Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of sulphone-based CRTh2 antagonists

Article abstract of DOI:10.1016/j.ejmech.2016.02.023

Monocyclic and bicyclic ring systems were investigated as the "core" section of a series of diphenylsulphone-containing acetic acid CRTh2 receptor antagonists. A range of potencies were observed and single-digit nanomolar potencies were obtained in both the monocyclic and bicyclic cores. Residence times for the monocyclic compounds were very short. Some of the bicyclic cores displayed better residence times. A methyl group in the northern part of the core, between the head and tail was a necessary requirement for the beginnings of long residence times. Variations of the tail substitution maximised potencies and residence times.

Full text of DOI:10.1016/j.ejmech.2016.02.023

Accepted Manuscript
Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of
sulphone-based CRTh2 antagonists
Maria Antonia Buil, Marta Calbet, Marcos Castillo, Jordi Castro, Cristina Esteve,
Manel Ferrer, Pilar Forns, Jacob González, Sara López, Richard. S. Roberts, Sara
Sevilla, Bernat Vidal, Laura Vidal, Pere Vilaseca
PII:
S0223-5234(16)30093-9
10.1016/j.ejmech.2016.02.023
EJMECH 8374
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 3 December 2015
Revised Date: 5 February 2016
Accepted Date: 7 February 2016
Please cite this article as: M.A. Buil, M. Calbet, M. Castillo, J. Castro, C. Esteve, M. Ferrer, P. Forns,
J. González, S. López, R.S. Roberts, S. Sevilla, B. Vidal, L. Vidal, P. Vilaseca, Structure-activity
relationships (SAR) and structure-kinetic relationships (SKR) of sulphone-based CRTh2 antagonists,
European Journal of Medicinal Chemistry (2016), doi: 10.1016/j.ejmech.2016.02.023.
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ACCEPTED MANUSCRIPT
Title
2 Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of
sulphone-based CRTh2 antagonists
Corresponding author (address until 24 feb 2016)
* Richard S. Roberts, Drug Discovery Division, Almirall R&D Centre, Laureano Miró, 408-410,
08980 Sant Feliu de Llobregat, Barcelona, Spain. Tel: +34 93 291 7540. Fax: +34 93 291 3420.
e-mail: rick.roberts@almirall.com
(address from 26 feb 2016)
* Richard S. Roberts, Minoryx Therapeutics S.L., TecnoCampus Mataró-Maresme, Av. Ernest
Lluch 32, TCM3, 08302 Mataró (Barcelona), Spain.
Tel: +34 93 544 14 66. e-mail: rroberts@minoryx.com
Graphical abstract
R1
HO
O
R2
"head"
S
O
O
"tail"
"core"
monocyclic or bicyclic
low nanomolar CRTh2 antagonists
Receptor dissociation half-lives up to 21 h

ACCEPTED MANUSCRIPT
CRTh2 Antagonist
Receptor residence time
Structure-Activity Relationship (SAR)
Structure-Kinetic Relationship (SKR)
Structure-activity relationships (SAR) and structure-
kinetic relationships (SKR) of sulphone-based CRTh2
antagonists
Maria Antonia Buil,a Marta Calbet,a Marcos Castillo,b Jordi
Castro,a Cristina Esteve,a Manel Ferrer,a Pilar Forns,b Jacob
González,a Sara López,a Richard. S. Roberts,a,c* Sara Sevilla,a
Bernat Vidal,a Laura Vidal,a Pere Vilaseca,a
1. Introduction
CRTh2 (chemoattractant receptor homologous molecule
expressed on Th2 lymphocytes) is a GPCR involved in the
chemotaxis of Th2 lymphocytes, eosinophils and basophils.1,2
CRTh2 also inhibits the apoptosis of Th2 lymphocytes3 and
stimulates the production of IL4, IL5, and IL13,4 cytokines
involved in pro-inflammatory biological responses. CRTh2
antagonists are therefore under active development as
potential treatments in pathologies related to allergic
inflammation. Several recent reviews have highlighted the
progress and most advanced series of CRTh2 antagonists, both
in pre-clinical5,6 and clinical development.7,8
a Almirall R&D Centre, Laureano Miró, 408-410, 08980 Sant
Feliu de Llobregat, Barcelona, Spain.
b Almirall-Barcelona Science Park Unit, Barcelona Science
Park, Josep Samitier 1-5, 08028 Barcelona, Spain
c Present address: Minoryx Therapeutics S.L. TecnoCampus
Mataró-Maresme, Av. Ernest Lluch 32, TCM3,
08302 Mataró (Barcelona), Spain. Tel: +34 93 544 14 66. e-
mail: rroberts@minoryx.com
As a continuation of our drug discovery program into potent,
oral CRTh2 antagonists with long receptor residence times,
we were keen to expand the Structure-Activity Relationship
(SAR) and more importantly the Structure-Kinetic
Relationship (SKR) around a series of diphenylsulphone-
containing acetic acid CRTh2 receptor antagonists. The
compounds could be split into three conceptual areas; the
acetic acid “head” group, a mono- or bicyclic aromatic “core”
ring system and a “tail” group. We, and others had previously
had success in finding potent antagonists when the tail groups
was a 2-(phenylsulphonyl)benzyl group. In this case, different
cores such as pyrazole 1,9 reverse pyrazole 2,10 indole 311 or
pyrrolopiperidinones (PPAs) 412 could all be successfully
introduced (Figure 1). Potency and dissociation time data for
compounds 1-4 are shown in Table 1. In a parallel line of
research, we had shown that the bicyclic core or a series of
biaryl CRTh2 antagonists was open to wide variation.13,14
Good potencies were generally accessible through
modification of the core. The core also had a profound effect
on the receptor residence half-life as demonstrated between
compounds 1 and 4. Clearly, there was scope to investigate
further structural modifications to the core. In a first
approximation, any core giving rise to a residence half-life
≥1h was of interest. Only those most promising cores would
then be taken forward with a view of finding compounds
displaying long receptor residence time, if possible ≥12h.
Corresponding author
* Richard S. Roberts, Drug Discovery Division, Almirall
R&D Centre, Laureano Miró, 408-410, 08980 Sant Feliu de
Llobregat, Barcelona, Spain. Tel: +34 93 291 7540. Fax: +34
93 291 3420.
e-mail: rick.roberts@almirall.com
Highlights
• Synthesis of sulphone-containing heteraromatic acetic acids
as CRTh2 antagonists
• A multitude of synthetic routes are given
• Structure-activity relationships (SAR) are discussed
• Structure-kinetic relationships (SKR) are discussed
• Potent and long resident compounds were identified
Graphical abstract
Abstract
Monocyclic and bicyclic ring systems were investigated as the
“core” section of a series of diphenylsulphone-containing
acetic acid CRTh2 receptor antagonists. A range of potencies
were observed and single-digit nanomolar potencies were
obtained in both the monocyclic and bicyclic cores. Residence
times for the monocyclic compounds were very short. Some
of the bicyclic cores displayed better residence times. A
methyl group in the northern part of the core, between the
head and tail was a necessary requirement for the beginnings
of long residence times. Variations of the tail substitution
maximised potencies and residence times.
Keywords

ACCEPTED MANUSCRIPT
Here we describe the various synthetic routes used to obtain
the various aromatic cores. Due to the wide variation of
structures, in many cases yields were not optimized, as
obtaining a sample for biological testing was the priority.
The general tail synthons were synthesized according to
Scheme 1. We limited ourselves to just three tails: (a)
unsubstituted, (b) para-fluoro in the terminal phenyl ring and
(c) a methoxy-fluoro disubstituted tail. Smooth addition of
sulphides 6 to ortho-fluoro aldehydes 5 gave sulphides 7
which were then oxidized to sulfones 8. Bromides 10 were
obtained by reduction of the aldehyde and bromination.
Amine 11a was obtained by a two-step reductive amination.
Fig. 1. Sulphone-containing CRTh2 antagonists.
Table 1
Monocyclic and bicyclic core SAR and SKR
Compound
Series
Dissociation
GTPγS
half-life (h)
IC50 (nM)
Pyrazole
Rev Pyr
Indole
PPA
7
85
14
5
0.1
0.02
1.3
1
2
3
4
2.3
2. Chemistry
Scheme 1. Synthetic route to tail synthons 8, 10 and 11 (0.2-
1.9 g scale).
In almost all cases, each different central core required a
separate synthetic route. In general, the acetic acid head group
was added from one of three synthons (Figure 2): when the
core contained an NH suitable for alkylation, a bromoacetate
was sufficient. When the head-to-core linkage was a carbon-
carbon bond, we used either Friedel-Crafts reaction with a
monooxalyl chloride followed by reduction, or an
organometallic coupling with an acetate zincate reagent. The
tails were added via a bromide, if alkylation was an option, or
in many case from an aldehyde by reductive alkylation. Other
methods were also used where appropriate.
The monocyclic cores were synthesized as follows:
Pyrazolone 16, a close analogue of our original pyrazole 1,
was synthesized as shown in Scheme 2. Knoevenagel
condensation of tail aldehyde 8a with ethyl acetoacetate15 gave
a mixture of regioisomers 12, and the double bond was then
reduced with hydrogen over palladium on carbon. This
process was generally higher yielding than direct alkylation of
ethyl acetoacetate with bromide 10a. Acetoacetate 13 was
condensed with phenyl hydrazine,16 again giving a mixture of
regioisomers and a low yield after a tricky separation. 14 was
alkylated with ethyl bromoacetate and ester hydrolysis gave
16.
Fig. 2. Typical synthetic strategies.

ACCEPTED MANUSCRIPT
Scheme 2. Synthesis of pyrazolone 16 (7 mg scale).
Imidazolone 20, a regioisomeric core of 16, was synthesized
according to Scheme 3. 2-Bromo-1-phenylpropan-1-one was
aminated with sodium diformylamide17 and resulting
aminoketone 17 was cyclized with ethyl 2-isocyanatoacetate.18
The completed core 18 was then alkylated with tail bromide
10b and ester hydrolysis gave the imidazolone 20.
EtO
O
OHC
CHO
EtO
O
N
N
O
O
O
Na
NCO
Br
NH2—HCl
NH
(1) MeCN
(1) NEt3
75 ºC, 36h
(2) 5N HCl
reflux, 45 min
acetone
0 ºC, 3h
(2) TFA
20 ºC, 1h
17
18
R3O
O
N
Scheme 4. Synthesis of triazolones 24 and 30 (85-100 mg
O
X006b
F
scale).
S
N
O
NEt3, K2CO3
O
DMF, 20 ºC, 18 h
Imidazole 36 was synthesized according to Scheme 5.
Hippuric acid (N-benzoyl glycine) was condensed with tail
aldehyde 8b in an Erlenmeyer-Plöchi azlactone synthesis.20
Hydrolysis of the azlactone (oxazolinone) of 31 gave 32 and
reduction of the double bond gave functionalized
phenylalanine 33. Methyl ketone 34 was synthesized through
an acylation-decarboxylation sequence using acetic anhydride.
We tried to synthesize 36 directly by condensation of 34 with
glycine, or glycine esters, however no reaction or
decomposition was observed. Finally we achieved cyclization
of 34 to the imidazole core by condensation with 2-
aminoethanol,21 albeit in a very poor 7% yield. However this
gave us sufficient material to obtain 36 via a Jones oxidation.22
19 R3 = Et
20 R3 = H
LiOH, THF/H2O
20 ºC, 18 h
Scheme 3. Synthesis of imidazolone 20 (34 mg scale).
Regioisomeric triazolones 25 and 30 were synthesized
according to Scheme 4. Benzohydrazide was condensed with
ethyl 2-isocyanatoacetate to give urea 21. This was cyclized
under highly basic conditions,19 also resulting in ester
hydrolysis. Carboxylic acid 22 was re-esterified prior to tail
alkylation. A second ester hydrolysis of 24 gave the desired
product. Regioisomer 30 was synthesized along similar lines,
but reversing the reactivity of the reagents. Here, tail amine
11a was converted to the isocyanate 26 and this was used for
condensation with benzohydrazide. After base-catalyzed
cyclization, the core of 23 was alkylated with ethyl
bromoacetate and hydrolysed as before to the desired product
30. In both cases, the base-catalyzed cyclization (21 → 22 and
28 → 29) was a dirty reaction with many sub-products. The
products of these reactions were not purified at this stage, but
used crude in the subsequent alkylations and purified at that
point.

ACCEPTED MANUSCRIPT
HO
O
O
8b
O
NaOH
NH
N
THF/H2O
80 ºC, 20 min
Ac2O
NaOAc
100 ºC, 2 h
O
O
O
S
31
F
O
OH
O
OH
O
O
Ac2O
Zn, AcOH
80 ºC, 8h
N
H
N
H
NEt3, DMAP
60 ºC, 1 h
O
S
O S
O
O
32
33
F
F
Scheme 7. Synthesis of pyridones 48 (130 mg scale).
HO
O
O
NH2
HO
F
N
S
N
O
H
AcOH
O
O
S
N
The final monocycle, pyridazinone 52 was synthesized
according to Scheme 8. Tail aldehyde 8a was condensed with
4-oxo-4-phenylbutanoic acid under dehydrating conditions.23
Treatment of furanone 49 with hydrazine gave the
pyridazinone core 50.24 Alkylation with tert-butyl
bromoacetate and ester hydrolysis gave the final compound
52.
reflux, 9h
O
35
34
F
HO
O
N
Jones' reagent
F
S
O
O
Acetone/H2O
20 ºC, 3h
N
36
O
O
Scheme 5. Synthesis of imidazole 36 (4 mg scale).
O
OH
NH2NH2
8a
O
O
S
O
EtOH
reflux, 4 h
Ac2O, NEt3
reflux, 3 h
We also synthesized some 6-membered monocyclic cores.
Pyridones 42 and 43 were synthesized according to Scheme 6.
Common intermediate 37 was obtained by hydrolysis of
commercial (6-chloropyridin-3-yl)acetic acid and then
esterified to give 38. Here we also chlorinated the core to at
least generate 2 final products from the same synthetic route.
Both pyridine cores were taken through to their final products
by alkylation with the tail and ester hydrolysis (38 → 40 → 42
and 39 → 41 → 43 respectively).
49
O
O
O S
R3O
O
tBuO
O
O
O
S
O
HN
N
N
N
Br
K2CO3, DMF
20 ºC, 2 h
50
TFA, CH2Cl2
20 ºC, 2 h
51 R3 = tBu
52 R3 = H
Scheme 8. Synthesis of pyridazinone 52 (54 mg scale).
The bicyclic cores we chose to study were also synthesized
following a range of synthetic routes. The first cores selected
were a crossover between the the monocycles and the
bicycles: pyrrole-based compounds 57, 58 and 59 all
possessed an aromatic monocycle fused to an aliphatic ring.
These compounds were also close analogues of our
pyrrolopiperidinones (PPAs, e.g. 4) and could be obtained by
similar synthetic routes, simply by varying the starting
cyclohexanone (Scheme 9).12 The route to 57 was fraught with
impurities, degradations and low yields (see Experimental
Section) but was short enough to rapidly obtain the final
product. Cyclohexanone was alkylated with chloroacetone to
give diketone 53 but in a highly crude mixture. Condensation
with ethyl glycinate gave pyrrole 54, also in a highly crude
form. In the final step, reductive alkylation with tail aldehyde
8a gave a tiny amount of the desired product, sufficient to
characterize biologically, but only after repeated purifications.
The same route starting from Meldrum’s acid (1,3-
cyclohexadione) gave far fewer problems. Alkylation
proceeded under milder basic conditions to give tricarbonyl
55. Condensation with ethyl glycinate proceeded smoothly to
56 and reductive alkylation gave the desired products 58 and
Scheme 6. Synthesis of pyridones 42 and 43 (23-83 mg scale).
Regioisomeric pyridone 48 was synthesized according to
Scheme 7. A classical carbon-chain homologation route was
used to obtain the acetate-substituted core, namely aldehyde
reduction to alcohol 44, chlorination (45), cyanide substitution
(46) and nitrile hydrolysis (47). The core was then alkylated
with tail bromide 10a and in situ ester hydrolysis have the
product 48.

ACCEPTED MANUSCRIPT
59. The extra carbonyl group (X = CO in Scheme 9) clearly
reduced the electron density of the pyrrole ring of the core to
make it a more stable and less prone to decompositions.
Scheme 9. Synthesis of pyrrole-derived cores 57, 58 and 59
(2-180 mg scale).
Moving to wholly aromatic bicyclic cores, two regioisomeric
phthalazinones 64 and 69 were synthesized according to
Scheme 10. As seen previously, the synthetic routes were just
variations of each other, swapping the reactivities of the head,
the core and tail portions accordingly. In the first case, Wittig
reagent of the core 60 was reacted with tail aldehyde 8a to
give the alkylidene 61.25 Condensation with hydrazine gave
the phthalazinone core 62.26 Alkylation with ethyl
bromoacetate and hydrolysis gave the product 64. In the case
of the reversed core, Wittig reagent of the head 65 was reacted
with phthalic anhydride to give alkylidene 66. As before,
condensation with hydrazine gave the reversed phthalazinone
core 67 and alkylation with tail bromide 10a and ester
hydrolysis gave the final product 69.
Scheme 10. Synthesis of phthalazinones 64 and 69 (28-33 mg
scale).
For the 5,6-bicyclic cores, we started with sulfamide 74
(Scheme 11). 3-Nitro-2-chloropyridine was substituted with
tail amine 11a. Reduction of the nitro group of 70 gave
diamine 71 which was cyclized with sulfamide under
microwave irradiation to give the thiadiazolopyridine dioxide
core 72.27 NH Alkylation and ester hydrolysis as before
completed the synthesis of 74.
Scheme 11. Synthesis of thiadiazolopyridine dioxide 74 (3 mg
scale).

ACCEPTED MANUSCRIPT
The remaining cores were all based on the same 5,6-bicyclic
structure and containing 2 nitrogen atoms, but altering the
position of the nitrogens around the 2 rings. The first core of
this type was imidazopyridine 79 (Scheme 12). Monoethyl
malonate was condensed with 2-cyanopyrine in a Blaise
reaction followed by Lewis acid-mediated decarboxylation.28
Reduction of the double bond double bond (75 → 76) gave the
acetate-substituted
aminomethylpyridine,
ready
for
cyclization. This was carried out with (2-iodophenyl)acetic
acid to form the imidazopyridine core of 77.29 The iodo group
then served as a handle and was displaced with sodium
phenylsulfinate, albeit in a low 15% yield. Ester hydrolysis
gave the final product 79.
Scheme 13. Synthesis of pyrrolo[1,2-c]pyrimidines 88 and 89
(20-50 mg scale).
Scheme 12. Synthesis of imidazopyridine 79 (6 mg scale).
Pyrrolo[1,2-a]pyrimidine 94 was synthesized in just 4 steps
according to Scheme 14. We used a Sonogashira coupling to
install all of the necessary carbon atoms for the head and core,
but in an open form (91). Copper-catalyzed isomerization of
the alkynopiperidine then gave the desired core.33 Again, we
used reductive alkylation to install the tail (92 → 93) and
basic ester hydrolysis to complete the synthesis.
Pyrrolo[1,2-c]pyrimidines 88 and 89 first required the
synthesis of the naked core fragment 83 (Scheme 13). This
was achieved in
4 steps: pyrrole-2-carbaldehyde was
brominated selectively in the 4-position. Compound 80 was
unstable to light and so was rapidly converted to the
pyrrolopyrimidine core 81 with TosMIC.30 Suzuki reaction
installed the methyl group in the 6-position of the core. We
settled on this bromine → methyl route as there were no better
options to source the 4-methyl-pyrrole-2-carbaldehyde.
Finally, we obtained the unsubstituted core 83 via a sodium
amalgam reductive desulfonylation,31 optimized to a decent
63% yield. With the core fragment 83 in hand, we could
install the tails from the corresponding aldehydes 8 via
reductive alkylation.32 The head group was then installed in 2
steps: Friedel-Crafts acylation with ethyl 2-chloro-2-
oxoacetate installed the 2-carbon chain. These compounds
were not isolated, but directly reduced with trimethylsilane
under acidic conditions to give the acetates (86 and 87). Basic
ester hydrolysis completed the synthesis.
Scheme 14. Synthesis of pyrrolo[1,2-a]pyrimidine 94 (15 mg
scale).
For the synthesis of the dimethyl 7-azindole core, we
developed two different routes according to the availability of
starting materials (Scheme 15). 2-Methyl-7-azaindole 95 was
readily prepared from 3-methyl-2-(Boc)aminopyridine. The
methyl group was lithiated, the neighbouring Boc group
directing the lithiation and the anion was added to the Weinreb

ACCEPTED MANUSCRIPT
acetamide. In situ acidic workup quenched the Weinreb
intermediate, de-protected the Boc group and condensed the
newly formed amine and ketone to give the azaindole 95.34 6-
Methyl-7-azaindole 98 was commercially available.35 From
the respective mono-methyl azaindoles, the dimethyl
azaindole core 102 was synthesized. 2-Methylazaindole 95
was N-oxidized and rearranged to the protected 6-
chloroazaindole 97 with ethyl chloroacetate. Suzuki coupling
introduced the 6-methyl substituent to give dimethyl fragment
102. In the other approach, 6-methyl azaindole 98 was
tosylated. We then used a directed ortho metalation (DOM) to
lithiate the 2-position of the azaindole and trap with methyl
iodide (100).36 Surprisingly, we also detected significant
amounts of 101, a product of double methylation, arising from
a second DOM at the ortho position of the tosyl protecting
group. Ultimately, we used an excess of butyllithium to force
the conversion of 99 to a mixture of 100 and 101 as
subsequent hydrolysis of the sulphonamides gave 102 from
both compounds. With core fragment 102 in hand the
synthesis was finished as follows: the head group was
installed by Friedel-Crafts acylation to 103 and triethylsilane
reduction to form the acetate 104. The tail was added by
alkylation with bromides 10a or 10b. The acetate group of
compounds 105 and 106 was clearly quite labile as some
transesterification was observed from just the methanol
solvent used in the purification. Hydrolysis of the ester
mixtures gave the desired carboxylic acids 107 and 108
respectively.
Scheme 15. Synthesis of 2,6-dimethyl-7-azaindoles 107 and
108 (8-9 mg scale).
Finally, a singly-methylate 7-azaindole 112 was synthesized
according to Scheme 16. The core fragment 98 was alkylated
with tail bromide 10c. The azaindole nucleus 109 was then
brominated in the 3-position and the head was introduced by
palladium cross-coupling with the acetate zincate reagent. tert-
Butyl ester deprotection with trifluoroacetic acid gave the final
product 112.
Scheme 16. Synthesis of 2-methyl-7-azaindole 112 (46 mg
scale).

