Design, synthesis, and evaluation of 3,4-disubstituted pyrazole analogues as anti-tumor CDK inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.05.092

Two series of 3,4-disubstituted pyrazole analogues, 3-(benzimidazol-2-yl)-4-[2-(pyridin-3-yl)-vinyl]-pyrazoles (2) and 3-(imidazol-2-yl)-4-[2-(pyridin-3-yl)-vinyl]-pyrazoles (3), were synthesized as novel cyclin-dependent kinase (CDK) inhibitors. Represen

Full text of DOI:10.1016/j.bmcl.2007.05.092

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4557–4561
Design, synthesis, and evaluation of 3,4-disubstituted
pyrazole analogues as anti-tumor CDK inhibitors
Ronghui Lin,* George Chiu, Yang Yu, Peter J. Connolly,* Shengjian Li, Yanhua Lu,
Mary Adams, Angel R. Fuentes-Pesquera, Stuart L. Emanuel and Lee M. Greenberger
Johnson & Johnson Pharmaceutical Research & Development L.L.C., 1000 Route 202, Raritan, NJ 08869, USA
Received 9 April 2007; revised 28 May 2007; accepted 30 May 2007
Available online 6 June 2007
Abstract—Two series of 3,4-disubstituted pyrazole analogues, 3-(benzimidazol-2-yl)-4-[2-(pyridin-3-yl)-vinyl]-pyrazoles (2) and 3-
(imidazol-2-yl)-4-[2-(pyridin-3-yl)-vinyl]-pyrazoles (3), were synthesized as novel cyclin-dependent kinase (CDK) inhibitors. Repre-
sentative compounds showed potent and selective CDK inhibitory activities and inhibited in vitro cellular proliferation in various
human tumor cells. The design, synthesis, and preliminary biological evaluation of these pyrazole compounds are reported.
Ó 2007 Elsevier Ltd. All rights reserved.
Cyclin-dependent kinases are members of a family
of serine–threonine protein kinases responsible for regu-
lation of the eukaryotic cell cycle.1 The conjunction of
CDK subunits with their corresponding cyclin regula-
tory subunits results in a subset of kinase complexes
with specific functions in the process of cell division.
The regulated activation of these complexes guides cells
through the cell cycle and ensures the accurate execution
of cell division. Cell proliferation occurs in distinct
phases, which are each controlled by different CDKs
coupled with a corresponding cyclin partner. Cancer is
well known as a disease of aberrant cellular proliferation
and most cancer cells exhibit deregulation of CDKs. As
a result, CDK inhibitors have been intensively pursued
as potential anti-cancer agents.2 A number of CDK
inhibitors,2,3 such as flavopiridol, 7-hydroxystaurospo-
rine (UCN-01), roscovitine (CYC202), BMS-387032
(SNS-032),4 PD0332991,5 and R547,6 have been studied
in clinical trials for the treatment of cancer.
recently, we reported that 3-benzimidazol-2-yl pyrazol-
o[3,4-b]pyridine analogues (1) were novel potent CDK
inhibitors and anti-proliferative agents.9 To discover
structurally different CDK inhibitors with improved
physicochemical, pharmacokinetic, and solubility prop-
erties, we have synthesized and evaluated two related
series of 3,4-disubstituted pyrazole analogues, in partic-
ular,
3-(benzimidazol-2-yl)-4-[2-(pyridin-3-yl)-vinyl]-
pyrazoles (2) and 3-(imidazol-2-yl)-4-[2-(pyridin-3-yl)-
vinyl]-pyrazoles (3), as novel CDK inhibitors. Herein
we report their design, synthesis, and preliminary bio-
logical evaluation.
R5
R6
N
R4
R3
NH
R2
N
N
1
N
R1
R4
In our program to develop CDK inhibitors as anti-cancer
agents, we have recently reported 1-acyl-1H-[1,2,4]tria-
zole-3,5-diamine analogues and 2-amino-3-benzoyl-6-
anilinopyridine analogues that are novel anti-cancer
CDK inhibitors and anti-proliferative agents.7,8 More
R2
R4
R2
R1
R3
N
R1
R3
N
NH
NH
N
N
N
N
N
H
N
H
2
3
Keywords: Pyrazole analogues; Cyclin-dependent kinase inhibitor;
Anti-tumor agents; Anti-proliferative agents.
Several properties of the 3-benzimidazoyl pyrazolo[3,4-b]
pyridine analogues (1), including aqueous solubility
and oral bioavailability, were targeted for improvement.
To address these areas, a structural modification was
*
Corresponding authors. Fax: +1 908 526 6465 (R.L.); fax: +1 609 655
6930 (P.J.C.); e-mail addresses: RLin@prdus.jnj.com; PConnoll@
prdus.jnj.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.05.092

