Evaluation of endo- and exo-aryl-substitutions and central scaffold modifications on diphenyl substituted alkanes as 5-lipoxygenase activating protein inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.04.064

A search for a suitable replacement for the central norbornyl scaffold presented in the recently disclosed novel FLAP inhibitors is herein described, as well as the SAR study performed on the endo and exo-aryl groups.

Full text of DOI:10.1016/j.bmcl.2012.04.064

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4133–4138
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Evaluation of endo- and exo-aryl-substitutions and central scaffold
modifications on diphenyl substituted alkanes as 5-lipoxygenase
activating protein inhibitors
⇑
Lin Chu , Helen M. Armstrong, Linda L. Chang, Amy F. Cheng, Lawrence Colwell, Jisong Cui, Jilly Evans,
Amy Galka, Mark T. Goulet , Nancy Hayes, Jane Lo, John Menke, Hyun O. Ok, Debra L. Ondeyka,
Minal Patel, Grace M. Quaker, Heather Sings à, Stephanie L. Witkin, Annie Zhao, Feroze Ujjainwalla
Discovery and Preclinical Sciences, Merck Research Laboratories, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A search for a suitable replacement for the central norbornyl scaffold presented in the recently disclosed
Received 9 March 2012
Revised 4 April 2012
Accepted 10 April 2012
Available online 20 April 2012
novel FLAP inhibitors is herein described, as well as the SAR study performed on the endo and exo-aryl
groups.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
5-Lipoxygenase activating protein
FLAP inhibitors
Antiasthmatic
N
Inhibition of leukotriene biosynthesis has been reported for the
treatment of allergic rhinitis, asthma, and other inflammatory con-
ditions.1 Inhibitors of the membrane protein 5-Lipoxygenase Act-
ing Protein (FLAP) have been described to block the formation of
cellular leukotrienes.2 Recently, Helgadottir et al. reported that
FLAP was genetically linked to the risk of myocardial infarction
and stroke in humans.3 FLAP inhibition therefore may be of thera-
peutic potential as a novel treatment for atherosclerotic disease.
A previous communication from our colleagues described the
identification of 5-benzothiazolyl-methoxy-2-pyridinyl carbamate
derivative (1, FLAP binding IC50 = 2.7 nM, HWBA IC50 = 36 nM) and
5-quinolinemethoxy-2-methyl ester 2 as pharmacologically active
(in vitro) FLAP inhibitors.4 The ester functionality in 2 not only pre-
sented a potential synthetic handle to access other structure–activ-
ity relationships, but also served as an acceptable benchmarking
substituent with which to explore SAR in other regions of the mol-
ecule. In this communication, we disclose the SARs in the methyl
ester series (2) for: replacement of the central norbornyl scaffold;
investigation of various amide and heterocyclic substituents at
the 2-position of the exo-aryl ring, and substitutions on the endo-
aryl ring. All compounds were prepared as racemic mixtures unless
indicated otherwise.
N
O
O
O
5
2
5
2
S
1
1
H
N
OMe
N
O
O
2
1
We first explored substitution on the endo-aryl ring. The synthetic
route to these analogues is outlined in Scheme 1 and is similar to
that shown in a previous report.4 The principal modifications to
the historic route are incorporation of tert-butyl-diphenylsilyl and
Boc protecting groups to avoid over-alkylation in step f. Table 1
summarizes our systematic survey of substituents on the endo-phe-
nyl ring. In short, meta-substitution generally furnished compounds
with improved potency in the human whole blood assay (HWBA)
versus ortho- or para-substitution (not all data shown). Among all
of the substituents surveyed, the 3-methoxy group afforded ana-
logue (13f) with the best activity in human whole blood.
Concurrently, we investigated different central scaffolds. Liver
microsome stability experiments with compound 2 and other re-
lated analogues revealed the sensitivity of the norbornyl group to-
ward metabolic oxidation. We reasoned that this may be a
contribution factor to the generally short half lives (t1/2) observed
⇑
Corresponding author. Tel.: +1 732 594 1125; fax: +1 732 594 5966.
E-mail address: lin_chu@merck.com (L. Chu).
Current department: DPS Strategic Operations.