ACCEPTED MANUSCRIPT
3. Results and Discussion
All potency data was determined by a [35S]GTPγS binding
assay. The monocycle cores were very disappointing from the
outset (Table 2). We were hoping for a wide structural
freedom in this part of the molecules, however imidazole 36
was the only compound with a single-digit nanomolar
potency. The only other compounds which displayed sub-
micromolar potencies were pyrazolone 16 and pyridone 43,
and even then, only just sub-micromolar.
Table 2
HO
O
HO
O
N
O
F
N
N
S
S
N
O
O
O
O
O
Fig. 3. Rank order of monocyclic cores and SAR map
O
20
16
Potent imidazole 36 was also testing for its receptor residence
time, but its half-life was measured at only 0.6 h, below our
minimum cut-off of 1 h. Hence we abandoned any further
work on the monocyclic cores.
HO
O
N
HO
O
O
O
N
N
S
S
N
N
N
O
O
O
30
25
At the same time we were synthesizing and testing the bicyclic
cores (Table 3).
O
HO
O
N
HO
O
O
S
F
42 R4 = H
43 R4 = Cl
Table 3
N
S
O
O
HO
O
N
HO
O
N
N
O
36
R4
O
F
F
S
S
O
O
O
O
O
O
O
57
HO
O
HO
O
58
O
O
S
O
S
N
N
N
O
O
O S
HO
O
N
HO
O
O
S
48
N
N
52
N
O
O
64
69
Monocyclic core SAR and SKR.
Cmpd
Core
Dissociation
half-life (h)
n.d.
GTPγS
IC50 (nM)
970
10000
2400
inactive
8
10000
860
inactive
inactive
HO
O
N
HO
O
O
O
N
S
S
S
Pyrazolone
Imidazolone
Triazolone
Triazolone
Imidazole
Pyridone
Pyridone
Pyridone
Pyridazinone
16
20
25
30
36
42
43
48
52
O
O
O
O
N
n.d.
n.d.
n.d.
0.6
n.d.
n.d.
n.d.
n.d.
88
HO
O
N
74
N
N
S
O
O
N
79
HO
O
N
HO
O
S
S
N
O
O
O
O
N
N
94
107
n.d. not determined. Inactive refers to < 25% antagonism
observed at 10 µM.
CF3
Bicyclic core SAR and SKR.
Cmpd
Core
Dissociation
half-life (h)
GTPγS
IC50 (nM)
104
Almost all of the monocycles structure included a carbonyl
group, a group which invariably helped in the synthesis of the
diverse cores, but which impacted negatively on the potency.
The SAR of the monocycles allowed us to generate some
rules-of-thumb for the cores (Fig. 2):37
(1) A methyl group in the North of the core is beneficial.
Polarity in the North is detrimental
(2) Polarity in the South West is not tolerated.
Pyrrole
Pyrrole
Phthalazinone
Phthalazinone
Sulfamide
n.d.
21
n.d.
0.04
n.d.
n.d.
0.2
0.05
1.3
57
58
64
69
74
79
88
94
107
2
inactive
65
1600
3000
28
Imidazopyridine
Pyrrolopyrimidine
Pyrrolopyrimidine
Azaindole
(3) Polarity in the South East is tolerated
(4) Lipophilicity somewhere in the South is beneficial.
47
14

ACCEPTED MANUSCRIPT
n.d. not determined. Inactive refers to < 25% antagonism
out in terms of residence time and could be added to the list of
observed at 10 µM. Bold numbers indicate dissociation half-
Figure 2:
lives of ≥12h.
(5) a methyl group in the North of the core was beneficial for
long(er) residence times.
Pyrrole 57 which had given such synthetic problems was only
moderately active. 58, a close analogue of our PPA 4 was
highly active at 2 nM. The pair of phthalazinones 64 and 69
were synthesized while we were still building our SAR rules
of thumb, but these compounds also obeyed the rules: 64, with
polarity in the North and SouthWest portions of the core was
inactive. 69 with polarity in the North and SouthEast of the
core was fairly potent at 65 nM. Unfortunately, although not
surprisingly, 69 suffered from a gradual decarboxylation upon
standing, and accelerated decarboxylation upon heating, so
this core was abandoned (Fig. 4).
Of the 4 compounds which displayed any kind of residence
time, where measured, beyond a few minutes, 16, 58, 88 and
107 all possessed this same methyl group in the core. As a
final optimization, we resynthesized the three bicyclic cores
from this group of 4, but with the methoxy-fluoro substitution
in the tail – a substitution pattern which had led to an
approximate ten-fold increase in residence time in the PPA
series12 (Table 4).
All of the compounds were highly potent, as to be expected.
Pyrrole 59 showed exactly the same potency and residence
half-life as its analogue 58. It seems that the methoxy-fluoro
tail substitution of 59 offered no advantage over the mono-
fluoro substitution of 58. Even so, both of these compounds
displayed dissociation half-lives of 21h, well above our
desired cut-off of 12 h. The methoxy-fluoro substituted tail
did improve the dissociation half-lives of both the other two
cores tested. Pyrrolopyrimidine 89 had a half-life of 1.5 h,
compared to 0.2 h for the unsubstituted tail analogue 88,
although this was still too short for our needs. Azaindole 108
showed a half-life of 13 h, and compared to 1.3 hours for
unsubstituted tail analogue 107. Thus 108 became the third
compound of this investigation to achieve what we set out to
discover, highly potent compounds with a residence half-life
above 12 h. As a final investigation into the SKR, we
synthesized azaindole 112, identical to 108 except for the
absence of the 2-methyl group in the North of the core. 112
was of a similar potency to 108. The residence half-life fell off
dramatically to just 30 min, just as the SKR rule-of-thumb
stated.
Fig. 4. Decarboxylation of phthalazinone 69.
Thiadiazolopyridine dioxide 74 and imidazopyridine 79 also
obeyed the SAR rules-of-thumb. Both cores possess an excess
of polarity in the North of the core, the electron-rich sulfamide
of 74, and the strong hydrogen bond acceptor nitrogen of 79.
Both compounds were accordingly in the micromolar range.
The remaining three 5,6-bicyclic cores, 88, 94 and 107, were
all sufficiently potent.
We next measured the residence times of the most potent
bicyclics. Pyrrole-derived 58 was a very long residence
compound with a dissociation half-life of 21 h. This was
maybe not too much of a surprise since it was a close analogue
of long resident PPAs 4, and it also possessed the para-fluoro
substituent in the tail, a group we had shown to favour longer
residence times.12 Phthalazinones 69 and pyrrolo[1,2-
a]pyrimidine 94, were very short residence compounds,
effectively losing all potency immediately after compound
washout. The pyrrolo[1,2-c]pyrimidine 88 and azaindole 107
had half-lives which were at least measurable, with 107
possessing a half-life of just over 1 h.
Table 4
Very few of the bicycles synthesized were apt for further
investigation, either because of lack of potency or for lack of
residence time. The GTPγS assay provided a semi-functional
readout: activation of CRTh2 in membrane preparations by
prostaglandin D2 (PGD2) triggers the binding of GTP to G-
proteins. A functional readout was also available by
measuring the activation (and antagonism thereof) of
eosinophils in human blood – the eosinophil shape-change
(ESC) assay. Only compound 88 was tested in the ESC assay
and showed an IC50 of 12 nM, within experimental variation
of the GTPγS IC50 of 28 nM. Since both assays gave similar
results, we could be confident that the GTPγS IC50s would be
a true reflection of functional antagonism in vivo.
Methoxy-fluoro tail substitution SAR and SKR.
Cmpd
Core
Dissociation
GTPγS
half-life (h)
IC50 (nM)
Pyrrole
Pyrrolopyrimidine
Azaindole
2
5a
4
59
89
108
112
21
1.5
13
Azaindole
18
0.5
Bold numbers indicate dissociation half-lives of ≥12h. IC50 in
ESC assay 6 nM.
In addition to the SAR rules-of-thumb that applied across both
the monocycles and the bicycles, a single observation stood
4. Conclusions

ACCEPTED MANUSCRIPT
The survey of different monocyclic and bicyclic cores
revealed that the SAR was not as open as we had hoped for.
Nevertheless, we could establish several rules-of-thumb for
the structural requirements needed to obtain potent
compounds, or at least to avoid weakly potent or inactive
compounds. The more active compounds were also
characterized for their receptor residence half-lives and again,
a structural requisite of SKR – a methyl group in the North of
the core in between the attachment points of the acetic acid
and the tail chains – was also revealed. How this methyl group
proportions longer residence times is unclear, however we can
offer a speculation: the methyl group will have a steric
influence over the possible conformations that these molecules
can adopt. The conformation of binding to the receptor does
not seem overly affected by the presence or absence of the
methyl group. However, if the transition state conformation of
the molecule as it makes its way from being unbound to its
ultimate binding site requires either the head or tail to be
squeezed close to the methyl group, this will imply and
energetic penalty and a consequent slowing down of both the
rates of association and dissociation. Whatever the reason may
be, this structural feature could be employed empirically, and
in combination with the methoxy-fluoro substitution pattern in
the tail, be used to design potent and long resident CRTh2
antagonists.

ACCEPTED MANUSCRIPT
(A): formic acid (1 ml) and water (1000 ml) (A), the gradients
5. Experimental Section
specified as follows: Method 5 (4.5 min): 5% to 100% B over
4.5 min.
General:
Reaction products were purified, when necessary, by flash
chromatography on silica gel (40-63 ꢀm) with the solvent
system indicated. Compounds obtained below 90% purity by
HPLC or UPLC are generally referred to as in crude form.
The UPLC chromatographic separations were obtained using
a Waters Acquity UPLC system coupled to a SQD mass
spectrometer detector. The system was equipped with an
ACQUITY UPLC BEH C-18 (2.1x50mm, 1.7 mm) column.
The mobile phase was formic acid (0.4 ml), ammonia (0.1
ml), methanol (500 ml) and acetonitrile (500 ml) (B) and
formic acid (0.5 ml), ammonia (0.125 ml) and water (1000
ml) (A). A gradient between 0 to 95% of B was used. The run
time was 3 or 5 minutes. The injection volume was 0.5
microliter. Chromatograms were processed at 210 nM or 254
nM. Mass spectra of the chromatograms were acquired using
positive and negative electrospray ionization.
Purifications in reverse phase were made in a Biotage SP1®
or a Biotage Isolera automated purification system equipped
with a C18 column and using a gradient of, unless otherwise
stated, water-acetonitrile/MeOH (1:1) (0.1% v/v ammonium
formate both phases) from 0% to 100% acetonitrile/MeOH
(1:1) in 80 column volumes.
The conditions “formic acid buffer” refer to the use of 0.1%
v/v formic acid in both phases.
1H Nuclear Magnetic Resonance Spectra were recorded on a
Varian Mercury plus operating at a frequency of 400MHz,
Varian Gemini-2000 spectrometer operating at a frequency of
300MHz or a Varian VNMRS operating at 600MHz and
equipped with a cold probe for the 1H spectra. Samples were
Preparative HPLC-MS were performed on
a Waters
instrument equipped with a 2767 injector/collector, a 2525
binary gradient pump, a 2996 PDA detector, a 515 pump as a
make-up pump and a ZQ4000 Mass spectrometer detector.
Preparative HPLC was also carried out on an Agilent 1200
Series (AE-0010) with diode array detection and peak
collection.
dissolved
in
the
specified
deuterated
solvent.
Tetramethylsilane was used as reference. Chemical shifts δ in
ppm, the following abbreviations are used: singlet (s), doublet
(d), triplet (t), quartet (q), double doublet (dd), multiplet (m),
broad signal (br. s).
Gas chromatography was performed using a Thermo Trace
Ultra gas chromatograph, coupled to a DSQ mass detector.
Injections were performed on a split/splitless injector and a
HP-1MS was the capillary column. Mass spectra were
obtained by electron impact ionisation at 70 eV.
"Bn"
Hꢀ4
Hꢀ5
Hꢀ6
"SO2Ph"
Hꢀ3
para
S
O
O
meta
ortho
Common identifiers of protons
The HPLC chromatographic separations were obtained using
a Waters 2795 system equipped with a Symmetry C18 (2.1 x
50 mm, 3.5 µM) column for methods 1, 2, 3 and 5 and a
Symmetry C18 (2.1 x 100 mm, 3.5 µM) for method 4. A
Waters 2996 diode array was used as a UV detector. Mass
spectra of the chromatograms were acquired using positive
and negative electrospray ionization in a Micromass ZMD or
in a Waters ZQ detectors coupled to the HPLC. The mobile
phases were (A): formic acid (0.5 ml), ammonia (0.125 ml)
and water (1000 ml), (B): formic acid (0.4 ml), ammonia (0.1
ml), methanol (500 ml) and acetonitrile (500 ml). the
following gradients were used.
Method 1 (5 min): 0% B, 0.2 min; 0 to 95% B, over 3 min;
95% B, 0.8 min. Method 2 (9 min): 0% B, 0.5 min; 0 to 95%
B, over 6.5 min; 95% B, 1 min. Method 3 (15 min): 0 to 95%
B, over 10.5 min; 95% B, 1,5 min. Method 4 (30 min): 0 to
95% B, over 20 min; 95% B, 4 min.
1. Scheme 1
1.1. 2-(Phenylthio)benzaldehyde (7a)
2-Fluorobenzaldehyde (9 ml, 90 mmol) and benzenethiol (8.8
ml, 90 mmol) were dissolved in 30 ml dimethylsulfoxide.
Potassium carbonate (26 g, 190 mmol) was added and the
mixture was heated at 100ºC for 4 h. The mixture was
allowed to cool and was poured into water. The aqueous layer
was extracted with ethyl acetate. The combined organics were
washed with water and brine and were dried over sodium
sulphate. Filtration and evaporation gave 7a (18.5 g, 78.3
mmol, 92% yield) as a yellow oil. Used as such without
further purification. Purity 91%. 1H NMR (400 MHz, CDCl3)
δ ppm 7.08 - 7.12 (m, 1H, Ar), 7.29 - 7.46 (m, 7H, Ar), 7.88
(dd, J=1.4, 1.6 Hz, 1H, PhCHO H-6), 10.40 (s, 1H, CHO).
HPLC/MS (9 min) retention time 6.53 min. LRMS: m/z 215
(M+1).
HPLC Chromatographic separations were also obtained using
a Waters 2795 system equipped with a Symmetry C18 (2.1 x
50 mm, 3.5 µM) column for methods E. The mobile phases
were (B): formic acid (0.7 ml) and acetonitrile (1000 ml) and
1.2. 2-[(4-Fluorophenyl)thio]benzaldehyde (7b)

