Novel pyrazolo[1,5-a]pyridines as PI3K inhibitors: Variation of the central linker group

Article abstract of DOI:10.1039/c3md00221g

As part of our investigation into the pyrazolo[1,5-a]pyridines as novel PI3K inhibitors, we report a range of analogues where the central linker portion of the molecule was varied while retaining the pyrazolo[1,5-a]pyridine and arylsulfonyl or arylcarbonyl groups. Isostere generating software BROOD was used to assist with producing ideas. The isoform selectivity of the compounds varied from pan-PI3K for compound 41 to p110α-selective for compound 58 or p110δ-selective for compound 57. The latter two compounds varied only in their sulphur oxidation state.

Full text of DOI:10.1039/c3md00221g

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Novel pyrazolo[1,5-a]pyridines as PI3K inhibitors:
variation of the central linker group†
ab
Cite this: Med. Chem. Commun., 2014,
5, 41
Andrew J. Marshall,a Anna C. Giddens,a Kit Yee Tsang,‡a
*
Jackie D. Kendall,
Maruta Boyd,a Raphael Frederick,§a Claire L. Lill,c Woo-Jeong Lee,c Sharada Kolekar,c
¨
´ ´
bc
Mindy Chao,c Alisha Malik,c Shuqiao Yu,c Claire Chaussade,{
Christina M. Buchanan,bc Gordon W. Rewcastle,ab Bruce C. Baguley,ab
Jack U. Flanagan,ab William A. Dennyab and Peter R. Shepherdbc
As part of our investigation into the pyrazolo[1,5-a]pyridines as novel PI3K inhibitors, we report a range of
analogues where the central linker portion of the molecule was varied while retaining the pyrazolo[1,5-a]
pyridine and arylsulfonyl or arylcarbonyl groups. Isostere generating software BROOD was used to assist
with producing ideas. The isoform selectivity of the compounds varied from pan-PI3K for compound 41
to p110a-selective for compound 58 or p110d-selective for compound 57. The latter two compounds
varied only in their sulphur oxidation state.
Received 30th July 2013
Accepted 26th October 2013
DOI: 10.1039/c3md00221g
www.rsc.org/medchemcomm
types. Two of the most common of these mutations (E545K and
H1047R) have been conrmed as activating mutations and
hence increase levels of PIP3.3 Mutations in p110b and p110d
have not been reported.4,5 Inhibitors of PI3K, and in particular,
selective inhibitors of p110a could prove to be an important
new strategy in cancer treatment.6 A number of inhibitors of
PI3K are currently in clinical trials, although none have yet
reached market.7,8
We have shown previously that pyrazolo[1,5-a]pyridines such
as 1 (ref. 9) and 2 (ref. 10) (Fig. 1) are potent and selective
inhibitors of the p110a isoform of PI3K. However, since the
sulfonohydrazide central portion of the molecule is a known
structural alert,11 we were interested in replacing this with an
alternative linker group. This has been investigated to a limited
extent by Hayakawa et al.12 with their related imidazo[1,2-a]-
pyridine series of compounds, however PI3K isoform selectivity
data was not reported for all compounds.
Molecular modelling of the pyrazolo[1,5-a]pyridines showed
that the pyrazolo nitrogen formed a key hydrogen bond with
Val851 of p110a;9 a residue interaction characteristic of many
other PI3K inhibitor complexes.13 Furthermore the sulfonyl
1. Introduction
Phosphoinositide 3-kinases (PI3Ks) are a group of lipid kinases
which phosphorylate the 30-hydroxyl group of phosphatidylino-
sitol diphosphate (PIP2) to phosphatidylinositol triphosphate
(PIP3). PIP3 then recruits protein kinase B (PKB, otherwise
known as AKT) to the cell membrane where it is in turn phos-
phorylated and activated, leading to a cascade of cell signalling
which controls a range of cellular processes like cell proliferation,
growth and survival.1 PI3Ks are oen over-expressed, and the
lipid phosphatase PTEN (which dephosphorylates PIP3) is oen
deleted or inactivated in many cancer types, leading to increased
levels of PIP3 and increased tumour survival.2
The PI3Ks are split into three sub-families (class I, II and III),
and class I is further split into class Ia and Ib based upon their
mechanism of activation. The class Ia PI3Ks are heterodimeric,
consisting of a catalytic subunit (p110a, p110b or p110d) in
complex with a regulatory subunit.1 PIK3CA, the gene encoding
for p110a, is oen over-expressed and mutated in many cancer
aAuckland Cancer Society Research Centre, School of Medical and Health Sciences, The
University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. E-mail: j.
