.4d.5g., 1p.2i.3b.4d.5g.,
1a.2m.3b.4d.5g., 1b.2m.3b.4d.5g., 1f.2m.3b.4d.5g., 1h.2m.3b.4d.5g.,
1j.2m.3b.4d.5g., 1p.2m.3b.4d.5g., 1a.2o.3b.4d.5g., 1b.2o.3b.4d.5g.,
1f.2o.3b.4d.5g., 1h.2o.3b.4d.5g., 1j.2o.3b.4d.5g., 1p.2o.3b.4d.5g.,
1a.2u.3b.4d.5g., 1b.2u.3b.4d.5g., 1f.2u.3b.4d.5g., 1h.2u.3b.4d.5g.,
1j.2u.3b.4d.5g., 1p.2u.3b.4d.5g., 1a.2y.3b.4d.5g., 1b.2y.3b.4d.5g.,
1f.2y.3b.4d.5g., 1h.2y.3b.4d.5g., 1j.2y.3b.4d.5g., 1p.2y.3b.4d.5g.,
1a.2a.3e.4d.5g., 1b.2a.3e.4d.5g., 1f.2a.3e.4d.5g., 1h.2a.3e.4d.5g.,
1j.2a.3e.4d.5g., 1p.2a.3e.4d.5g., 1a.2b.3e.4d.5g., 1b.2b.3e.4d.5g.,
1f.2b.3e.4d.5g., 1h.2b.3e.4d.5g., 1j.2b.3e.4d.5g., 1p.2b.3e.4d.5g.,
1a.2e.3e.4d.5g., 1b.2e.3e.4d.5g., 1f.2e.3e.4d.5g., 1h.2e.3e.4d.5g.,
1j.2e.3e.4d.5g., 1p.2e.3e.4d.5g., 1a.2f.3e.4d.5g., 1b.2f.3e.4d.5g.,
1f.2f.3e.4d.5g., 1h.2f.3e.4d.5g., 1j.2f.3e.4d.5g., 1p.2f.3e.4d.5g.,
1a.2i.3e.4d.5g., 1b.2i.3e.4d.5g., 1f.2i.3e.4d.5g., 1h.2i.3e.4d.5g.,
1j.2i.3e.4d.5g., 1p.2i.3e.4d.5g., 1a.2m.3e.4d.5g., 1b.2m.3e.4d.5g.,
1f.2m.3e.4d.5g., 1h.2m.3e.4d.5g., 1j.2m.3e.4d.5g., 1p.2m.3e.4d.5g.,
1a.2o.3e.4d.5g., 1b.2o.3e.4d.5g., 1f.2o.3e.4d.5g., 1h.2o.3e.4d.5g.,
1j.2o.3e.4d.5g., 1p.2o.3e.4d.5g., 1a.2u.3e.4d.5g., 1b.2u.3e.4d.5g.,
1f.2u.3e.4d.5g., 1h.2u.3e.4d.5g., 1j.2u.3e.4d.5g., 1p.2u.3e.4d.5g.,
1a.2y.3e.4d.5g., 1b.2y.3e.4d.5g., 1f.2y.3e.4d.5g., 1h.2y.3e.4d.5g.,
1j.2y.3e.4d.5g., 1p.2y.3e.4d.5g., 1a.2a.3g.4d.5g., 1b.2a.3g.4d.5g.,
1f.2a.3g.4d.5g., 1h.2a.3g.4d.5g., 1j.2a.3g.4d.5g., 1p.2a.3g.4d.5g.,
1a.2b.3g.4d.5g., 1b.2b.3g.4d.5g., 1f.2b.3g.4d.5g., 1h.2b.3g.4d.5g.,
1j.2b.3g.4d.5g., 1p.2b.3g.4d.5g., 1a.2e.3g.4d.5g., 1b.2e.3g.4d.5g.,
1f.2e.3g.4d.5g., 1h.2e.3g.4d.5g., 1j.2e.3g.4d.5g., 1p.2e.3g.4d.5g.,
1a.2f.3g.4d.5g., 1b.2f.3g.4d.5g., 1f.2f.3g.4d.5g., 1h.2f.3g.4d.5g.,
1j.2f.3g.4d.5g., 1p.2f.3g.4d.5g., 1a.2i.3g.4d.5g., 1b.2i.3g.4d.5g.,
1f.2i.3g.4d.5g., 1h.2i.3g.4d.5g., 1j.2i.3g.4d.5g., 1p.2i.3g.4d.5g.,
1a.2m.3g.4d.5g., 1b.2m.3g.4d.5g., 1f.2m.3g.4d.5g., 1h.2m.3g.4d.5g.,
1j.2m.3g.4d.5g., 1p.2m.3g.4d.5g., 1a.2o.3g.4d.5g., 1b.2o.3g.4d.5g.,
1f.2o.3g.4d.5g., 1h.2o.3g.4d.5g., 1j.2o.3g.4d.5g., 1p.2o.3g.4d.5g.,
1a.2u.3g.4d.5g., 1b.2u.3g.4d.5g., 1f.2u.3g.4d.5g., 1h.2u.3g.4d.5g.,
1j.2u.3g.4d.5g., 1p.2u.3g.4d.5g., 1a.2y.3g.4d.5g., 1b.2y.3g.4d.5g.,
1f.2y.3g.4d.5g., 1h.2y.3g.4d.5g., 1j.2y.3g.4d.5g., 1p.2y.3g.4d.5g.,
1a.2a.3a.4f.5g., 1b.2a.3a.4f.5g., 1f.2a.3a.4f.5g., 1h.2a.3a.4f.5g.,
1j.2a.3a.4f.5g., 1p.2a.3a.4f.5g., 1a.2b.3a.4f.5g., 1b.2b.3a.4f.5g.,
1f.2b.3a.4f.5g., 1h.2b.3a.4f.5g., 1j.2b.3a.4f.5g., 1p.2b.3a.4f.5g.,
1a.2e.3a.4f.5g., 1b.2e.3a.4f.5g., 1f.2e.3a.4f.5g., 1h.2e.3a.4f.5g.,
1j.2e.3a.4f.5g., 1p.2e.3a.4f.5g., 1a.2f.3a.4f.5g., 1b.2f.3a.4f.5g.,
1f.2f.3a.4f.5g., 1h.2f.3a.4f.5g., 1j.2f.3a.4f.5g., 1p.2f.3a.4f.5g.,
1a.2i.3a.4f.5g., 1b.2i.3a.4f.5g., 1f.2i.3a.4f.5g., 1h.2i.3a.4f.5g.,
1j.2i.3a.4f.5g., 1p.2i.3a.4f.5g., 1a.2m.3a.4f.5g., 1b.2m.3a.4f.5g.,
1f.2m.3a.4f.5g., 1h.2m.3a.4f.5g., 1j.2m.3a.4f.5g., 1p.2m.3a.4f.5g.,
1a.2o.3a.4f.5g., 1b.2o.3a.4f.5g., 1f.2o.3a.4f.5g., 1h.2o.3a.4f.5g.,
1j.2o.3a.4f.5g., 1p.2o.3a.4f.5g., 1a.2u.3a.4f.5g., 1b.2u.3a.4f.5g.,
1f.2u.3a.4f.5g., 1h.2u.3a.4f.5g., 1j.2u.3a.4f.5g., 1p.2u.3a.4f.5g.,
1a.2y.3a.4f.5g., 1b.2y.3a.4f.5g., 1f.2y.3a.4f.5g., 1h.2y.3a.4f.5g.,
1j.2y.3a.4f.5g., 1p.2y.3a.4f.5g., 1a.2a.3b.4f.5g., 1b.2a.3b.4f.5g.,
1f.2a.3b.4f.5g., 1h.2a.3b.4f.5g., 1j.2a.3b.4f.5g., 1p.2a.3b.4f.5g.,
1a.2b.3b.4f.5g., 1b.2b.3b.4f.5g., 1f.2b.3b.4f.5g., 1h.2b.3b.4f.5g.,
1j.2b.3b.4f.5g., 1p.2b.3b.4f.5g., 1a.2e.3b.4f.5g., 1b.2e.3b.4f.5g.,
1f.2e.3b.4f.5g., 1h.2e.3b.4f.5g., 1j.2e.3b.4f.5g., 1p.2e.3b.4f.5g.,
1a.2f.3b.4f.5g., 1b.2f.3b.4f.5g., 1f.2f.3b.4f.5g., 1h.2f.3b.4f.5g.,
1j.2f.3b.4f.5g., 1p.2f.3b.4f.5g., 1a.2i.3b.4f.5g., 1b.2i.3b.4f.5g.,
1f.2i.3b.4f.5g., 1h.2i.3b.4f.5g., 1j.2i.3b.4f.5g., 1p.2i.3b.4f.5g.,
1a.2m.3b.4f.5g., 1b.2m.3b.4f.5g., 1f.2m.3b.4f.5g., 1h.2m.3b.4f.5g.,
1j.2m.3b.4f.5g., 1p.2m.3b.4f.5g., 1a.2o.3b.4f.5g., 1b.2o.3b.4f.5g.,
1f.2o.3b.4f.5g., 1h.2o.3b.4f.5g., 1j.2o.3b.4f.5g., 1p.2o.3b.4f.5g.,
1a.2u.3b.4f.5g., 1b.2u.3b.4f.5g., 1f.2u.3b.4f.5g., 1h.2u.3b.4f.5g.,
1j.2u.3b.4f.5g., 1p.2u.3b.4f.5g., 1a.2y.3b.4f.5g., 1b.2y.3b.4f.5g.,
1f.2y.3b.4f.5g., 1h.2y.3b.4f.5g., 1j.2y.3b.4f.5g., 1p.2y.3b.4f.5g.,
1a.2a.3e.4f.5g., 1b.2a.3e.4f.5g., 1f.2a.3e.4f.5g., 1h.2a.3e.4f.5g.,
1j.2a.3e.4f.5g., 1p.2a.3e.4f.5g., 1a.2b.3e.4f.5g., 1b.2b.3e.4f.5g.,
1f.2b.3e.4f.5g., 1h.2b.3e.4f.5g., 1j.2b.3e.4f.5g., 1p.2b.3e.4f.5g.,
1a.2e.3e.4f.5g., 1b.2e.3e.4f.5g., 1f.2e.3e.4f.5g., 1h.2e.3e.4f.5g.,
1j.2e.3e.4f.5g., 1p.2e.3e.4f.5g., 1a.2f.3e.4f.5g., 1b.2f.3e.4f.5g.,
1f.2f.3e.4f.5g., 1h.2f.3e.4f.5g., 1j.2f.3e.4f.5g., 1p.2f.3e.4f.5g.,
1a.2i.3e.4f.5g., 1b.2i.3e.4f.5g., 1f.2i.3e.4f.5g., 1h.2i.3e.4f.5g.,
1j.2i.3e.4f.5g., 1p.2i.3e.4f.5g., 1a.2m.3e.4f.5g., 1b.2m.3e.4f.5g.,
1f.2m.3e.4f.5g., 1h.2m.3e.4f.5g., 1j.2m.3e.4f.5g., 1p.2m.3e.4f.5g.,
1a.2o.3e.4f.5g., 1b.2o.3e.4f.5g., 1f.2o.3e.4f.5g., 1h.2o.3e.4f.5g.,
1j.2o.3e.4f.5g., 1p.2o.3e.4f.5g., 1a.2u.3e.4f.5g., 1b.2u.3e.4f.5g.,
1f.2u.3e.4f.5g., 1h.2u.3e.4f.5g., 1j.2u.3e.4f.5g., 1p.2u.3e.4f.5g.,
1a.2y.3e.4f.5g., 1b.2y.3e.4f.5g., 1f.2y.3e.4f.5g., 1h.2y.3e.4f.5g.,
1j.2y.3e.4f.5g., 1p.2y.3e.4f.5g., 1a.2a.3g.4f.5g., 1b.2a.3g.4f.5g.,
1f.2a.3g.4f.5g., 1h.2a.3g.4f.5g., 1j.2a.3g.4f.5g., 1p.2a.3g.4f.5g.,
1a.2b.3g.4f.5g., 1b.2b.3g.4f.5g., 1f.2b.3g.4f.5g., 1h.2b.3g.4f.5g.,
1j.2b.3g.4f.5g., 1p.2b.3g.4f.5g., 1a.2e.3g.4f.5g., 1b.2e.3g.4f.5g.,
1f.2e.3g.4f.5g., 1h.2e.3g.4f.5g., 1j.2e.3g.4f.5g., 1p.2e.3g.4f.5g.,
1a.2f.3g.4f.5g., 1b.2f.3g.4f.5g., 1f.2f.3g.4f.5g., 1h.2f.3g.4f.5g.,
1j.2f.3g.4f.5g., 1p.2f.3g.4f.5g., 1a.2i.3g.4f.5g., 1b.2i.3g.4f.5g.,
1f.2i.3g.4f.5g., 1h.2i.3g.4f.5g., 1j.2i.3g.4f.5g., 1p.2i.3g.4f.5g.,
1a.2m.3g.4f.5g., 1b.2m.3g.4f.5g., 1f.2m.3g.4f.5g., 1h.2m.3g.4f.5g.,
1j.2m.3g.4f.5g., 1p.2m.3g.4f.5g., 1a.2o.3g.4f.5g., 1b.2o.3g.4f.5g.,
1f.2o.3g.4f.5g., 1h.2o.3g.4f.5g., 1j.2o.3g.4f.5g., 1p.2o.3g.4f.5g.,
1a.2u.3g.4f.5g., 1b.2u.3g.4f.5g., 1f.2u.3g.4f.5g., 1h.2u.3g.4f.5g.,
1j.2u.3g.4f.5g., 1p.2u.3g.4f.5g., 1a.2y.3g.4f.5g., 1b.2y.3g.4f.5g.,
1f.2y.3g.4f.5g., 1h.2y.3g.4f.5g., 1j.2y.3g.4f.5g., 1p.2y.3g.4f.5g.,
1a.2a.3a.4g.5g., 1b.2a.3a.4g.5g., 1f.2a.3a.4g.5g., 1h.2a.3a.4g.5g.,
1j.2a.3a.4g.5g., 1p.2a.3a.4g.5g., 1a.2b.3a.4g.5g., 1b.2b.3a.4g.5g.,
1f.2b.3a.4g.5g., 1h.2b.3a.4g.5g., 1j.2b.3a.4g.5g., 1p.2b.3a.4g.5g.,
1a.2e.3a.4g.5g., 1b.2e.3a.4g.5g., 1f.2e.3a.4g.5g., 1h.2e.3a.4g.5g.,
1j.2e.3a.4g.5g., 1p.2e.3a.4g.5g., 1a.2f.3a.4g.5g., 1b.2f.3a.4g.5g.,
1f.2f.3a.4g.5g., 1h.2f.3a.4g.5g., 1j.2f.3a.4g.5g., 1p.2f.3a.4g.5g.,
1a.2i.3a.4g.5g., 1b.2i.3a.4g.5g., 1f.2i.3a.4g.5g., 1h.2i.3a.4g.5g.,
1j.2i.3a.4g.5g., 1p.2i.3a.4g.5g., 1a.2m.3a.4g.5g., 1b.2m.3a.4g.5g.,
1f.2m.3a.4g.5g., 1h.2m.3a.4g.5g., 1j.2m.3a.4g.5g., 1p.2m.3a.4g.5g.,
1a.2o.3a.4g.5g., 1b.2o.3a.4g.5g., 1f.2o.3a.4g.5g., 1h.2o.3a.4g.5g.,
1j.2o.3a.4g.5g., 1p.2o.3a.4g.5g., 1a.2u.3a.4g.5g., 1b.2u.3a.4g.5g.,
1f.2u.3a.4g.5g., 1h.2u.3a.4g.5g., 1j.2u.3a.4g.5g., 1p.2u.3a.4g.5g.,
1a.2y.3a.4g.5g., 1b.2y.3a.4g.5g., 1f.2y.3a.4g.5g., 1h.2y.3a.4g.5g.,
1j.2y.3a.4g.5g., 1p.2y.3a.4g.5g., 1a.2a.3b.4g.5g., 1b.2a.3b.4g.5g.,
1f.2a.3b.4g.5g., 1h.2a.3b.4g.5g., 1j.2a.3b.4g.5g., 1p.2a.3b.4g.5g.,
1a.2b.3b.4g.5g., 1b.2b.3b.4g.5g., 1f.2b.3b.4g.5g., 1h.2b.3b.4g.5g.,
1j.2b.3b.4g.5g., 1p.2b.3b.4g.5g., 1a.2e.3b.4g.5g., 1b.2e.3b.4g.5g.,
1f.2e.3b.4g.5g., 1h.2e.3b.4g.5g., 1j.2e.3b.4g.5g., 1p.2e.3b.4g.5g.,
1a.2f.3b.4g.5g., 1b.2f.3b.4g.5g., 1f.2f.3b.4g.5g., 1h.2f.3b.4g.5g.,
1j.2f.3b.4g.5g., 1p.2f.3b.4g.5g., 1a.2i.3b.4g.5g., 1b.2i.3b.4g.5g.,
1f.2i.3b.4g.5g., 1h.2i.3b.4g.5g., 1j.2i.3b.4g.5g., 1p.2i.3b.4g.5g.,
1a.2m.3b.4g.5g., 1b.2m.3b.4g.5g., 1f.2m.3b.4g.5g., 1h.2m.3b.4g.5g.,
1j.2m.3b.4g.5g., 1p.2m.3b.4g.5g., 1a.2o.3b.4g.5g., 1b.2o.3b.4g.5g.,
1f.2o.3b.4g.5g., 1h.2o.3b.4g.5g., 1j.2o.3b.4g.5g., 1p.2o.3b.4g.5g.,
1a.2u.3b.4g.5g., 1b.2u.3b.4g.5g., 1f.2u.3b.4g.5g., 1h.2u.3b.4g.5g.,
1j.2u.3b.4g.5g., 1p.2u.3b.4g.5g., 1a.2y.3b.4g.5g., 1b.2y.3b.4g.5g.,
1f.2y.3b.4g.5g., 1h.2y.3b.4g.5g., 1j.2y.3b.4g.5g., 1p.2y.3b.4g.5g.,
1a.2a.3e.4g.5g., 1b.2a.3e.4g.5g., 1f.2a.3e.4g.5g., 1h.2a.3e.4g.5g.,
1j.2a.3e.4g.5g., 1p.2a.3e.4g.5g., 1a.2b.3e.4g.5g., 1b.2b.3e.4g.5g.,
1f.2b.3e.4g.5g., 1h.2b.3e.4g.5g., 1j.2b.3e.4g.5g., 1p.2b.3e.4g.5g.,
1a.2e.3e.4g.5g., 1b.2e.3e.4g.5g., 1f.2e.3e.4g.5g., 1h.2e.3e.4g.5g.,
1j.2e.3e.4g.5g., 1p.2e.3e.4g.5g., 1a.2f.3e.4g.5g., 1b.2f.3e.4g.5g.,
1f.2f.3e.4g.5g., 1h.2f.3e.4g.5g., 1j.2f.3e.4g.5g., 1p.2f.3e.4g.5g.,
1a.2i.3e.4g.5g., 1b.2i.3e.4g.5g., 1f.2i.3e.4g.5g., 1h.2i.3e.4g.5g.,
1j.2i.3e.4g.5g., 1p.2i.3e.4g.5g., 1a.2m.3e.4g.5g., 1b.2m.3e.4g.5g.,
1f.2m.3e.4g.5g., 1h.2m.3e.4g.5g., 1j.2m.3e.4g.5g., 1p.2m.3e.4g.5g.,
1a.2o.3e.4g.5g., 1b.2o.3e.4g.5g., 1f.2o.3e.4g.5g., 1h.2o.3e.4g.5g.,
1j.2o.3e.4g.5g., 1p.2o.3e.4g.5g., 1a.2u.3e.4g.5g., 1b.2u.3e.4g.5g.,
1f.2u.3e.4g.5g., 1h.2u.3e.4g.5g., 1j.2u.3e.4g.5g., 1p.2u.3e.4g.5g.,
1a.2y.3e.4g.5g., 1b.2y.3e.4g.5g., 1f.2y.3e.4g.5g., 1h.2y.3e.4g.5g.,
1j.2y.3e.4g.5g., 1p.2y.3e.4g.5g., 1a.2a.3g.4g.5g., 1b.2a.3g.4g.5g.,
1f.2a.3g.4g.5g., 1h.2a.3g.4g.5g., 1j.2a.3g.4g.5g., 1p.2a.3g.4g.5g.,
1a.2b.3g.4g.5g., 1b.2b.3g.4g.5g., 1f.2b.3g.4g.5g., 1h.2b.3g.4g.5g.,
1j.2b.3g.4g.5g., 1p.2b.3g.4g.5g., 1a.2e.3g.4g.5g., 1b.2e.3g.4g.5g.,
1f.2e.3g.4g.5g., 1h.2e.3g.4g.5g., 1j.2e.3g.4g.5g., 1p.2e.3g.4g.5g.,
1a.2f.3g.4g.5g., 1b.2f.3g.4g.5g., 1f.2f.3g.4g.5g., 1h.2f.3g.4g.5g.,
1j.2f.3g.4g.5g., 1p.2f.3g.4g.5g., 1a.2i.3g.4g.5g., 1b.2i.3g.4g.5g.,
1f.2i.3g.4g.5g., 1h.2i.3g.4g.5g., 1j.2i.3g.4g.5g., 1p.2i.3g.4g.5g.,
1a.2m.3g.4g.5g., 1b.2m.3g.4g.5g., 1f.2m.3g.4g.5g., 1h.2m.3g.4g.5g.,
1j.2m.3g.4g.5g., 1p.2m.3g.4g.5g., 1a.2o.3g.4g.5g., 1b.2o.3g.4g.5g.,
1f.2o.3g.4g.5g., 1h.2o.3g.4g.5g., 1j.2o.3g.4g.5g., 1p.2o.3g.4g.5g.,
1a.2u.3g.4g.5g., 1b.2u.3g.4g.5g., 1f.2u.3g.4g.5g., 1h.2u.3g.4g.5g.,
1j.2u.3g.4g.5g., 1p.2u.3g.4g.5g., 1a.2y.3g.4g.5g., 1b.2y.3g.4g.5g.,
1f.2y.3g.4g.5g., 1h.2y.3g.4g.5g., 1j.2y.3g.4g.5g., 1p.2y.3g.4g.5g.,
1a.2a.3a.4h.5g., 1b.2a.3a.4h.5g., 1f.2a.3a.4h.5g., 1h.2a.3a.4h.5g.,
1j.2a.3a.4h.5g., 1p.2a.3a.4h.5g., 1a.2b.3a.4h.5g., 1b.2b.3a.4h.5g.,
1f.2b.3a.4h.5g., 1h.2b.3a.4h.5g., 1j.2b.3a.4h.5g., 1p.2b.3a.4h.5g.,
1a.2e.3a.4h.5g., 1b.2e.3a.4h.5g., 1f.2e.3a.4h.5g., 1h.2e.3a.4h.5g.,
1j.2e.3a.4h.5g., 1p.2e.3a.4h.5g., 1a.2f.3a.4h.5g., 1b.2f.3a.4h.5g.,
1f.2f.3a.4h.5g., 1h.2f.3a.4h.5g., 1j.2f.3a.4h.5g., 1p.2f.3a.4h.5g.,
1a.2i.3a.4h.5g., 1b.2i.3a.4h.5g., 1f.2i.3a.4h.5g., 1h.2i.3a.4h.5g.,
1j.2i.3a.4h.5g., 1p.2i.3a.4h.5g., 1a.2m.3a.4h.5g., 1b.2m.3a.4h.5g.,
1f.2m.3a.4h.5g., 1h.2m.3a.4h.5g., 1j.2m.3a.4h.5g., 1p.2m.3a.4h.5g.,
1a.2o.3a.4h.5g., 1b.2o.3a.4h.5g., 1f.2o.3a.4h.5g., 1h.2o.3a.4h.5g.,
1j.2o.3a.4h.5g., 1p.2o.3a.4h.5g., 1a.2u.3a.4h.5g., 1b.2u.3a.4h.5g.,
1f.2u.3a.4h.5g., 1h.2u.3a.4h.5g., 1j.2u.3a.4h.5g., 1p.2u.3a.4h.5g.,
1a.2y.3a.4h.5g., 1b.2y.3a.4h.5g., 1f.2y.3a.4h.5g., 1h.2y.3a.4h.5g.,
1j.2y.3a.4h.5g., 1p.2y.3a.4h.5g., 1a.2a.3b.4h.5g., 1b.2a.3b.4h.5g.,
1f.2a.3b.4h.5g., 1h.2a.3b.4h.5g., 1j.2a.3b.4h.5g., 1p.2a.3b.4h.5g.,
1a.2b.3b.4h.5g., 1b.2b.3b.4h.5g., 1f.2b.3b.4h.5g., 1h.2b.3b.4h.5g.,
1j.2b.3b.4h.5g., 1p.2b.3b.4h.5g., 1a.2e.3b.4h.5g., 1b.2e.3b.4h.5g.,
1f.2e.3b.4h.5g., 1h.2e.3b.4h.5g., 1j.2e.3b.4h.5g., 1p.2e.3b.4h.5g.,
1a.2f.3b.4h.5g., 1b.2f.3b.4h.5g., 1f.2f.3b.4h.5g., 1h.2f.3b.4h.5g.,
1j.2f.3b.4h.5g., 1p.2f.3b.4h.5g., 1a.2i.3b.4h.5g., 1b.2i.3b.4h.5g.,
1f.2i.3b.4h.5g., 1h.2i.3b.4h.5g., 1j.2i.3b.4h.5g., 1p.2i.3b.4h.5g.,
1a.2m.3b.4h.5g., 1b.2m.3b.4h.5g., 1f.2m.3b.4h.5g., 1h.2m.3b.4h.5g.,
1j.2m.3b.4h.5g., 1p.2m.3b.4h.5g., 1a.2o.3b.4h.5g., 1b.2o.3b.4h.5g.,
1f.2o.3b.4h.5g., 1h.2o.3b.4h.5g., 1j.2o.3b.4h.5g., 1p.2o.3b.4h.5g.,
1a.2u.3b.4h.5g., 1b.2u.3b.4h.5g., 1f.2u.3b.4h.5g., 1h.2u.3b.4h.5g.,
1j.2u.3b.4h.5g., 1p.2u.3b.4h.5g., 1a.2y.3b.4h.5g., 1b.2y.3b.4h.5g.,
1f.2y.3b.4h.5g., 1h.2y.3b.4h.5g., 1j.2y.3b.4h.5g., 1p.2y.3b.4h.5g.,
1a.2a.3e.4h.5g., 1b.2a.3e.4h.5g., 1f.2a.3e.4h.5g., 1h.2a.3e.4h.5g.,
1j.2a.3e.4h.5g., 1p.2a.3e.4h.5g., 1a.2b.3e.4h.5g., 1b.2b.3e.4h.5g.,
1f.2b.3e.4h.5g., 1h.2b.3e.4h.5g., 1j.2b.3e.4h.5g., 1p.2b.3e.4h.5g.,
1a.2e.3e.4h.5g., 1b.2e.3e.4h.5g., 1f.2e.3e.4h.5g., 1h.2e.3e.4h.5g.,
1j.2e.3e.4h.5g., 1p.2e.3e.4h.5g., 1a.2f.3e.4h.5g., 1b.2f.3e.4h.5g.,
1f.2f.3e.4h.5g., 1h.2f.3e.4h.5g., 1j.2f.3e.4h.5g., 1p.2f.3e.4h.5g.,
1a.2i.3e.4h.5g., 1b.2i.3e.4h.5g., 1f.2i.3e.4h.5g., 1h.2i.3e.4h.5g.,
1j.2i.3e.4h.5g., 1p.2i.3e.4h.5g., 1a.2m.3e.4h.5g., 1b.2m.3e.4h.5g.,
1f.2m.3e.4h.5g., 1h.2m.3e.4h.5g., 1j.2m.3e.4h.5g., 1p.2m.3e.4h.5g.,
1a.2o.3e.4h.5g., 1b.2o.3e.4h.5g., 1f.2o.3e.4h.5g., 1h.2o.3e.4h.5g.,
1j.2o.3e.4h.5g., 1p.2o.3e.4h.5g., 1a.2u.3e.4h.5g., 1b.2u.3e.4h.5g.,
1f.2u.3e.4h.5g., 1h.2u.3e.4h.5g., 1j.2u.3e.4h.5g., 1p.2u.3e.4h.5g.,
1a.2y.3e.4h.5g., 1b.2y.3e.4h.5g., 1f.2y.3e.4h.5g., 1h.2y.3e.4h.5g.,
1j.2y.3e.4h.5g., 1p.2y.3e.4h.5g., 1a.2a.3g.4h.5g., 1b.2a.3g.4h.5g.,
1f.2a.3g.4h.5g., 1h.2a.3g.4h.5g., 1j.2a.3g.4h.5g., 1p.2a.3g.4h.5g.,
1a.2b.3g.4h.5g., 1b.2b.3g.4h.5g., 1f.2b.3g.4h.5g., 1h.2b.3g.4h.5g.,
1j.2b.3g.4h.5g., 1p.2b.3g.4h.5g., 1a.2e.3g.4h.5g., 1b.2e.3g.4h.5g.,
1f.2e.3g.4h.5g., 1h.2e.3g.4h.5g., 1j.2e.3g.4h.5g., 1p.2e.3g.4h.5g.,
1a.2f.3g.4h.5g., 1b.2f.3g.4h.5g., 1f.2f.3g.4h.5g., 1h.2f.3g.4h.5g.,
1j.2f.3g.4h.5g., 1p.2f.3g.4h.5g., 1a.2i.3g.4h.5g., 1b.2i.3g.4h.5g.,
1f.2i.3g.4h.5g., 1h.2i.3g.4h.5g., 1j.2i.3g.4h.5g., 1p.2i.3g.4h.5g.,
1a.2m.3g.4h.5g., 1b.2m.3g.4h.5g., 1f.2m.3g.4h.5g., 1h.2m.3g.4h.5g.,
1j.2m.3g.4h.5g., 1p.2m.3g.4h.5g., 1a.2o.3g.4h.5g., 1b.2o.3g.4h.5g.,
1f.2o.3g.4h.5g., 1h.2o.3g.4h.5g., 1j.2o.3g.4h.5g., 1p.2o.3g.4h.5g.,
1a.2u.3g.4h.5g., 1b.2u.3g.4h.5g., 1f.2u.3g.4h.5g., 1h.2u.3g.4h.5g.,
1j.2u.3g.4h.5g., 1p.2u.3g.4h.5g., 1a.2y.3g.4h.5g., 1b.2y.3g.4h.5g.,
1f.2y.3g.4h.5g., 1h.2y.3g.4h.5g., 1j.2y.3g.4h.5g., 1p.2y.3g.4h.5g.,
1a.2a.3a.4i.5g., 1b.2a.3a.4i.5g., 1f.2a.3a.4i.5g., 1h.2a.3a.4i.5g.,
1j.2a.3a.4i.5g., 1p.2a.3a.4i.5g., 1a.2b.3a.4i.5g., 1b.2b.3a.4i.5g.,
1f.2b.3a.4i.5g., 1h.2b.3a.4i.5g., 1j.2b.3a.4i.5g., 1p.2b.3a.4i.5g.,
1a.2e.3a.4i.5g., 1b.2e.3a.4i.5g., 1f.2e.3a.4i.5g., 1h.2e.3a.4i.5g.,
1j.2e.3a.4i.5g., 1p.2e.3a.4i.5g., 1a.2f.3a.4i.5g., 1b.2f.3a.4i.5g.,
1f.2f.3a.4i.5g., 1h.2f.3a.4i.5g., 1j.2f.3a.4i.5g., 1p.2f.3a.4i.5g.,
1a.2i.3a.4i.5g., 1b.2i.3a.4i.5g., 1f.2i.3a.4i.5g.,
1h.2i.3a.4i.5g.,
1j.2i.3a.4i.5g., 1p.2i.3a.4i.5g., 1a.2m.3a.4i.5g., 1b.2m.3a.4i.5g.,
1f.2m.3a.4i.5g., 1h.2m.3a.4i.5g., 1j.2m.3a.4i.5g., 1p.2m.3a.4i.5g.,
1a.2o.3a.4i.5g., 1b.2o.3a.4i.5g., 1f.2o.3a.4i.5g., 1h.2o.3a.4i.5g.,
1j.2o.3a.4i.5g., 1p.2o.3a.4i.5g., 1a.2u.3a.4i.5g., 1b.2u.3a.4i.5g.,
1f.2u.3a.4i.5g., 1h.2u.3a.4i.5g., 1j.2u.3a.4i.5g., 1p.2u.3a.4i.5g.,
1a.2y.3a.4i.5g., 1b.2y.3a.4i.5g., 1f.2y.3a.4i.5g., 1h.2y.3a.4i.5g.,
1j.2y.3a.4i.5g., 1p.2y.3a.4i.5g., 1a.2a.3b.4i.5g., 1b.2a.3b.4i.5g.,
1f.2a.3b.4i.5g., 1h.2a.3b.4i.5g., 1j.2a.3b.4i.5g., 1p.2a.3b.4i.5g.,
1a.2b.3b.4i.5g., 1b.2b.3b.4i.5g., 1f.2b.3b.4i.5g., 1h.2b.3b.4i.5g.,
1j.2b.3b.4i.5g., 1p.2b.3b.4i.5g., 1a.2e.3b.4i.5g., 1b.2e.3b.4i.5g.,
1f.2e.3b.4i.5g., 1h.2e.3b.4i.5g., 1j.2e.3b.4i.5g., 1p.2e.3b.4i.5g.,
1a.2f.3b.4i.5g., 1b.2f.3b.4i.5g., 1f.2f.3b.4i.5g., 1h.2f.3b.4i.5g.,
1j.2f.3b.4i.5g., 1p.2f.3b.4i.5g., 1a.2i.3b.4i.5g., 1b.2i.3b.4i.5g.,
1f.2i.3b.4i.5g., 1h.2i.3b.4i.5g., 1j.2i.3b.4i.5g., 1p.2i.3b.4i.5g.,
1a.2m.3b.4i.5g., 1b.2m.3b.4i.5g., 1f.2m.3b.4i.5g., 1h.2m.3b.4i.5g.,
1j.2m.3b.4i.5g., 1p.2m.3b.4i.5g., 1a.2o.3b.4i.5g., 1b.2o.3b.4i.5g.,
1f.2o.3b.4i.5g., 1h.2o.3b.4i.5g., 1j.2o.3b.4i.5g., 1p.2o.3b.4i.5g.,
1a.2u.3b.4i.5g., 1b.2u.3b.4i.5g., 1f.2u.3b.4i.5g., 1h.2u.3b.4i.5g.,
1j.2u.3b.4i.5g., 1p.2u.3b.4i.5g., 1a.2y.3b.4i.5g., 1b.2y.3b.4i.5g.,
1f.2y.3b.4i.5g., 1h.2y.3b.4i.5g., 1j.2y.3b.4i.5g., 1p.2y.3b.4i.5g.,
1a.2a.3e.4i.5g., 1b.2a.3e.4i.5g., 1f.2a.3e.4i.5g., 1h.2a.3e.4i.5g.,
1j.2a.3e.4i.5g., 1p.2a.3e.4i.5g., 1a.2b.3e.4i.5g., 1b.2b.3e.4i.5g.,
1f.2b.3e.4i.5g., 1h.2b.3e.4i.5g., 1j.2b.3e.4i.5g., 1p.2b.3e.4i.5g.,
1a.2e.3e.4i.5g., 1b.2e.3e.4i.5g., 1f.2e.3e.4i.5g., 1h.2e.3e.4i.5g.,
1j.2e.3e.4i.5g., 1p.2e.3e.4i.5g., 1a.2f.3e.4i.5g., 1b.2f.3e.4i.5g.,
1f.2f.3e.4i.5g., 1h.2f.3e.4i.5g., 1j.2f.3e.4i.5g., 1p.2f.3e.4i.5g.,
1a.2i.3e.4i.5g., 1b.2i.3e.4i.5g., 1f.2i.3e.4i.5g., 1h.2i.3e.4i.5g.,
1j.2i.3e.4i.5g., 1p.2i.3e.4i.5g., 1a.2m.3e.4i.5g., 1b.2m.3e.4i.5g.,
1f.2m.3e.4i.5g., 1h.2m.3e.4i.5g., 1j.2m.3e.4i.5g., 1p.2m.3e.4i.5g.,
1a.2o.3e.4i.5g., 1b.2o.3e.4i.5g., 1f.2o.3e.4i.5g., 1h.2o.3e.4i.5g.,
1j.2o.3e.4i.5g., 1p.2o.3e.4i.5g., 1a.2u.3e.4i.5g., 1b.2u.3e.4i.5g.,
1f.2u.3e.4i.5g., 1h.2u.3e.4i.5g., 1j.2u.3e.4i.5g., 1p.2u.3e.4i.5g.,
1a.2y.3e.4i.5g., 1b.2y.3e.4i.5g., 1f.2y.3e.4i.5g., 1h.2y.3e.4i.5g.,
1j.2y.3e.4i.5g., 1p.2y.3e.4i.5g., 1a.2a.3g.4i.5g., 1b.2a.3g.4i.5g.,
1f.2a.3g.4i.5g., 1h.2a.3g.4i.5g., 1j.2a.3g.4i.5g., 1p.2a.3g.4i.5g.,
1a.2b.3g.4i.5g., 1b.2b.3g.4i.5g., 1f.2b.3g.4i.5g., 1h.2b.3g.4i.5g.,
1j.2b.3g.4i.5g., 1p.2b.3g.4i.5g., 1a.2e.3g.4i.5g., 1b.2e.3g.4i.5g.,
1f.2e.3g.4i.5g., 1h.2e.3g.4i.5g., 1j.2e.3g.4i.5g., 1p.2e.3g.4i.5g.,
1a.2f.3g.4i.5g., 1b.2f.3g.4i.5g., 1f.2f.3g.4i.5g., 1h.2f.3g.4i.5g.,
1j.2f.3g.4i.5g., 1p.2f.3g.4i.5g., 1a.2i.3g.4i.5g., 1b.2i.3g.4i.5g.,
1f.2i.3g.4i.5g., 1h.2i.3g.4i.5g., 1j.2i.3g.4i.5g., 1p.2i.3g.4i.5g.,
1a.2m.3g.4i.5g., 1b.2m.3g.4i.5g., 1f.2m.3g.4i.5g., 1h.2m.3g.4i.5g.,
1j.2m.3g.4i.5g., 1p.2m.3g.4i.5g., 1a.2o.3g.4i.5g., 1b.2o.3g.4i.5g.,
1f.2o.3g.4i.5g., 1h.2o.3g.4i.5g., 1j.2o.3g.4i.5g., 1p.2o.3g.4i.5g.,
1a.2u.3g.4i.5g., 1b.2u.3g.4i.5g., 1f.2u.3g.4i.5g., 1h.2u.3g.4i.5g.,
1j.2u.3g.4i.5g., 1p.2u.3g.4i.5g., 1a.2y.3g.4i.5g., 1b.2y.3g.4i.5g.,
1f.2y.3g.4i.5g., 1h.2y.3g.4i.5g., 1j.2y.3g.4i.5g., 1p.2y.3g.4i.5g.,
1a.2a.3a.4a.5h., 1b.2a.3a.4a.5h., 1f.2a.3a.4a.5h., 1h.2a.3a.4a.5h.,
1j.2a.3a.4a.5h., 1p.2a.3a.4a.5h., 1a.2b.3a.4a.5h., 1b.2b.3a.4a.5h.,
1f.2b.3a.4a.5h., 1h.2b.3a.4a.5h., 1j.2b.3a.4a.5h., 1p.2b.3a.4a.5h.,
1a.2e.3a.4a.5h., 1b.2e.3a.4a.5h., 1f.2e.3a.4a.5h., 1h.2e.3a.4a.5h.,
1j.2e.3a.4a.5h., 1p.2e.3a.4a.5h., 1a.2f.3a.4a.5h., 1b.2f.3a.4a.5h.,
1f.2f.3a.4a.5h., 1h.2f.3a.4a.5h., 1j.2f.3a.4a.5h., 1p.2f.3a.4a.5h.,
1a.2i.3a.4a.5h., 1b.2i.3a.4a.5h., 1f.2i.3a.4a.5h., 1h.2i.3a.4a.5h.,
1j.2i.3a.4a.5h., 1p.2i.3a.4a.5h., 1a.2m.3a.4a.5h., 1b.2m.3a.4a.5h.,
1f.2m.3a.4a.5h., 1h.2m.3a.4a.5h., 1j.2m.3a.4a.5h., 1p.2m.3a.4a.5h.,
1a.2o.3a.4a.5h., 1b.2o.3a.4a.5h., 1f.2o.3a.4a.5h., 1h.2o.3a.4a.5h.,
1j.2o.3a.4a.5h., 1p.2o.3a.4a.5h., 1a.2u.3a.4a.5h., 1b.2u.3a.4a.5h.,
1f.2u.3a.4a.5h., 1h.2u.3a.4a.5h., 1j.2u.3a.4a.5h., 1p.2u.3a.4a.5h.,
1a.2y.3a.4a.5h., 1b.2y.3a.4a.5h., 1f.2y.3a.4a.5h., 1h.2y.3a.4a.5h.,
1j.2y.3a.4a.5h., 1p.2y.3a.4a.5h., 1a.2a.3b.4a.5h., 1b.2a.3b.4a.5h.,
1f.2a.3b.4a.5h., 1h.2a.3b.4a.5h., 1j.2a.3b.4a.5h., 1p.2a.3b.4a.5h.,
1a.2b.3b.4a.5h., 1b.2b.3b.4a.5h., 1f.2b.3b.4a.5h., 1h.2b.3b.4a.5h.,
1j.2b.3b.4a.5h., 1p.2b.3b.4a.5h., 1a.2e.3b.4a.5h., 1b.2e.3b.4a.5h.,
1f.2e.3b.4a.5h., 1h.2e.3b.4a.5h., 1j.2e.3b.4a.5h., 1p.2e.3b.4a.5h.,
1a.2f.3b.4a.5h., 1b.2f.3b.4a.5h., 1f.2f.3b.4a.5h., 1h.2f.3b.4a.5h.,
1j.2f.3b.4a.5h., 1p.2f.3b.4a.5h., 1a.2i.3b.4a.5h., 1b.2i.3b.4a.5h.,
1f.2i.3b.4a.5h., 1h.2i.3b.4a.5h., 1j.2i.3b.4a.5h., 1p.2i.3b.4a.5h.,
1a.2m.3b.4a.5h., 1b.2m.3b.4a.5h., 1f.2m.3b.4a.5h., 1h.2m.3b.4a.5h.,
1j.2m.3b.4a.5h., 1p.2m.3b.4a.5h., 1a.2o.3b.4a.5h., 1b.2o.3b.4a.5h.,
1f.2o.3b.4a.5h., 1h.2o.3b.4a.5h., 1j.2o.3b.4a.5h., 1p.2o.3b.4a.5h.,
1a.2u.3b.4a.5h., 1b.2u.3b.4a.5h., 1f.2u.3b.4a.5h., 1h.2u.3b.4a.5h.,
1j.2u.3b.4a.5h., 1p.2u.3b.4a.5h., 1a.2y.3b.4a.5h., 1b.2y.3b.4a.5h.,
1f.2y.3b.4a.5h., 1h.2y.3b.4a.5h., 1j.2y.3b.4a.5h., 1p.2y.3b.4a.5h.,
1a.2a.3e.4a.5h., 1b.2a.3e.4a.5h., 1f.2a.3e.4a.5h., 1h.2a.3e.4a.5h.,
1j.2a.3e.4a.5h., 1p.2a.3e.4a.5h., 1a.2b.3e.4a.5h., 1b.2b.3e.4a.5h.,
1f.2b.3e.4a.5h., 1h.2b.3e.4a.5h., 1j.2b.3e.4a.5h., 1p.2b.3e.4a.5h.,
1a.2e.3e.4a.5h., 1b.2e.3e.4a.5h., 1f.2e.3e.4a.5h., 1h.2e.3e.4a.5h.,
1j.2e.3e.4a.5h., 1p.2e.3e.4a.5h., 1a.2f.3e.4a.5h., 1b.2f.3e.4a.5h.,
1f.2f.3e.4a.5h., 1h.2f.3e.4a.5h., 1j.2f.3e.4a.5h., 1p.2f.3e.4a.5h.,
1a.2i.3e.4a.5h., 1b.2i.3e.4a.5h., 1f.2i.3e.4a.5h., 1h.2i.3e.4a.5h.,
1j.2i.3e.4a.5h., 1p.2i.3e.4a.5h., 1a.2m.3e.4a.5h., 1b.2m.3e.4a.5h.,
1f.2m.3e.4a.5h., 1h.2m.3e.4a.5h., 1j.2m.3e.4a.5h., 1p.2m.3e.4a.5h.,
1a.2o.3e.4a.5h., 1b.2o.3e.4a.5h., 1f.2o.3e.4a.5h., 1h.2o.3e.4a.5h.,
1j.2o.3e.4a.5h., 1p.2o.3e.4a.5h., 1a.2u.3e.4a.5h., 1b.2u.3e.4a.5h.,
1f.2u.3e.4a.5h., 1h.2u.3e.4a.5h., 1j.2u.3e.4a.5h., 1p.2u.3e.4a.5h.,
1a.2y.3e.4a.5h., 1b.2y.3e.4a.5h., 1f.2y.3e.4a.5h., 1h.2y.3e.4a.5h.,
1j.2y.3e.4a.5h., 1p.2y.3e.4a.5h., 1a.2a.3g.4a.5h., 1b.2a.3g.4a.5h.,
1f.2a.3g.4a.5h., 1h.2a.3g.4a.5h., 1j.2a.3g.4a.5h., 1p.2a.3g.4a.5h.,
1a.2b.3g.4a.5h., 1b.2b.3g.4a.5h., 1f.2b.3g.4a.5h., 1h.2b.3g.4a.5h.,
1j.2b.3g.4a.5h., 1p.2b.3g.4a.5h., 1a.2e.3g.4a.5h., 1b.2e.3g.4a.5h.,
1f.2e.3g.4a.5h., 1h.2e.3g.4a.5h., 1j.2e.3g.4a.5h., 1p.2e.3g.4a.5h.,
1a.2f.3g.4a.5h., 1b.2f.3g.4a.5h., 1f.2f.3g.4a.5h., 1h.2f.3g.4a.5h.,
1j.2f.3g.4a.5h., 1p.2f.3g.4a.5h., 1a.2i.3g.4a.5h., 1b.2i.3g.4a.5h.,
1f.2i.3g.4a.5h., 1h.2i.3g.4a.5h., 1j.2i.3g.4a.5h., 1p.2i.3g.4a.5h.,
1a.2m.3g.4a.5h., 1b.2m.3g.4a.5h., 1f.2m.3g.4a.5h., 1h.2m.3g.4a.5h.,
1j.2m.3g.4a.5h., 1p.2m.3g.4a.5h., 1a.2o.3g.4a.5h., 1b.2o.3g.4a.5h.,
1f.2o.3g.4a.5h., 1h.2o.3g.4a.5h., 1j.2o.3g.4a.5h., 1p.2o.3g.4a.5h.,
1a.2u.3g.4a.5h., 1b.2u.3g.4a.5h., 1f.2u.3g.4a.5h., 1h.2u.3g.4a.5h.,
1j.2u.3g.4a.5h., 1p.2u.3g.4a.5h., 1a.2y.3g.4a.5h., 1b.2y.3g.4a.5h.,
1f.2y.3g.4a.5h., 1h.2y.3g.4a.5h., 1j.2y.3g.4a.5h., 1p.2y.3g.4a.5h.,
1a.2a.3a.4d.5h., 1b.2a.3a.4d.5h., 1f.2a.3a.4d.5h., 1h.2a.3a.4d.5h.,
1j.2a.3a.4d.5h., 1p.2a.3a.4d.5h., 1a.2b.3a.4d.5h., 1b.2b.3a.4d.5h.,
1f.2b.3a.4d.5h., 1h.2b.3a.4d.5h., 1j.2b.3a.4d.5h., 1p.2b.3a.4d.5h.,
1a.2e.3a.4d.5h., 1b.2e.3a.4d.5h., 1f.2e.3a.4d.5h., 1h.2e.3a.4d.5h.,
1j.2e.3a.4d.5h., 1p.2e.3a.4d.5h., 1a.2f.3a.4d.5h., 1b.2f.3a.4d.5h.,
1f.2f.3a.4d.5h., 1h.2f.3a.4d.5h., 1j.2f.3a.4d.5h., 1p.2f.3a.4d.5h.,
1a.2i.3a.4d.5h., 1b.2i.3a.4d.5h., 1f.2i.3a.4d.5h., 1h.2i.3a.4d.5h.,
1j.2i.3a.4d.5h., 1p.2i.3a.4d.5h., 1a.2m.3a.4d.5h., 1b.2m.3a.4d.5h.,
1f.2m.3a.4d.5h., 1h.2m.3a.4d.5h., 1j.2m.3a.4d.5h., 1p.2m.3a.4d.5h.,
1a.2o.3a.4d.5h., 1b.2o.3a.4d.5h., 1f.2o.3a.4d.5h., 1h.2o.3a.4d.5h.,
1j.2o.3a.4d.5h., 1p.2o.3a.4d.5h., 1a.2u.3a.4d.5h., 1b.2u.3a.4d.5h.,
1f.2u.3a.4d.5h., 1h.2u.3a.4d.5h., 1j.2u.3a.4d.5h., 1p.2u.3a.4d.5h.,
1a.2y.3a.4d.5h., 1b.2y.3a.4d.5h., 1f.2y.3a.4d.5h., 1h.2y.3a.4d.5h.,
1j.2y.3a.4d.5h., 1p.2y.3a.4d.5h., 1a.2a.3b.4d.5h., 1b.2a.3b.4d.5h.,
1f.2a.3b.4d.5h., 1h.2a.3b.4d.5h., 1j.2a.3b.4d.5h., 1p.2a.3b.4d.5h.,
1a.2b.3b.4d.5h., 1b.2b.3b.4d.5h., 1f.2b.3b.4d.5h., 1h.2b.3b.4d.5h.,
1j.2b.3b.4d.5h., 1p.2b.3b.4d.5h., 1a.2e.3b.4d.5h., 1b.2e.3b.4d.5h.,
1f.2e.3b.4d.5h., 1h.2e.3b.4d.5h., 1j.2e.3b.4d.5h., 1p.2e.3b.4d.5h.,
1a.2f.3b.4d.5h., 1b.2f.3b.4d.5h., 1f.2f.3b.4d.5h., 1h.2f.3b.4d.5h.,
1j.2f.3b.4d.5h., 1p.2f.3b.4d.5h., 1a.2i.3b.4d.5h., 1b.2i.3b.4d.5h.,
1f.2i.3b.4d.5h., 1h.2i.3b.4d.5h., 1j.2i.3b.4d.5h., 1p.2i.3b.4d.5h.,
1a.2m.3b.4d.5h., 1b.2m.3b.4d.5h., 1f.2m.3b.4d.5h., 1h.2m.3b.4d.5h.,
1j.2m.3b.4d.5h., 1p.2m.3b.4d.5h., 1a.2o.3b.4d.5h., 1b.2o.3b.4d.5h.,
1f.2o.3b.4d.5h., 1h.2o.3b.4d.5h., 1j.2o.3b.4d.5h., 1p.2o.3b.4d.5h.,
1a.2u.3b.4d.5h., 1b.2u.3b.4d.5h., 1f.2u.3b.4d.5h., 1h.2u.3b.4d.5h.,
1j.2u.3b.4d.5h., 1p.2u.3b.4d.5h., 1a.2y.3b.4d.5h., 1b.2y.3b.4d.5h.,
1f.2y.3b.4d.5h., 1h.2y.3b.4d.5h., 1j.2y.3b.4d.5h., 1p.2y.3b.4d.5h.,
1a.2a.3e.4d.5h., 1b.2a.3e.4d.5h., 1f.2a.3e.4d.5h., 1h.2a.3e.4d.5h.,
1j.2a.3e.4d.5h., 1p.2a.3e.4d.5h., 1a.2b.3e.4d.5h., 1b.2b.3e.4d.5h.,
1f.2b.3e.4d.5h., 1h.2b.3e.4d.5h., 1j.2b.3e.4d.5h., 1p.2b.3e.4d.5h.,
1a.2e.3e.4d.5h., 1b.2e.3e.4d.5h., 1f.2e.3e.4d.5h., 1h.2e.3e.4d.5h.,
1j.2e.3e.4d.5h., 1p.2e.3e.4d.5h., 1a.2f.3e.4d.5h., 1b.2f.3e.4d.5h.,
1f.2f.3e.4d.5h., 1h.2f.3e.4d.5h., 1j.2f.3e.4d.5h., 1p.2f.3e.4d.5h.,
1a.2i.3e.4d.5h., 1b.2i.3e.4d.5h., 1f.2i.3e.4d.5h., 1h.2i.3e.4d.5h.,
1j.2i.3e.4d.5h., 1p.2i.3e.4d.5h., 1a.2m.3e.4d.5h., 1b.2m.3e.4d.5h.,
1f.2m.3e.4d.5h., 1h.2m.3e.4d.5h., 1j.2m.3e.4d.5h., 1p.2m.3e.4d.5h.,
1a.2o.3e.4d.5h., 1b.2o.3e.4d.5h., 1f.2o.3e.4d.5h., 1h.2o.3e.4d.5h.,
1j.2o.3e.4d.5h., 1p.2o.3e.4d.5h., 1a.2u.3e.4d.5h., 1b.2u.3e.4d.5h.,
1f.2u.3e.4d.5h., 1h.2u.3e.4d.5h., 1j.2u.3e.4d.5h., 1p.2u.3e.4d.5h.,
1a.2y.3e.4d.5h., 1b.2y.3e.4d.5h., 1f.2y.3e.4d.5h., 1h.2y.3e.4d.5h.,
1j.2y.3e.4d.5h., 1p.2y.3e.4d.5h., 1a.2a.3g.4d.5h., 1b.2a.3g.4d.5h.,
1f.2a.3g.4d.5h., 1h.2a.3g.4d.5h., 1j.2a.3g.4d.5h., 1p.2a.3g.4d.5h.,
1a.2b.3g.4d.5h., 1b.2b.3g.4d.5h., 1f.2b.3g.4d.5h., 1h.2b.3g.4d.5h.,
1j.2b.3g.4d.5h., 1p.2b.3g.4d.5h., 1a.2e.3g.4d.5h., 1b.2e.3g.4d.5h.,
1f.2e.3g.4d.5h., 1h.2e.3g.4d.5h., 1j.2e.3g.4d.5h., 1p.2e.3g.4d.5h.,
1a.2f.3g.4d.5h., 1b.2f.3g.4d.5h., 1f.2f.3g.4d.5h., 1h.2f.3g.4d.5h.,
1j.2f.3g.4d.5h., 1p.2f.3g.4d.5h., 1a.2i.3g.4d.5h., 1b.2i.3g.4d.5h.,
1f.2i.3g.4d.5h., 1h.2i.3g.4d.5h., 1j.2i.3g.4d.5h., 1p.2i.3g.4d.5h.,
1a.2m.3g.4d.5h., 1b.2m.3g.4d.5h., 1f.2m.3g.4d.5h., 1h.2m.3g.4d.5h.,
1j.2m.3g.4d.5h., 1p.2m.3g.4d.5h., 1a.2o.3g.4d.5h., 1b.2o.3g.4d.5h.,
1f.2o.3g.4d.5h., 1h.2o.3g.4d.5h., 1j.2o.3g.4d.5h., 1p.2o.3g.4d.5h.,
1a.2u.3g.4d.5h., 1b.2u.3g.4d.5h., 1f.2u.3g.4d.5h., 1h.2u.3g.4d.5h.,
1j.2u.3g.4d.5h., 1p.2u.3g.4d.5h., 1a.2y.3g.4d.5h., 1b.2y.3g.4d.5h.,
1f.2y.3g.4d.5h., 1h.2y.3g.4d.5h., 1j.2y.3g.4d.5h., 1p.2y.3g.4d.5h.,
1a.2a.3a.4f.5h., 1b.2a.3a.4f.5h., 1f.2a.3a.4f.5h., 1h.2a.3a.4f.5h.,
1j.2a.3a.4f.5h., 1p.2a.3a.4f.5h., 1a.2b.3a.4f.5h., 1b.2b.3a.4f.5h.,
1f.2b.3a.4f.5h., 1h.2b.3a.4f.5h., 1j.2b.3a.4f.5h., 1p.2b.3a.4f.5h.,
1a.2e.3a.4f.5h., 1b.2e.3a.4f.5h., 1f.2e.3a.4f.5h., 1h.2e.3a.4f.5h.,
1j.2e.3a.4f.5h., 1p.2e.3a.4f.5h., 1a.2f.3a.4f.5h., 1b.2f.3a.4f.5h.,
1f.2f.3a.4f.5h., 1h.2f.3a.4f.5h., 1j.2f.3a.4f.5h., 1p.2f.3a.4f.5h.,
1a.2i.3a.4f.5h., 1b.2i.3a.4f.5h., 1f.2i.3a.4f.5h., 1h.2i.3a.4f.5h.,
1j.2i.3a.4f.5h., 1p.2i.3a.4f.5h., 1a.2m.3a.4f.5h., 1b.2m.3a.4f.5h.,
1f.2m.3a.4f.5h., 1h.2m.3a.4f.5h., 1j.2m.3a.4f.5h., 1p.2m.3a.4f.5h.,
1a.2o.3a.4f.5h., 1b.2o.3a.4f.5h., 1f.2o.3a.4f.5h., 1h.2o.3a.4f.5h.,
1j.2o.3a.4f.5h., 1p.2o.3a.4f.5h., 1a.2u.3a.4f.5h., 1b.2u.3a.4f.5h.,
1f.2u.3a.4f.5h., 1h.2u.3a.4f.5h., 1j.2u.3a.4f.5h., 1p.2u.3a.4f.5h.,
1a.2y.3a.4f.5h., 1b.2y.3a.4f.5h., 1f.2y.3a.4f.5h., 1h.2y.3a.4f.5h.,
1j.2y.3a.4f.5h., 1p.2y.3a.4f.5h., 1a.2a.3b.4f.5h., 1b.2a.3b.4f.5h.,
1f.2a.3b.4f.5h., 1h.2a.3b.4f.5h., 1j.2a.3b.4f.5h., 1p.2a.3b.4f.5h.,
1a.2b.3b.4f.5h., 1b.2b.3b.4f.5h., 1f.2b.3b.4f.5h., 1h.2b.3b.4f.5h.,
1j.2b.3b.4f.5h., 1p.2b.3b.4f.5h., 1a.2e.3b.4f.5h., 1b.2e.3b.4f.5h.,
1f.2e.3b.4f.5h., 1h.2e.3b.4f.5h., 1j.2e.3b.4f.5h., 1p.2e.3b.4f.5h.,
1a.2f.3b.4f.5h., 1b.2f.3b.4f.5h., 1f.2f.3b.4f.5h., 1h.2f.3b.4f.5h.,
1j.2f.3b.4f.5h., 1p.2f.3b.4f.5h., 1a.2i.3b.4f.5h., 1b.2i.3b.4f.5h.,
1f.2i.3b.4f.5h., 1h.2i.3b.4f.5h., 1j.2i.3b.4f.5h., 1p.2i.3b.4f.5h.,
1a.2m.3b.4f.5h., 1b.2m.3b.4f.5h., 1f.2m.3b.4f.5h., 1h.2m.3b.4f.5h.,
1j.2m.3b.4f.5h., 1p.2m.3b.4f.5h., 1a.2o.3b.4f.5h., 1b.2o.3b.4f.5h.,
1f.2o.3b.4f.5h., 1h.2o.3b.4f.5h., 1j.2o.3b.4f.5h., 1p.2o.3b.4f.5h.,
1a.2u.3b.4f.5h., 1b.2u.3b.4f.5h., 1f.2u.3b.4f.5h., 1h.2u.3b.4f.5h.,
1j.2u.3b.4f.5h., 1p.2u.3b.4f.5h., 1a.2y.3b.4f.5h., 1b.2y.3b.4f.5h.,
1f.2y.3b.4f.5h., 1h.2y.3b.4f.5h., 1j.2y.3b.4f.5h., 1p.2y.3b.4f.5h.,
1a.2a.3e.4f.5h., 1b.2a.3e.4f.5h., 1f.2a.3e.4f.5h., 1h.2a.3e.4f.5h.,
1j.2a.3e.4f.5h., 1p.2a.3e.4f.5h., 1a.2b.3e.4f.5h., 1b.2b.3e.4f.5h.,
1f.2b.3e.4f.5h., 1h.2b.3e.4f.5h., 1j.2b.3e.4f.5h., 1p.2b.3e.4f.5h.,
1a.2e.3e.4f.5h., 1b.2e.3e.4f.5h., 1f.2e.3e.4f.5h., 1h.2e.3e.4f.5h.,