ACCEPTED MANUSCRIPT
1
2-Fluorobenzaldehyde (1.86 g, 15.0 mmol) was treated with
4-fluorobenzenethiol (1.6 ml, 15.0 mmol) and potassium
carbonate (4.67 g, 33.8 mmol) according to the method of 7a
to give 7b (2.95 g, 11.8 mmol, 79% yield) as a yellow oil.
g, 7.11 mmol, 89% yield) as a yellow solid. Purity 100%. H
NMR (400 MHz, DMSO-d6) δ ppm 7.51 (t, J=8.8 Hz, 2H,
SO2PhF meta), 7.87 - 7.99 (m, 3H, Ar), 8.07 - 8.16 (m, 2H,
Ar), 8.20 (d, J=7.0 Hz, 1H, PhCHO H-3), 10.66 (s, 1H,
CHO). GC/MS (18 min) retention time 10.0 min. LRMS: m/z
265 (M+1).
1
Used as such without further purification. Purity 93%. H
NMR (400 MHz, DMSO-d6) δ ppm 6.87 (d, J=8.2 Hz, 1H,
PhCHO H-3), 7.27 - 7.46 (m, 3H, Ar), 7.49 - 7.56 (m, 1H,
Ar), 7.56 - 7.63 (m, 2H, Ar), 7.97 (d, J=7.4 Hz, 1H, PhCHO
H-6), 10.22 (s, 1H, CHO). HPLC/MS (9 min) retention time
6.57 min. LRMS: m/z 233 (M+1).
1.6. 2-[(4
methoxybenzaldehyde (8c)
Fluorophenyl)sulfonyl]-5-
Thioether 7c (2.9 g, 10.8 mmol) was treated with
3-chloroperbenzoic acid (77% purity, 7.5 g, 33.5 mmol)
following the method of 8a. The resulting residue was
partially purified using the SP1 Purification System (ethyl
acetate:hexane gradient, 0:100 rising 25:75) to give 8c (600
mg). Used as such without further purification. Purity 80%.
1H NMR (400 MHz, CDCl3) δ ppm 3.91 (s, 3H, MeO),
7.17 - 7.24 (m, 3H, Ar), 7.49 (d, J=2.7 Hz, 1H, PhCHO H-6),
7.87 - 7.93 (m, 2H, Ar), 8.14 (d, J=9.0 Hz, 1H, PhCHO H-3),
10.79 (s, 1H, CHO). HPLC/MS (9 min) retention time 5.88
min. LRMS: m/z 295 (M+1).
1.3. 2-[(4
(7c)
Fluorophenyl)thio]-5-methoxybenzaldehyde
2–Fluoro-5-methoxybenzaldehyde (2.5 g, 16.2 mmol) was
treated with 4-fluorobenzenethiol (2.1 g, 16.4 mmol) and
potassium carbonate (4.5 g, 32.6 mmol) following the method
of 7a. The resulting residue was purified using the SP1
Purification System (ethyl acetate:hexane gradient, 0:100
rising to 5:95) to give 7c (2.9 g, 10.8 mmol, 67% yield) as a
yellow solid. Purity 98%. 1H NMR (400 MHz, CDCl3) δ ppm
3.86 (s, 3H, MeO), 7.02 – 6.95 (m, 2H, Ar), 7.08 (dd, J=3.0,
8.7 Hz, 1H PhCHO H-3), 7.25 – 7.18 (m, 2H, Ar), 7.28 (d,
J=8.6 Hz, 1H, PhCHO H-4), 7.44 (d, J=3.0 Hz, 1H, PhCHO
H-6), 10.48 (s, 1H, CHO), HPLC/MS (9 min) retention time
6.80 min. LRMS: m/z 263 (M+1).
1.7. [2-(Phenylsulfonyl)phenyl]methanol (9a)
Aldehyde 8a (1.98 g, 8.0 mmol) was suspended in 16 ml
methanol. Sodium borohydride (150 mg, 3.86 mmol) was
added in portions and the mixture was stirred at room
temperature for 30 min. 5% Hydrochloric acid solution (4 ml)
was added and the mixture was evaporated. The residue was
taken up in water and the aqueous was extracted twice with
dichloromethane. The combined organics were washed with
brine and dried over sodium sulphate. Filtration and
evaporation gave 9a (1.9 g, 7.3 mmol, 95% yield) as a white
solid. Purity 96%. 1H NMR (400 MHz, CDCl3) δ ppm 4.74 (s,
2H, CH2), 7.49 - 7.58, (m, 4H, Ar), 7.61 (d, J=7.5 Hz, 1H,
Ar), 7.64 (d, J=7.5 Hz, 1H, Ar), 7.90 (d, J=7.4 Hz, 2H, SO2Ph
ortho), 8.15 (d, J=7.8 Hz, 1H, Bn H-3). HPLC/MS (9 min)
retention time 4.97 min. LRMS: m/z 249 (M+1).
1.4. 2-(Phenylsulfonyl)benzaldehyde (8a)
Thioether 7a (3.5 g, 16.3 mmol) was dissolved in 50 ml
dichloromethane. 3-Chloroperbenzoic acid (77% purity, 11 g,
49 mmol) was added in portions and the mixture was stirred
at room temperature overnight. The mixture was washed with
sodium carbonate 5% solution, water and brine. The resulting
organic layer was dried over sodium sulphate, filtered and
evaporated. The residue was purified using the SP1
Purification System (ethyl acetate-hexane gradient, 0:100
rising to 30:70) to give 8a (1.9 g, 7.7 mmol, 47% yield) as a
1
white solid. Purity 100%. H NMR (400 MHz, DMSO-d6) δ
ppm 7.67 (t, J=7.6 Hz, 2H, SO2Ph meta), 7.75 (t, J=7.4 Hz,
1H, PhCHO H-4), 7.88 - 7.99 (m, 3H, Ar), 8.02 (d, J=7.4 Hz,
2H, SO2Ph ortho), 8.20 (d, J=7.8 Hz, 1H, PhCHO H-3), 10.68
(s, 1H, CHO). HPLC/MS (9 min) retention time 5.47 min.
LRMS: m/z 247 (M+1).
1.8. [2-(4-Fluorophenylsulfonyl)phenyl]methanol (9b)
Aldehyde 8b (1.0 g, 3.8 mmol) was treated with sodium
borohydride (70 mg, 1.8 mmol) following the method of 9a to
give 9b (1.0 g, 3.8 mmol, 100% yield) as a white solid. Purity
1
96%. H NMR (400 MHz, CDCl3) δ ppm 4.75 (s, 2H, CH2),
7.21 (t, J=8.4 Hz, 2H, SO2PhF meta), 7.53 (t, J=7.6 Hz, 1H,
Bn H-4), 7.58 (d, J=7.4 Hz, 1H, Bn H-6), 7.64 (t, J=7.4 Hz,
1H, Bn H-5), 7.92 (dd, J=5.1, 9.0 Hz, 2H, SO2PhF ortho),
8.11 (d, J=7.8 Hz, 1H, Bn H-3). HPLC/MS (9 min) retention
time 5.17 min. LRMS: m/z 267 (M+1).
1.5. 2-[(4-Fluorophenyl)sulfonyl]benzaldehyde (8b)
Thioether 7b (2.0 g, 7.96 mmol) was dissolved in 30 ml
dichloromethane and the mixture was cooled in an ice-bath.
3-Chloroperbenzoic acid (77% purity, 4.1 g, 24 mmol) was
added in portions and the mixture was stirred at room
temperature for 2 h. The mixture was washed sequentially
with 25% solution potassium hydrogen sulphate, 1N sodium
hydroxide and brine. The resulting organic layer was dried
over sodium sulphate, filtered and evaporated to give 8b (1.88
1.9. [2-(4-Fluorophenylsulfonyl)-5-
methoxyphenyl]methanol (9c)
Crude Aldehyde 8c (0.32 g, 1.1 mmol) was treated with
sodium borohydride (20 mg, 0.53 mmol) following the

ACCEPTED MANUSCRIPT
method of 9a to give 9c (0.32 g, 1.1 mmol, 19% yield over
1.13.
[2-(Phenylsulfonyl)phenyl]methylamine (11a)
two steps) as a colourless oil. Purity 100%. 1H NMR
spectrum not recorded. UPLC/MS (3 min) retention time 1.46
min. LRMS: m/z 297 (M+1).
Aldehyde 8a (2.0 g, 8.1 mmol) was dissolved in 20 ml
ethanol. A solution of hydroxylamine hydrochloride (0.63 g,
9.1 mmol) and sodium bicarbonate (0.68 g, 8.1 mmol)
dissolved in 20 ml water was added and the mixture was
stirred for 2 h at room temperature. The mixture was partially
evaporated and was partitioned between ethyl acetate and
brine. The aqueous was extracted with ethyl acetate and the
combined organics were evaporated under reduced pressure.
1.10.1-(Bromomethyl)-2-(phenylsulfonyl)benzene (10a)
Alcohol 9a (1.9 g, 7.3 mmol) was suspended in 20 ml
chlorobenzene. Thionyl bromide (1.46 ml, 18.3 mmol) was
slowly added and the mixture was heated at 110ºC for 1 h.
The mixture was concentrated under reduced pressure and the
residue was partitioned between water and dichloromethane.
The aqueous phase was basified with potassium carbonate
and extracted three times with dichloromethane. The
combined organics were washed with water and brine, dried
over sodium sulphate and evaporated. The residue was
purified by column chromatography (ethyl acetate-hexane
gradient, 0:100 rising to 8:92) to give 10a (1.95 g, 5.89 mmol,
80% yield) as an orange oil. Purity 94%. 1H NMR (400 MHz,
CDCl3) δ ppm 4.89 (s, 2H, CH2), 7.48 - 7.64 (m, 6H, Ar),
7.92 (d, J=7.4 Hz, 2H, SO2Ph ortho), 8.19 (d, J=7.8 Hz, 1H,
Bn H-3). HPLC/MS (9 min) retention time 6.03 min. LRMS:
m/z 328, 330 (M+18).
The residue was dissolved in
a mixture of 35 ml
tetrahydrofuran and 40 ml 2N hydrochloric acid. Zinc dust
(5.0 g, 76.5 mmol) was added and the mixture was stirred at
reflux for 1 h. The mixture was allowed to cool and was
filtered through a pad of Celite, washing through with
dichloromethane. The aqueous phase was basified to pH >10
with 8N sodium hydroxide solution and the phases were
separated. The aqueous was extracted with dichloromethane
and the combined organics were washed with water, brine,
dried over magnesium sulphate and evaporated under reduced
pressure to give 11a (1.9 g, 7.7 mmol, 95% yield) as a pale
1
yellow oil. Purity 97%. H NMR (400 MHz, CDCl3) δ ppm
3.97 (s, 2H, CH2), 7.47 (t, J=8.2 Hz, 1H, Bn H-6), 7.50 - 7.55
(m, 3H, Ar), 7.56 - 7.65 (m, 2H, Ar), 7.89 (d, J=7.4 Hz, 2H,
SO2Ph ortho), 8.18 (d, J=7.8 Hz, 1H, Bn H-3). HPLC/MS (9
min) retention time 3.32 min. LRMS: m/z 248 (M+1).
1.11.1-(Bromomethyl)-2-(4-fluorophenylsulfonyl)benzene
(10b)
Alcohol 9b (1.1 g, 4.1 mmol) was suspended in 10 ml
chlorobenzene. Thionyl bromide (0.73 ml, 9.4 mmol) was
slowly added and the mixture was heated at 110ºC for 1 h.
The mixture was concentrated under reduced pressure and the
residue was partitioned between water and dichloromethane.
The aqueous phase was basified with potassium carbonate
and extracted three times with dichloromethane. The
combined organics were washed with water, brine and dried
over sodium sulphate and evaporated to give 10b (1.1 g, 3.2
mmol, 77% yield) as a white solid. Purity 95%. 1H NMR (400
MHz, CDCl3) δ ppm 4.89 (s, 2H, CH2), 7.21 (t, J=8.2 Hz, 2H,
SO2PhF meta), 7.51 (t, J=7.6 Hz, 1H, Bn H-4), 7.57 (d, J=7.5
Hz, 1H, Bn H-6), 7.62 (t, J=7.4 Hz, 1H Bn H-5), 7.95 (dd,
J=5.3, 8.0 Hz, 2H, SO2PhF ortho), 8.18 (d, J=7.8 Hz, 1H, Bn
H-3). HPLC/MS (9 min) retention time 6.23 min. LRMS: m/z
346, 348 (M+18).
2. Scheme 2
2.1. Ethyl 2-acetyl-3-[2-(phenylsulfonyl)phenyl]acrylate
(12)
Aldehyde 8a (1.14 g, 4.6 mmol) was dissolved in 8 ml
ethanol containing activated 4Ǻ molecular sieves. Ethyl 3-
oxobutanoate (0.60 g, 4.6 mmol), piperidine (0.39 g, 4.6
mmol) and acetic acid (0.27 g, 4.6 mmol) were added. The
mixture was stirred at reflux for 2 h and then allowed to cool
to room temperature. The mixture was filtered through a plug
of Celite, washing through with ethyl acetate. The combined
filtrate was evaporated under reduced pressure and the residue
was purified using the Isolera system (ethyl acetate-hexane
gradient, 0:100 rising to 50:50) to give 12 (1.48 g, 4.1 mmol,
90% yield) as a yellow solid and a 60:40 mixture of isomers.
1
Purity 100%. H NMR (400 MHz, CDCl3) Major isomer: δ
ppm 0.79 (t, J=7.0 Hz, 3H, OCH2CH3), 2.44 (s, 3H, COMe),
3.87 (q, J=7.0 Hz, 2H, OCH2CH3), 7.35 (d, J=6.6 Hz, 1H,
Ar), 7.42 - 7.64 (m, 5H, Ar), 7.82 (d, J=7.4 Hz, 2H, SO2Ph
ortho), 8.26 (d, J=7.4 Hz, 1H, vinylPh H-3), 8.27 (s, 1H, vinyl
H). Minor isomer: δ ppm 1.38 (t, J=7.0 Hz, 3H, OCH2CH3),
1.65 (s, 3H, COMe), 4.34 (q, J=7.2 Hz, 2H, OCH2CH3), 7.28
(d, J=7.4 Hz, 1H, Ar), 7.42 - 7.64 (m, 5H, Ar), 7.90 (d, J=7.4
Hz, 2H, SO2Ph ortho), 8.17 (s, 1H, vinyl H), 8.32 (d, J=7.4
Hz, 1H, vinylPh H-3). HPLC/MS (9 min) retention time 5.98
(major) and 6.18 (minor) min. LRMS: m/z 359 (M+1).
1.12.
1-(Bromomethyl)-2-(4-fluorophenylsulfonyl)-5-
methoxybenzene (10c)
Alcohol 9c (0.25 g, 86 mmol) was treated with thionyl
bromide (0.17 ml, 2.2 mmol) following the method of 10a.
The residue was purified by column chromatography (ethyl
acetate-hexane gradient, 0:100 rising to 18:82) to give 10c
(0.21 g, 0.59 mmol, 69% yield) as a white solid. Purity 100%.
NMR spectrum not recorded. UPLC/MS (3 min) retention
time 1.79 min. LRMS: m/z 376, 378 (M+18).

ACCEPTED MANUSCRIPT
2.2. Ethyl 3-oxo-2-[2-(phenylsulfonyl)benzyl]butanoate
organics were washed with brine, dried over sodium sulphate,
filtered and evaporated. The residue was partially purified
using the Isolera system (methanol-dichloromethane gradient,
0:100 rising to 50:50) to give 45 mg crude product. This was
re-purified by reverse-phase chromatography using the Isolera
to give 15 (16 mg, 0.033 mmol, 9% yield) as a white solid.
Purity 100%. Regiochemistry was confirmed by nOe
experiment. 1H NMR (300 MHz, CDCl3) δ ppm 1.17 (t, J=6.2
Hz, 3H, OCH2CH3), 2.04 (s, 3H, pyrazolone Me), 3.93 (s, 2H,
CH2Ph), 4.10 (q, J=6.8 Hz, 2H, OCH2CH3), 4.21 (s, 2H,
CH2COEt), 7.23 - 7.60 (m, 11H, Ar), 7.88 (d, J=6.0 Hz, 2H,
SO2Ph ortho), 8.24 (d, J=6.6 Hz, 1H, CH2Ph H-3). UPLC/MS
(3 min) retention time 1.69 min. LRMS: m/z 491 (M+1).
(13)
Alkene 12 (1.48 g, 4.1 mmol) was dissolved in 30 ml ethanol
and 30 ml tetrahydrofuran. 10% Palladium on carbon (0.44 g)
was added and the mixture was agitated under a hydrogen
atmosphere (20 psi) for 20 min. The mixture was filtered
through
a
plug of Celite, washing through with
tetrahydrofuran. The combined filtrate was evaporated under
reduced pressure and the residue was purified using the
Isolera system (ethyl acetate-hexane gradient, 0:100 rising to
35:65) to give 13 (1.37 g, 3.80 mmol, 92% yield) as a pale
1
yellow oil. Purity 96%. H NMR (400 MHz, CDCl3) δ ppm
1.22 (t, J=7.2 Hz, 3H, OCH2CH3), 2.25 (s, 3H, COMe), 3.20
(dd, J=8.2, 14.1 Hz, 1H, CHAHBPh), 3.38 (dd, J=5.7, 13.9 Hz,
1H, CHAHBPh), 4.08 - 4.20 (m, 3H, OCH2CH3 and
COCHCO), 7.29 (dd, J=1.6, 7.4 Hz, 1H, Bn H-6), 7.41 - 7.49
(m, 2H, Ar), 7.51 (t, J=7.0 Hz, 2H, SO2Ph meta), 7.59 (t,
J=7.2 Hz, 1H, SO2Ph para), 7.84 (d, J=7.0 Hz, 2H, SO2Ph
ortho), 8.19 (dd, J=1.8, 7.6 Hz, 1H, Bn H-3). HPLC/MS (9
min) retention time 6.20 min. LRMS: m/z 359 (M-1).
2.5. {5-Methyl-3-oxo-2-phenyl-4-[2-
(phenylsulfonyl)benzyl]-2,3-dihydro-1H-pyrazol-1-
yl}acetic acid (16)
Ester 15 (16 mg, 0.033 mmol) was dissolved in 0.5 ml
tetrahydrofuran and 0.5 ml water. Lithium hydroxide
monohydrate (5.5 mg, 0.13 mmol) was added and the mixture
was stirred for 90 min. The organics were evaporated and the
remaining aqueous was acidified with 0.5N hydrochloric acid
forming a precipitate. The solid was collected by filtration,
was washed with water and was dried under vacuum to give
16 (6.6 mg, 0.013 mmol, 43% yield) as a white solid. Purity
2.3. 5-Methyl-2-phenyl-4-[2-(phenylsulfonyl)benzyl]-
1,2-dihydro-3H-pyrazol-3-one (14)
Dicarbonyl 13 (0.50 g, 1.4 mmol) was dissolved in 10 ml
glacial acetic acid. Sodium acetate (0.57 g, 6.9 mmol) and
phenylhydrazine (0.17 g, 1.67 mmol) were added and the
mixture was stirred at 70 ºC for 90 min. The mixture was
allowed to cool and was partitioned between ethyl acetate and
water. The aqueous phase was extracted twice with ethyl
acetate. The combined organics were washed with brine,
dried over sodium sulphate, filtered and evaporated. The
residue was triturated with ether to give a precipitate which
was collected by filtration and dried in a stream of air to give
14 (0.39 g, 0.97 mmol, 69% yield) as a white solid. Purity
1
97%. H NMR (300 MHz, CDCl3) δ ppm 1.92 (s, 3H, Me),
3.92 (s, 2H, CH2Ph), 4.12 (s, 2H, CH2COOH), 7.26 - 7.45 (m,
8H, Ar), 7.48 (d, J=7.7 Hz, 2H, SO2Ph meta), 7.55 (t, J=7.2
Hz, 1H, SO2Ph para), 7.85 (d, J=8.0 Hz, 2H, SO2Ph ortho),
8.18 (d, J=7.1 Hz, 1H, CH2Ph H-3). HPLC/MS (30 min)
retention time 13.50 min. LRMS: m/z 463 (M+1).
3. Scheme 3
3.1. 2-Amino-1-phenylpropan-1-one hydrochloride (17)
Sodium diformylamide (1.1 g, 11.6 mmol) was suspended in
20 ml acetonitrile. 2-Bromo-1-phenylpropanone (2.0 g, 9.4
mmol) was added drop-wise and with stirring. The mixture
was then stirred at 75 ºC for 36 h. The mixture was hot
filtered and the solid was washed twice with acetonitrile. The
combined organics were evaporated under reduced pressure
and the residue was suspended in 9 ml 5N hydrochloric acid.
The mixture was stirred at reflux for 45 min and was then
evaporated under reduced pressure. The residue was re-
evaporated twice from isopropanol and was then triturated
with ether to give a precipitate. The solid was collected by
filtration, washed twice with ether and dried in vacuo to give
17 (1.4 g, 7.5 mmol, 80% yield) as a white solid. Purity
1
94%. H NMR (300 MHz, DMSO-d6) δ ppm 2.51 (s, 3H,
pyrazolone Me), 3.81 (s, 2H, CH2Ph), 7.11 - 7.26 (m, 2H,
Ar), 7.42 (t, J=7.8 Hz, 2H, NPh meta), 7.54 (t, J=7.6 Hz, 1H,
Ar), 7.58 - 7.80 (m, 6H, Ar), 7.92 (d, J=7.4 Hz, 2H, SO2Ph
ortho), 8.19 (d, J=7.7 Hz, 1H, Bn H-3), 11.00 (br. s., 1H,
NH). UPLC/MS (3 min) retention time 1.57 min. LRMS: m/z
405 (M+1).
2.4. Ethyl
{5-methyl-3-oxo-2-phenyl-4-[2-
(phenylsulfonyl)benzyl]-2,3-dihydro-1H-pyrazol-1-
yl}acetate (15)
Pyrazolone 14 (140 mg, 0.35 mmol) was dissolved in 2.5 ml
anhydrous dimethyformamide. Potassium carbonate (53 mg,
0.38 mmol) was added and the mixture was stirred for 45 min.
Ethyl bromoacetate (42 µl, 0.38 mmol) was added and the
mixture was stirred for 1 h. The mixture was partitioned
between ethyl acetate and water. The aqueous phase was
extracted three times with ethyl acetate. The combined
1
100%. H NMR (400 MHz, D2O) δ ppm 1.42 (d, J=7.0 Hz,
3H, Me), 5.02 (q, J=7.0 Hz, 1H, CH), 7.44 (t, J=7.2 Hz, 2H,
Ph meta), 7.60 (t, J=7.2 Hz, 1H, Ph para), 7.84 (d, J=7.4 Hz,
2H, Ph ortho). HPLC/MS (9 min) retention time 1.13 min.
LRMS: m/z 150 (M+1).