kendall@auckland.ac.nz
bMaurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland,
Private Bag 92019, Auckland 1142, New Zealand
cDepartment of Molecular Medicine and Pathology, School of Medical and Health
Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3md00221g
‡ Present address: Universal Display Corporation, Hong Kong.
´
§ Present address: Universite Catholique de Louvain (UCL), Louvain Drug Research
Institute, Medicinal Chemistry Research Group, 73 Avenue E. Mounier, bte
B1.73.10, B-1200 Brussels, Belgium.
Fig.
1 Structures of our previous pyrazolo[1,5-a]pyridine PI3K
{ Present address: Centre Hospitalier Universitaire de Nice, Nice, France.
inhibitors.
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group formed a hydrogen bond with the p110a specic residue
Gln859,9 and the nitro group was also critical for good potency
and selectivity.10 We postulated that linking the pyrazolo[1,5-a]-
pyridine and nitroaryl sulfonyl moieties in an appropriate way
would generate a p110a selective PI3K inhibitor with lower
toxicity.
2. Results and discussion
2.1. Selection of sulfonohydrazide replacements
To increase our sulfonohydrazide replacement ideas, the bio-
isostere generating programme BROOD (v1.1.1; Openeye
Scientic Soware) was used select a set of alternative linking
groups that t the conformation of the sulfonohydrazide in a
model of the pyrazolo[1,5-a]pyridines bound to p110a. Of the
top 200 replacement fragments retrieved, only 51 unique iso-
steres were considered useful aer visual inspection. Of these,
only 42 hits contained a functional group we considered
capable of hydrogen-bonding to the side chain amine of the
p110a specic amino acid Gln859. The group was further nar-
rowed down to 11 based on lipophilicity of the whole candidate
compound, determined by comparison of the c log P values
(calculated using ACD/PhysChem v. 7.10, Advanced Chemistry
Development, Inc.) with the c log P value for 1 of 2.43.
Compounds with c log P greater than 2.43 were discarded since
such compounds would be more lipophilic and hence are likely
to have lower aqueous solubility than 1. The group was nally
reduced to 4 (Fig. 2) by assessment of the number of hydrogen-
bond acceptors, in accordance with Lipinski rules.14
Fig. 2 Filtered set of sulfonohydrazide isosteres generated by BROOD
v1.1.1.
We also chose some linker groups of our own devising: an
allylic sulfone to mimic the shape of the sulfonohydrazide
without containing the two nitrogens, a set of amine-containing
linkers which could improve water solubility, and other
heterocyclic linking groups.
2.2. Chemistry
Allylic sulfone 7 was made starting from pyrazolo[1,5-a]pyridine
3 (ref. 9) by iodination at the 3-position with N-iodosuccinimide
(NIS) to form 4 (Scheme 1). Sulnate 5 was reacted with acrolein
Scheme
1 Reagents: (i) NIS, MeCN; (ii) acrolein, AcOH; (iii)
iPrMgCl$LiCl, THF, ꢀ40 ꢁC then 6; (iv) MsCl, DBU, MeCN.