Current department: Global Scientific and Medical Publications.
à
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.04.064

4134
L. Chu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4133–4138
OH
OMe
OMe
OMe
a
b
OH
a
b
c
O
O
OH
Cl
OMe
OMe
OMe
R1
R1
3 O
26
4
6
27
28
OH
OSitBuPh2
OSitBuPh2
OH
c
d
e
OH
OH
OBoc
OBoc
R1
R1
R1
N
29
7
8
9
N
Scheme 2. Partial synthesis of compound 14. Reagents and conditions: (a)
PhB(OH)2, Pd(PPh3)4, Cs2CO3, toluene, 100 °C; (b) dimethyl zinc, TiCl3, DCM,
À50 °C; (c) boron tribrimide, DCM, 0 °C to rt.
O
O
g
f
OBoc
10
OH
O
OH
R1
R1
OH
OH
OH
11
a
+
N
N
O
OH
30
31
5
h
i
OTf
OMe
Scheme 3. Partial synthesis of compound 15. Reagents and conditions: (a) pTsOH
hydrate, toluene, reflux.
R1
R1
O
12
13
OMe
OMe
Scheme 1. Synthesis of compounds for investigation of endo-aryl SAR. Reagents
and conditions: (a) R1MgX, 0 °C in THF or ether; (b) Hydroquinone (5), AlCl3, reflux
in toluene; (c) tert-butyl-diphenylsilyl chloride, imidazole, DMF, rt; (d) Boc
anhydride; (e) TBAF, THF, 0 °C; (f) 2-chloromethylquinoline, NaH, DMF; (g) KOH,
MeOH/THF, reflux; (h) triflic anhydride, pyridine, toluene; (i) Pd(OAc)2, dppf,
triethylamine, CO, DMF/MeOH.
OMe O
a
b
c
HO
O
H
OMe
OMe
32
33
OMe
27
OMe
OMe
OH
Table 1
Selected analogues from endo-aryl SAR study and their corresponding in vitro assay
data
R
d
e
R
R
HO
Compounds
R1
FLAP binding5 IC50 (nM)
HWBA6 IC50 (nM)
OMe
OMe
OH
R
=
2
H
2-F
3-F
4-F
3-Me
3-CF3
3-OMe
3,5-di-F
3,5-di-Me
2.1
4.0
2.3
9.5
5.5
7.4
2.5
3.4
3.5
460
1600
472
1400
940
>8600
322
34
35
36
13a
13b
13c
13d
13e
13f
13g
13h
Scheme 4. Partial synthesis of compounds 16 & 18. Reagents and conditions: (a)
PhMgBr, THF, À10 °C; (b) Swern; (c) RMgX, ether, À10 °C; (d) triethyl silane, TFA,
DCM, rt; (e) boron tribromide, DCM, 0 °C to rt.
1315
2304
OMe
OMe
OMe
c
a
b
O
(HO)2B
HO
OMe
OMe
OMe
with these compounds when dosed in rats. Therefore, we focused
our efforts on designing metabolically robust scaffolds, in the hope
of improving t1/2. Syntheses of these analogues are described in
Schemes 2–8. Scheme 2 describes the synthesis of hydroquinone
29. Interestingly, while treatment of ketone 27 with dimethyl zinc
and titanium trichloride in DCM afforded the dimethyl analogue 28
in good yields, the analogous diethyl compound could not be ob-
tained via this route. Instead, a Friedel–Crafts approach was uti-
lized (Scheme 3). In addition, although the Grignard reactions of
ketone 27 (Scheme 4) with both the neopentyl or cyclohexyl de-
rived reagents went smoothly, no product was detected with
tert-butyl Grignard. This is presumably due to steric congestion,
which led to the development of an alternative in which the tert-
butyl group is introduced at an earlier stage via a Pd-catalyzed
transformation (Scheme 5).
37
39
38
OH
OMe
d
OH
OMe
41
40
Scheme 5. Partial synthesis of compound 17. Reagents and conditions: (a)
Pd(PPh3)4, Cs2CO3, pivaloyl chloride, toluene, 100 °C; (b) PhMgBr, ether, 0 °C; (c)
triethyl silane, TFA, DCM, rt; (d) boron tribromide, DCM, 0 °C to rt.