ACCEPTED MANUSCRIPT
residue was purified by reverse-phase chromatography to give
3.2. Ethyl
(4-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-
20 (34 mg, 0.070 mmol, 55% yield) as a white solid. Purity
1
imidazol-1-yl)acetate trifluoroacetate (18)
99%. H NMR (400 MHz, CDCl3) δ ppm 1.73 (s, 3H, Me),
Amine salt 17 (250 mg, 1.35 mmol) was suspended in 15 ml
acetone and the mixture cooled in an ice bath. Ethyl 2-
isocyanatoacetate (192 mg, 1.49 mmol) was added drop-wise
and with stirring, followed by triethylamine (0.75 ml, 5.4
mmol). The mixture was stirred at 0 ºC for 3 h. 2 ml
Trifluoroacetic acid was added and the mixture was stirred for
a further 1 h at room temperature. The mixture was
partitioned between chloroform and saturated sodium
bicarbonate solution. The organics were dried over sodium
sulphate, filtered and evaporated to give 18 (345 mg, 0.88
4.29 (s, 2H, COCH2), 5.24 (s, 2H, CH2Ph), 7.13 (m, 1H, Bn
H-6), 7.16 - 7.23 (m, 2H, Ar), 7.23 - 7.29 (m, 3H, Ar), 7.35 -
7.44 (m, 3H, Ar), 7.45 - 7.53 (m, 1H, Ar), 7.60 (m, 1H, Ar),
7.91 - 7.97 (m, 2H, SO2Ph ortho), 8.19 - 8.24 (m, 1H, Bn H-
3). HPLC/MS (30 min) retention time 15.98 min. LRMS: m/z
481 (M+1).
4. Scheme 4
4.1. Ethyl
(21)
N-[(2-benzoylhydrazino)carbonyl]glycinate
1
mmol, 65% yield) as a pale yellow solid. Purity 95%. H
Benzohydrazide (0.53 g, 3.9 mmol) was dissolved in 10 ml
tetrahydrofuran under nitrogen and the mixture stirred at 50
ºC. Ethyl 2-isocyanatoacetate (0.50 g, 3.9 mmol) was added
drop-wise and with stirring. The mixture was then stirred at
50 ºC overnight, forming a precipitate. The solid was
collected by filtration, was washed with ether and dried in a
stream of air to give 21 (1.00 g, 3.8 mmol, 97% yield) as a
NMR (400 MHz, CDCl3) δ ppm 1.20 (t, J=7.2 Hz, 3H,
OCH2CH3), 2.07 (s, 3H, Me), 4.14 (q, J=7.3 Hz, 2H,
OCH2CH3), 4.31 (s, 2H, CH2CO), 7.25 (d, J=7.5 Hz, 2H, Ph
ortho), 7.35 (t, J=7.2 Hz, 1H, Ph para), 7.41 (t, J=7.2 Hz, 2H,
Ph meta), 9.57 (br. s., 1H, NH). 19F NMR (376 MHz, CDCl3)
δ ppm -75.68 (s, 3F). HPLC/MS (9 min) retention time 5.38
min. LRMS: m/z 261 (M+1).
1
white solid. Purity 100%. H NMR (400 MHz, DMSO-d6) δ
ppm 1.19 (t, J=7.0 Hz, 3H, OCH2CH3), 3.78 (d, J=5.9 Hz,
2H, CH2CO), 4.09 (q, J=7.3 Hz, 2H, OCH2CH3), 6.86 (br. s.,
1H, NH), 7.48 (t, J=7.4 Hz, 2H, Ph meta), 7.56 (t, J=7.4 Hz,
1H, Ph para), 7.90 (d, J=7.4 Hz, 2H, Ph ortho), 8.20 (br. s.,
1H, NH), 10.22 (s, 1H, NH). HPLC/MS (9 min) retention
time 3.93 min. LRMS: m/z 266 (M+1).
3.3. Ethyl
(3-{2-[(4-fluorophenyl)sulfonyl]benzyl}-4-
methyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-
yl)acetate (19)
Imidazolone salt 18 (150 mg, 0.40 mmol) was dissolved in 5
ml dimethylformamide. Triethylamine (60 µl, 0.43 mmol)
was added and the mixture was stirred for 15 min. Bromide
10b (400 mg, 1.22 mmol) and potassium carbonate (170 mg,
1.23 mmol) were added and the mixture was stirred at room
temperature overnight. The mixture was partitioned between
ethyl acetate and water. The aqueous phase was extracted
twice with ethyl acetate. The combined organics were washed
with brine, dried over sodium sulphate, filtered and
evaporated. The residue was purified by reverse-phase
chromatography to give 19 (65 mg, 0.13 mmol, 32% yield) as
a white solid. Purity 92%. 1H NMR (400 MHz, CDCl3) δ ppm
1.20 (t, J=7.0 Hz, 3H, OCH2CH3), 1.75 (s, 3H, Me), 4.13 (q,
J=7.0 Hz, 2H, OCH2CH3), 4.35 (s, 2H, CH2CO), 5.22 (s, 2H,
CH2Ph), 7.15 (d, J=7.8 Hz, 1H, Bn H-6), 7.19 - 7.26 (m, 4H,
Ar), 7.35 - 7.46 (m, 3H, Ar), 7.50 (t, J=7.6 Hz, 1H, Ar), 7.60
(t, J=6.6 Hz, 1H, Ar), 7.94 (dd, J=4.9, 8.8 Hz, 2H, SO2Ph
ortho), 8.23 (d, J=7.8 Hz, 1H, Bn H-3). HPLC/MS (9 min)
retention time 6.77 min. LRMS: m/z 509 (M+1).
4.2. (5-Oxo-3-phenyl-1,5-dihydro-4H-1,2,4-triazol-4-
yl)acetic acid (22)
Acyl semicarbazide 21 (0.50 g, 1.88 mmol) was suspended in
10 ml 5N sodium hydroxide solution and the mixture was
stirred at reflux overnight. The mixture was allowed to cool
and was acidified with 5N hydrochloric acid. The aqueous
was extracted with ethyl acetate, the organics were washed
with brine, dried over sodium sulphate, filtered and
1
evaporated to give crude 22 (0.25 g). Purity 71%. H NMR
(400 MHz, DMSO-d6) δ ppm 4.43 (s, 2H, CH2CO), 7.51 (t,
J=7.4 Hz, 2H, Ph meta), 7.63 (t, J=7.4 Hz, 1H, Ph para), 7.95
(d, J=7.4 Hz, 2H, Ph ortho), 12.03 (s, 1H, NH), 13.05 (br. s.,
1H, OH). HPLC/MS (9 min) retention time 3.85 min. LRMS:
m/z 220 (M+1).
4.3. Ethyl (5-oxo-3-phenyl-1,5-dihydro-4H-1,2,4-triazol-
4-yl)acetate (23)
3.4. (3-{2-[(4-Fluorophenyl)sulfonyl]benzyl}-4-methyl-2-
oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)acetic
acid (20)
Crude Triazolone 22 (0.25 g) was dissolved in 4 ml ethanol.
0.2 ml Concentrated sulphuric acid was added and the
mixture was stirred at relux overnight. The mixture was
evaporated under reduced pressure. The residue was
partitioned between dichloromethane and saturated sodium
bicarbonate solution. The organics were washed with water,
dried over sodium sulphate, filtered and evaporated to give
Ester 19 (65 mg, 0.13 mmol) was dissolved in 3 ml
tetrahydrofuran and
3
ml water. Lithium hydroxide
monohydrate (30 mg, 0.71 mmol) was added and the mixture
was stirred overnight. The organics were evaporated and

ACCEPTED MANUSCRIPT
crude 23 (150 mg) as an oil. Purity 60%. 1H NMR (400 MHz,
CDCl3) δ ppm 1.23 (t, J=7.3 Hz, 3H, OCH2CH3), 4.20 (q,
J=7.3 Hz, 2H, OCH2CH3), 4.48 (s, 2H, CH2CO), 7.44 (t,
J=7.8 Hz, 2H, Ph meta), 7.56 (t, J=7.4 Hz, 1H, Ph para), 8.05
(d, J=7.4 Hz, 2H, Ph ortho), 9.48 (br. s., 1H, NH). HPLC/MS
(9 min) retention time 4.78 min. LRMS: m/z 248 (M+1).
ml tetrahydrofuran was then added drop-wise and with
stirring. The mixture was removed from the ice-bath and was
stirred for 2.5 h, warming to room temperature. Pentane was
added while stirring to form a precipitate. The mixture was
filtered and the filtrate was evaporated to give 26 (0.53 g, 1.94
mmol, 96% yield) as a colourless oil. Used as such without
further purification. Purity 95%. NMR spectrum not recorded.
HPLC/MS (9 min) sample dissolved in methanol: retention
time 5.35 min. LRMS: m/z 305 (M+MeOH+1).
4.4. Ethyl {5-oxo-3-phenyl-1-[2-(phenylsulfonyl)benzyl]-
1,5-dihydro-4H-1,2,4-triazol-4-yl}acetate (24)
Crude triazolone 23 (150 mg) was dissolved in 10 ml
acetonitrile. Bromide 10a (115 mg, 0.37 mmol) and
potassium carbonate (100 mg, 0.72 mmol) were added and
the mixture was stirred at reflux overnight. The mixture was
evaporated under reduced pressure and the residue was
partitioned between ethyl acetate and water. The organic
phase was washed with water, brine, dried over sodium
sulphate, filtered and evaporated. The residue was purified
using the Isolera system (ethyl acetate-hexane gradient, 0:100
rising to 60:40) to give 24 (140 mg, 0.29 mmol, 16% yield
4.7. 2-Benzoyl-N-[2-
(phenylsulfonyl)benzyl]hydrazinecarboxamide (27)
Benzohydrazide (265 mg, 1.95 mmol) was dissolved in 10 ml
tetrahydrofuran under nitrogen and the mixture was stirred at
50 ºC. Isocyanate 26 (530 mg, 1.94 mmol) was added drop-
wise and the mixture was stirred at 50 ºC overnight. The
mixture was allowed to cool and was evaporated under
reduced pressure. The oily residue was taken up in ether and
sonicated. The ether was decanted and the process repeated
until a solid was obtained. The solid was collected by filtration
and was dried in a stream of air to give 27 (790 mg, 1.93
mmol, 99% yield) as a white solid. Purity 93%. 1H NMR (400
MHz, CDCl3) δ ppm 4.55 (d, J=3.5 Hz, 2H, CH2Ph), 6.58 (t,
J=3.5 Hz, 1H, NHCH2), 7.39 - 7.60 (m, 9H, Ar), 7.63 (d,
J=7.4 Hz, 1H, Ar), 7.85 (app t, J=7.6 Hz, 4H, Ar), 8.09 (d,
J=7.8 Hz, 1H, Bn H-6), 9.00 (br. s., 1H, NH). HPLC/MS (9
min) retention time 5.35 min. LRMS: m/z 410 (M+1).
1
over three steps) as a white solid. Purity 98%. H NMR (400
MHz, CDCl3) δ ppm 1.23 (t, J=7.2 Hz, 3H, OCH2CH3), 4.19
(q, J=7.0 Hz, 2H, OCH2CH3), 4.51 (s, 2H, CH2CO), 5.46 (s,
2H, NCH2Ph), 7.19 (d, J=7.8 Hz, 1H, Bn H-6), 7.45 - 7.62
(m, 10H, Ar), 7.95 (d, J=7.4 Hz, 2H, SO2Ph ortho), 8.22 (d,
J=7.4 Hz, 1H, Bn H-3). HPLC/MS (9 min) retention time
6.37 min. LRMS: m/z 478 (M+1).
4.5. {5-Oxo-3-phenyl-1-[2-(phenylsulfonyl)benzyl]-1,5-
dihydro-4H-1,2,4-triazol-4-yl}acetic acid (25)
Ester 24 (140 mg, 0.29 mmol) was dissolved in 5 ml
4.8. 5-Phenyl-4-[2-(phenylsulfonyl)benzyl]-2,4-dihydro-
3H-1,2,4-triazol-3-one (28)
Semicarbazide 27 (400 mg, 0.98 mmol) was suspended in 8
ml 5N sodium hydroxide solution and was stirred at reflux
overnight. A further 4 ml 5N sodium hydroxide solution was
added and the mixture was stirred at reflux for a further night.
The mixture was allowed to cool and was acidified with
concentrated hydrochloric acid. The mixture was extracted
with dichloromethane and the organic phase was washed with
water, brine, dried over sodium sulphate, filtered and
evaporated to give crude 28 (280 mg) as a solid. Purity 85%.
NMR spectrum not recorded. HPLC/MS (9 min) retention
time 5.68 min. LRMS: m/z 392 (M+1).
tetrahydrofuran and
5
ml water. Lithium hydroxide
monohydrate (75 mg, 1.8 mmol) was added and the mixture
was stirred for 3 h. The organics were evaporated and the
remaining aqueous was acidified with 2N hydrochloric acid
forming a oily residue. The aqueous was extracted with ethyl
acetate and the organics dried over sodium sulphate, filtered
and evaporated. The residue was sonnicated in ether to give a
solid which was collected by filtration, washed with ether and
was dried under vacuum to give 25 (85 mg, 0.19 mmol, 64%
1
yield) as a white solid. Purity 97%. H NMR (400 MHz,
DMSO-d6) δ ppm 4.46 (s, 2H, CH2CO), 5.23 (s, 2H,
NCH2Ph), 7.10 (d, J=7.4 Hz, 1H, Bn H-6), 7.42 – 7.51 (m,
4H, Ar), 7.57 – 7.71 (m, 6H, Ar), 7.94 (d, J=7.4 Hz, 2H,
SO2Ph ortho), 8.16 (d, J=7.4 Hz, 1H, Bn H-3). HPLC/MS (30
min) retention time 14.82 min. LRMS: m/z 450 (M+1).
4.9. tert-Butyl
{5-oxo-3-phenyl-4-[2-
(phenylsulfonyl)benzyl]-4,5-dihydro-1H-1,2,4-
triazol-1-yl}acetate (29)
Crude triazolone 28 (280 mg) was dissolved in 10 ml
acetonitrile. Potassium carbonate (170 mg, 1.23 mmol) and
tert-butyl bromoacetate (118 mg, 0.60 mmol) were added and
the mixture was stirred at reflux for 24 h. The mixture allowed
to cool and was evaporated under reduced pressure. The
residue was partitioned between ethyl acetate and water. The
aqueous phase was extracted twice with ethyl acetate. The
combined organics were washed with water, brine, dried over
4.6. 1-(Isocyanatomethyl)-2-(phenylsulfonyl)benzene (26)
Triphosgene (0.60 g, 2.0 mmol) was dissolved in 20 ml
dichloromethane and the mixture cooled in an ice bath. A
solution of amine 11a (0.50 g, 2.0 mmol) dissolved in 5 ml
tetrahydrofuran was added drop-wise and with stirring. A
mixture of triethylamine (0.60 ml, 2.1 mmol) dissolved in 5

ACCEPTED MANUSCRIPT
sodium sulphate, filtered and evaporated. The residue was
5.2. (2E)-2-(Benzoylamino)-3-{2-[(4-
purified using the SP1 purification system (ethyl acetate-
hexane gradient, 20:80 rising to 40:60) to give 29 (180 mg,
0.36 mmol, 36% yield over two steps) as a white solid. Purity
fluorophenyl)sulfonyl]phenyl}acrylic acid (32)
Azlactone 31 (2.18 g, 5.35 mmol) was suspended in 10 ml
tetrahydrofuran and the mixture was stirred at reflux (bath
temperature 100 ºC). 104 ml of a 1% w/v solution of
potassium hydroxide was added slowly while still in the oil
bath and the mixture was then stirred for 20 min at 80 ºC. The
mixture was hot filtered and the filtrate was partially
evaporated under reduced pressure. The filtrate was allowed
to cool and was acidified to pH 2 with concentrated
hydrochloric acid, forming a precipitate. The solid was
collected by filtration, was washed with water and was dried
at 40 ºC under reduced pressure overnight to give 32 (1.86 g,
1
93%. H NMR (400 MHz, CDCl3) δ ppm 1.49 (s, 9H, tBu),
4.58 (s, 2H, CH2CO), 5.31 (s, 2H, CH2Ph), 7.19 (d, J=7.4 Hz,
1H, Bn H-6), 7.23 - 7.31 (m, 4H, Ar), 7.37 (t, J=7.2 Hz, 1H,
Bn H-4), 7.48 (t, J=7.8 Hz, 2H, SO2Ph meta), 7.52 - 7.65 (m,
3H, Ar), 7.84 (d, J=7.4 Hz, 2H, SO2Ph ortho), 8.25 (d, J=7.8
Hz, 1H, Bn H-3). HPLC/MS (9 min) retention time 6.70 min.
LRMS: m/z 506 (M+1).
4.10. {5-Oxo-3-phenyl-4-[2-(phenylsulfonyl)benzyl]-4,5-
dihydro-1H-1,2,4-triazol-1-yl}acetic acid (30)
1
4.37 mmol, 82% yield) as a white solid. Purity 100%. H
Ester 29 (180 mg, 0.36 mmol) was dissolved in 3 ml
dichloromethane. 3 ml Trifluoroacetic acid was added and the
mixture was stirred for 90 min at room temperature. The
mixture was evaporated under reduced pressure and the
residue was taken up in a little water, frozen and lyophilized.
The solid obtained was suspended in a little ether and was
broken up by sonication. The solid was collected by filtration
and dried in a stream of air to give 30 (100 mg, 0.23 mmol,
66% yield) as a white solid. Purity 100%. 1H NMR (400 MHz,
DMSO-d6) δ ppm 4.60 (s, 2H, CH2CO), 5.19 (s, 2H, CH2Ph),
7.06 - 7.13 (m, 1H, Ar), 7.13 - 7.22 (m, 4H, Ar), 7.30 - 7.42
(m, 1H, Ar), 7.52 - 7.74 (m, 5H, Ar), 7.87 (d, J=7.4 Hz, 2H,
SO2Ph ortho), 8.23 (d, J=7.4 Hz, 1H, Bn H-3). HPLC/MS (30
min) retention time 14.25 min. LRMS: m/z 450 (M+1).
NMR (400 MHz, DMSO-d6) δ ppm 7.42 - 7.52 (m, 4H, COPh
meta and SO2PhF meta, coincident), 7.56 (t, J=6.8 Hz, 1H,
Ar), 7.60 - 7.65 (m, 1H, Ar), 7.69 (m, 2H, Ar), 7.81 (d, J=7.4
Hz, 2H, COPh ortho), 7.86 (s, 1H, vinyl H), 7.92 - 8.01 (m,
2H, SO2PhF ortho), 8.17 (d, J=7.4 Hz, 1H, C=CPh H-3), 9.81
(br. s., 1H, NH), 13.06 (br. s., 1H, COOH). HPLC/MS (30
min) retention time 12.32 min. LRMS: m/z 426 (M+1).
5.3. N-Benzoyl-2-[(4-
fluorophenyl)sulfonyl]phenylalanine (33)
Acrylic acid 32 (1.86 g, 4.37 mmol) was suspended in 65 ml
acetic acid and the mixture was stirred at 80 ºC to dissolve the
solid. Zinc dust (3.0 g, 46 mmol) was added and the mixture
was stirred vigorously at 80 ºC for 8 h. The mixture was hot
filtered through a plug of Celite, washing through with
tetrahydrofuran once cool. The filtrate was re-filtered through
filter paper and was partially evaporated under reduced
pressure to remove the tetrahydrofuran. The organics were
diluted by slow addition of water to form a precipitate. The
solid was collected by filtration, was washed with water and
was dried at 40 ºC under reduced pressure overnight to give
33 (1.71 g, 4.00 mmol, 92% yield) as a white solid. Purity
100%. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.10 (dd,
J=11.3, 13.7 Hz, 1H, CHACHBPh), 3.62 (dd, J=3.7, 13.9 Hz,
1H, CHACHBPh), 4.65 (ddd, J=3.7, 8.6, 11.3 Hz, 1H, CHCO),
7.43 - 7.48 (m, 3H, Ar), 7.49 - 7.55 (m, 4H, Ar), 7.59 (t,
J=6.8 Hz, 1H, COPh para), 7.77 (d, J=7.0 Hz, 2H, COPh
ortho), 7.98 (dd, J=4.9, 8.8 Hz, 2H, SO2PhF ortho), 8.10 (d,
J=7.0 Hz, 1H, Bn H-3), 8.73 (d, J=8.6 Hz, 1H, NH), 12.73 -
12.91 (br. s., 1H, COOH). HPLC/MS (9 min) retention time
7.17 min. LRMS: m/z 428 (M+1).
5. Scheme 5
5.1. (4E)-4-{2-[(4-Fluorophenyl)sulfonyl]benzylidene}-2-
phenyl-1,3-oxazol-5(4H)-one (31)
A mixture of hippuric acid (1.7 g, 9.49 mmol), aldehyde 8b
(2.51 g, 9.49 mmol), sodium acetate (1.32 g, 16.1 mmol) and
acetic anhydride (2.7 ml, 28.6 mmol) was stirred together at
100 ºC under argon for 2 h. The mixture was allowed to cool,
was diluted with 8 ml ethanol and the resulting suspension
was stirred for a further 1 h at room temperature. The solid
was collected by filtration and was washed successively with
ethanol and water. The solid was dried at 40 ºC under reduced
pressure overnight to give 31 (2.45 g, 6.0 mmol, 63% yield)
1
as a pale yellow solid. Purity 100%. H NMR (400 MHz,
CDCl3) δ ppm 7.17 (t, J=8.6 Hz, 2H, oxazolinone-Ph meta),
7.53 (t, J=7.6 Hz, 2H, SO2PhF meta), 7.64 (t, J=7.6 Hz, 2H,
C=CPh H-4 and H-5 coincident), 7.75 (t, J=7.6 Hz, 1H,
oxazolinone-Ph para), 7.95 (dd, J=4.9, 8.8 Hz, 2H, SO2PhF
ortho), 8.10 (s, 1H, vinyl H), 8.13 (d, J=7.4 Hz, 2H,
oxazolinone-Ph ortho), 8.37 (d, J=7.8 Hz, 1H, C=CPh H-6),
8.75 (d, J=7.8 Hz, 1H, C=CPh H-3). HPLC/MS (9 min)
retention time 7.25 min. LRMS: m/z 408 (M+1).
5.4. N-(1-{2-[(4-Fluorophenyl)sulfonyl]benzyl}-2-
oxopropyl)benzamide (34)
Carboxylic acid 33 (600 mg, 1.40 mmol) was suspended in
acetic anhydride (0.53 ml, 5.6 mmol). Triethylamine (0.28 ml,
2.0 mmol) and 4-(N,N-dimethylamino)pyridine (7 mg, 0.06
mmol) were added and the mixture was stirred at 60 ºC for 30