Scheme 2 Reagents: (i) CbzCl, Na2CO3, acetone; (ii) TFAA, NEt3, CH2Cl2; (iii) NIS, MeCN; (iv) boronic ester, PdCl2(dppf), aq. Na2CO3, toluene,
EtOH; (v) H2, Pd/C, DMF; (vi) NaNO2, H2O, 47% HBr then CuBr, 47% HBr; (vii) 2-methyl-5-nitrobenzenesulfonyl chloride, NEt3, CH2Cl2; (viii) 2-
methyl-5-nitrobenzoyl chloride, NEt3, CH2Cl2.
42 | Med. Chem. Commun., 2014, 5, 41–46
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Scheme 3 Reagents: (i) amine, AcOH, CH2Cl2 then Na(CN)BH3, EtOH; (ii) TFA, CH2Cl2; (iii) 2-methyl-5-nitrobenzenesulfonyl chloride, NEt3, DMF
or MeCN or CH2Cl2; (iv) 2-methyl-5-nitrobenzoyl chloride, NEt3, DMF or MeCN or CH2Cl2.
to form aldehyde 6, which was subsequently reacted with the to give 29 in good yield. Benzylic chloride 26 was displaced with
Grignard reagent derived from 4 followed by dehydration with potassium cyanide to give the phenylacetonitrile intermediate,
MsCl and DBU to afford 7. The position of the double bond was which was subsequently reacted with phosphorous pentasulde
conrmed by NOE interactions observed between the pyrazolo in ethanol under mild conditions to give thioamide 30.15
[1,5-a]pyridine C4–H (7.65 ppm) and alkene CH (6.52 ppm), and Dithiocarbamate 31 was also prepared from 26 by rstly con-
between the allylic CH2 (4.07 ppm) and aryl methyl protons verting it to the more reactive bromide followed by displace-
(2.85 ppm).
ment with a large excess of ammonium dithiocarbamate.16
Cyclic amine derivatives 16–19 were made starting from Sulfonyl chloride 27 was reacted with cyanamide, followed by
amine 8 (ref. 9) (Scheme 2). Amine 8 was protected as either
benzyl carbamate 9 or triuoroacetamide 10, then iodinated at
the 3-position to afford 11 and 12. Next, a palladium catalysed
coupling with a cyclic vinyl boronate installed the amine ring.
When 12 was used, the triuoroacetamide protecting group was
lost during this step. Hydrogenation over Pd/C then reduced the
double bond from the amine ring and removed the benzyl
carbamate to leave Boc protected compounds 13–15. Then
diazotisation converted the free amine to a bromide and also
removed the Boc group under the acidic conditions used, and
nally sulfonylation or acylation afforded compounds 16–19.
Aminomethylene-linked compounds 23a–h and 24a–g which
contain a basic amine to increase aqueous solubility were made
by reductive amination of aldehyde 20 (ref. 9) to afford amines
21a–h (Scheme 3). Removal of the Boc group was then followed
by sulfonylation to give sulfonamides 23a–h or acylation to give
carboxamides 24a–g.
Thiazoles were made using a Hantzsch thiazole synthesis
from an a-bromoketone and a thioamide. The syntheses of the
required thioamides 29–34 are depicted in Scheme 4. Carboxylic
acid 25 was converted to thioamide 29 by formation of the acid
chloride followed by treatment with ammonia to give the
primary amide, followed by thionation with Lawesson’s reagent reflux; (xii) KOH, MeOH, 40 ꢁC.
Scheme 4 Reagents: (i) SOCl2 then aq. NH3, CH2Cl2; (ii) Lawesson’s
reagent, MeOH, reflux; (iii) KCN, DMSO; (iv) P2S5, EtOH, reflux; (v) LiBr,
+
THF, reflux; (vi) H2NCS2ꢀ NH4 , EtOH, reflux; (viii) Na2NCN, H2O, 40 ꢁC
then Na2S2O3, 4.5 M aqueous H2SO4; (ix) Na2SO3, NaHCO3, H2O then
bromoacetonitrile, DMF; (x) H2S, NEt3, THF; (xi) PhCONCS, acetone,
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thiolysis using in situ generation of thiosulfuric acid to give C6–H (8.88 ppm), whereas N-methylthiazole 45 had NOE
thiourea 32. Thioamide 33 was accessed by displacement of interactions between the N-methyl protons (3.46 ppm) and
bromoacetonitrile with the sulnate salt of 27 to give the nitrile, pyrazolo[1,5-a]pyridine C2–H (7.97 ppm) and C4–H (7.65 ppm).