The achiral norbonyl analogue 19 was prepared in analogous
fashion to the approach outlined in Scheme 1 (Scheme 6).

L. Chu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4133–4138
4135
A systematic survey of the optimal ring size in the central scaf-
fold was conducted. Cyclobutyl (22), cyclopentyl (21), and cyclo-
hexyl (20) compounds and their derivatives were synthesized
(Scheme 7, Table 2). Another reaction of interest was the ring
opening by hydrogenation of the spiro-cyclopropyl group in com-
pound 53 (Scheme 7). No reaction was observed when palladium
on carbon was used. When platinum oxide was employed, the de-
sired cyclopropyl ring opening was accomplished with undesired,
concomitant saturation of the endo-phenyl ring. Fortunately, the
a
b
OH
OH
O
44
42
43
OH
OH
c
45
Scheme 6. Partial synthesis of compound 19. Reagents and conditions: (a) PhMgBr,
THF, 0 °C; (b) Pd on carbon, H2, EtOH; (c) hydroquinone (5), pTsOH hydrate, toluene,
reflux.
Table 2
Summary of central scaffold replacements and their corresponding in vitro assay data
N
R2
O
OMe
OMe
OMe
OMe
O
O
a
b
c
Compounds
R2
FLAP binding5 IC50 (nM)
2.1
HWBA6 IC50 (nM)
460
Cl
O
OMe
OMe
OMe
Cl
46
47
48
2
OH
OMe
14a
15b
58
96
>9000
>9000
O
d
OH
OMe
50
49
16c
16
>9000
OMe
OH
17d
18c
5.5
3
670
f
e
49
OMe
OH
2000
51
52
g
19e
20f
5.6
15
1300
1560
OH
OMe
OMe
h
i
OH
OMe
OMe
21f
22f
8.5
20
3700
53
54
55
>7000
OMe
OH
O
23f
24g
3.2
50
1100
j
k
49
F
OMe
OH
F
>9000
56
57
j
OMe
OMe
OH
O
25f
5.2
1400
O
k
+
a
For synthesis to intermediate 29, see Scheme 2, then follow the analogous
transformations outlined in Scheme 1.
For synthesis to intermediate 31, see Scheme 3, then follow the analogous
transformations outlined in Scheme 1.
For synthesis to intermediate 36, see Scheme 4, then follow the analogous
transformations outlined in Scheme 1.
For synthesis to intermediate 41, see Scheme 5, then follow the analogous
transformations outlined in Scheme 1.
For synthesis to intermediate 45, see Scheme 6, then follow the analogous
transformations outlined in Scheme 1.
For synthesis to intermediates 50, 52, 55, 57, 60, see Scheme 7, then follow the
analogous transformations outlined in Scheme 1.
OMe
OMe
OH
b
58
59
60
c
Scheme 7. Partial synthesis of compound 20,21,22, 23,
&
25. Reagents and
conditions: (a) PhMgBr, ether, À10 °C; pTsOH hydrate, MeOH, 90 °C; (b) trichloro-
acetyl chloride, Zn dust, ether, sonication; (c) Zn, AcOH, 70 °C; (d) hydrazine, 160 °C,
then diethylene glycol, KOH, 150 °C; boron tribromide, DCM, 0 °C to rt; (e) MeMgBr,
ether, 0 °C; pTsOH, benzene, 90 °C; (f) Pd on carbon, H2, EtOH; boron tribromide,
DCM, 0 °C to rt; (g) diethyl zinc, chloroiodomethane, DCE, 0 °C; (h) Pt on carbon
(sulfided), H2, MeOH, AcOH overnight; (i) Boron tribromide, DCM, 0 °C to rt; (j)
TMS-diazomethane, trimethyl aluminum, DCM, À78 °C to À25 °C; (k) hydrazine,
160 °C, then diethylene glycol, KOH, 150 °C; boron tribromide, DCM, 0 °C to rt.
d
e
f
g
For synthesis of 24, see Scheme 8.