1j.2e.3e.4f.5h., 1p.2e.3e.4f.5h., 1a.2f.3e.4f.5h., 1b.2f.3e.4f.5h.,
1f.2f.3e.4f.5h., 1h.2f.3e.4f.5h., 1j.2f.3e.4f.5h., 1p.2f.3e.4f.5h.,
1a.2i.3e.4f.5h., 1b.2i.3e.4f.5h., 1f.2i.3e.4f.5h., 1h.2i.3e.4f.5h.,
1j.2i.3e.4f.5h., 1p.2i.3e.4f.5h., 1a.2m.3e.4f.5h., 1b.2m.3e.4f.5h.,
1f.2m.3e.4f.5h., 1h.2m.3e.4f.5h., 1j.2m.3e.4f.5h., 1p.2m.3e.4f.5h.,
1a.2o.3e.4f.5h., 1b.2o.3e.4f.5h., 1f.2o.3e.4f.5h., 1h.2o.3e.4f.5h.,
1j.2o.3e.4f.5h., 1p.2o.3e.4f.5h., 1a.2u.3e.4f.5h., 1b.2u.3e.4f.5h.,
1f.2u.3e.4f.5h., 1h.2u.3e.4f.5h., 1j.2u.3e.4f.5h., 1p.2u.3e.4f.5h.,
1a.2y.3e.4f.5h., 1b.2y.3e.4f.5h., 1f.2y.3e.4f.5h., 1h.2y.3e.4f.5h.,
1j.2y.3e.4f.5h., 1p.2y.3e.4f.5h., 1a.2a.3g.4f.5h., 1b.2a.3g.4f.5h.,
1f.2a.3g.4f.5h., 1h.2a.3g.4f.5h., 1j.2a.3g.4f.5h., 1p.2a.3g.4f.5h.,
1a.2b.3g.4f.5h., 1b.2b.3g.4f.5h., 1f.2b.3g.4f.5h., 1h.2b.3g.4f.5h.,
1j.2b.3g.4f.5h., 1p.2b.3g.4f.5h., 1a.2e.3g.4f.5h., 1b.2e.3g.4f.5h.,
1f.2e.3g.4f.5h., 1h.2e.3g.4f.5h., 1j.2e.3g.4f.5h., 1p.2e.3g.4f.5h.,
1a.2f.3g.4f.5h., 1b.2f.3g.4f.5h., 1f.2f.3g.4f.5h., 1h.2f.3g.4f.5h.,
1j.2f.3g.4f.5h., 1p.2f.3g.4f.5h., 1a.2i.3g.4f.5h., 1b.2i.3g.4f.5h.,
1f.2i.3g.4f.5h., 1h.2i.3g.4f.5h., 1j.2i.3g.4f.5h., 1p.2i.3g.4f.5h.,
1a.2m.3g.4f.5h., 1b.2m.3g.4f.5h., 1f.2m.3g.4f.5h., 1h.2m.3g.4f.5h.,
1j.2m.3g.4f.5h., 1p.2m.3g.4f.5h., 1a.2o.3g.4f.5h., 1b.2o.3g.4f.5h.,
1f.2o.3g.4f.5h., 1h.2o.3g.4f.5h., 1j.2o.3g.4f.5h., 1p.2o.3g.4f.5h.,
1a.2u.3g.4f.5h., 1b.2u.3g.4f.5h., 1f.2u.3g.4f.5h., 1h.2u.3g.4f.5h.,
1j.2u.3g.4f.5h., 1p.2u.3g.4f.5h., 1a.2y.3g.4f.5h., 1b.2y.3g.4f.5h.,
1f.2y.3g.4f.5h., 1h.2y.3g.4f.5h., 1j.2y.3g.4f.5h., 1p.2y.3g.4f.5h.,
1a.2a.3a.4g.5h., 1b.2a.3a.4g.5h., 1f.2a.3a.4g.5h., 1h.2a.3a.4g.5h.,
1j.2a.3a.4g.5h., 1p.2a.3a.4g.5h., 1a.2b.3a.4g.5h., 1b.2b.3a.4g.5h.,
1f.2b.3a.4g.5h., 1h.2b.3a.4g.5h., 1j.2b.3a.4g.5h., 1p.2b.3a.4g.5h.,
1a.2e.3a.4g.5h., 1b.2e.3a.4g.5h., 1f.2e.3a.4g.5h., 1h.2e.3a.4g.5h.,
1j.2e.3a.4g.5h., 1p.2e.3a.4g.5h., 1a.2f.3a.4g.5h., 1b.2f.3a.4g.5h.,
1f.2f.3a.4g.5h., 1h.2f.3a.4g.5h., 1j.2f.3a.4g.5h., 1p.2f.3a.4g.5h.,
1a.2i.3a.4g.5h., 1b.2i.3a.4g.5h., 1f.2i.3a.4g.5h., 1h.2i.3a.4g.5h.,
1j.2i.3a.4g.5h., 1p.2i.3a.4g.5h., 1a.2m.3a.4g.5h., 1b.2m.3a.4g.5h.,
1f.2m.3a.4g.5h., 1h.2m.3a.4g.5h., 1j.2m.3a.4g.5h., 1p.2m.3a.4g.5h.,
1a.2o.3a.4g.5h., 1b.2o.3a.4g.5h., 1f.2o.3a.4g.5h., 1h.2o.3a.4g.5h.,
1j.2o.3a.4g.5h., 1p.2o.3a.4g.5h., 1a.2u.3a.4g.5h., 1b.2u.3a.4g.5h.,
1f.2u.3a.4g.5h., 1h.2u.3a.4g.5h., 1j.2u.3a.4g.5h., 1p.2u.3a.4g.5h.,
1a.2y.3a.4g.5h., 1b.2y.3a.4g.5h., 1f.2y.3a.4g.5h., 1h.2y.3a.4g.5h.,
1j.2y.3a.4g.5h., 1p.2y.3a.4g.5h., 1a.2a.3b.4g.5h., 1b.2a.3b.4g.5h.,
1f.2a.3b.4g.5h., 1h.2a.3b.4g.5h., 1j.2a.3b.4g.5h., 1p.2a.3b.4g.5h.,
1a.2b.3b.4g.5h., 1b.2b.3b.4g.5h., 1f.2b.3b.4g.5h., 1h.2b.3b.4g.5h.,
1j.2b.3b.4g.5h., 1p.2b.3b.4g.5h., 1a.2e.3b.4g.5h., 1b.2e.3b.4g.5h.,
1f.2e.3b.4g.5h., 1h.2e.3b.4g.5h., 1j.2e.3b.4g.5h., 1p.2e.3b.4g.5h.,
1a.2f.3b.4g.5h., 1b.2f.3b.4g.5h., 1f.2f.3b.4g.5h., 1h.2f.3b.4g.5h.,
1j.2f.3b.4g.5h., 1p.2f.3b.4g.5h., 1a.2i.3b.4g.5h., 1b.2i.3b.4g.5h.,
1f.2i.3b.4g.5h., 1h.2i.3b.4g.5h., 1j.2i.3b.4g.5h., 1p.2i.3b.4g.5h.,
1a.2m.3b.4g.5h., 1b.2m.3b.4g.5h., 1f.2m.3b.4g.5h., 1h.2m.3b.4g.5h.,
1j.2m.3b.4g.5h., 1p.2m.3b.4g.5h., 1a.2o.3b.4g.5h., 1b.2o.3b.4g.5h.,
1f.2o.3b.4g.5h., 1h.2o.3b.4g.5h., 1j.2o.3b.4g.5h., 1p.2o.3b.4g.5h.,
1a.2u.3b.4g.5h., 1b.2u.3b.4g.5h., 1f.2u.3b.4g.5h., 1h.2u.3b.4g.5h.,
1j.2u.3b.4g.5h., 1p.2u.3b.4g.5h., 1a.2y.3b.4g.5h., 1b.2y.3b.4g.5h.,
1f.2y.3b.4g.5h., 1h.2y.3b.4g.5h., 1j.2y.3b.4g.5h., 1p.2y.3b.4g.5h.,
1a.2a.3e.4g.5h., 1b.2a.3e.4g.5h., 1f.2a.3e.4g.5h., 1h.2a.3e.4g.5h.,
1j.2a.3e.4g.5h., 1p.2a.3e.4g.5h., 1a.2b.3e.4g.5h., 1b.2b.3e.4g.5h.,
1f.2b.3e.4g.5h., 1h.2b.3e.4g.5h., 1j.2b.3e.4g.5h., 1p.2b.3e.4g.5h.,
1a.2e.3e.4g.5h., 1b.2e.3e.4g.5h., 1f.2e.3e.4g.5h., 1h.2e.3e.4g.5h.,
1j.2e.3e.4g.5h., 1p.2e.3e.4g.5h., 1a.2f.3e.4g.5h., 1b.2f.3e.4g.5h.,
1f.2f.3e.4g.5h., 1h.2f.3e.4g.5h., 1j.2f.3e.4g.5h., 1p.2f.3e.4g.5h.,
1a.2i.3e.4g.5h., 1b.2i.3e.4g.5h., 1f.2i.3e.4g.5h., 1h.2i.3e.4g.5h.,
1j.2i.3e.4g.5h., 1p.2i.3e.4g.5h., 1a.2m.3e.4g.5h., 1b.2m.3e.4g.5h.,
1f.2m.3e.4g.5h., 1h.2m.3e.4g.5h., 1j.2m.3e.4g.5h., 1p.2m.3e.4g.5h.,
1a.2o.3e.4g.5h., 1b.2o.3e.4g.5h., 1f.2o.3e.4g.5h., 1h.2o.3e.4g.5h.,
1j.2o.3e.4g.5h., 1p.2o.3e.4g.5h., 1a.2u.3e.4g.5h., 1b.2u.3e.4g.5h.,
1f.2u.3e.4g.5h., 1h.2u.3e.4g.5h., 1j.2u.3e.4g.5h., 1p.2u.3e.4g.5h.,
1a.2y.3e.4g.5h., 1b.2y.3e.4g.5h., 1f.2y.3e.4g.5h., 1h.2y.3e.4g.5h.,
1j.2y.3e.4g.5h., 1p.2y.3e.4g.5h., 1a.2a.3g.4g.5h., 1b.2a.3g.4g.5h.,
1f.2a.3g.4g.5h., 1h.2a.3g.4g.5h., 1j.2a.3g.4g.5h.,
1p.2a.3g.4g.5h.,
1a.2b.3g.4g.5h., 1b.2b.3g.4g.5h., 1f.2b.3g.4g.5h., 1h.2b.3g.4g.5h.,
1j.2b.3g.4g.5h., 1p.2b.3g.4g.5h., 1a.2e.3g.4g.5h., 1b.2e.3g.4g.5h.,
1f.2e.3g.4g.5h., 1h.2e.3g.4g.5h., 1j.2e.3g.4g.5h., 1p.2e.3g.4g.5h.,
1a.2f.3g.4g.5h., 1b.2f.3g.4g.5h., 1f.2f.3g.4g.5h., 1h.2f.3g.4g.5h.,
1j.2f.3g.4g.5h., 1p.2f.3g.4g.5h., 1a.2i.3g.4g.5h., 1b.2i.3g.4g.5h.,
1f.2i.3g.4g.5h., 1h.2i.3g.4g.5h., 1j.2i.3g.4g.5h., 1p.2i.3g.4g.5h.,
1a.2m.3g.4g.5h., 1b.2m.3g.4g.5h., 1f.2m.3g.4g.5h., 1h.2m.3g.4g.5h.,
1j.2m.3g.4g.5h., 1p.2m.3g.4g.5h., 1a.2o.3g.4g.5h., 1b.2o.3g.4g.5h.,
1f.2o.3g.4g.5h., 1h.2o.3g.4g.5h., 1j.2o.3g.4g.5h., 1p.2o.3g.4g.5h.,
1a.2u.3g.4g.5h., 1b.2u.3g.4g.5h., 1f.2u.3g.4g.5h., 1h.2u.3g.4g.5h.,
1j.2u.3g.4g.5h., 1p.2u.3g.4g.5h., 1a.2y.3g.4g.5h., 1b.2y.3g.4g.5h.,
1f.2y.3g.4g.5h., 1h.2y.3g.4g.5h., 1j.2y.3g.4g.5h., 1p.2y.3g.4g.5h.,
1a.2a.3a.4h.5h., 1b.2a.3a.4h.5h., 1f.2a.3a.4h.5h., 1h.2a.3a.4h.5h.,
1j.2a.3a.4h.5h., 1p.2a.3a.4h.5h., 1a.2b.3a.4h.5h., 1b.2b.3a.4h.5h.,
1f.2b.3a.4h.5h., 1h.2b.3a.4h.5h., 1j.2b.3a.4h.5h., 1p.2b.3a.4h.5h.,
1a.2e.3a.4h.5h., 1b.2e.3a.4h.5h., 1f.2e.3a.4h.5h., 1h.2e.3a.4h.5h.,
1j.2e.3a.4h.5h., 1p.2e.3a.4h.5h., 1a.2f.3a.4h.5h., 1b.2f.3a.4h.5h.,
1f.2f.3a.4h.5h., 1h.2f.3a.4h.5h., 1j.2f.3a.4h.5h., 1p.2f.3a.4h.5h.,
1a.2i.3a.4h.5h., 1b.2i.3a.4h.5h., 1f.2i.3a.4h.5h., 1h.2i.3a.4h.5h.,
1j.2i.3a.4h.5h., 1p.2i.3a.4h.5h., 1a.2m.3a.4h.5h., 1b.2m.3a.4h.5h.,
1f.2m.3a.4h.5h., 1h.2m.3a.4h.5h., 1j.2m.3a.4h.5h., 1p.2m.3a.4h.5h.,
1a.2o.3a.4h.5h., 1b.2o.3a.4h.5h., 1f.2o.3a.4h.5h., 1h.2o.3a.4h.5h.,
1j.2o.3a.4h.5h., 1p.2o.3a.4h.5h., 1a.2u.3a.4h.5h., 1b.2u.3a.4h.5h.,
1f.2u.3a.4h.5h., 1h.2u.3a.4h.5h., 1j.2u.3a.4h.5h., 1p.2u.3a.4h.5h.,
1a.2y.3a.4h.5h., 1b.2y.3a.4h.5h., 1f.2y.3a.4h.5h., 1h.2y.3a.4h.5h.,
1j.2y.3a.4h.5h., 1p.2y.3a.4h.5h., 1a.2a.3b.4h.5h., 1b.2a.3b.4h.5h.,
1f.2a.3b.4h.5h., 1h.2a.3b.4h.5h., 1j.2a.3b.4h.5h., 1p.2a.3b.4h.5h.,
1a.2b.3b.4h.5h., 1b.2b.3b.4h.5h., 1f.2b.3b.4h.5h., 1h.2b.3b.4h.5h.,
1j.2b.3b.4h.5h., 1p.2b.3b.4h.5h., 1a.2e.3b.4h.5h., 1b.2e.3b.4h.5h.,
1f.2e.3b.4h.5h., 1h.2e.3b.4h.5h., 1j.2e.3b.4h.5h., 1p.2e.3b.4h.5h.,
1a.2f.3b.4h.5h., 1b.2f.3b.4h.5h., 1f.2f.3b.4h.5h., 1h.2f.3b.4h.5h.,
1j.2f.3b.4h.5h., 1p.2f.3b.4h.5h., 1a.2i.3b.4h.5h., 1b.2i.3b.4h.5h.,
1f.2i.3b.4h.5h., 1h.2i.3b.4h.5h., 1j.2i.3b.4h.5h., 1p.2i.3b.4h.5h.,
1a.2m.3b.4h.5h., 1b.2m.3b.4h.5h., 1f.2m.3b.4h.5h., 1h.2m.3b.4h.5h.,
1j.2m.3b.4h.5h., 1p.2m.3b.4h.5h., 1a.2o.3b.4h.5h., 1b.2o.3b.4h.5h.,
1f.2o.3b.4h.5h., 1h.2o.3b.4h.5h., 1j.2o.3b.4h.5h., 1p.2o.3b.4h.5h.,
1a.2u.3b.4h.5h., 1b.2u.3b.4h.5h., 1f.2u.3b.4h.5h., 1h.2u.3b.4h.5h.,
1j.2u.3b.4h.5h., 1p.2u.3b.4h.5h., 1a.2y.3b.4h.5h., 1b.2y.3b.4h.5h.,
1f.2y.3b.4h.5h., 1h.2y.3b.4h.5h., 1j.2y.3b.4h.5h., 1p.2y.3b.4h.5h.,
1a.2a.3e.4h.5h., 1b.2a.3e.4h.5h., 1f.2a.3e.4h.5h., 1h.2a.3e.4h.5h.,
1j.2a.3e.4h.5h., 1p.2a.3e.4h.5h., 1a.2b.3e.4h.5h., 1b.2b.3e.4h.5h.,
1f.2b.3e.4h.5h., 1h.2b.3e.4h.5h., 1j.2b.3e.4h.5h., 1p.2b.3e.4h.5h.,
1a.2e.3e.4h.5h., 1b.2e.3e.4h.5h., 1f.2e.3e.4h.5h., 1h.2e.3e.4h.5h.,
1j.2e.3e.4h.5h., 1p.2e.3e.4h.5h., 1a.2f.3e.4h.5h., 1b.2f.3e.4h.5h.,
1f.2f.3e.4h.5h., 1h.2f.3e.4h.5h., 1j.2f.3e.4h.5h., 1p.2f.3e.4h.5h.,
1a.2i.3e.4h.5h., 1b.2i.3e.4h.5h., 1f.2i.3e.4h.5h., 1h.2i.3e.4h.5h.,
1j.2i.3e.4h.5h., 1p.2i.3e.4h.5h., 1a.2m.3e.4h.5h., 1b.2m.3e.4h.5h.,
1f.2m.3e.4h.5h., 1h.2m.3e.4h.5h., 1j.2m.3e.4h.5h., 1p.2m.3e.4h.5h.,
1a.2o.3e.4h.5h., 1b.2o.3e.4h.5h., 1f.2o.3e.4h.5h., 1h.2o.3e.4h.5h.,
1j.2o.3e.4h.5h., 1p.2o.3e.4h.5h., 1a.2u.3e.4h.5h., 1b.2u.3e.4h.5h.,
1f.2u.3e.4h.5h., 1h.2u.3e.4h.5h., 1j.2u.3e.4h.5h., 1p.2u.3e.4h.5h.,
1a.2y.3e.4h.5h., 1b.2y.3e.4h.5h., 1f.2y.3e.4h.5h., 1h.2y.3e.4h.5h.,
1j.2y.3e.4h.5h., 1p.2y.3e.4h.5h., 1a.2a.3g.4h.5h., 1b.2a.3g.4h.5h.,
1f.2a.3g.4h.5h., 1h.2a.3g.4h.5h., 1j.2a.3g.4h.5h., 1p.2a.3g.4h.5h.,
1a.2b.3g.4h.5h., 1b.2b.3g.4h.5h., 1f.2b.3g.4h.5h., 1h.2b.3g.4h.5h.,
1j.2b.3g.4h.5h., 1p.2b.3g.4h.5h., 1a.2e.3g.4h.5h., 1b.2e.3g.4h.5h.,
1f.2e.3g.4h.5h., 1h.2e.3g.4h.5h., 1j.2e.3g.4h.5h., 1p.2e.3g.4h.5h.,
1a.2f.3g.4h.5h., 1b.2f.3g.4h.5h., 1f.2f.3g.4h.5h., 1h.2f.3g.4h.5h.,
1j.2f.3g.4h.5h., 1p.2f.3g.4h.5h., 1a.2i.3g.4h.5h., 1b.2i.3g.4h.5h.,
1f.2i.3g.4h.5h., 1h.2i.3g.4h.5h., 1j.2i.3g.4h.5h., 1p.2i.3g.4h.5h.,
1a.2m.3g.4h.5h., 1b.2m.3g.4h.5h., 1f.2m.3g.4h.5h., 1h.2m.3g.4h.5h.,
1j.2m.3g.4h.5h., 1p.2m.3g.4h.5h., 1a.2o.3g.4h.5h., 1b.2o.3g.4h.5h.,
1f.2o.3g.4h.5h., 1h.2o.3g.4h.5h., 1j.2o.3g.4h.5h., 1p.2o.3g.4h.5h.,
1a.2u.3g.4h.5h., 1b.2u.3g.4h.5h., 1f.2u.3g.4h.5h., 1h.2u.3g.4h.5h.,
1j.2u.3g.4h.5h., 1p.2u.3g.4h.5h., 1a.2y.3g.4h.5h., 1b.2y.3g.4h.5h.,
1f.2y.3g.4h.5h., 1h.2y.3g.4h.5h., 1j.2y.3g.4h.5h., 1p.2y.3g.4h.5h.,
1a.2a.3a.4i.5h., 1b.2a.3a.4i.5h., 1f.2a.3a.4i.5h., 1h.2a.3a.4i.5h.,
1j.2a.3a.4i.5h., 1p.2a.3a.4i.5h., 1a.2b.3a.4i.5h., 1b.2b.3a.4i.5h.,
1f.2b.3a.4i.5h., 1h.2b.3a.4i.5h., 1j.2b.3a.4i.5h., 1p.2b.3a.4i.5h.,
1a.2e.3a.4i.5h., 1b.2e.3a.4i.5h., 1f.2e.3a.4i.5h., 1h.2e.3a.4i.5h.,
1j.2e.3a.4i.5h., 1p.2e.3a.4i.5h., 1a.2f.3a.4i.5h., 1b.2f.3a.4i.5h.,
1f.2f.3a.4i.5h., 1h.2f.3a.4i.5h., 1j.2f.3a.4i.5h., 1p.2f.3a.4i.5h.,
1a.2i.3a.4i.5h., 1b.2i.3a.4i.5h., 1f.2i.3a.4i.5h., 1h.2i.3a.4i.5h.,
1j.2i.3a.4i.5h., 1p.2i.3a.4i.5h., 1a.2m.3a.4i.5h., 1b.2m.3a.4i.5h.,
1f.2m.3a.4i.5h., 1h.2m.3a.4i.5h., 1j.2m.3a.4i.5h., 1p.2m.3a.4i.5h.,
1a.2o.3a.4i.5h., 1b.2o.3a.4i.5h., 1f.2o.3a.4i.5h., 1h.2o.3a.4i.5h.,
1j.2o.3a.4i.5h., 1p.2o.3a.4i.5h., 1a.2u.3a.4i.5h., 1b.2u.3a.4i.5h.,
1f.2u.3a.4i.5h., 1h.2u.3a.4i.5h., 1j.2u.3a.4i.5h., 1p.2u.3a.4i.5h.,
1a.2y.3a.4i.5h., 1b.2y.3a.4i.5h., 1f.2y.3a.4i.5h., 1h.2y.3a.4i.5h.,
1j.2y.3a.4i.5h., 1p.2y.3a.4i.5h., 1a.2a.3b.4i.5h., 1b.2a.3b.4i.5h.,
1f.2a.3b.4i.5h., 1h.2a.3b.4i.5h., 1j.2a.3b.4i.5h., 1p.2a.3b.4i.5h.,
1a.2b.3b.4i.5h., 1b.2b.3b.4i.5h., 1f.2b.3b.4i.5h., 1h.2b.3b.4i.5h.,
1j.2b.3b.4i.5h., 1p.2b.3b.4i.5h., 1a.2e.3b.4i.5h., 1b.2e.3b.4i.5h.,
1f.2e.3b.4i.5h., 1h.2e.3b.4i.5h., 1j.2e.3b.4i.5h., 1p.2e.3b.4i.5h.,
1a.2f.3b.4i.5h., 1b.2f.3b.4i.5h., 1f.2f.3b.4i.5h., 1h.2f.3b.4i.5h.,
1j.2f.3b.4i.5h., 1p.2f.3b.4i.5h., 1a.2i.3b.4i.5h., 1b.2i.3b.4i.5h.,
1f.2i.3b.4i.5h., 1h.2i.3b.4i.5h., 1j.2i.3b.4i.5h., 1p.2i.3b.4i.5h.,
1a.2m.3b.4i.5h., 1b.2m.3b.4i.5h., 1f.2m.3b.4i.5h., 1h.2m.3b.4i.5h.,
1j.2m.3b.4i.5h., 1p.2m.3b.4i.5h., 1a.2o.3b.4i.5h., 1b.2o.3b.4i.5h.,
1f.2o.3b.4i.5h., 1h.2o.3b.4i.5h., 1j.2o.3b.4i.5h., 1p.2o.3b.4i.5h.,
1a.2u.3b.4i.5h., 1b.2u.3b.4i.5h., 1f.2u.3b.4i.5h., 1h.2u.3b.4i.5h.,
1j.2u.3b.4i.5h., 1p.2u.3b.4i.5h., 1a.2y.3b.4i.5h., 1b.2y.3b.4i.5h.,
1f.2y.3b.4i.5h., 1h.2y.3b.4i.5h., 1j.2y.3b.4i.5h., 1p.2y.3b.4i.5h.,
1a.2a.3e.4i.5h., 1b.2a.3e.4i.5h., 1f.2a.3e.4i.5h., 1h.2a.3e.4i.5h.,
1j.2a.3e.4i.5h., 1p.2a.3e.4i.5h., 1a.2b.3e.4i.5h., 1b.2b.3e.4i.5h.,
1f.2b.3e.4i.5h., 1h.2b.3e.4i.5h., 1j.2b.3e.4i.5h., 1p.2b.3e.4i.5h.,
1a.2e.3e.4i.5h., 1b.2e.3e.4i.5h., 1f.2e.3e.4i.5h., 1h.2e.3e.4i.5h.,
1j.2e.3e.4i.5h., 1p.2e.3e.4i.5h., 1a.2f.3e.4i.5h., 1b.2f.3e.4i.5h.,
1f.2f.3e.4i.5h., 1h.2f.3e.4i.5h., 1j.2f.3e.4i.5h., 1p.2f.3e.4i.5h.,
1a.2i.3e.4i.5h., 1b.2i.3e.4i.5h., 1f.2i.3e.4i.5h., 1h.2i.3e.4i.5h.,
1j.2i.3e.4i.5h., 1p.2i.3e.4i.5h., 1a.2m.3e.4i.5h., 1b.2m.3e.4i.5h.,
1f.2m.3e.4i.5h., 1h.2m.3e.4i.5h., 1j.2m.3e.4i.5h., 1p.2m.3e.4i.5h.,
1a.2o.3e.4i.5h., 1b.2o.3e.4i.5h., 1f.2o.3e.4i.5h., 1h.2o.3e.4i.5h.,
1j.2o.3e.4i.5h., 1p.2o.3e.4i.5h., 1a.2u.3e.4i.5h., 1b.2u.3e.4i.5h.,
1f.2u.3e.4i.5h., 1h.2u.3e.4i.5h., 1j.2u.3e.4i.5h., 1p.2u.3e.4i.5h.,
1a.2y.3e.4i.5h., 1b.2y.3e.4i.5h., 1f.2y.3e.4i.5h., 1h.2y.3e.4i.5h.,
1j.2y.3e.4i.5h., 1p.2y.3e.4i.5h., 1a.2a.3g.4i.5h., 1b.2a.3g.4i.5h.,
1f.2a.3g.4i.5h., 1h.2a.3g.4i.5h., 1j.2a.3g.4i.5h., 1p.2a.3g.4i.5h.,
1a.2b.3g.4i.5h., 1b.2b.3g.4i.5h., 1f.2b.3g.4i.5h., 1h.2b.3g.4i.5h.,
1j.2b.3g.4i.5h., 1p.2b.3g.4i.5h., 1a.2e.3g.4i.5h., 1b.2e.3g.4i.5h.,
1f.2e.3g.4i.5h., 1h.2e.3g.4i.5h., 1j.2e.3g.4i.5h., 1p.2e.3g.4i.5h.,
1a.2f.3g.4i.5h., 1b.2f.3g.4i.5h., 1f.2f.3g.4i.5h., 1h.2f.3g.4i.5h.,
1j.2f.3g.4i.5h., 1p.2f.3g.4i.5h., 1a.2i.3g.4i.5h., 1b.2i.3g.4i.5h.,
1f.2i.3g.4i.5h., 1h.2i.3g.4i.5h., 1j.2i.3g.4i.5h., 1p.2i.3g.4i.5h.,
1a.2m.3g.4i.5h., 1b.2m.3g.4i.5h., 1f.2m.3g.4i.5h., 1h.2m.3g.4i.5h.,
1j.2m.3g.4i.5h., 1p.2m.3g.4i.5h., 1a.2o.3g.4i.5h., 1b.2o.3g.4i.5h.,
1f.2o.3g.4i.5h., 1h.2o.3g.4i.5h., 1j.2o.3g.4i.5h., 1p.2o.3g.4i.5h.,
1a.2u.3g.4i.5h., 1b.2u.3g.4i.5h., 1f.2u.3g.4i.5h., 1h.2u.3g.4i.5h.,
1j.2u.3g.4i.5h., 1p.2u.3g.4i.5h., 1a.2y.3g.4i.5h., 1b.2y.3g.4i.5h.,
1f.2y.3g.4i.5h., 1h.2y.3g.4i.5h., 1j.2y.3g.4i.5h., 1p.2y.3g.4i.5h.,
1a.2a.3a.4a.5i., 1b.2a.3a.4a.5i., 1f.2a.3a.4a.5i., 1h.2a.3a.4a.5i.,
1j.2a.3a.4a.5i., 1p.2a.3a.4a.5i., 1a.2b.3a.4a.5i., 1b.2b.3a.4a.5i.,
1f.2b.3a.4a.5i., 1h.2b.3a.4a.5i., 1j.2b.3a.4a.5i., 1p.2b.3a.4a.5i.,
1a.2e.3a.4a.5i., 1b.2e.3a.4a.5i., 1f.2e.3a.4a.5i., 1h.2e.3a.4a.5i.,
1j.2e.3a.4a.5i., 1p.2e.3a.4a.5i., 1a.2f.3a.4a.5i., 1b.2f.3a.4a.5i.,
1f.2f.3a.4a.5i., 1h.2f.3a.4a.5i., 1j.2f.3a.4a.5i., 1p.2f.3a.4a.5i.,
1a.2i.3a.4a.5i., 1b.2i.3a.4a.5i., 1f.2i.3a.4a.5i., 1h.2i.3a.4a.5i.,
1j.2i.3a.4a.5i., 1p.2i.3a.4a.5i., 1a.2m.3a.4a.5i., 1b.2m.3a.4a.5i.,
1f.2m.3a.4a.5i., 1h.2m.3a.4a.5i., 1j.2m.3a.4a.5i., 1p.2m.3a.4a.5i.,
1a.2o.3a.4a.5i., 1b.2o.3a.4a.5i., 1f.2o.3a.4a.5i., 1h.2o.3a.4a.5i.,
1j.2o.3a.4a.5i., 1p.2o.3a.4a.5i., 1a.2u.3a.4a.5i., 1b.2u.3a.4a.5i.,
1f.2u.3a.4a.5i., 1h.2u.3a.4a.5i., 1j.2u.3a.4a.5i., 1p.2u.3a.4a.5i.,
1a.2y.3a.4a.5i., 1b.2y.3a.4a.5i., 1f.2y.3a.4a.5i., 1h.2y.3a.4a.5i.,
1j.2y.3a.4a.5i., 1p.2y.3a.4a.5i., 1a.2a.3b.4a.5i., 1b.2a.3b.4a.5i.,
1f.2a.3b.4a.5i., 1h.2a.3b.4a.5i., 1j.2a.3b.4a.5i., 1p.2a.3b.4a.5i.,
1a.2b.3b.4a.5i., 1b.2b.3b.4a.5i., 1f.2b.3b.4a.5i., 1h.2b.3b.4a.5i.,
1j.2b.3b.4a.5i., 1p.2b.3b.4a.5i., 1a.2e.3b.4a.5i., 1b.2e.3b.4a.5i.,
1f.2e.3b.4a.5i., 1h.2e.3b.4a.5i., 1j.2e.3b.4a.5i., 1p.2e.3b.4a.5i.,
1a.2f.3b.4a.5i., 1b.2f.3b.4a.5i., 1f.2f.3b.4a.5i., 1h.2f.3b.4a.5i.,
1j.2f.3b.4a.5i., 1p.2f.3b.4a.5i., 1a.2i.3b.4a.5i., 1b.2i.3b.4a.5i.,
1f.2i.3b.4a.5i., 1h.2i.3b.4a.5i., 1j.2i.3b.4a.5i., 1p.2i.3b.4a.5i.,
1a.2m.3b.4a.5i., 1b.2m.3b.4a.5i., 1f.2m.3b.4a.5i., 1h.2m.3b.4a.5i.,
1j.2m.3b.4a.5i., 1p.2m.3b.4a.5i., 1a.2o.3b.4a.5i., 1b.2o.3b.4a.5i.,
1f.2o.3b.4a.5i., 1h.2o.3b.4a.5i., 1j.2o.3b.4a.5i., 1p.2o.3b.4a.5i.,
1a.2u.3b.4a.5i., 1b.2u.3b.4a.5i., 1f.2u.3b.4a.5i., 1h.2u.3b.4a.5i.,
1j.2u.3b.4a.5i., 1p.2u.3b.4a.5i., 1a.2y.3b.4a.5i., 1b.2y.3b.4a.5i.,
1f.2y.3b.4a.5i., 1h.2y.3b.4a.5i., 1j.2y.3b.4a.5i., 1p.2y.3b.4a.5i.,
1a.2a.3e.4a.5i., 1b.2a.3e.4a.5i., 1f.2a.3e.4a.5i., 1h.2a.3e.4a.5i.,
1j.2a.3e.4a.5i., 1p.2a.3e.4a.5i., 1a.2b.3e.4a.5i., 1b.2b.3e.4a.5i.,
1f.2b.3e.4a.5i., 1h.2b.3e.4a.5i., 1j.2b.3e.4a.5i., 1p.2b.3e.4a.5i.,
1a.2e.3e.4a.5i., 1b.2e.3e.4a.5i., 1f.2e.3e.4a.5i., 1h.2e.3e.4a.5i.,
1j.2e.3e.4a.5i., 1p.2e.3e.4a.5i., 1a.2f.3e.4a.5i., 1b.2f.3e.4a.5i.,
1f.2f.3e.4a.5i., 1h.2f.3e.4a.5i., 1j.2f.3e.4a.5i., 1p.2f.3e.4a.5i.,
1a.2i.3e.4a.5i., 1b.2i.3e.4a.5i., 1f.2i.3e.4a.5i., 1h.2i.3e.4a.5i.,
1j.2i.3e.4a.5i., 1p.2i.3e.4a.5i., 1a.2m.3e.4a.5i., 1b.2m.3e.4a.5i.,
1f.2m.3e.4a.5i., 1h.2m.3e.4a.5i., 1j.2m.3e.4a.5i., 1p.2m.3e.4a.5i.,
1a.2o.3e.4a.5i., 1b.2o.3e.4a.5i., 1f.2o.3e.4a.5i., 1h.2o.3e.4a.5i.,
1j.2o.3e.4a.5i., 1p.2o.3e.4a.5i., 1a.2u.3e.4a.5i., 1b.2u.3e.4a.5i.,
1f.2u.3e.4a.5i., 1h.2u.3e.4a.5i., 1j.2u.3e.4a.5i., 1p.2u.3e.4a.5i.,
1a.2y.3e.4a.5i., 1b.2y.3e.4a.5i., 1f.2y.3e.4a.5i., 1h.2y.3e.4a.5i.,
1j.2y.3e.4a.5i., 1p.2y.3e.4a.5i., 1a.2a.3g.4a.5i., 1b.2a.3g.4a.5i.,
1f.2a.3g.4a.5i., 1h.2a.3g.4a.5i., 1j.2a.3g.4a.5i., 1p.2a.3g.4a.5i.,
1a.2b.3g.4a.5i., 1b.2b.3g.4a.5i., 1f.2b.3g.4a.5i., 1h.2b.3g.4a.5i.,
1j.2b.3g.4a.5i., 1p.2b.3g.4a.5i., 1a.2e.3g.4a.5i., 1b.2e.3g.4a.5i.,
1f.2e.3g.4a.5i., 1h.2e.3g.4a.5i., 1j.2e.3g.4a.5i., 1p.2e.3g.4a.5i.,
1a.2f.3g.4a.5i., 1b.2f.3g.4a.5i., 1f.2f.3g.4a.5i., 1h.2f.3g.4a.5i.,
1j.2f.3g.4a.5i., 1p.2f.3g.4a.5i., 1a.2i.3g.4a.5i., 1b.2i.3g.4a.5i.,
1f.2i.3g.4a.5i., 1h.2i.3g.4a.5i., 1j.2i.3g.4a.5i., 1p.2i.3g.4a.5i.,
1a.2m.3g.4a.5i., 1b.2m.3g.4a.5i., 1f.2m.3g.4a.5i., 1h.2m.3g.4a.5i.,
1j.2m.3g.4a.5i., 1p.2m.3g.4a.5i., 1a.2o.3g.4a.5i., 1b.2o.3g.4a.5i.,
1f.2o.3g.4a.5i., 1h.2o.3g.4a.5i., 1j.2o.3g.4a.5i., 1p.2o.3g.4a.5i.,
1a.2u.3g.4a.5i., 1b.2u.3g.4a.5i., 1f.2u.3g.4a.5i., 1h.2u.3g.4a.5i.,
1j.2u.3g.4a.5i., 1p.2u.3g.4a.5i., 1a.2y.3g.4a.5i., 1b.2y.3g.4a.5i.,
1f.2y.3g.4a.5i., 1h.2y.3g.4a.5i., 1j.2y.3g.4a.5i., 1p.2y.3g.4a.5i.,
1a.2a.3a.4d.5i., 1b.2a.3a.4d.5i., 1f.2a.3a.4d.5i., 1h.2a.3a.4d.5i.,
1j.2a.3a.4d.5i., 1p.2a.3a.4d.5i., 1a.2b.3a.4d.5i., 1b.2b.3a.4d.5i.,
1f.2b.3a.4d.5i., 1h.2b.3a.4d.5i., 1j.2b.3a.4d.5i., 1p.2b.3a.4d.5i.,
1a.2e.3a.4d.5i., 1b.2e.3a.4d.5i., 1f.2e.3a.4d.5i., 1h.2e.3a.4d.5i.,
1j.2e.3a.4d.5i., 1p.2e.3a.4d.5i., 1a.2f.3a.4d.5i., 1b.2f.3a.4d.5i.,
1f.2f.3a.4d.5i., 1h.2f.3a.4d.5i., 1j.2f.3a.4d.5i., 1p.2f.3a.4d.5i.,
1a.2i.3a.4d.5i., 1b.2i.3a.4d.5i., 1f.2i.3a.4d.5i., 1h.2i.3a.4d.5i.,
1j.2i.3a.4d.5i., 1p.2i.3a.4d.5i., 1a.2m.3a.4d.5i., 1b.2m.3a.4d.5i.,
1f.2m.3a.4d.5i., 1h.2m.3a.4d.5i., 1j.2m.3a.4d.5i., 1p.2m.3a.4d.5i.,
1a.2o.3a.4d.5i., 1b.2o.3a.4d.5i., 1f.2o.3a.4d.5i., 1h.2o.3a.4d.5i.,
1j.2o.3a.4d.5i., 1p.2o.3a.4d.5i., 1a.2u.3a.4d.5i., 1b.2u.3a.4d.5i.,
1f.2u.3a.4d.5i., 1h.2u.3a.4d.5i., 1j.2u.3a.4d.5i., 1p.2u.3a.4d.5i.,
1a.2y.3a.4d.5i., 1b.2y.3a.4d.5i., 1f.2y.3a.4d.5i., 1h.2y.3a.4d.5i.,
1j.2y.3a.4d.5i., 1p.2y.3a.4d.5i., 1a.2a.3b.4d.5i., 1b.2a.3b.4d.5i.,
1f.2a.3b.4d.5i., 1h.2a.3b.4d.5i., 1j.2a.3b.4d.5i., 1p.2a.3b.4d.5i.,
1a.2b.3b.4d.5i., 1b.2b.3b.4d.5i., 1f.2b.3b.4d.5i., 1h.2b.3b.4d.5i.,
1j.2b.3b.4d.5i., 1p.2b.3b.4d.5i., 1a.2e.3b.4d.5i., 1b.2e.3b.4d.5i.,
1f.2e.3b.4d.5i., 1h.2e.3b.4d.5i., 1j.2e.3b.4d.5i., 1p.2e.3b.4d.5i.,
1a.2f.3b.4d.5i., 1b.2f.3b.4d.5i., 1f.2f.3b.4d.5i., 1h.2f.3b.4d.5i.,
1j.2f.3b.4d.5i., 1p.2f.3b.4d.5i., 1a.2i.3b.4d.5i., 1b.2i.3b.4d.5i.,
1f.2i.3b.4d.5i., 1h.2i.3b.4d.5i., 1j.2i.3b.4d.5i., 1p.2i.3b.4d.5i.,
1a.2m.3b.4d.5i., 1b.2m.3b.4d.5i., 1f.2m.3b.4d.5i., 1h.2m.3b.4d.5i.,
1j.2m.3b.4d.5i., 1p.2m.3b.4d.5i., 1a.2o.3b.4d.5i., 1b.2o.3b.4d.5i.,
1f.2o.3b.4d.5i., 1h.2o.3b.4d.5i., 1j.2o.3b.4d.5i., 1p.2o.3b.4d.5i.,
1a.2u.3b.4d.5i., 1b.2u.3b.4d.5i., 1f.2u.3b.4d.5i., 1h.2u.3b.4d.5i.,
1j.2u.3b.4d.5i., 1p.2u.3b.4d.5i., 1a.2y.3b.4d.5i., 1b.2y.3b.4d.5i.,
1f.2y.3b.4d.5i., 1h.2y.3b.4d.5i., 1j.2y.3b.4d.5i., 1p.2y.3b.4d.5i.,
1a.2a.3e.4d.5i., 1b.2a.3e.4d.5i., 1f.2a.3e.4d.5i., 1h.2a.3e.4d.5i.,
1j.2a.3e.4d.5i., 1p.2a.3e.4d.5i., 1a.2b.3e.4d.5i., 1b.2b.3e.4d.5i.,
1f.2b.3e.4d.5i., 1h.2b.3e.4d.5i., 1j.2b.3e.4d.5i., 1p.2b.3e.4d.5i.,
1a.2e.3e.4d.5i., 1b.2e.3e.4d.5i., 1f.2e.3e.4d.5i., 1h.2e.3e.4d.5i.,
1j.2e.3e.4d.5i., 1p.2e.3e.4d.5i., 1a.2f.3e.4d.5i., 1b.2f.3e.4d.5i.,
1f.2f.3e.4d.5i., 1h.2f.3e.4d.5i., 1j.2f.3e.4d.5i., 1p.2f.3e.4d.5i.,
1a.2i.3e.4d.5i., 1b.2i.3e.4d.5i., 1f.2i.3e.4d.5i., 1h.2i.3e.4d.5i.,
1j.2i.3e.4d.5i., 1p.2i.3e.4d.5i., 1a.2m.3e.4d.5i., 1b.2m.3e.4d.5i.,
1f.2m.3e.4d.5i., 1h.2m.3e.4d.5i., 1j.2m.3e.4d.5i., 1p.2m.3e.4d.5i.,
1a.2o.3e.4d.5i., 1b.2o.3e.4d.5i., 1f.2o.3e.4d.5i., 1h.2o.3e.4d.5i.,
1j.2o.3e.4d.5i., 1p.2o.3e.4d.5i., 1a.2u.3e.4d.5i., 1b.2u.3e.4d.5i.,
1f.2u.3e.4d.5i., 1h.2u.3e.4d.5i., 1j.2u.3e.4d.5i., 1p.2u.3e.4d.5i.,
1a.2y.3e.4d.5i., 1b.2y.3e.4d.5i., 1f.2y.3e.4d.5i., 1h.2y.3e.4d.5i.,
1j.2y.3e.4d.5i., 1p.2y.3e.4d.5i., 1a.2a.3g.4d.5i., 1b.2a.3g.4d.5i.,
1f.2a.3g.4d.5i., 1h.2a.3g.4d.5i., 1j.2a.3g.4d.5i., 1p.2a.3g.4d.5i.,
1a.2b.3g.4d.5i., 1b.2b.3g.4d.5i., 1f.2b.3g.4d.5i., 1h.2b.3g.4d.5i.,
1j.2b.3g.4d.5i., 1p.2b.3g.4d.5i., 1a.2e.3g.4d.5i., 1b.2e.3g.4d.5i.,
1f.2e.3g.4d.5i., 1h.2e.3g.4d.5i., 1j.2e.3g.4d.5i., 1p.2e.3g.4d.5i.,
1a.2f.3g.4d.5i., 1b.2f.3g.4d.5i., 1f.2f.3g.4d.5i., 1h.2f.3g.4d.5i.,
1j.2f.3g.4d.5i., 1p.2f.3g.4d.5i., 1a.2i.3g.4d.5i., 1b.2i.3g.4d.5i.,
1f.2i.3g.4d.5i., 1h.2i.3g.4d.5i., 1j.2i.3g.4d.5i., 1p.2i.3g.4d.5i.,
1a.2m.3g.4d.5i., 1b.2m.3g.4d.5i., 1f.2m.3g.4d.5i., 1h.2m.3g.4d.5i.,
1j.2m.3g.4d.5i., 1p.2m.3g.4d.5i., 1a.2o.3g.4d.5i., 1b.2o.3g.4d.5i.,
1f.2o.3g.4d.5i., 1h.2o.3g.4d.5i., 1j.2o.3g.4d.5i., 1p.2o.3g.4d.5i.,
1a.2u.3g.4d.5i., 1b.2u.3g.4d.5i., 1f.2u.3g.4d.5i., 1h.2u.3g.4d.5i.,
1j.2u.3g.4d.5i., 1p.2u.3g.4d.5i., 1a.2y.3g.4d.5i., 1b.2y.3g.4d.5i.,
1f.2y.3g.4d.5i., 1h.2y.3g.4d.5i., 1j.2y.3g.4d.5i., 1p.2y.3g.4d.5i.,
1a.2a.3a.4f.5i., 1b.2a.3a.4f.5i., 1f.2a.3a.4f.5i., 1h.2a.3a.4f.5i.,
1j.2a.3a.4f.5i., 1p.2a.3a.4f.5i., 1a.2b.3a.4f.5i., 1b.2b.3a.4f.5i.,
1f.2b.3a.4f.5i., 1h.2b.3a.4f.5i., 1j.2b.3a.4f.5i., 1p.2b.3a.4f.5i.,
1a.2e.3a.4f.5i., 1b.2e.3a.4f.5i., 1f.2e.3a.4f.5i., 1h.2e.3a.4f.5i.,
1j.2e.3a.4f.5i., 1p.2e.3a.4f.5i., 1a.2f.3a.4f.5i., 1b.2f.3a.4f.5i.,
1f.2f.3a.4f.5i., 1h.2f.3a.4f.5i., 1j.2f.3a.4f.5i., 1p.2f.3a.4f.5i.,
1a.2i.3a.4f.5i., 1b.2i.3a.4f.5i., 1f.2i.3a.4f.5i., 1h.2i.3a.4f.5i.,
1j.2i.3a.4f.5i., 1p.2i.3a.4f.5i., 1a.2m.3a.4f.5i., 1b.2m.3a.4f.5i.,
1f.2m.3a.4f.5i., 1h.2m.3a.4f.5i., 1j.2m.3a.4f.5i., 1p.2m.3a.4f.5i.,
1a.2o.3a.4f.5i., 1b.2o.3a.4f.5i., 1f.2o.3a.4f.5i., 1h.2o.3a.4f.5i.,
1j.2o.3a.4f.5i., 1p.2o.3a.4f.5i., 1a.2u.3a.4f.5i., 1b.2u.3a.4f.5i.,
1f.2u.3a.4f.5i., 1h.2u.3a.4f.5i., 1j.2u.3a.4f.5i., 1p.2u.3a.4f.5i.,
1a.2y.3a.4f.5i., 1b.2y.3a.4f.5i., 1f.2y.3a.4f.5i., 1h.2y.3a.4f.5i.,
1j.2y.3a.4f.5i., 1p.2y.3a.4f.5i., 1a.2a.3b.4f.5i., 1b.2a.3b.4f.5i.,
1f.2a.3b.4f.5i., 1h.2a.3b.4f.5i., 1j.2a.3b.4f.5i., 1p.2a.3b.4f.5i.,
1a.2b.3b.4f.5i., 1b.2b.3b.4f.5i., 1f.2b.3b.4f.5i., 1h.2b.3b.4f.5i.,
1j.2b.3b.4f.5i., 1p.2b.3b.4f.5i., 1a.2e.3b.4f.5i., 1b.2e.3b.4f.5i.,
1f.2e.3b.4f.5i., 1h.2e.3b.4f.5i., 1j.2e.3b.4f.5i., 1p.2e.3b.4f.5i.,
1a.2f.3b.4f.5i., 1b.2f.3b.4f.5i., 1f.2f.3b.4f.5i., 1h.2f.3b.4f.5i.,
1j.2f.3b.4f.5i., 1p.2f.3b.4f.5i., 1a.2i.3b.4f.5i., 1b.2i.3b.4f.5i.,
1f.2i.3b.4f.5i., 1h.2i.3b.4f.5i., 1j.2i.3b.4f.5i., 1p.2i.3b.4f.5i.,
1a.2m.3b.4f.5i., 1b.2m.3b.4f.5i., 1f.2m.3b.4f.5i., 1h.2m.3b.4f.5i.,
1j.2m.3b.4f.5i., 1p.2m.3b.4f.5i., 1a.2o.3b.4f.5i.,
1b.2o.3b.4f.5i.,
1f.2o.3b.4f.5i., 1h.2o.3b.4f.5i., 1j.2o.3b.4f.5i., 1p.2o.3b.4f.5i.,
1a.2u.3b.4f.5i., 1b.2u.3b.4f.5i., 1f.2u.3b.4f.5i., 1h.2u.3b.4f.5i.,
1j.2u.3b.4f.5i., 1p.2u.3b.4f.5i., 1a.2y.3b.4f.5i., 1b.2y.3b.4f.5i.,
1f.2y.3b.4f.5i., 1h.2y.3b.4f.5i., 1j.2y.3b.4f.5i., 1p.2y.3b.4f.5i.,
1a.2a.3e.4f.5i., 1b.2a.3e.4f.5i., 1f.2a.3e.4f.5i., 1h.2a.3e.4f.5i.,
1j.2a.3e.4f.5i., 1p.2a.3e.4f.5i., 1a.2b.3e.4f.5i., 1b.2b.3e.4f.5i.,
1f.2b.3e.4f.5i., 1h.2b.3e.4f.5i., 1j.2b.3e.4f.5i., 1p.2b.3e.4f.5i.,
1a.2e.3e.4f.5i., 1b.2e.3e.4f.5i., 1f.2e.3e.4f.5i., 1h.2e.3e.4f.5i.,
1j.2e.3e.4f.5i., 1p.2e.3e.4f.5i., 1a.2f.3e.4f.5i., 1b.2f.3e.4f.5i.,
1f.2f.3e.4f.5i., 1h.2f.3e.4f.5i., 1j.2f.3e.4f.5i., 1p.2f.3e.4f.5i.,
1a.2i.3e.4f.5i., 1b.2i.3e.4f.5i., 1f.2i.3e.4f.5i., 1h.2i.3e.4f.5i.,
1j.2i.3e.4f.5i., 1p.2i.3e.4f.5i., 1a.2m.3e.4f.5i., 1b.2m.3e.4f.5i.,
1f.2m.3e.4f.5i., 1h.2m.3e.4f.5i., 1j.2m.3e.4f.5i., 1p.2m.3e.4f.5i.,
1a.2o.3e.4f.5i., 1b.2o.3e.4f.5i., 1f.2o.3e.4f.5i., 1h.2o.3e.4f.5i.,
1j.2o.3e.4f.5i., 1p.2o.3e.4f.5i., 1a.2u.3e.4f.5i., 1b.2u.3e.4f.5i.,
1f.2u.3e.4f.5i., 1h.2u.3e.4f.5i., 1j.2u.3e.4f.5i., 1p.2u.3e.4f.5i.,
1a.2y.3e.4f.5i., 1b.2y.3e.4f.5i., 1f.2y.3e.4f.5i., 1h.2y.3e.4f.5i.,
1j.2y.3e.4f.5i., 1p.2y.3e.4f.5i., 1a.2a.3g.4f.5i., 1b.2a.3g.4f.5i.,
1f.2a.3g.4f.5i., 1h.2a.3g.4f.5i., 1j.2a.3g.4f.5i., 1p.2a.3g.4f.5i.,
1a.2b.3g.4f.5i., 1b.2b.3g.4f.5i., 1f.2b.3g.4f.5i., 1h.2b.3g.4f.5i.,
1j.2b.3g.4f.5i., 1p.2b.3g.4f.5i., 1a.2e.3g.4f.5i., 1b.2e.3g.4f.5i.,
1f.2e.3g.4f.5i., 1h.2e.3g.4f.5i., 1j.2e.3g.4f.5i., 1p.2e.3g.4f.5i.,
1a.2f.3g.4f.5i., 1b.2f.3g.4f.5i., 1f.2f.3g.4f.5i., 1h.2f.3g.4f.5i.,
1j.2f.3g.4f.5i., 1p.2f.3g.4f.5i., 1a.2i.3g.4f.5i., 1b.2i.3g.4f.5i.,
1f.2i.3g.4f.5i., 1h.2i.3g.4f.5i., 1j.2i.3g.4f.5i., 1p.2i.3g.4f.5i.,
1a.2m.3g.4f.5i., 1b.2m.3g.4f.5i., 1f.2m.3g.4f.5i., 1h.2m.3g.4f.5i.,
1j.2m.3g.4f.5i., 1p.2m.3g.4f.5i., 1a.2o.3g.4f.5i., 1b.2o.3g.4f.5i.,
1f.2o.3g.4f.5i., 1h.2o.3g.4f.5i., 1j.2o.3g.4f.5i., 1p.2o.3g.4f.5i.,
1a.2u.3g.4f.5i., 1b.2u.3g.4f.5i., 1f.2u.3g.4f.5i., 1h.2u.3g.4f.5i.,
1j.2u.3g.4f.5i., 1p.2u.3g.4f.5i., 1a.2y.3g.4f.5i., 1b.2y.3g.4f.5i.,
1f.2y.3g.4f.5i., 1h.2y.3g.4f.5i., 1j.2y.3g.4f.5i., 1p.2y.3g.4f.5i.,
1a.2a.3a.4g.5i., 1b.2a.3a.4g.5i., 1f.2a.3a.4g.5i., 1h.2a.3a.4g.5i.,
1j.2a.3a.4g.5i., 1p.2a.3a.4g.5i., 1a.2b.3a.4g.5i., 1b.2b.3a.4g.5i.,
1f.2b.3a.4g.5i., 1h.2b.3a.4g.5i., 1j.2b.3a.4g.5i., 1p.2b.3a.4g.5i.,
1a.2e.3a.4g.5i., 1b.2e.3a.4g.5i., 1f.2e.3a.4g.5i., 1h.2e.3a.4g.5i.,
1j.2e.3a.4g.5i., 1p.2e.3a.4g.5i., 1a.2f.3a.4g.5i., 1b.2f.3a.4g.5i.,
1f.2f.3a.4g.5i., 1h.2f.3a.4g.5i., 1j.2f.3a.4g.5i., 1p.2f.3a.4g.5i.,
1a.2i.3a.4g.5i., 1b.2i.3a.4g.5i., 1f.2i.3a.4g.5i., 1h.2i.3a.4g.5i.,
1j.2i.3a.4g.5i., 1p.2i.3a.4g.5i., 1a.2m.3a.4g.5i., 1b.2m.3a.4g.5i.,
1f.2m.3a.4g.5i., 1h.2m.3a.4g.5i., 1j.2m.3a.4g.5i., 1p.2m.3a.4g.5i.,
1a.2o.3a.4g.5i., 1b.2o.3a.4g.5i., 1f.2o.3a.4g.5i., 1h.2o.3a.4g.5i.,
1j.2o.3a.4g.5i., 1p.2o.3a.4g.5i., 1a.2u.3a.4g.5i., 1b.2u.3a.4g.5i.,
1f.2u.3a.4g.5i., 1h.2u.3a.4g.5i., 1j.2u.3a.4g.5i., 1p.2u.3a.4g.5i.,
1a.2y.3a.4g.5i., 1b.2y.3a.4g.5i., 1f.2y.3a.4g.5i., 1h.2y.3a.4g.5i.,
1j.2y.3a.4g.5i., 1p.2y.3a.4g.5i., 1a.2a.3b.4g.5i., 1b.2a.3b.4g.5i.,
1f.2a.3b.4g.5i., 1h.2a.3b.4g.5i., 1j.2a.3b.4g.5i., 1p.2a.3b.4g.5i.,
1a.2b.3b.4g.5i., 1b.2b.3b.4g.5i., 1f.2b.3b.4g.5i., 1h.2b.3b.4g.5i.,
1j.2b.3b.4g.5i., 1p.2b.3b.4g.5i., 1a.2e.3b.4g.5i., 1b.2e.3b.4g.5i.,
1f.2e.3b.4g.5i., 1h.2e.3b.4g.5i., 1j.2e.3b.4g.5i., 1p.2e.3b.4g.5i.,
1a.2f.3b.4g.5i., 1b.2f.3b.4g.5i., 1f.2f.3b.4g.5i., 1h.2f.3b.4g.5i.,
1j.2f.3b.4g.5i., 1p.2f.3b.4g.5i., 1a.2i.3b.4g.5i., 1b.2i.3b.4g.5i.,
1f.2i.3b.4g.5i., 1h.2i.3b.4g.5i., 1j.2i.3b.4g.5i., 1p.2i.3b.4g.5i.,
1a.2m.3b.4g.5i., 1b.2m.3b.4g.5i., 1f.2m.3b.4g.5i., 1h.2m.3b.4g.5i.,
1j.2m.3b.4g.5i., 1p.2m.3b.4g.5i., 1a.2o.3b.4g.5i., 1b.2o.3b.4g.5i.,
1f.2o.3b.4g.5i., 1h.2o.3b.4g.5i., 1j.2o.3b.4g.5i., 1p.2o.3b.4g.5i.,
1a.2u.3b.4g.5i., 1b.2u.3b.4g.5i., 1f.2u.3b.4g.5i., 1h.2u.3b.4g.5i.,
1j.2u.3b.4g.5i., 1p.2u.3b.4g.5i., 1a.2y.3b.4g.5i., 1b.2y.3b.4g.5i.,
1f.2y.3b.4g.5i., 1h.2y.3b.4g.5i., 1j.2y.3b.4g.5i., 1p.2y.3b.4g.5i.,
1a.2a.3e.4g.5i., 1b.2a.3e.4g.5i., 1f.2a.3e.4g.5i., 1h.2a.3e.4g.5i.,
1j.2a.3e.4g.5i., 1p.2a.3e.4g.5i., 1a.2b.3e.4g.5i., 1b.2b.3e.4g.5i.,
1f.2b.3e.4g.5i., 1h.2b.3e.4g.5i., 1j.2b.3e.4g.5i., 1p.2b.3e.4g.5i.,
1a.2e.3e.4g.5i., 1b.2e.3e.4g.5i., 1f.2e.3e.4g.5i., 1h.2e.3e.4g.5i.,
1j.2e.3e.4g.5i., 1p.2e.3e.4g.5i., 1a.2f.3e.4g.5i., 1b.2f.3e.4g.5i.,
1f.2f.3e.4g.5i., 1h.2f.3e.4g.5i., 1j.2f.3e.4g.5i., 1p.2f.3e.4g.5i.,
1a.2i.3e.4g.5i., 1b.2i.3e.4g.5i., 1f.2i.3e.4g.5i., 1h.2i.3e.4g.5i.,
1j.2i.3e.4g.5i., 1p.2i.3e.4g.5i., 1a.2m.3e.4g.5i., 1b.2m.3e.4g.5i.,
1f.2m.3e.4g.5i., 1h.2m.3e.4g.5i., 1j.2m.3e.4g.5i., 1p.2m.3e.4g.5i.,
1a.2o.3e.4g.5i., 1b.2o.3e.4g.5i., 1f.2o.3e.4g.5i., 1h.2o.3e.4g.5i.,
1j.2o.3e.4g.5i., 1p.2o.3e.4g.5i., 1a.2u.3e.4g.5i., 1b.2u.3e.4g.5i.,
1f.2u.3e.4g.5i., 1h.2u.3e.4g.5i., 1j.2u.3e.4g.5i., 1p.2u.3e.4g.5i.,
1a.2y.3e.4g.5i., 1b.2y.3e.4g.5i., 1f.2y.3e.4g.5i., 1h.2y.3e.4g.5i.,
1j.2y.3e.4g.5i., 1p.2y.3e.4g.5i., 1a.2a.3g.4g.5i., 1b.2a.3g.4g.5i.,
1f.2a.3g.4g.5i., 1h.2a.3g.4g.5i., 1j.2a.3g.4g.5i., 1p.2a.3g.4g.5i.,