ACCEPTED MANUSCRIPT
min, evolving a gas. Once no more gas was evolved, 2 ml
7.33 (d, J=7.0 Hz, 1H, Ar), 7.37 (t, J=7.3 Hz, 2H, SO2PhF
meta), 7.39 - 7.45 (m, 4H, Ar), 7.49 (t, J=7.6 Hz, 1H, Ar),
7.59 (t, J=7.3 Hz, 1H, Ar), 7.92 (m, 2H, SO2PhF ortho), 8.12
(d, J=7.6 Hz, 1H, Bn H-3), 8.19 (br. s., 1H, COOH).
HPLC/MS (30 min) retention time 10.67 min. LRMS: m/z 465
(M+1).
acetic acid were added and the mixture was stirred at 60 ºC
for a further 30 min. The mixture was allowed to cool and
was evaporated under reduced pressure. The residue was re-
suspended in 2N sodium hydroxide, forming a paste. The
paste was triturated with ether to form a solid. The solid was
collected by filtration and was dried at 40 ºC under reduced
pressure to give 34 (374 mg, 0.88 mmol, 63% yield) as a
white solid. Purity 100%. 1H NMR (400 MHz, CDCl3) δ ppm
2.32 (s, 3H, Me), 3.18 (dd, J=4.3, 14.1 Hz, 1H, CHACHBPh),
3.39 (dd, J=11.7, 14.1 Hz, 1H, CHACHBPh), 4.94 (ddd, J=4.7,
7.2, 11.5 Hz, 1H, CHCO), 7.22 (t, J=8.6 Hz, 2H, SO2PhF
meta), 7.39 - 7.44 (m, 3H, Ar), 7.45 - 7.53 (m, 2H, Ar), 7.58
(t, J=7.2 Hz, 1H, COPh para), 7.80 (d, J=7.4 Hz, 2H, COPh
ortho), 7.85 - 7.92 (m, 3H, SO2PhF ortho and NH), 8.08 (d,
J=7.4 Hz, 1H, Bn H-3). HPLC/MS (9 min) retention time
6.08 min. LRMS: m/z 426 (M+1).
6. Scheme 6
6.1. (6-Oxo-1,6-dihydropyridin-3-yl)acetic acid (37)
(6-Chloropyridin-3-yl)acetic acid (2.2 g, 12.8 mmol) was
suspended in 22 ml glacial acetic acid and 6 ml water. The
mixture was stirred at 160 ºC under microwave irradiation for
8 h. The mixture was allowed to cool and was evaporated
under reduced pressure. The residue was re-evaporated from
toluene to give 37 (1.96 g, 12.8 mmol, 100% yield) as a pale
1
brown solid. Purity 92%. H NMR (300 MHz, DMSO-d6) δ
ppm 3.38 (s, 2H, CH2), 6.33 (d, J=9.3 Hz, 1H, H-5), 7.28 (s,
1H, H-2), 7.38 (dd, J=2.5, 9.3 Hz, 1H, H-4). UPLC/MS (3
min) retention time 0.42 min. LRMS: m/z 152 (M-1).
5.5. 2-(4-{2-[(4-Fluorophenyl)sulfonyl]benzyl}-5-methyl-
2-phenyl-1H-imidazol-1-yl)ethanol (35)
Ketone 34 (150 mg, 0.35 mmol) was suspended in 4 ml
xylene. Ethanolamine (32 µl, 0.53 mmol) and 2.6 ml acetic
acid were added and the mixture was stirred at 130 ºC for 5 h.
Further ethanolamine (64 µl, 1.06 mmol) was added and the
mixture was stirred at 130 ºC for a further 4 h. The mixture
was allowed to cool and was partitioned between ethyl acetate
and saturated sodium bicarbonate solution. The organic phase
was dried over sodium sulphate, filtered and evaporated. The
residue was purified by reverse-phase chromatography to give
35 (11 mg, 0.024 mmol, 7% yield) as a solid. Purity 100%. 1H
NMR (400 MHz, CDCl3) δ ppm 2.06 (s, 3H, Me), 3.75 (t,
J=5.9 Hz, 2H, NCH2CH2OH), 4.09 (t, J=5.9 Hz, 2H,
NCH2CH2OH), 4.18 (s, 2H, CH2Ph), 7.16 (t, J=8.6 Hz, 2H,
SO2PhF meta), 7.30 (d, J=7.8 Hz, 1H, Ar), 7.34 - 7.52 (m,
5H, Ar), 7.57 (d, J=7.4 Hz, 2H, imidazole-Ph ortho), 7.91
(dd, J=5.1, 9.0 Hz, 2H, SO2PhF ortho), 8.21 (d, J=7.8 Hz, 1H,
Bn H-3). HPLC/MS (9 min) retention time 4.23 min. LRMS:
m/z 451 (M+1).
6.2. Ethyl (6-oxo-1,6-dihydropyridin-3-yl)acetate (38)
Acid 37 (1.96 g, 12.8 mmol) was suspended in 40 ml ethanol
and 16 drops of concentrated sulphuric acid were added. The
mixture was stirred at reflux for 5 h and was then left to cool.
The mixture was evaporated under reduced pressure and the
residue partitioned between brine and dichloromethane. The
aqueous phase was extracted with dichloromethane and the
combined organics were dried over anhydrous sodium
sulphate, filtered and evaporated under reduced pressure to
give 38 (1.95 g, 10.8 mmol, 84% yield) as a pale yellow solid.
Purity 94%. 1H NMR (300 MHz, CDCl3) δ ppm 1.27 (t, J=7.0
Hz, 3H, OCH2CH3), 3.40 (s, 2H, CH2CO), 4.16 (q, J=7.0 Hz,
2H, OCH2CH3), 6.63 (d, J=9.1 Hz, 1H, H-5), 7.36 (s, 1H, H-
2), 7.50 (d, J=9.0 Hz, 1H, H-4). UPLC/MS (3 min) retention
time 0.81 min. LRMS: m/z 182 (M+1).
6.3. Ethyl
yl)acetate (39)
(5-chloro-6-oxo-1,6-dihydropyridin-3-
Pyridone 38 (300 mg, 1.79 mmol) was dissolved in 6 ml
dimethylformamide and the mixture cooled in an ice-bath. N-
Chlorosuccinimide (287 mg, 2.15 mmol) was added portion-
wise and with stirring. The mixture was alowed to warm to
room temperature and was stirred for 3 h. The mixture was
partitioned between water and ethyl acetate. The aqueous
phase was extracted with ethyl acetate and the combined
organics were dried over anhydrous sodium sulphate, filtered
and evaporated under reduced pressure. The residue was
partially purified by flash chromatography to give crude 39
(150 mg) as a solid. Purity 85%. NMR spectrum not recorded.
UPLC/MS (3 min) retention time 1.02 min. LRMS: m/z 216
(M+1).
5.6. (4-{2-[(4-Fluorophenyl)sulfonyl]benzyl}-5-methyl-2-
phenyl-1H-imidazol-1-yl)acetic acid (36)
A solution of Jones’ reagent was prepared by dissolving
chromium trioxide (67 mg, 0.63 mmol) and concentrated
sulphuric acid (58 µl) and 0.25 ml water at 0 ºC. Alcohol 35 (8
mg, 0.018 mmol) was dissolved in 0.8 ml acetone and cooled
to 0 ºC. Jones reagent solution (30 µl) was added and the
mixture was stirred for 3 h, warming to room temperature. The
mixture was evaporated under reduced pressure and the
residue was purified by preparative HPLC to give 36 (3.9 mg,
1
0.0083 mmol, 37% yield) as a solid. Purity 95%. H NMR
(600 MHz, DMSO-d6) δ ppm 1.84 (s, 3H, Me), 4.03 (s, 2H,
CH2Ph), 4.27 (br. s., 2H, CH2CO), 7.30 (d, J=7.6 Hz, 1H, Ar),

ACCEPTED MANUSCRIPT
6.4. Ethyl
{6-oxo-1-[2-(phenylsulfonyl)benzyl]-1,6-
with water and acidified to pH 3-4 with 2N hydrochloric acid.
dihydropyridin-3-yl}acetate (40)
The aqueous phase was extracted twice with dichloromethane
and the combined organics were dried over anhydrous
magnesium sulphate, filtered and evaporated under reduced
pressure to give 42 (83 mg, 0.22 mmol, 94% yield) as a white
solid. Purity 99%. 1H NMR (300 MHz, CDCl3) δ ppm 3.34 (s,
2H, CH2CO), 5.46 (s, 2H, NCH2Ph), 6.64 (d, J=9.3 Hz, 1H,
pyridone H-5), 7.17 (d, J=1.9 Hz, 1H, pyridone H-2), 7.20 (d,
J=7.4 Hz, 1H, Bn H-6), 7.34 (dd, J=2.5, 9.3 Hz, 1H, pyridone
H-4), 7.45 - 7.59 (m, 4H, Ar), 7.63 (t, J=7.1 Hz, 1H, Ar), 7.89
(d, J=7.1 Hz, 2H, SO2Ph ortho), 8.21 (dd, J=1.5, 7.6 Hz, 1H,
Bn H-3). HPLC/MS (30 min) retention time 11.20 min.
LRMS: m/z 384 (M+1).
Pyridone 38 (100 mg, 0.56 mmol) was dissolved in 4 ml
dimethylformamide. Bromide 10a (288 mg, 0.93 mmol) and
potassium carbonate (84 mg, 0.60 mmol) were added and the
mixture was stirred at 70 ºC overnight. The mixture was
evaporated under reduced pressure and the residue was
partitioned between ethyl acetate and water. The organic
phase was washed twice with water, dried over magnesium
sulphate, filtered and evaporated. The residue was purified by
flash chromatography using the Isolera system (ethyl acetate-
hexane gradient, 0:100 rising to 100:0) to give 40 (98 mg,
1
0.24 mmol, 44% yield) as a colourless oil. Purity 100%. H
NMR (300 MHz, CDCl3) δ ppm 1.26 (t, J=7.1 Hz, 3H,
OCH2CH3), 3.31 (s, 2H, CH2CO), 4.16 (q, J=7.1 Hz, 2H,
OCH2CH3), 5.47 (s, 2H, NCH2Ph), 6.61 (d, J=9.3 Hz, 1H,
pyridone H-5), 7.15 (d, J=1.9 Hz, 1H, pyridone H-2), 7.19 (d,
J=7.4 Hz, 1H, Bn H-6), 7.35 (dd, J=2.5, 9.3 Hz, 1H, pyridine
H-4), 7.45 - 7.60 (m, 4H, Ar), 7.64 (t, J=7.1 Hz, 1H, Ar), 7.92
(d, J=7.1 Hz, 2H, SO2Ph ortho), 8.24 (dd, J=1.2, 7.6 Hz, 1H,
Bn H-3). UPLC/MS (3 min) retention time 1.56 min. LRMS:
m/z 412 (M+1).
6.7. {5-Chloro-6-oxo-1-[2-(phenylsulfonyl)benzyl]-1,6-
dihydropyridin-3-yl}acetic acid (43)
Ester 41 (50 mg, 0.11 mmol) was dissolved in 1 ml
tetrahydrofuran and 1.5 ml water. Lithium hydroxide
monohydrate (7 mg, 0.17 mmol) was added and the mixture
was stirred for 3 h at room temperature. The organics were
evaporated under reduced pressure. The solution was diluted
with water and was washed with ethyl acetate. The aqueous
phase was acidified to pH 3 with 2N hydrochloric acid
forming a turbid solution. The aqueous phase was extracted
twice with dichloromethane and the combined organics were
dried over anhydrous magnesium sulphate, filtered and
evaporated under reduced pressure to give 43 (23 mg, 0.060
mmol, 53% yield) as a white solid. Purity 99%. 1H NMR (300
MHz, DMSO-d6) δ ppm 3.3 (approx, CH2CO signal under
water peak), 5.43 (s, 2H, NCH2Ph), 6.77 (d, J=7.4 Hz, 1H, Bn
H-6), 7.54 (d, J=1.9 Hz, 1H, pyridine H-2), 7.58 - 7.71 (m,
4H, Ar), 7.74 (d, J=7.4 Hz, 1H, Ar), 7.79 (d, J=2.2 Hz, 1H,
Ar), 7.98 (d, J=7.4 Hz, 2H, SO2Ph ortho), 8.19 (d, J=7.4 Hz,
1H, Bn H-3). HPLC/MS (30 min) retention time 12.17 min.
LRMS: m/z 418 (M+1).
6.5. Ethyl {5-chloro-6-oxo-1-[2-(phenylsulfonyl)benzyl]-
1,6-dihydropyridin-3-yl}acetate (41)
Crude pyridone 39 (100 mg) was dissolved in 3 ml
dimethylformamide under argon and the mixture was cooled
in an ice-bath. Sodium hydride (60% dispersion in oil, 20 mg,
0.50 mmol) was added and the mixture was stirred at 0 ºC for
30 min. A solution of bromide 10a (194 mg, 0.62 mmol)
dissolved in 1 ml dimethylformamide was added and the
mixture was stirred at room temperature for 2 h. The mixture
was partitioned between ethyl acetate and water. The organic
phase was dried over magnesium sulphate, filtered and
evaporated. The residue was purified by flash
chromatography using the Isolera system (diethyl ether-
hexane gradient) to give 41 (50 mg, 0.11 mmol, 9% yield
over two steps) as a colourless oil. Purity 95%. 1H NMR (300
MHz, CDCl3) δ ppm 1.26 (t, J=7.1 Hz, 3H, OCH2CH3), 3.29
(s, 2H, CH2CO), 4.16 (q, J=7.1 Hz, 2H, OCH2CH3), 5.51 (s,
2H, NCH2Ph), 7.20 (br. s., 1H, pyridone H-2), 7.25 (d, J=7.1
Hz, 1H, Bn H-3), 7.45 - 7.69 (m, 6H, Ar), 7.88 (d, J=7.1 Hz,
2H, SO2Ph ortho), 8.20 (d, J=7.5 Hz, 1H, Bn H-3). UPLC/MS
(3 min) retention time 1.68 min. LRMS: m/z 446 (M+1).
7. Scheme 7
7.1. (2-Methoxypyridin-3-yl)methanol (44)
Sodium borohydride (0.17 g, 4.5 mmol) was dissolved in 20
ml ethanol under argon and the mixture cooled to -40 ºC in a
cryo-cool. A solution of 2-methoxynicotinaldehyde (2.0 g,
14.6 mmol) dissolved in 4 ml ethanol was added drop-wise
and with stirring. The mixture was stirred at -40 ºC for 45
min. 10 ml Brine was added carefully and the mixture was
then allowed to warm to room temperature. The organics
were evaporated under reduced pressure. The mixture was
partitioned between ethyl acetate and water. The aqueous
phase was extracted with ethyl acetate and the combined
organics were dried over magnesium sulphate, filtered and
evaporated to give 44 (1.90 g, 13.7 mmol, 94% yield) as a
6.6. {6-Oxo-1-[2-(phenylsulfonyl)benzyl]-1,6-
dihydropyridin-3-yl}acetic acid (42)
Ester 40 (95 mg, 0.23 mmol) was dissolved in 1.5 ml
tetrahydrofuran and 1.5 ml water. Lithium hydroxide
monohydrate (14 mg, 0.33 mmol) was added and the mixture
was stirred for 1 h at room temperature. The organics were
evaporated under reduced pressure. The solution was diluted
1
pale yellow oil. Purity 100%. H NMR (300 MHz, CDCl3) δ
ppm 2.30 (t, J=6.5 Hz, 1H, OH), 4.00 (s, 3H, MeO), 4.66 (d,

ACCEPTED MANUSCRIPT
J=6.3 Hz, 2H, CH2), 6.90 (dd, J=5.0, 7.1 Hz, 1H, H-5), 7.58
Pyridone 47 (0.30 g, 1.66 mmol) was dissolved in 5 ml
dimethylformamide and the mixture was cooled in an ice-
bath. Sodium hydride (60% dispersion in oil, 0.17 g, 4.3
mmol) was added portion-wise and with stirring and the
mixture was stirred for 30 min at 0 ºC. Bromide 10a (0.77 g,
2.5 mmol) dissolved in 4 ml dimethylformamide was added
and the mixture was stirred for 2 h at room temperature. The
mixture was partitioned between ethyl acetate and water. The
aqueous was extracted with ethyl acetate and was then
acidified with 2N hydrochloric acid forming a suspension.
The mixture was extracted with dichloromethane and the
organic phase was dried over magnesium sulphate, filtered
and evaporated to give 48 (0.13 g, 0.34 mmol, 21% yield) as a
(d, J=7.1 Hz, 1H, H-4), 8.11 (d, J=4.9 Hz, 1H, H-6).
UPLC/MS (3 min) retention time 0.77 min. LRMS: m/z 140
(M+1).
7.2. 3-(Chloromethyl)-2-methoxypyridine (45)
Alcohol 44 (1.0 g, 7.2 mmol) was dissolved in 35 ml
dichloromethane. Thionyl chloride (9.4 ml, 18 mmol) was
added drop-wise and with stirring and the mixture was stirred
for 1 h at room temperature. The mixture was concentrated
under reduced pressure. The residue was re-suspended in
dichloromethane and saturated sodium bicarbonate solution
was added carefully. The mixture was stirred for 10 min and
the organic phase was then separated, dried over magnesium
sulphate, filtered and evaporated to give 45 (1.05 g, 6.7 mmol,
1
white solid. Purity 97%. H NMR (300 MHz, CDCl3) δ ppm
3.66 (s, 2H, CH2CO), 5.59 (s, 2H, CH2Ph), 6.39 (t, J=7.0 Hz,
1H, pyridone H-5), 7.06 - 7.16 (m, 1H, Ar), 7.23 - 7.31 (m,
1H, Ar), 7.39 - 7.49 (m, 2H, Ar), 7.50 - 7.68 (m, 4H, Ar),
7.90 (d, J=7.4 Hz, 2H, SO2Ph ortho), 8.22 (d, J=7.4 Hz, 1H,
Bn H-3). HPLC/MS (30 min) retention time 11.83 min.
LRMS: m/z 384 (M+1).
1
93% yield) as a pale yellow oil. Purity 95%. H NMR (300
MHz, CDCl3) δ ppm 4.01 (s, 3H, MeO), 4.60 (s, 2H, CH2),
6.90 (dd, J=5.1, 7.0 Hz, 1H, H-5), 7.65 (d, J=7.1 Hz, 1H, H-
4), 8.13 (d, J=4.7 Hz, 1H, H-6). UPLC/MS (3 min) retention
time 1.46 min. LRMS: m/z no ionization.
7.3. (2-Methoxypyridin-3-yl)acetonitrile (46)
8. Scheme 8
Chloride 45 (0.50 g, 3.2 mmol) was dissolved in 2 ml
dimethylformamide. Sodium cyanide (0.31 g, 6.33 mmol)
was added and the mixture was agitated at 50 ºC for 3 h and
then at 70 ºC overnight. The mixture was allowed to cool and
was partitioned between ethyl acetate and water. The organic
phase was washed twice with water, was dried over
magnesium sulphate, filtered and evaporated. The residue was
purified using the Isolera (ethyl acetate-hexane, 25:75) to give
46 (0.37 g, 2.50 mmol, 79% yield) as a pale yellow oil. Purity
8.1. (3Z)-5-Phenyl-3-[2-
(phenylsulfonyl)benzylidene]furan-2(3H)-one (49)
4-Oxo-4-phenylbutanoic acid (200 mg, 1.12 mmol) and
aldehyde 8a (275 mg, 1.12 mmol) were mixed under nitrogen
atmosphere. 5 ml Acetic anhydride and 10 drops of
triethylamine were added and the mixture was stirred at reflux
for 3 h. The mixture was poured over ice-water. Ethyl acetate
was added and the organic phase was separated. The aqueous
was extracted three times with ethyl acetate and the combined
organics were washed twice with water, twice with brine,
dried over magnesium sulphate, filtered and evaporated. The
residue was triturated with acetonitrile to give a solid. The
solid was collected by filtration to give 49 (110 mg, 0.28
1
96%. H NMR (300 MHz, CDCl3) δ ppm 3.67 (s, 2H, CH2),
4.00 (s, 3H, MeO), 6.93 (dd, J=5.1, 7.3 Hz, 1H, H-5), 7.68 (d,
J=7.4 Hz, 1H, H-4), 8.15 (d, J=4.1 Hz, 1H, H-6). UPLC/MS
(3 min) retention time 1.08 min. LRMS: m/z 149 (M+1).
1
mmol, 25% yield) as a bright yellow solid. Purity 94%. H
7.4. Ethyl (2-oxo-1,2-dihydropyridin-3-yl)acetate (47)
Nitrile 46 (0.23 g, 1.55 mmol) was dissolved in 3 ml ethanol
in a sealed tube. Acetyl chloride (1.1 ml, 15.4 mmol) was
added drop-wise and with stirring (Exotherm !). The vessel
was then sealed and the mixture was stirred at 50 ºC
overnight. The mixture was allowed to cool and was
evaporated under reduced pressure. The residue was triturated
with ether to give a solid. The solid was collected by filtration
and dried in a stream of air to give 47 (0.37 g, 2.50 mmol,
79% yield) as a white solid. Purity 75%. NMR spectrum not
recorded. UPLC/MS (3 min) retention time 0.83 min. LRMS:
m/z 182.
NMR (400 MHz, CDCl3) δ ppm 6.40 (s, 1H, furanone H),
7.33 - 7.52 (m, 6H, Ar), 7.53 - 7.74 (m, 5H, Ar), 7.90 (d,
J=7.0 Hz, 2H, PhSO2 ortho), 7.97 (s, 1H, vinyl H), 8.38 (d,
J=7.8 Hz, 1H, C=CPh H-3). HPLC/MS (9 min) retention time
+
7.00 min. LRMS: m/z 406 (M+NH4 ).
8.2. 6-Phenyl-4-[2-(phenylsulfonyl)benzyl]pyridazin-
3(2H)-one (50)
Lactone 49 (110 mg, 0.28 mmol) was dissolved in 2 ml
ethanol. 2 ml Hydrazine hydrate was added and the mixture
was stirred at reflux for 4 h. The mixture was allowed to cool
and was evaporated under reduced pressure. The residue was
partitioned between ethyl acetate and water. The aqueous was
extracted three times with ethyl acetate and the combined
organics were washed three times with water, twice with
brine, dried over magnesium sulphate, filtered and evaporated
7.5. {2-Oxo-1-[2-(phenylsulfonyl)benzyl]-1,2-
dihydropyridin-3-yl}acetic acid (48)