4136
L. Chu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4133–4138
N
O
a
O
B
Br
O
R
R
a
b
f
NHNHBoc
NHNH2
61
62
O
O
OH
= RCOOH
c
75
76
OBn
O
OH
OBn
b
c
e
g
h
d
TfO
HO
62
f
HO
R
CO2Me
R
R
R
R
R
CO2Me
63
CO2Me
N
O
N
77
65
64
O
N
O
N
O
N
O
N
N
N
N
O
OBn
OBn
NH
N
NH
O 79
Me
S
80 Me 81 H 82
H N 78
2
O
d
e
65
+
Cl
CO2Me
CO2Me
Cl
R
R
i
j
k
67
66
ROTf
N
N
RCN
NHOH
12 (R1=H)
O
85
R
OBn
OBn
NH 84
H
83
F
F
O
l
g
h
m
R
CO2Me
CO2Me
N
N
N
N
R
R
O
69
N N
68
R
Me
Me
o
n
N
N
N
N
N
N N
N
86
OH
O
88
R
N
N
N
N
N
F
F
F
F
H
i
87
F
F
91
90
N
N
N
N
CO2Me
CO2Me
89
70
24
Scheme 10. Synthesis of compounds 77–91. Reagents and conditions: (a) Boc-
hydrazide, HATU, DIPEA, DMF; (b) HCl/dioxane, DCM; (c) (1) acetamide oxime, DIC,
HOBT, DMF/DCM. (2) CH3CO2Na, EtOH, H2O, 85 °C;7 (d) NaHCO3, BrCN, dioxane/
H2O, 25 °C; (e) Phosgene, DCM, -78 °C; (f) thiophosgene, THF, À78 °C; (g) (1) Acetyl
chloride, TEA, DCM. (2) SOCl2, 25 °C; (h) CH(OEt)3, cat. TsOH; (i) Zn(CN)2, Pd2(dba)3,
dppf, NMP, 140 °C; (j) NH2OH hydrate, EtOH, 120 °C; (k) CH(OEt)3, cat. TsOH,
125 °C; (l) Acetyl chloride, pyridine; (m) Me3SnN3, toluene, 120 °C; (n) K2CO3, R’X,
DMF, rt; (o) NaH, ClCHF2, rt.
Scheme 8. Synthesis of compound 24. Reagents and conditions: (a) Bis(pinacola-
to)diboron, PdCl2(PPh3)2, triphenylphosphine, PhOK, toluene, 50 °C; (b) Benzyl
alcohol, triphenylphosphine, DIAD, THF, 0 °C; (c) triflic anhydride pyridine, DCM;
(d) PdCl2(dppf)2, K2CO3, DMF, 80 °C; (e) trichloroacetyl chloride, Zn-Cu couple,
ether/DME, 50 °C; (f) Zn, AcOH, 70 °C; (g) DeoxofluorÒ, DCM, EtOH; (h) Pd on
carbon, H2, EtOH; (i) 2-chloromethylquinoline, KI, K2CO3, DMF.
Table 4
N
Compounds 77–91 and their in vitro assay data
O
O
O
O
O
O
N
O
a
b
R3
OMe
OH71
2
R4
Scheme 9. Synthesis of compounds 72–74. Reagents and conditions: (a) KOH, THF/
propylene glycol, 110 °C; (b) R3 H, HATU, DIPEA, DMF.
Compounds
R4
FLAP binding5 IC50 (nM)
HWBA6 IC50 (nM)
1018
N
O
N
77
6.3
Table 3
Me
Compounds 72–74 and their in vitro assay data
Compounds R3
FLAP binding5 IC50 (nM) HWBA6 IC50 (nM)
O
N
N
78
79
80
2.2
2.5
1.1
258
796
753
H2N
2
2.1
5.8
460
O
OMe
O
O
N
N
72
2164
O
N
H
NH
73
48
964
O
N
H
O
S
N
NH
74
7.1
1727
O
N

L. Chu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4133–4138
4137
application of platinum on sulfided carbon (100 wt%) resolved the
selectivity issue.
Table 4 (continued)
Compounds
R4
FLAP binding5 IC50 (nM)
HWBA6 IC50 (nM)
When a similar approach as described in Scheme 7 was adopted
to prepare the difluoro analogue 24 from ketone 49, the difluoro
cyclobutyl moiety decomposed during the de-methylation step.