1a.2b.3g.4g.5i., 1b.2b.3g.4g.5i., 1f.2b.3g.4g.5i., 1h.2b.3g.4g.5i.,
1j.2b.3g.4g.5i., 1p.2b.3g.4g.5i., 1a.2e.3g.4g.5i., 1b.2e.3g.4g.5i.,
1f.2e.3g.4g.5i., 1h.2e.3g.4g.5i., 1j.2e.3g.4g.5i., 1p.2e.3g.4g.5i.,
1a.2f.3g.4g.5i., 1b.2f.3g.4g.5i., 1f.2f.3g.4g.5i., 1h.2f.3g.4g.5i.,
1j.2f.3g.4g.5i., 1p.2f.3g.4g.5i., 1a.2i.3g.4g.5i., 1b.2i.3g.4g.5i.,
1f.2i.3g.4g.5i., 1h.2i.3g.4g.5i., 1j.2i.3g.4g.5i., 1p.2i.3g.4g.5i.,
1a.2m.3g.4g.5i., 1b.2m.3g.4g.5i., 1f.2m.3g.4g.5i., 1h.2m.3g.4g.5i.,
1j.2m.3g.4g.5i., 1p.2m.3g.4g.5i., 1a.2o.3g.4g.5i., 1b.2o.3g.4g.5i.,
1f.2o.3g.4g.5i., 1h.2o.3g.4g.5i., 1j.2o.3g.4g.5i., 1p.2o.3g.4g.5i.,
1a.2u.3g.4g.5i., 1b.2u.3g.4g.5i., 1f.2u.3g.4g.5i., 1h.2u.3g.4g.5i.,
1j.2u.3g.4g.5i., 1p.2u.3g.4g.5i., 1a.2y.3g.4g.5i., 1b.2y.3g.4g.5i.,
1f.2y.3g.4g.5i., 1h.2y.3g.4g.5i., 1j.2y.3g.4g.5i., 1p.2y.3g.4g.5i.,
1a.2a.3a.4h.5i., 1b.2a.3a.4h.5i., 1f.2a.3a.4h.5i., 1h.2a.3a.4h.5i.,
1j.2a.3a.4h.5i., 1p.2a.3a.4h.5i., 1a.2b.3a.4h.5i., 1b.2b.3a.4h.5i.,
1f.2b.3a.4h.5i., 1h.2b.3a.4h.5i., 1j.2b.3a.4h.5i., 1p.2b.3a.4h.5i.,
1a.2e.3a.4h.5i., 1b.2e.3a.4h.5i., 1f.2e.3a.4h.5i., 1h.2e.3a.4h.5i.,
1j.2e.3a.4h.5i., 1p.2e.3a.4h.5i., 1a.2f.3a.4h.5i., 1b.2f.3a.4h.5i.,
1f.2f.3a.4h.5i., 1h.2f.3a.4h.5i., 1j.2f.3a.4h.5i., 1p.2f.3a.4h.5i.,
1a.2i.3a.4h.5i., 1b.2i.3a.4h.5i., 1f.2i.3a.4h.5i., 1h.2i.3a.4h.5i.,
1j.2i.3a.4h.5i., 1p.2i.3a.4h.5i., 1a.2m.3a.4h.5i., 1b.2m.3a.4h.5i.,
1f.2m.3a.4h.5i., 1h.2m.3a.4h.5i., 1j.2m.3a.4h.5i., 1p.2m.3a.4h.5i.,
1a.2o.3a.4h.5i., 1b.2o.3a.4h.5i., 1f.2o.3a.4h.5i., 1h.2o.3a.4h.5i.,
1j.2o.3a.4h.5i., 1p.2o.3a.4h.5i., 1a.2u.3a.4h.5i., 1b.2u.3a.4h.5i.,
1f.2u.3a.4h.5i., 1h.2u.3a.4h.5i., 1j.2u.3a.4h.5i., 1p.2u.3a.4h.5i.,
1a.2y.3a.4h.5i., 1b.2y.3a.4h.5i., 1f.2y.3a.4h.5i., 1h.2y.3a.4h.5i.,
1j.2y.3a.4h.5i., 1p.2y.3a.4h.5i., 1a.2a.3b.4h.5i., 1b.2a.3b.4h.5i.,
1f.2a.3b.4h.5i., 1h.2a.3b.4h.5i., 1j.2a.3b.4h.5i., 1p.2a.3b.4h.5i.,
1a.2b.3b.4h.5i., 1b.2b.3b.4h.5i., 1f.2b.3b.4h.5i., 1h.2b.3b.4h.5i.,
1j.2b.3b.4h.5i., 1p.2b.3b.4h.5i., 1a.2e.3b.4h.5i., 1b.2e.3b.4h.5i.,
1f.2e.3b.4h.5i., 1h.2e.3b.4h.5i., 1j.2e.3b.4h.5i., 1p.2e.3b.4h.5i.,
1a.2f.3b.4h.5i., 1b.2f.3b.4h.5i., 1f.2f.3b.4h.5i., 1h.2f.3b.4h.5i.,
1j.2f.3b.4h.5i., 1p.2f.3b.4h.5i., 1a.2i.3b.4h.5i., 1b.2i.3b.4h.5i.,
1f.2i.3b.4h.5i., 1h.2i.3b.4h.5i., 1j.2i.3b.4h.5i., 1p.2i.3b.4h.5i.,
1a.2m.3b.4h.5i., 1b.2m.3b.4h.5i., 1f.2m.3b.4h.5i., 1h.2m.3b.4h.5i.,
1j.2m.3b.4h.5i., 1p.2m.3b.4h.5i., 1a.2o.3b.4h.5i., 1b.2o.3b.4h.5i.,
1f.2o.3b.4h.5i., 1h.2o.3b.4h.5i., 1j.2o.3b.4h.5i., 1p.2o.3b.4h.5i.,
1a.2u.3b.4h.5i., 1b.2u.3b.4h.5i., 1f.2u.3b.4h.5i., 1h.2u.3b.4h.5i.,
1j.2u.3b.4h.5i., 1p.2u.3b.4h.5i., 1a.2y.3b.4h.5i., 1b.2y.3b.4h.5i.,
1f.2y.3b.4h.5i., 1h.2y.3b.4h.5i., 1j.2y.3b.4h.5i., 1p.2y.3b.4h.5i.,
1a.2a.3e.4h.5i., 1b.2a.3e.4h.5i., 1f.2a.3e.4h.5i., 1h.2a.3e.4h.5i.,
1j.2a.3e.4h.5i., 1p.2a.3e.4h.5i., 1a.2b.3e.4h.5i., 1b.2b.3e.4h.5i.,
1f.2b.3e.4h.5i., 1h.2b.3e.4h.5i., 1j.2b.3e.4h.5i., 1p.2b.3e.4h.5i.,
1a.2e.3e.4h.5i., 1b.2e.3e.4h.5i., 1f.2e.3e.4h.5i., 1h.2e.3e.4h.5i.,
1j.2e.3e.4h.5i., 1p.2e.3e.4h.5i., 1a.2f.3e.4h.5i., 1b.2f.3e.4h.5i.,
1f.2f.3e.4h.5i., 1h.2f.3e.4h.5i., 1j.2f.3e.4h.5i., 1p.2f.3e.4h.5i.,
1a.2i.3e.4h.5i., 1b.2i.3e.4h.5i., 1f.2i.3e.4h.5i., 1h.2i.3e.4h.5i.,
1j.2i.3e.4h.5i., 1p.2i.3e.4h.5i., 1a.2m.3e.4h.5i., 1b.2m.3e.4h.5i.,
1f.2m.3e.4h.5i., 1h.2m.3e.4h.5i., 1j.2m.3e.4h.5i., 1p.2m.3e.4h.5i.,
1a.2o.3e.4h.5i., 1b.2o.3e.4h.5i., 1f.2o.3e.4h.5i., 1h.2o.3e.4h.5i.,
1j.2o.3e.4h.5i., 1p.2o.3e.4h.5i., 1a.2u.3e.4h.5i., 1b.2u.3e.4h.5i.,
1f.2u.3e.4h.5i., 1h.2u.3e.4h.5i., 1j.2u.3e.4h.5i., 1p.2u.3e.4h.5i.,
1a.2y.3e.4h.5i., 1b.2y.3e.4h.5i., 1f.2y.3e.4h.5i., 1h.2y.3e.4h.5i.,
1j.2y.3e.4h.5i., 1p.2y.3e.4h.5i., 1a.2a.3g.4h.5i., 1b.2a.3g.4h.5i.,
1f.2a.3g.4h.5i., 1h.2a.3g.4h.5i., 1j.2a.3g.4h.5i., 1p.2a.3g.4h.5i.,
1a.2b.3g.4h.5i., 1b.2b.3g.4h.5i., 1f.2b.3g.4h.5i., 1h.2b.3g.4h.5i.,
1j.2b.3g.4h.5i., 1p.2b.3g.4h.5i., 1a.2e.3g.4h.5i., 1b.2e.3g.4h.5i.,
1f.2e.3g.4h.5i., 1h.2e.3g.4h.5i., 1j.2e.3g.4h.5i., 1p.2e.3g.4h.5i.,
1a.2f.3g.4h.5i., 1b.2f.3g.4h.5i., 1f.2f.3g.4h.5i., 1h.2f.3g.4h.5i.,
1j.2f.3g.4h.5i., 1p.2f.3g.4h.5i., 1a.2i.3g.4h.5i., 1b.2i.3g.4h.5i.,
1f.2i.3g.4h.5i., 1h.2i.3g.4h.5i., 1j.2i.3g.4h.5i., 1p.2i.3g.4h.5i.,
1a.2m.3g.4h.5i., 1b.2m.3g.4h.5i., 1f.2m.3g.4h.5i., 1h.2m.3g.4h.5i.,
1j.2m.3g.4h.5i., 1p.2m.3g.4h.5i., 1a.2o.3g.4h.5i., 1b.2o.3g.4h.5i.,
1f.2o.3g.4h.5i., 1h.2o.3g.4h.5i., 1j.2o.3g.4h.5i., 1p.2o.3g.4h.5i.,
1a.2u.3g.4h.5i., 1b.2u.3g.4h.5i., 1f.2u.3g.4h.5i., 1h.2u.3g.4h.5i.,
1j.2u.3g.4h.5i., 1p.2u.3g.4h.5i., 1a.2y.3g.4h.5i., 1b.2y.3g.4h.5i.,
1f.2y.3g.4h.5i., 1h.2y.3g.4h.5i., 1j.2y.3g.4h.5i., 1p.2y.3g.4h.5i.,
1a.2a.3a.4i.5i., 1b.2a.3a.4i.5i., 1f.2a.3a.4i.5i., 1h.2a.3a.4i.5i.,
1j.2a.3a.4i.5i., 1p.2a.3a.4i.5i., 1a.2b.3a.4i.5i., 1b.2b.3a.4i.5i.,
1f.2b.3a.4i.5i., 1h.2b.3a.4i.5i., 1j.2b.3a.4i.5i., 1p.2b.3a.4i.5i.,
1a.2e.3a.4i.5i., 1b.2e.3a.4i.5i., 1f.2e.3a.4i.5i., 1h.2e.3a.4i.5i.,
1j.2e.3a.4i.5i., 1p.2e.3a.4i.5i., 1a.2f.3a.4i.5i., 1b.2f.3a.4i.5i.,
1f.2f.3a.4i.5i., 1h.2f.3a.4i.5i., 1j.2f.3a.4i.5i., 1p.2f.3a.4i.5i.,
1a.2i.3a.4i.5i., 1b.2i.3a.4i.5i., 1f.2i.3a.4i.5i., 1h.2i.3a.4i.5i.,
1j.2i.3a.4i.5i., 1p.2i.3a.4i.5i., 1a.2m.3a.4i.5i., 1b.2m.3a.4i.5i.,
1f.2m.3a.4i.5i., 1h.2m.3a.4i.5i., 1j.2m.3a.4i.5i., 1p.2m.3a.4i.5i.,
1a.2o.3a.4i.5i., 1b.2o.3a.4i.5i., 1f.2o.3a.4i.5i., 1h.2o.3a.4i.5i.,
1j.2o.3a.4i.5i., 1p.2o.3a.4i.5i., 1a.2u.3a.4i.5i., 1b.2u.3a.4i.5i.,
1f.2u.3a.4i.5i., 1h.2u.3a.4i.5i., 1j.2u.3a.4i.5i., 1p.2u.3a.4i.5i.,
1a.2y.3a.4i.5i., 1b.2y.3a.4i.5i., 1f.2y.3a.4i.5i., 1h.2y.3a.4i.5i.,
1j.2y.3a.4i.5i., 1p.2y.3a.4i.5i., 1a.2a.3b.4i.5i., 1b.2a.3b.4i.5i.,
1f.2a.3b.4i.5i., 1h.2a.3b.4i.5i., 1j.2a.3b.4i.5i., 1p.2a.3b.4i.5i.,
1a.2b.3b.4i.5i., 1b.2b.3b.4i.5i., 1f.2b.3b.4i.5i., 1h.2b.3b.4i.5i.,
1j.2b.3b.4i.5i., 1p.2b.3b.4i.5i., 1a.2e.3b.4i.5i., 1b.2e.3b.4i.5i.,
1f.2e.3b.4i.5i., 1h.2e.3b.4i.5i., 1j.2e.3b.4i.5i., 1p.2e.3b.4i.5i.,
1a.2f.3b.4i.5i., 1b.2f.3b.4i.5i., 1f.2f.3b.4i.5i., 1h.2f.3b.4i.5i.,
1j.2f.3b.4i.5i., 1p.2f.3b.4i.5i., 1a.2i.3b.4i.5i., 1b.2i.3b.4i.5i.,
1f.2i.3b.4i.5i., 1h.2i.3b.4i.5i., 1j.2i.3b.4i.5i., 1p.2i.3b.4i.5i.,
1a.2m.3b.4i.5i., 1b.2m.3b.4i.5i., 1f.2m.3b.4i.5i., 1h.2m.3b.4i.5i.,
1j.2m.3b.4i.5i., 1p.2m.3b.4i.5i., 1a.2o.3b.4i.5i., 1b.2o.3b.4i.5i.,
1f.2o.3b.4i.5i., 1h.2o.3b.4i.5i., 1j.2o.3b.4i.5i., 1p.2o.3b.4i.5i.,
1a.2u.3b.4i.5i., 1b.2u.3b.4i.5i., 1f.2u.3b.4i.5i., 1h.2u.3b.4i.5i.,
1j.2u.3b.4i.5i., 1p.2u.3b.4i.5i., 1a.2y.3b.4i.5i., 1b.2y.3b.4i.5i.,
1f.2y.3b.4i.5i., 1h.2y.3b.4i.5i., 1j.2y.3b.4i.5i., 1p.2y.3b.4i.5i.,
1a.2a.3e.4i.5i., 1b.2a.3e.4i.5i., 1f.2a.3e.4i.5i., 1h.2a.3e.4i.5i.,
1j.2a.3e.4i.5i., 1p.2a.3e.4i.5i., 1a.2b.3e.4i.5i., 1b.2b.3e.4i.5i.,
1f.2b.3e.4i.5i., 1h.2b.3e.4i.5i., 1j.2b.3e.4i.5i., 1p.2b.3e.4i.5i.,
1a.2e.3e.4i.5i., 1b.2e.3e.4i.5i., 1f.2e.3e.4i.5i., 1h.2e.3e.4i.5i.,
1j.2e.3e.4i.5i., 1p.2e.3e.4i.5i., 1a.2f.3e.4i.5i., 1b.2f.3e.4i.5i.,
1f.2f.3e.4i.5i., 1h.2f.3e.4i.5i., 1j.2f.3e.4i.5i., 1p.2f.3e.4i.5i.,
1a.2i.3e.4i.5i., 1b.2i.3e.4i.5i., 1f.2i.3e.4i.5i., 1h.2i.3e.4i.5i.,
1j.2i.3e.4i.5i., 1p.2i.3e.4i.5i., 1a.2m.3e.4i.5i., 1b.2m.3e.4i.5i.,
1f.2m.3e.4i.5i., 1h.2m.3e.4i.5i., 1j.2m.3e.4i.5i., 1p.2m.3e.4i.5i.,
1a.2o.3e.4i.5i., 1b.2o.3e.4i.5i., 1f.2o.3e.4i.5i., 1h.2o.3e.4i.5i.,
1j.2o.3e.4i.5i., 1p.2o.3e.4i.5i., 1a.2u.3e.4i.5i., 1b.2u.3e.4i.5i.,
1f.2u.3e.4i.5i., 1h.2u.3e.4i.5i., 1j.2u.3e.4i.5i., 1p.2u.3e.4i.5i.,
1a.2y.3e.4i.5i., 1b.2y.3e.4i.5i., 1f.2y.3e.4i.5i., 1h.2y.3e.4i.5i.,
1j.2y.3e.4i.5i., 1p.2y.3e.4i.5i., 1a.2a.3g.4i.5i., 1b.2a.3g.4i.5i.,
1f.2a.3g.4i.5i., 1h.2a.3g.4i.5i., 1j.2a.3g.4i.5i., 1p.2a.3g.4i.5i.,
1a.2b.3g.4i.5i., 1b.2b.3g.4i.5i., 1f.2b.3g.4i.5i., 1h.2b.3g.4i.5i.,
1j.2b.3g.4i.5i., 1p.2b.3g.4i.5i., 1a.2e.3g.4i.5i., 1b.2e.3g.4i.5i.,
1f.2e.3g.4i.5i., 1h.2e.3g.4i.5i., 1j.2e.3g.4i.5i., 1p.2e.3g.4i.5i.,
1a.2f.3g.4i.5i., 1b.2f.3g.4i.5i., 1f.2f.3g.4i.5i., 1h.2f.3g.4i.5i.,
1j.2f.3g.4i.5i., 1p.2f.3g.4i.5i., 1a.2i.3g.4i.5i., 1b.2i.3g.4i.5i.,
1f.2i.3g.4i.5i., 1h.2i.3g.4i.5i., 1j.2i.3g.4i.5i., 1p.2i.3g.4i.5i.,
1a.2m.3g.4i.5i., 1b.2m.3g.4i.5i., 1f.2m.3g.4i.5i., 1h.2m.3g.4i.5i.,
1j.2m.3g.4i.5i., 1p.2m.3g.4i.5i., 1a.2o.3g.4i.5i., 1b.2o.3g.4i.5i.,
1f.2o.3g.4i.5i., 1h.2o.3g.4i.5i., 1j.2o.3g.4i.5i., 1p.2o.3g.4i.5i.,
1a.2u.3g.4i.5i., 1b.2u.3g.4i.5i., 1f.2u.3g.4i.5i., 1h.2u.3g.4i.5i.,
1j.2u.3g.4i.5i., 1p.2u.3g.4i.5i., 1a.2y.3g.4i.5i., 1b.2y.3g.4i.5i.,
1f.2y.3g.4i.5i., 1h.2y.3g.4i.5i., 1j.2y.3g.4i.5i., and
1p.2y.3g.4i.5i..
[0437] In still yet another embodiment, the compound of the present
invention has an inhibition activity against P450 at a level equal
to or better than the inhibition activity of a compound as
represented by an IC.sub.50 of less than about 2000 nM, less than
about 1500 nM, less than about 1000 nM, less than about 900 nM,
less than about 800 nM, less than about 700 nM, less than about 650
nM, less than about 600 nM, less than about 550 nM, less than about
500 nM, less than about 400 nM, less than about 350 nM, less than
about 300 nM, less than about 250 nM, less than about 200 nM, less
than about 100 nM, or less than about 50 nM.
[0438] In still yet another embodiment, the compound of the present
invention has an inhibition activity against an isozyme of P450,
e.g., 3A in a range represented by IC.sub.50 from about 2000 nM to
about 100 nM, from about 1000 nM to about 100 nM, from about 900 nM
to about 200 nM, from about 800 nM to about 300 nM, from about 700
nM to about 200 nM, from about 600 nM to about 200 nM, from about
500 nM to about 200 nM, from about 700 nM to about 300 nM, from
about 600 nM to about 300 nM, from about 700 nM to about 400 nM,
from about 600 nM to about 400 nM, from about 400 nM to about 100
nM, from about 300 nM to about 100 nM, or from about 600 nM to
about 150 nM.
[0439] In still yet another embodiment, the compound of the present
invention has an inhibition activity against P450 at a level equal
to or better than the inhibition activity of a compound as
represented by an IC.sub.50 of less than about 2000 nM, less than
about 1500 nM, less than about 1000 nM, less than about 900 nM,
less than about 800 nM, less than about 700 nM, less than about 650
nM, less than about 600 nM, less than about 550 nM, less than about
500 nM, less than about 400 nM, less than about 350 nM, less than
about 300 nM, less than about 250 nM, less than about 200 nM, less
than about 100 nM, or less than about 50 nM, provided that such
compound also does not substantially exhibit biological activities
other than its inhibition activity against P450. For example, the
compound of the present invention can have a reduced or not
significant activity of protease inhibition, including without any
limitation a level of protease inhibition as represented by HIV
EC.sub.50 of greater than about 1000 nM, greater than about 900 nM,
greater than about 800 nM, greater than about 700 nM, greater than
about 600 nM, greater than about 500 nM, greater than about 400 nM,
greater than about 300 nM, greater than about 200 nM, greater than
about 100 nM, greater than about 50 nM, greater than about 40 nM,
greater than about 30 nM, greater than about 20 nM, greater than
about 10 nM, greater than about 5 nM, or greater than about 1
nM.
[0440] In yet another embodiment, the compound of the present
invention has an inhibition activity specifically against one or
more isozymes of P450 including without limitation 1A2, 2B6, 2C8,
2C19, 2C9, 2D6, 2E1, and 3A4, 5, 7, etc.
[0441] In yet another embodiment, the compound of the present
invention has an inhibition activity specifically against an
isozyme of P450 that is involved in metabolizing anti-viral drugs,
e.g., indinavir, nelfinavir, ritonavir, saquinavir etc.
[0442] In still yet another embodiment, the compound of the present
invention has an inhibition activity specifically against one or
more isozymes of P450, but not the other(s). For example, the
compound of the present invention can have an inhibition activity
specifically against P450 3A, but a reduced, insubstantial, or
minimum inhibition activity against another isozyme of P450, e.g.,
P450 2C9.
Pharmaceutical Formulations
[0443] 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.
[0444] 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, e.g. a compound of the present invention, 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.
[0445] 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.
[0446] 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.
[0447] 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.
[0448] 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.
[0449] 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.
[0450] 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.
[0451] 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.
[0452] 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.
[0453] 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.
[0454] 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.
[0455] 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.
[0456] 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.
[0457] 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.
[0458] 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.
[0459] 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.
[0460] 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.
[0461] 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.
[0462] 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.
[0463] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
[0464] 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.
[0465] 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.
[0466] 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.
[0467] 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.
[0468] It should be understood that in addition to the ingredients
provided by the present invention 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.
[0469] The invention further provides veterinary compositions
comprising at least one active ingredient, e.g., a compound of the
present invention together with a veterinary carrier.
[0470] 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.
[0471] 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.
[0472] 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 100 mg/kg body weight
per day. Typically, from about 0.01 to about 10 mg/kg body weight
per day. More typically, from about 0.01 to about 5 mg/kg body
weight per day. 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 1 mg
to 1000 mg, or between 5 mg and 500 mg, and may take the form of
single or multiple doses.
[0473] 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, and a pharmaceutically acceptable carrier or
excipient.
[0474] 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
therapeutic agent, and a pharmaceutically acceptable carrier or
excipient.
[0475] According to the present invention, the therapeutic 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
therapeutic agent used in combination with the compound of the
present invention can be any agent that is accessible to oxidative
metabolism by cytochrome P450 enzymes, especially cytochrome P450
monooxygenase, e.g., 1A2, 2B6, 2C8, 2C19, 2C9, 2D6, 2E1, 3A4,5,7,
etc.
[0476] In another example, the therapeutic agent used in
combination with the compound of the present invention can be any
anti-viral agent, e.g., anti-HIV, anti-HCV, etc., anti-bacterial
agent, anti-fungal agent, immuno-modulator, e.g.,
immunosuppressant, anti-neoplastic agent, chemotherapeutic agent,
agents useful for treating cardiovascular conditions, neurological
conditions, etc.
[0477] In yet another example, the therapeutic agent used in
combination with the compound of the present invention can be any
proton pump inhibitor, anti-epileptics, NSAID, oral hypoglycemic
agent, angiotensin II, sulfonylureas, beta blocker, antidepressant,
antipsychotics, or anesthetics, or a combination thereof.
[0478] In yet another example, the therapeutic agent used in
combination with the compound of the present invention can be any
1) macrolide antibiotics, e.g., clarithromycin, erythromycin,
telithromycin, 2) anti-arrhythmics, e.g., quinidine=>3-OH, 3)
benzodiazepines, e.g., alprazolam, diazepam=>3OH, midazolam,
triazolam, 4) immune modulators, e.g., cyclosporine, tacrolimus
(FK506), 5) HIV antivirals, e.g., indinavir, nelfinavir, ritonavir,
saquinavir, 6) prokinetic, e.g., cisapride, 7) antihistamines,
e.g., astemizole, chlorpheniramine, terfenidine, 8) calcium channel
blockers, e.g., amlodipine, diltiazem, felodipine, lercanidipine,
nifedipine, nisoldipine, nitrendipine, verapamil, 9) HMG CoA
reductase inhibitors, e.g., atorvastatin, cerivastatin, lovastatin,
simvastatin, or 10) steroid 6beta-OH, e.g., estradiol,
hydrocortisone, progesterone, testosterone.
[0479] In still yet another example, the therapeutic agent used in
combination with the compound of the present invention can be any
alfentanyl, aprepitant, aripiprazole, buspirone, cafergot,
caffeine, TMU, cilostazol, cocaine, codeine-N-demethylation,
dapsone, dextromethorphan, docetaxel, domperidone, eplerenone,
fentanyl, finasteride, gleevec, haloperidol, irinotecan, LAAM,
lidocaine, methadone, nateglinide, ondansetron, pimozide,
propranolol, quetiapine, quinine, salmeterol, sildenafil,
sirolimus, tamoxifen, taxol, terfenadine, trazodone, vincristine,
zaleplon, or zolpidem or a combination thereof.
[0480] In one 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
therapeutic agent selected from the group consisting of HIV
protease inhibiting compounds, HIV non-nucleoside inhibitors of
reverse transcriptase, HIV nucleoside inhibitors of reverse
transcriptase, HIV nucleotide inhibitors of reverse transcriptase,
HIV integrase inhibitors, non-nucleoside inhibitors of HCV, CCR5
inhibitors, and combinations thereof, and a pharmaceutically
acceptable carrier or excipient.
[0481] 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
therapeutic agent selected from the group consisting of amprenavir,
atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir,
nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126,
TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423,
RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100,
DG35, AG 1859, capravirine, emivirine, delaviridine, efavirenz,
nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961,
DPC-963, MIV-150, TMC-120, TMC-278 (rilpivirene), BILR 355 BS, VRX
840773, UK-453061, RDEA806, zidovudine, emtricitabine, didanosine,
stavudine, zalcitabine, lamivudine, abacavir, amdoxovir,
elvucitabine, alovudine, MIV-210, Racivir (.+-.-FTC), D-d4FC,
phosphazide, fozivudine tidoxil, apricitibine AVX754, amdoxovir,
KP-1461, and fosalvudine tidoxil (formerly HDP 99.0003), tenofovir
disoproxil fumarate, adefovir dipivoxil, GS-9131, curcumin,
derivatives of curcumin, chicoric acid, derivatives of chicoric
acid, 3,5-dicaffeoylquinic acid, derivatives of
3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of
aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives
of caffeic acid phenethyl ester, tyrphostin, derivatives of
tyrphostin, quercetin, derivatives of quercetin, S-1360, zintevir
(AR-177), L-870812, L-870810, MK-0518 (raltegravir), elvitegravir,
BMS-538158, GSK364735C, BMS-707035, MK-2048, BA 011, enfuvirtide,
sifuvirtide, FB006M, TRI-1144, AMD-070, SP01A, BMS-488043,
BlockAide/CR, immunitin, benzimidazole derivatives,
benzo-1,2,4-thiadiazine derivatives, phenylalanine derivatives,
aplaviroc, vicriviroc, and maraviroc, cyclosporine, FK-506,
rapamycin, taxol, taxotere, clarithromycin, A-77003, A-80987,
MK-639, saquinavir, VX-478, AG1343, DMP-323, XM-450, BILA 2011 BS,
BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629
(N,N-dimethylglycyl-N-(2-hydroxy-3-(((4-methoxyphenyl)sulphonyl)(2-methyl-
propyl)amino)-1-(phenylmethyl)propyl)-3-methyl-L-valinamide),
KNI-272, CGP 53437, CGP 57813 and U-103017 and a pharmaceutically
acceptable carrier or excipient.
[0482] In still another embodiment, the present invention provides
pharmaceutical compositions comprising a compound of the present
invention, or a pharmaceutically acceptable salt, solvate, and/or
ester thereof, in combination with two or three additional
therapeutic agents. For example, a compound of the present
invention, or a pharmaceutically acceptable salt, solvate, and/or
ester thereof, is combined with two or three additional therapeutic
agents selected from the classes of HIV protease inhibitors, HIV
non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside
inhibitors of reverse transcriptase, HIV nucleotide inhibitors of
reverse transcriptase, and HIV integrase inhibitors. The two or
three additional therapeutic agents can be different therapeutic
agents selected from the same class of therapeutic agents, or they
can be selected from different classes of therapeutic agents. The
compounds of the present invention in such ternary or quaternary
combinations can include any of the compounds of Formula I
disclosed herein, for example a compounds of Formula IIA-D or
Formula IV. In a particular embodiment, the pharmaceutical
compositions of the present invention comprises a compound of
Formula IV, or a pharmaceutically acceptable salt, solvate, and/or
ester thereof, combined with two or three additional therapeutic
agents selected from the classes of HIV protease inhibitors, HIV
non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside
inhibitors of reverse transcriptase, HIV nucleotide inhibitors of
reverse transcriptase, and HIV integrase inhibitors. In a still
more particular embodiment, the pharmaceutical composition of the
present invention comprises Example P, S, or X, or a
pharmaceutically acceptable salt, solvate, and/or ester thereof, in
combination with two or three additional therapeutic agents
selected from the classes of HIV protease inhibitors, HIV
non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside
inhibitors of reverse transcriptase, HIV nucleotide inhibitors of
reverse transcriptase, and HIV integrase inhibitors. For example,
such combinations can comprise Example P, S, or X, or a
pharmaceutically acceptable salt, solvate, and/or ester thereof in
combination with two or three additional therapeutic agents
selected from the group consisting of tenofovir disoproxil
fumarate, GS-9131, emtricitabine, elvitegravir, efavrenz,
atazanavir, darunavir, raltegravir, and rilpivirine (or
pharmaceutically acceptable salts, solvates, and/or esters
thereof).
[0483] Specific embodiments of ternary combinations comprise, for
example, Example P/tenofovir disoproxil fumarate/GS-9131, Example
P/tenofovir disoproxil fumarate/emtricitabine, Example P/tenofovir
disoproxil fumarate/elvitegravir, Example P/tenofovir disoproxil
fumarate/efavrenz, Example P/tenofovir disoproxil
fumarate/atazanavir, Example P/tenofovir disoproxil
fumarate/darunavir, Example P/tenofovir disoproxil
fumarate/raltegravir, Example P/tenofovir disoproxil
fumarate/rilpivirine, Example P/GS-9131/emtricitabine, Example
P/GS-9131/elvitegravir, Example P/GS-9131/efavrenz, Example
P/GS-9131/atazanavir, Example P/GS-9131/darunavir, Example
P/GS-9131/raltegravir, Example P/GS-9131/rilpivirine, Example
P/emtricitabine/elvitegravir, Example P/emtricitabine/efavrenz,
Example P/emtricitabine/atazanavir, Example
P/emtricitabine/darunavir, Example P/emtricitabine/raltegravir,
Example P/emtricitabine/rilpivirine, Example
P/elvitegravir/efavrenz, Example P/elvitegravir/atazanavir, Example
P/elvitegravir/darunavir, Example P/elvitegravir/raltegravir,
Example P/elvitegravir/rilpivirine, Example P/efavrenz/atazanavir,
Example P/efavrenz/darunavir, Example P/efavrenz/raltegravir,
Example P/efavrenz/rilpivirine, Example P/atazanavir/darunavir,
Example P/atazanavir/raltegravir, Example P/atazanavir/rilpivirine,
Example P/darunavir/raltegravir, Example P/darunavir/rilpivirine,
Example P/raltegravir/rilpivirine, Example S/tenofovir disoproxil
fumarate/GS-9131, Example S/tenofovir disoproxil
fumarate/emtricitabine, Example S/tenofovir disoproxil
fumarate/elvitegravir, Example S/tenofovir disoproxil
fumarate/efavrenz, Example S/tenofovir disoproxil
fumarate/atazanavir, Example S/tenofovir disoproxil
fumarate/darunavir, Example S/tenofovir disoproxil
fumarate/raltegravir, Example S/tenofovir disoproxil
fumarate/rilpivirine, Example S/GS-9131/emtricitabine, Example
S/GS-9131/elvitegravir, Example S/GS-9131/efavrenz, Example
S/GS-9131/atazanavir, Example S/GS-9131/darunavir, Example
S/GS-9131/raltegravir, Example S/GS-9131/rilpivirine, Example
S/emtricitabine/elvitegravir, Example S/emtricitabine/efavrenz,
Example S/emtricitabine/atazanavir, Example
S/emtricitabine/darunavir, Example S/emtricitabine/raltegravir,
Example S/emtricitabine/rilpivirine, Example
S/elvitegravir/efavrenz, Example S/elvitegravir/atazanavir, Example
S/elvitegravir/darunavir, Example S/elvitegravir/raltegravir,
Example S/elvitegravir/rilpivirine, Example S/efavrenz/atazanavir,
Example S/efavrenz/darunavir, Example S/efavrenz/raltegravir,
Example S/efavrenz/rilpivirine, Example S/atazanavir/darunavir,
Example S/atazanavir/raltegravir, Example S/atazanavir/rilpivirine,
Example S/darunavir/raltegravir, Example S/darunavir/rilpivirine,
Example S/raltegravir/rilpivirine, Example X/tenofovir disoproxil
fumarate/GS-9131, Example X/tenofovir disoproxil
fumarate/emtricitabine, Example X/tenofovir disoproxil
fumarate/elvitegravir, Example X/tenofovir disoproxil
fumarate/efavrenz, Example X/tenofovir disoproxil
fumarate/atazanavir, Example X/tenofovir disoproxil
fumarate/darunavir, Example X/tenofovir disoproxil
fumarate/raltegravir, Example X/tenofovir disoproxil
fumarate/rilpivirine, Example X/GS-9131/emtricitabine, Example
X/GS-9131/elvitegravir, Example X/GS-9131/efavrenz, Example
X/GS-9131/atazanavir, Example X/GS-9131/darunavir, Example
X/GS-9131/raltegravir, Example X/GS-9131/rilpivirine, Example
X/emtricitabine/elvitegravir, Example X/emtricitabine/efavrenz,
Example X/emtricitabine/atazanavir, Example
X/emtricitabine/darunavir, Example X/emtricitabine/raltegravir,
Example X/emtricitabine/rilpivirine, Example
X/elvitegravir/efavrenz, Example X/elvitegravir/atazanavir, Example
X/elvitegravir/darunavir, Example X/elvitegravir/raltegravir,
Example X/elvitegravir/rilpivirine, Example X/efavrenz/atazanavir,
Example X/efavrenz/darunavir, Example X/efavrenz/raltegravir,
Example X/efavrenz/rilpivirine, Example X/atazanavir/darunavir,
Example X/atazanavir/raltegravir, Example X/atazanavir/rilpivirine,
Example X/darunavir/raltegravir, Example X/darunavir/rilpivirine,
and Example X/raltegravir/rilpivirine (including pharmaceutically
acceptable salts, solvates, and/or esters of any of the above).