ACCEPTED MANUSCRIPT
to give crude pyridazinone 50 (99 mg) as a pale yellow solid.
9.2. Ethyl
(2-methyl-4,5,6,7-tetrahydro-1H-indol-1-
Purity 74%. NMR spectrum not recorded. HPLC/MS (9 min)
yl)acetate (54)
retention time 6.15 min. LRMS: m/z 403 (M+1).
The crude sample of 53 (1.2 g) was dissolved in 5 ml ethanol.
Ethyl 2-aminoacetate hydrochloride (0.45 g, 3.2 mmol) and
sodium acetate (0.52 g, 6.3 mmol) were added and the
mixture was stirred overnight at room temperature. The
mixture was evaporated under reduced pressure and the
residue was re-suspended in dichloromethane, filtered and the
filtrate evaporated under reduced pressure. The residue was
partially purified by reverse-phase chromatography crude 54
(0.08 g) as a red oil. Purity 48%. Used as such without further
purification. HPLC/MS (30 min) retention time 14.77 min.
LRMS: m/z 222 (M+1).
8.3. tert-Butyl
[6-oxo-3-phenyl-5-[2-
(phenylsulfonyl)benzyl]pyridazin-1(6H)-yl]acetate
(51)
Crude pyridazinone 50 (99 mg) was dissolved in 4 ml
dimethylformamide. tert-Butyl 2-bromoacetate (82 µl, 0.55
mmol) and potassium carbonate (75 mg, 0.55 mmol) were
added and the mixture was stirred at room temperature for 2
h. The mixture was poured over ice-water forming a
precipitate. The solid was collected by filtration and was
dissolved in dichloromethane, dried over magnesium
sulphate, filtered and evaporated. The residue was purified
using the SP1 purification system (ethyl acetate-hexane
gradient, 0:100 rising to 60:40) to give 51 (70 mg, 0.14 mmol,
46% yield over two steps) as a colourless oil. Purity 98%.
NMR spectrum not recorded. HPLC/MS (9 min) retention
time 7.15 min. LRMS: m/z 517 (M+1).
9.3. 2-(2-Oxopropyl)cyclohexane-1,3-dione (55)
Cyclohexane-1,3-dione (1 g, 8.9 mmol) was dissolved in 12
ml chloroform. Chloroacetone (0.71 ml, 8.9 mmol) and
potassium carbonate (1.23 g, 8.9 mmol) were added and the
mixture was stirred for 2 h, forming a dark brown gum. The
solvents were decanted and the gummy residue was extracted
several times with ethyl acetate. The combined organics were
evaporated under reduced pressure and the residue was
purified using the SP-1 purification system (ethyl acetate-
hexane gradient, 0:100 rising to 100:0) to give 55 (0.31 g, 1.8
8.4. [6-Oxo-3-phenyl-5-[2-
(phenylsulfonyl)benzyl]pyridazin-1(6H)-yl]acetic
acid (52)
1
Ester 51 (70 mg, 0.14 mmol) was dissolved in 2 ml
dichloromethane and 1 ml trifluoroacetic acid and the mixture
was stirred for 2 h at room temperature. The mixture was
evaporated under reduced pressure and the residue was
triturated with ether to give a solid. The solid was collected by
filtration and was dried at 40 ºC under reduced pressure to
give 52 (54 mg, 0.12 mmol, 87% yield) as a white solid.
Purity 100%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.22 (s,
2H, CH2CO), 4.86 (s, 2H, CH2Ph), 6.56 (s, 1H, pyridazinone
H), 7.36 - 7.48 (m, 9H, Ar), 7.66 - 7.71 (m, 1H, Ar), 7.72 -
7.77 (m, 3H, Ar), 8.29 (dd, J=1.6, 7.8 Hz, 1H, Bn H-3), 13.14
(s, 1H, COOH). HPLC/MS (30 min) retention time 15.47 min.
LRMS: m/z 461 (M+1).
mmol, 21% yield) as a pale yellow oil. Purity 92%. H NMR
(400 MHz, CDCl3) mixture of keto and enol tautomers. Keto
form (partial) δ ppm 3.08 (d, J=5.1 Hz, 2H, MeCOCH2CH),
3.75 (t, J=4.9 Hz, 1H, MeCOCH2CH). Enol form (partial) δ
ppm 3.43 (s, 2H, MeCOCH2). HPLC/MS (9 min) retention
time 3.22 min. LRMS: m/z 169 (M+1).
9.4. Ethyl (2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-
1-yl)acetate (56)
Triketone 55 (0.30 mg, 1.8 mmol) was dissolved in 3 ml
ethanol. Ethyl 2-aminoacetate hydrochloride (0.23 g, 1.64
mmol) and sodium acetate (0.27 g, 3.3 mmol) were added and
the mixture was stirred overnight at room temperature. The
mixture was evaporated under reduced pressure and the
residue was re-suspended in dichloromethane, filtered and the
filtrate evaporated under reduced pressure. The residue was
purified using the SP-1 purification system (ethyl acetate-
hexane gradient, 0:100 rising to 65:35) to give 56 (0.265 g,
9. Scheme 9
9.1. 2-(2-Oxopropyl)cyclohexanone (53)
Lithium hexamethyldisilazide (1M in tetrahydrofuran, 12 ml,
12 mmol) was diluted with 20 ml anhydrous toluene under
nitrogen atmosphere and the mixture was cooled to 0 ºC.
Cyclohexanone (1 g, 10.2 mmol) dissolved in 20 ml
anhydrous toluene was added drop-wise and with stirring and
the mixture was stirred for 5 min at 0 ºC. Chloroacetone (0.82
ml, 10.3 mmol) dissolved in 10 ml anhydrous toluene was
added drop-wise and with stirring and the mixture was stirred
at 0 ºC for 10 min. The mixture was evaporated under
reduced pressure to give crude 53 (1.2 g). Purity 41% by gas
chromatography. Used as such without further purification.
1
1.12 mmol, 68% yield). Purity 100%. H NMR (400 MHz,
CDCl3) δ ppm 1.30 (t, J=7.2 Hz, 3H, COCH2CH3), 2.08 -
2.17 (m, 2H, CH2CH2CH2CO), 2.18 (s, 3H, Me), 2.45 (d,
J=7.0 Hz, 2H, CH2CH2CH2CO), 2.67 (t, J=6.1 Hz, 2H,
CH2CH2CH2CO), 4.25 (q, J=7.0 Hz, 2H, COCH2CH3), 4.51
(s, 2H, NCH2), 6.30 (s, 1H, pyrrole H). HPLC/MS (9 min)
retention time 4.77 min. LRMS: m/z 236 (M+1).
9.5. (3-{2-[(4-Fluorophenyl)sulfonyl]benzyl}-2-methyl-
4,5,6,7-tetrahydro-1H-indol-1-yl)acetic acid (57)

ACCEPTED MANUSCRIPT
Crude ester 54 (80 mg) was dissolved in 1 ml anhydride
acetic. Hydriodic acid (57% solution, 0.27 ml, 2.0 mmol) was
added drop-wise and with stirring (exotherm).
Ester 56 (150 mg, 0.64 mmol) was dissolved in 1.5 ml
anhydride acetic. Hydriodic acid (57% solution, 1.2 ml, 9.1
mmol) was added drop-wise and with stirring (exotherm).
Hypophosphorous acid (50% solution, 0.33 ml, 3.3 mmol)
was added followed by crude aldehyde 8c (265 mg). The
mixture was stirred for 3 d at room temperature. The mixture
was partitioned between dichloromethane and water. The
aqueous phase was extracted twice with dichloromethane and
the combined organics were dried over anhydrous sodium
sulphate, filtered and evaporated under reduced pressure. The
residue was purified using the SP-1 purification system (ethyl
acetate-hexane gradient, 0:100 rising to 50:50) to give the
ethyl ester of 59 (0.26 g, 0.51 mmol, 79% yield). Purity 96%.
HPLC/MS (9 min) retention time 6.42 min. LRMS: m/z 514
(M+1).
Hypophosphorous acid (50% solution, 0.07 ml, 0.7 mmol)
was added followed by aldehyde 8b (46 mg, 0.17 mmol) and
the dark red mixture was stirred for 1 h at room temperature.
The mixture was partitioned between dichloromethane and
water. The aqueous phase was extracted twice with
dichloromethane and the combined organics were dried over
anhydrous sodium sulphate, filtered and evaporated under
reduced pressure. The residue was partially purified by
reverse-phase chromatography to give 9 mg of a crude sample
of the ethyl ester of 57. Purity 76%. HPLC/MS (9 min)
retention time 7.40 min. LRMS: m/z 470 (M+1).
The ester was dissolved in 0.5 ml tetrahydrofuran and 0.25
ml water. Lithium hydroxide monohydrate (3 mg, 0.07 mmol)
was added and the mixture was stirred for 1 h at room
temperature. The mixture was acidified to pH 4 with acetic
acid and was stirred for 2 h, forming a precipitate. This was
collected by filtration, washed with a little water and dried at
35 ºC in vacuo to give crude 57 (2 mg) as a pale green solid.
Purity 83%. The solid was further purified by analytical
HPLC to give 57 (0.7 mg, 1.6 µmol, 0.02% yield over three
steps). NMR spectrum not recorded. HPLC/MS (30 min)
retention time 17.43 min. LRMS: m/z 442 (M+1).
The ester was dissolved in 3 ml tetrahydrofuran and 1.5 ml
water. Lithium hydroxide monohydrate (63 mg, 1.5 mmol)
was added and the mixture was stirred for 45 min at room
temperature. The organics were evaporated under reduced
pressure and the remaining aqueous was acidified to pH 4
with acetic acid and was stirred for 2 h, forming a precipitate.
This was collected by filtration, washed with a little water and
dried at 35 ºC in vacuo to give 59 (180 mg, 0.37 mmol 58%
1
overall yield) as a white solid. Purity 100%. H NMR (400
MHz, DMSO-d6) δ ppm 1.59 (s, 3H, Me), 1.91 - 2.02 (m, 2H,
CH2CH2CH2CO), 2.16 - 2.26 (m, 2H, CH2CH2CH2CO), 2.63
- 2.72 (m, 2H, CH2CH2CH2CO), 3.68 (s, 3H, OMe), 4.08 (s,
2H, NCH2), 4.65 (s, 2H, CH2Ph), 6.31 (m, 1H, Bn H-6), 7.01
(d, J=8.2 Hz, 1H, Bn H-4), 7.46 (t, J=8.2 Hz, 2H, SO2PhF
meta), 7.93 (t, J=4.7 Hz, 2H, SO2PhF ortho), 8.11 (d, J=8.6
Hz, 1H, Bn H-3). HPLC/MS (30 min) retention time 14.25
min. LRMS: m/z 486 (M+1).
9.6. (3-{2-[(4-Fluorophenyl)sulfonyl]benzyl}-2-methyl-4-
oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)acetic
acid
(58)
Ester 56 (100 mg, 0.43 mmol) was dissolved in 0.8 ml
anhydride acetic. Hydriodic acid (57% solution, 0.67 ml, 5.1
mmol) was added drop-wise and with stirring (exotherm).
Hypophosphorous acid (50% solution, 0.22 ml, 2.1 mmol)
was added followed by aldehyde 8b (146 mg, 0.55 mmol).
The mixture was stirred for 3 d at room temperature. The
mixture was partitioned between dichloromethane and water.
The aqueous phase was extracted twice with dichloromethane
and the combined organics were dried over anhydrous sodium
sulphate, filtered and evaporated under reduced pressure. The
residue was purified by reverse-phase chromatography to give
58 (67 mg, 0.15 mmol 34% yield) as a white solid. Purity
10. Scheme 10
10.1. (3-Oxo-1,3-dihydro-2-benzofuran-1-
yl)(triphenyl)phosphonium bromide (60)
3-Bromoisobenzofuran-1(3H)-one (0.5 g, 2.35 mmol) was
suspended in 2 ml acetonitrile. Triphenylphosphine (0.62 g,
2.35 mmol) was added and the mixture was stirred at reflux
for 2.5 h. The mixture was allowed to cool and was filtered.
The solid was washed with ether and was dried at 40 ºC under
reduced pressure to give crude 60 (0.56 g) as a white solid.
Purity 85%. Used as such without further purification. NMR
spectrum not recorded. HPLC/MS (4.5 min) retention time
2.99 min. LRMS: m/z 395 (cation M+).
1
99%. H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (s, 3H,
Me), 1.95 (quin, J=6.0 Hz, 2H, CH2CH2CH2CO), 2.19 (t,
J=6.1 Hz, 2H, CH2CH2CH2CO), 2.64 (t, J=5.7 Hz, 2H,
CH2CH2CH2CO), 4.13 (s, 2H, CH2Ph), 4.54 (s, 2H, NCH2),
6.87 (d, J=7.4 Hz, 1H, Bn H-6), 7.40 - 7.57 (m, 4H, Ar), 7.97
(dd, J=5.1, 8.6 Hz, 2H, SO2PhF ortho), 8.13 (d, J=7.8 Hz, 1H,
Bn H-3). HPLC/MS (30 min) retention time 13.98 min.
LRMS: m/z 456 (M+1).
10.2. (3Z)-3-[2-(Phenylsulfonyl)benzylidene]-2-
benzofuran-1(3H)-one (61)
Crude phosphine salt 60 (0.56 g) was suspended in 10 ml
dichloromethane. Aldehyde 8a (0.29 g, 1.17 mmol) was
added. Triethylamine (0.16 ml, 1.17 mmol) was added drop-
wise and with stirring and the mixture was stirred at room
temperature for 2.5 h. The mixture was acidified with 1N
9.7. (3-{2-[(4-Fluorophenyl)sulfonyl]-5-methoxybenzyl}-
2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-
yl)acetic acid (59)

ACCEPTED MANUSCRIPT
hydrochloric acid. The organic phase was separated, dried
HPLC/MS (4.5 min) retention time 3.99 min. LRMS: m/z 463
(M+1).
over magnesium sulphate, filtered and evaporated. The
residue was purified using the SP1 purification system (ethyl
acetate-hexane gradient, 15:85 rising to 70:30) to give 61
(0.14 g, 0.37 mmol, 16% yield over two steps) as a yellow
10.5. [1-Oxo-4-[2-(phenylsulfonyl)benzyl]phthalazin-
2(1H)-yl]acetic acid (64)
1
Ester 63 (40 mg, 0.086 mmol) was dissolved in 3 ml
tetrahydrofuran and 1.5 ml water. Lithium hydroxide
monohydrate (8 mg, 0.34 mmol) was added and the mixture
was stirred for 90 min at room temperature. The organics
were evaporated under reduced pressure. The solution was
diluted with water and was washed with ethyl acetate. The
aqueous phase was acidified to pH 3 with 2N hydrochloric
acid forming a turbid solution. The aqueous phase was
extracted twice with ethyl acetate and the combined organics
were dried over anhydrous magnesium sulphate, filtered and
evaporated under reduced pressure. The residue was purified
by reverse-phase chromatography to give 64 (28 mg, 0.064
solid. Purity 95%. H NMR (400 MHz, CDCl3) δ ppm 6.18
(d, J=7.8 Hz, 1H, Bn H-6), 7.00 (s, 1H, vinyl H), 7.02 - 7.10
(m, 3H, Ar), 7.15 (t, J=7.3 Hz, 1H, Ar), 7.39 (t, J=7.5 Hz, 1H,
SO2Ph para), 7.48 (d, J=7.5 Hz, 1H, phthalazinone H-8), 7.65
- 7.74 (m, 4H, Ar), 7.77 (d, J=7.8 Hz, 1H, Bn H-3), 8.47 (dd,
J=2.2, 7.0 Hz, 1H, phthalazinone H-5). HPLC/MS (4.5 min)
retention time 3.86 min. LRMS: m/z 363 (M+1).
10.3. 4-[2-(Phenylsulfonyl)benzyl]phthalazin-1(2H)-one
(62)
Lactone 61 (0.14 g, 0.37 mmol) was suspended in 5 ml
methanol. Hydrazine hydrate (54 µl, 1.2 mmol) was added and
the mixture was stirred at reflux for 1 h. The mixture was
evaporated under reduced pressure and the residue was
partitioned between dichloromethane and water. The organic
phase was dried over magnesium sulphate, filtered and
evaporated. to give 62 (76 mg, 0.20 mmol, 54% yield) as a
1
mmol, 74% yield) as a white solid. Purity 100%. H NMR
(400 MHz, CDCl3) δ ppm 4.57 (s, 2H, CH2CO), 4.81 (s, 2H,
CH2Ph), 7.11 (d, J=6.4 Hz, 1H, Bn H-6), 7.39 - 7.52 (m, 5H,
Ar), 7.55 (t, J=7.4 Hz, 1H, SO2Ph para), 7.66 (t, J=7.1 Hz,
1H, Ar), 7.72 (t, J=7.4 Hz, 1H, Ar), 7.83 (d, J=7.4 Hz, 2H,
SO2Ph ortho), 8.33 (d, J=9.2 Hz, 1H, phthalazinone H-5),
8.41 (d, J=7.6 Hz, 1H, Bn H-3). HPLC/MS (30 min) retention
time 13.98 min. LRMS: m/z 435 (M+1).
1
white solid. Purity 97%. H NMR (400 MHz, DMSO-d6) δ
ppm 4.54 (s, 2H, CH2), 7.29 (d, J=7.2 Hz, 1H, Bn H-6), 7.41
(t, J=7.8 Hz, 2H, PhSO2 meta), 7.50 - 7.65 (m, 4H, Ar), 7.72
(d, J=7.6 Hz, 2H, PhSO2 ortho), 7.78 - 7.85 (m, 2H, Ar), 8.18
- 8.25 (m, 2H, phthalazinone H-5 and Bn H-3), 8.21 (s, 1H),
12.21 (s, 1H, NH). HPLC/MS (4.5 min) retention time 3.64
min. LRMS: m/z 377 (M+1).
10.6. Ethyl (triphenylphosphoranylidene)acetate (65)
Ethyl 2-bromoacetate (1.4 ml, 12.6 mmol) and
triphenylphosphine (3.3 g, 12.6 mmol) were dissolved in in
15 ml benzene and the mixture was stirred at reflux overnight
forming a precipitate. The mixture was allowed to cool and
the solid was collected by filtration. The solid was washed
with benzene and was re-dissolved in dichloromethane. The
organics were shaken with 10% sodium hydroxide solution,
dried over anhydrous magnesium sulphate, filtered and
evaporated under reduced pressure to give 65 (3.81 g, 10.9
mmol, 87% yield) as a white solid. Purity 98%. NMR
spectrum not recorded. HPLC/MS (4.5 min) retention time
3.06 min. LRMS: m/z 349 (M+1).
10.4. Ethyl
[1-oxo-4-[2-
(phenylsulfonyl)benzyl]phthalazin-2(1H)-yl]acetate
(63)
Sodium hydride (60% dispersion in oil, 16 mg, 0.40 mmol)
was suspended in 1 ml dimethylformamide Phthalazinone 62
(76 mg, 0.20 mmol) dissolved in 1 ml dimethylformamide
was added and the mixture was stirred at room temperature
for 50 min. Ethyl 2-bromoacetate (34 µl, 0.30 mmol) was
added and the mixture was stirred for 20 min. The mixture
was partitioned between ethyl acetate and water. The organic
phase was dried over magnesium sulphate, filtered and
evaporated. The residue was purified using the SP1
purification system (ethyl acetate-hexane gradient) to give 63
(40 mg, 0.086 mmol, 22% yield) as a colourless oil. Purity
10.7. Ethyl
(2Z)-(3-oxo-2-benzofuran-1(3H)-
ylidene)acetate (66)
Phthalic anhydride (0.50 g, 3.37 mmol) and Wittig reagent 65
(1.29 g, 3.70 mmol) were dissolved in 8 ml dioxane and the
mixture was stirred at reflux for 2 h. The mixture was allowed
to cool and was evaporated under reduced pressure. The
residue was purified by flash chromatography (ethyl acetate-
hexane gradient, 0:100 rising to 80:20) to give 66 (0.42 g, 1.9
1
96%. H NMR (400 MHz, CDCl3) δ ppm 1.28 (t, J=7.1 Hz,
3H, OCH2CH3), 4.22 (q, J=7.2 Hz, 2H, OCH2CH3), 4.55 (s,
2H, CH2Ph), 4.80 (s, 2H, CH2CO), 7.12 (dd, J=2.0, 7.5 Hz,
1H, Bn H-6), 7.38 - 7.46 (m, 3H, Ar), 7.47 (t, J=8.1 Hz, 2H,
SO2Ph meta), 7.57 (t, J=7.5 Hz, 1H, SO2Ph para), 7.62 (td,
J=7.8, 1.2 Hz, 1H, Bn H-4), 7.70 (t, J=7.3 Hz, 1H, Ar), 7.86
(d, J=7.4 Hz, 2H, SO2Ph ortho), 8.34 (dd, J=2.1, 7.2 Hz, 1H,
phthalazinone H-5), 8.41 (d, J=7.4 Hz, 1H, Bn H-3).
1
mmol, 57% yield) as a yellow solid. Purity 100%. H NMR
(400 MHz, CDCl3) δ ppm 1.37 (t, J=7.1 Hz, 3H, OCH2CH3),
4.30 (q, J=7.0 Hz, 2H, OCH2CH3), 6.16 (s, 1H, vinyl H), 7.71
(t, J=7.4 Hz, 1H, H-5 or H-6), 7.82 (t, J=7.7 Hz, 1H, H-6 or