which underwent thiolysis with hydrogen sulde. Thiourea 34
2-Thiothiazoles 47, 50, 52 and 55 were accessed via copper-
was prepared from aniline 28 by reaction with benzoyl iso- mediated coupling19 of thione 46 with phenyl boronic acids to
thiocyanate followed by hydrolysis according to published give moderate yields of the desired thioethers (Scheme 6).
routes.17,18
Thione 46 could be prepared in good yield by reaction of a-
Methylketone 35 (ref. 9) was brominated under standard bromoketone 36 with fresh ammonium dithiocarbamate.
conditions to give versatile intermediate a-bromoketone 36, Oxidation with either Oxone® or MMPP gave the sulfoxide and/
which underwent a modied Hantzsch reaction with thio- or sulfone, depending on the substrate and choice of oxidant.
amides 29–34 to give thiazoles 37–42 (Scheme 5). Thioether 39 Oxone® oxidation of 47 gave exclusively sulfoxide 48, and MMPP
was oxidized with MMPP (magnesium bis(monoperoxyph- oxidation afforded sulfone 49. MMPP oxidation of the more
thalate)) to give sulfone 43. Sulfonamide 40 was methylated sterically hindered 2-methylphenyl compound 50 gave only
with methyl iodide under mild conditions to give two sulfoxide 51 under microwave heating, whereas 5-cyano-2-
regioisomeric products 44 and 45. The sites of methylation were uorophenyl compound 52 afforded a mixture of sulfoxide 53
identied by NMR experiments. N-Methylsulfonamide 44 and sulfone 54 aer reaction with the same reagent at room
showed NOE interactions between the N-methyl protons (3.65 temperature. In contrast, 55 which did not bear a 2-phenyl
ppm) and those of the aryl methyl protons (2.67 ppm) and aryl substituent gave exclusively sulfone 56, suggesting that the
Scheme 5 Reagents: (i) Br2, 33% HBr/AcOH, (ii) 29–34, EtOH; (iii) MMPP, CH2Cl2, EtOH, H2O, (iv) MeI, DMF.
ꢀ
Scheme 6 Reagents: (i) H2NCS2 NH4+, MeOH then AcOH, reflux; (ii) aryl boronic acid, Cu(OAc)2, 1,10-phenanthroline, 1,2-dichloroethane,
reflux; (iii) Oxone®, solvent; (iv) MMPP, CH2Cl2, EtOH; (v) amine, THF.
44 | Med. Chem. Commun., 2014, 5, 41–46
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Table 1 Inhibition of class Ia PI3K isoforms
IC50 (mM)
IC50 (mM)
p110a
Cmpd
p110a
p110b
p110d
Cmpd
p110b
p110d
1a
7
16
17
18
19
23a
23b
23c
23d
23e
23f
23g
23h
24a
24b
24c
24d
24e
24f
24g
0.0009
0.046
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
0.049
3.35 ꢂ 0.41
37
38
39
40
41
42
43
44
45
47
48
49
51
53
54
56
57
58
59
60
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
0.14 ꢂ 0.05
3.00 ꢂ 0.80
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
0.59 ꢂ 0.20
1.26 ꢂ 0.41
0.24 ꢂ 0.13
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
>1
0.14 ꢂ 0.01
0.09 ꢂ 0.05
>1
>1
>1
>1
>1
>1
>1
1.55 ꢂ 0.27
>1
>1
>1
>1
0.74 ꢂ 0.01
0.63 ꢂ 0.18
1.28 ꢂ 0.22
0.30 ꢂ 0.01
0.72 ꢂ 0.02
0.17 ꢂ 0.02
4.03 ꢂ 1.65
0.37 ꢂ 0.15
2.47 ꢂ 0.69
2.13 ꢂ 0.29
4.42 ꢂ 1.83
0.32 ꢂ 0.17
0.25 ꢂ 0.05
>1
5.45 ꢂ 0.30
>1
>1
>1
>1
0.20 ꢂ 0.03
0.44 ꢂ 0.03
0.15 ꢂ 0.12
0.25 ꢂ 0.03
2.00 ꢂ 0.48
0.64 ꢂ 0.14
0.24 ꢂ 0.13
4.34 ꢂ 1.76
3.56 ꢂ 0.08
>1
>1
a
Data from ref. 9.