[0484] Specific embodiments of quaternary combinations comprise,
for example, Example P/tenofovir disoproxil
fumarate/GS-9131/emtricitabine, Example P/tenofovir disoproxil
fumarate/GS-9131/elvitegravir, Example P/tenofovir disoproxil
fumarate/GS-9131/efavrenz, Example P/tenofovir disoproxil
fumarate/GS-9131/atazanavir, Example P/tenofovir disoproxil
fumarate/GS-9131/darunavir, Example P/tenofovir disoproxil
fumarate/GS-9131/raltegravir, Example P/tenofovir disoproxil
fumarate/GS-9131/rilpivirine, Example P/tenofovir disoproxil
fumarate/emtricitabine/elvitegravir, Example P/tenofovir disoproxil
fumarate/emtricitabine/efavrenz, Example P/tenofovir disoproxil
fumarate/emtricitabine/atazanavir, Example P/tenofovir disoproxil
fumarate/emtricitabine/darunavir, Example P/tenofovir disoproxil
fumarate/emtricitabine/raltegravir, Example P/tenofovir disoproxil
fumarate/emtricitabine/rilpivirine, Example P/tenofovir disoproxil
fumarate/elvitegravir/efavrenz, Example P/tenofovir disoproxil
fumarate/elvitegravir/atazanavir, Example P/tenofovir disoproxil
fumarate/elvitegravir/darunavir, Example P/tenofovir disoproxil
fumarate/elvitegravir/raltegravir, Example P/tenofovir disoproxil
fumarate/elvitegravir/rilpivirine, Example P/tenofovir disoproxil
fumarate/efavrenz/atazanavir, Example P/tenofovir disoproxil
fumarate/efavrenz/darunavir, Example P/tenofovir disoproxil
fumarate/efavrenz/raltegravir, Example P/tenofovir disoproxil
fumarate/efavrenz/rilpivirine, Example P/tenofovir disoproxil
fumarate/atazanavir/darunavir, Example P/tenofovir disoproxil
fumarate/atazanavir/raltegravir, Example P/tenofovir disoproxil
fumarate/atazanavir/rilpivirine, Example P/tenofovir disoproxil
fumarate/darunavir/raltegravir, Example P/tenofovir disoproxil
fumarate/darunavir/rilpivirine, Example P/tenofovir disoproxil
fumarate/raltegravir/rilpivirine, Example
P/GS-9131/emtricitabine/elvitegravir, Example
P/GS-9131/emtricitabine/efavrenz, Example
P/GS-9131/emtricitabine/atazanavir, Example
P/GS-9131/emtricitabine/darunavir, Example
P/GS-9131/emtricitabine/raltegravir, Example
P/GS-9131/emtricitabine/rilpivirine, Example
P/GS-9131/elvitegravir/efavrenz, Example
P/GS-9131/elvitegravir/atazanavir, Example
P/GS-9131/elvitegravir/darunavir, Example
P/GS-9131/elvitegravir/raltegravir, Example
P/GS-9131/elvitegravir/rilpivirine, Example
P/GS-9131/efavrenz/atazanavir, Example
P/GS-9131/efavrenz/darunavir, Example
P/GS-9131/efavrenz/raltegravir, Example
P/GS-9131/efavrenz/rilpivirine, Example
P/GS-9131/atazanavir/darunavir, Example
P/GS-9131/atazanavir/raltegravir, Example
P/GS-9131/atazanavir/rilpivirine, Example
P/GS-9131/darunavir/raltegravir, Example
P/GS-9131/darunavir/rilpivirine, Example
P/GS-9131/raltegravir/rilpivirine, Example
P/emtricitabine/elvitegravir/efavrenz, Example
P/emtricitabine/elvitegravir/atazanavir, Example
P/emtricitabine/elvitegravir/darunavir, Example
P/emtricitabine/elvitegravir/raltegravir, Example
P/emtricitabine/elvitegravir/rilpivirine, Example
P/emtricitabine/efavrenz/atazanavir, Example
P/emtricitabine/efavrenz/darunavir, Example
P/emtricitabine/efavrenz/raltegravir, Example
P/emtricitabine/efavrenz/rilpivirine, Example
P/emtricitabine/atazanavir/darunavir, Example
P/emtricitabine/atazanavir/raltegravir, Example
P/emtricitabine/atazanavir/rilpivirine, Example
P/emtricitabine/darunavir/raltegravir, Example
P/emtricitabine/darunavir/rilpivirine, Example
P/emtricitabine/raltegravir/rilpivirine, Example
P/elvitegravir/efavrenz/atazanavir, Example
P/elvitegravir/efavrenz/darunavir, Example
P/elvitegravir/efavrenz/raltegravir, Example
P/elvitegravir/efavrenz/rilpivirine, Example
P/elvitegravir/atazanavir/darunavir, Example
P/elvitegravir/atazanavir/raltegravir, Example
P/elvitegravir/atazanavir/rilpivirine, Example
P/elvitegravir/darunavir/raltegravir, Example
P/elvitegravir/darunavir/rilpivirine, Example
P/elvitegravir/raltegravir/rilpivirine, Example
P/efavrenz/atazanavir/darunavir, Example
P/efavrenz/atazanavir/raltegravir, Example
P/efavrenz/atazanavir/rilpivirine, Example
P/efavrenz/darunavir/raltegravir, Example
P/efavrenz/darunavir/rilpivirine, Example
P/efavrenz/raltegravir/rilpivirine, Example
P/atazanavir/darunavir/raltegravir, Example
P/atazanavir/darunavir/rilpivirine, Example
P/darunavir/raltegravir/rilpivirine, Example S/tenofovir disoproxil
fumarate/GS-9131/emtricitabine, Example S/tenofovir disoproxil
fumarate/GS-9131/elvitegravir, Example S/tenofovir disoproxil
fumarate/GS-9131/efavrenz, Example S/tenofovir disoproxil
fumarate/GS-9131/atazanavir, Example S/tenofovir disoproxil
fumarate/GS-9131/darunavir, Example S/tenofovir disoproxil
fumarate/GS-9131/raltegravir, Example S/tenofovir disoproxil
fumarate/GS-9131/rilpivirine, Example S/tenofovir disoproxil
fumarate/emtricitabine/elvitegravir, Example S/tenofovir disoproxil
fumarate/emtricitabine/efavrenz, Example S/tenofovir disoproxil
fumarate/emtricitabine/atazanavir, Example S/tenofovir disoproxil
fumarate/emtricitabine/darunavir, Example S/tenofovir disoproxil
fumarate/emtricitabine/raltegravir, Example S/tenofovir disoproxil
fumarate/emtricitabine/rilpivirine, Example S/tenofovir disoproxil
fumarate/elvitegravir/efavrenz, Example S/tenofovir disoproxil
fumarate/elvitegravir/atazanavir, Example S/tenofovir disoproxil
fumarate/elvitegravir/darunavir, Example S/tenofovir disoproxil
fumarate/elvitegravir/raltegravir, Example S/tenofovir disoproxil
fumarate/elvitegravir/rilpivirine, Example S/tenofovir disoproxil
fumarate/efavrenz/atazanavir, Example S/tenofovir disoproxil
fumarate/efavrenz/darunavir, Example S/tenofovir disoproxil
fumarate/efavrenz/raltegravir, Example S/tenofovir disoproxil
fumarate/efavrenz/rilpivirine, Example S/tenofovir disoproxil
fumarate/atazanavir/darunavir, Example S/tenofovir disoproxil
fumarate/atazanavir/raltegravir, Example S/tenofovir disoproxil
fumarate/atazanavir/rilpivirine, Example S/tenofovir disoproxil
fumarate/darunavir/raltegravir, Example S/tenofovir disoproxil
fumarate/darunavir/rilpivirine, Example S/tenofovir disoproxil
fumarate/raltegravir/rilpivirine, Example
S/GS-9131/emtricitabine/elvitegravir, Example
S/GS-9131/emtricitabine/efavrenz, Example
S/GS-9131/emtricitabine/atazanavir, Example
S/GS-9131/emtricitabine/darunavir, Example S/GS-9131/emtr,
citabine/raltegravir, Example S/GS-9131/emtricitabine/rilpivirine,
Example S/GS-9131/elvitegravir/efavrenz, Example
S/GS-9131/elvitegravir/atazanavir, Example
S/GS-9131/elvitegravir/darunavir, Example
S/GS-9131/elvitegravir/raltegravir, Example
S/GS-9131/elvitegravir/rilpivirine, Example
S/GS-9131/efavrenz/atazanavir, Example
S/GS-9131/efavrenz/darunavir, Example
S/GS-9131/efavrenz/raltegravir, Example
S/GS-9131/efavrenz/rilpivirine, Example
S/GS-9131/atazanavir/darunavir, Example
S/GS-9131/atazanavir/raltegravir, Example
S/GS-9131/atazanavir/rilpivirine, Example
S/GS-9131/darunavir/raltegravir, Example
S/GS-9131/darunavir/rilpivirine, Example
S/GS-9131/raltegravir/rilpivirine, Example
S/emtricitabine/elvitegravir/efavrenz, Example
S/emtricitabine/elvitegravir/atazanavir, Example
S/emtricitabine/elvitegravir/darunavir, Example
S/emtricitabine/elvitegravir/raltegravir, Example
S/emtricitabine/elvitegravir/rilpivirine, Example
S/emtricitabine/efavrenz/atazanavir, Example
S/emtricitabine/efavrenz/darunavir, Example
S/emtricitabine/efavrenz/raltegravir, Example
S/emtricitabine/efavrenz/rilpivirine, Example
S/emtricitabine/atazanavir/darunavir, Example
S/emtricitabine/atazanavir/raltegravir, Example
S/emtricitabine/atazanavir/rilpivirine, Example
S/emtricitabine/darunavir/raltegravir, Example
S/emtricitabine/darunavir/rilpivirine, Example
S/emtricitabine/raltegravir/rilpivirine, Example
S/elvitegravir/efavrenz/atazanavir, Example
S/elvitegravir/efavrenz/darunavir, Example
S/elvitegravir/efavrenz/raltegravir, Example
S/elvitegravir/efavrenz/rilpivirine, Example
S/elvitegravir/atazanavir/darunavir, Example
S/elvitegravir/atazanavir/raltegravir, Example
S/elvitegravir/atazanavir/rilpivirine, Example
S/elvitegravir/darunavir/raltegravir, Example
S/elvitegravir/darunavir/rilpivirine, Example
S/elvitegravir/raltegravir/rilpivirine, Example
S/efavrenz/atazanavir/darunavir, Example
S/efavrenz/atazanavir/raltegravir, Example
S/efavrenz/atazanavir/rilpivirine, Example
S/efavrenz/darunavir/raltegravir, Example
S/efavrenz/darunavir/rilpivirine, Example
S/efavrenz/raltegravir/rilpivirine, Example
S/atazanavir/darunavir/raltegravir, Example
S/atazanavir/darunavir/rilpivirine, Example
S/darunavir/raltegravir/rilpivirine, Example X/tenofovir disoproxil
fumarate/GS-9131/emtricitabine, Example X/tenofovir disoproxil
fumarate/GS-9131/elvitegravir, Example X/tenofovir disoproxil
fumarate/GS-9131/efavrenz, Example X/tenofovir disoproxil
fumarate/GS-9131/atazanavir, Example X/tenofovir disoproxil
fumarate/GS-9131/darunavir, Example X/tenofovir disoproxil
fumarate/GS-9131/raltegravir, Example X/tenofovir disoproxil
fumarate/GS-9131/rilpivirine, Example X/tenofovir disoproxil
fumarate/emtricitabine/elvitegravir, Example X/tenofovir disoproxil
fumarate/emtricitabine/efavrenz, Example X/tenofovir disoproxil
fumarate/emtricitabine/atazanavir, Example X/tenofovir disoproxil
fumarate/emtricitabine/darunavir, Example X/tenofovir disoproxil
fumarate/emtricitabine/raltegravir, Example X/tenofovir disoproxil
fumarate/emtricitabine/rilpivirine, Example X/tenofovir disoproxil
fumarate/elvitegravir/efavrenz, Example X/tenofovir disoproxil
fumarate/elvitegravir/atazanavir, Example X/tenofovir disoproxil
fumarate/elvitegravir/darunavir, Example X/tenofovir disoproxil
fumarate/elvitegravir/raltegravir, Example X/tenofovir disoproxil
fumarate/elvitegravir/rilpivirine, Example X/tenofovir disoproxil
fumarate/efavrenz/atazanavir, Example X/tenofovir disoproxil
fumarate/efavrenz/darunavir, Example X/tenofovir disoproxil
fumarate/efavrenz/raltegravir, Example X/tenofovir disoproxil
fumarate/efavrenz/rilpivirine, Example X/tenofovir disoproxil
fumarate/atazanavir/darunavir, Example X/tenofovir disoproxil
fumarate/atazanavir/raltegravir, Example X/tenofovir disoproxil
fumarate/atazanavir/rilpivirine, Example X/tenofovir disoproxil
fumarate/darunavir/raltegravir, Example X/tenofovir disoproxil
fumarate/darunavir/rilpivirine, Example X/tenofovir disoproxil
fumarate/raltegravir/rilpivirine, Example
X/GS-9131/emtricitabine/elvitegravir, Example
X/GS-9131/emtricitabine/efavrenz, Example
X/GS-9131/emtricitabine/atazanavir, Example
X/GS-9131/emtricitabine/darunavir, Example
X/GS-9131/emtricitabine/raltegravir, Example
X/GS-9131/emtricitabine/rilpivirine, Example
X/GS-9131/elvitegravir/efavrenz, Example
X/GS-9131/elvitegravir/atazanavir, Example
X/GS-9131/elvitegravir/darunavir, Example
X/GS-9131/elvitegravir/raltegravir, Example
X/GS-9131/elvitegravir/rilpivirine, Example
X/GS-9131/efavrenz/atazanavir, Example
X/GS-9131/efavrenz/darunavir, Example
X/GS-9131/efavrenz/raltegravir, Example
X/GS-9131/efavrenz/rilpivirine, Example
X/GS-9131/atazanavir/darunavir, Example
X/GS-9131/atazanavir/raltegravir, Example
X/GS-9131/atazanavir/rilpivirine, Example
X/GS-9131/darunavir/raltegravir, Example
X/GS-9131/darunavir/rilpivirine, Example
X/GS-9131/raltegravir/rilpivirine, Example
X/emtricitabine/elvitegravir/efavrenz, Example
X/emtricitabine/elvitegravir/atazanavir, Example
X/emtricitabine/elvitegravir/darunavir, Example
X/emtricitabine/elvitegravir/raltegravir, Example
X/emtricitabine/elvitegravir/rilpivirine, Example
X/emtricitabine/efavrenz/atazanavir, Example
X/emtricitabine/efavrenz/darunavir, Example
X/emtricitabine/efavrenz/raltegravir, Example
X/emtricitabine/efavrenz/rilpivirine, Example
X/emtricitabine/atazanavir/darunavir, Example
X/emtricitabine/atazanavir/raltegravir, Example
X/emtricitabine/atazanavir/rilpivirine, Example
X/emtricitabine/darunavir/raltegravir, Example
X/emtricitabine/darunavir/rilpivirine, Example
X/emtricitabine/raltegravir/rilpivirine, Example
X/elvitegravir/efavrenz/atazanavir, Example
X/elvitegravir/efavrenz/darunavir, Example
X/elvitegravir/efavrenz/raltegravir, Example
X/elvitegravir/efavrenz/rilpivirine, Example
X/elvitegravir/atazanavir/darunavir, Example
X/elvitegravir/atazanavir/raltegravir, Example
X/elvitegravir/atazanavir/rilpivirine, Example
X/elvitegravir/darunavir/raltegravir, Example
X/elvitegravir/darunavir/rilpivirine, Example
X/elvitegravir/raltegravir/rilpivirine, Example
X/efavrenz/atazanavir/darunavir, Example
X/efavrenz/atazanavir/raltegravir, Example
X/efavrenz/atazanavir/rilpivirine, Example
X/efavrenz/darunavir/raltegravir, Example
X/efavrenz/darunavir/rilpivirine, Example
X/efavrenz/raltegravir/rilpivirine, Example
X/atazanavir/darunavir/raltegravir, Example
X/atazanavir/darunavir/rilpivirine, and Example
X/darunavir/raltegravir/rilpivirine (including pharmaceutically
acceptable salts, solvates, and/or esters of any of the above).
[0485] In yet another embodiment, the present application provides
a combination pharmaceutical agent comprising:
[0486] a) a first pharmaceutical composition comprising a compound
of the present invention, or a pharmaceutically acceptable salt,
solvate, or ester thereof; and
[0487] b) a second pharmaceutical composition comprising at least
one additional therapeutic agent selected from the group consisting
of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors
of reverse transcriptase, HIV nucleoside inhibitors of reverse
transcriptase, HIV nucleotide inhibitors of reverse transcriptase,
HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120
inhibitors, CCR5 inhibitors, interferons, ribavirin analogs, NS3
protease inhibitors, alpha-glucosidase 1 inhibitors,
hepatoprotectants, non-nucleoside inhibitors of HCV, and other
drugs for treating HCV, and combinations thereof.
Routes of Administration
[0488] 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
[0489] In one embodiment, the compounds of the present invention
can be used alone, e.g., for inhibiting cytochrome P450
monooxygenase. In another embodiment, the compounds of the present
invention are used in combination with other active therapeutic
ingredients or agents. Preferably, the other active therapeutic
ingredients or agents are metabolized or accessible to the
oxidative metabolism by cytochrome P450 enzymes, e.g.,
monooxygenase enzymes such as 1A2, 2B6, 2C8, 2C19, 2C9, 2D6, 2E1,
3A4,5,7, etc. Combinations of the compounds of the present
invention 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.,
HIV or HCV), the compositions of the invention are combined with
anti-infective agents (such as those described herein).
[0490] In one embodiment, non-limiting examples of suitable
combinations include combinations of one or more compounds of the
present invention with one or more anti-viral agents, e.g.,
anti-HIV, anti-HCV, etc., anti-bacterial agents, anti-fungal
agents, immuno-modulators, e.g., immunosuppressant, anti-neoplastic
agents, chemotherapeutic agents, agents useful for treating
cardiovascular conditions, neurological conditions, etc.
[0491] In another embodiment, non-limiting examples of suitable
combinations include combinations of one or more compounds of the
present invention with one or more proton pump inhibitors,
anti-epileptics, NSAIDs, oral hypoglycemic agents, angiotensin II,
sulfonylureas, beta blockers, antidepressants, antipsychotics, or
anesthetics, or a combination thereof.
[0492] In yet another embodiment, non-limiting examples of suitable
combinations include combinations of one or more compounds of the
present invention with one or more 1) macrolide antibiotics, e.g.,
clarithromycin, erythromycin, telithromycin, 2) anti-arrhythmics,
e.g., quinidine=>3-OH, 3) benzodiazepines, e.g., alprazolam,
diazepam=>3OH, midazolam, triazolam, 4) immune modulators, e.g.,
cyclosporine, tacrolimus (FK506), 5) HIV antivirals, e.g.,
indinavir, nelfinavir, ritonavir, saquinavir, 6) prokinetic, e.g.,
cisapride, 7) antihistamines, e.g., astemizole, chlorpheniramine,
terfenidine, 8) calcium channel blockers, e.g., amlodipine,
diltiazem, felodipine, lercanidipine, nifedipine, nisoldipine,
nitrendipine, verapamil, 9) HMG CoA reductase inhibitors, e.g.,
atorvastatin, cerivastatin, lovastatin, simvastatin, or 10) steroid
6beta-OH, e.g., estradiol, hydrocortisone, progesterone,
testosterone.
[0493] In still yet another embodiment, non-limiting examples of
suitable combinations include combinations of one or more compounds
of the present invention with one or more compounds selected from
the group consisting of alfentanyl, aprepitant, aripiprazole,
buspirone, cafergot, caffeine=>TMU, cilostazol, cocaine,
codeine-N-demethylation, dapsone, dextromethorphan, docetaxel,
domperidone, eplerenone, fentanyl, finasteride, gleevec,
haloperidol, irinotecan, LAAM, lidocaine, methadone, nateglinide,
odanestron, pimozide, propranolol, quetiapine, quinine, salmeterol,
sildenafil, sirolimus, tamoxifen, taxol, terfenadine, trazodone,
vincristine, zaleplon, and zolpidem or a combination thereof.
[0494] In still yet another embodiment, non-limiting examples of
suitable combinations include combinations of one or more compounds
of the present invention with one or more HIV protease inhibiting
compounds, HIV non-nucleoside inhibitors of reverse transcriptase,
HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide
inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41
inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors,
and other drugs for treating HIV, interferons, ribavirin analogs,
HCV NS3 protease inhibitors, alpha-glucosidase 1 inhibitors,
hepatoprotectants, nucleoside or nucleotide inhibitors of HCV,
non-nucleoside inhibitors of HCV, and other drugs for treating
HCV.
[0495] More specifically, one or more compounds of the present
invention may be combined with one or more compounds selected from
the group consisting of 1) amprenavir, atazanavir, fosamprenavir,
indinavir, lopinavir, ritonavir, nelfinavir, saquinavir,
tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir
(DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681,
DPC-684, GW640385X, DG17, GS-8374, PPL-100, DG35, and AG 1859, 2) a
HIV non-nucleoside inhibitor of reverse transcriptase, e.g.,
capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+)
calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963,
MIV-150, and TMC-120, TMC-278 (rilpivirene), efavirenz, BILR 355
BS, VRX 840773, UK-453061, and RDEA806, 3) a HIV nucleoside
inhibitor of reverse transcriptase, e.g., zidovudine,
emtricitabine, didanosine, stavudine, zalcitabine, lamivudine,
abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, racivir
(.+-.-FTC), D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil,
apricitibine (AVX754), GS-7340, KP-1461, and fosalvudine tidoxil
(formerly HDP 99.0003), 4) a HIV nucleotide inhibitor of reverse
transcriptase, e.g., tenofovir disoproxil fumarate and adefovir
dipivoxil, 5) a HIV integrase inhibitor, e.g., curcumin,
derivatives of curcumin, chicoric acid, derivatives of chicoric
acid, 3,5-dicaffeoylquinic acid, derivatives of
3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of
aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives
of caffeic acid phenethyl ester, tyrphostin, derivatives of
tyrphostin, quercetin, derivatives of quercetin, S-1360, zintevir
(AR-177), L-870812, and L-870810, MK-0518 (raltegravir),
elvitegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, and BA
011, 6) a gp41 inhibitor, e.g., enfuvirtide, sifuvirtide, FB006M,
and TRI-1144, 7) a CXCR4 inhibitor, e.g., AMD-070, 8) an entry
inhibitor, e.g., SP01A, 9) a gp120 inhibitor, e.g., BMS-488043 or
BlockAide/CR, 10) a G6PD and NADH-oxidase inhibitor, e.g.,
immunitin, 11) a CCR5 inhibitor, e.g., aplaviroc, vicriviroc,
maraviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5 mAb004,
12) other drugs for treating HIV, e.g., BAS-100, SPI-452, REP 9,
SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat),
Ampligen, HRG214, Cytolin, VGX-410, KD-247, AMZ 0026, CYT
99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS
119, ALG 889, and PA-1050040 (PA-040), 13) an interferon, e.g.,
pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b,
rIFN-alpha 2a, consensus IFN alpha (infergen), feron, reaferon,
intermax alpha, r-IFN-beta, infergen+actimmune, IFN-omega with
DUROS, albuferon, locteron, Albuferon, Rebif, Oral interferon
alpha, IFNalpha-2b XL, AVI-005, PEG-Infergen, and Pegylated
IFN-beta, 14) a ribavirin analog, e.g., rebetol, copegus,
viramidine (taribavirin), 15) a NS5b polymerase inhibitor, e.g.,
NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB
1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554,
and GSK625433, 16) A NS3 protease inhibitor, e.g., SCH-503034
(SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339, and ITMN-191,
17) an alpha-glucosidase 1 inhibitor, e.g., MX-3253 (celgosivir),
UT-231B, 18) hepatoprotectants, e.g., IDN-6556, ME 3738, LB-84451,
and MitoQ, 19) a non-nucleoside inhibitor of HCV, e.g.,
benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives,
phenylalanine derivatives, A-831, GS-9190, and A-689; and 20) other
drugs for treating HCV, e.g., zadaxin, nitazoxanide (alinea),
BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon
(CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA
971, NOV-205, tarvacin, EHC-18, NIM811, DEBIO-025, VGX-410C,
EMZ-702, AVI 4065, Bavituximab, Oglufanide, and VX-497
(merimepodib).
[0496] It is also contemplated that the compounds of the present
invention can be used with any other active therapeutic agent or
ingredient which is appreciably metabolized by cytochrome P450
monooxygenase enzymes, e.g. cytochrome P450 monooxygenase 3A,
thereby reducing the amount or rate at which the other active
therapeutic agent or ingredient is metabolized, whereby the
pharmacokinetics of the other active therapeutic agent or
ingredient is improved. Such improvements can include elevating the
blood plasma levels of the other therapeutic agent or ingredient or
maintaining a more therapeutically effective blood plasma level of
the other therapeutic active agent or ingredient--compared to blood
plasma levels of the other therapeutic agent or ingredient
administered without the compound of the present invention.
[0497] It is also possible to combine any compound of the invention
with one or more other active therapeutic 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.
[0498] Co-administration of a compound of the invention with one or
more other active therapeutic agents generally refers to
simultaneous or sequential administration of a compound of the
invention and one or more other active therapeutic agents, such
that therapeutically effective amounts of the compound of the
invention and one or more other active therapeutic agents are both
present in the body of the patient.
[0499] 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 therapeutic agents, for
example, administration of the compounds of the invention within
seconds, minutes, or hours of the administration of one or more
other active therapeutic 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 therapeutic agents. Alternatively, a unit dose
of one or more other therapeutic 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
therapeutic agents. In other cases, it may be desirable to
administer a unit dose of one or more other active therapeutic
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.
[0500] 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.
[0501] In yet another embodiment, the present application provides
a method for improving the pharmacokinetics of a drug which is
metabolized by cytochrome P450 monooxygenase, comprising
administering to a patient treated with said drug, a
therapeutically effective amount of a compound of the present
invention, or a pharmaceutically acceptable salt, solvate, and/or
ester thereof.
[0502] In yet another embodiment, the present application provides
a method for improving the pharmacokinetics of a drug which is
metabolized by cytochrome P450 monooxygenase, comprising
administering to a patient treated with said drug, a
therapeutically effective amount of a combination comprising said
drug and a compound of the present invention, or a pharmaceutically
acceptable salt, solvate, and/or ester thereof.
[0503] In yet another embodiment, the present application provides
a method for improving the pharmacokinetics of a drug which is
metabolized by cytochrome P450 monooxygenase 3A, comprising
administering to a patient treated with said drug, a
therapeutically effective amount of a compound of the present
invention, or a pharmaceutically acceptable salt, solvate, and/or
ester thereof.
[0504] In yet another embodiment, the present application provides
a method for increasing blood plasma levels of a drug which is
metabolized by cytochrome P450 monooxygenase, comprising
administering to a patient treated with said drug, a
therapeutically effective amount of a compound of the present
invention, or a pharmaceutically acceptable salt, solvate, and/or
ester thereof.
[0505] In yet another embodiment, the present application provides
a method for increasing blood plasma levels of a drug which is
metabolized by cytochrome P450 monooxygenase, comprising
administering to a patient treated with said drug, a
therapeutically effective amount of a combination comprising said
drug and a compound of the present invention, or a pharmaceutically
acceptable salt, solvate, and/or ester thereof.
[0506] In yet another embodiment, the present application provides
a method for increasing blood plasma levels of a drug which is
metabolized by cytochrome P450 monooxygenase 3A, comprising
administering to a patient treated with said drug, a
therapeutically effective amount of a compound of the present
invention, or a pharmaceutically acceptable salt, solvate, and/or
ester thereof.
[0507] In yet another embodiment, the present application provides
a method for increasing blood plasma levels of a drug which is
metabolized by cytochrome P450 monooxygenase, comprising
administering to a patient treated with said drug, a
therapeutically effective amount of a compound of the present
invention, or a pharmaceutically acceptable salt, solvate, and/or
ester thereof, and wherein the amount of the compound of the
present invention administered is effective to inhibit cytochrome
P450 monooxygenase.
[0508] In yet another embodiment, the present application provides
a method for inhibiting cytochrome P450 monooxygenase in a patient
comprising administering to a patient in need thereof an amount of
a compound of the present invention, or a pharmaceutically
acceptable salt, solvate, and/or ester thereof, effective to
inhibit cytochrome P450 monooxygenase.
[0509] In yet another embodiment, the present application provides
a method for inhibiting cytochrome P450 monooxygenase 3A in a
patient comprising administering to a patient in need thereof an
amount of a compound of the present invention, or a
pharmaceutically acceptable salt, solvate, and/or ester thereof,
effective to inhibit cytochrome P450 monooxygenase 3A.
[0510] In yet another embodiment, the present application provides
a method for inhibiting cytochrome P450 monooxygenase comprising
contacting cytochrome P450 monooxygenase with an amount of a
compound of the present invention, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof, effective to inhibit
cytochrome P450 monooxygenase.
[0511] In yet another embodiment, the present application provides
a method for inhibiting cytochrome P450 monooxygenase 3A comprising
contacting cytochrome P450 monooxygenase 3A with an amount of a
compound of the present invention, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof, effective to inhibit
cytochrome P450 monooxygenase 3A.
[0512] In yet another embodiment, the present application provides
a method for treating an HIV infection comprising administering to
a patient in need thereof a therapeutically effective amount of a
compound of the present invention, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof, in combination with a
therapeutically effective amount of one or more additional
therapeutic agents selected from the group consisting of HIV
protease inhibiting compounds, HIV non-nucleoside inhibitors of
reverse transcriptase, HIV nucleoside inhibitors of reverse
transcriptase, HIV nucleotide inhibitors of reverse transcriptase,
HIV integrase inhibitors, and CCR5 inhibitors.
[0513] In yet another embodiment, the present application provides
a method for treating an HIV infection comprising administering to
a patient in need thereof a therapeutically effective amount of a
compound of the present invention, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof, in combination with a
therapeutically effective amount of one or more additional
therapeutic agents selected from the group consisting of
amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir,
ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir,
darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776),
L-756423, RO0334649, KNI-272, DPC-681, DPC-684, and GW640385X,
DG17, PPL-100, DG35, AG 1859, capravirine, emivirine, delaviridine,
efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634,
DPC-083, DPC-961, DPC-963, MIV-150, TMC-120, TMC-278 (rilpivirene),
efavirenz, BILR 355 BS, VRX 840773, UK-453061, RDEA806, zidovudine,
emtricitabine, didanosine, stavudine, zalcitabine, lamivudine,
abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, racivir
(.+-.-FTC), D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil,
apricitibine (AVX754), amdoxovir, KP-1461, fosalvudine tidoxil
(formerly HDP 99.0003), tenofovir disoproxil fumarate, adefovir
dipivoxil, curcumin, derivatives of curcumin, chicoric acid,
derivatives of chicoric acid, 3,5-dicaffeoylquinic acid,
derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid,
derivatives of aurintricarboxylic acid, caffeic acid phenethyl
ester, derivatives of caffeic acid phenethyl ester, tyrphostin,
derivatives of tyrphostin, quercetin, derivatives of quercetin,
S-1360, zintevir (AR-177), L-870812, L-870810, MK-0518
(raltegravir), elvitegravir, BMS-538158, GSK364735C, BMS-707035,
MK-2048, and BA 011, enfuvirtide, sifuvirtide, FB006M, and
TRI-1144, AMD-070, an entry inhibitor, SP01A, BMS-488043,
BlockAide/CR, a G6PD and NADH-oxidase inhibitor, immunitin,
aplaviroc, vicriviroc, maraviroc, maraviroc, PRO-140, INCB15050,
PF-232798 (Pfizer), CCR5 mAb004, BAS-100, SPI-452, REP 9, SP-01A,
TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat),
Ampligen, HRG214, Cytolin, VGX-410, KD-247, AMZ 0026, CYT
99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS
119, ALG 889, and PA-1050040 (PA-040).
[0514] In yet another embodiment, the present application provides
a method for treating an HCV infection comprising administering to
a patient in need thereof a therapeutically effective amount of a
compound of the present invention, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof, in combination with a
therapeutically effective amount of one or more additional
therapeutic agents selected from the group consisting of pegylated
rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha
2a, consensus IFN alpha (infergen), feron, reaferon, intermax
alpha, r-IFN-beta, infergen+actimmune, IFN-omega with DUROS,
locteron, albuferon, rebif, Oral interferon alpha, IFNalpha-2b XL,
AVI-005, PEG-Infergen, and pegylated IFN-beta, rebetol, copegus,
viramidine (taribavirin), NM-283, valopicitabine, R1626, PSI-6130
(R1656), HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107, R7128
(R4048), VCH-759, PF-868554, GSK625433, SCH-503034 (SCH-7), VX-950
(telaprevir), BILN-2065, BMS-605339, ITMN-191, MX-3253
(celgosivir), UT-231B, IDN-6556, ME 3738, LB-84451, MitoQ,
benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives,
phenylalanine derivatives, A-831, A-689, zadaxin, nitazoxanide
(alinea), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002,
actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL-6865,
ANA 971, NOV-205, tarvacin, EHC-18, NIM811, DEBIO-025, VGX-410C,
EMZ-702, AVI 4065, Bavituximab, Oglufanide, and VX-497
(merimepodib).
[0515] 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 inhibiting cytochrome P450
monooxygenase in a patient.
[0516] 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 an HIV
infection.
[0517] 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 increasing blood plasma
levels of the drug which is metabolized by cytochrome P450
monooxygenase.
[0518] 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 improving the
pharmacokinetics of a drug which is metabolized by cytochrome P450
monooxygenase.
EXAMPLES
Preparation of Example A
##STR00165##
[0519] Compound 2
[0520] To a solution of Compound 1 (ritonavir) (1.8 g, 2.5 mmol) in
1,2-dichloroethane (15 mL) was added 1,1'-thiocarbonyldiimidazole
(890 mg, 5.0 mmol). The mixture was heated at 75.degree. C. for 6
hours and cooled to 25.degree. C. Evaporation under reduced
pressure gave a white solid. Purification by flash column
chromatography (stationary phase: silica gel; eluent: EtOAc) gave
Compound 2 (1.6 g). m/z: 831.1 (M+H).sup.+.
Example A
[0521] To the refluxing solution of tributyltin hydride (0.78 mL,
2.9 mmol) in toluene (130 mL) was added a solution of Compound 2
(1.6 g, 1.9 mmol) and 2,2'-azobisisobutyronitrile (31 mg, 0.19
mmol) in toluene (30 mL) over 30 minutes. The mixture was heated at
115.degree. C. for 6 hours and cooled to 25.degree. C. Toluene was
removed under reduced pressure. Purification by flash column
chromatography (stationary phase: silica gel; eluent:
hexane/EtOAc=1/10) gave Example A (560 mg). m/z: 705.2 (M+H).sup.+.
.sup.1H-NMR (CDCl.sub.3) .delta. 8.79 (1H, s), 7.82 (1H, s),
7.26-7.05 (10H, m), 6.98 (1H, s), 6.28 (1H, m), 6.03 (1H, m), 5.27
(1H, m), 5.23 (2H, s), 4.45-4.22 (2H, m), 4.17 (1H, m), 3.98 (1H,
m), 3.75 (1H, m), 3.25 (1H, m), 2.91 (3H, s), 2.67 (4H, m), 2.36
(1H, m), 1.6-1.2 (10H, m), 0.85 (6H, m).
Preparation of Example B
##STR00166##
[0522] Example B
[0523] To a solution of Compound 1 (ritonavir) (98 mg, 0.136 mmol)
in dichloromethane (4 mL) was added Dess-Martin periodinane (61 mg,
0.143 mmol). The mixture was stirred at room temperature for 6
hours. The mixture was then partitioned between dichloromethane and
brine, the dichloromethane layer was separated, dried and
evaporated to dryness. Purification with CombiFlash.RTM.
(stationary phase: silica gel; eluent: 40-80% EtOAc/Hexane
gradient) gave Example B as a white solid. Example B was further
purified by trituration with MeOH/hexane to give 83 mg of a white
solid. m/z: 719 (M+H).sup.+.
Preparation of Example C
##STR00167##
[0524] Compound 3
[0525] Compound 3 was prepared according to the procedures of J.
Med. Chem. 1998, 41, 602, herein incorporated by reference in its
entirety for all purposes.
Compound 4
[0526] A flask was charged with cyclopropylamine (8.2 mL, 117.8
mmol) at room temperature. A solution of Compound 3 (1 g, 4.71
mmol) in MeCN (8.5 mL) was added dropwise over 5 min. to produce a
clear yellow solution that was allowed to stand at room temperature
overnight. Volatiles were removed in vacuo, and the resulting
residue was purified via silica gel chromatography (gradient
elution, 0 to 50% EtOAc/hexane) to afford 0.65 g (70%) of 4 as a
yellow liquid (LC/MS m/z 197 (M+H).sup.+; 218 (M+Na).sup.+).
##STR00168##
Compound 5
[0527] Compound 5 was purchased from Aldrich or alternatively
prepared according to the procedures of J. Org. Chem. 1994, 59,
1937, herein incorporated by reference in its entirety for all
purposes.
Compound 6
[0528] To a solution of Compound 4 in DCM (3 mL) at room
temperature was added 5 (0.1 mL, 0.695 mmol). The resulting clear
solution was allowed to stand at room temperature for 2 h. The
solvent was removed in vacuo, and the residue was chromatographed
directly using silica gel chromatography (gradient elution, 0 to
50% EtOAc/hexane) to produce 0.218 g (89%) of 6 (LC/MS m/z 354
(M+H).sup.+; 729 (2M+Na).sup.+) as a colorless glass.
Compound 7
[0529] Compound 6 was taken up in THF (5 mL) at room temperature,
and LiOH (1 M in H.sub.2O) was added. The resulting reaction
mixture was then stirred vigorously for 1.5 h. The reaction mixture
was acidified with 1 M HCl to a pH of 3 (monitored using pH test
strips). The acidified reaction mixture was then extracted several
times with EtOAc. The combined organic phases were washed with
brine, dried over anhydrous Na.sub.2SO.sub.4, and concentrated in
vacuo to produce 0.20 g (quantitative yield) of 7 (LC/MS m/z 340
(M+H).sup.+) as a colorless film. This material was used without
further purification.
##STR00169##
Example C
[0530] Compounds 7 (0.034 g, 0.100 mmol) and 8, (0.034 g, 0.083
mmol) were diluted in THF (2 mL) at room temperature. To the
resulting solution were added N,N-diisopropylethylamine (0.022 mL,
0.125 mmol), EDC (0.018 mL, 0.099 mmol) and HOBt (0.013 g, 0.099
mmol). The solution was then allowed to stand overnight at room
temperature. The solvent was removed in vacuo and the residue was
taken up in MeCN (0.5 mL) and passed through an Acrodisc LC13 PVDF
filter (0.45 .mu.M) prior to purification by preparatory HPLC to
afford 0.043 g (71%) of Example C as a fluffy white solid.
(.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.79 (s, 1H); 7.82 (s,
1H); 7.27-7.02 (m, 10H); 6.81 (s, 1H); 5.97 (br d, J=8.7 Hz, 1H);
5.76 (br d, J=7.2 Hz, 1H); 5.21 (dt, J=7.5, 12.6 Hz, 2H); 5.02, br
d, J=8.4 Hz, 1H); 4.58 (s, 2H); 4.16 (m, 1H); 3.99 (br t, J=6.6 Hz,
1H); 3.79 (m, 1H); 3.27 (pent, J=6.6 Hz, 1H); 2.85-2.50 (m, 3H);
2.23 (m, 1H); 1.82 (br s, 2H); 1.60-1.22 (m, 4H); 1.36 (d, J=6.6
Hz, 6H); 0.91 (d, J=6.6 Hz, 3H); 0.90-0.7 (m, 4H); 0.80 (d, J=6.6
Hz, 3H); LC/MS m/z 731 (M.sup.+)).
Preparation of Examples D-I
##STR00170##
[0531] Compound 9
[0532] Compound 9 was prepared according to the procedures of J.
Med. Chem. 1998, 41, 602.
Compound 10
[0533] The structures of Compound 10 were prepared according to the
procedures of J. Med. Chem. 1998, 41, 602.
Compound 11
[0534] The structures of Compound 11 were purchased from Aldrich or
prepared according to the procedures of J. Org. Chem. 1994, 59,
1937.
Compound 12
[0535] Method 1: To a solution of Compound 9 (0.8 mmol) in THF (2
mL) was added a carbamate of Compound 10 (0.6 mmol), followed by
DMAP (16 mg) and triethylamine (0.25 mL). The resulting mixture was
heated at 70.degree. C. for two hours and diluted with EtOAc. The
organic phase was separated, and washed sequentially with saturated
aqueous Na.sub.2CO.sub.3, water, and brine, then concentrated under
reduced pressure. Purification of the residue by flash column
chromatography (silica gel, 1/1-1/3 hexanes/EtOAc gradient) gave
compounds of Structure 12.
[0536] Method 2: To a solution of Compound 9 (2.4 mmol) in
CH.sub.2Cl.sub.2 (2 mL) was added an isocyanate of Compound 11 (2
mmol). The resulting mixture was stirred for 4 hours and
concentrated. Purification of the residue by flash column
chromatography (silica gel, hexane/EtOAc 1/1-1/3) gave structures
of Compound 12.
Compound 13
[0537] To a solution of structures of Compound 12 (1.8 mmol) in
dioxane (8 mL) and water (8 mL) was added sodium hydroxide (3.6
mmol). The resulting reaction mixture was stirred for 1 hour and
acidified with HCl in dioxane (3.6 mmol). The reaction mixture was
extracted with EtOAc and the organic phase was dried with anhydrous
MgSO.sub.4. Concentration of the dried organic phase gave
structures of Compound 13.
##STR00171##
Compound 16
[0538] To a solution of Compound 15 (obtained commercially from
Molekula) (17 mmol) in DCM (40 mL) was added Compound 14 (19 mmol),
followed by triethylamine (26 mmol). The resulting reaction mixture
was stirred for 12 hour and concentrated under reduced pressure.
The reaction mixture was diluted with EtOAc and washed sequentially
with saturated aqueous Na.sub.2CO.sub.3, water, and brine. The
solvent was removed under reduced pressure. Purification of the
residue by flash column chromatography (silica gel, eluent:
hexanes/EtOAc=1/1) gave Compound 16 (4.7 g).
##STR00172##
Compound 17
[0539] Compound 17 was prepared according to the procedures of
Tetrahedron 1997, 53, 4769, herein incorporated by reference in its
entirety for all purposes.
Compound 18
[0540] Compound 18 was prepared according to the procedures of J.
Org. Chem. 1987, 52, 3759, herein incorporated by reference in its
entirety for all purposes.
Compound 19
[0541] A suspension of Compound 18 (7.4 mmol) in THF (200 mL) was
heated under reflux until a clear solution was obtained. The
solution was cooled to -78.degree. C. and n-butyllithium (14.8
mmol) was added dropwise to provide a solution of the dianion of
sulfone 18.
[0542] To a DIBAL-H solution (7.8 mmol) at 0.degree. C. was added a
solution of MeOH (7.8 mmol) in THF (5 mL). The mixture was stirred
for 5 minutes and cooled to -78.degree. C. A solution of Compound
17 (6.6 mmol) in THF (5 mL) was added to the above DIBAL-H/MeOH
solution, and the resulting reaction mixture was stirred for
another 5 minutes. The resulting solution of aldehyde complexes was
transferred to solution of the dianion of sulfone 18. The resulting
mixture was stirred at -78.degree. C. for 30 minutes, quenched with
an aqueous solution of NH.sub.4Cl, and warmed to 25.degree. C. The
mixture was then extracted with EtOAc, and concentrated to give
Compound 19 as a mixture of diastereomers. (m/z 737.3
(M+Na).sup.+.
Example 20
[0543] To a solution of Compound 19 in DCM (20 mL) was added
Ac.sub.2O (1.5 mL), followed by pyridine (3 mL). The resulting
mixture was stirred for 12 hours and concentrated. The concentrate
was dissolved in MeOH (30 mL) and cooled to 0.degree. C.
NaH.sub.2PO.sub.4 (4.9 g) was added to the solution, followed by
freshly prepared Na--Hg (6%, 6 g). The resulting mixture was warmed
to 25.degree. C. and stirred for 12 hours. Water (50 mL) was then
added, and the mixture was filtered and concentrated. The
concentrate was diluted with EtOAc and washed with brine. The
organic phase was concentrated. Purification by flash column
chromatography (silica gel, eluent: hexanes/EtOAc=10/1) gave
Compound 20 (1.4 g).
Compound 21
[0544] To liquid ammonia (25 mL) at -33.degree. C. was added a
solution of Compound 20 (1.4 g) in THF (2.5 mL). Sodium was slowly
added until the blue color of the solution persisted. The resulting
mixture was stirred for 1 hour. Solid NH.sub.4Cl (6 g) was then
added slowly, the mixture was warmed to 25.degree. C., and the
ammonia was evaporated. The mixture was diluted with EtOAc, and
washed sequentially with water and brine. The solvent was removed
under reduced pressure. Purification of the resulting residue by
flash column chromatography (silica gel, eluent: hexanes/EtOAc=5/1)
gave Compound 21 (1.15 g).
Compound 22
[0545] A mixture of Compound 21 (1.15 g) and 10% Pd/C (160 mg) in
MeOH (20 mL) was hydrogenated for 12 hours. CELITE was added and
the resulting mixture was stirred for 5 minutes. The mixture was
then filtered and concentrated to give an intermediate (1 g). The
intermediate (700 mg) was dissolved in DCM (20 mL) and TFA (4 mL),
and the resulting mixture was stirred for 4 hours, then
concentrated under reduced pressure. The concentrated mixture was
diluted with EtOAc, and washed sequentially with saturated aqueous
Na.sub.2CO.sub.3, water, and brine. Concentration of the washed
EtOAc mixture gave Compound 22 (420 mg).
Compound 8
[0546] To a solution of Compound 22 (1.57 mmol) in CH.sub.3CN (16
mL) was added Compound 16 (1.57 mmol), followed by
diisopropylethylamine (3.14 mmol). The resulting mixture was
stirred for 12 hours. The mixture was then diluted with EtOAc, and
washed sequentially with saturated aqueous Na.sub.2CO.sub.3, water
and brine. Purification by reverse-phase HPLC (Phenomenex
Synergi.RTM. Comb-HTS column, eluent: 25%-100% CH.sub.3CN in water)
gave Compound 8 (460 mg).
Example D
[0547] To the solution of Compound 13a (R.dbd.H; 0.08 mmol) and
Compound 8 (0.06 mmol) in THF (1 mL) were added HOBt (15 mg), EDC
(26 mg), and disopropylethylamine (0.25 mL). The mixture was
stirred for 12 hours and concentrated. Purification by reverse
phase HPLC (Phenomenex Synergi.RTM. Comb-HTS column, eluent:
25%-100% CH.sub.3CN in water) gave Example D (27 mg). m/z 663.1
(M+H).sup.+. .sup.1H-NMR (CDCl.sub.3) .delta. 8.79 (1H, s), 7.83
(1H, s), 7.25-7.04 (10H, m), 6.98 (1H, s), 6.25 (1H, m), 5.25 (3H,
m), 4.40 (2H, s), 4.12 (1H, m), 3.8 (3H, m), 3.22 (1H, m), 2.95
(3H, s), 2.70 (4H, m), 1.60 (4H, m), 1.26 (6H, d, J=7 Hz).
Example E
[0548] Example E was prepared following the procedure for Example D
(30 mg), except that Compound 13b was used instead of Compound 13a.
m/z 677.1 (M+H).sup.+.
Example F
[0549] Compound F was prepared following the procedure for Example
D (40 mg), except that Compound 13c was used instead of Compound
13a. m/z 691.2 (M+H).sup.+. .sup.1H-NMR (CDCl.sub.3) .delta. 8.80
(1H, s), 7.83 (1H, s), 7.25-7.06 (10H, m), 6.98 (1H, s), 6.35 (1H,
m), 6.23 (1H, m), 5.24 (2H, s), 5.12 (1H, m), 4.34 (2H, s), 4.10
(2H, m), 3.78 (1H, m), 3.23 (1H, m), 2.90 (3H, s), 2.68 (4H, m),
1.90 (2H, m), 1.7-1.4 (4H, m), 1.36 (6H, d, J=7.0 Hz), 0.90 (3H, t,
J=7.3 Hz)
Example G
[0550] Example G was prepared following the procedure for Example D
(84 mg), except that Compound 13d was used instead of Compound 13a.
m/z 783.2 (M+H).sup.+.
Example H
[0551] Example H was prepared following the procedure for Example D
(90 mg), except that Compound 13e was used instead of Compound 13a.
m/z 763.2 (M+H).sup.+.
Example I
[0552] Example H (24 mg) was dissolved in TFA (2 mL) and the
mixture was stirred for 12 hours, then concentrated. Purification
by reverse phase HPLC (Phenomenex Synergi.RTM. Comb-HTS column,
eluent: 25%-100% CH.sub.3CN in water) gave Example I (14 mg). m/z
707.2 (M+H).sup.+. .sup.1H-NMR (CDCl.sub.3) .delta. 8.82 (1H, s),
7.85 (1H, s), 7.26-7.04 (10H, m), 7.0 (1H, s), 5.25 (2H, s), 4.86
(1H, m), 4.56 (1H, m), 4.37 (2H, m), 4.13 (1H, m), 4.06 (1H, m),
3.86 (1H, m), 3.32 (1H, m), 2.99 (3H, s), 2.8-2.6 (4H, m), 1.6-1.4
(4H, m), 1.37 (6H, m), 1.15 (3H, m).
Preparation of Example T
##STR00173##
[0553] Example T
[0554] Compound 23 was prepared following the procedure for
Compound 13, with the exception that methyl 3-isocyanatopropionate
was used instead of Compound 11.
[0555] Example J was prepared following the procedure for Example D
(37 mg), except that Compound 23 was used instead of Compound 13a.
m/z 677.2 (M+H).sup.+.
Preparation of Example K
##STR00174##
[0556] Example K
Compound 3a
[0557] Compound 5a was prepared following the literature procedure
of Synthesis 823, 1976, herein incorporated by reference in its
entirety for all purposes.
Compound 3b
[0558] To the solution of Compound 3a (700 mg, 3.9 mmol) in THF (10
mL) was added water (69 .mu.L, 3.9 mmol), followed by
triphenylphosphine (1.06 g, 4.0 mmol). The mixture was stirred for
12 hours. Solvents were removed and the mixture was dried to give
Compound 3b, which was used for next step without further
purification.
Compound 3c
[0559] To a solution of triphosgene (110 mg, 0.37 mmol) in
CH.sub.2C.sub.12 (2 mL) at 0.degree. C. was added a solution of
Compound 3b (1 mmol) and iPrNEt.sub.2 (0.38 mL, 2.2 mmol) in
CH.sub.2Cl.sub.2 (3.5 mL) over 30 minutes period. The mixture was
stirred for 30 minutes, and a solution of amino N-methyl leucine
methyl ester HCl salt (182 mg, 1 mmol) and iPrNEt.sub.2 (0.34 mL,
2.2 mmol) in CH.sub.2Cl.sub.2 (2 mL) was added. The mixture was
stirred for 12 hours, and diluted with EtOAc. The solution was
washed with sat. Na.sub.2CO.sub.3 (2.times.), water (2.times.), and
brine, and dried over Na.sub.2SO.sub.4. Concentration and
purification with silica gel flash column gave Compound 5c (300
mg).
Compound 3d
[0560] Compound 3d was prepared following the procedure for
Compound 13, with the exception that Compound 3c was used instead
of Compound 12.
Example K
[0561] Example K was prepared following the procedure for Example D
(7 mg), except that Compound 3d was used instead of Compound 13a.
m/z 705.2 (M+H).sup.+. .sup.1H-NMR (CDCl.sub.3) .delta. 8.8 (1H,
m), 7.86 (1H, s), 7.26-6.8 (11H, m), 6.10 (1H, m), 5.5-5.10 (4H,
m), 4.46 (2H, m), 4.2-3.75 (3H, m), 3.25 (1H, m), 2.82/2.4 (3H),
2.8-2.5 (4H, m), 2.17 (1H, m), 1.7-1.2 (10H, m), 0.8 (6H, m).
Preparation of Example L
##STR00175##
[0562] Example L
[0563] To a solution of Compound 22 (1.57 mmol) in CH.sub.3CN (16
mL) was added Compound 16 (3.14 mmol), followed by triethylamine
(4.71 mmol). The resulting mixture was stirred for 12 hours. The
reaction mixture was diluted with EtOAc and washed sequentially
with saturated aqueous Na.sub.2CO.sub.3, water, and brine. The
solvent was removed under reduced pressure. Purification of the
residue by flash column chromatography (silica gel, eluent:
hexanes/EtOAc=1/1) gave Example L (460 mg). m/z 551.2 (M+H).sup.+.
(CDCl.sub.3) .delta. 8.81 (2H, s), 7.85 (2H, s), 7.26-7.0 (10H, m),
5.24 (4H, s), 4.50 (2H, m), 3.87 (2H, m), 2.73 (4H, m), 1.4-1.2
(4H, m).
Alternate Preparation of Compound 22
##STR00176##
[0564] Compound 25
[0565] Compound 25 was prepared following the literature procedure
described in J. Org. Chem. 1996, 61, 444 (herein incorporated by
reference in its entirety), except that the L-isomer was prepared
instead of the D-isomer.
Compound 26
[0566] A mixture of Compound 25 (7.4 g) and
1,1'-thiocarbonyldiimidaxole (4.5 g) in THF (260 mL) was heated at
65.degree. C. for 54 hours. Solvent was removed from the mixture
under reduced pressure. Purification by flash column chromatography
(silica gel, hexanes/EtOAc=1/1) gave Compound 26 (7.33 g).
Compound 27
[0567] The mixture of Compound 26 (7.3 g) and triethylphosphite
(100 mL) was heated at 160.degree. C. for 4 hours. Excess reagents
were removed under reduced pressure. Purification by flash column
chromatography (silica gel, hexanes/EtOAc=3/1) gave Compound 27 (5
g).
Compound 22
[0568] A mixture of Compound 27 (250 mg) in i-PrOH/EtOAc (5 mL/5
mL) was hydrogenated for 14 hours in the presence of 10% Pd/C (75
mg). CELITE was added to the mixture, and the mixture was stirred
for 5 minutes. Filtration and evaporation of solvents gave Compound
22 (116 mg).
[0569] The skilled practitioner will recognize that the procedure
outlined in Scheme 12 can be used to prepare a variety of
1,4-substituted 1,4-diamines analogous to Compound 22. For example,
an amine-protected 2,3-dihydroxy-1,4-diamine analogous to Compound
25 can be prepared:
##STR00177##
[0570] wherein L.sup.3, A, Ar, and P are as defined herein, and
protecting group "P" is any amine protecting group described in
described in Protective Groups in Organic Synthesis, Theodora W.
Greene and Peter G. M. Wuts (John Wiley & Sons, Inc., New York,
1999, ISBN 0-471-16019-9), which is herein incorporated by
reference in its entirety for all purposes. The analogs of Compound
25 can then be transformed, according to the methods outlined in
Scheme 12, to form analogs of Compound 26:
##STR00178##
[0571] analogs of Compound 27:
##STR00179##
and
[0572] analogs of Compound 22:
##STR00180##
Preparation of Examples M and N
##STR00181##
[0573] Compound 29
[0574] Compound 28 was prepared using a procedure similar to that
used to prepare Compound 6 (described in Scheme 4) except that
Compound 9 was used instead of Compound 4.
[0575] To a solution of Compound 28 (0.757 g, 2.31 mmol) in THF (9
mL) at room temperature was added freshly prepared 1M LiOH (4.6 mL,
4.6 mmol). After 1.5 h, 1 M HCl (7 mL, 7 mmol) was added and the
reaction mixture extracted thoroughly with EtOAc (5.times.15 mL).
The combined organic layers were dried over anhydrous
Na.sub.2SO.sub.4 and the volatiles removed in vacuo to afford 0.677
g (93%) of Compound 29 as a colorless glassy solid (LC/MS m/z 314.0
(M+H).sup.+) that was used in the following procedures without
further purification.
##STR00182## ##STR00183##
Compound 30
[0576] Compound 30 was purchased from Aldrich Chemical Co., and
used without further purification.
Compound 31
[0577] To a solution of Compound 30 (8.25 g, 80 mmol) in MeOH (50
mL), was added benzaldehyde (8.1 mL, 80 mmol) and the resulting
solution was allowed to stir at room temperature. After 2 h, the
reaction mixture was cooled to 0.degree. C. and NaBH.sub.4 (3.33 g,
88 mmol) was added in portions. After allowing the reaction mixture
to warm to room temperature over 2 h, glacial acetic acid (2 mL)
was added. The resulting viscous solution was concentrated in
vacuo. EtOAc and H.sub.2O (50 mL each) were added and the aqueous
phase was extracted with EtOAc. The combined organic phases were
washed with saturated NaHCO.sub.3, brine, and concentrated in
vacuo. The resulting material was taken up in THF (25 mL) and
H.sub.2O (25 mL) at room temperature and Boc.sub.2O (15.1 g, 69.2
mmol) was added to produce an opaque suspension that was stirred
vigorously for 2 h at room temperature. THF was removed in vacuo,
and the aqueous layer was extracted with EtOAc. The combined
organic layers were washed with brine and dried over anhydrous
MgSO.sub.4 and concentrated in vacuo. Chromatography on SiO.sub.2
(3/1 Hex/EtOAC) afforded 18.5 g (79%) of Compound 31 as a colorless
oil (LC/MS m/z 293.9 (M+H).sup.+.
Compound 32
[0578] Compound 31 (5.95 g, 20.3 mmol) and Et.sub.3N (9.9 mL, 71
mmol) were diluted in DMSO (65 mL) and allowed to age at room
temperature for 30 min before cooling to 0.degree. C.
Pyridine.SO.sub.3 was added in one portion and the reaction mixture
was maintained at 5.degree. C. to prevent freezing. After 45 min,
the reaction mixture was poured into icewater and extracted with
EtOAc. The combined organic layers were washed with saturated
NaHCO.sub.3, H.sub.2O, and dried over anhydrous MgSO.sub.4 prior to
concentration in vacuo (bath temperature 25.degree. C.) to produce
4.39 g (74%) of Compound 32 as a clear, yellow colored oil that was
used without further purification. .sup.1H-NMR (CDCl.sub.3, 300
MHz) .delta. (major rotamer) 9.36 (br s, 1H); 5.01 (d, J=15 Hz,
1H); 4.12 (d, J=15 Hz, 1H); 3.45 (m, 1H); 2.04-1.88 (m, 1H);
1.80-1.58 (m, 1H); 1.54-1.20 (m, 2H); 1.47 (s, 9H); 0.91 (t, J=7.2
Hz, 3H). (minor rotamer) 9.46 (br s, 1H); 4.71 (d, J=15 Hz, 1H);
4.20 (d, J=15 Hz, 1H); 3.78 (m, 1H); 2.04-1.88 (m, 1H); 1.80-1.58
(m, 1H); 1.54-1.20 (m, 2H); 1.47 (s, 9H); 0.91 (t, J=7.2 Hz,
3H)
Compound 34
[0579] A suspension of Compound 33 (6.23 g, 16.6 mmol) in THF (500
mL) was heated under reflux until a homogeneous solution was
obtained. The solution was cooled to -78.degree. C. and 1.6M n-BuLi
(19.7 mL, 31.5 mmol) was introduced to produce a clear yellow
solution. Meanwhile, DIBAL-OMe was prepared by dilution of DIBAL-H
(1M in hexanes, 18.1 mL, 18.1 mmol) in THF (8 mL) and cooling to
0.degree. C. prior to addition of MeOH (0.73 mL, 18.1 mmol). This
solution was allowed to age while Compound 32 (4.39 g, 15.1 mmol)
was diluted in THF (15 mL) and cooled to -78.degree. C. The
DIBAL-OMe solution was cannulated to the solution of Compound 32
and allowed to age for 5 min prior to cannulation to the sulfur
dianion solution. The resulting clear yellow solution was allowed
to age at -78.degree. C. for 1 h. The reaction was quenched by
addition of saturated NH.sub.4Cl (100 mL) at -78.degree. C. and
allowed to warm to room temperature. Water was added until all
precipitated solids were dissolved and the layers separated. The
THF layer was concentrated in vacuo while the aqueous layer was
extracted with EtOAc. The recombined organic layers were washed
with brine, and the resulting emulsion was treated with solid NaOH
until homogeneous bilayers resulted. The aqueous layer was
extracted with EtOAc and the combined organics dried over anhydrous
Na.sub.2SO.sub.4. Concentration in vacuo produced 9.57 g (95%) of
Compound 34 as an amorphous white solid (LC/MS m/z: 689.3
(M+Na).sup.+) that was used in the following procedures without
further purification.
Compound 35
[0580] Crude Compound 34 was suspended in CH.sub.2Cl.sub.2 (65 mL)
followed by addition of pyridine (6.7 mL, 83 mmol) and acetic
anhydride (3.5 mL, 36.5 mmol). The resulting solution was allowed
to age at room temperature overnight. MeOH (6 mL) was added and
after 10 min, the reaction was poured into brine. Addition of water
produced a bilayer that was separated and the aqueous phase was
repeatedly extracted with CH.sub.2Cl.sub.2. The combined organic
layers were dried over anhydrous MgSO.sub.4 and concentrated in
vacuo to produce 8.95 g (88%) of a white solid that was immediately
taken up in MeOH (100 mL). Na.sub.2HPO.sub.4 (11.4 g, 80.3 mmol)
was added and the resulting slurry was cooled to 0.degree. C. prior
to addition of Na--Hg (6%, 14.5 g, 37.8 mmol) in portions. After
aging at room temperature overnight, H.sub.2O (30 mL) was added and
the reaction was filtered through a celite pad. MeOH was removed in
vacuo and the aqueous residue was extracted with EtOAc. The
combined organic layers were washed with brine, dried over
anhydrous MgSO.sub.4 and concentrated in vacuo to a yellow oil that
was purified by chromatography on SiO.sub.2 (0-15% EtOAc/hexanes)
to afford 2.14 g (34%) of Compound 35 as a colorless oil (LC/MS
m/z: 531.2 (M+Na).sup.+).