ACCEPTED MANUSCRIPT
H-5), 7.97 (d, J=7.6 Hz, 1H, H-4), 9.06 (d, J=8.0 Hz, 1H, H-
7). HPLC/MS (4.5 min) retention time 4.10 min. LRMS: m/z
219 (M+1).
diluted with water and was washed with ethyl acetate. The
aqueous phase was acidified to pH 3 with 1N hydrochloric
acid forming a turbid solution. The aqueous phase was
extracted twice with ethyl acetate and the combined organics
were dried over anhydrous magnesium sulphate, filtered and
evaporated to give 69 (33 mg, 0.76 mmol, 100% yield) as a
white solid. Purity 100%. 1H NMR (400 MHz, CDCl3) δ ppm
3.89 (s, 2H, CH2CO), 5.76 (s, 2H, CH2Ph), 6.97 (dd, J=3.8,
5.2 Hz, 1H, Bn H-6), 7.26-7.46 (m, 2H, Bn H-4 and H-5),
7.51 (t, J=7.8 Hz, 2H, SO2Ph meta), 7.57 (t, J=7.2 Hz, 1H,
SO2Ph para), 7.70 (d, J=7.8 Hz, 1H, phthalazinone H-8), 7.78
(t, J=7.1 Hz, 1H, phthalazinone H-6 or H-7), 7.83 (t, J=6.9
Hz, 1H, phthalazinone H-7 or H-6), 7.95 (d, J=7.2 Hz, 2H,
SO2Ph ortho), 8.17 - 8.25 (m, 1H, phthalazinone H-5), 8.44
(d, J=7.4 Hz, 1H, Bn H-3). HPLC/MS (30 min) retention time
13.63 min. LRMS: m/z 435 (M+1).
10.8. Ethyl (4-oxo-3,4-dihydrophthalazin-1-yl)acetate (67)
Lactone 66 (0.39 g, 1.77 mmol) was dissolved in 6 ml
ethanol. Hydrazine monohydrate (0.26 ml, 5.32 mmol) was
added and the mixture was stirred at 60 ºC for 2 h. The
mixture was evaporated under reduced pressure and the
residue was purified using the Biotage purification system
(ethyl acetate-hexane gradient) to give 67 (116 mg, 0.50
1
mmol, 28% yield) as a yellow solid. Purity 100%. H NMR
(400 MHz, CDCl3) δ ppm 1.24 (t, J=7.1 Hz, 3H, OCH2CH3),
3.97 (s, 2H, CH2CO2), 4.20 (q, J=7.2 Hz, 2H, OCH2CH3),
7.75 (d, J=8.0 Hz, 1H, H-8), 7.80 (t, J=6.9 Hz, 1H, H-6 or H-
7), 7.85 (t, J=7.6 Hz, 1H, H-7 or H-6), 8.48 (d, J=7.6 Hz, 1H,
H-5). HPLC/MS (4.5 min) retention time 3.12 min. LRMS:
m/z 233 (M+1).
11. Scheme 11
11.1. 3-Nitro-N-[2-(phenylsulfonyl)benzyl]pyridin-2-
amine (70)
10.9. Ethyl
{4-oxo-3-[2-(phenylsulfonyl)benzyl]-3,4-
dihydrophthalazin-1-yl}acetate (68)
Chloro-3-nitropyridine (250 mg, 1.58 mmol) was dissolved in
diisopropylethylamine (0.33 ml, 1.9 mmol) in 2.5 ml ethanol.
Amine 11a (468 mmol, 1.9 mmol) was added and the mixture
was stirred and heated at 140 ºC under microwave irradiation
for 30 min. The mixture was allowed to cool and was
partitioned between water and ethyl acetate, forming a
precipitate. The solid was collected by filtration, washed with
ether and dried in a stream of air to give 70 (502 mg, 1.36
Phthalazinone 67 (98 mg, 0.42 mmol) was dissolved in 1.4 ml
dimethylformamide. Sodium hydride (60% dispersion in oil,
34 mg, 0.85 mmol) was added and the mixture was stirred at
room temperature for 1 h. Bromide 10a (197 mg, 0.63 mmol)
was added and the mixture was stirred for 1 h. The mixture
was partitioned between dichloromethane and brine. The
aqueous was extracted twice with dichloromethane and the
combined organics were dried over magnesium sulphate,
filtered and evaporated. The residue was partially purified
using the Biotage purification system (ethyl acetate-hexane
gradient, 0:100 rising to 100:0). The residue obtained was re-
purified by reverse-phase chromatography to give 68 (35 mg,
0.075 mmol, 18% yield) as a white solid. 1H NMR (400 MHz,
CDCl3) δ ppm 1.21 (t, J=7.1 Hz, 3H, OCH2CH3), 3.87 (s, 2H,
CH2CO2), 4.15 (q, J=7.0 Hz, 2H, OCH2CH3), 5.77 (s, 2H,
CH2Ph), 6.97 (dd, J=3.9, 5.1 Hz, 1H, Bn H-6), 7.43 – 7.47
(m, 2H, Bn H-4 and H-5), 7.54 (t, J=7.8 Hz, 2H, SO2Ph
meta), 7.60 (t, J=7.0 Hz, 1H, SO2Ph para), 7.70 (d, J=8.0 Hz,
1H, phthalazinone H-8), 7.77 (t, J=7.1 Hz, 1H, phthalazinone
H-6 or H-7), 7.83 (t, J=7.2 Hz, 1H, phthalazinone H-7 or H-
6), 7.98 (d, J=7.2 Hz, 2H, SO2Ph ortho), 8.22 - 8.27 (m, 1H,
phthalazinone H-5), 8.43 (d, J=7.4 Hz, 1H, Bn H-3).
HPLC/MS (4.5 min) retention time 3.95 min. LRMS: m/z 463
(M+1).
1
mmol, 86% yield). Purity 95%. H NMR (300 MHz, DMSO-
d6) δ ppm 4.99 (d, J=6.0 Hz, 2H, CH2), 6.73 (dd, J=4.4, 8.2
Hz, 1H, pyridine H-5), 7.47 (d, J=7.4 Hz, 1H, Bn H-6), 7.51 -
7.69 (m, 4H, SO2Ph meta and 2×Ar), 7.72 (t, J=7.4 Hz, 1H,
SO2Ph para), 7.93 (d, J=7.4 Hz, 2H, SO2Ph ortho), 8.10 - 8.18
(m, 2H, Bn H-3 and Ar), 8.40 (d, J=8.2 Hz, 1H, pyridine H-
6), 8.93 (t, J=5.8 Hz, 1H, NH). UPLC/MS (3 min) retention
time 1.81 min. LRMS: m/z 370 (M+1).
11.2. N-2-[2-(Phenylsulfonyl)benzyl]pyridine-2,3-diamine
(71)
Nitropyridine 70 (450 mg, 1.22 mmol) was suspended in 10
ml ethanol and 10 ml tetrahydrofuran. 10% Palladium on
carbon (145 mg) was added and the mixture was stirred under
a hydrogen atmosphere (1 atm) for 1 h at room temperature.
The mixture was filtered through a plug of Celite, washing
through with methanol. The combined filtrate was evaporated
under reduced pressure to give 71 (402 mg, 1.19 mmol, 97%
1
10.10.{4-Oxo-3-[2-(phenylsulfonyl)benzyl]-3,4-
dihydrophthalazin-1-yl}acetic acid (69)
Ester 68 (35 mg, 0.076 mmol) was dissolved in 2 ml
yield) as a pale brown semi-solid. Purity 97%. H NMR (300
MHz, DMSO-d6) δ ppm 4.72 (br. s., 2H, NH2), 4.77 (d, J=5.5
Hz, 2H, CH2), 6.19 (t, J=5.5 Hz, 1H, NH), 6.33 (dd, J=5.1,
7.3 Hz, 1H, pyridine H-5), 6.70 (d, J=7.4 Hz, 1H, pyridine H-
6), 7.12 (d, J=4.9 Hz, 1H, pyridine H-4), 7.43 (d, J=7.7 Hz,
1H, Bn H-6), 7.53 (t, J=7.6 Hz, 1H, Bn Ar), 7.63 (t, J=7.2 Hz,
tetrahydrofuran and
2
ml water. Lithium hydroxide
monohydrate (4 mg, 0.17 mmol) was added and the mixture
was stirred at room temperature for 2 h. The solution was

ACCEPTED MANUSCRIPT
2H, SO2Ph meta), 7.64 - 7.70 (m, 1H, Bn Ar), 7.73 (t, J=7.2
dichloromethane gradient, 0:100 rising to 10:90) to give 74
Hz, 1H, SO2Ph para), 7.94 (d, J=7.4 Hz, 2H, SO2Ph ortho),
8.12 (d, J=7.7 Hz, 1H, Bn H-3). UPLC/MS (3 min) retention
time 0.93 min. LRMS: m/z 340 (M+1).
(2.5 mg, 0.0054 mmol, 2% yield over three steps). Purity
1
98%. H NMR (300 MHz, DMSO-d6) δ ppm 3.99 (s, 2H,
CH2CO), 5.26 (s, 2H, CH2Ph), 6.94 (dd, J=5.0, 7.7 Hz, 1H,
thiadiazolopyridine H-6), 7.11 (d, J=7.7 Hz, 1H,
thiadiazolopyridine H-6), 7.49 (d, J=7.4 Hz, 1H, Bn H-6),
7.56 (d, J=5.2 Hz, 1H, thiadiazolopyridine H-8), 7.63 - 7.72
(m, 4H, SO2Ph meta + 2Ar), 7.76 (t, J=7.3 Hz, 1H, SO2Ph
para), 7.98 (d, J=7.7 Hz, 2H, SO2Ph ortho), 8.18 (d, J=7.4 Hz,
1H, Bn H-3). HPLC/MS (30 min) retention time 14.52 min.
LRMS: m/z 460 (M+1).
11.3. 3-[2-(Phenylsulfonyl)benzyl]-1,3-
dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide
(72)
Diamine 71 (100 mg, 0.29 mmol) was suspended in 1 ml
pyridine. Sulphuric diamide (102 mg, 1.06 mmol) was added
and the mixture was stirred and heated at 160 ºC for 15 min
under microwave irradiation. The mixture was allowed to
cool and was poured over water. The mixture was extracted
three times with ethyl acetate, the combined organics were
washed with brine, dried over anhydrous sodium sulphate,
filtered and evaporated under reduced pressure. The residue
was partially purified using the Isolera purification system
(methanol-dichloromethane gradient, 0:100 rising to 10:90) to
12. Scheme 12
12.1. Ethyl (2Z)-3-amino-3-pyridin-2-ylacrylate (75)
Sodium ethoxide (6.4 g, 94 mmol) was dissolved in 80 ml
ethanol. Ethyl malonate (10 g, 75 mmol) dissolved in 20 ml
ethanol was added and the mixture was strirred for 1 h
forming a precipitate. The solid was collected by filtration
and dried at 40 ºC under vacuum to give sodium ethyl
malonate (6.62 g, 43 mmol, 57% yield). 2-Cyanopyridine (2.7
g, 25.9 mmol) was dissolved in 55 ml dichloroethane under
nitrogen in a flask fitted with a Dean-Stark head. Sodium
ethyl malonate (6.62 g, 43 mmol), zinc(II) chloride (2.62 g,
13 mmol) and diisopropylethylamine (0.45 ml, 2.6 mmol)
were added and the mixture was stirred at reflux for 4 h. The
mixture was allowed to cool and 25 ml saturated ammonium
chloride solution was added. The organic phase was
separated, dried over anhydrous sodium sulphate, filtered and
evaporated under reduced pressure. The residue was purified
using the SP-1 purification system (ethyl acetate-hexane
gradient, 0:100 rising to 20:80) to give 75 (4.37 g, 22.7 mmol,
1
give crude 72 (35 mg). Purity 85%. H NMR spectrum not
recorded. UPLC/MS (3 min) retention time 1.46 min. LRMS:
m/z 402 (M+1).
11.4. Ethyl
[2,2-dioxido-3-[2-
(phenylsulfonyl)benzyl][1,2,5]thiadiazolo[3,4-
b]pyridin-1(3H)-yl]acetate (73)
Crude sulfamide 72 (35 mg) was dissolved in 1 ml anhydrous
dimethylformamide. Potassium carbonate (48 mg, 0.35 mmol)
was added and the mixture was stirred for 15 min. Ethyl
bromoacetate (42 µl, 0.38 mmol) was added and the mixture
was stirred for 2.5 h. The mixture was partitioned between
ethyl acetate and water. The aqueous phase was extracted
three times with ethyl acetate. The combined organics were
washed with brine, dried over sodium sulphate, filtered and
evaporated to give crude 73 (45 mg). Purity 53%. Used as
such without further purification. 1H NMR spectrum not
recorded. UPLC/MS (3 min) retention time 1.76 min. LRMS:
m/z 488 (M+1).
1
88% yield). Purity 100%. H NMR spectrum not recorded.
HPLC/MS (9 min) retention time 5.35 min. LRMS: m/z 193
(M+1).
12.2. Ethyl 3-amino-3-pyridin-2-ylpropanoate (76)
Amino acrylate 75 (2.0 g, 10.4 mmol) was dissolved in 65 ml
ethanol containing 1.2 ml acetic acid. Palladium hydroxide
(20% on carbon, 1.1 g, 1.6 mmol) was added and the mixture
was stirred under hydrogen atmosphere (14 psi) for 4 h. The
mixture was filtered through a plug of Celite and the filtrate
was evaporated under reduced pressure. The residue was
partitioned between dichloromethane and saturated potassium
carbonate solurtion. The organic phase was washed with
water, brine, dried over anhydrous sodium sulphate, filtrered
and evaporated under reduced pressure to give 76 (1.48 g, 7.6
mmol, 73% yield) as a pale yellow oil. Purity 100%. 1H NMR
spectrum not recorded. UPLC/MS (3 min) retention time 0.58
min. LRMS: m/z 195 (M+1).
11.5. [2,2-Dioxido-3-[2-
(phenylsulfonyl)benzyl][1,2,5]thiadiazolo[3,4-
b]pyridin-1(3H)-yl]acetic acid (74)
Crude ester 73 (45 mg) was dissolved in 1 ml tetrahydrofuran
and 1 ml water. Lithium hydroxide monohydrate (8 mg, 0.19
mmol) was added and the mixture was stirred for 90 min at
room temperature. The organics were evaporated under
reduced pressure. The remaining aqueous solution was diluted
with water and was washed three times with ethyl acetate.
The aqueous phase was acidified with 2N hydrochloric acid
forming a turbid solution. The aqueous phase was extracted
three times with ethyl acetate and the combined organics were
dried over anhydrous magnesium sulphate, filtered and
evaporated under reduced pressure. The residue was purified
using the Isolera purification system (methanol-
12.3. Ethyl
[3-(2-iodobenzyl)imidazo[1,5-a]pyridin-1-
yl]acetate (77)