Redesign of the synthesis focused on incorporation of the methyl
ester functionality early in the synthetic sequence (Scheme 8). Vi-
nyl boronate ester 62 was obtained in moderate but reproducible
yields only when freshly prepared potassium phenoxide was used
in the coupling step. The palladium catalyzed coupling of boronate
ester 62 with triflate 65 went smoothly. The resulting styrene com-
pound 66 was subjected to dichloroketene cyclization followed by
reaction with DeoxofluorÒ to generate the difluorocyclobutane 69.
Subsequent debenzylation and alkylation afforded the desired
compound 24.
Activities of compounds prepared according to the routes de-
scribed in Schemes 2–8 are summarized in Table 2. While acyclic
gem-disubstituted analogues (14, 15) showed substantial loss of
FLAP binding and whole blood activity, cyclic variations such as
cyclobutyl (22), cyclopentyl (21) and cyclohexyl (20) groups were
better tolerated. Among these, the cyclopentyl analogue (21)
exhibited consistently better activity in the FLAP binding assay.
However, if the cyclobutyl ring was appropriately substituted,
improvements in potency could be realized (23–25), which is con-
sistent with a hypothesis that the central scaffold binds within a
lipophilic pocket. Finally, mono-alkyl replacements, such as those
shown in the tert-butyl (17) and neopentyl (18) analogues demon-
strate comparable in vitro activities to the bench-mark norbornyl
compound 2.
O
N
N
81
82
85
86
87
5.0
456
Me
O
H
N
2.9
5.4
1.6
2.9
376
721
189
5718
N
N
H
N
O
N
N
O
Me
N
N
N
N
H
N
N
N
88
89
2.8
2.4
313
177
N
Me
N
N
N
N
N
N
N
Since the SAR of the 5-substituent on the exo-aryl ring had been
previously optimized,4 we focused our attention to the modifica-
tions at the 2-position of the exo-ring. Various amides were pre-
pared initially (Scheme 9). We quickly discovered that although
this modification could maintain binding affinity to FLAP, it rou-
tinely came at the expense of human whole blood activity (Table 3),
possibly due to a large serum shift and/or poor cellular permeabil-
ity. We subsequently explored the possibility of using heterocycles
90
91
1.7
2.4
149
502
N
N
N
N
N
F
F
Table 5
Compounds 92–96 and their in vitro assay data and pharmacokinetic data9
N
O
R2
N
NH
R1
O
O
Compounds
R1
H
R2
FLAP binding5
IC50 (nM)
HWBA6 IC50 (nM)
Cl
Vd (L/kg)
iv AUCN
M. h. kg/mg)
Cmax
(lM)
t1/2 (h)
F
(%)
(ml/min/kg)
(
l
92a
0.8
469
7.3
1.0
0.58
0.40
1.0
12
93a
94a
3-OMe
H
1.1
1.9
375
534
7.2
29
0.7
5.3
0.79
0.34
0.67
0.25
1.2
4.3
17
27
Me
Me
95a
96a
H
H
3.6
2.6
834
695
71
32
7.5
3.1
0.05
0.19
0.01
0.12
1.7
2.0
9
Me
17
a
Compounds 92–95 are chiral compounds with stereochemistry as shown. Compound 96 is either cis or trans in configuration.

4138
L. Chu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4133–4138
as replacements. In contrast to the amides prepared, a wide variety
of heterocycles were well tolerated at the 2-position of the exo-
phenyl ring (Scheme 10, Table 4). Regioisomeric oxadiazoles as
well as alkylated tetrazoles all exhibited comparable FLAP binding.
The most striking disconnect between binding and HWB was
observed with analogue 87, which was likely due to the poor cellu-
lar permeability of this acidic-proton containing compound at
physiologoical pH8 and/or high degree of plasma protein binding.
Although alkylated tetrazoles exhibited good HWB potency, they
generally suffered from poor PK due to rapid dealkylation in vivo.