Compound 36
[0581] Compound 35 (1.73 g, 3.4 mmol) was diluted in MeOH (7.5 mL)
and 10% Pd/C (0.36 g, 0.34 mmol) was added. The atmosphere was
replaced with a H.sub.2 balloon and the reaction mixture allowed to
age at room temperature. After 2 h, the reaction mixture was
filtered through a pad of celite, the filtrate was washed several
times with MeOH, and the combined organic layers were concentrated
in vacuo to afford 1.45 g (83%) of Compound 36 as a colorless oil
(LC/MS m/z: 533.2 (M+Na).sup.+) that was used in the following
procedures without further purification.
Compound 37
[0582] Compound 36 (0.528 g, 1.03 mmol) was diluted in THF (3 mL)
and added to liquefied ammonia (approx. 20 mL) at -35.degree. C.
Small pieces of Na were added until a blue color persisted. After
1.5 h, solid NH.sub.4Cl was added in portions until the remaining
Na was destroyed and the ammonia was allowed to escape at ambient
temperature. Water and EtOAc (20 mL each) were added, and the
aqueous layer was extracted with EtOAc. The combined organic layers
were washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated in vacuo to afford 0.395 g (91%) of Compound 37 as an
amorphous white solid that was used without further purification in
the following procedures (LC/MS m/z: 421.1 (M+H).sup.+; 443.2
(M+Na).sup.+).
Compound 38
[0583] Compound 37 (0.362 g, 0.861 mmol) was diluted in
CH.sub.2Cl.sub.2 (3.2 mL). Trifluoroacetic acid (0.8 mL) was added
and the clear solution was allowed to age overnight. Following
concentration in vacuo, the residue was azeotroped with toluene
several times to remove residual TFA. 0.382 g (99%) of the
bis-trifluoroacetate salt of Compound 38 was collected as a
colorless oil that was used without further purification (LC/MS
m/z: 221.1 (M+H).sup.+).
##STR00184##
Compounds 39 and 40
[0584] Compound 38 (0.382 g, 0.852 mmol) was diluted in MeCN (10
mL) and N,N-diisopropylethylamine (0.60 mL, 3.41 mmol) was added,
followed by a solution of Compound 16 in MeCN (1.5 mL). The clear,
yellow solution was allowed to age at room temperature for 4 h and
the volatiles were removed in vacuo. The residue was taken up in a
3/1 CHCl.sub.3/IPA (v/v, 13 mL) and treated with saturated
Na.sub.2CO.sub.3 (3 mL). The resulting suspension was diluted with
H.sub.2O (3 mL), and the aqueous phase thoroughly extracted with
3/1 CHCl.sub.3/IPA. The combined organic layers were dried over a
3/2 (w/w) mixture of anhydrous Na.sub.2SO.sub.4/anhydrous
Na.sub.2CO.sub.3 and concentrated in vacuo. Chromatography on
SiO.sub.2 (0-20% MeOH/CH.sub.2Cl.sub.2) afforded 0.043 g (14%) of
Compound 39 as a colorless film (LC/MS m/z: 362.1 (M+H).sup.+) and
0.105 g (34%) of Compound 40 as a colorless film (LC/MS m/z: 362.1
(M+H).sup.+).
Example M
[0585] A flask was charged with Compound 39 (0.048 g, 0.133 mmol)
and Compound 29 was added as a 0.2 M solution in THF (0.8 mL, 0.160
mmol). THF (1 mL) was added, followed by DIPEA (0.026 mL, 0.145
mmol), HOBt (0.022 g, 0.160 mmol) and finally EDC (0.028 mL, 0.160
mmol). The clear, colorless solution was allowed to age overnight.
Volatiles were removed in vacuo and the residue chromatographed on
SiO.sub.2 (0-20% MeOH/CH.sub.2Cl.sub.2). Fractions containing the
desired compound were concentrated in vacuo and submitted to
preparatory LC/MS purification to afford 0.018 g (20%) of Example M
as a colorless film LC/MS m/z: 657.2 (M+H).sup.+; .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. 8.95 (s, 1H); 7.88 (br s, 1H);
7.27-7.04 (m, 5H); 7.04 (s, 1H); 6.60-6.20 (m, 2H); 5.22 (m, 2H);
5.12 (d, J=9.3 Hz, 1H); 4.50 (m, 2H); 4.01 (br s, 1H); 3.83 (m,
2H); 3.38 (m, 1H); 3.10-2.94 (m, 3H); 2.74 (m, 2H); 2.23 (m, 1H);
1.64-1.15 (m, 8H); 1.40 (d, J=6.9 Hz, 6H); 0.96 (m, 6H); 0.83 (t,
J=6.9 Hz, 3H).
Example N
[0586] Example N was prepared using procedures similar to those
used to prepare Example M, using the following reagents: Compound
40 (0.055 g, 0.152 mmol); Compound 29 (0.92 mL of 0.2 M THF
solution, 0.183 mmol); THF (1 mL); DIPEA (0.040 mL, 0.228 mmol);
HOBt (0.025 g, 0.182 mmol); EDC (0.032 mL, 0.182 mmol). 0.087 g
(87%) of Example N was isolated as a colorless film (LC/MS m/z:
657.2 (M+H).sup.+; .sup.1H-NMR CDCl.sub.3, 300 MHz) .delta. 8.84
(s, 1H); 7.86 (s, 1H); 7.27-7.04 (m, 5H); 7.04 (s, 1H); 6.28 (br s,
1H); 6.12 (br s, 1H); 5.25 (m, 2H); 5.11 (d, J=9.0 Hz, 1H);
4.62-4.32 (m, 2H); 4.19 (m, 1H); 4.01 (br s, 1H); 3.53 (m, 1H);
3.10-2.90 (m, 3H); 2.72 (d, J=6.0 Hz, 2H); 2.29 (m, 1H); 1.65-1.18
(m, 8H); 1.39 (d, J=6.9 Hz, 6H); 1.00-0.78 (m, 9H).
Preparation of Examples O and P
##STR00185##
[0587] Compound 41
[0588] Compound 41 was prepared following the procedure described
in J. Org. Chem. 1996, 61, 444-450.
Compound 42
[0589] A mixture of Compound 41 (1.73 g, 3 mmol) and
1,1'-thiocarbonyldiimidazole (1.14 g, 6.1 mmol) in THF (60 mL) was
heated at 65.degree. C. for 72 hours. Solvent was removed under
reduced pressure. The mixture was diluted with EtOAc, and washed
successively with 1N HCl, water, and brine, and dried over
MgSO.sub.4. Purification by flash column chromatography (silica
gel, hexanes/EtOAc=1/1) gave Compound 42 (980 mg). m/z: 611.1
(M+H).sup.+.
Compound 43
[0590] A mixture of Compound 42 (980 mg) and triethyl phosphite (10
mL) was heated at 160.degree. C. for 14 hours. The excess reagents
were removed under reduced pressure. Recrystallization from a
mixture of hexanes (11 mL) and EtOAc (3.6 mL) gave Compound 57 (580
mg). m/z: 557.3 (M+Na).sup.+.
Compound 44
[0591] A mixture of Compound 43 (580 mg) in i-PrOH/EtOAc (12 mL/12
mL) was hydrogenated under high pressure (100 psi) for 24 hours in
the presence of 10% Pd/C (200 mg). Celite was added and the mixture
was stirred for 5 minutes. Filtration and evaporation gave Compound
44 (285 mg). m/z: 269.1 (M+H).sup.+.
[0592] The skilled practitioner will recognize that the procedure
outlined in Scheme 16 can be used to prepare a variety of
1,4-substituted 1,4-diamines analogous to Compound 44. For example,
an amine-protected 2,3-dihydroxy-1,4-diamine analogous to Compound
41 can be prepared:
##STR00186##
[0593] wherein L.sup.3, A, Ar, and P are as defined herein, and
protecting group "P" is any amine protecting group described in
described in Protective Groups in Organic Synthesis, Theodora W.
Greene and Peter G. M. Wuts (John Wiley & Sons, Inc., New York,
1999, ISBN 0-471-16019-9). The analogs of Compound 41 can then be
transformed, according to the methods outlined in Scheme 16, to
form analogs of Compound 42:
##STR00187##
[0594] analogs of Compound 43:
##STR00188##
and
[0595] analogs of Compound 44:
##STR00189##
[0596] It will also be recognized that stereochemical
configurations other than those shown (i.e., enantiomers or
diasteriomers) can be prepared by the selection of analogs of
Compound 41 having the appropriate stereochemical configuration at
the chiral centers.
##STR00190##
Compound 46
[0597] To the solution of Compound 45 (950 mg, 3.5 mmol) in
CH.sub.3CN (36 mL) at 0.degree. C. was added Compound 16 (892 mg,
3.2 mmol), followed by diisopropylethylamine (1.2 mL, 7 mmol). The
mixture was stirred for 12 hours at 25.degree. C. The mixture was
diluted with EtOAc, and washed successively with saturated
Na.sub.2CO.sub.3, water, and brine. Purification by flash column
chromatography (silica gel, 100% EtOAc to
CH.sub.2Cl.sub.2/MeOH=4/1) gave Compound 46 (770 mg). m/z: 410.1
(M+H).sup.+.
[0598] The skilled practitioner will recognize that the procedure
outlined in Scheme 17 can be used to prepare a variety of compounds
analogous to Compound 46. For example, 1,4-diamines analogous to
Compound 44 can be prepared as discussed above:
##STR00191##
[0599] The analogs of Compound 44 can then be reacted with analogs
of Compound 16:
##STR00192##
[0600] (wherein Z.sup.2, X, and R.sup.9 are as defined herein) to
form analogs of Compound 46:
##STR00193##
[0601] It will also be recognized that stereochemical
configurations other than those shown (i.e., enantiomers or
diasteriomers) can be prepared by the selection of analogs of
Compound 44 having the appropriate stereochemical configuration at
the chiral centers.
##STR00194##
Compound 47
[0602] Compound 47 is commercially available from TCI.
Compound 48
[0603] To a solution of Compound 9 (500 mg, 3 mmol) in
CH.sub.2Cl.sub.2 (3 mL) was added Compound 47 (500 mg, 2.5 mmol).
The mixture was stirred for 14 hours. Purification by flash column
chromatography (hexanes/EtOAc=1/1.5) gave Compound 48 (242 mg).
m/z: 372.1 (M+H).sup.+.
Compound 49
[0604] To a solution of Compound 48 (240 mg, 0.65 mmol) in dioxane
(4 mL) and water (4 mL) was added sodium hydroxide (40 mg, 1 mmol).
The mixture was stirred for 1 hour and acidified with 4 N HCl in
dioxane (0.25 mL, 1 mmol). The mixture was extracted with EtOAc and
organic phase was dried with MgSO.sub.4. Concentration gave
Compound 49 (200 mg). m/z: 356.2 (M-H).sup.+.
Example O
[0605] To a solution of corresponding acid 49 (30 mg, 0.08 mmol)
and Compound 46 (22 mg, 0.05 mmol) in THF (1 mL) were added HOBt
(15 mg, 0.11 mmol), EDC (20 .mu.L, 0.11 mmol), and
disopropylethylamine (0.2 mL). The mixture was stirred for 12 hours
and concentrated. Purification by flash column chromatography
(hexanes/EtOAc=1/5 to 0/100) gave Example O (17 mg). m/z: 749.3
(M+H).sup.+.
Example P
[0606] To Example O (17 mg) was added TFA (2 mL). The mixture was
stirred for 3 hours and concentrated. The mixture was diluted with
THF (2 mL) and 1.0 N NaOH solution was added until pH 11. The
mixture was stirred for 10 minutes, and extracted with EtOAc. The
organic phase was washed with water and brine. Purification by
flash column chromatography (EtOAc) gave Example P (12 mg).
.sup.1H-NMR (CDCl.sub.3) .delta. 8.76 (1H, s), 7.79 (1H, s),
7.25-6.9 (11H, m), 6.51 (1H, broad), 5.42 (1H, m), 5.18 (2H, m),
4.42 (2H, m), 4.22 (1H, m), 4.10 (1H, m), 3.95 (1H, m), 3.79 (1H,
m), 3.58 (1H, m), 3.23 (1H, m), 2.93 (3H, s), 2.9-2.5 (4H, m),
1.6-1.2 (10H, m); m/z: 693.2 (M+H).sup.+.
Preparation of Examples O, R, and S
##STR00195##
[0607] Compound 50
[0608] Compound 50 is commercially available from Chem Impex
International, and used without further purification.
Compound 51
[0609] Compound 50 (7.0 g, 26.0 mmol) was dissolved in
CH.sub.2Cl.sub.2 (330 mL) and 1,1-carbonyldiimidazole (4.22 g, 26.0
mmol) was added, followed by i-Pr.sub.2NEt (19 mL, 104 mmol). The
solution was stirred at 25.degree. C. for 12 hours. Compound 9
(4.44 g, 26.0 mmol) was dissolved in 20 mL of CH.sub.2Cl.sub.2 and
added to the reaction mixture. The solution was stirred at
25.degree. C. for 7 hours. The solvent was removed in vacuo and the
residue was diluted with ethyl acetate and washed with water and
brine. The organic layers were dried (Na.sub.2SO.sub.4), filtered,
and evaporated. Purification by Combiflash.RTM. (stationary phase:
silica gel; eluent: 66-100% EtOAc/Hexane gradient) gave Compound 51
(7.34 g). m/z: 429.0 (M+H).sup.+.
Compound 52
[0610] Compound 51 (7.34 g, 17.13 mmol) was dissolved in THF (90
mL) and 1M aqueous LiOH (35 mL) was added. The mixture was stirred
at 25.degree. C. for 0.5 hour. The reaction was quenched with 1M
HCl (51 mL) and the mixture was adjusted to pH 2. The mixture was
extracted with ethyl acetate. The organic layers were dried over
Na.sub.2SO.sub.4, filtered, and evaporated to provide Compound 52
(7.00 g). The recovered Compound 52 was used in the next step
without further purification. m/z: 415.0 (M+H).sup.+.
[0611] The skilled practitioner will recognize that the procedure
outlined in Scheme 19 can be used to prepare a variety of compounds
analogous to Compounds 51 and 52. For example, amines analogous to
Compound 9 can be reacted with the appropriate amino ester
analogous to Compound 50:
##STR00196##
[0612] to form compounds analogous to Compound 51, which are
further reacted to form compounds analogous to Compound 52:
##STR00197##
[0613] wherein R.sup.1, R.sup.2, R.sup.7, R.sup.8 and Y are as
defined herein.
[0614] It will also be recognized that stereochemical
configurations other than those shown (i.e., enantiomers or
diasteriomers) can be prepared by the selection of analogs of
Compound 50 having the appropriate stereochemical configuration at
the chiral center.
Example O
[0615] Compound 52 (2.57 g, 6.21 mmol) was dissolved in THF (67
mL). Compound 8 (2.10 g, 5.13 mmol) was added, followed by HOBt
(1.04 g, 7.70 mmol), i-Pr.sub.2NEt (3.67 mL, 20.52 mmol), and EDC
(1.82 mL, 10.26 mmol). The mixture was stirred at 25.degree. C. for
12 hours. The solvent was removed under reduced pressure. The
residue was diluted with ethyl acetate and washed sequentially with
saturated aqueous Na.sub.2CO.sub.3, water, and brine. The organic
phase was dried over Na.sub.2SO.sub.4, filtered, and evaporated.
Purification by flash column chromatography (stationary phase:
silica gel; eluent: 5% iPrOH/CH.sub.2Cl.sub.2) gave Example Q (3.02
g). m/z: 806.2 (M+H).sup.+.
Example R
[0616] Example Q (3.02 g, 3.74 mmol) was suspended in 4.0 N
HCl/dioxane solution (30 mL) and stirred at 25.degree. C. for 3
hours. Solvent was removed under reduced pressure and Et.sub.2O was
poured into the reaction mixture. The resulting suspension was
stirred vigorously for 1.5 hours. The solid was allowed to settle
and the ether layer was decanted. Washing of the precipitate with
Et.sub.2O was repeated two more times. The product was dried in
vacuo to afford a white solid (3.18 g, quantitative yield).
Saturated aqueous Na.sub.2CO.sub.3 solution was added to above
solid (3.18 g) with stirring until solid disappeared. The aqueous
solution was extracted with ethyl acetate. The organic phases were
dried over Na.sub.2SO.sub.4, filtered, and evaporated to afford
Example R as a yellow foam (2.44 g, 81%). The recovered Example R
was used without further purification in the next step. m/z: 706.1
(M+H).sup.+.
Example S
[0617] Method I:
[0618] Example R (1.00 g, 1.42 mmol) was dissolved in DMF (20 mL)
and bromoethyl ether (196 .mu.L, 1.56 mmol) was added dropwise,
followed by NaHCO.sub.3 (0.239 g, 2.84 mmol). The reaction mixture
was stirred at 25.degree. C. for 2 hours. The solution was heated
to 65.degree. C. and stirred for 12 hours. The solvent was removed
under reduced pressure. The residue was diluted with EtOAc and
washed sequentially with water and brine. The organic phase was
dried over Na.sub.2SO.sub.4 filtered, and evaporated. Purification
by reverse-phase HPLC (Phenomenex Synergi.RTM. Comb-HTS column,
eluent: 5-95% CH.sub.3CN/water) gave Compound 70 (580 mg, 53%).
.sup.1H NMR (CDCl.sub.3) .delta. 8.98 (s, 1H); 7.90 (s, 1H); 7.75
(m, 1H); 7.40-7.00 (m, 11H), 6.55 (br s, 1H); 5.58 (m, 1H); 5.28,
5.19 (d.sub.AB, J=14 Hz, 2H); 4.70-4.37 (m, 3H); 3.99 (m, 5H); 3.76
(br s, 1H); 3.65-3.30 (m, 3H); 2.97 (m, 5H); 2.90-2.60 (m, 6H);
2.28 (br s, 1H); 1.91 (br s, 1H); 1.60-1.30 (m, 10H). m/z: 776.2
(M+H).sup.+
[0619] Method II:
##STR00198##
Compound 54
[0620] Compound 54 was prepared following the procedure described
in J. Med. Chem. 1993, 36, 1384 (herein incorporated by reference
in its entirety for all purposes).
[0621] To solution of Compound 53 (0.550 g, 5.28 mmol)
(Sigma-Aldrich) in H.sub.2O (8.8 mL) at 0.degree. C. was added
NaIO4 (1.016 g, 4.75 mmol). The mixture was allowed to slowly warm
to 25.degree. C. and stirred for 12 hours. Solid NaHCO.sub.3 was
added to the reaction mixture until pH 7. CHCl.sub.3 (16 mL) was
added and the mixture was allowed to stir for 5 minutes. The
mixture was filtered and the solid was washed with CHCl.sub.3 (6
mL). The combined H.sub.2O/CHCl.sub.3 solution was used directly in
the next step without further purification.
##STR00199##
Example S
[0622] To a solution of Example R (70 mg, 0.1 mmol) in CH.sub.3CN
(5 mL) was added sodium cyanoborohydride (50 mg) in water (5 mL).
To the above mixture was added a solution of dialdehyde Compound 54
(0.6 mmol) in CHCl.sub.3/H.sub.2O) (4 mL/1 mL). The mixture was
stirred for 12 hours, and basified with saturated Na.sub.2CO.sub.3
solution. The mixture was extracted with EtOAc, and organic phase
was washed with water and brine, and dried over Na.sub.2SO.sub.4.
Purification by reverse-phase HPLC (Phenomenex Synergi.RTM.
Comb-HTS column) gave Example S (57 mg).
[0623] Method III
##STR00200##
Compound 55
[0624] Compound 51 (0.28 g, 0.66 mmol) was dissolved in
CH.sub.2Cl.sub.2 (4 mL) and TFA (1 mL) was added dropwise. The
reaction was allowed to stir at 25.degree. C. for 1 hour. The
solvent was removed under reduced pressure to afford Compound 55
(0.39 g). m/z: 329.0 (M+H).sup.+.
Compound 56
[0625] To a solution of Compound 55 (0.39 g, 0.89 mmol) in
CH.sub.3CN (45 mL) was added NaBH.sub.3CN (0.45 g, 7.12 mmol) and
H.sub.2O (45 mL). A solution of Compound 54 (0.55 g, 5.34 mmol) in
CHCl.sub.3/H.sub.2O (40 mL) was added. The mixture was stirred at
25.degree. C. for 12 hours. The reaction mixture was made basic
with saturated aqueous Na.sub.2CO.sub.3 and extracted sequentially
with ethyl acetate and dichloromethane. The combined organic layers
were washed sequentially with H.sub.2O and brine, dried over
Na.sub.2SO.sub.4, filtered, and evaporated. Purification by
Combiflash.RTM. (stationary phase: silica gel; eluent: 0-10%
MeOH/CH.sub.2Cl.sub.2 gradient) gave Compound 56 (0.17 g). m/z:
399.1 (M+H).sup.+.
Compound 57
[0626] Compound 56 (377 mg, 0.95 mmol) was dissolved in THF (4 mL)
and 1M aqueous LiOH (1.90 mL) was added. The mixture was stirred at
25.degree. C. for 1 hour. The reaction was neutralized with 1M HCl.
THF was removed under reduced pressure and the aqueous solution was
lyophilized to afford Compound 57 (365 mg). The material was used
directly in the next step without further purification. m/z: 385.1
(M+H).sup.+.
Example S
[0627] Example S (185 mg, 57%) was prepared following the same
procedure as for Example Q, except that Compound 57 (160 mg, 0.42
mmol) was used instead of Compound 52. mass m/z: 776.2
(M+H).sup.+.
[0628] The skilled practitioner will recognize that the procedure
outlined in Scheme 22 can be used to prepare a variety of compounds
analogous to Compounds 55-57:
##STR00201##
wherein R.sup.7, R.sup.8 and Y are as defined herein.
[0629] It will also be recognized that stereochemical
configurations other than those shown (i.e., enantiomers or
diasteriomers) can be prepared by the selection of analogs of
Compound 51 having the appropriate stereochemical configuration at
the chiral center.
[0630] Method IV
##STR00202##
Compound 59
[0631] To a solution of Compound 122 (33 g, 112 mmol) (see Scheme
69) in ethanol (366 mL) at 0.degree. C. was added a solution of
sodium hydroxide (4.7 g, 117 mmol) in water (62 mL). The mixture
was stirred for one hour at 25.degree. C., and solvents were
removed under reduced pressure. The mixture was coevaporated with
ethanol (3.times.400 mL), and dried at 60.degree. C. for two hours
under high vacuum to give a white solid. To the solution of above
solid in DMF (180 mL) was added benzyl bromide (16.2 mL, 136 mmol).
The mixture was stirred for 16 hours under darkness, and was
quenched with water (300 mL). The mixture was extracted with EtOAc
(4.times.300 mL). The combined organic phase was washed with water
(5.times.) and brine, and dried over Na.sub.2SO.sub.4.
Concentration gave Compound 59 (48 g), which was used in the next
step without further purification.
Compound 60
[0632] A mixture of Compound 59 (33 g, 74 mmol) in DMSO (225 mL)
and Et.sub.3N (36 mL) was stirred for 30 minutes. The mixture was
cooled to 0-10.degree. C., SO.sub.3-pyridine (45 g) was added, and
the stirring was continued for 60 minutes. Ice (300 g) was added,
and the mixture was stirred for 30 minutes. EtOAc (300 mL) was
added and sat. Na.sub.2CO.sub.3 was added until pH was 9.about.10.
The organic phase was separated from the aqueous phase, and the
aqueous phase was extracted with EtOAc (2.times.300 ml). The
combined organic phases were washed with sat Na.sub.2CO.sub.3
(2.times.), water (3.times.), and brine. The mixture was dried over
Na.sub.2SO.sub.4 and concentrated to give Compound 60 (32 g), which
was used directly in next step without further purification.
Compound 61
[0633] To a solution of Compound 60 (32 g) in CH.sub.3CN (325 mL)
was added morpholine (12.9 mL, 148 mmol), with a water bath around
the reaction vessel, followed by HOAc (8.9 mL, 148 mmol), and
NaBH(OAc).sub.3 (47 g, 222 mmol). The mixture was stirred for 12
hours. CH.sub.3CN was removed under reduced pressure, and the
mixture was diluted with EtOAc (300 mL). Sat. Na.sub.2CO.sub.3 was
added until the pH was 9.about.10. The organic phase was separated
from the aqueous phase, and the aqueous phase was extracted with
EtOAc (2.times.300 mL). The combined organic phases were washed
with sat Na.sub.2CO.sub.3 (2.times.), water (1.times.), and brine
(1.times.). The mixture was dried over Na.sub.2SO.sub.4. The
resulting residue was concentrated and purified by silica gel
column chromatography (EtOAc to DCM/iPrOH=10/1) to give Compound 61
(30 g).
Compound 57
[0634] To a solution of Compound 61 (26.5 g, 56 mmol) in ethanol
(160 mL) at 0.degree. C. was added a solution of sodium hydroxide
(2.5 g, 62 mmol) in water (30 mL). The mixture was stirred for one
hour at 25.degree. C., and solvents were removed under reduced
pressure. The mixture was diluted with water (200 mL), and was
washed with CH.sub.2Cl.sub.2 (6.times.100 mL). The water phase was
acidified with 12 N HCl (5.2 mL), and was dried under reduced
pressure to give Compound 57 (22 g).
Example S
[0635] Compound 57 was converted to Example S using the procedure
described in Method III, above.
Preparation of Compounds T and U
##STR00203##
[0636] Example T
Method I
[0637] The hydrochloride salt of Example R (100 mg, 0.13 mmol) was
suspended in CH.sub.2Cl.sub.2 (2 mL) and dissolved by addition of
iPr.sub.2NEt (69 .mu.L). Acetyl chloride (11 .mu.L) was added
dropwise and the mixture was allowed to stir at 25.degree. C. for 4
hours. The solvent was removed in vacuo. Purification of the
residue by flash column chromatography (stationary phase: silica
gel; eluent: 8% iPrOH/CH.sub.2Cl.sub.2) gave Example T (39 mg,
40%). m/z: 748.2 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .delta. 8.85
(s, 1H); 7.87 (s, 1H); 7.73 (s, 1H); 7.40-7.00 (m, 13H); 6.45 (br
s, 1H); 5.70 (m, 1H); 5.32, 5.22 (d.sub.AB, J=13 Hz, 2H); 4.51 (s,
2H); 4.20-3.90 (m, 4H); 3.78 (m, 1H); 3.38 (m, 2H); 3.20-2.50 (m,
8H); 1.95 (s, 4H); 1.82 (m, 2H); 1.41 (m, 6H).
Method II
[0638] Saturated aqueous Na.sub.2CO.sub.3 solution was added to the
hydrochloride salt of Example R (3.18 g, 3.46 mmol) while stirring
until the solid disappeared. The aqueous solution was extracted
with ethyl acetate. The organic phases were dried over
Na.sub.2SO.sub.4, filtered, and evaporated to afford Example R as a
yellow foam (2.44 g, 81%). This material was used without further
purification in the next step. m/z: 706.1 (M+H).sup.+.
[0639] Example R (300 mg, 0.43 mmol) was dissolved in THF (5.5 mL).
Acetic acid (37 .mu.L, 0.64 mmol) was added, followed by HOBt (85
mg, 0.64 mmol), iPr.sub.2NEt (304 .mu.L, 1.70 mmol), and EDC (151
.mu.L, 0.85 mmol). The reaction mixture was allowed to stir at
25.degree. C. for 12 hours. The solvent was removed under reduced
pressure. The residue was diluted with EtOAc and washed
sequentially with saturated aqueous Na.sub.2CO.sub.3, water, and
brine. The organic phase was dried over Na.sub.2SO.sub.4, filtered,
and evaporated. Purification by Combiflash.RTM. (stationary phase:
silica gel; eluent: 10% MeOH/CH.sub.2Cl.sub.2) gave Example T (249
mg, 77%). m/z: 748.2 (M+H).sup.+.
Example U
[0640] Example R (100 mg, 0.13 mmol) was suspended in
CH.sub.2Cl.sub.2 (2 mL) and dissolved by addition of iPr.sub.2NEt
(69 .mu.L). Methanesulfonyl chloride (12 .mu.L) was added dropwise
and the mixture was allowed to stir at 25.degree. C. for 4 hours.
The solvent was removed in vacuo. Purification of the residue by
flash column chromatography (stationary phase: silica gel; eluent:
8% iPrOH/CH.sub.2Cl.sub.2) gave Example U (55 mg, 54%). m/z: 784.2
(M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .delta. 8.90 (s, 1H); 7.88
(s, 1H); 7.40-7.00 (m, 12H); 6.54 (br s, 1H); 6.19 (br s, 1H); 5.25
(s, 2H); 4.53 (s, 2H); 4.38 (m, 1H); 4.12 (m, 1H); 3.79 (m, 1H);
3.79 (m, 1H); 3.48 (m, 1H); 2.99 (s, 3H); 2.90 (m, 3H); 2.73 (m,
6H); 2.00 (m, 1H); 1.79 (m, 1H); 1.60-1.18 (m, 10H).
Preparation of Examples V, W, X and Y
##STR00204##
[0641] Example V
[0642] Example V (692 mg) was prepared following the same procedure
used for preparing Example Q, except that Compound 46 was used
instead of Compound 8. m/z: 806.2 (M+H).sup.+.
Example W
[0643] Example W (770 mg, quantitative yield) was prepared
following the same procedure for Example R except that Example V
was used instead of Example Q. m/z: 706.2 (M+H).sup.+. .sup.1H NMR
(CD.sub.3OD) .delta. 9.86 (s, 1H); 8.23 (s, 1H); 7.66 (s, 1H);
7.40-7.00 (m, 10H); 5.29, 5.17 (d.sub.AB, J=13 Hz, 2H); 4.80-4.60
(m, 2H); 4.18 (s, 2H); 4.26 (m, 2H); 3.67 (br s, 1H); 3.55 (m, 2H);
3.03 (m, 3H); 2.90-2.60 (m, 8H); 2.53 (s, 2H); 2.00-1.80 (m, 2H);
1.85-1.30 (m, 10H).
Example X
Method I
[0644] Example X (107 mg, 55%) was prepared following the Method I
procedure for Example T except that Example W was used instead of
Example R. m/z: 748.2 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .delta.
8.80 (s, 1H); 7.85 (s, 1H); 7.40 (m, 1H); 7.38-7.00 (m, 10H), 6.94
(s, 1H); 6.30 (m, 2H); 5.75 (m, 1H); 5.30, 5.23 (d.sub.AB, J=13 Hz,
2H); 4.54, 4.46 (d.sub.AB, J=8 Hz, 2H); 4.20-3.90 (m, 2H); 3.74 (br
s, 1H); 3.46 (br s, 1H); 3.28 (m, 1H); 2.98 (s, 3H); 2.83 (m, 3H);
2.72 (m, 1H); 2.62 (m, 1H); 2.05-1.20 (m, 15H).
Method II
[0645] Example X (205 mg, 65%) was prepared following the Method II
procedure for Example T except that Example W was used instead of
Example R. m/z: 748.2 (M+H).sup.+.
Example Y
[0646] Example Y (106 mg, 50%) was prepared following the same
procedure for Example U, except that Example W was used instead of
Example R. m/z: 784.2 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .delta.
8.81 (s, 1H); 7.85 (s, 1H); 7.40-7.05 (m, 10H), 6.98 (s, 1H); 6.22
(br s, 1H); 5.78 (s, 1H); 5.25 (m, 4H); 4.29 (m, 2H); 4.33 (br s,
1H); 4.12 (br s, 1H); 3.77 (br s, 1H); 3.10 (br s, 1H); 2.98 (s,
3H); 2.90 (s, 3H); 2.73 (m, 6H); 2.00-1.20 (m, 12H).
Preparation of Examples Z-AD
##STR00205##
[0647] Compound 62
[0648] Tert-butyl 2-aminoethylcarbamate (62) is commercially
available from Aldrich, and was used without further
purification.
Compound 63
[0649] To a solution of Compound 62 (2.0 mmol) in CH.sub.3CN (15
mL) was added Compound 16 (1.82 mmol), followed by the addition of
N,N-diisopropylethylamine (0.61 mL). The mixture was stirred at
25.degree. C. for 12 hours. The solvent was removed in vacuo, and
the residue was diluted with ethyl acetate and washed sequentially
with saturated aqueous Na.sub.2CO.sub.3, water, and brine. The
organic layers were dried with Na.sub.2SO.sub.4, filtered, and
evaporated. Purification by Combiflash.RTM. (stationary phase:
silica gel; eluent: 25-100% EtOAc/hexane gradient) gave Compound
63. m/z: 301.9 (M+H).sup.+.
Compound 64
[0650] To a solution of Compound 63 (1.05 mmol) in EtOAc (3 mL) was
added 4N HCl/dioxane solution (1.1 mL). The mixture was allowed to
stir at 25.degree. C. for 12 hours. The solvent was removed under
reduced pressure, and Compound 64 was obtained as a white powder.
This material was used in the next step without further
purification. m/z: 216.0 (M+H).sup.+.
Example Z
[0651] Compound 64 (70 mg, 0.29 mmol) was dissolved in THF (2.2
mL). Compound 29 (91 mg, 0.29 mmol) was added to the reaction flask
as a 1.0M solution in THF, followed by HOBt (59 mg, 0.44 mmol),
N,N-diisopropylethylamine (207 .mu.L, 1.16 mmol), and EDC (103
.mu.L, 0.58 mmol). The reaction was allowed to stir for 12 hours at
25.degree. C. and concentrated under reduced pressure. The residue
was diluted with EtOAc and washed sequentially with saturated
aqueous Na.sub.2CO.sub.3, water, and brine. The organic layers were
dried with Na.sub.2SO.sub.4, filtered, and evaporated. Purification
by Combiflash.RTM. (stationary phase: silica gel; eluent: 0-10%
MeOH/CH.sub.2Cl.sub.2 gradient) gave Example Z (54 mg, 38%). m/z:
497.1 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .delta. 8.78 (s, 1H);
7.83 (s, 1H); 6.99 (s, 1H); 6.80 (br s, 1H); 6.22 (br s, 1H); 5.87
(br s, 1H); 5.25 (s, 2H); 4.43 (s, 2H); 3.97 (m, 1H); 3.34 (m,
41-1); 2.95 (s, 3H); 2.22 (m, 2H); 1.38 (d, J=7 Hz, 6H); 0.97 (d,
J=7 Hz, 6H).
Example AA
[0652] Example AA was prepared following the procedures for steps
I-III (Scheme 20) for Example Z, with the exception that tert-butyl
3-aminopropylcarbamate was used instead of tert-butyl
2-aminoethylcarbamate (Compound 62). After Combiflash.RTM.
purification, 38 mg (34%) of Example AA was obtained. m/z: 511.1
(M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .delta. 8.78 (s, 1H); 7.84
(s, 1H); 6.96 (s, 2H); 6.17 (br s, 1H); 5.80 (m, 1H); 5.26 (m, 2H);
4.44 (s, 2H); 4.09 (m, 1H); 3.40-3.10 (m, 5H); 2.97 (s, 3H); 2.20
(m, 1H); 1.60 (m, 2H); 1.36 (d, J=7 Hz, 6H); 0.96 (d, J=7 Hz,
6H).
Example AB
[0653] Example AB was prepared following the procedures for steps
I-III (Scheme 20) for Example Z, with the exception that tert-butyl
1-piperazinecarboxylate was used instead of tert-butyl
2-aminoethylcarbamate (Compound 62). After Combiflash.RTM.
purification, 64 mg (45%) of Example AB was obtained. m/z: 523.1
(M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .delta. 8.82 (s, 1H); 7.89
(s, 1H); 6.96 (s, 1H); 5.93 (br s, 1H); 5.35 (s, 2H); 4.62 (m, 1H);
4.50 (m, 2H); 3.80-3.40 (m, 8H); 3.34 (m, 1H); 3.00 (s, 3H); 1.97
(m, 1H); 1.40 (d, J=7 Hz, 6H); 0.96, 0.93 (d, J=7 Hz, 6H).
Example AC
[0654] Example AC was prepared following the procedures for steps
I-III (Scheme 20) for Example Z, with the exception that tert-butyl
4-amino-1-piperidinecarboxylate was used instead of tert-butyl
2-aminoethylcarbamate (Compound 62). After Combiflash.RTM.
purification, 60 mg (44%) of Example AC was obtained. m/z: 537.1
(M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .delta. 8.82 (s, 1H); 7.87
(s, 1H); 6.97 (s, 1H); 5.82 (br s, 1H); 5.30 (m, 3H); 4.80-4.40 (m,
5H); 4.03 (m, 1H); 3.72 (br s, 1H); 3.34 (m, 1H); 3.18 (m, 1H);
3.01 (s, 3H); 2.79 (m, 1H); 2.20-1.90 (m, 4H); 1.40 (d, J=7 Hz,
6H); 0.97, 0.90 (d, J=7 Hz, 6H).
Example AD
[0655] Example AD was prepared following the procedures I-III for
Example Z, with the exception that tert-butyl
4-piperidinylcarbamate was used instead of tert-butyl
2-aminoethylcarbamate (Compound 62). After Combiflash.RTM.
purification, 49 mg (36%) of Example AD was obtained. m/z: 537.1
(M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .delta. 8.82 (s, 1H); 7.87
(s, 1H); 7.01 (s, 1H); 6.33 (br s, 1H); 6.11 (br s, 1H); 5.32 (s,
2H); 4.47 (s, 2H); 4.20-3.80 (m, 4H); 3.35 (m, 1H); 3.10-2.80 (m,
6H); 2.21 (m, 2H); 1.90 (m, 2H); 1.40 (d, J=7 Hz, 6H); 0.97 (d, J=7
Hz, 6H).
Preparation of Examples AE-AG
##STR00206##
[0656] Compound 65
[0657] Compound 65 is commercially available from Chem Impex
International, and was used without further purification.
Compound 66
[0658] Compound 65 (956 mg, 4.0 mmol) was dissolved in
CH.sub.2Cl.sub.2 (45 mL) and 1,1-carbonyldiimidiazole (648 mg, 4.0
mmol) was added, followed by i-Pr.sub.2NEt (2.8 mL, 16 mmol). The
solution was stirred at 25.degree. C. for 12 hours. Compound 9 (679
mg, 4.0 mmol) was dissolved in CH.sub.2Cl.sub.2 (5 mL) and added to
the reaction. The mixture was allowed to stir for 5 hours. Then,
the solvent was removed under reduced pressure. The residue was
diluted with ethyl acetate and filtered through celite. The ethyl
acetate was then removed in vacuo. Purification by flash column
chromatography (stationary phase: silica gel; eluent: EtOAc) gave
Compound 66 (841 mg). m/z: 400.0 (M+H).sup.+.
Compound 67
[0659] Compound 66 (841 mg, 2.11 mmol) was dissolved in THF (9 mL)
and 2N aqueous NaOH was added. The solution was stirred at
25.degree. C. for 2 hours. The reaction was adjusted to pH 2 with
1N HCl. The mixture was extracted with ethyl acetate, dried over
Na.sub.2SO.sub.4, filtered, and evaporated. Compound 67 (772 mg)
was used directly in the next step without further purification.
m/z: 386.0 (M+H).sup.+.
Example AE
[0660] Compound 67 (569 mg, 1.48 mmol) was dissolved in THF (17
mL). Compound 8 (970 mg, 2.37 mmol) was added, followed by HOBt
(300 mg, 2.22 mmol), i-Pr.sub.2NEt (1.06 mL, 5.92 mmol), and EDC
(0.52 mL, 2.96 mmol). The mixture was stirred at 25.degree. C. for
36 hours. The solvent was removed under reduced pressure. The
resulting residue was diluted with ethyl acetate and washed
sequentially with saturated aqueous Na.sub.2CO.sub.3, water, and
brine. The organic phase was dried over Na.sub.2SO.sub.4, filtered,
and evaporated. Purification by flash column chromatography
(stationary phase: silica gel; eluent: 8% iPrOH/CH.sub.2Cl.sub.2)
gave Example AE (3.02 g). m/z: 777.2 (M+H).sup.+.
Example AF
[0661] Example AE (100 mg, 0.13 mmol) was dissolved in neat TFA (3
mL). The mixture was stirred at 25.degree. C. for 2 hours. The
solvent was removed under reduced pressure. Purification by
reverse-phase HPLC (Phenomenex Synergi.RTM. Comb-HTS column,
eluent: 5-95% CH.sub.3CN/H.sub.2O gradient) gave Example AF (20 mg,
21%). m/z: 721.2 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .delta. 8.92
(s, 1H); 7.91 (s, 1H); 7.40-7.00 (m, 11H); 6.41 (br s, 1H); 6.12
(br s, 1H); 5.40-5.00 (m, 3H); 4.70-4.50 (m, 3H); 4.05 (br s, 1H);
3.81 (br s, 1H); 3.51 (br s, 1H); 2.97 (s, 3H); 2.90-2.60 (m, 6H);
1.41 (d, J=7 Hz, 10H).
Example AG
[0662] Example AF (70 mg, 0.10 mmol) was dissolved in dioxane (0.5
mL). DMF (83 .mu.L), pyridine (25 .mu.L, 0.29 mmol),
di-tert-butyldicarbonate (27 mg, 0.13 mmol), and ammonium
bicarbonate (15 mg, 0.19 mmol) were added. The mixture was stirred
at 25.degree. C. for 48 hours, then diluted with ethyl acetate and
washed sequentially with water and brine. The organic phase was
dried over Na.sub.2SO.sub.4, filtered, and evaporated. Purification
by reverse-phase HPLC (Phenomenex Synergi.RTM. Comb-HTS column,
eluent: 5-95% CH.sub.3CN/H.sub.2O gradient) gave Example AG (35 mg,
50%). .sup.1H NMR (CDCl.sub.3) .delta. 8.80 (s, 1H); 7.84 (s, 1H);
7.40-7.00 (m, 10H); 7.08 (s, 1H); 6.83 (m, 1H); 6.65 (m, 1H);
5.40-5.10 (m, 4H); 4.60-4.40 (m, 3H); 4.06 (m, 1H); 3.79 (m, 1H);
3.36 (m, 1H); 2.97 (s, 3H); 2.90-2.60 (m, 6H); 2.45 (m, 1H);
1.70-1.20 (m, 10H).
Preparation of Compounds 68 and 69
##STR00207##
[0663] Compound 15
[0664] Compound 15 is commercially available from Molekula, and was
used without further purification.
Compound 68
[0665] Compound 15 (6.81 g, 59.1 mmol) was dissolved in CH.sub.3CN
(340 mL) and methanesulfonyl chloride (7.03 mL, 65.1 mmol) was
added, followed by triethylamine (9.03 mL, 65.1 mmol). After the
mixture was stirred for 20 min, 40% wt. methylamine/water (516 mL)
was added to the reaction mixture. The solution was stirred for 12
hours at 25.degree. C. Solvent was removed under reduced pressure
and the residue was partitioned between saturated aqueous
Na.sub.2CO.sub.3 and CH.sub.2Cl.sub.2. The organic phase was
separated, dried over Na.sub.2SO.sub.4, filtered, and evaporated.
Purification by flash chromatography (stationary phase: silica gel;
eluent: 0-10% MeOH/CH.sub.2Cl.sub.2 gradient) gave Compound 68
(5.07 g). m/z: 128.9 (M+H).sup.+.
Compound 69
[0666] Compound 15 (10.0 g, 80 mmol) was dissolved in CH.sub.3CN
(500 mL) and methanesulfonyl chloride (7.0 mL, 88 mmol) was added,
followed by triethylamine (12.3 mL, 88 mmol). After the mixture was
stirred for 2 h, cyclopropylamine (140 mL, 2000 mmol) in CH.sub.3CN
(500 mL) was added to the reaction mixture. The solution was
stirred for 36 hours at 25.degree. C. Solvent was removed under
reduced pressure and the slurry was partitioned between saturated
aqueous Na.sub.2CO.sub.3 and 3:1 CH.sub.2Cl.sub.2:i-PrOH. The
organic phase was separated, dried over Na.sub.2SO.sub.4, filtered,
and evaporated. Compound 69 (12.81 g) was used in the next step
without further purification. m/z: 155.0 (M+H).sup.+.
Preparation of Examples AH and AI
##STR00208##
[0667] Compound 70
[0668] Compound 68 (1.00 g, 7.80 mmol) was dissolved in THF (25 mL)
and Compound 10e (2.51 g, 7.09 mmol) was added, followed by
N,N-dimethaminopyridine (200 mg, 1.63 mmol), and triethylamine
(4.34 mL, 31.2 mmol). The mixture was allowed to stir at 60.degree.
C. for 6 hours. Solvent was removed under reduced pressure. The
residue was diluted with ethyl acetate and washed sequentially with
saturated aqueous Na.sub.2CO.sub.3, H.sub.2O, and brine. The
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
evaporated. The resulting residue was purified by Combiflash.RTM.
(stationary phase: silica gel; eluent: 20-100% EtOAc/Hexane
gradient) to give Compound 70 (2.14 g). m/z: 343.9 (M+H).sup.+.
Compound 71
[0669] Compound 70 (2.14 g, 6.23 mmol) was dissolved in THF (25 mL)
and 1M aqueous LiOH (12.5 mL) was added. The mixture was stirred at
25.degree. C. for 2 hours. The reaction was quenched with 1M HCl
(15 mL) and the mixture was adjusted to pH 2. The mixture was
extracted with ethyl acetate. The organic layers were dried over
Na.sub.2SO.sub.4, filtered, and evaporated to provide Compound 71
(1.96 g). This material was used in the next step without further
purification. m/z: 330.0 (M+H).sup.+.
Example AH
[0670] Compound 71 (43 mg, 0.13 mmol) was dissolved in THF (1.5
mL). Compound 8 (50 mg, 0.12 mmol) was added, followed by HOBt (24
mg, 0.18 mmol), iPr.sub.2NEt (86 .mu.L, 0.48 mmol), and EDC (42
.mu.L, 0.24 mmol). The mixture was stirred at 25.degree. C. for 12
hours. The solvent was removed under reduced pressure, and the
resulting residue was diluted with ethyl acetate and washed
sequentially with saturated aqueous Na.sub.2CO.sub.3, water, and
brine. The organic phase was dried over Na.sub.2SO.sub.4, filtered,
and evaporated. Purification by flash column chromatography
(stationary phase: silica gel; eluent: 1-10% MeOH/CH.sub.2Cl.sub.2
gradient) gave Example AH (66 mg). m/z: 721.2 (M+H).sup.+.
Compound AI
[0671] Example AH (66 mg, 0.09 mmol) was dissolved in TFA and
allowed to stir at 25.degree. C. for 3 hours. The solvent was
removed under reduced pressure and the residue was diluted with THF
(3 mL) and 2N aqueous NaOH was added until pH 12. The mixture was
allowed to stir for 20 min and extracted with EtOAc. The organic
layer was washed sequentially with water and brine, dried over
Na.sub.2SO.sub.4, filtered, and evaporated. Purification by flash
chromatography (stationary phase: silica gel; eluent: 0-20%
i-PrOH/CH.sub.2Cl.sub.2 gradient) gave Example AI (71 mg, 97%).
m/z: 665.2 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .delta. 8.84 (s,
1H); 8.80 (s, 1H); 7.85 (s, 1H); 7.79 (s, 1H); 7.40-7.00 (m, 10H);
6.69 (m, 1H); 5.34 (m, 1H); 5.24 (s, 2H); 4.86 (m, 2H); 4.73, 4.59
(d.sub.AB, J=16 Hz, 2H); 4.30 (s, 1H); 4.15 (m, 2H); 3.86 (br s,
1H); 2.88 (s, 3H); 2.85-2.60 (m, 4H); 2.01 (s, 1H); 1.58 (s, 2H);
1.44 (s, 2H); 1.09 (d, J=6 Hz, 3H).
Preparation of Examples AJ and AK
##STR00209##
[0672] Compound 47
[0673] Compound 47 is commercially available from TCI America, and
was used without further purification.
Compound 72
[0674] Compound 72 was prepared following procedure for Compound 48
(Method II), except that Compound 68 was used instead of Compound
9.
Compound 73
[0675] Compound 73 was prepared following procedure for Compound
49, except that Compound 72 was used instead of Compound 48.
Example AJ
[0676] Example AJ (70 mg) was prepared following the same procedure
used to prepare Example AH, with the exception that Compound 73 (41
mg, 0.13 mmol) was used instead of Compound 71. m/z: 707.2
(M+H).sup.+.
Example AK
[0677] Example AK (43 mg, 67%) was prepared following the same
procedure used to prepare Example AI, with the exception that
Example AJ (70 mg, 0.10 mmol) was used instead of Example AH. m/z:
651.2 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .delta. 8.83 (s, 2H);
7.84 (s, 1H); 7.79 (s, 1H); 7.40-7.00 (m, 10H); 6.65 (br s, 1H);
5.47 (br s, 1H); 5.24 (s, 2H); 4.90 (m, 1H); 4.82-4.50 (m, 2H);
4.30-4.00 (m, 3H); 3.84 (br s, 1H); 3.49 (m, 1H); 2.87 (s, 3H);
2.75 (br s, 5H); 1.60-1.20 (m, 4H).
Preparation of Examples AL and AM
##STR00210##
[0678] Compound 74
[0679] Compound 69 (1.56 g, 10.1 mmol) was dissolved in
CH.sub.2Cl.sub.2 (10 mL). Compound 47 (1.7 g, 8.5 mmol) in
CH.sub.2Cl.sub.2 (20 mL) was added, followed by iPr.sub.2NEt (3.02
mL, 16.9 mmol). The reaction was stirred at 25.degree. C. for 12
hours. The solvent was removed under reduced pressure. The residue
was diluted with ethyl acetate and washed sequentially with water
and brine, dried over Na.sub.2SO.sub.4, filtered, and evaporated.
Purification by Combiflash.RTM. (stationary phase: silica gel;
eluent: 50-100% EtOAc/hexane gradient) gave Compound 74 (2.92 g).
m/z: 356.0 (M+H).sup.+.
Compound 75
[0680] Compound 74 (0.97 mmol) was taken up in THF (3 mL) and
treated with freshly prepared 1M LiOH (2 mmol) and stirred
vigorously for 1 h. The reaction was quenched with 1M HCl (2.5
mmol) and extracted with EtOAc (3.times.15 mL). The combined
organics were washed with brine (25 mL), dried over anhydrous
Na.sub.2SO.sub.4 and concentrated in vacuo to produce 0.331 g
(quant) of Compound 75 as a colorless film (m/z 342.0
(M+H).sup.+).
Example AL
[0681] Example AL (2.20 g) was prepared following the same
procedure used to prepare Example AH, with the exception that
Compound 75 (2.00 g, 4.88 mmol) was used instead of Compound 71.
m/z: 733.2 (M+H).sup.+.
Example AM
[0682] Example AM (1.88 g, 92%) was prepared following the same
procedure used to prepare Example AI, with the exception that
Example AL (2.20 g, 3.01 mmol) was used instead of Example AH. m/z:
677.2 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .delta. 8.79 (s, 1H);
8.72 (s, 1H); 7.82 (s, 1H); 7.77 (s, 1H); 7.40-7.00 (m, 10H); 6.59
(m, 1H); 6.31 (m, 1H); 5.23 (s, 2H); 5.00 (m, 1H); 4.72, 4.60
(d.sub.AB, J=15 Hz, 2H); 4.18 (s, 2H); 4.03 (m, 1H); 3.84 (br s,
1H); 3.48 (m, 1H); 2.85-2.60 (m, 4H); 2.37 (br s, 2H); 1.58 (s,
2H); 1.41 (s, 2H); 0.93 (m, 2H); 0.76 (m, 2H).
##STR00211##
Compound 76
[0683] Compound 76 (m/z 117.0 (M+H).sup.+ of diamine) was prepared
using a procedure similar to that used to prepare Compound 22
(described in Scheme 12) except that CBZ-L-alininol was used
instead of CBZ-L-phenylalininol and Step III was performed with 1 M
HCl added.
Compound 77
[0684] Compound 77 (m/z 145.0 (M+H).sup.+ of diamine) was prepared
using a procedure similar to that used to prepare Compound 76
except that (S)-(+)-2-CBZ-amino-1-butanol was used instead of
CBZ-L-alininol.
Compound 78
[0685] Compound 76 (7.93 mmol) is added to a solution of NaOH (16.7
mmol) in H.sub.2O (5 mL) that is cooled to 0.degree. C. and diluted
with MeCN (40 mL). DIPEA is added (2.1 mL, 11.9 mmol). Compound 16
(7.9 mmol) is taken up in MeCN (40 mL) and added to the reaction
solution dropwise via an addition funnel over 1 h. The resulting
solution is allowed to warm to room temperature overnight. The
solvent is removed in vacuo and the residue taken up in 3/1
CHCl.sub.3/IPA (50 mL). The resulting solution is washed with sat.
Na.sub.2CO.sub.3 (50 mL) and water is added until the aqueous layer
is homogeneous. The aqueous layer is extracted with 3/1
CHCl.sub.3/IPA (3.times.25 mL). The combined organics are washed
with saturated Na.sub.2CO.sub.3 (50 mL), water (50 mL) and brine
(50 mL) and are dried over anhydrous Na.sub.2SO.sub.4. The solvent
is removed in vacuo and the residue purified by column
chromatography on SiO.sub.2 (100% EtOAc, then 0 to 20% MeOH/DCM) to
produce 0.63 g (31%) of 78 as an off-white solid. (m/z 258.0
(M+H).sup.+).
Compound 79
[0686] Compound 79 (m/z 286.1 (M+H).sup.+) was prepared following
the procedure for Compound 78 except that Compound 77 was used
instead of Compound 76.
##STR00212##
Example AN
[0687] Example AN (68 mg) was prepared following the same procedure
used to prepare Example AH, with the exceptions that Compound 49
(68 mg, 0.19 mmol) was used instead of Compound 71, and Compound 79
(50 mg, 0.18 mmol) was used instead of Compound 8. m/z: 625.2
(M+H).sup.+.
Example AO
[0688] Example AO (66 mg, 76%) was prepared following the same
procedure used to prepare Example AI, with the exception that
Example AN (43 mg, 0.13 mmol) was used instead of Example AH. m/z:
569.2 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .delta. 8.85 (s, 1H);
7.89 (s, 1H); 7.08 (s, 1H); 6.81 (m, 1H); 5.29 (s, 2H); 4.87 (m,
1H); 4.63, 4.48 (d.sub.AB, J=16 Hz, 2H); 4.31 (m, 1H); 4.11 (m,
1H); 3.76 (m, 2H); 3.44 (m, 2H); 3.02 (m, 4H); 1.60-1.20 (m, 14H);
1.00-0.70 (m, 6H).
Preparation of Examples AP and AO
##STR00213##
[0689] Compound 13e
[0690] Compound 13e (1.39 g) was prepared following the same
procedure used to prepare Compound 71, with the exception that
Compound 12e (1.53 g, 3.97 mmol) was used instead of Compound 70
m/z: 372.0 (M+H).sup.+.
Example AP
[0691] Example AP (87 mg) was prepared following the same procedure
used to prepare Example AH, with the exception that Compound 13e
(71 mg, 0.19 mmol) was used instead of Compound 71, and Compound 79
(50 mg, 0.18 mmol) was used instead of Compound 8. m/z: 639.2
(M+H).sup.-.