presence of an ortho-phenyl substituent had a detrimental effect and 49 were less than 10-fold selective over p110b but were
on sulfur oxidation. Nucleophilic displacement of the activated slightly more potent against p110d than p110a.
2- or 4-uorobenzenes (53, 54 and 56) with alkyl amines at room
temperature gave the corresponding amino derivatives 57–60.
The removal of the nitro group (51) decreased p110a activity
in comparison to 48 by 2-fold. Benzonitrile derivatives 53, 54
and 56–60 all demonstrated PI3K IC50 of less than 1 mM against
at least one of the class Ia isoforms, however the selectivity
varied with the nature of the other phenyl substituent and
sulfur oxidation state. Fluorophenyl compounds 53, 54 and 56
all had p110a IC50 under 1 mM and were all similarly active
against p110d. In contrast, amine-containing compounds 57, 59
and 60 all demonstrated modest selectivity, albeit for p110d
over p110a (by 16-fold, 4-fold and 9-fold, respectively). In
contrast 58, the sulfone analogue of sulfoxide 57, was 5-fold
selective for p110a over p110d.
2.3. Biological activity
We have shown previously that both 5-bromo- and 5-cyanopyr-
azolo[1,5-a]pyridines are highly potent and selective inhibitors
of the p110a isoform of PI3K,9,10 so these building blocks were
chosen for further elaboration around the central hydrazone
portion of the molecule. Compounds were assayed for their
inhibition of the three class Ia isoforms of PI3K: p110a, p110b
and p110d (Table 1).
Replacement of the hydrazone with allylic sulfone 7, where
the hydrazone nitrogens atoms were replaced by carbons, was
150-fold less active against p110a than 1, while retaining some
selectivity over p110b and p110d. None of the cyclic amine
derivatives 16–19, 23a–h and 24a–g had IC50 less than 1 mM for
any of the class Ia PI3K isoforms, with the sole exception of 3-
substituted piperidine 17 with a modest p110a IC50 of 0.59 mM.
These compounds were not investigated further, and we instead
focussed our efforts on aromatic heterocyclic linker groups.
Of the 2-methyl-5-nitrophenyl compounds 37–45, only 41
had p110a IC50 less than 1 mM, however this compound lost all
selectivity for p110a over the other class Ia PI3K isoforms
(p110a/b/d IC50 0.24/0.14/0.09 mM). By comparison of 3-nitro-
phenyl compounds 47, 48 and 49, the addition of at least one
3. Conclusions
A range of pyrazolo[1,5-a]pyridines were prepared where the
central portion of the molecule was varied with cyclic and
acyclic, aromatic and aliphatic linking groups to investigate the
PI3K potencies. We found that the thiazole group was preferred,
however the isoform selectivity could be varied by changes of
the sulfur oxidation state and phenyl ring substituents. These
compounds were not sufficiently potent in comparison with our
earlier sulfonohydrazides, and were not investigated further.