We then combined various findings from our SAR investigations,
specifically the meta-methoxy substituent from the endo-aryl
study and the tert-butyl and dimethyl/monomethyl-cyclobutyl
groups from the central scaffold. For the substituent at the
2-position of the exo-ring, we decided to use the keto-oxadiazole
unit (79) as our standard template due to the balance of PK and
potency. The general synthetic sequence was similar to that
outlined in Scheme 10. The in vitro assay results and the pharma-
cokinetic evaluation of these hybrids are summarized in Table 5.
Among the compounds tabulated, the tert-butyl analogue 94 was
shown to have some slight advantage in its PK profile (improved
Vd and bioavailability) over the others while retaining FLAP inhibi-
tion activity.
tolereated at the 2-position of the exo-phenyl ring, laying the
groundwork for further studies which will be the subject of future
publications.
References and notes
1. (a) Friesen, R. W.; Riendeau, D. Ann. Rep. Med. Chem. 2005, 40, 199; (b) Funk, C. D.
Nat. Rev. Drug Disc. 2005, 4, 664.
2. Miller, D. K.; Gillard, J. W.; Vickers, P. J.; Sadowski, S.; Léveillé, C.; Mancini, J. A.;
Charleson, P.; Dixon, R. A.; Ford-Hutchinson, A. W.; Fortin, R.; Gauthier, J. Y.;
Rodkey, J.; Rosen, R.; Rouzer, C.; Sigal, I. S.; Strader, C. D.; Evans, J. F. Nature 1990,
343, 278.
3. Helgadottir, A. et al Nat. Genet. 2004, 36, 233.
4. Macdonald, D.; Drideau, C.; Chan, C. C.; Falgueyret, J.-P.; Frenette, R.; Guay, J.;
Hutchinson, J. H.; Perrier, H.; Prasit, P.; Riendeau, D.; Tagari, P.; Therien, M.;
Young, R. N.; Girard, Y. Bioorg. Med. Chem. Lett. 2008, 18, 2023.
5. IC50 data are derived from the ability of the tested compound to inhibit binding
of 125I radiolabeled FLAP ligand to human polymorphonuclear membranes. Also
see Charleson, S.; Prasit, P.; Léger, S.; Gillard, J. W.; Vickers, P. J.; Mancini, J. A.;
Charleson, P.; Guay, J.; Ford-Hutchinson, A. W.; Evans, J. F. Mol. Pharmacol. 1992,
41, 873.
6. IC50 data are derived from the ability of the tested compound to inhibit calcium
ionophore-stimulated LTB4 production by isolated human polymorphonuclear
cells in presence of whole human blood (HWBA). Also see Brideau, C.; Chan, C.;
Charleson, S.; Denis, D.; Evans, J. F.; Ford-Hutchinson, A. W.; Fortin, R.; Gillard, J.
W.; Guay, D.; Guévremond, D.; Hutchinson, J. H.; Jones, T. R.; Léger, S.; Mancini,
J. A.; McFarlane, C. S.; Pickett, C.; Piechuta, H.; Prasit, P.; Riendeau, D.; Rouzer, C.
A.; Tagari, P.; Vickers, P. J.; Young, R. N.; Abranham, W. M. Can. J. Physiol.
Pharmacol. 1992, 70, 799.
In conclusion, we have shown that an unsubstituted endo-
phenyl group is optimal, although substitution at the 3-position
is consistently tolerated. In addition, the tert-butyl group appears
to be an effective surrogate for the bicyclic moiety in the central
scaffold. Its smaller size provides opportunities for additional
substitutions elsewhere in the molecule without exceeding a
desirable molecular weight range. Furthermore, we have
7. Hamzé, A.; Hernandez, J.-F.; Fulcrand, P.; Martinez, J. J. Org. Chem. 2003, 68,
7316.
8. Kerns, E. H.; Di, L. Drug-Like Properties: Concepts, Structure Design and Methods;
Academic Press, 2008.
9. Pharmacokinetic experiments in the rat: Male Sprague–Dawley rats were dosed
with the test compounds individually at 1 mg/kg IV and 2 mg/kg PO. Plasma
concentrations were taken at t = 0–8 h and PK parameters determined
therewith.
demonstrated that
a wide variety of heterocyles were well