Compound AO
[0692] Example AQ (61 mg, 76%) was prepared following the same
procedure used to prepare Example AI, with the exception that
Example AP (87 mg, 0.14 mmol) was used instead of Example AH. m/z:
583.2 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .delta. 8.81 (s, 1H);
7.87 (s, 1H); 7.01 (s, 1H); 6.87 (m, 1H); 6.52 (s, 1H); 5.28 (m,
2H); 4.47 (m, 1H); 4.59, 4.43 (d.sub.AB, J=16 Hz, 2H); 4.45 (m,
1H); 4.17 (br s, 1H); 3.75 (br s, 1H); 3.52 (br s, 1H); 3.35 (br s,
1H); 3.01 (m, 3H); 2.07 (br s, 1H); 1.60-1.10 (m, 17H); 1.00-0.70
(m, 6H).
Preparation of Example AR
##STR00214##
[0693] Compound 80
[0694] Compound 80 is commercially available from Chem Impex
International, and was used without further purification.
Compound 81
[0695] Compound 80 (2.0 g, 11.0 mmol) was dissolved in
CH.sub.2Cl.sub.2 (170 mL) and 1,1-carbonyldiimidazole (1.78 g, 11.0
mmol) was added, followed by iPr.sub.2NEt (7.83 mL, 43.8 mmol). The
solution was allowed to stir at 25.degree. C. for 12 hours.
Compound 9 (1.86 g, 11.0 mmol) was dissolved in 20 mL of
CH.sub.2Cl.sub.2 and added to the reaction mixture. The solution
was stirred at 25.degree. C. for 12 hours. The solvent was removed
in vacuo and the residue was diluted with ethyl acetate and washed
water and brine. The organic layers were dried over
Na.sub.2SO.sub.4, filtered, and evaporated. Purification by
Combiflash.RTM. (stationary phase: silica gel; eluent: 66-100%
EtOAc/Hexane gradient) gave Compound 81 (0.252 mg). m/z: 343.0
(M+H).sup.+.
Compound 82
[0696] Compound 82 (0.252 g, 0.74 mmol) was dissolved in THF (4 mL)
and 1M aqueous LiOH (1.48 mL) was added. The mixture was stirred at
25.degree. C. for 3 hours. The reaction was quenched with 1M HCl (2
mL) and the mixture was adjusted to pH 2. The mixture was extracted
with ethyl acetate. The organic layers were dried over
Na.sub.2SO.sub.4, filtered, and evaporated to afford Compound 82
(0.18 g). This material was used in the next step without further
purification. m/z: 329.1 (M+H).sup.+.
Example AR
[0697] Compound 82 (182 mg, 0.55 mmol) was dissolved in THF (7.15
mL). Compound 46 (225 mg, 0.55 mmol) was added, followed by HOBt
(112 mg, 0.83 mmol), iPr.sub.2NEt (393 .mu.L, 2.20 mmol), and EDC
(194 .mu.L, 1.10 mmol). The mixture was stirred at 25.degree. C.
for 12 hours. The solvent was removed under reduced pressure. The
residue was diluted ethyl acetate and washed sequentially with
saturated aqueous Na.sub.2CO.sub.3, water, and brine. The organic
phase was dried over Na.sub.2SO.sub.4, filtered, and evaporated.
Purification by flash column chromatography (stationary phase:
silica gel; eluent: 5-10% MeOH/CH.sub.2Cl.sub.2 gradient) gave
Example AR (208 mg, 53%). m/z: 720.2 (M+H).sup.+. .sup.1H NMR
(CDCl.sub.3) .delta. 8.80 (s, 1H); 7.84 (s, 1H); 7.40-7.00 (m,
10H); 6.97 (s, 1H); 6.83 (m, 1H); 6.65 (br s, 1H); 5.99 (m, 1H);
5.40-5.10 (m, 4H); 4.52 (m, 3H); 4.06 (m, 1H); 3.79 (m, 1H); 3.34
(m, 1H); 2.97 (s, 3H); 2.90-2.60 (m, 5H); 2.50-2.40 (br s, 1H);
1.80-1.20 (m, 10H).
Preparation of Example AS
##STR00215##
[0698] Compound 85a
[0699] Compound 85a was prepared following the same procedure as
Compound 4, except that 4-chloromethylthiazole (purchased from TCI
America) was used instead of Compound 3, and methylamine was used
instead of isopropylamine.
Compound 83
[0700] To compound 85a (0.40 g, 3.12 mmol) in CH.sub.2Cl.sub.2 (9
mL) was added N,N-diisopropylethylamine (1.04 mL, 5.85 mmol),
followed by Compound 5 (280 .mu.L, 1.95 mmol). The reaction mixture
was stirred for 3.5 hours at 25.degree. C. Solvent was removed
under reduced pressure. Purification by Combiflash.RTM. (stationary
phase: silica gel; eluent: 90-100% EtOAc/Hexane gradient) gave
Compound 83 (0.51 g). m/z: 286.0 (M+H).sup.+.
Compound 84
[0701] Compound 83 (0.51 g, 1.77 mmol) was dissolved in THF (10 mL)
and 1M aqueous LiOH (3.54 mL) was added. The mixture was stirred at
25.degree. C. for 2 hours. The reaction was quenched with 1M HCl
(4.8 mL) and the mixture was adjusted to pH 2. The mixture was
extracted with ethyl acetate. The organic layers were dried over
Na.sub.2SO.sub.4, filtered, and evaporated to afford Compound 84
(0.430 g). This material was used in the next step without further
purification. m/z: 272.0 (M+H).sup.+.
Example AS
[0702] Compound 84 (150 mg, 0.55 mmol) was dissolved in THF (7.15
mL). Compound 8 (225 mg, 0.55 mmol) was added, followed by HOBt
(112 mg, 0.83 mmol), iPr.sub.2NEt (393 .mu.L, 2.20 mmol), and EDC
(198 .mu.L, 1.11 mmol). The mixture was stirred at 25.degree. C.
for 12 hours. The solvent was removed under reduced pressure. The
residue was diluted ethyl acetate and washed sequentially with
saturated aqueous Na.sub.2CO.sub.3, water, and brine. The organic
phase was dried over Na.sub.2SO.sub.4, filtered, and evaporated.
Purification by flash column chromatography (stationary phase:
silica gel; eluent: 7% i-PrOH/CH.sub.2Cl.sub.2) gave Example AS
(219 mg, 60%). m/z: 663.1 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3)
.delta. 8.87 (s, 1H); 8.76 (s, 1H); 7.84 (s, 1H); 7.40-7.00 (m,
10H); 6.22 (br s, 1H); 5.73 (br s, 1H); 5.22 (m, 2H); 4.50 (m, 2H);
4.16 (br s, 1H); 4.05 (br s, 1H); 3.75 (m, 1H); 2.93 (s, 3H);
2.90-2.60 (m, 5H); 2.90 (m, 1H); 2.31 (m, 1H); 1.60-1.30 (m, 4H);
1.00-0.80 (m, 6H).
Preparation of Example AT
##STR00216##
[0703] Compound 87
[0704] Compound 87 (386 mg) was prepared from Compound 86 following
the same procedure used to prepare Compound 7 from Compound 6,
except that Compound 68 was used was used instead of Compound 4.
m/z 286.0 (M+H).sup.+
Preparation of Example AU
##STR00217##
[0705] Compound 85b
[0706] Compound 85b was prepared following the same procedure as
Compound 4, except that 4-chloromethylthiazole (obtained from TCI
America) was used instead of Compound 3.
Compound 88
[0707] Compound 88 (341 mg) was prepared following the same
procedure used to prepare Compound 83, with the exception that
Compound 85b (300 mg, 1.95 mmol) was used instead of Compound 85a.
m/z: 312.0 (M+H).sup.+.
Compound 89
[0708] Compound 89 (341 mg) was prepared following the same
procedure for 84, with the exception that Compound 88 (293 mg, 0.99
mmol) was used instead of Compound 83. m/z: 298.0 (M+H).sup.+.
Example AU
[0709] Example AU (226 mg, 64%) was prepared following the same
procedure used to prepare Example AS, with the exception that
Compound 89 (150 mg, 0.51 mmol) was used instead of Compound 84.
m/z: 689.1 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .delta. 8.87 (s,
1H); 8.74 (s, 1H); 7.83 (s, 1H); 7.40-7.00 (m, 10H); 6.21 (m, 1H);
5.73 (m, 1H); 5.29 (m, 1H); 5.17 (m, 2H); 4.88 (d, J=16 Hz, 1H);
4.47 (d, J=16 Hz, 1H); 4.18 (m, 1H); 3.75 (br s, 1H); 2.90-2.60 (m,
6H); 2.51 (br s, 1H); 2.31 (m, 1H); 1.60-1.30 (m, 4H); 1.00-0.80
(m, 10H).
Preparation of Example AV
##STR00218##
[0710] Compound 90
[0711] Compound 90 (190 mg) was prepared following the procedure
used to prepare Compound 4, except that
4-(chloromethyl)-2-methylthiazole was used instead of Compound 3.
m/z 141.1 (M-H)
Compound 91
[0712] Compound 91 (400 mg) was prepared following the same
procedure used to prepare Compound 6 except that Compound 90 was
used instead of Compound 4. m/z 300.0 (M+H).sup.+
Compound 92
[0713] Compound 92 (188 mg) was prepared following the same
procedure as Compound 7 except that Compound 91 was used instead of
Compound 6. m/z 284.0 (M-H).sup.-
Example AV
[0714] Example AV (107 mg) was prepared following the procedure
used to prepare Example C, except Compound 92 was used instead of
Compound 7. .sup.1H NMR (CDCl.sub.3) .delta. 8.76 (s, 1H), 7.78 (s,
1H), 7.27-7.07 (m, 10H), 6.93 (s, 1H), 6.25 (m, 2H), 5.39 (m, 1H),
5.19 (m, 2H), 4.37-4.32 (m, 2H), 4.06 (m, 1H), 3.81 (br s, 1H),
2.83 (m, 4H), 2.65 (br s, 7H), 2.28-2.22 (m, 1H), 1.51-1.37 (m,
4H), 0.82 (m, 6H): m/z 677.2 (M+H).sup.+
Preparation of Example AW
##STR00219##
[0715] Compound 93
[0716] Compound 93 is commercially available from TCI, and was used
without further purification.
Compound 94
[0717] To a solution of Compound 93 (500 mg, 3.76 mmol) in methanol
(20 mL) was added thionyl chloride (0.5 mL, 6.6 mmol) dropwise. The
mixture was stirred at 60.degree. C. for 20 minutes, and
concentrated in vacuo to gave Compound 94.
Compound 95
[0718] To a stirred solution of Compound 94 (3.7 mmol) and
diisopropylethylamine (1.4 mL, 8.3 mmol) in dichloromethane (50 mL)
was added CDI (609 mg, 3.7 mmol). The mixture was stirred for 12
hours. Compound 9 was added, and the mixture was stirred for 12
additional hours. Concentration and purification by flash column
chromatography (0-100%: EtOAc/hexane) gave Compound 95 (100 mg).
m/z 344.3 (M+H).sup.+
Compound 96
[0719] Compound 96 (39 mg) was prepared following the same
procedure used to prepare Compound 7 except that Compound 95 was
used instead of Compound 6. m/z 328.3 (M-H).sup.-
Example AW
[0720] Example AW (107 mg) was prepared following the procedure for
Example C, except that Compound 96 was used instead of Compound 7.
.sup.1H NMR (CDCl.sub.3) .delta. 8.79 (s, 1H), 7.82 (s, 1H),
7.27-7.09 (m, 10H), 6.95 (s, 1H), 6.23 (m, 1H), 6.14 (s, 1H), 5.22
(s, 3H), 4.45 (m, 2H), 4.35-4.0 (m, 3H), 3.8 (m, 1H), 3.6 (m, 1H),
3.25 (s, 3H), 3.21 (m, 2H), 2.95 (s, 3H), 2.8-2.6 (m, 4H), 2.0-1.4
(m, 4H), 1.25 (m, 4H), 1.05 (m, 4H): m/z 721.3 (M+H).sup.+
Preparation of Examples AX and AY
##STR00220##
[0721] Example AX
[0722] To a solution of Example I (650 mg, 1.00 mmol) in DMSO (3.5
mL) was added triethylamine (0.5 mL). The mixture was stirred for
30 minutes. Pyridine SO.sub.3 was added to the mixture at 5.degree.
C. then stirred for 60 minutes. The mixture was poured on to
ice-water, then stirred for 30 minutes. The mixture was diluted
with EtOAc and washed with water, sat. NaHCO.sub.3, and brine.
Concentration gave Example AX. m/z 705.2 (M+H).sup.+
Example AY
[0723] To a stirred solution of Example AX (70 mg, 0.099 mmol) and
methylamine (1.5 mL, 2M) in MeOH (1.5 mL) was added AcOH (119 mg,
1.99 mmol). The mixture was stirred for 2 hours. NaBH(OAc).sub.3
(94 mg) was added, and the mixture was stirred for 2 hours.
Concentration and purification by prep. HPLC gave Example AY (30
mg). .sup.1H NMR (CDCl.sub.3) .delta. 8.79 (s, 1H), 7.82 (s, 1H),
7.27-7.09 (m, 10H), 6.95 (s, 1H), 6.23 (m, 1H), 6.14 (s, 1H), 5.22
(s, 2H), 4.45 (m, 1H), 4.35-4.0 (m, 4H), 3.8 (m, 1H), 3.6 (m, 1H),
3.21 (m, 1H), 2.95 (s, 3H), 2.93 (s, 3H), 2.8-2.6 (m, 4H), 2.0-1.4
(m, 4H), 1.25 (m, 4H), 1.05 (m, 4H): m/z 720.3 (M+H).sup.+
Preparation of Example AZ
##STR00221##
[0724] Example AZ
[0725] Compound AZ (61 mg) was prepared following the procedure for
Example C, except that Compound 87 was used instead of Compound 7
and Compound 79 was used instead of Compound 8. .sup.1H NMR
(CDCl.sub.3) .delta. 8.77 (s, 1H), 8.72 (s, 1H), 7.78 (s, 1H), 7.71
(s, 1H), 6.23 (d, 1H), 5.28-5.24 (m, 2H), 4.85 (d, 1H), 4.71-4.57
(m, 2H), 4.08-4.03 (m, 1H), 3.78 (br s, 1H), 3.51 (br s, 1H), 2.87
(s, 3H), 2.33 (br s, 1H), 2.13-2.06 (m, 1H), 1.49-1.33 (m, 8H),
0.93-0.80 (m, 12H): m/z 539.2 (M+H).sup.+
Preparation of Examples BA and BB
##STR00222##
[0726] Compound 97
[0727] Compound 97 is commercially available from TCI, and was used
as received.
Compound 98
[0728] To a stirred solution of Compound 97 (1 g, 2.2 mmol) and
diisopropylethylamine (1.6 mL, 8.9 mmol) in dichloromethane (26 mL)
was added CDI (362 mg, 2.2 mmol). The mixture was stirred for 12
hours. Compound 9 was added, and the mixture was stirred for 12
additional hours. Concentration and purification by flash column
chromatography (0-8%: MeOH/DCM) gave Compound 98 (1.2 g). m/z 608.1
(M+H).sup.+
Compound 99
[0729] Compound 99 (1.2 g) was prepared following the same
procedure used to prepare Compound 67, with the exception that
Compound 98 was used instead of Compound 66. m/z 592.2
(M-H).sup.-
Example BA
[0730] Example BA (111 mg) was prepared following the procedure
used to prepare Example C, except that Compound 99 was used instead
of Compound 7. m/z 986.1 (M+H).sup.+
Example BB
[0731] To a stirred solution of Example BA (111 mg, 0.113 mmol) and
TFA (1.4 mL) was added Et.sub.3SiH (0.1 mL). The mixture was
stirred for 60 minutes, then concentrated and partitioned with
EtOAc and sat. NaHCO.sub.3, followed by extraction with EtOAc
(2.times.) and drying over Na.sub.2SO.sub.4. Concentration and
purification by flash column chromatography (0-15%: MeOH/DCM) gave
Example BB (50 mg). .sup.1H-NMR (CDCl.sub.3) .delta. 8.75 (s, 1H),
7.79 (s, 1H), 7.42 (s, 1H), 7.22-7.12 (m, 9H), 6.99-6.96 (m, 2H),
6.86 (s, 1H), 6.71 (m, 2H), 5.51 (br s, 1H), 5.17 (m, 2H),
4.57-4.52 (m, 1H), 4.39-4.35 (m, 2H), 4.07 (m, 1H), 3.74 (br s 1H),
3.28-3.19 (m, 1H,), 3.09-2.76 (m, 6H), 3.65-2.58 (m, 3H), 1.49 (m,
2H), 1.36-1.20 (m, 8H); m/z 743.2 (M+H).sup.+
Preparation of Example BC
##STR00223##
[0732] Example BC
[0733] Example BC (95 mg) was prepared following the procedure used
to prepare Example C, except that Compound 29 was used instead of
Compound 7, and Compound 78 was used instead of Compound 8. .sup.1H
NMR (CDCl.sub.3) .delta. 8.75 (s, 1H), 7.80 (s, 1H), 6.93 (s, 1H),
6.28 (d, 1H), 6.18 (m, 1H), 5.26-5.21 (m, 3H), 4.47-4.30 (m, 2H),
4.11-4.00 (m, 1H), 3.91 (br s, 1H), 3.59 (br s, 1H), 3.28 (m, 1H),
2.97-2.90 (m, 3H), 2.26-2.19 (m, 1H), 1.39-1.24 (m, 10H), 1.09-1.01
(m, 6H), 0.94-0.86 (m, 6H): m/z 553.1 (M+H).sup.+
Preparation of Examples BD and BE
##STR00224##
[0734] Example BD
[0735] Example BD (148 mg) was prepared following the procedure
used to prepare Example C, except that Compound 13e was used
instead of Compound 7, and Compound 78 was used instead of amine 8.
m/z 611.1 (M+H).sup.+
Example BE
[0736] Example BD (148 mg, 0.242 mmol) was dissolved in TFA (3 mL)
and allowed to stir at 25.degree. C. for 3 hours. The solvent was
removed under reduced pressure and the residue was diluted with THF
(3 mL) and 2N aqueous NaOH was added until pH 10. The mixture was
allowed to stir for 20 min and extracted with EtOAc. The organic
layer was washed sequentially with water and brine, dried over
Na.sub.2SO.sub.4, filtered, and evaporated. Purification by flash
chromatography (0-10% MeOH/CH.sub.2Cl.sub.2) gave Example BE (109
mg). .sup.1H NMR (CDCl.sub.3) .delta. 8.75 (s, 1H), 7.80 (s, 1H),
6.97-6.94 (d, 1H), 6.90 (s, 1H), 6.32 (br s, 1H), 5.26-5.22 (m,
2H), 5.12 (d, 1H), 4.51-4.39 (m, 3H), 4.25-4.22 (m, 2H), 3.87 (br
s, 1H), 3.62 (br s, 1H), 3.27-3.18 (m, 1H), 2.94 (s, 3H), 1.41-1.31
(m, 10H), 1.13-1.00 (m, 9H). m/z: 555.1 (M+H).sup.+.
Preparation of Example BF
##STR00225##
[0737] Compound 100
[0738] Compound 100 was prepared using the same method used to
prepare Compound 122, except that Compound 9 was replaced with
Compound 68 (see Scheme 70).
Compound 101
[0739] Compound 100 (108 mg, 0.423 mmol) was dissolved in THF (2
mL), then 847 .mu.l of 1 M LiOH/H.sub.2O was added. After stirring
overnight, 843 .mu.l of 1 N HCl was added. Concentration gave
Compound 101.
Example BF
[0740] Example BF (24 mg) was prepared following the procedure used
to prepare Example C, except that Compound 101 was used instead of
Compound 7. .sup.1H NMR (CDCl.sub.3) .delta. 8.77 (s, 1H), 8.73 (s,
1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.27-7.10 (m, 10H), 6.55-6.52 (d,
1H), 5.84 (d, 1H), 5.21-5.19 (m, 3H), 4.77-4.53 (m, 2H), 4.39 (br
s, 1H), 4.11-3.99 (m, 2H), 3.81 (br s, 1H), 3.58 (m, 2H), 2.86 (s,
3H), 2.81-1.72 (m, 5H), 2.04 (m, 1H), 1.85 (m, 1H), 1.66-1.37 (m,
6H): m/z 665.2 (M+H).sup.+
Preparation of Example BG
##STR00226##
[0741] Example BG
[0742] Example R (102 mg, 0.137 mmol) was dissolved in THF (2 mL),
then 2 mL of ethyltrifluoroactate was added. Then 1.3 eq of MeI and
excess Cs.sub.2CO.sub.3 were added. After stirring for 1 day, the
mixture was partitioned with EtOAc and sat. Na.sub.2CO.sub.3,
extracted with EtOAc (2.times.), and dried over Na.sub.2SO.sub.4.
Purification by flash chromatography (0-20% MeOH/CH.sub.2Cl.sub.2)
gave Example BG (6.5 mg). .sup.1H NMR (CD.sub.3OD) .delta. 9.94 (s,
1H), 8.27 (s, 1H), 7.73 (s, 1H), 7.30-7.10 (m, 10H), 5.29, 5.17 (d
2H), 4.72 (s, 3H), 4.29 (m, 1H), 4.15 (br s, 1H), 3.83 (br s, 1H),
3.61 (m, 2H), 3.07 (s, 3H), 2.93 (m, 2H), 2.82-2.70 (m, 4H),
2.68-2.58 (m, 2H), 2.42 (s, 3H), 2.05 (m, 2H), 1.70-1.40 (m, 10H).
m/z: 720.2 (M+H).sup.+.
Preparation of Example BH
##STR00227##
[0743] Example BH
[0744] Example BH (78 mg) was prepared following the procedure used
to prepare Example C, except that Compound 87 was used instead of
Compound 7, and Compound 46 was used instead of Compound 8. .sup.1H
NMR (CDCl.sub.3) .delta. 8.73 (s, 1H), 8.68 (s, 1H), 7.76 (s, 1H),
7.68 (s, 1H), 7.18-7.09 (m, 10H), 6.26 (m, 1H), 5.76 (m, 1H),
5.22-5.18 (m, 4H), 4.71-4.65 (d, 1H), 4.46-4.40 (d, 1H), 4.11-4.04
(m, 2H), 3.81 (br s, 1H), 3.14 (br s, 1H), 2.83 (s, 3H), 2.76-2.52
(m, 4H), 1.88 (m, 1H), 1.51-1.37 (m, 2H), 0.73-0.69 (m, 6H) m/z
663.2 (M+H).sup.+
Preparation of Examples BI and BT
##STR00228##
[0745] Example BI
[0746] Example BI (1.78 g) was prepared following the procedure
used to prepare
[0747] Example C, except that Compound 99 was used instead of
Compound 7, and Compound 46 was used instead of Compound 8. m/z
986.1 (M+H).sup.+
Example BJ
[0748] Example BJ (728 mg) was prepared following the procedure
used to prepare Example BB, except that Example BI was used instead
of Example BA. .sup.1H-NMR (CDCl3) .delta. 8.75 (s, 1H), 7.79 (s,
1H), 7.42 (s, 1H), 7.22-7.12 (m, 9H), 6.99-6.96 (m, 2H), 6.86 (s,
1H), 6.71 (m, 2H), 5.51 (br s, 1H), 5.17 (m, 2H), 4.57-4.52 (m,
1H), 4.39-4.35 (m, 2H), 4.07 (m, 1H), 3.74 (br s 1H), 3.28-3.19 (m,
1H,), 3.09-2.76 (m, 6H), 3.65-2.58 (m, 3H), 1.49 (m, 2H), 1.36-1.20
(m, 8H); m/z 743.2 (M+H).sup.+
Preparation of Compounds 104-115
##STR00229##
[0749] Compound 102
[0750] Compound 102 is commercially available from Aldrich Chemical
Co., and was used without further purification.
Compound 103
[0751] Compound 102 (5.5 mmol) was suspended in MeCN (55 mL) and
DIPEA (8.25 mmol) was added. Carbonyl diimidazole (5.5 mmol) was
diluted in MeCN (20 mL) and the solution added slowly to the
reaction mixture over 45 min. The resulting mixture was allowed to
age overnight. Compound 9 (5.5 mmol) was diluted in MeCN (10 mL)
and treated with DIPEA (8.25 mmol) before being added to the
reaction mixture, which was then allowed to age overnight. The
volatiles were removed in vacuo and the residue taken up in EtOAc
(50 mL) and washed with 1M HCl (50 mL). The layers were separated
and the aqueous layer extracted with EtOAc (3.times.50 mL). The
combined organic layers were washed with sat. Na.sub.2CO.sub.3
until the pH of the washes was .about.pH 8. A brine wash (30 mL)
was followed by drying over anhydrous MgSO.sub.4. Following
concentration in vacuo, the residue was purified on SiO.sub.2
(0-65% EtOAc/hex) to provide 0.340 g (20%) of Compound 103 as an
amorphous white solid (m/z 314.0 (M+H).sup.+).
Compound 104
[0752] Compound 103 (1.1 mmol) was diluted in THF (5 mL) and
treated with freshly prepared 1M LiOH (2.2 mmol). The biphasic
reaction was stirred vigorously for 2 h before being quenched with
1M HCl (3 mmol). The reaction was extracted with EtOAc (5.times.15
mL) and the combined organics were washed with brine (30 mL), dried
over anhydrous Na.sub.2SO.sub.4 and concentrated to provide 0.282 g
(86%) of Compound 104 as an amorphous white powder that was used
with further purification .sup.1H-NMR (CDCl.sub.3, 300 MHz): 7.06
(s, 1H); 4.37 (s, 1H); 3.28 (p, J=6.9 Hz, 1H); 3.00 (s, 3H); 1.62
(s, 6H); 1.39 (d, J=6.9 Hz, 6H).
##STR00230##
Compound 105
[0753] Compound 105 is commercially available from Aldrich Chemical
Co., and was used without further purification.
Compound 106
[0754] Racemic Compound 105 (12.2 mmol) was diluted in MeOH (100
mL). HCl/dioxane solution (4M, 25 mmol) was added and the solution
was refluxed overnight. Volatiles were removed in vacuo to produce
2.60 g (97%) of Compound 106 as a racemic mixture. The foamy white
solid was used without further purification (m/z 147.0
(M+H).sup.+).
Compound 107
[0755] Compound 106 (5 mmol) was diluted in MeCN (65 mL) and
treated with DIPEA (25 mmol). The resulting solution was added
slowly via addition funnel to a solution of CDI (5 mmol) in MeCN
(30 mL) and allowed to age overnight. Compound 9 (5 mmol) and DIPEA
(3 mmol) were added to the reaction solution which was allowed to
age overnight. The volatiles were removed in vacuo and the residue
was taken up in EtOAc and sat. Na.sub.2CO.sub.3 (30 mL each). The
aqueous layer was extracted with EtOAc (3.times.25 mL) and the
combined organics were washed with brine (50 mL) and dried over
anhydrous MgSO.sub.4. Following concentration in vacuo,
purification by column chromatography on SiO.sub.2 (0-10% MeOH/DCM)
provided 0.36 g (21%) of racemic Compound 107 as a yellow oil (m/z
343.1 (M+H).sup.+).
Compound 108
[0756] Compound 107 (1.05 mmol) was taken up in THF (5 mL) and
treated with freshly prepared 1M LiOH solution (2.1 mmol). The
solution was stirred vigorously for 2 h and quenched with 1M HCl
(2.1 mmol). The volatiles were removed in vacuo, and the resulting
oil was azeotroped with toluene until a quantitative yield of
racemic Compound 108 was produced as an amorphous white solid that
was used without further purification (m/z 329.1 (M+H).sup.+).
##STR00231##
Compound 109
[0757] Compound 109 is commercially available from Bachem, and was
used as received.
Compound 110
[0758] Compound 109 (4.1 mmol) was diluted in DCM (5 mL) and
treated with N-methylmorpholine (8.2 mmol). This solution was added
slowly to a DCM (5 mL) solution of 4-nitrophenyl chloroformate (4.1
mmol) at 0.degree. C. The reaction was then allowed to warm to room
temperature overnight. The volatiles were removed in vacuo and the
residue was taken up in EtOAc and sat. Na.sub.2CO.sub.3. The
aqueous layer was extracted with EtOAc (3.times.10 mL) and the
combined organics were washed with brine (30 mL) prior to being
dried over anhydrous Na.sub.2SO.sub.4. Following concentration in
vacuo, the residue was purified by column chromatography on
SiO.sub.2 (0-25% EtOAc/Hex) to produce 0.75 g (51%) of Compound 110
as an amorphous white solid (m/z 354.8 (M+H).sup.+).
Compound 111
[0759] Compound 110 (1.1 mmol) was diluted in THF (3.5 mL).
Compound 9 (1.4 mmol) was diluted in THF (3 mL), treated with
Et.sub.3N (2.8 mmol) and transferred to the reaction solution. DMAP
(0.11 mmol) was added and the reaction was heated to 70.degree. C.
for 2 h. After cooling to room temperature, EtOAc (10 mL) and sat.
Na.sub.2CO.sub.3 were added. The aqueous phase was extracted with
EtOAc (3.times.10 mL) and the combined organics were washed with
saturated Na.sub.2CO.sub.3, H.sub.2O, and brine (15 mL each). After
drying over anhydrous MgSO.sub.4, volatiles were removed in vacuo
and the residue was purified by column chromatography on SiO.sub.2
(0-50% EA/hex) to produce 0.346 g (82%) of Compound III (m/z 386.0
(M+H).sup.+).
Compound 112
[0760] Compound III (0.88 mmol) was taken up in THF (4 mL) and
treated with freshly prepared 1M LiOH (1.8 mmol). The reaction
mixture was stirred vigorously for 1.5 h and quenched with 1M HCl
(2.5 mmol). The reaction mixture was extracted with EtOAc
(3.times.10 mL), and the combined organics were washed with brine
(30 mL) and dried over anhydrous Na.sub.2SO.sub.4. Concentration in
vacuo produced 0.300 g (92%) of Compound 112 as a colorless film
that was used without further purification (m/z 372.0
(M+H).sup.+).
##STR00232##
Compound 113
[0761] Compound 113 is commercially available from Chem-Impex, and
was used without further purification.
Compound 114
[0762] Compound 113 (3.2 mmol) was diluted in THF (15 mL).
TMSCHN.sub.2 (3.2 mmol) was added slowly, followed by MeOH (5 mL).
The solution rapidly became colorless, and heavy evolution of gas
was observed. After aging overnight, the volatiles were removed in
vacuo and the residue purified by column chromatography on
SiO.sub.2 (0-50% EtOAc/hex) to produce 0.805 g (52%) of Compound
114 (m/z 505.2 (M+Na).sup.+).
Compound 115
[0763] Compound 114 (1.7 mmol) was diluted in DMF (4 mL) and
piperidine (1 mL) was added. After 30 min, the volatiles were
removed in vacuo and the residue was purified by column
chromatography on SiO.sub.2 (0-5% MeOH/DCM) to provide 0.414 (94%)
of Compound 115 as an amorphous white solid (m/z 261.0
(M+H).sup.+).
Preparation of Example BK
##STR00233##
[0764] Compound BK
[0765] Compound 79 (0.70 mmol) and Compound 29 (0.91 mmol) were
combined in THF (7 mL). HOBt (0.91 mmol), DIPEA (1.05 mmol) and EDC
(0.91 mmol) were added consecutively at room temperature and the
reaction was allowed to age overnight. The volatiles were removed
in vacuo and the residue taken up in 3/1 CHCl.sub.3/IPA and sat.
Na.sub.2CO.sub.3 (15 mL each). The aqueous layer was extracted with
3/1 CHCl.sub.3/IPA (3.times.10 mL) and the combined organics were
washed with sat. Na.sub.2CO.sub.3, water, and brine (15 mL each).
Following drying over anhydrous MgSO.sub.4, the volatiles were
removed in vacuo and the residue was purified by column
chromatography on SiO.sub.2 (0-10% MeOH/DCM) to produce 8.5 mg (2%)
of Compound BK m/z 581.2 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3, 300
MHz): 8.91 (s, 1H); 7.89 (s, 1H); 7.15 (s, 1H); 6.52-6.0 (br m,
2H); 5.26 (s, 2H); 5.18 (br d, J=8.1 Hz, 1H); 4.55 (s, 2H); 4.06
(br s, 1H); 3.79 (br s, 1H); 3.48 (m, 2H); 3.09 (s, 3H, minor
rotamer); 3.01 (s, 3H, major rotamer); 2.34 (m, 1H); 1.60-1.30 (m,
8H); 1.42 (d, J=6.9 Hz, 6H); 0.98 (t, J=7.2 Hz, 6H); 0.86 (m,
6H).
Preparation of Example BL
##STR00234##
[0766] Example BL
[0767] Example BL was prepared in a similar fashion to Example BK
using Compound 104 (0.26 mmol) and Compound 8 (0.29 mmol) to
produce 0.087 g (64%) of Example BL as an amorphous white solid m/z
691.3 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3, 300 MHz): 8.82 (s, 1H);
7.82 (s, 1H); 7.30-7.10 (m, 11H); 7.06 (s, 1H); 6.54 (d, J=9.6 Hz,
1H); 5.89 (d, J=8.4 Hz, 1H); 5.22 (s, 1H); 5.07 (m, 1H); 4.45 (AB
d, J=16.5 Hz, 1H); 4.37 (AB d, J=15.6 Hz, 1H); 4.07 (m, 1H); 3.68
(m, 1H); 3.40 (m, 1H); 3.06 (s, 3H, minor rotamer); 2.89 (s, 3H,
major rotamer); 2.90-2.54 (m, 4H); 1.60-1.25 (m, 16H).
Preparation of Example BMa and BMb
##STR00235##
[0768] Examples BMa and BMb
[0769] Examples BMa and BMb were prepared in a similar fashion to
Compound BK using racemic Compound 108 (0.36 mmol) and Compound 8
(0.28 mmol). The enantiomeric products were separated by
preparatory HPLC (Chiralcel OD-H (250.times.4.6 mm, 70:30
Heptane/IPA, 30 min) to produce 0.008 g (4%) of enantiomer BMa
(HPLC R.sub.T=11.71 min) m/z 720.3 (M+H).sup.+; .sup.1H-NMR
(CDCl.sub.3, 300 MHz): 8.73 (s, 1H); 7.78 (s, 1H); 7.41 (br s, 1H);
7.30-7.00 (m, 11H); 6.94 (s, 1H); 5.40 (br s, 1H); 5.18 (br s, 2H);
4.56 (AB d, J=15 Hz, 1H); 4.48 (AB d, J=16 Hz, 1H); 4.39 (br s,
1H); 4.05 (br s, 1H); 3.73 (br s, 1H); 3.25 (s, 3H, minor rotamer);
3.23 (m, 1H); 2.98 (s, 3H, major rotamer); 2.82-2.30 (m, 10H);
1.60-1.20 (m, 6H); 1.32 (d, J=7 Hz, 6H) and 0.010 g (5%) of
enantiomer BMb (HPLC R.sub.T=15.41 min). (m/z 720.3 (M+H).sup.+;
.sup.1H-NMR (CDCl.sub.3, 300 MHz): 8.78 (s, 1H); 7.83 (s, 1H); 7.38
(br d, J=8 Hz, 1H); 7.30-7.7.05 (m, 11H); 7.02 (s, 1H); 5.52 (d,
J=9 Hz, 1H); 5.25 (AB d, J=13 Hz, 1H); 5.21 (AB d, J=13 Hz, 1H);
4.85-4.62 (m, 2H); 4.44 (d, J=16 Hz, 1H); 3.99 (br s, 1H); 3.78 (br
s, 1H); 3.37 (br s, 3H, minor rotamer); 3.26 (m, 1H); 3.07 (s, 3H,
major rotamer); 2.77 (s, 6H); 2.86-2.60 (m, 4H); 1.6-1.3 (m, 6H);
1.35 (d, J=7 Hz, 6H).
Preparation of Examples BN and BO
##STR00236##
[0770] Example BN
[0771] Example BN was prepared in a similar fashion to Example BK
using Compound 112 (0.78 mmol) and Compound 8 (0.60 mmol) to
produce 0.227 g (50%) of Compound BN as colorless film. (m/z 763.3
(M+H).sup.+).
Example BO
Example BO was prepared in a similar fashion to Example AM
using
[0772] Example BN (0.29 mmol) to produce 0.149 g (72%) of Example
BO as an amorphous white solid. (m/z 707.3 (M+H).sup.+; .sup.1H-NMR
(CDCl.sub.3, 300 MHz): 8.82 (s, 1H); 7.84 (s, 1H); 7.26-7.03 (m,
11H); 6.99 (s, 1H); 6.69 (d, J=9.6, 1H); 6.42 (br s, 1H); 5.47 (br
d, J=8.7 Hz, 1H); 5.27 (AB d, J=13 Hz, 1H); 5.22 (AB d, J=13 Hz,
1H); 4.55 (AB d, J=16 Hz, 1H); 4.43 (AB d, J=16 Hz, 1H); 4.18 (m,
1H); 4.00 (m, 2H); 3.72 (hr s, 1H); 2.25 (m, 1H); 2.99 (s, 3H);
2.84-2.60 (m, 3H); 2.54-2.42 (m, 1H); 1.64-1.12 (m, 4H); 1.37 (d,
J=7 Hz, 6H); 1.11 (d, J=6 Hz, 3H).
Preparation of Examples BP-BR
##STR00237##
[0773] Example BP
[0774] Example BP was prepared in a similar fashion to Example BK
using Compound 52 (0.22 mmol) and Compound 78 (0.20 mmol) to
produce 0.091 g (71%) of Example BP as colorless film (m/z 654.2
(M+H).sup.+).
Example BQ
[0775] Example BP (0.14 mmol) was treated with 4M HCl in dioxane (2
mL) to produce a white precipitate within 5 min. The solvents were
removed, and the solid was taken up in MeOH. Concentration in vacuo
afforded 0.083 g (99%) of the HCl salt of Example BQ as a colorless
film (m/z 554.1 (M+H).sup.+; .sup.1H-NMR (CD.sub.3OD, 300 MHz):
10.03 (s, 1H); 8.41 (s, 1H); 7.81 (s, 1H); 5.48 (s, 2H, minor
rotamer); 5.35 (s, 2H, major rotamer); 4.74 (s, 2H); 4.34 (br s,
1H); 3.90 (br s, 1H); 3.78-3.54 (m, 2H); 3.20-2.98 (m, 5H); 2.20
(br s, 1H); 2.07 (br s, 1H); 1.60-1.4 (m, 10H); 1.12 (m, 6H).
Example BR
[0776] Example BQ (0.11 mmol) was taken up in MeOH (1.5 mL).
Formaldehyde (37% in H.sub.2O, 13.4 mmol) was added and aged 10
min. NaHB(OAc).sub.3 (0.324 mmol) was added, and the reaction
mixture was allowed to age at room temperature overnight. More
formaldehyde (13.4 mmol) and NaHB(OAc).sub.3 (0.324 mmol) were
added and allowed to age an additional 6 h at room temperature. The
solvents were removed in vacuo and the product was isolated by
preparatory HPLC to produce 0.058 g (77%) of the TFA salt of
Example BR as an amorphous solid. m/z 582.3 (M+H).sup.+;
.sup.1H-NMR (CD.sub.3OD, 300 MHz): 9.07 (s, 1H); 7.91 (s, 1H); 7.25
(s, 1H); 5.47 (s, 2H, minor rotamer); 5.28 (s, 2H, major rotamer);
4.59 (AB d, J=16 Hz, 1H); 4.53 (AB d, J=16 Hz, 1H); 4.31 (dd,
J=9.2, 5 Hz, 1H); 3.88 (m, 1H); 3.59 (m, 1H); 3.32 (m, 1H); 3.20
(m, 2H); 2.98 (s, 3H); 2.89 (br s, 6H); 2.23 (m, 1H); 2.00 (m, 1H);
1.44 (m, 4H); 1.37 (d, J=7 Hz, 6H); 1.10 (m, 6H).
Preparation of Examples BS and BT
##STR00238##
[0777] Compound 116
[0778] Compound 116 was prepared in a similar fashion to Compound
75 using Compound 4 (0.76 mmol) and Compound 47 (0.64 mmol) to
produce 0.218 g (90%) of Compound 116 as a foamy white solid (m/z
384.1 (M+H).sup.+).
Example BS
[0779] Example BS was prepared in a similar fashion to Example BK
using Compound 116 (0.28 mmol) and Compound 8 (0.25 mmol) to
produce 0.139 g (72%) of Example BS as a colorless film (m/z 775.3
(M+H).sup.+).
Example BT
[0780] Example BT was prepared in a similar fashion to Example AM
using Example BS (0.18 mmol) to produce 0.080 g (62%) of Example BT
as an amorphous white solid. m/z 719.3 (M+H).sup.+; .sup.1H-NMR
(CDCl.sub.3, 300 MHz): 8.79 (s, 1H); 7.82 (s, 1H); 7.27-7.0 (m,
10H); 6.98-6.82 (m, 1H); 6.85 (s, 1H); 6.44 (br s, 1H); 5.30 (s,
2H, minor rotamer); 5.22 (s, 2H, major rotamer); 5.04 (br s, 1H);
4.62 (AB d, J=15 Hz, 1H); 4.54 (AB d, J=15 Hz, 1H); 4.27 (br s,
1H); 4.11 (br s, 1H); 3.97 (br d, J=10 Hz, 1H); 3.82, br s, 1H);
3.57 (br s, 1H); 3.40-3.10 (m, 2H); 2.80-2.60 (m, 4H); 2.55 (m,
1H); 1.54 (m, 2H); 1.46-1.30 (m, 2H); 1.35 (d, J=7 Hz, 6H);
0.94-0.72 (m, 4H).
Preparation of Examples BU and BV
##STR00239##
[0781] Compound 117
[0782] Compound 117 was prepared in a similar fashion to Compound
13d except that Compound 4 (1.5 mmol) and the L-enantiomer of
Compound 10d (1.15 mmol) were used to ultimately produce 0.328 g
(88%) of Compound 190 as a foamy white solid (m/z 398.1
(M+H).sup.+).
Example BU
[0783] Example BU was prepared in a similar fashion to Example AL
using Compound 117 (0.33 mmol) and Compound 8 (0.30 mmol) to
produce 0.196 g (84%) of Example BU as an amorphous white solid
(m/z 789.3 (M+H).sup.+).
Example BV
[0784] Example BV was prepared in a similar fashion to Example AM
using Example BU (0.29 mmol) to produce 0.140 g (77%) of Example BV
as an amorphous white solid. m/z 733.3 (M+H).sup.+; .sup.1H-NMR
(CDCl.sub.3, 300 MHz): 8.80 (s, 1H); 7.84 (s, 1H); 7.27-7.10 (m,
10H); 6.70-6.10 (m, 1H); 6.86 (s, 1H); 6.20 (br d, J=7 Hz, 1H);
5.24 (s, 2H); 4.81 (br d, J=7 Hz, 1H); 4.82 (s, 2H); 4.34 (br d,
J=7 Hz, 1H); 4.16 (br s, 1H); 4.07 (br d, J=6 Hz, 1H); 3.86 (br s,
1H); 3.38 (br s, 1H); 2.69 (m, 6H); 1.62-1.50 (m, 2H); 1.50-1.34
(m, 2H); 1.38 (m, 6H); 1.13 (d, J=6 Hz, 3H); 0.98-0.76 (m, 4H).
Preparation of Examples BW and BX
##STR00240##
[0785] Example BW
[0786] Example BW was prepared in a similar fashion to Example BK
using Compound 75 (0.27 mmol) and Compound 46 (0.24 mmol) to
provide 0.154 g (86%) of Example BW as an amorphous white solid
(m/z 733.3 (M+H).sup.+).
Example BX
[0787] Example BX was prepared in a similar fashion to Example AM
using Example BW (0.21 mmol) to provide 0.091 g (98%) of the TFA
salt of Example BX as an amorphous white solid. m/z 677.5
(M+H).sup.+; .sup.1H-NMR (CDCl.sub.3, 300 MHz): 8.83 (s, 1H); 8.77
(s, 1H); 7.84 (s, 1H); 7.77 (s, 1H); 7.27-7.00 (m, 10H); 6.62 (d,
J=9 Hz, 1H); 6.44 (d, J=6 Hz, 1H); 5.35 (d, J=10 Hz, 1H); 5.24 (s,
2H); 4.69 (AB d, J=15 Hz, 1H); 4.62 (AB d, J=16 Hz, 1H); 4.14 (br
m, 2H); 3.96-3.78 (m, 2H); 3.51 (dd, J=11, 4.5 Hz, 1H); 3.38 (br s,
1H); 2.82-2.58 (m, 4H); 2.41 (m, 1H); 1.70-1.24 (m, 4H); 1.20-0.88
(m, 2H); 0.88-0.54 (m, 2H).
Preparation of Examples BY and BZ
##STR00241##
[0788] Compound 118
[0789] Compound 118 was prepared in a similar fashion to Compound
104 except that Compound 115 (0.40 mmol) was used instead of
Compound 102, which was reacted with Compound 9 (0.48 mmol) to
ultimately provide 0.075 g (89%) of Compound 118 as a foamy white
solid (m/z 443.4 (M+H).sup.+).
Example BY
[0790] Example BY was prepared in a similar fashion to Example BM
using Compound 118 (0.17 mmol) and Compound 8 (0.15 mmol) to
produce 0.079 g (62%) of Example BY as an amorphous white solid
(m/z 834.3 (M+H).sup.+).
Example BZ
[0791] Example BZ was prepared in a similar fashion to Example BQ
using Example BY (0.095 mmol) to provide 0.082 g (99%) of the HCl
salt of Example BZ as an amorphous white solid m/z 734.2
(M+H).sup.+; .sup.1H-NMR (DMSO-d.sub.6, 300 MHz): 8.08 (s, 1H);
7.86 (br m, 3H); 7.58 (d, J=9 Hz, 1H); 7.25-7.00 (m, 11H); 6.32 (br
s, 1H); 5.16 (s, 2H); 4.99 (br m, 4H); 4.48 (AB d, J=15 Hz, 1H);
4.43 (AB d, J=15 Hz, 1H); 4.02 (m, 1H); 3.89 (m, 1H); 3.63 (m, 1H);
3.22 (hep, J=7 Hz, 1H); 2.87 (s, 3H); 2.76-2.56 (m, 4H); 1.58-1.15
(m, 10H); 1.29 (d, J=7 Hz, 6H).
Preparation of Example CA
##STR00242##
[0792] Example CA
[0793] Example R (0.11 mmol) was diluted in DCM (1 mL) and treated
with 4-morpholinecarbonyl chloride (0.13 mmol) and DIPEA (0.16
mmol). After 2 h, volatiles were removed in vacuo and the residue
was purified by column chromatography on SiO.sub.2 (0-20% MeOH/DCM)
to afford 0.068 g (76%) of Example CA as an amorphous white solid
m/z 819.1 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3, 300 MHz): 8.82 (s,
1H); 7.85 (s, 1H); 7.27-7.07 (m, 12H); 6.94 (s, 1H); 6.26 (br s,
1H); 5.73 (d, J=8 Hz, 1H); 5.28 (AB d, J=13 Hz, 1H); 5.22 (AB d,
J=13 Hz, 1H); 4.50 (AB d, J=16 Hz, 1H); 4.44 (AB d, J=16 Hz, 1H);
4.17 (m, 1H); 3.98 (br s, 1H) 3.76 (br s, 1H); 3.68 (br s, 1H);
3.60 (m, 4H); 3.40 (m, 2H), 3.32 (m, 4H); 2.97 (s, 3H); 2.87 (dd,
J=13, 5 Hz, 2H); 2.73, (m, 2H); 2.57 (m, 2H); 1.79 (m, 2H);
1.60-1.20 (m, 6H); 1.37 (d, J=7 Hz, 6H).
Preparation of Compound CB
##STR00243##
[0794] Example CB
[0795] Example AF (0.15 mmol) was diluted in THF (1 mL) and treated
with morpholine (0.61 mmol), HOBt (0.18 mmol) and finally EDC (0.18
mmol). The reaction mixture was allowed to age overnight. The
reaction mixture was then diluted in EtOAc and sat.
Na.sub.2CO.sub.3. The aqueous layer was extracted with EtOAc and
the combined organic layers were washed with brine, dried over
anhydrous MgSO.sub.4 and concentrated in vacuo. The resulting
residue was purified via preparatory HPLC to provide 0.024 g (20%)
of Example CB as an amorphous white solid. m/z 790.4 (M+H).sup.+;
.sup.1H-NMR (CDCl.sub.3, 300 MHz): 8.81 (s, 1H); 7.84 (s, 1H);
7.27-7.10 (m, 10H); 6.96 (s, 1H); 6.78 (d, J=8 Hz, 1H); 6.67 (s,
1H); 5.36 (d, J=9 Hz, 1H); 5.27 (AB d, J=13 Hz, 1H); 5.20 (AB d,
J=13 Hz, 1H); 4.59 (s, 1H); 4.51 (s, 2H); 4.02 (m, 1H); 3.80-3.30
(m, 10H); 2.98 (s, 3H); 2.90-2.45 (m, 6H); 1.52 (m, 2H); 1.39 (d,
J=7 Hz, 6H); 1.32 (m, 2H).
Preparation of Compound CC
##STR00244##
[0796] Example CC
[0797] Example CC was prepared in a similar fashion to Example CB
except that N-methylpiperazine (0.16 mmol) was reacted with
Compound AF (0.10 mmol) instead of morpholine and DIPEA (0.19 mmol)
was added to produce 0.009 g (11%) of Example CC as an amorphous
white solid m/z 803.4 (M+H).sup.+; .sup.1H-NMR (CDCl.sub.3, 300
MHz): 8.80 (s, 1H); 7.84 (s, 1H); 7.27-7.10 (m, 11H); 6.91 (s, 1H);
6.78 (m, 2H); 5.27 (AB d, J=13 Hz, 1H); 5.21 (AB d, J=13 Hz, 1H);
4.59 (m, 1H); 4.49 (AB d, J=16 Hz, 4.44 (AB d, J=16 Hz, 1H); 4.01
(m, 1H); 3.90-3.40 (m, 4H); 3.27 (hep, J=7 Hz, 1H); 3.10-2.90 (m,
1H); 2.97 (s, 3H); 2.90-2.30 (m, 11H); 1.60-1.25 (m, 6H); 1.37 (d,
J=7 Hz, 6H).
Preparation of Example CD
##STR00245##
[0798] Example CD
[0799] To a solution of Example R (30.5 mg, 0.043 mmol) in methanol
(1.5 mL) was added formaldehyde (1 mL, 37% in H.sub.2O). After
stirring for 10 minutes, NaBH(OAc).sub.3 (49 mg, 0.23 mmol) was
added and the resulting mixture was stirred for 10 h. The reaction
was monitored with LC/MS. When LC/MS indicated the absence of
starting material Example R, the reaction mixture was evaporated to
dryness, and filtered through a cotton plug. The crude product was
then purified through CombiFlash (10% MeOH/CH.sub.2Cl.sub.2) to
give 29.7 mg of Example CD .sup.1H-NMR (CDCl.sub.3, 500 MHz): 8.78
(s, 1H); 7.83 (s, 1H); 7.12-7.22 (m, 10H); 6.85 (s, 1H); 5.83 (d,
1H, J=8.5 Hz), 5.23 (d.sub.AB, 2H, J=13.1 Hz); 4.49 (d.sub.AB, 2H,
J=16.5 Hz); 4.29 (m, 1H); 4.15 (m, 1H); 3.75 (m, 1H); 3.30 (m, 1H);
2.93 (s, 3H); 2.87 (dd, 1H, J1=5.5 Hz, J2=13.5 Hz); 2.72 (m, 2H);
2.66 (dd, J1=7.3 Hz, J2=13.3 Hz), 2.47 (br s, 1H), 2.36 (br s, 1H),
2.23 (s, 6H), 1.91 (m, 2H), 1.56 (m, 2H), 1.40 (m, 2H), 1.40 (d,
6H, J=6.8 Hz). m/z 734 (M+H).sup.+; 756 (M+Na).sup.+;
Preparation of Example CE
##STR00246##
[0800] Compound 119
[0801] Compound 119 is commercially available from Aldrich, and was
used as received.
Compound 120
[0802] A mixture of Compound 119 (200 mg, 0.91 mmol), Compound 8
(373.7 mg, 0.91 mmol), EDC (212 mg, 1.37 mmol), HOBt (160.3 mg,
1.19 mmol) and iPr.sub.2NEt (794.7 .mu.L, 4.56 mmol) in THF was
stirred for 10 h at room temperature. The mixture was then
evaporated to a small volume and purified by CombiFlash (eluted
with 1 to 10% MeOH/CH.sub.2Cl.sub.2). The fractions containing the
target Compounds were collected and re-purified by CombiFlash
(40-100% EtOAc/hexanes) to give 449 mg of Compound 120 as oil. (m/z
611.0 (M+H).sup.+).
Example CE
[0803] Compound 120 (449 mg, 0.74 mmol) was treated with
HCl/dioxane (3 mL). The resulting mixture was evaporated to dryness
and lyophilized to provide 373.6 mg of a white solid.
[0804] To a solution of the above white compound (52.5 mg, 0.096
mmol) in CH.sub.2Cl.sub.2 (10 mL) was added Compound 9 (19.8 mg,
0.096 mmol), CDI (15.6 mg, 0.096 mmol) followed by iPr.sub.2NEt
(33.4 .mu.L, 0.192 mmol). The mixture was stirred for 20 h before
it was evaporated to dryness. The mixture was added
CH.sub.2Cl.sub.2, then filtered through a cotton plug. The filtrate
was evaporated to dryness and purified with CombiFlash. The
fractions with Example CE was collected and re-purified on the TLC
to give 15.1 mg of Example CE. (CDCl.sub.3, 300 MHz): 8.79 (s, 1H);
7.82 (s, 1H); 7.09-7.27 (m, 10H), 6.94 (s, 1H); 6.25 (d, 2H, J=8.7
Hz); 5.23 (s, 2H); 5.17 (br s, 1H); 4.43 (d.sub.AB, 2H, J=16.5 Hz);
4.29 (m, 1H); 4.13 (m, 1H), 3.76 (m, 2H); 3.48 (m, 1H); 3.29 (s,
3H); 3.25 (m, 1H), 2.94 (s, 3H), 2.65-2.82 (m, 4H), 1.75 (m, 2H),
1.54 (m, 2H), 1.39 (d, 5H, J=6.9 Hz). m/z 707 (M+H).sup.+; 729
(M+Na).sup.+.
Preparation of Example CF
##STR00247##
[0805] Example CF
[0806] Example CF was prepared using the same method as Example CE,
except that Compound 9 was replaced with Compound 68. .sup.1H-NMR
(CDCl.sub.3, 300 MHz): 8.79 (s, 1H); 8.74 (s, 1H), 7.81 (s, 1H),
7.73 (s, 1H); 7.12-7.27 (m, 10H); 6.15 (d, 1H, J=8.7 Hz), 5.39 (d,
1H, J=6.8 Hz); 5.21 (s, 2H), 5.06 (d, J=9.1 Hz, 1H); 4.64
(d.sub.AB, 2H, J=15.5 Hz); 4.28 (m, 1H); 4.134 (m, 1H), 3.79 (m,
1H), 3.70 (m, 1H); 3.34 (m, 1H); 3.28 (s, 3H); 2.87 (s, 3H); 2.72
(m, 4H); 1.57 (m, 2H); 1.50 (m, 2H). (m/z 665.2 (M+H).sup.+; 687.3
(M+Na).sup.+.