ACCEPTED MANUSCRIPT
Aminoester 76 (0.92 g, 4.50 mmol) and 2-(2-
iodophenyl)acetic acid (1.36 g, 5.2 mmol) were dissolved in
23 ml butyl acetate. 1-Propanephosphonic anhydride solution
(T3P, 7 ml, 11.7 mmol) was added and the mixture was
stirred for 1 h at room termpature and then 1 h at reflux. The
mixture was allowed to cool to room temperature and was
washed twice with 4% sodium bicarbonate solution. The
organics were dried over anhydrous sodium sulphate, filtrered
and evaporated under reduced pressure. The residue was
purified using the SP-1 purification system (ethyl acetate-
hexane gradient, 0:100 rising to 30:70) to give 77 (1.1 g, 2.62
purified by preparative HPLC to give 79 (6 mg, 0.014 mmol,
1
21% yield). Purity 86%. H NMR (400 MHz, DMSO-d6) δ
ppm 3.63 (s, 2H, CH2CO2), 4.57 (s, 2H, CH2Ph), 6.54 (t,
J=6.6 Hz, 1H, imidazopyridine H-6), 6.68 (dd, J=6.4, 9.2 Hz,
1H, imidazopyridine H-7), 7.03 (d, J=7.8 Hz, 1H, Bn H-6),
7.51 (t, J=8.0 Hz, 2H, PhSO2 meta), 7.54 - 7.68 (m, 5H, Ar),
7.79 (d, J=7.8 Hz, 2H, PhSO2 ortho), 8.19 (d, J=7.4 Hz, 1H,
Bn H-3). HPLC/MS (30 min) retention time 10.97 min.
LRMS: m/z 407 (M+1).
13. Scheme 13
1
mmol, 58% yield) as a pale yellow solid. Purity 100%. H
13.1. 4-Bromo-1H-pyrrole-2-carbaldehyde (80)
NMR spectrum not recorded. UPLC/MS (3 min) retention
time 1.76 min. LRMS: m/z 421 (M+1).
1H-Pyrrole-2-carbaldehyde (20 g, 210 mmol) was dissolved
in 250 ml tetrahydrofuran and the mixture was cooled to -78
ºC. N-Bromosuccinimide (37 g, 210 mmol) was added
portion-wise over 1 h with stirring and the mixture was stirred
for a further 6.5 at -78 ºC. The mixture was allowed to warm
to 0 ºC and was partitioned between water and hexane and
protected from the light. The aqueous phase was extracted
with cold hexane and the combined organics were washed
with water, dried over anhydrous sodium sulphate and
filtered. The organics were concentrated under reduced
pressure until a precipitate formed. The solid was cold-
filtered, washed with cold hexane and dried under vacuum to
give 12.8 g of 80. The filtrates were concentrated again under
reduced pressure until further precipitate formed. This was
collected by filtration as before and combined with the first
obtained solid to give 80 (18.9 g, 109 mmol, 53% yield).
12.4. Ethyl
{3-[2-(phenylsulfonyl)benzyl]imidazo[1,5-
a]pyridin-1-yl}acetate (78)
Iodide 77 (200 mg, 0.48 mmol) was dissolved in 1 ml
dimethylsulphoxide under nitrogen. Benzene sulphinic acid
sodium salt (94 mg, 0.5 mmol), copper(I) triflate-benzene
complex
(13
mg,
0.02
mmol)
and
N,N'-
dimethylethylenediamine (5 µl, 0.05 mmol) were added and
the mixture was stirred at 110 ºC overnight. The mixture was
allowed to cool, was diluted with ethyl acetate and was
filtered through a plug of Celite. The filtrate was washed
twice with water, brine, dried over anhydrous sodium
sulphate, filtrered and evaporated under reduced pressure.
The residue was purified using the SP-1 purification system
(ethyl acetate-hexane gradient, 0:100 rising to 50:50) to give
1
Purity 96%. Stored at 4 ºC in the dark. H NMR (400 MHz,
1
78 (30 mg, 0.069 mmol, 15% yield). Purity 100%. H NMR
CDCl3) δ ppm 6.96 - 6.99 (m, 1H, H-3), 7.11 - 7.14 (m, 1H,
H-5), 9.47 (s, 1H, CHO), 9.88 (br. s., 1H, NH). UPLC/MS (3
min) retention time 1.18 min. LRMS: m/z 172, 174 (M-1).
(400 MHz, CDCl3) δ ppm 1.26 (t, J=7.2 Hz, 3H, OCH2CH3),
3.89 (s, 2H, CH2CO2), 4.17 (q, J=7.0 Hz, 2H, OCH2CH3),
4.61 (s, 2H, CH2Ph), 6.39 (t, J=6.6 Hz, 1H, imidazopyridine
H-6), 6.64 (dd, J=6.4, 9.2 Hz, 1H, imidazopyridine H-7), 6.86
(d, J=7.0 Hz, 1H, Bn H-6), 7.36 - 7.48 (m, 4H, Ar), 7.51 (t,
J=7.6 Hz, 2H, PhSO2 meta), 7.60 (t, J=7.4 Hz, 1H, PhSO2
para), 7.88 (d, J=7.4 Hz, 2H, PhSO2 ortho), 8.31 (d, J=7.4 Hz,
1H, Bn H-3). UPLC/MS (3 min) retention time 1.66 min.
LRMS: m/z 435 (M+1).
13.2. 6-Bromo-3-[(4-methylphenyl)sulfonyl]pyrrolo[1,2-
c]pyrimidine (81)
Aldehyde 80 (3.1 g, 13.0 mmol) was dissolved in 160 ml
anhydrous
tetrahydrofuran
under
argon.
Toluenesulfonylmethyl isocyanide (3.8 g, 19.5 mmol) and
1,8-diazabicycloundec-7-ene (2.9 g, 19.4 mmol) were added
and the mixture was stirred for 3 h at room temperature. The
mixture was adjusted to pH 6-7 with acetic acid and was
evaporated under reduced pressure. The residue was purified
by flash chromatography using the Isolera system (ethyl
acetate-hexane gradient, 0:100 rising to 100:0) to give 81
(3.43 g, 9.8 mmol, 75% yield) as a beige solid. Purity 100%.
1H NMR (300 MHz, CDCl3) δ ppm 2.42 (s, 3H, Me), 6.85 (s,
1H, H-5), 7.34 (d, J=8.0 Hz, 2H, SO2Ph meta), 7.52 (s, 1H,
H-7), 7.94 (d, J=8.0 Hz, 2H, SO2Ph ortho), 8.18 (s, 1H, H-4),
8.65 (s, 1H, H-1). UPLC/MS (3 min) retention time 1.78 min.
LRMS: m/z 351, 353 (M+1).
12.5. {3-[2-(Phenylsulfonyl)benzyl]imidazo[1,5-a]pyridin-
1-yl}acetic acid (79)
Ester 78 (30 mg, 0.07 mmol) was dissolved in 1.5 ml
tetrahydrofuran and 1.5 ml water. Lithium hydroxide
monohydrate (12 mg, 0.29 mmol) was added and the mixture
was stirred for 2 h at room temperature. The organics were
evaporated under reduced pressure. The solution was diluted
with water and was washed with ethyl acetate. The aqueous
phase was acidified to pH 4 with acetic acid and was stirred
for 90 min forming a turbid solution. The mixture was
extracted three times with ethyl acetate and the combined
organics were dried over anhydrous sodium sulphate, filtrered
and evaporated under reduced pressure. The residue was

ACCEPTED MANUSCRIPT
13.3. 6-Methyl-3-[(4-methylphenyl)sulfonyl]pyrrolo[1,2-
partitioned between ethyl acetate and ice-water. The aqueous
phase was extracted twice with ethyl acetate. The combined
organics were washed with 4% sodium bicarbonate solution,
brine, dried over anhydrous sodium sulphate, filtered and
evaporated under reduced pressure. The residue was purified
using the Isolera purification system (ether-hexane gradient)
to give 84 (299 mg, 0.83 mmol, 35% yield) as a pale yellow
solid. Purity 94%. 1H NMR (300 MHz, CDCl3) δ ppm 2.17 (s,
3H, Me), 4.45 (s, 2H, CH2), 6.31 (s, 1H, pyrrolopyrimidine
H-5), 6.55 (d, J=7.4 Hz, 1H, Bn H-6), 7.11 (dd, J=1.4, 6.3 Hz,
1H, pyrrolopyrimidine H-4), 7.29 (d, J=6.3 Hz, 1H,
pyrrolopyrimidine H-3), 7.37 (td, J=7.6, 1.2 Hz, 1H, Bn H-4),
7.45 (t, J=7.3 Hz, 1H, Bn H-5), 7.60 (t, 2H, SO2Ph meta),
7.61 (d, J=1.4 Hz, pyrrolopyrimidine H-1), 7.68 (t, J=7.4 Hz,
1H, SO2Ph para), 7.97 (d, J=7.4 Hz, 2H, SO2Ph ortho), 8.31
(dd, J=1.4, 7.7 Hz, 1H, Bn-3). UPLC/MS (3 min) retention
time 1.85 min. LRMS: m/z 363 (M+1).
c]pyrimidine (82)
Bromide 81 (5.0 g, 14.3 mmol) was dissolved in 11 ml
dimethoxyethane under nitrogen. Potassium carbonate (6.0 g,
43.4 mmol), trimethyl boroxine (2.2 ml, 16.0 mmol) and
[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (0.61 g, 0.69 mmol) were
added. The mixture was subjected to a vacuum-nitrogen cycle
and was then heated at 120 ºC under microwave irradiation
for 30 min. the mixture was allowed to cool and was filtered
through
a
plug of Celite, washing through with
dichloromethane. The mixture was evaporated under reduced
pressure and the residue was triturated with ether and
dichloromethane to give 82 (3.7 g, 12.9 mmol, 90% yield) as
1
a brown solid. Purity 93%. H NMR (300 MHz, CDCl3) δ
ppm 2.35 (s, 3H, ArMe), 2.41 (s, 3H, SO2PhMe), 6.64 (s, 1H,
H-5), 7.29 (s, 1H, H-7), 7.32 (d, J=8.0 Hz, 2H, SO2Ph meta),
7.94 (d, J=8.2 Hz, 2H, SO2Ph ortho), 8.14 (s, 1H, H-4), 8.62
(s, 1H, H-1). UPLC/MS (3 min) retention time 1.70 min.
LRMS: m/z 287 (M+1).
13.6. 7-{2-[(4-Fluorophenyl)sulfonyl]-5-methoxybenzyl}-
6-methylpyrrolo[1,2-c]pyrimidine (85)
Pyrrolopyrimidine 83 (220 mg, 1.67 mmol) was dissolved in
4 ml anhydride acetic under nitrogen and the mixture was
cooled to 0 ºC. Hydriodic acid (57% solution, 2.1 ml, 15.9
mmol) was added drop-wise and with stirring over 20 min
(exotherm), warming to room temperature. Hypophosphorous
acid (50% solution, 0.86 ml, 8.3 mmol) was added followed
by crude aldehyde 8c (440 mg) and the mixture was stirred
for 2 h at room temperature. The mixture was partitioned
between ethyl acetate and ice-water. The aqueous phase was
extracted twice with ethyl acetate. The combined organics
were washed with 4% sodium bicarbonate solution, brine,
dried over anhydrous sodium sulphate, filtered and
evaporated under reduced pressure. The residue was purified
using the Isolera purification system (ether-hexane gradient)
to give 85 (196 mg, 0.48 mmol, 32% yield) as a white solid.
13.4. 6-Methylpyrrolo[1,2-c]pyrimidine (83)
Disodium phosphate (0.60 g, 4.2 mmol) and 5%
sodium/mercury amalgam (0.94 g, 2.1 mmol) were suspended
in 12 ml anhydrous methanol and the mixture was degassed
with a stream of argon. Sulphone 82 (300 mg, 1.05 mmol)
dissolved in 8 ml tetrahydrofuran was added over 5 min and
the mixture was stirred vigorously overnight under argon.
Further 5% sodium/mercury amalgam (0.94 g, 2.1 mmol) was
added and the mixture was stirred vigorously for 2 h. The
mixture was partitioned between water and ether. The
aqueous phase was extracted twice with ether and the
combined organics were dried over anhydrous sodium
sulphate, filtered and evaporated under reduced pressure. The
residue was purified using the Isolera purification system
(ether-hexane gradient) to give 83 (87 mg, 0.66 mmol, 63%
1
Purity 96%. H NMR (300 MHz, CDCl3) δ ppm 2.18 (s, 3H,
1
yield) as a yellow oil. Purity 95%. H NMR (300 MHz,
ArMe), 3.68 (s, 3H, OMe), 4.41 (s, 2H, CH2), 6.08 (s, 1H,
pyrrolopyrimidine H-5), 6.31 (s, 1H, Bn H-6), 6.90 (dd,
J=2.3, 8.7 Hz, 1H, pyrrolopyrimidine H-4), 7.13 (d, J=6.3 Hz,
1H, pyrrolopyrimidine H-3), 7.19 - 7.36 (m, 3H, Ar), 7.86 (s,
1H, pyrrolopyrimidine H-1), 7.90 - 8.00 (m, 2H, SO2Ph
ortho), 8.27 (d, J=8.8 Hz, 1H, Bn H-3). UPLC/MS (3 min)
retention time 1.91 min. LRMS: m/z 411 (M+1).
CDCl3) δ ppm 2.34 (s, 3H, Me), 6.27 (br. s., 1H, H-5), 7.14
(d, J=6.3 Hz, 1H, H-4), 7.17 (s, 1H, H-7), 7.35 (d, J=6.3 Hz,
1H, H-3), 8.69 (s, 1H, H-1). UPLC/MS (3 min) retention time
1.00 min. LRMS: m/z 133 (M+1).
13.5. 6-Methyl-7-[2-(phenylsulfonyl)benzyl]pyrrolo[1,2-
c]pyrimidine (84)
Pyrrolopyrimidine 83 (370 mg, 2.8 mmol) was dissolved in 7
ml anhydride acetic under nitrogen and the mixture was
cooled to 0 ºC. Hydriodic acid (57% solution, 3.3 ml, 25.0
mmol) was added drop-wise and with stirring over 20 min
(exotherm), warming to room temperature. Hypophosphorous
acid (50% solution, 1.37 ml, 13.2 mmol) was added followed
by aldehyde 8a (580 mg, 2.4 mmol) and the mixture was
stirred for 100 min at room temperature. The mixture was
13.7. Ethyl {6-methyl-7-[2-
(phenylsulfonyl)benzyl]pyrrolo[1,2-c]pyrimidin-5-
yl}acetate (86)
Aluminium trichloride (0.16 g, 1.25 mmol) was dissolved in 2
ml chlorobenzene and the mixture was degassed with nitrogen
and cooled to 0 ºC. Ethyl 2-chloro-2-oxoacetate (0.14 ml,
1.25 mmol) was added drop-wise and with stirring and the
mixture stirred for 15 min at 0 ºC giving a bright yellow
solution. Pyrrolopyrimidine 84 (0.15 g, 0.41 mmol) dissolved

ACCEPTED MANUSCRIPT
in 1 ml chlorobenzene was added drop-wise and with
UPLC/MS (3 min) retention time 1.92 min. LRMS: m/z 511
vigorous stirring at 0 ºC, giving a dark red solution. The
mixture was stirred at 0 ºC for 3 h and then overnight at room
temperature. The mixture was partitioned between ethyl
acetate and 16% aqueous ammonia solution. The aqueous
phase was extratcted with ethyl acetate and the combined
organics were washed with brine, dried over anhydrous
sodium sulphate, filtered and evaporated under reduced
pressure to give 190 mg of the crude oxoacetate. used directly
without further purification. UPLC/MS (5 min) retention time
2.18 min. LRMS: m/z 463 (M+1).
The crude oxoacetate (190 mg) was dissolved in 1.6 ml
trifluoroacetic acid under argon. Triethylsilane (2.0 ml, 12.6
mmol) as added and the mixture was stirred at 80 ºC
overnight. The mixture was allowed to cool and was basified
with dilute aqueous ammonia. The mixture was extracted
three times with ethyl acetate and the combined organics were
washed brine, dried over anhydrous magnesium sulphate,
filtered and evaporated under reduced pressure. The residue
was purified using the Isolera purification system (ether-
hexane gradient, 50:50 rising to 100:0) to give 86 (53 mg,
0.12 mmol, 29% yield over two steps) as a pale yellow solid.
Purity 97%. 1H NMR (300 MHz, CDCl3) δ ppm 1.26 (t, J=7.1
Hz, 3H, COCH2CH3), 2.14 (s, 3H, ArMe), 3.69 (s, 2H,
CH2CO), 4.16 (q, J=7.0 Hz, 2H, COCH2CH3), 4.46 (s, 2H,
CH2Ph), 6.57 (d, J=7.4 Hz, 1H, Bn H-6), 7.15 (d, J=6.6 Hz,
1H, pyrrolopyrimidine H-4), 7.31 (d, J=6.6 Hz, 1H,
pyrrolopyrimidine H-3), 7.38 (t, J=6.9 Hz, 1H, Bn H-4), 7.46
(t, J=7.6 Hz, 1H, Bn H-5), 7.58 (s, 1H, pyrrolopyrimidine H-
1), 7.60 (t, J=7.2 Hz, 2H, SO2Ph meta), 7.69 (t, J=7.2 Hz, 1H,
SO2Ph para), 7.97 (d, J=7.1 Hz, 2H, SO2Ph ortho), 8.32 (d,
J=8.0 Hz, 1H, Bn H-3). UPLC/MS (3 min) retention time
1.87 min. LRMS: m/z 449 (M+1).
(M+1).
The crude oxoacetate (190 mg) was dissolved in 1.5 ml
trifluoroacetic acid under nitrogen. Triethylsilane (2.0 ml,
12.6 mmol) was added and the mixture was stirred at 80 ºC
overnight. The mixture was allowed to cool and was basified
with dilute aqueous ammonia. The mixture was extracted
three times with chloroform and the combined organics were
washed brine, dried over anhydrous sodium sulphate, filtered
and evaporated under reduced pressure. The residue was
purified using the Isolera purification system (ether-hexane
gradient, 30:70 rising to 100:0) to give 87 (34 mg, 0.068
mmol, 19% over two steps) as a pale yellow solid. Purity
1
100%. H NMR (300 MHz, CDCl3) δ ppm 1.25 (t, J=7.1 Hz,
3H, COCH2CH3), 2.12 (s, 3H, ArMe), 3.68 (s, 5H, OMe and
CH2CO), 4.14 (q, J=7.1 Hz, 2H, COCH2CH3), 4.40 (s, 2H,
CH2Ph), 6.08 (s, 1H, Bn H-6), 6.89 (dd, J=2.5, 8.8 Hz, 1H,
Bn H-4), 7.16 (d, J=6.3 Hz, 1H, pyrrolopyrimidine H-4), 7.21
- 7.30 (m, 2H, SO2Ph meta), 7.33 (d, J=6.6 Hz, 1H,
pyrrolopyrimidine H-3), 7.82 (s, 1H, pyrrolopyrimidine H-1),
7.89 - 8.01 (m, 2H, SO2Ph para), 8.27 (d, J=8.8 Hz, 1H, Bn
H-3). UPLC/MS (3 min) retention time 1.93 min. LRMS: m/z
497 (M+1).
13.9. {6-Methyl-7-[2-(phenylsulfonyl)benzyl]pyrrolo[1,2-
c]pyrimidin-5-yl}acetic acid (88)
Ester 86 (53 mg, 0.12 mmol) was dissolved in 1 ml
tetrahydrofuran and
1
ml water. Lithium hydroxide
monohydrate (20 mg, 0.48 mmol) was added and the mixture
was stirred for 1 h at room temperature. The organics were
evaporated under reduced pressure. The solution was diluted
with water and was washed with ethyl acetate. The aqueous
phase was neutralized to pH 7 with 1N hydrochloric acid,
forming a precipitate. The solid was collected by filtration,
was washed with a little water and was dried at 40 ºC under
vacuum to give 88 (50 mg, 0.12 mmol, 99% yield) as a white
13.8. Ethyl
(7-{2-[(4-fluorophenyl)sulfonyl]-5-
methoxybenzyl}-6-methylpyrrolo[1,2-c]pyrimidin-5-
yl)acetate (87)
1
solid. Purity 99%. H NMR (300 MHz, DMSO-d6) δ ppm
1.89 (s, 3H, Me), 3.62 (s, 2H, CH2CO), 4.48 (s, 2H, CH2Ph),
6.59 (d, J=6.0 Hz, 1H, Bn H-6), 7.23 (d, J=6.0 Hz, 1H,
pyrrolopyrimidine H-4), 7.34 (d, J=6.0 Hz, 1H,
pyrrolopyrimidine H-3), 7.45 - 7.62 (m, 3H, Ar), 7.68 (t,
J=7.1 Hz, 2H, SO2Ph meta), 7.78 (t, J=7.0 Hz, 1H, SO2Ph
para), 7.92 - 8.08 (m, 3H, SO2Ph ortho and pyrrolopyrimidine
H-1), 8.24 (d, J=6.3 Hz, 1H, Bn H-3). HPLC/MS (30 min)
retention time 13.92 min. LRMS: m/z 421 (M+1).
Aluminium trichloride (0.14 g, 1.05 mmol) was dissolved in 2
ml chlorobenzene and the mixture was degassed with nitrogen
and cooled to 0 ºC. Ethyl 2-chloro-2-oxoacetate (0.12 ml,
1.05 mmol) was added drop-wise and with stirring and the
mixture stirred for 10 min at 0 ºC, giving a bright yellow
solution. Pyrrolopyrimidine 85 (0.15 g, 0.35 mmol) dissolved
in 1.5 ml chlorobenzene was added drop-wise and with
vigorous stirring at 0 ºC, giving a dark red solution. The
mixture was then stirred overnight at room temperature. The
mixture was partitioned between ethyl acetate and 16%
aqueous ammonia solution. The aqueous phase was extratcted
with ethyl acetate and the combined organics were washed
brine, dried over anhydrous sodium sulphate, filtered and
evaporated under reduced pressure to give crude oxoacetate
(190 mg). Used directly without further purification.
13.10.(7-{2-[(4-Fluorophenyl)sulfonyl]-5-
methoxybenzyl}-6-methylpyrrolo[1,2-c]pyrimidin-5-
yl)acetic acid (89)
Ester 87 (34 mg, 0.068 mmol) was dissolved in 0.8 ml
tetrahydrofuran and 0.8 ml water. Lithium hydroxide
monohydrate (32 mg, 0.76 mmol) was added and the mixture