4. Experimental
4.1. Molecular modelling
oxygen on sulfur was necessary for p110a IC50 less than 1 mM The bioisostere generating programme BROOD (v1.1.1; Open-
although there was little difference between sulfoxide 48 and eye Scientic Soware) was used with a 3-dimensional model of
sulfone 49 (p110a IC50 48: 0.74 mM and 49: 0.63 mM). Both 48 the sulfonohydrazide core based on the top ranked predicted
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binding mode of N0-((5-bromopyrazolo[1,5-a]pyridin-3-yl)methy-
lene)-N,2-dimethyl-5-nitrobenzenesulfonohydrazide
2 M. C. Hollander, G. M. Blumenthal and P. A. Dennis, Nat.
Rev. Cancer, 2011, 11, 289–301.
(compound 5m in ref. 9) in the ATP binding site of p110a.
BROOD settings were kept at default values, and the electro-
static tanimoto similarity value was calculated. The f5 multi-
conformer fragment library consisting of 3-dimensional
models of 140 000 fragments was searched. The electrostatic
tanimoto similarity hit list was ranked according to the
combined electrostatic shape and electrostatic tanimoto values
then visually inspected. The 2D scheme of the full compounds
was generated for further analysis.
3 C. Chaussade, K. Cho, C. Mawson, G. W. Rewcastle and
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Methods and characterisation for all novel compounds are
detailed in the ESI.†
´ ´
9 J. D. Kendall, P. D. O’Connor, A. J. Marshall, R. Frederick,
4.3. Enzyme assays
E. S. Marshall, C. L. Lill, W.-J. Lee, S. Kolekar, M. Chao,
A. Malik, S. Yu, C. Chaussade, C. Buchanan,
G. W. Rewcastle, B. C. Baguley, J. U. Flanagan,
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The Class Ia PI3K assays were performed using a basic thin layer
chromatography technique, as described previously.20 The
p110d/p85 PI3K was from Upstate and the p110a/p85 and
p110b/p85 isoforms were prepared as described previously.20
Reactions were made containing 0.1 mg recombinant enzyme,
10 mg L-a-phosphatidylinositol, inhibitor (DMSO only or
DMSO + inhibitor to a nal concentration of 1%), 2ꢃ lipid
kinase buffer (40 mM Tris–HCl pH 7.4, 200 mM NaCl, 1 mM
EDTA), and activated upon the addition of an ATP mix (5 mM
MgCl2, 100 mM ATP, 0.1 mL [g33P]ATP). Reactions were incu-
bated at room temperature for 1 h following which the reactions
were stopped by the addition of 1 M HCl. The lipids were then
extracted using a two step procedure. Firstly, 200 mL of chlor-
oform : methanol (1 : 1) was added, the biphasic reactions
mixed and centrifuged briey, and the inorganic phase was
removed and discarded. Following this 80 mL of meth-
anol : hydrochloric acid (1 : 1) was added and the same proce-
dure followed. Next, 70 mL of the organic phase was transferred
to a clean 1.6 mL tube and the reactions were dried using a
speed vac, with no heating, for 30 min. The reactions were
spotted onto TLC plates (Merck Ltd) and developed for 1 h in 1-
propanol : 2 M acetic acid (13 : 7). The TLC plates were then
dried at room temperature and quantied using a phosphor-
imager (StormImager, Amersham). Nine inhibitor concentra-
tions were used to determine the IC50. Each experiment was
performed twice and the average IC50 value used.
´ ´
10 J. D. Kendall, A. C. Giddens, K. Y. Tsang, R. Frederick,
E. S. Marshall, R. Singh, C. L. Lill, W.-J. Lee, S. Kolekar,
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G. W. Rewcastle, B. C. Baguley, J. U. Flanagan,
S. M. F. Jamieson, W. A. Denny and P. R. Shepherd, Bioorg.
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Acknowledgements
The authors would like to thank the Health Research Council of
New Zealand, Maurice Wilkins Centre for Molecular Biodiscovery,
and Pathway Therapeutics for their nancial assistance.
´
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