Preparation of Compound CG
##STR00248##
[0807] Compound 121
[0808] Compound 121 is commercially available from Aldrich, and was
used as received.
Compound 122
[0809] To a suspension of Compound 121 (2.05 g, 11.3 mmol) in
CH.sub.2Cl.sub.2 (40 mL) was added. iPr.sub.2NEt (5.87 mL, 33.9
mmol) followed by CDI (1.86 g, 11.3 mmol). The resulting mixture
was stirred at room temperature for 6 h, then Compound 9 (2.33 g,
11.3 mmol) was added. The resulting mixture was stirred for another
10 h before it was evaporated to dryness. The mixture was
re-dissolved in CH.sub.2Cl.sub.2 and the solid was removed by
filtration. The filtrate was evaporated to dryness and purified by
CombiFlash (eluted with 20-80% EtOAc/hexanes) to give 3.2 g of
Compound 207 as a pale yellow oil. m/z 298.0 (M+H).sup.+.
Compound 123
[0810] To a solution of Compound 122 (3.2 g, 10.8 mmol) in THF (100
mL) was added freshly prepared 1M LiOH (10.8 mmol). The biphasic
reaction was stirred vigorously at room temperature for 16 h before
being quenched with 1M HCl. The pH of the mixture was adjusted to
2.5-3, and then evaporated to a small volume. The mixture was
partitioned between CH.sub.2Cl.sub.2 and brine (50 mL), the aqueous
layer was separated and extracted with CH.sub.2Cl.sub.2 twice. The
combined CH.sub.2Cl.sub.2 layers were dried over anhydrous
Na.sub.2SO.sub.4 and concentrated to give 3.37 g of Compound 123 a
pale yellow oil that is used with further purification. m/z 316.0
(M+H).sup.+, 338 (M+Na).sup.+;
Example CG
[0811] Example CG was prepared following the same procedure for
Example C instead that Compound 123 was used instead of Compound 7.
.sup.1H-NMR (CDCl.sub.3, 500 MHz): 8.80 (s, 1H); 7.83 (s, 1H),
7.11-7.26 (m, 10H), 6.96 (s, 1H); 7.12-7.27 (m, 10H); 6.52 (br s,
1H), 6.40 (br s, 1H), 5.23 (s, 2H), 5.20 (m, 1H), 4.44 (d.sub.AB,
2H, J=15.5 Hz), 4.39 (m, 1H), 4.11 (m, 1H), 3.80 (m, 1H), 3.61 (m,
2H), 3.28 (sep, 1H, J=7.0 Hz); 2.94 (s, 3H), 2.79 (dd, 1H, J1=6.1
Hz, J2=13.4 Hz); 2.71 (m, 3H), 1.93 (m, 1H), 1.71 (m, 1H), 1.54 (m,
1H), 1.38 (d, 6H, J=7.0 Hz) 1.37 (m, 1H). (:).sup.+; m/z 707.3
(M+H).sup.+), 729.2 (M+Na).sup.+.
Preparation of Compound 100
##STR00249##
[0813] Compound 100 was prepared using the same method used to
prepare Compound 122, except that Compound 9 was replaced with
Compound 68.
Preparation of Example CH
##STR00250## ##STR00251##
[0814] Compounds 124 and 125
[0815] To a solution of Compound 29 (135 mg, 0.43 mmol) and
Compound 22 (116 mg, 0.43 mmol) in THF (5 mL) were added HOBt (70
mg, 0.52 mmol), EDC (94 .mu.L, 0.52 mmol), and
diisopropylethylamine (150 .mu.L, 0.83 mmol). The mixture was
stirred for 12 hours and concentrated. Purification by reverse HPLC
gave Compound 124 (70 mg) and Compound 125 (120 mg). Compound 124:
.sup.1H-NMR (CDCl.sub.3) .delta. 7.2-7.1 (10H, m), 7.0 (2H, s),
6.45 (2H, m), 6.15 (2H, m), 4.45 (4H, s), 4.1 (2H, m), 3.96 (2H,
m), 3.3 (2H, m), 2.98 (6H, s), 2.7 (4H, m), 2.1 (2H, m), 1.6-1.3
(16H, m), 0.90 (12H, m). m/z 859.3 (M+H).sup.+; Compound 125: m/z
564.3 (M+H).sup.+
Compound 126
[0816] To a solution of Compound 125 (120 mg, 0.21 mmol) in
CH.sub.3CN (1 mL) was added 37% formaldehyde solution (17 .mu.L,
0.23 mmol), followed by HOAc (24 .mu.l, 0.42 mmol). The mixture was
stirred for 2 hours, and NaBH(OAc).sub.3 (140 mg, 0.63 mmol) was
added. The mixture was stirred for 2 additional hours and diluted
with EtOAc. The organic phase was washed with saturated
Na.sub.2CO.sub.3 solution, water, and brine, and dried over
Na.sub.2SO.sub.4. Concentration gave Compound 126, which was used
in the next step without further purification. m/z 578.3
(M+H).sup.+
Example CH
[0817] Example CH (26 mg) was prepared following the procedure used
to prepare Example L, except that Compound 126 was used instead of
Compound 22. .sup.1H-NMR (CDCl.sub.3) .delta. 8.91 (1H, m), 7.82
(1H, m), 7.2-7.0 (11H, m), 6.4 (1H, m), 6.2 (1H, m), 5.23-5.05 (2H,
m), 4.44 (2H, s), 4.44 (1H, m), 4.2 (1H, m), 3.95 (1H, m), 3.32
(1H, m), 2.98 (3H, s), 2.8-2.5 (7H, m), 2.15 (1H, m), 1.7-1.2 (10H,
m), 0.88 (6H, m). m/z 719.3 (M+H).sup.+
Preparation of Example CI
##STR00252##
[0818] Compound 127
[0819] Compound 127 (110 mg) was prepared following the procedure
used to prepare Compound 126, except that Compound 8 was used
instead of Compound 125. m/z 424.4 (M+H).sup.+
Example CI
[0820] Example CI (7 mg) was prepared following the procedure used
to prepare Example C, except that Compounds 127 and 29 were used
instead of Compounds 8 and 7. .sup.1H-NMR (CDCl.sub.3) .delta. 9.0
(1H, s), 8.92 (1H, s), 7.4-7.0 (11H, m), 5.25 (2H, m), 4.6-4.0 (5H,
m), 3.4 (1H, m), 3.1-2.6 (10H, m), 1.9 (1H, m), 1.8 (10H, m), 0.9
(6H, m); m/z 719.2 (M+H).sup.+
Preparation of Compound CI
##STR00253##
[0821] Compound 128
[0822] To a solution of Compound 21 (100 mg) in dichloromethane mL)
was added TFA (1 mL). The mixture was stirred for 3 hours, and
excess reagents were evaporated. The oil was diluted with EtOAc,
and then was washed with saturated Na.sub.2CO.sub.3 solution
(2.times.), water (2.times.), and brine, and dried over
Na.sub.2SO.sub.4. Concentration gave Compound 128 (46 mg). m/z
267.1 (M+H).sup.+
Compound 129
[0823] Compound 129 (44 mg) was prepared following the procedure
for Compound 8, except that Compound 128 was used instead of
Compound 22. m/z 408.10 (M+H).sup.+
Example CJ
[0824] Example CJ (55 mg) was prepared following the procedure for
Example C, except that Compounds 129 and 29 were used instead of
Compounds 8 and 7. .sup.1H-NMR (CDCl.sub.3) .delta. 8.81 (1H, s),
7.85 (1H, s), 7.2-7.0 (11H, m), 6.4 (1H, m), 6.12 (1H, m), 5.44
(2H, m), 5.26 (2H, s), 4.85 (1H, m), 4.70 (1H, m), 4.4 (3H, m),
4.06 (1H, m), 3.25 (1H, m), 2.98 (3H, s), 2.78 (4H, m), 2.21 (1H,
m), 1.38 (6H, m), 0.88 (6H, m); m/z 703.2 (M+H).sup.+
Preparation of Compounds CK and CL
##STR00254##
[0825] Example CK
[0826] Example CK (88 mg) was prepared following the procedure used
to prepare Example C, except that Compound 49 was used instead of
Compound 7. m/z 749.2 (M+H).sup.+
Example CL
[0827] A mixture of Example CK (85 mg) and TFA (5 mL) was stirred
for 3 hours. Excess TFA was evaporated and the mixture was dried
under high vacuum. The mixture was dissolved in THF (5 mL), and 1.0
N sodium hydroxide solution was added until the pH was 11. The
solution was stirred for 10 minutes, and extracted with EtOAc. The
organic phase was washed with water, brine, and dried over
Na.sub.2SO.sub.4. Concentration and purification by flash column
chromatography (EtOAc) gave Example CL (66 mg). .sup.1H-NMR (CDCl3)
.delta. 8.81 (1H, s), 7.84 (1H, s), 7.30-6.96 (11H, m), 5.22 (2H,
s), 4.90 (1H, m), 4.45 (1H, m), 4.35-4.0 (4H, m), 3.8 (1H, m), 3.6
(1H, m), 3.21 (1H, m), 2.95 (3H, s), 2.8-2.6 (4H, m), 2.0-1.4 (4H,
m), 1.25 (6H, m). m/z 693.2 (M+H).sup.+.
Preparation of Example CM
##STR00255##
[0828] Compound 130
[0829] Compound 130 is commercially available from (TCI), and was
used as received.
Compound 131
[0830] To the solution of Compound 130 (510 mg, 3 mmol) in methanol
(12 mL) at 0.degree. C. was added thionyl chloride (0.5 mL, 6.6
mmol), dropwise. The mixture was stirred at 0.degree. C. for 30
minutes and brought to reflux for 3 hours. Concentration gave
Compound 131 as a white solid.
Compound 132
[0831] To a stirred solution of Compound 131 (3 mmol) and
diisopropylethylamine (2 mL, 12 mmol) in dichloromethane (35 mL)
was added CDI (486 mg, 3 mmol). The mixture was stirred for 12
hours. Compound 9 was added, and the mixture was stirred for 12
additional hours. Concentration and purification by flash column
chromatography (CH.sub.2Cl.sub.2/iPrOH=10/1) gave Compound 132 (414
mg). m/z 380.0 (M+H).sup.+
Compound 133
[0832] Compound 133 was prepared following the procedure for
Compound 67, except that Compound 132 was used instead of Compound
66. m/z 364.0 (M-H).sup.-
Example CM
[0833] Example CM (600 mg) was prepared following the procedure for
Example C, except Compound 133 was used instead of Compound 7.
.sup.1HNMR (CDCl.sub.3) .delta. 9.18 (1H, s), 8.35 (1H, s), 7.95
(1H, s), 7.6 (1H, m), 7.3-7.0 (11H, m), 5.22 (2H, m), 4.70 (1H, m),
4.50 (2H, m), 4.05 (1H, m), 3.86 (3H, s), 3.80 (2H, m), 3.55 (1H,
m), 3.10 (1H, m), 2.90 (3H, s), 2.70 (4H, m), 1.45 (10H, m); m/z
757.3 (M+H).sup.+
Preparation of Examples O, P, CN, and CO
##STR00256##
[0834] Example O
[0835] Example O (17 mg) was prepared following the procedure for
Example C, except Compounds 46 and 49 were used instead of
Compounds 8 and 7. m/z 749.3 (M+H).sup.+
Example CN
[0836] Example CN (22 mg) was prepared following the procedure used
to prepare Example C, except Compounds 46 and 13e were used instead
of Compounds 8 and 7. m/z 763.2 (M+H).sup.+
Example P
[0837] Example P (12 mg) was prepared following the procedure used
to prepare Example CL, except Example O was used instead of Example
CK. .sup.1H-NMR (CDCl.sub.3) .delta. 8.76 (1H, s), 7.79 (1H, s),
7.25-6.9 (11H, m), 6.51 (1H, broad), 5.42 (1H, m), 5.18 (2H, m),
4.42 (2H, m), 4.22 (1H, m), 4.10 (1H, m), 3.95 (1H, m), 3.79 (1H,
m), 3.58 (1H, m), 3.23 (1H, m), 2.93 (3H, s), 2.9-2.5 (4H, m),
1.6-1.2 (10H, m); m/z: 693.2 (M+H).sup.+.
Compound CO
[0838] Example CO (13 mg) was prepared following the procedure used
to prepare Example CL, except Example CN was used instead of
Compound CK. .sup.1H-NMR (CDCl.sub.3) .delta. 8.85 (1H, m), 7.88
(1H, m), 7.3-7.0 (11H, m), 6.55 (1H, m), 6.24 (1H, m), 5.45 (1H,
m), 5.23 (2H, m), 4.6 (2H, m), 4.2 (1H, m), 4.0 (2H, m), 3.7 (1H,
m), 3.5 (1H, m), 3.02 (3H, s), 2.70 (4H, m), 1.6-1.0 (13H, m); m/z:
707.3 (M+H).sup.+.
Preparation of Examples CP-CS
##STR00257##
[0839] Compound 134
[0840] Compound 134 was prepared using procedure described for
Compound 76, except that CBZ-D-alaminol was used instead of
CBZ-L-alaminol.
Compound 135
[0841] Compound 135 was prepared following the procedure used to
prepare Compound 8, except Compound 134 was used instead of
Compound 22.
Example CP
[0842] Example CP (12 mg) was prepared following the procedure used
to prepare Example C, except Compounds 135 and 49 were used instead
of Compounds 8 and 7. m/z 597.2 (M+H).sup.+.
Example CQ
[0843] Example CQ (11 mg) was prepared following the procedure used
to prepare Example C, except Compounds 135 and 13d were used
instead of Compounds 8 and 7. m/z 611.2 (M+H)--.
Example CR
[0844] Example CR (7 mg) was prepared following the procedure used
to prepare Example P, except that Example CP was used instead of
Example O. .sup.1H-NMR (CDCl.sub.3) .delta. 8.82 (1H, s), 7.88 (1H,
s), 7.02 (1H, s), 6.92 (1H, m), 5.28 (2H, s), 5.10 (1H, m), 4.5
(2H, m), 4.15 (2H, m), 3.88 (1H, m), 3.8-3.5 (2H, m), 3.35 (1H, m),
3.0 (3H, s), 1.5-1.0 (16H, m); m/z: 541.1 (M+H).sup.+.
Example CS
[0845] Example CS (8 mg) was prepared following the procedure used
to prepare Example CO, except that Example CQ was used instead of
Example CN. .sup.1H-NMR (CDCl.sub.3) .delta. 8.83 (1H, s), 7.88
(1H, s), 6.98 (1H, s), 6.81 (1H, m), 6.58 (1H, m), 5.28 (2H, s),
5.18 (1H, m), 4.4-4.3 (2H, m), 4.03 (1H, m), 3.85 (1H, m), 3.58
(2H, m), 3.3 (1H, m), 2.99 (3H, s), 1.5-0.98 (19H, m); m/z: 555.2
(M+H).sup.+.
Preparation of Examples CT-CV
##STR00258##
[0846] Compound 136
[0847] Compounds 136a-c are commercially available
(Sigma-Aldrich).
Compound 137
[0848] To a solution of Compound 136 (20 mmol) in methanol (25 mL)
was added benzaldehyde (40 mmol) dropwise. The mixture was stirred
for 2 hours and was cooled to 0.degree. C. Sodium borohydride (44
mmol) was added in portions. The mixture was warmed to 25.degree.
C. and stirred for 2 hours. Acetic acid (10 mL) was added and the
mixture was stirred for 10 minutes. Methanol was removed and the
mixture was partitioned between EtOAc and 3 N NaOH solution. The
organic layer was separated and water phase was extracted with
EtOAc (2.times.). The combined organic layers was washed with
water, brine, and dried over Na.sub.2SO.sub.4. Concentration gave
Compound 137.
Compound 138
[0849] Compound 138 was prepared following the procedure used to
prepare Compound 8, except that Compound 137 was used instead of
Compound 22.
Example CT
[0850] Example CT (70 mg) was prepared following the procedure used
to prepare Example C, except that Compounds 29 and 138a was used
instead of Compounds 7 and 8. .sup.1H-NMR (CDCl.sub.3) .delta. 8.79
(1H, s), 7.86 (1H, s), 6.97 (1H, s), 6.49 (1H, m), 6.15 (1H, m),
5.28 (2H, s), 5.20 (1H, m), 4.44 (2H, m), 4.05 (1H, m), 3.25 (5H,
m), 3.0 (3H, s), 2.24 (1H, m), 1.8-1.45 (4H, m), 1.38 (6H, m), 0.97
(6H, m); m/z: 525.2 (M+H).sup.+.
Example CU
[0851] Example CU (140 mg) was prepared following the procedure
used to prepare Example C, except that Compounds 29 and 138b was
used instead of Compounds 7 and 8. .sup.1H-NMR (CDCl.sub.3) .delta.
8.78 (1H, s), 7.85 (1H, m), 7.4-7.05 (10H, m), 6.93 (1H, s), 5.90
(1H, m), 5.35 (2H, s), 4.9-4.6 (2H, m), 4.6-4.4 (4H, m), 4.2 (1H,
m), 3.4-3.05 (5H, m), 3.0 (3H, s), 2.0 (1H, m), 1.8-1.3 (10H, m),
0.90 (6H, m); m/z: 705.2 (M+H).sup.+.
Example CV
[0852] Example CV (145 mg) was prepared following the procedure
used to prepare Example C, except that Compounds 29 and 138c was
used instead of Compounds 7 and 8. .sup.1H NMR (CDCl.sub.3) .delta.
8.76 (1H, m), 7.86 (1H, m), 7.4-7.02 (10H, m), 6.97 (1H, m), 5.75
(1H, m), 5.38 (2H, m), 4.95-4.3 (6H, m), 4.15 (1H, m), 3.4-3.0 (5H,
m), 3.0 (3H, s), 2.2-1.6 (3H, m), 1.4 (6H, m), 0.88 (6H, m); m/z:
691.2 (M+H).sup.+.
Preparation of Example CW
##STR00259##
[0854] Example CW could be prepared, e.g. by reacting Compound 8
with a compound having the following structure:
##STR00260##
where "LG" is a leaving group such as a halogen. Such compounds
could be prepared by one-carbon degradation of the corresponding
carboxylic acid or ester (e.g., Compounds 28 or 29) by known
methods such as the Hunsdieker reaction or the Kochi reaction or
similar methods.
Preparation of Example CX
##STR00261##
[0855] Example K
[0856] Example R (hydrochloride salt) was synthesized following the
procedure described in WO 2008/010921 A2 (herein incorporated by
reference in its entirety for all purposes) or as described
above.
Example CX
[0857] To a suspension of Example R (hydrochloride salt) (150 mg,
0.2 mmol) in THF (2 mL) was added diisopropylethylamine (70
.quadrature.l, 0.4 mmol). The mixture was stirred until a clear
solution was obtained. To this solution was added trimethylsilyl
isocyanate (30 .quadrature.l, 0.22 mmol) dropwise, and the mixture
was stirred for 12 hours. The solvent was removed and the mixture
was coevaporated twice with 5 mL of MeOH. Purification with
preparative thin layer chromatography (preparative TLC) gave
Example CX (86 mg). m/z: 749.2 (M+H).sup.+. .sup.1H NMR
(CD.sub.3OD) .delta. 8.99 (s, 1H); 7.83 (s, 1H); 7.72 (m, 1H);
7.30-7.00 (m, 11H); 5.22 (s, 2H); 4.54 (s, 2H); 4.19 (s, 1H); 4.07
(m, 1H); 3.75 (m, 1H); 3.28 (m, 1H); 3.30-2.90 (m, 2H); 2.97 (s,
3H); 2.71 (m, 4H); 1.79 (m, 2H); 1.50 (m, 4H); 1.38 (d, 6H, J=7
Hz).
Preparation of Example CY
##STR00262##
[0858] Example CY
[0859] To a solution of Example R (hydrochloride salt) (269 mg,
0.36 mmol) in pyridine (3 mL) was added diformylhydrazine (95 mg,
1.1 mmol), followed by chlorotrimethylsilane (2.7 mL) and
triethylamine (0.34 mL). The mixture was heated at 100.degree. C.
for 14 hours, and solvents were removed. The mixture was quenched
with water, and extracted three times with EtOAc. The organic layer
was dried over Na.sub.2SO.sub.4 and concentrated to give a white
solid. Purification by HPLC and preparative TLC (5% MeOH in
dichloromethane) gave Example CY (5 mg). m/z: 758.3 (M+H).sup.+.
.sup.1H NMR (CD.sub.3OD) .delta. 8.98 (s, 1H); 8.50 (s, 2H); 7.83
(s, 1H); 7.30-7.00 (m, .sup.1H); 5.21 (s, 2H); 4.54 (m, 2H); 4.11
(m, 4H); 3.76 (m, 1H); 3.28 (m, 1H); 2.95 (s, 3H); 2.69 (m, 4H);
2.04 (m, 2H); 1.70-1.20 (m, 10H).
Preparation of Example CZ
##STR00263##
[0860] Example CZ
[0861] To a suspension of Example R (hydrochloride salt) (200 mg,
0.27 mmol) and sodium bicarbonate (92 mg, 1.1 mmol) in DMF (2 mL)
was added a solution of methyl 4-bromobutyrate (74 .quadrature.l,
0.54 mmol) in DMF (1 mL). The mixture was heated at 65.degree. C.
for 20 hours and the solvent was removed under reduced pressure.
The mixture was quenched with water, and extracted with EtOAc. The
organic layer was washed three times with water, twice with sodium
carbonate solution, and once with brine, and dried over
Na.sub.2SO.sub.4. Concentration followed by purification using HPLC
gave Example CZ as a white solid (23 mg). m/z: 774.3 (M+H).sup.+.
.sup.1H NMR (CD.sub.3OD) .delta. 8.99 (s, 1H); 7.84 (s, 1H);
7.30-7.00 (m, 11H); 5.22 (s, 2H); 4.55 (m, 2H); 4.09 (m, 2H);
3.90-3.60 (m, 1H); 3.55-3.10 (m, 5H); 2.98 (s, 3H); 2.71 (m, 4H);
2.37 (m, 2H); 2.04 (m, 2H); 1.81 (m, 2H); 1.70-1.20 (m, 10H).
Preparation of Example DA
##STR00264##
[0862] Example DA
[0863] To a suspension of Example R (hydrochloride salt) (250 mg,
0.34 mmol) in acetic acid (0.73 mL) was added sodium acetate (153
mg, 1.9 mmol), followed by 2,5-dimethoxyTHF (44 .quadrature.l, 0.34
mmol). The mixture was heated at 125.degree. C. for 90 minutes, and
the solvent was removed under reduced pressure. The residue was
quenched with saturated sodium bicarbonate solution and extracted
with EtOAc. The organic layer was washed sequentially with
saturated NaHCO.sub.3 solution, water, and brine, and dried over
Na.sub.2SO.sub.4. Concentration and purification by HPLC gave a
white solid, which was further purified by preparative TLC to give
Example DA (25 mg). m/z: 756.3 (M+H).sup.+. .sup.1H NMR
(CD.sub.3OD) .delta. 8.96 (s, 1H); 7.82 (s, 1H); 7.30-7.00 (m,
11H); 6.62 (s, 2H); 6.02 (s, 2H); 5.20 (s, 2H); 4.51 (s, 2H);
4.20-3.95 (m, 2H); 3.88 (m, 2H); 3.75 (m, 1H); 3.26 (m, 1H); 2.93
(s, 3H); 2.70 (m, 4H); 2.01 (m, 2H); 1.70-1.20 (m, 10H).
Preparation of Example DB
##STR00265##
[0864] Example DB
[0865] To Example R (220 mg, 0.34 mmol) in propanol (1.9 mL) was
added aqueous ammonia (39 mg, 0.34 mmol, 28-30%). The mixture was
stirred for 5 minutes. To the above mixture was added a solution of
glyoxal (53 mg, 0.37 mmol, 40% wt) and formaldehyde (30 mg, 0.37
mmol, 37% wt) in propanol (3.7 mL) dropwise. The mixture was heated
at 80.degree. C. for 5 hours. The solvent was removed under reduced
pressure, and the residue was diluted with EtOAc. The organic layer
was washed with water and brine, and dried over Na.sub.2SO.sub.4.
Concentration of the organic layer and purification by HPLC gave
Example DB as a white powder (101 mg). m/z: 757.3 (M+H).sup.+.
.sup.1H NMR (CD.sub.3OD) .delta. 8.97 (s, 1H); 7.82 (s, 1H); 7.60
(s, 1H); 7.30-7.00 (m, 12H); 6.96 (s, 1H); 5.20 (s, 2H); 4.53 (m,
2H); 4.20-3.90 (m, 4H); 3.76 (m, 1H); 3.28 (m, 1H); 2.95 (s, 3H);
2.70 (m, 4H); 2.02 (m, 2H); 1.70-1.20 (m, 10H).
Preparation of Example DC
##STR00266##
[0866] Example DC
[0867] To a solution of Example R (220 mg, 0.34 mmol) in
dichloromethane (1.5 mL) was added succinic anhydride (41 mg, 0.41
mmol). The mixture was heated at 45.degree. C. for 12 hours. The
solvent was removed and a white solid was dried under high vacuum.
To this solid was added sodium acetate (10 mg, 0.12 mmol), followed
by acetic anhydride (1.5 mL). The mixture was heated at 85.degree.
C. for 1 hour, and the solvent was removed under reduced pressure.
The residue was diluted with EtOAc, and was washed sequentially
with water, saturated NaHCO.sub.3, water, and brine, and dried over
Na.sub.2SO.sub.4. Concentration gave Example DC (190 mg). m/z:
788.2 (M+H).sup.+. .sup.1H NMR (CD.sub.3OD) .delta. 8.99 (s, 1H);
7.84 (s, 1H); 7.30-7.00 (m, 11H); 5.22 (s, 2H); 4.70-4.40 (m, 2H);
4.20-3.90 (m, 2H); 3.75 (m, 1H); 3.54 (m, 1H); 3.42 (m, 1H); 3.28
(m, 1H); 2.98 (s, 3H); 2.67 (m, 8H); 2.00 (m, 1H); 1.81 (m, 1H);
1.70-1.20 (m, 10H).
Preparation of Example DD
##STR00267##
[0868] Example DD
[0869] To a solution of Example R (220 mg, 0.34 mmol) in DMF (3 mL)
was added sodium carbonate (100 mg), followed by
2,2,2-trifluoroethyl trichloromethanesulfonate (112 .quadrature.l,
0.68 mmol). The mixture was stirred for 3 days and the solvent was
removed under reduced pressure. The residue was diluted with EtOAc.
The organic layer was sequentially washed twice with saturated
sodium carbonate solution, once with water, and once with brine,
and dried over Na.sub.2SO.sub.4. Concentration and purification by
flash column chromatography (9% MeOH in dichloromethane) gave
Example DD (109 mg). m/z: 788.2 (M+H).sup.+. .sup.1H NMR
(CD.sub.3OD) .delta. 8.98 (s, 1H); 7.82 (s, 1H); 7.62 (d, 1H, J=9
Hz); 7.30-7.00 (m, 11H); 6.85 (d, 1H, J=9 Hz); 5.20 (m, 2H); 4.54
(s, 2H); 4.23 (m, 1H); 4.11 (m, 1H); 3.77 (m, 1H); 3.31 (m, 2H);
3.12 (q, 2H, J=10 Hz); 2.95 (m, 3H); 3.80-2.50 (m, 6H); 1.77 (m,
2H); 1.70-1.20 (m, 10H). .sup.19F NMR (CD.sub.3OD) .quadrature.
-73.28 (t, 1H, J=10 Hz).
Preparation of Example DE
##STR00268##
[0870] Example DE
[0871] To a clear solution of dimethyl N-cyanodithioiminocarbonate
(50 mg, 0.34 mmol) in ethanol (0.5 mL) was added slowly a solution
of Example R (220 mg, 0.34 mmol) in ethanol (2.5 mL). The mixture
was stirred for 12 hours. To the above mixture was added a solution
of methylamine in EtOH (1.6 mL, 33% wt). The mixture was stirred
for 6 hours, and solvents were removed under reduced pressure.
Purification by HPLC gave Example DE (92 mg). m/z: 787.3
(M+H).sup.+. .sup.1H NMR (CD.sub.3OD) .delta. 8.98 (s, 1H); 7.83
(s, 1H); 7.30-7.00 (m, 11H); 5.21 (s, 2H); 4.51 (s, 2H); 4.18 (m,
1H); 4.09 (m, 1H); 3.77 (m, 1H); 3.28 (m, 2H); 3.16 (m, 1H); 2.97
(s, 3H); 2.80 (s, 3H); 2.715 (m, 4H); 1.84 (m, 1H); 1.70 (m, 1H);
1.65-1.20 (m, 10H).
Preparation of Examples DF-DG
##STR00269##
[0872] Example DF
[0873] To a solution of Example R (220 mg, 0.34 mmol) in DMF (1 mL)
was added sodium carbonate (72 mg, 0.68 mmol), followed by a
solution of 2-bromoethanol (24 .quadrature.l, 0.34 mmol) in DMF
(0.4 mL). The mixture was heated at 70.degree. C. for 12 hours.
Concentration under high vacuum gave Example DF. m/z: 750.2
Example DG
[0874] To a suspension of Example DF (0.34 mmol) in THF (3.4 mL)
was added carbonyldiimidazole (CDI) (83 mg, 0.51 mmol), followed by
DMAP (4 mg). The mixture was heated at 70.degree. C. for 3 hours,
and the solvent was removed. The residue was diluted with EtOAc,
and was washed with water and brine, and dried over
Na.sub.2SO.sub.4. Concentration and purification with preparative
TLC gave Example DG (83 mg). m/z: 776.2 (M+H).sup.+. .sup.1H NMR
(CD.sub.3OD) .delta. 8.98 (s, 1H); 7.83 (s, 1H); 7.67 (m, 1H);
7.30-7.00 (m, 11H); 6.87 (m, 1H); 6.49 (m, 1H); 5.21 (s, 2H);
4.70-4.40 (m, 2H); 4.34 (t, 2H, J=8 Hz); 4.18 (m, 1H); 4.06 (m,
1H); 3.76 (m, 1H); 3.60 (t, 2H, J=8 Hz); 3.24 (m, 3H); 2.97 (s,
3H); 2.71 (m, 4H); 1.86 (m, 2H); 1.70-1.20 (m, 10H).
Preparation of Example DH
##STR00270##
[0875] Example W
[0876] Example W was synthesized following the procedure described
in WO2008/010921 A2, and as described above in Scheme 25.
Example DH
[0877] Example DH (100 mg) was prepared following the procedure
used to prepare example CY, except that Example W was used instead
of Example R. .sup.1H NMR (CD.sub.3OD): .delta. 8.97 (s, 1H), 8.40
(s, 2H), 7.81 (s, 1H), 7.15 (m, 10H), 5.20 (s, 2H), 4.54 (m, 2H),
4.20 (m, 1H), 4.07 (m, 1H), 3.87 (m, 3H), 3.24 (m, 1H), 2.95 (s,
3H), 2.85 (m, 1H), 2.60 (m, 3H), 1.81 (m, 2H), 1.60-1.43 (m, 4H),
1.33 (d, J=7.2 Hz, 6H). Mass Spectrum (m/e): (M+H).sup.+ 758.2,
(M-H).sup.- 755.9.
Preparation of Example DI
##STR00271##
[0878] Example DI
[0879] Example DI (28 mg) was prepared following the procedure used
to prepare Example CZ, except that compound W (160 mg) was used
instead of Example R. m/z: 774.2 (M+H).sup.+. .sup.1H NMR
(CD.sub.3OD) .delta. 8.97 (1H, s), 7.81 (1H, s), 7.24-7.02 (11H,
m), 5.20 (2H, s), 4.54 (2H, m), 4.18 (1H, m), 4.0 (1H, m), 3.75
(1H, m), 3.20 (4H, m), 3.01 (1H, m), 2.99 (3H, s), 2.8-2.5 (4H, m),
2.38 (2H, m), 2.04 (2H, m), 1.62-1.40 (6H, m), 1.31 (6H, m).
Preparation of Example DJ
##STR00272##
[0880] Example DJ
[0881] Example DJ (44 mg) was prepared following the procedure used
to prepare Example DB, except that Example W (160 mg) was used
instead of Example R. m/z: 757.3 (M+H).sup.+. .sup.1H NMR
(CD.sub.3OD) .delta. 8.97 (1H, s), 7.83 (1H, s), 7.50 (1H, s),
7.25-7.04 (11H, m), 6.99-6.96 (2H, m), 5.20 (2H, s), 4.52 (2H, m),
4.20 (1H, m), 4.03 (1H, m), 3.78 (3H, m), 3.22 (1H, m), 2.95 (3H,
s), 2.9-2.4 (4H, m), 1.8 (2H, m), 1.7-1.4 (4H, m), 1.31 (6H,
m).
Preparation of Examples DK-DL
##STR00273##
[0882] Example DK
[0883] Example DK was prepared following the procedure used to
prepare Example DF, except that Example W (160 mg) was used instead
of Example R.
Example DL
[0884] Example DL (28 mg) was prepared following the procedure used
to prepare Example DG, except that Example DK was used instead of
Example DF. m/z: 776.2 (M+H).sup.+. .sup.1H NMR (CD.sub.3OD)
.delta. 8.97 (1H, s), 7.81 (1H, s), 7.25-7.05 (11H, m), 5.20 (2H,
s), 4.55 (2H, m), 4.31 (2H, m), 4.2-4.0 (2H, m), 3.75 (1H, m), 3.44
(2H, m), 3.3-3.0 (3H, m), 2.98 (3H, s), 2.8-2.4 (4H, m), 1.7-1.4
(6H, m), 1.32 (6H, m).
Preparation of Examples DM(a-c)
##STR00274##
[0885] Compound 8
[0886] Compound 8 was synthesized following the procedure described
in WO2008/010921 A2, and as described above.
Compounds 138a/138b/138c
[0887] Compounds 138a, 138b, and 138c were obtained from
Aldrich.
Compound 139a
[0888] To a solution of acid 138a (266 mg, 1.0 mmol) and amine 8
(409 mg, 1.0 mmol) in THF (10 mL) were added HOBt (203 mg, 1.5
mmol), EDC (294 .quadrature.l, 2.0 mmol), and diisopropylethylamine
(0.835 mL, 4.0 mmol). The mixture was stirred for 12 hours and the
solvents were removed. The residue was diluted with EtOAc. The
organic phase was washed three times with saturated
Na.sub.2CO.sub.3 solution, twice with water, and once with brine,
and dried over Na.sub.2SO.sub.4. Concentration and purification by
flash column chromatography (0%-10% MeOH in dichloromethane) gave
Compound 139a (509 mg). m/z: 658.1 (M+H).sup.+.
Compound 139b
[0889] Compound 139b (543 mg) was prepared following the procedure
used to prepare Compound 139a, except that Compound 138b was used
instead of Compound 138a. m/z: 658.1 (M+H).sup.+.
Compound 139c
[0890] Compound 139c (587 mg) was prepared following the procedure
used to prepare Compound 139a, except that Compound 138c was used
instead of Compound 138a. m/z: 658.2 (M+H).sup.+.
Compound 140a
[0891] To Compound 139a (500 mg) was added 10 mL of HCl/dioxane
solution (4N, 40 mmol). The mixture was stirred for 1 hour, and the
solvents were removed. The residue was diluted with diethyl ether,
and stirred for 1 hour. The diethyl ether layer was decanted. The
solid was washed with diethyl ether (2.times.) and dried under
vacuum. The resulting Compound 140a was a brown powder (520 mg).
m/z: 558.3 (M+H).sup.+.
Compound 140b
[0892] Compound 140b (476 mg) was prepared following the procedure
used to prepare Compound 140a, except that Compound 139b was used
instead of Compound 139a. m/z: 558.2 (M+H).sup.+.
Compound 140c
[0893] Compound 140c (536 mg) was prepared following the procedure
used to prepare Compound 140a, except that Compound 139c was used
instead of Compound 139a. m/z: 558.3 (M+H).sup.+.
Compound 9
[0894] Compound 9 was synthesized following the procedure described
in WO2008/010921 A2.
Example DM(a)
[0895] To the stirred solution of Compound 140a (520 mg, 0.75 mmol)
and diisopropylethylamine (0.52 mL, 3.0 mmol) in dichloromethane (6
mL) was added CDI (122 mg, 0.75 mmol). The mixture was stirred for
12 hours. To this mixture was added a solution of Compound 9 (128
mg, 0.75 mmol) in dichloromethane (2 mL), and the mixture was
stirred for 5 additional hours. The solvents were removed, and the
residue was diluted with EtOAc. The organic layer was washed twice
with water and once with brine, and dried over Na.sub.2SO.sub.4.
Concentration and purification by HPLC gave Example DM(a) (270 mg).
m/z: 754.3 (M+H).sup.+. .sup.1H NMR (CD.sub.3OD) .delta. 8.97 (s,
1H); 8.41 (m, 1H); 7.82 (s, 1H); 7.70 (m, 2H); 7.30-7.00 (m, 11H);
6.99 (s, 1H); 5.21 (s, 2H); 4.56 (m, 1H); 4.48 (s, 2H); 4.02 (m,
1H); 3.72 (m, 1H); 3.28 (m, 1H); 3.15-2.90 (m, 2H); 2.93 (s, 3H);
2.68 (m, 4H); 1.60-1.30 (m, 10H).
Example DM(b)
[0896] Example DM(b) (36 mg) was prepared following the procedure
used to prepare Example DM(a), except that Compound 140b was used
instead of Compound 140a. m/z: 754.3 (M+H).sup.+. .sup.1H NMR
(CD.sub.3OD) .delta. 8.97 (s, 1H); 8.38 (m, 2H); 7.83 (s, 1H); 7.68
(m, 1H); 7.33 (m, 1H); 7.30-7.00 (m, 10H); 6.96 (s, 1H); 5.21 (s,
2H); 4.45 (m, 3H); 4.01 (m, 1H); 3.72 (m, 1H); 3.28 (m, 1H);
3.15-2.90 (m, 2H); 2.90 (s, 3H); 2.68 (m, 4H); 1.60-1.30 (m,
10H).
Example DM(c)
[0897] Example DM(c) (283 mg) was prepared following the procedure
used to prepare Example DM(a), except that Compound 140c was used
instead of Compound 140a. m/z: 754.3 (M+H).sup.+. .sup.1H NMR
(CD.sub.3OD) .delta. 8.97 (s, 1H); 8.39 (d, 2H, J=6 Hz); 7.82 (s,
1H); 7.27 (d, 2H, J=6 Hz); 7.30-7.00 (m, 10H); 6.94 (s, 1H); 5.21
(s, 2H); 4.53 (m, 1H); 4.45 (s, 2H); 4.03 (m, 1H); 3.74 (m, 1H);
3.32 (m, 1H); 3.10-2.90 (m, 2H); 2.90 (s, 3H); 2.72 (m, 4H);
1.60-1.30 (m, 10H).
Preparation of Example DN
##STR00275##
[0898] Compound 141
[0899] Compound 141 was obtained from TCI.
Compound 142
[0900] To a solution of Compound 141 (1.0 g, 6.4 mmol) in methanol
(20 mL) at 0.degree. C. was added thionyl chloride (1.0 mL, 14.2
mmol) dropwise. The mixture was stirred at 0.degree. C. for 30
minutes and brought to reflux for 3 hours. Concentration gave
Compound 142 as a white solid.
Compound 143
[0901] Compound 143 (1.68 g) was prepared following the procedure
used to prepare Example DM(a), except that Compound 142 was used
instead of Compound 140a. m/z: 366.0 (M+H).sup.+.
Compound 144
[0902] To a solution of Compound 143 (1.68 g, 4.8 mmol) in
MeOH/H.sub.2O (20 mL/20 mL) at 0.degree. C. was added sodium
hydroxide (229 mg, 5.74 mmol). The mixture was stirred for 1 hour
and the solvents were removed under reduced pressure. Hydrochloric
acid in dioxane (1.5 mL, 4 N, 6 mmol) was added, and the mixture
was evaporated and dried under high vacuum. Compound 144 was
obtained as a white solid (1.8 g).
Example DN
[0903] Example DN (260 mg) was prepared following the procedure
used to prepare Compound 139a, except that Compound 144 was used
instead of Compound 138a. m/z: 743.2 (M+H).sup.+. .sup.1H NMR
(CDCl.sub.3) .delta. 8.78 (1H, s), 7.81 (1H, s), 7.44 (1H, s), 7.39
(1H, s), 7.3-7.0 (10H, m), 6.95 (2H, m), 6.7 (1H, br), 6.2 (1H, m),
5.3 (1H, m), 5.2 (2H, m), 4.5-4.2 (5H, m), 4.1 (1H, m), 3.70 (1H,
m), 3.22 (1H, m), 2.96 (3H, s), 2.8-2.5 (4H, m), 1.5-1.2 (10H,
m).
Preparation of Example DO
##STR00276##
[0904] Compound 46
[0905] Compound 46 was synthesized following the procedure
described in WO2008/010921 A2.
Example DO
[0906] Example DO (215 mg) was prepared following the procedure
used to prepare Compound 139a, except that Compounds 144 and 46
were used instead of Compounds 8 and 138a. m/z: 743.2 (M+H).sup.+.
.sup.1H NMR (CD.sub.3OD) .delta. 8.97 (s, 1H); 7.82 (s, 1H); 7.45
(s, 1H); 7.30-7.00 (m, 13H); 6.19 (s, 1H); 5.20 (s, 2H); 4.60-4.40
(m, 2H); 4.21 (m, 2H); 4.09 (m, 1H); 3.25 (m, 1H); 2.93 (s, 3H);
2.90-2.50 (m, 5H); 1.70-1.20 (m, 10H).
Preparation of Examples DP-DT
##STR00277##
[0907] Example AF
[0908] Example AF was synthesized following the procedure described
in WO2008/010921 A2, and as described above in Scheme 27.
Example DP
[0909] Example DP (23 mg) was prepared following the procedure used
to prepare Compound 139a, except that Example AF and
2-aminopyridine were used instead of Compounds 8 and 138a. m/z:
797.2 (M+H).sup.+. .sup.1H NMR (DMSO-d.sub.6) .delta. 10.45 (1H,
s), 9.06 (1H, s), 8.31 (1H, m), 8.04 (1H, m), 7.85 (1H, m), 7.75
(1H, m), 7.55 (1H, m); 7.2-7.0 (13H, m), 6.54 (1H, m), 5.12 (2H,
s), 4.52 (1H, m), 4.43 (2H, s), 3.93 (1H, m), 3.58 (1H, m), 3.17
(1H, m), 2.85 (3H, s), 2.8-2.4 (6H, m), 1.36 (4H, m), 1.25 (6H,
m).
Example DQ
[0910] Example DQ (32 mg) was prepared following the procedure used
to prepare Compound 139a, except that Example AF and
3-aminopyridine were used instead of Compounds 8 and 138a. m/z:
797.2 (M+H).sup.+. .sup.1H NMR (DMSO-d6) .delta. 10.39 (1H, s),
9.06 (1H, s), 8.88 (1H, s), 8.36 (1H, m), 8.18 (1H, m), 7.85 (1H,
s), 7.54 (2H, m), 7.2-7.0 (12H, m), 6.60 (1H, m), 5.14 (2H, s),
4.55 (1H, m), 4.45 (2H, s), 4.0-3.5 (2H, m), 3.19 (1H, m), 2.86
(3H, s), 2.8-2.4 (6H, m), 1.37 (4H, m), 1.26 (6H, m).
Example DR
[0911] Example DR (30 mg) was prepared following the procedure used
to prepare Compound 139a, except that Example AF and
4-aminopyridine were used instead of Compounds 8 and 138a. m/z:
797.3 (M+H).sup.+. .sup.1H NMR (DMSO-d6) .delta. 11.24 (1H, s),
9.05 (1H, s), 8.61 (2H, d, J=6.3 Hz), 7.96 (2H, d, J=6.3 Hz), 7.84
(1H, s), 7.58 (1H, m), 7.2-7.0 (12H, m), 6.65 (1H, m), 5.14 (2H,
s), 4.6 (1H, m), 4.46 (2H, s), 3.9 (1H, m), 3.4 (1H, m), 3.20 (1H,
m), 2.87 (3H, s), 2.7-2.4 (6H, m), 1.37 (4H, m), 1.25 (6H, m).
Example DS
[0912] Example DS (50 mg) was prepared following the procedure used
to prepare Compound 139a, except that Example AF and
1-aminopyrrolidine were used instead of Compounds 8 and 138a. m/z:
789.2 (M+H).sup.+. .sup.1H NMR (DMSO-d6) .delta. 9.06 (1H, s), 8.63
(1H, s), 8.26 (1H, s), 7.85 (1H, s), 7.55 (1H, m), 7.35 (1H, m),
7.2-7.0 (10H, m); 6.40 (1H, m), 5.15 (2H, s), 4.55-4.30 (3H, m),
3.85 (1H, m), 3.63 (1H, m), 3.4-3.1 (5H, m), 2.86 (3H, s), 2.8-2.4
(6H, m), 1.66 (4H, m), 1.4-1.2 (10H, m).
Example DT
[0913] Example DT (50 mg) was prepared following the procedure used
to prepare Compound 139a, except that Example AF and
methanesulfonamide were used instead of Compounds 8 and 138a. m/z:
798.2 (M+H).sup.+. .sup.1H NMR (DMSO-d6) .delta. 11.65 (1H, s),
9.10 (1H, s), 7.88 (1H, s), 7.50 (1H, m), 7.2-7.0 (12H, m), 6.6
(1H, m), 5.15 (2H, s), 4.5-4.4 (3H, m), 4.0-3.4 (2H, m), 3.20 (1H,
m), 3.15 (3H, s), 2.85 (3H, s), 2.7-2.4 (6H, m), 1.4-1.2 (10H,
m).
Preparation of Examples DU(a-c)
##STR00278##
[0914] Compound 122
[0915] Compound 122 was synthesized following the procedure
described in WO2008/010921 A2, and as described above in Scheme
69.
Compound 145
[0916] To a solution of Compound 122 (1.0 g, 4 mmol) in
dichloromethane (5 mL) was added ethyl alcohol (1.5 mL, 25.6 mmol),
followed by iodotrimethylsilane (2 mL, 14.3 mmol). The mixture was
stirred for 6 hours and the mixture was used directly for the next
step. m/z: 453.9 (M+H).sup.+.
Compound 146a
[0917] To a solution of Compound 145 (1 mmol) in dichloromethane (2
mL) was added a solution of (R)-3-hydroxypyrrolidine (435 mg, 5
mmol) in dichloromethane (1 mL). The mixture was stirred for 12
hours and the solvents were removed under reduced pressure.
Purification by flash column chromatography (0-20% MeOH in
dichloromethane) gave Compound 146a (230 mg). m/z: 413.1
(M+H).sup.+.
Compound 146b
[0918] Compound 146b (200 mg) was prepared following the procedure
used to prepare Compound 146a, except that compound
(S)-3-hydroxypyrrolidine was used instead of compound
(R)-3-hydroxypyrrolidine. m/z: 413.1 (M+H).sup.+.
Compound 146c
[0919] Compound 146c (380 mg) was prepared following the procedure
used to prepare Compound 146a, except that compound
4-hydroxypiperidine was used instead of compound
(R)-3-hydroxypyrrolidine. m/z: 427.1 (M+H).sup.+.
Compound 147a
[0920] Compound 147a (250 mg) was prepared following the procedure
used to prepare Compound 144, except that Compound 146a was used
instead of Compound 143.
Compound 147b
[0921] Compound 147b (210 mg) was prepared following the procedure
used to prepare Compound 144, except that Compound 146b was used
instead of Compound 143.
Compound 147c
[0922] Compound 147c (400 mg) was prepared following the procedure
used to prepare Compound 144, except that Compound 146c was used
instead of Compound 143.
Example DU(a)
[0923] Example DU(a) (250 mg) was prepared following the procedure
used to prepare Compound 139a, except that Compound 147a was used
instead of Compound 138a. m/z: 776.3 (M+H).sup.+. .sup.1H NMR
(CD.sub.3OD) .delta. 8.97 (1H, s), 7.81 (1H, s), 7.25-7.05 (11H,
m), 5.19 (2H, m), 4.54 (2H, m), 4.25 (1H, m), 4.2-4.1 (2H, m), 3.75
(1H, m), 3.22 (1H, m), 2.94 (3H, s), 2.8-2.7 (6H, m), 2.5-2.3 (4H,
m), 2.1-1.8 (2H, m), 1.7-1.4 (6H, m), 1.37 (6H, m).
Example DU(b)
[0924] Example DU(b) (253 mg) was prepared following the procedure
used to prepare Compound 139a, except that compound 147b was used
instead of Compound 138a. m/z: 776.3 (M+H).sup.+. .sup.1H NMR
(CD.sub.3OD) .delta. 8.97 (1H, s), 7.81 (1H, s), 7.22-7.05 (11H,
m), 5.18 (2H, m), 4.5 (2H, m), 4.25 (1H, m), 4.2-4.1 (2H, m), 3.78
(1H, m), 3.25 (1H, m), 2.95 (3H, s), 2.8-2.6 (6H, m), 2.6-2.3 (4H,
m), 2.1-1.8 (2H, m), 1.8-1.4 (6H, m), 1.37 (6H, m).
Example DU(c)
[0925] Example DU(c) (450 mg) was prepared following the procedure
used to prepare Compound 139a, except that Compound 147c was used
instead of Compound 138a. m/z: 790.3 (M+H).sup.+. .sup.1H NMR
(CD.sub.3OD) .delta. 8.97 (1H, s), 7.81 (1H, s), 7.25-7.05 (11H,
m), 5.20 (2H, m), 4.54 (2H, m), 4.2-4.0 (2H, m), 3.75 (1H, m), 3.58
(1H, m), 3.25 (1H, m), 2.97 (3H, s), 2.8-2.6 (6H, m), 2.25 (2H, m),
2.08 (2H, m), 1.9-1.6 (4H, m), 1.6-1.4 (6H, m), 1.38 (6H, m).
Preparation of Example DV
##STR00279##
[0926] Example DV
[0927] A mixture of Example DU(c) (230 mg, 0.29 mmol) and
triethylamine (0.14 mL) in DMSO (1 mL) was stirred at 25.degree. C.
for 30 minutes, and then was cooled to 5-10.degree. C. Sulfur
trioxide pyridine complex (0.17 g) was added to above reaction
mixture and the mixture was stirred for 1 hour at 5-10.degree. C.
The mixture was poured into ice water, and stirred for 20 minutes,
and was extracted with EtOAc. The organic phase was washed twice
with water, twice with saturated NaHCO.sub.3 solution, twice with
water, and once with brine, and dried over Na.sub.2SO.sub.4.
Concentration and purification by flash column chromatography
(0-20% MeOH in dichloromethane) gave Example DV (67 mg). m/z: 788.3
(M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .delta. 8.78 (1H, s), 7.81
(1H, s), 7.3-7.1 (10H, m), 6.90 (1H, s), 6.5 (1H, br), 5.35 (1H,
m), 5.22 (2H, s), 4.4-4.0 (4H, m), 3.78 (1H, m), 3.23 (1H, m), 2.93
(3H, s), 2.8-2.5 (8H, m), 2.4-2.2 (6H, m), 2.0-1.4 (6H, m), 1.32
(6H, m).
Preparation of Example DW
##STR00280##
[0928] Example DW
[0929] Example DW (78 mg) was prepared following the procedure used
to prepare Example DV, except that Example DU(a) was used instead
of Example DU(c). m/z: 774.3 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3)
.delta. 8.78 (1H, s), 7.82 (1H, s), 7.3-7.0 (10H, m), 6.89 (1H, s),
6.55 (1H, br), 5.40 (1H, m), 5.21 (2H, s), 4.5-4.2 (3H, m), 4.15
(1H, m), 3.78 (1H, m), 3.23 (1H, m), 3.1-2.9 (4H, m), 2.9 (3H, s),
2.8-2.5 (6H, m), 2.40 (2H, m), 1.90 (2H, m), 1.55 (2H, m), 1.38
(8H, m).
Preparation of Examples DX(a-f)
##STR00281## ##STR00282##
[0930] Compound 60
[0931] Compound 60 was synthesized following the procedure
described in WO2008/010921 A2, and as described above in Scheme
23.
Compound 148a
[0932] To a solution of Compound 60 (800 mg, 2 mmol) in CH.sub.3CN
(8 mL) was added a solution of 1-acetylpiperazine (512 mg, 4 mmol)
in CH.sub.3CN (1 mL), followed by HOAc (240 ul, 4 mmol) and
NaBH(OAc).sub.3 (1.33 g, 6 mmol). The mixture was stirred for 12
hours and was diluted with EtOAc. The organic phase was washed with
saturated Na.sub.2CO.sub.3 solution, water, and brine, and dried
over Na.sub.2SO.sub.4. Concentration and purification by flash
column chromatography (0-12% iPrOH in dichloromethane) gave
Compound 148a (250 mg). m/z: 516.1 (M+H).sup.+.
Compound 148b
[0933] Compound 148b (530 mg) was prepared following the procedure
used to prepare Compound 148a, except that
1-ethylsulfonylpiperazine was used instead of 1-acetylpiperazine.
m/z: 566.1 (M+H).sup.+.
Compound 148c
[0934] Compound 148c (384 mg) was prepared following the procedure
used to prepare Compound 148a, except that
4-trifluoromethylpiperidine was used instead of 1-acetylpiperazine.
m/z: 541.2 (M+H).sup.+.
Compound 148d
[0935] Compound 148d (342 mg) was prepared following the procedure
used to prepare Compound 148a, except that 4,4-difluoropiperidine
was used instead of 1-acetylpiperazine. m/z: 509.1 (M+H).sup.+.
Compound 148e
[0936] Compound 148e (320 mg) was prepared following the procedure
used to prepare Compound 148a, except that 4-fluoropiperidine was
used instead of 1-acetylpiperazine. m/z: 491.1 (M+H).sup.+.
Compound 148f
[0937] Compound 148f (389 mg) was prepared following the procedure
used to prepare Compound 148a, except that 3,3-difluoropiperidine
was used instead of 1-acetylpiperazine. m/z: 509.1 (M+H).sup.+.
Example 149a
[0938] To a solution of Compound 148a (250 mg, 0.48 mmol) in ethyl
alcohol (3 mL) was added 1.0 N sodium hydroxide solution (0.53 mL,
0.53 mmol). The mixture was stirred for 1 hour and the solvents
were removed under reduced pressure. 4.0 N Hydrochloric acid in
dioxane (0.13 mL, 0.52 mmol) was added, and the mixture was
evaporated. Coevaporation with DMF (2.times.100 mL) gave Compound
149a, which was used without further purification in the next
step.
Example 149b
[0939] Compound 149b was prepared following the procedure used to
prepare Compound 149a, except that Compound 148b was used instead
of Compound 148a.
Example 149c
[0940] Compound 149c was prepared following the procedure used to
prepare Compound 149a, except that Compound 148c was used instead
of Compound 148a.
Example 149d
[0941] Compound 149d was prepared following the procedure used to
prepare Compound 149a, except that Compound 148d was used instead
of Compound 148a.
Example 149e
[0942] Compound 149e was prepared following the procedure used to
prepare Compound 149a, except that Compound 148e was used instead
of Compound 148a.
Example 149f
[0943] Compound 149f was prepared following the procedure used to
prepare Compound 149a, except that Compound 148f was used instead
of Compound 148a.
Example DX(a)
[0944] Example DX(a) (90 mg) was prepared following the procedure
used to prepare Compound 139a, except that Compound 149a was used
instead of Compound 138a. m/z: 817.3 (M+H).sup.+. .sup.1H NMR
(CDCl.sub.3) .quadrature. 8.78 (1H, s), 7.81 (1H, s), 7.3-7.0 (10H,
m), 6.90 (1H, s), 6.40 (1H, m), 5.40 (1H, m), 5.22 (2H, s), 4.6-4.3
(2H, m), 4.3-4.1 (2H, m), 3.78 (1H, m), 3.5-3.2 (5H, m), 2.92 (3H,
s), 2.9-2.6 (4H, m), 2.4-2.2 (6H, m), 2.07 (3H, s), 1.9 (2H, m),
1.6-1.3 (10H, m).
Example DX(b)
[0945] Example DX(b) (150 mg) was prepared following the procedure
used to prepare Compound 139a, except that Compound 149b was used
instead of Compound 138a. m/z: 867.3 (M+H).sup.+. .sup.1H NMR
(CDCl.sub.3) .quadrature. 8.78 (1H, s), 7.81 (1H, s), 7.3-7.0 (10H,
m), 6.92 (1H, s), 6.4 (1H, br), 5.35 (1H, br), 5.2 (2H, s), 4.6-4.0
(4H, m), 3.78 (1H, m), 3.3-3.1 (5H, m), 2.92 (5H, m), 2.8-2.6 (4H,
m), 2.5-2.2 (6H, m), 1.90 (2H, m), 1.6-1.3 (13H, m).
Example DX(c)
[0946] Example DX(c) (427 mg) was prepared following the procedure
used to prepare Compound 139a, except that Compound 149c was used
instead of Compound 138a. m/z: 842.2 (M+H).sup.+. .sup.1H NMR
(CDCl.sub.3) .quadrature. 8.77 (1H, s), 7.80 (1H, s), 7.3-7.0 (10H,
m), 6.88 (1H, s), 6.40 (1H, br), 5.50 (1H, br), 5.20 (2H, m),
4.7-4.3 (2H, m), 4.18 (2H, m), 3.75 (1H, m), 3.23 (1H, m), 3.05-2.8
(4H, m), 2.8-2.6 (4H, m), 2.25 (2H, m), 2.0-1.65 (6H, m), 1.6-1.2
(14H, m).
Example DX(d)
[0947] Example DX(d) (390 mg) was prepared following the procedure
used to prepare Compound 139a, except that Compound 149d was used
instead of Compound 138a. m/z: 810.2 (M+H).sup.+. .sup.1H NMR
(CDCl.sub.3) .quadrature. 8.78 (1H, s), 7.81 (1H, s), 7.4-7.0 (10H,
m), 6.89 (1H, s), 6.40 (1H, br), 5.40 (1H, br), 5.22 (2H, m),
4.6-4.3 (2H, m), 4.22 (2H, m), 3.78 (1H, m), 3.24 (1H, m), 3.0-2.6
(7H, m), 2.5-2.2 (6H, m), 2.0-1.7 (6H, m), 1.6-1.2 (10H, m).
Example DX(e)
[0948] Example DX(e) (160 mg) was prepared following the procedure
used to prepare Compound 139a, except that Compound 149e was used
instead of Compound 138a. m/z: 792.3 (M+H).sup.+. .sup.1H NMR
(CDCl.sub.3) .quadrature. 8.77 (1H, s), 7.81 (1H, s), 7.3-7.0 (10H,
m), 6.87 (1H, s), 6.45 (1H, br), 5.55 (1H, br), 5.20 (2H, m),
4.9-4.3 (3H, m), 4.3-4.1 (2H, m), 3.75 (1H, m), 3.25 (1H, m),
3.1-2.8 (5H, m), 2.8-2.6 (4H, m), 2.6-2.1 (6H, m), 2.0-1.4 (8H, m),
1.37 (6H, m).
Example DX(f)
[0949] Example DX(f) (480 mg) was prepared following the procedure
used to prepare Compound 139a, except that Compound 149f was used
instead of Compound 138a. m/z: 810.2 (M+H).sup.+. .sup.1H NMR
(CDCl.sub.3) .quadrature. 8.77 (1H, s), 7.80 (1H, s), 7.3-7.0 (10H,
m), 6.93 (1H, br), 6.84 (1H, s), 6.40 (1H, br), 5.50 (1H, br), 5.20
(2H, m), 4.5-4.3 (2H, m), 4.3-4.1 (2H, m), 3.75 (1H, m), 3.24 (1H,
m), 3.05-2.8 (5H, m), 2.8-2.6 (4H, m), 2.5-2.2 (6H, m), 2.0-1.75
(4H, m), 1.7-1.37 (10H, m).
Preparation of Example DY
##STR00283##
[0950] Compound 150
[0951] Compound 150 was obtained from Aldrich.
Compound 151
[0952] To a suspension of Compound 150 (25 g, 137 mmol) in THF (400
mL) was added triethylamine (21 mL, 151 mmol), followed by
Boc.sub.2O (31.5 g, 144 mmol). The mixture was stirred for 48
hours, and the solvents were removed. The residue was diluted with
EtOAc, and washed twice with saturated sodium carbonate solution,
once with water, and once with brine, and dried over
Na.sub.2SO.sub.4. Concentration gave Compound 151 (25 g).
Compound 152
[0953] To a solution of Compound 151 (2.0 g, 10 mmol) in MeOH (20
mL) at 0.degree. C. was added 4.4 N sodium methoxide solution in
methanol (0.46 mL, 2 mmol). The mixture was stirred for 45 minutes,
and quenched with saturated NH.sub.4Cl solution. The solvent was
evaporated, and the residue was diluted with EtOAc. The organic
phase was washed with saturated NH.sub.4Cl solution, water, and
brine, and dried over Na.sub.2SO.sub.4. Concentration gave Compound
152 (2.6 g).
Compound 153
[0954] Compound 153 (1.9 g) was prepared following the procedure
used to prepare Example DV, except that Compound 152 was used
instead of Example DU(c).
Compound 154
[0955] Compound 154 (1.65 g) was prepared following the procedure
used to prepare Compound 148a, except that Compound 153 and
4-thiomorpholine were used instead of Compound 60 and
1-acetylpiperazine.
Compound 155
[0956] To a solution of Compound 154 (1.55 g, 4.86 mmol) in
acetone/water (270 mL/70 mL) was added 4-methylmorpholine N-oxide
(1.25 g, 10 mmol), followed by OsO.sub.4/tBuOH solution (6.8 mL,
2.5%). The mixture was stirred for 12 hours and the solvents were
removed under reduced pressure. Purification by flash column
chromatography (60-100% EtAOc in hexanes) gave Compound 155 (1.44
g).
Compound 156
[0957] Compound 156 was prepared following the procedure used to
prepare Compound 140a, except that Compound 155 was used instead of
Compound 139a.
Compound 157
[0958] Compound 157 (660 mg) was prepared following the procedure
used to prepare Example DM(a), except that Compound 156 was used
instead of Compound 140a. m/z: 447.0 (M+H).sup.+.
Compound 158
[0959] Compound 158 was prepared following the procedure used to
prepare Compound 144, except that Compound 157 was used instead of
Compound 143. m/z: 433.1 (M+H).sup.+.
Example DY
Example DY (350 mg) was prepared following the procedure used to
prepare
[0960] Compound 139a, except that Compound 158 was used instead of
Compound 138a. m/z: 824.2 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3)
.quadrature. 8.80 (1H, s), 7.82 (1H, s), 7.2-7.0 (10H, m), 6.96
(1H, s), 6.71 (1H, br), 6.4 (1H, br), 5.21 (2H, m), 5.15 (1H, br),
4.5-4.1 (4H, m), 3.80 (1H, m), 3.22 (1H, m), 3.0-2.8 (11H, m),
2.8-.2.6 (4H, m), 2.47 (2H, m), 2.0-1.7 (2H, m), 1.6-1.3 (10H,
m).
Preparation of Examples DZ-EA
##STR00284##
[0961] Compounds 159/160
[0962] To a solution of Compound 60 (1.6 mmol) in EtOH/H.sub.2O
(1.6 mL/1.6 mL) was added ammonium carbonate (600 mg, 6.4 mmol),
followed by sodium cyanide (158 mg). The mixture was heated at
90.degree. C. for 16 hours and cooled to 25.degree. C. 1 N
hydrochloric acid was added until pH=3-4. The residue was diluted
with EtOAc, and washed with water and brine. The organic phase was
dried over Na.sub.2SO.sub.4 and concentrated to give Compounds 159
and 160, which were used without further purification in the next
step.
Examples DZ/EA
[0963] Examples DZ (80 mg) and EA (60 mg) were prepared following
the procedure used to prepare Compound 139a, except that Compounds
159 and 160 were used instead of Compound 138a. Example DZ: m/z:
732.3 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .quadrature. 8.75 (1H,
m), 7.80 (1H, m), 7.3-7.0 (10H, m), 6.95 (1H, m), 6.8 (1H, br),
6.40 (1H, br), 5.8 (1H, br), 5.20 (2H, m), 4.40 (2H, m), 4.2-3.8
(3H, m), 3.78 (1H, m), 3.23 (1H, m), 2.95 (3H, m), 2.8-2.3 (6H, m),
1.6-1.3 (10H, m). Example EA: m/z: 775.2 (M+H).sup.+. .sup.1H NMR
(CDCl.sub.3) U 8.81 (1H, s), 8.02 (1H, br), 7.9 (1H, s), 7.85 (1H,
br), 7.3-7.0 (11H, m), 6.3 (1H, br), 5.4-5.1 (3H, m), 4.6-4.3 (2H,
m), 4.2-3.8 (2H, m), 3.8-3.4 (1H, m), 3.3 (1H, m), 3.1-2.9 (3H, m),
2.8-2.4 (4H, m), 2.15 (2H, m), 1.7-1.2 (10H, m).
Preparation of Example EB
##STR00285##
[0964] Compound 161
[0965] Compound 161 (11 g) was prepared following the procedure
used to prepare Compound 148a, except that Compounds 153 and
morpholine were used instead of Compounds 60 and
1-acetylpiperazine. m/z: 303.0 (M+H).sup.+.
Compound 162
[0966] Compound 162 (10.4 g) was prepared following the procedure
used to prepare Compound 140a, except that Compound 161 was used
instead of Compound 139a. m/z: 203.1 (M+H).sup.+.
Example 3b
[0967] Compound 3b was synthesized following the procedure
described in WO2008/010921 A2, and as described above in Scheme
10.
Example 163
[0968] Compound 163 (540 mg) was prepared following the procedure
used to prepare Example DM(a), except that Compounds 162 and 36
were used instead of Compounds 140a and 9. m/z: 385.1
(M+H).sup.+.
Example 164
[0969] Compound 164 (780 mg) was prepared following the procedure
used to prepare Compound 144, except that Compound 163 was used
instead of Compound 143. m/z: 371.0 (M+H).sup.+.
Example EB
[0970] Example EB (210 mg) was prepared following the procedure
used to prepare Compound 139a, except that Compound 164 was used
instead of Compound 138a. m/z: 762.2 (M+H).sup.+. .sup.1H NMR
(DMSO-d6) .quadrature. 9.06 (1H, s), 7.85 (1H, s), 7.7 (1H, br),
7.2-7.0 (12H, m), 6.55 (1H, br), 6.20 (1H, br), 5.18 (2H, s), 4.23
(2H, m), 4.15-3.8 (2
[0971] H, m), 3.65 (1H, m), 3.55 (4H, m), 3.2 (1H, m), 2.7-2.4 (6H,
m), 2.3-2.0 (6H, m), 1.5-1.2 (10H, m).
Preparation of Compound 166
##STR00286##
[0972] Compound 3
[0973] Compound 3 was synthesized following the procedure described
in WO2008/010921 A2.
Compound 165
[0974] To a suspension of Compound 3 (2.65 g, 12.5 mmol) in water
(10 mL) was added sodium hydroxide (1.5 g, 38 mmol). The mixture
was heated at 90.degree. C. for 12 hours and cooled to 25.degree.
C. The mixture was extracted with EtOAc. The organic layer was
washed with brine and dried over Na.sub.2SO.sub.4. Purification by
flash column chromatography (50% EtOAc in hexanes) gave Compound
165 (810 mg).
Compound 166
[0975] To a solution of Compound 165 (810 mg, 5.2 mmol) in DCM (12
mL) was added bis(4-nitrophenyl)carbonate (1.73 g, 5.7 mmol),
followed by triethylamine (1.1 mL, 7.8 mmol). The mixture was
stirred for 14 hours, and the solvents were removed. The residue
was diluted with EtOAc, and washed twice with saturated sodium
carbonate, followed by water, and then brine, and was dried over
Na.sub.2SO.sub.4. Concentration and purification by flash column
chromatography (20% EtOAc in hexanes) gave Compound 166 (1.4
g).
Preparation of Example EC
##STR00287##
[0976] Compound 167
[0977] Compound 167 was prepared following the procedure used to
prepare Compound 144, except that Compound 161 was used instead of
Compound 143.
Compound 168
[0978] Compound 168 (1.2 g) was prepared following the procedure
used to prepare Compound 139a, except that Compound 167 was used
instead of Compound 138a. m/z: 680.3 (M+H).sup.+.
Compound 169
[0979] To a solution of Compound 168 (1.2 g, 1.8 mmol) in MeOH (10
mL) was added 4 N hydrochloric acid (4.4 mL, 17.6 mmol). The
mixture was stirred for 6 hours, and the solvents were removed. The
residue was basified with 2 N sodium hydroxide solution (pH=11),
and extracted with EtOAc. The organic layer was washed with brine
and dried over Na.sub.2SO.sub.4. Concentration gave Compound 169
(1.0 g)
Example EC
[0980] To a solution of Compound 169 (116 mg, 0.2 mmol) in
CH.sub.3CN (2 mL) was added Compound 166 (71 mg, 0.22 mmol),
followed by triethylamine (71 .quadrature.L, 0.4 mmol). The mixture
was stirred for 48 hours, and was diluted with EtOAc. The organic
layer was washed with saturated sodium carbonate solution, water,
and brine, was dried over Na.sub.2SO.sub.4. Purification by flash
column chromatography (0-15% iPrOH in DCM) gave compound 1073 (130
mg). m/z: 763.3 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .quadrature.
8.75 (1H, s), 7.78 (1H, s), 7.67 (1H, br), 7.3-7.0 (11H, m), 6.22
(1H, m), 5.24 (2H, s), 5.16 (2H, s), 5.10 (1H, br), 4.28-4.10 (2H,
m), 3.8 (1H, m), 3.6 (4H, m), 3.32 (1H, m), 2.9-2.6 (4H, m),
2.4-2.1 (6H, m), 1.8 (2H, m), 1.6 (2H, m), 1.4 (8H, m).
Preparation of Compound 173
##STR00288##
[0981] Compound 170
[0982] Compound 170 was obtained from Aldrich.
Compound 171
[0983] Hydrogen sulfide gas was passed through a solution of
Compound 170 (1.8 mL, 20 mmol) in pyridine (100 mL) and
triethylamine (4.4 mL) for 5 hours. The solution was purged with
nitrogen for 10 minutes, and the solvents were removed. The residue
was coevaporated three times with 10 mL of ethyl alcohol.
Purification by flash column chromatography (10% iPrOH in DCM) gave
Compound 171 (2.0 g).
Compound 172
[0984] To a solution of Compound 171 (2 g, 17 mmol) in acetone (30
mL) was added 1,3-dichloroacetone (2.1 g, 17 mmol), followed by
MgSO.sub.4 (2.0 g, 17 mmol). The mixture was refluxed for 12 hours
and cooled to 25.degree. C. The mixture was filtered. Concentration
gave Compound 172. m/z: 191.9 (M+H).sup.+.
Compound 173
[0985] To a solution of 40% methylamine in water (36 mL) was added
a solution of Compound 172 (17 mmol) in water (10 mL). The mixture
was stirred for 1 hour, and concentrated under reduced pressure.
Purification by flash column chromatography (10% MeOH in DCM) gave
Compound 173. m/z: 187.0 (M+H).sup.+.
Preparation of Compound 177
##STR00289##
[0986] Compound 174
[0987] To a solution of Compound 151 (10.5 g, 50 mmol) in ethyl
alcohol (160 mL) was added sodium hydroxide solution (2.1 g, 52.5
mmol, 30 mL). The mixture was stirred for 1 hour, and the solvent
was removed under reduced pressure. The residue was coevaporated
three times with 200 mL of ethyl alcohol. The white solid was dried
at 60.degree. C. for 2 hours under high vacuum. To this solid was
added DMF (80 mL), followed by benzyl bromide (7.3 mL, 61 mmol).
The mixture was stirred for 12 hours in darkness and diluted with
EtOAc. The organic phase was washed five times with water followed
once with brine, and was then dried over Na.sub.2SO.sub.4.
Concentration gave Compound 174 (15 g).
Compound 175
[0988] Compound 175 was prepared following the procedure used to
prepare Example DV, except that Compound 174 was used instead of
Example DU(c).
Compound 176
[0989] Compound 176 was prepared following the procedure used to
prepare Compound 148a, except that Compound 175 and morpholine were
used instead of Compound 60 and 1-acetylpiperazine.
Compound 177
[0990] Compound 177 (3.4 g) was prepared following the procedure
used to prepare example 140a, except that Compound 176 was used
instead of Compound 139a. m/z: 279.1 (M+H).sup.+.
Preparation of Example ED
##STR00290##
[0991] Compound 178
[0992] Compound 178 (300 mg) was prepared following the procedure
used to prepare Example DM(a), except that Compounds 173 and 177
were used instead of Compounds 140a and 9. m/z: 491.3
(M+H).sup.+.
Compound 179
[0993] Compound 179 was prepared following the procedure used to
prepare Compound 149a, except that Compound 178 was used instead of
Compound 148a.
Example ED
[0994] Example ED (370 mg) was prepared following the procedure
used to prepare Compound 139a, except that Compound 179 was used
instead of Compound 138a. m/z: 792.3 (M+H).sup.+. .sup.1H NMR
(CD.sub.3OD) .quadrature. 8.98 (1H, s), 7.83 (1H, s), 7.20-7.08
(11H, m), 5.20 (2H, m), 4.55 (2H, m), 4.3-4.0 (4H, m), 3.75 (3H,
m), 3.4 (2H, m), 3.2-3.0 (4H, m), 2.99 (3H, s), 2.70 (4H, m),
2.1-1.8 (2H, m), 1.7-1.4 (10H, m).
Preparation of Example EE
##STR00291##
[0995] Compound 180
[0996] Compound 180 was obtained from Aldrich.
Compound 181
[0997] Compound 181 (1.6 g) was prepared following the procedure
used to prepare Compound 139a, except that Compounds 180 and 9 were
used instead of Compounds 8 and 138a. m/z: 327.9 (M+H).sup.+.
Compound 182
[0998] To a suspension of sodium hydride (52 mg, 60%, 1.3 mmol) in
DMF (4 mL) was added a solution of Compound 181 (327 mg, 1 mmol) in
DMF (1 mL). The mixture was stirred for 90 minutes, and a solution
of 2-morpholineethyl bromide (212 mg, 1.1 mmol) in DMF (1 mL) was
added dropwise. The mixture was stirred for 12 hours, and quenched
with water. The aqueous phase was extracted three times with EtOAc.
The combined organic phases were washed five times with water and
once with brine, and dried over Na.sub.2SO.sub.4. The dried organic
phases were concentrated and purified by flash column
chromatography (0-10% MeOH in DCM) to give Compound 182 (267 mg).
m/z: 441.1 (M+H).sup.+.
Compound 183
[0999] Compound 183 (175 mg) was prepared following the procedure
used to prepare Compound 169, except that Compound 182 was used
instead of Compound 168. m/z: 341.2 (M+H).sup.+.
Example EE
[1000] To a solution of triphosgene (56 mg, 0.19 mmol) in DCM (1
mL) at 0.degree. C. was added a solution of Compound 8 (210 mg,
0.51 mmol) and DIPEA (194 .quadrature.l) in DCM (1.8 mL). The
mixture was stirred for 30 minutes, and a solution of Compound 183
(175 mg, 0.51 mmol) and DIPEA (194 .quadrature.l) in DCM (1 mL) was
added. The mixture was warmed to 25.degree. C. and stirred for 12
hours. The mixture was diluted with EtOAc, and washed twice with
saturated sodium carbonate, once with water, and once with brine,
and was dried over Na.sub.2SO.sub.4. The dried organic phases were
concentrated and purified by flash column chromatography (15% iPrOH
in DCM) gave Example EE (150 mg). m/z: 776.3 (M+H).sup.+. .sup.1H
NMR (CD.sub.3OD) .quadrature. 8.97 (1H, s), 7.82 (1H, s), 7.25-7.05
(11H, m), 5.21 (2H, s), 4.6 (2H, m), 4.3-4.1 (2H, m), 3.95 (1H, m),
3.75 (1H, s), 3.47 (4H, m), 3.3 (5H, m), 3.06/2.94 (3H, s), 2.7
(4H, m), 2.30 (4H, m), 1.6-1.2 (10H, m).
Preparation of Examples EF-EH
##STR00292##
[1001] Compound 184
[1002] Compound 184 was obtained from Aldrich.
Compound 185
[1003] Compound 185 (291 mg) was prepared following the procedure
used to prepare Example DM(a), except that Compound 184 and
methylamine were used instead of Compounds 140a and 9. m/z: 289.9
(M+H).sup.+.
Compound 186
[1004] Compound 186 was prepared following the procedure used to
prepare Compound 144, except that Compound 185 was used instead of
Compound 143. m/z: 275.9 (M+H).sup.+.
Example EF
[1005] Example EF (102 mg) was prepared following the procedure
used to prepare Compound 139a, except that Compound 186 was used
instead of Compound 138a. m/z: 667.1 (M+H).sup.+.
Example EG
[1006] Example EG (144 mg) was prepared following the procedure
used to prepare Compound 169, except that Example EF was used
instead of Compound 168 m/z: 567.2 (M+H).sup.+.
Compound 54
[1007] Compound 54 was synthesized following the procedure
described in WO2008/010921 A2.
Example EH
[1008] Example EH (25 mg) was prepared following the procedure used
to prepare Compound 148a, except that Example EG and Compound 54
were used instead of Compound 60 and 1-acetylpiperazine. m/z: 637.3
(M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .quadrature. 9.00 (br s, 1H);
7.94 (br s, 1H); 7.72 (br s, 1H); 7.40-7.00 (m, 10H); 5.49 (m, 1H);
5.25 (s, 2H); 4.47 (m, 1H); 4.30 (m, 1H); 4.02 (br s, 1H); 3.65 (m,
2H); 3.41 (m, 2H); 2.76 (m, 9H); 2.25-1.70 (m, 4H); 1.70-1.40 (m,
6H).
Preparation of Example EI-EJ
##STR00293## ##STR00294##
[1009] Compound 187
[1010] Compound 187 was obtained from Aldrich.
Compound 188
[1011] Compound 188 (897 mg) was prepared following the procedure
used to prepare Example DM(a), except that Compound 187 was used
instead of Compound 140a. m/z: 298.0 (M+H).sup.+.
Compound 189
[1012] Compound 189 (1.24 g) was prepared following the procedure
used to prepare Compound 174, except that Compound 188 was used
instead of Compound 151. m/z: 406.1 (M+H).sup.+.
Compound 190
[1013] Compound 190 (712 mg) was prepared following the procedure
used to prepare Example DV, except that Compound 189 was used
instead of Example DU(c). m/z: 40.4.0 (M+H).sup.+.
Compound 191
[1014] Compound 191 (384 mg) was prepared following the procedure
used to prepare Compound 148a, except that Compound 190 and
morpholine were used instead of Compound 60 and 1-acetylpiperazine.
m/z: 475.1 (M+H).sup.+.
Compound 192
[1015] Compound 192 (900 mg) was prepared following the procedure
used to prepare Compound 149a, except that Compound 191 was used
instead of Compound 148a. m/z: 385.0 (M+H).sup.+.
Example EI
[1016] Example EI (151 mg) was prepared following the procedure
used to prepare Compound 139a, except that Compound 192 was used
instead of Compound 138a. m/z: 776.2 (M+H).sup.+. .sup.1H NMR
(CD.sub.3OD) .quadrature. 8.97 (1H, s), 7.82 (1H, s), 7.3-7.1 (11H,
m), 5.2 (2H, s), 4.5 (2H, m), 4.18 (2H, m), 3.78 (1H, m), 3.59 (4H,
m), 3.23 (1H, m), 2.97 (3H, s), 2.8-2.5 (4H, m), 2.5-2.1 (6H, m),
1.9-1.6 (2H, m), 1.6-1.3 (10H, m).
Example EJ
[1017] Example EI was purified with HPLC (chiral cel OD-H column by
Chiral Technologies Inc, heptane/iPrOH=70/30) to give Example EJ.
m/z: 776.2 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3) .quadrature. 8.98
(s, 1H); 7.90 (s, 1H); 7.75 (m, 1H); 7.40-7.00 (m, 15H), 6.55 (br
s, 1H); 5.92 (br s, 1H); 7.75 (d, 1H); 5.28, 5.19 (d.sub.AB, J=14
Hz, 2H); 4.70-4.37 (m, 3H); 3.99 (m, 5H); 3.76 (br s, 1H);
3.65-3.30 (m, 3H); 2.97 (m, 5H); 2.90-2.60 (m, 7H); 2.28 (br s,
2H); 1.91 (br s, 2H); 1.6-1.3 (m, 12H).
Preparation of Example EK
##STR00295##
[1018] Compound 193
[1019] Compound 193 was synthesized following the procedure from J.
Med. Chem., 41(4), 1998, 602-617 (herein incorporated by reference
in its entirety for all purposes).
Compound 194
[1020] Compound 193 (1.4 g, 7 mmol) was dissolved in anhydrous THF
(7 mL) and added dropwise over 1 hour into a 1 M LiAlH.sub.4
solution in THF stirring at 0.degree. C. under nitrogen gas. The
reaction mixture was then allowed to warm to room temperature and
stirred for 1 hour, at which time HPLC showed that reaction was
complete. The reaction mixture was cooled in an ice bath and
methanol was slowly added. Aqueous potassium sodium tartarate
solution was then added. The organic solution was extracted with
ethyl acetate and then dried over anhydrous sodium sulfate and
concentrated under reduced pressure to give Compound 194 (1 g,
91%), which was used in the next reaction without further
purification.
Compound 195
[1021] Compound 194 (1 g, 6.37 mmol) was dissolved in anhydrous
toluene (6 mL). To the resulting solution was added PCl.sub.5 (1.3
g, 6.37 mmol). After the reaction mixture was stirred for 1 hour,
the reaction was complete. Solid sodium bicarbonate was added to
the reaction mixture, which was then diluted with ethyl acetate and
washed with saturated aqueous sodium bicarbonate solution, followed
by saturated aqueous sodium chloride solution. The organic layer
was dried over anhydrous sodium sulfate and concentrated under
reduced pressure to yield Compound 195 (0.91 g, 81%).
Compound 196
[1022] Compound 195 (0.91 g, 5.2 mmol) was dissolved in 2 M
methylamine in methanol (15 mL). The reaction mixture was stirred
for 15 hours, then concentrated under reduced pressure. The
resulting oil was dissolved in dilute aqueous HCl solution to give
a solution with a pH of 2. The solution was then washed with ethyl
acetate. The aqueous layer was concentrated under reduced pressure.
The residue was purified by preparative HPLC to give Compound 196
(0.6 g, 56%).
Example EK
[1023] Example EK (14 mg) was prepared following the procedure used
to prepare Example DM(a), except that Compounds 169 and 196 were
used instead of Compounds 140a and 9. .sup.1H NMR (CD.sub.3OD):
.quadrature. 8.98 (s, 1H), 7.82 (s, 1H), 7.55 (s, 1H), 7.19 (m,
10H), 5.21 (m, 2H), 4.68 (m, 2H), 4.20 (m, 1H), 4.15 (m, 1H), 3.79
(m, 1H), 3.64 (m, 4H), 3.25 (m, 1H), 2.98 (s, 3H), 2.73 (m, 4H),
2.23-2.40 (m, 6H), 1.90-1.70 (m, 2H), 1.51 (m, 4H), 1.36 (d, J=6.9
Hz, 6H). Mass Spectrum (m/e): (M+H).sup.+ 776.3, (M-H).sup.-
773.9
Preparation of Example EL
##STR00296##
[1024] Example EL
[1025] Example W (71 mg, 0.1 mmol) and
1,1-bis(methylthio)-2-nitroethylene (17 mg, 0.1 mmol) was dissolved
in anhydrous DMF (2 mL). The resulting mixture was stirred at room
temperature for 90 minutes, followed by another 16 hours at
40.degree. C. An additional 10% of
1,1-bis(methylthio)-2-nitroethylene was added and the mixture was
stirred at 60.degree. C. for 8 hours. A solution of 2 M methylamine
in methanol (1.2 mL, 2.4 mmol) was added and the mixture was
stirred for 3 hours at room temperature. The mixture was diluted
with ethyl acetate and washed with saturated aqueous sodium
bicarbonate solution and saturated aqueous sodium chloride
solution. The organic layer was dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The crude product obtained
was purified by flash silica gel column chromatography (3-10% MeOH
in DCM). Final purification with C.sub.18-reverse phase prep HPLC
gave Example EL (55 mg, 68%). .sup.1H NMR (CD.sub.3OD):
.quadrature. 8.97 (s, 1H), 7.81 (s, 1H), 7.16 (m, 10H), 6.66 (s,
1H), 5.20 (s, 2H), 4.54 (m, 2H), 4.17 (m, 2H), 3.80 (m, 1H), 3.35
(s, 3H), 3.23 (m, 1H), 3.00-2.80 (m, 9H), 2.63 (m, 3H), 1.60-1.43
(m, 6H), 1.33 (d, J=7.2 Hz, 6H). Mass Spectrum (m/e): (M+H).sup.+
806.3, (M-H).sup.- 804.1.
Preparation of Examples EM-EN
##STR00297##
[1026] Compound 197
[1027] Compound 122 (460 mg, 1.5 mmol) was dissolved in anhydrous
DCM. To the resulting solution was added EtOH (540 .quadrature.L,
9.28 mmol), followed by TMS-I (663 .quadrature.L, 4.6 mmol)
dropwise. The mixture was stirred for 2 hours at room temperature.
Additional TMS-I (200 .quadrature.L) was added and the mixture was
stirred for 1 hour. The reaction mixture was concentrated under
reduced pressure. The residue was dissolved in EtOH and
concentrated under reduced pressure. The residue was again
dissolved in another portion of EtOH. The resulting oil was
dissolved in anhydrous DMSO (5 mL). KCN was added, and the
resulting mixture was stirred at room temperature for 0.16 hours.
The mixture was diluted with ethyl acetate and washed sequentially
with saturated aqueous sodium bicarbonate solution and saturated
aqueous sodium chloride solution. The organic layer was dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified with flash silica gel column
chromatography (EtOAc). The product (260 mg, 0.74 mmol) was
dissolved in EtOH and stirred in an ice bath. NaOH (33 mg, 0.82
mmol) was dissolved in water and added to the EtOH solution in
portions. The reaction mixture was acidified with 10% citric acid
to a pH of 2-3 and extracted with EtOAc. The organic layer was
dried over anhydrous sodium sulfate and concentrated under reduced
pressure. The resulting Compound 197 (228 mg, 47%) was used in the
next step without further purification.
Example EM
[1028] Compound 197 (228 mg, 0.7 mmol) was dissolved in anhydrous
THF (5 mL). EDC (202 mg, 1.05 mmol) and HOBt (162 mg, 1.05 mmol)
were added to the solution and the resulting mixture was stirred
for 30 minutes. Compound 8 (214 mg, 0.7 mmol) was added to the
reaction mixture along with anhydrous DMF (3 mL) and TEA (294
.quadrature.L, 2.11 mmol). The mixture was stirred for 90 minutes,
then diluted with EtOAc and washed sequentially with saturated
aqueous sodium bicarbonate solution and saturated aqueous sodium
chloride solution. The organic layer was dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue
was purified with flash silica gel column chromatography (0-10%
MeOH in DCM). Final purification with C.sub.18-reverse phase prep
HPLC gave Example EM (291 mg, 58%). .sup.1H NMR (CD.sub.3OD): D
8.97 (s, 1H), 7.83 (s, 1H), 7.17 (m, 10H), 5.22 (s, 2H), 4.53 (s,
2H), 4.23 (m, 1H), 4.06 (m, 1H), 3.77 (m, 1H), 3.27 (m, 1H), 2.96
(s, 3H), 2.72 (m, 4H), 2.37 (m, 2H), 1.88 (m, 2H), 1.52 (m, 4H),
1.38 (d, J=7.2 Hz, 6H). Mass Spectrum (m/e): (M+H).sup.+ 716.2,
(M-H).sup.- 713.9.
Example EN
[1029] Example EM (120 mg, 0.168 mmol) was dissolved in anhydrous
MeOH (5 mL) and concentrated under reduced pressure. This process
was repeated twice with fresh portions of MeOH. The residue was
dissolved in MeOH (5 mL) and stirred in an ice bath under nitrogen
gas. HCl gas was bubbled into the MeOH solution for 5-10 minutes to
saturate the solution. The reaction vessel was sealed and the
reaction mixture was stirred at 0.degree. C. for 8 hours. The
reaction mixture was then concentrated under reduced pressure at
room temperature. The residue was dissolved in EtOAc and washed
twice with 10% aqueous sodium carbonate solution, followed by
saturated aqueous sodium chloride solution. The organic layer was
dried over anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was dissolved in 2-methoxy ethanol (5 mL).
Sulfamide (161 mg, 1.68 mmol) was added to the solution, which was
stirred at 80.degree. C. for 8 hours and then at room temperature
for 16 hours. The reaction mixture was concentrated under reduced
pressure. The residue was dissolved in EtOAc and washed with
saturated aqueous sodium bicarbonate solution, followed by
saturated aqueous sodium chloride solution. The organic layer was
dried over anhydrous sodium sulfate and concentrated under reduced
pressure. The crude material was purified with flash silica gel
column chromatography (0-10% MeOH in DCM). Final purification with
C.sub.18-reverse phase prep HPLC gave Example EN (16 mg, 12%).
.sup.1H NMR (CD.sub.3OD): .quadrature. 8.98 (s, 1H), 7.83 (s, 1H),
7.67 (m, 1H), 7.16 (m, 10H), 6.82 (m, 1H), 5.21 (s, 2H), 4.53 (m,
2H), 4.15 (m, 2H), 3.77 (m, 1H), 3.28 (m, 1H), 2.96 (s, 3H), 2.68
(m, 4H), 2.21 (m, 2H), 1.88 (m, 2H), 1.45 (m, 4H), 1.35 (d, J=7.2
Hz, 6H). Mass Spectrum (m/e): (M+H).sup.+812.1, (M-H).sup.-
810.0.
Preparation of Example EO
##STR00298##
[1030] Compound 68
[1031] Compound 68 was synthesized following the procedure
described in WO2008/010921 A2.
Example EO
[1032] Example EO (39 mg) was prepared following the procedure used
to prepare Example DM(a), except that Compounds 68 and 169 were
used instead of Compounds 140a and 9. .sup.1H NMR (CD.sub.3OD):
.quadrature. 8.98 (s, 1H), 8.93 (s, 1H), 7.82 (s, 2H), 7.19 (m,
10H), 5.21 (s, 2H), 4.60 (m, 2H), 4.20 (m, 1H), 4.10 (m, 1H), 3.77
(m, 1H), 3.64 (m, 4H), 2.93 (s, 3H), 2.74 (m, 4H), 2.38-2.28 (m,
6H), 1.84-1.70 (m, 2H), 1.50 (m, 4H). Mass Spectrum (m/e):
(M+H).sup.+ 734.3, (M-H).sup.- 731.9
Preparation of Example EP-EQ
##STR00299##
[1033] Compound 198
[1034] Compound 198 was obtained from Aldrich.
Compound 199
[1035] Compound 198 (205 mg, 1 mmol) was mixed with Compound 46
(446 mg, 1 mmol) and HOBt (230 mg, 1.5 mmol) in anhydrous DMF (5
mL). EDC (230 mg, 1.2 mmol) was then added. The resulting mixture
was stirred for 30 minutes. DIPEA (348 .quadrature.L, 2 mmol) was
added. The mixture was stirred for 2 hours, then diluted with
EtOAc, washed sequentially with saturated aqueous sodium
bicarbonate solution and saturated aqueous sodium chloride
solution. The organic layer was dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The crude material was
purified with flash silica gel column chromatography (0-100% EtOAc
in DCM) to give Compound 199 (345 mg, 58%).
Compound 200
[1036] Compound 199 (345 mg, 0.58 mmol) was dissolved in a small
amount of MeOH. A solution of 4 N HCl in dioxane (5 mL) was added.
The resulting mixture was stirred for 1 hour and concentrated under
reduced pressure. The residue was dissolved in EtOAc and washed
sequentially with saturated aqueous sodium bicarbonate solution and
saturated aqueous sodium chloride solution. The organic layer was
dried over anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was dissolved in anhydrous DCM (10 mL).
Pyridine (163 .quadrature.L, 2 mmol) and t-butyldimethylsilyl
chloride (166 mg, 1.1 mmol) were added. The resulting mixture was
stirred for 15 hours. More pyridine (1630L) and TBS-Cl (60 mg) were
added. The resulting mixture was stirred for another 24 hours. The
mixture was concentrated under reduced pressure. The residue was
dissolved in EtOAc and washed sequentially with saturated aqueous
sodium bicarbonate solution and saturated aqueous sodium chloride
solution. The organic layer was dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The crude material was
purified by flash silica gel column chromatography (0-5% MeOH in
DCM) to give Compound 200 (248 mg, 69%).
Example EP
[1037] Example EP was prepared following the procedure used to
prepare Example DM(a), except that Compounds 200 and 68 were used
instead of Compounds 140a and 9.
Example EQ
[1038] To Example EP was added 4 N HCl in dioxane (4 mL). The
mixture was stirred for 1 hour and the solvent was evaporated. The
residue was diluted with EtOAc, and washed sequentially with
saturated aqueous sodium carbonate, water, and brine. The organic
layer was dried over Na.sub.2SO.sub.4, then concentrated. The
residue was purified by flash column chromatography (10% iPrOH in
DCM) to give Example EQ (35 mg). .sup.1H NMR (CD.sub.3OD): .delta.
8.97 (s, 1H), 8.89 (s, 1H), 7.81 (s, 2H), 7.70 (m, 1H), 7.19 (m,
10H), 6.92 (m, 1H), 5.20 (s, 2H), 4.73 (m, 2H), 4.22 (m, 1H), 4.13
(m, 1H), 3.78 (m, 1H), 3.56 (d, J=5.4 Hz, 2H), 3.31 (m, 1H), 2.94
(s, 3H), 2.67 (m, 4H), 1.45 (m, 4H). Mass Spectrum (m/e):
(M+H).sup.+ 651.2, (M-H).sup.- 648.8.
IC.sub.50 Determinations for Human Liver Cytochrome P450
Materials and General Methods
[1039] Pooled (n.gtoreq.15 donors) human hepatic microsomal
fraction was obtained from BD-Gentest (Woburn, Mass.) who also
supplied hydroxy-terfenadine, 4'-hydroxydiclofenac and NADPH
regenerating system. Ritonavir was prepared from commercial
Norvir.RTM. oral solution (Abbott Laboratories, Abbott Park, Ill.).
Other reagents were from Sigma-Aldrich (St. Louis, Mo.) and
included terfenadine, fexofenadine, BRL 15572, diclofenac and
mefenamic acid.
[1040] Incubations were performed in duplicate in 50 mM potassium
phosphate buffer, pH 7.4 with NADPH regenerating system used as
described by the manufacturer. The final microsomal protein
concentrations had previously been determined to be within the
linear range for activity and resulted in less than 20% consumption
of substrate over the course of the incubation. The final substrate
concentrations used were equal to the apparent Km values for the
activities determined under the same conditions. Inhibitors were
dissolved in DMSO, and the final concentration of DMSO, from both
substrate and inhibitor vehicles, was 1% (v/v). Incubations were
performed at 37.degree. C. with shaking and were initiated by
addition of substrate. Aliquots were then removed at 0, 7 and 15
minutes. Samples were quenched by treatment with an acetonitrile,
formic acid, water (94.8%/0.2%/5%, v/v/v) mixture containing
internal standard. Precipitated protein was removed by
centrifugation at 3000 rpm for 10 min and aliquots of the
supernatant were then subjected to LC-MS analysis.
[1041] The LC-MS system consisted of a Waters Acquity UPLC, with a
binary solvent manager and a refrigerated (8.degree. C.) sample
organizer and sample manager, interfaced to a Micromass Quattro
Premier tandem mass spectrometer operating in electrospray
ionization mode. The column was a Waters Acquity UPLC BEH C.sub.18
2.1.times.50 mm, 1.7 .mu.m pore size. Mobile phases consisted of
mixtures of acetonitrile, formic acid and water, the composition
for mobile phase A being 1%/0.2%/98.8% (v/v/v) and that for mobile
phase B being 94.8%/0.2%/5% (v/v/v). The injection volumes were 5
.mu.L and the flow rate was 0.8 mL/min. Concentrations of
metabolites were determined by reference to standard curves
generated with authentic analytes under the same conditions as the
incubations.
[1042] IC.sub.50 values (the concentration of inhibitor reducing
CYP3A activity by 50%) were calculated by non-linear regression
using GraphPad Prism 4.0 software and a sigmoidal model.
CYP3A Inhibition Assay
[1043] The potencies of the compounds as inhibitors of human
hepatic cytochromes P450 of the CYP3A subfamily (particularly
CYP3A4) were assessed using terfenadine oxidase, a
well-characterized CYP3A-selective activity described in Ling,
K.-H. J., et al Drug Metab. Dispos. 23, 631-636, (1995) and
Jurima-Romet, et al Drug Metab. Dispos. 22, 849-857, (1994). The
final concentrations of microsomal protein and terfenadine
substrate were 0.25 mg/mL and 3 .mu.M, respectively. Metabolic
reactions were terminated by treatment with seven volumes of quench
solution containing 0.1 .mu.M BRL 15572 as internal standard. A
further 8 volumes of water were added before centrifugation and
aliquots of the supernatant were removed for analysis.
[1044] For LC-MS analysis chromatographic elution was achieved by a
series of linear gradients starting at 20% B and holding for 0.1
minutes, then increasing to 80% B over 1.5 minutes, holding for 0.4
minutes and then returning to the starting conditions for 0.05 min.
The system was allowed to re-equilibrate for at least 0.25 minutes
prior to the next injection. The mass spectrometer was operated in
positive ion mode and the following precursor ([M+H].sup.+)/product
ion pairs were monitored and quantified using MassLynx 4.0 (SP4,
525) software: hydroxy-terfenadine 488.7/452.4, fexofenadine
502.7/466.4 and BRL 15572 407.5/209.1. Terfenadine oxidase activity
was determined from the sum of hydroxy-terfenadine and
carboxy-terfenadine (fexofenadine) metabolites.
CYP2C9 Inhibition Assay
[1045] The potencies of the compounds as inhibitors of human
hepatic CYP2C9 were assessed using diclofenac 4'-hydroxylase, an
activity specific for this enzyme, as described in Leeman, T., et
al Life Sci. 52, 29-34, (1992). The final concentrations of
microsomal protein and diclofenac substrate were 0.08 mg/mL and 4
.mu.M, respectively. Metabolic reactions were terminated by
treatment with three volumes of quench solution containing 1 .mu.M
mefenamic acid as internal standard. After centrifugation a further
4 volumes of water were added. Aliquots of the supernatant were
then subjected to LC-MS analysis.
[1046] For LC-MS analysis chromatographic elution was achieved by a
series of linear gradients starting at 20% B and holding for 0.3
minutes, then increasing to 99% B over 1.2 minutes, holding for 0.5
minutes and then returning to the starting conditions for 0.25 min.
The system was allowed to re-equilibrate for at least 0.25 minutes
prior to the next injection. The mass spectrometer was operated in
negative ion mode and the following precursor ([M-H].sup.-)/product
ion pairs were monitored and quantified: 4'-hydroxy-diclofenac
312.4/294.2 and mefenamic acid 242.4/224.2.
Biological Assays Used for the Characterization of HIV Protease
Inhibitors
HIV-1 Protease Enzyme Assay (Ki)
[1047] The assay is based on the fluorimetric detection of
synthetic hexapeptide substrate cleavage by HIV-1 protease in a
defined reaction buffer as initially described by M. V. Toth and G.
R. Marshall, Int. J. Peptide Protein Res. 36, 544 (1990) (herein
incorporated by reference in its entirety for all purposes).
[1048] The assay employed
(2-aminobenzoyl)Thr-Ile-Nle-(p-nitro)Phe-Gln-Arg as the substrate
and recombinant HIV-1 protease expressed in E. Coli as the enzyme.
Both of the reagents were supplied by Bachem California, Inc.
(Torrance, Calif.; Cat. no. H-2992). The buffer for this reaction
was 100 mM ammonium acetate, pH 5.3, 1 M sodium chloride, 1 mM
ethylendiaminetetraacetic acid, 1 mM dithiothreitol, and 10%
dimethylsulfoxide.
[1049] To determine the inhibition constant K.sub.i, a series of
solutions were prepared containing identical amount of the enzyme
(1 to 2.5 nM) and the inhibitor to be tested at different
concentrations in the reaction buffer. The solutions were
subsequently transferred into a white 96-well plate (190 .mu.l
each) and preincubated for 15 min at 37.degree. C. The substrate
was solubilzed in 100% dimethylsulfoxide at a concentration of 800
.mu.M and 10 .mu.l of 800 .mu.M substrate was added into each well
to reach a final substrate concentration of 40 .mu.M. The real-time
reaction kinetics was measured at 37.degree. C. using a Gemini
96-well plate fluorimeter (Molecular Devices, Sunnyvale, Calif.) at
.lamda.(Ex)=330 nm and .lamda.(Em)=420 nm. Initial velocities of
the reactions with different inhibitor concentrations were
determined and the K value (in picomolar concentration units) was
calculated by using EnzFitter program (Biosoft, Cambridge, U.K.)
according to an algorithm for tight-binding competitive inhibition
described by Ermolieff J., Lin X., and Tang J., Biochemistry 36,
12364 (1997).
HIV-1 Protease Enzyme Assay (IC50)
[1050] As for the K assay, above, the IC.sub.50 assay is based on
the fluorimetric detection of synthetic hexapeptide substrate
cleavage by HIV-1 protease in a defined reaction buffer as
initially described by M. V. Toth and G. R. Marshall, Int. T.
Peptide Protein Res. 36, 544 (1990).
[1051] The assay employed
(2-aminobenzoyl)Thr-Ile-Nle-(p-nitro)Phe-Gln-Arg as the substrate
and recombinant HIV-1 protease expressed in E. Coli as the enzyme.
Both of the reagents were supplied by Bachem California, Inc.
(Torrance, Calif.; Cat. nos. H-2992 and H-9040, respectively). The
buffer for this reaction was 100 mM ammonium acetate, pH 5.5, 1 M
sodium chloride, 1 mM ethylendiaminetetraacetic acid, and 1 mM
dithiothreitol, and 10% dimethylsulfoxide.
[1052] To determine the IC.sub.50 value, 170 .mu.L of reaction
buffer was transferred into the wells of a white 96-well microtiter
plate. A series of 3-fold dilutions in DMSO of the inhibitor to be
tested was prepared, and 10 .mu.L of the resulting dilutions was
transferred into the wells of the microtiter plate. 10 .mu.L of a
20-50 nM enzyme stock solution in reaction buffer was added to each
well of the 96-well plate to provide a final enzyme concentration
of 1-2.5 nM. The plates were then preincubated for 10 minutes at
37.degree. C. The substrate was solubilzed in 100%
dimethylsulfoxide at a concentration of 400 .mu.M and 10 .mu.l of
the 400 .mu.M substrate was added into each well to reach a final
substrate concentration of 20 .mu.M. The real-time reaction
kinetics were measured using a Gemini 96-well plate fluorimeter
(Molecular Devices, Sunnyvale, Calif.) at .lamda.(Ex)=330 nm and
.lamda.(Em)=420 nm. Initial velocities of the reactions with
different inhibitor concentrations were determined and the
IC.sub.50 value (in nanomolar concentration units) was calculated
by using GraphPad Prism.TM. software to fit nonlinear regression
curves.
Anti-HIV-1 Cell Culture Assay (EC50)
[1053] The assay is based on quantification of the HIV-1-associated
cytopathic effect by a colorimetric detection of the viability of
virus-infected cells in the presence or absence of tested
inhibitors. HIV-1-induced cell death was determined using a
metabolic substrate
2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide
(XTT) which is converted only by intact cells into a product with
specific absorption characteristics as described by Weislow O S,
Kiser R, Fine D L, Bader J, Shoemaker R H and Boyd M R, J. Natl.
Cancer Inst. 81, 577 (1989) (herein incorporated by reference in
its entirety for all purposes).
[1054] MT2 cells (NIH AIDS reagent program, Cat #237) maintained in
RPMI-1640 medium supplemented with 5% fetal bovine serum and
antibiotics were infected with the wild-type HIV-1 strain IIIB
(Advanced Biotechnologies, Columbia, Md.) for 3 hours at 37.degree.
C. using the virus inoculum corresponding to a multiplicity of
infection equal to 0.01. The infected cells in culture media were
distributed into a 96-well plate (20,000 cells in 100 .mu.l/well),
and incubated in the presence of a set of solutions containing
5-fold serial dilutions of the tested inhibitor (100 .mu.l/well)
for 5 days at 37.degree. C. Samples with untreated infected and
untreated mock-infected control cells were also distributed to the
96-well plate and incubated under the same conditions.
[1055] To determine the antiviral activity of the tested
inhibitors, a substrate XTT solution (6 mL per assay plate) at a
concentration of 2 mg/mL in a phosphate-buffered saline pH 7.4 was
heated in water-bath for 5 min at 55.degree. C. before 50 .mu.l of
N-methylphenazonium methasulfate (5 .mu.g/mL) was added per 6 mL of
XTT solution. After removing 100 .mu.l media from each well on the
assay plate, 100 .mu.l of the XTT substrate solution was added to
each well. The cells and the XTT solution were incubated at
37.degree. C. for 45 to 60 min in a CO.sub.2 incubator. To
inactivate the virus, 20 .mu.l of 2% Triton X-100 was added to each
well. Viability, as determined by the amount of XTT metabolites
produced, was quantified spectrophotometrically by the absorbance
at 450 nm (with subtraction of the background absorbance at 650
nm). Data from the assay was expressed as the percentage absorbance
relative to untreated control and the fifty percent effective
concentration (EC.sub.50) was calculated as the concentration of
compound that effected an increase in the percentage of XTT
metabolite production in infected, compound treated cells to 50% of
that produced by uninfected, compound-free cells.
Anti-HIV-1 Cell Culture Assay (EC.sub.50) in Presence of 40% Human
Serum or Human Serum Proteins
[1056] This assay is almost identical to the Anti-HIV-1 Cell
Culture Assay described above, except that the infection was made
in the presence or absence of 40% human serum (Type AB Male Cambrex
14-498E) or human serum proteins (Human .alpha.-acid Glycoprotein,
Sigma G-9885; Human Serum Albumin, Sigma A1653, 96-99%) at
physiological concentration. The HIV-1-induced cell death was
determined as described above, except that the infected cells
distributed in the 96-well plate were incubated in 80% Human Serum
(2.times. concentration) or in 2 mg/mL Human .alpha.-acid
Glycoprotein+70 mg/mL HSA (2.times. concentration) rather than in
culture media.
Cytotoxicity Cell Culture Assay (CC.sub.50)
[1057] The assay is based on the evaluation of cytotoxic effect of
tested compounds using a metabolic substrate
2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide
(XTT) as described by Weislow O S, Kiser R, Fine D L, Bader J,
Shoemaker R H and Boyd M R, J. Natl. Cancer Inst. 81, 577 (1989).
This assay is almost identical to the previous assay described
(Anti-HIV-1 Cell Culture Assay), except that the cells were not
infected. The compound induced cell death (or growth reduction) was
determined as previously described.
[1058] MT-2 cells maintained in RPMI-1640 medium supplemented with
5% fetal bovine serum and antibiotics were distributed into a
96-well plate (20,000 cells in 100 .mu.l/well) and incubated in the
presence or absence of 5-fold serial dilutions of the tested
inhibitor (100 .mu.l/well) for 5 days at 37.degree. C. Controls
included untreated infected cells and infected cells protected by 1
.mu.M of P4405 (Podophyllotoxin, Sigma Cat #P4405).
[1059] To determine cytotoxicity, an XTT solution (6 mL per assay
plate) at a concentration of 2 mg/mL in phosphate-buffered saline
pH 7.4 was heated in the dark in a water-bath for 5 min at
55.degree. C. before 50 .mu.l of N-methylphenazonium methasulfate
(5 .mu.g/mL) was added per 6 mL of XTT solution. After removing 100
.mu.L media from each well on the assay plate, 100 .mu.L of the XTT
substrate solution was added to each well. The cells and the XTT
solution were incubated at 37.degree. C. for 45 to 60 min in a
CO.sub.2 incubator. To inactivate the virus, 20 .mu.l of 2% Triton
X-100 was added to each well. Viability, as determined by the
amount of XTT metabolites produced, is quantified
spectrophotometrically by the absorbance at 450 nm (with
subtraction of the background absorbance at 650 nm). Data from the
assay is expressed as the percentage absorbance relative to
untreated control, and the fifty percent cytotoxicity concentration
(EC.sub.50) was calculated as the concentration of compound that
effected an increase in the percentage of cell growth in compound
treated cells to 50% of the cell growth provided by uninfected,
compound-free cells.
[1060] Experimental data based on representative Examples A-EQ
demonstrate that the compounds of Formula (IV) of the present
invention can have a CYP450 3A4 inhibition activity in a range
represented by an IC.sub.50 from about 100 nM to about 4700 nM, and
a CYP450 2C.sub.9 inhibition activity in a range represented by an
IC.sub.50 from about 100 nM to about 10,000 nM.
[1061] Experimental data based on representative Examples A-EQ
demonstrate that the compounds of Formula (IV) of the present
invention can have a protease inhibition activity in a range
represented by HIV EC.sub.50 from about 140 nM to greater than
about 30000 nM.
[1062] Experimental data based on representative Examples P, S, and
T have a CYP450 3A4 inhibition activity in a range represented by
an IC.sub.50 from about 80-150 nM, a CYP450 2C.sub.9 inhibition
activity in a range represented by an IC.sub.50 from about
1000-10,000 nM, and a protease inhibition activity in a range
represented by HIV EC.sub.50 greater than about 30,000 nM.
* * * * *