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R. Lin et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4557–4561
proposed to replace both bicyclic rings with monocycles
while retaining necessary binding elements of the phar-
macophore. Specifically, SAR of the previous 3-ben-
zimidazoyl pyrazolo[3,4-b] pyridine series (1) revealed
that pyrazole, imidazole, and pyridinyl or isoquinoyl
groups were critical for CDK inhibitory activity. Thus,
we envisioned using an (E)-4-vinyl pyrazole moiety to
replace the core bicyclic pyrazolopyridine, and also
using imidazole to replace the benzimidazole, as shown
in structures 2 and 3.
Alternatively, SEM-protected 3-benzimidazolyl-5-bro-
mopyrazole 8 was coupled with commercially available
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyri-
dine-3-carboxaldehyde to give compound 9h, in 28%
yield. The carboxaldehyde group of 9h underwent a
reductive amination with ethylamine and NaBH4 in
55% yield, and consequent de-protection of the SEM
protecting group gave compound 2h in 72% yield.
The stepwise Stille and Heck coupling could be simpli-
fied with a one-step Suzuki coupling using a vinyl het-
eroaryl boronate. As shown in Scheme 2,
hydroboration of commercially available 3-ethynyl-pyr-
A general approach to synthesize the target compounds
2 and 3 was designed to use commercially available 4-
iodo-pyrazole-3-carboxylic acid (4) and 4-bromo-pyra-
zole-3-carboxaldehyde (10). Key steps for the synthesis
involved benzimidazole or imidazole ring formation by
cyclization of the 3-carboxaldehyde or 3-carboxylic acid
group of 4 or 10; and an arylvinylation at the 4-position
of the pyrazole ring via stepwise Stille and Heck
couplings or via one-step Suzuki coupling.
O
CH
O
B
B
a
O
+
O
H
b
N
12
13
N
14
Br
CHO
Br
CHO
As outlined in Scheme 1, commercially available 4-iodo-
pyrazole-3-carboxylic acid (4) was coupled with 4-meth-
oxy-benzene-1,2-diamine to give amide 5, followed by
cyclization in glacial acetic acid. Efficient Suzuki or
Stille coupling on the pyrazole substrates required N-
protection on the pyrazole ring, accomplished using
SEM chloride to provide 7. Next, the vinylation at the
4-position of the SEM-protected 7 was achieved via
Stille coupling with tributyl vinyl stannane. Then, 4-vi-
nyl pyrazole 8 underwent Heck reaction with a heteroa-
ryl bromide to give coupled compound 9. Subsequent
SEM-de-protection gave the targeted compound (2).
For unsymmetric substitution patterns on the benzimid-
azole ring, 7–9 could be a mixture of two isomers (only
one isomer shown in Scheme 1). A series of target ana-
logues 2a–f were prepared by this general approach. Fi-
nally, the carboxylic ester of compound 2f was
hydrolyzed and the resultant carboxylic acid was further
coupled with ethylamine to form amide compound 2g.
c
N
N
CHO
N
N
H
SEM
N
N
10
11
SEM
N
15
N
d
N
N
N
N
N
HN
e
HN
N
N
N
N
N
N
H
2i
SEM
16
Scheme 2. Synthetic approach toward 3-(1H-benzimidazol-2-yl)-4-[2-
(pyridine-3-yl)-vinyl]-pyrazole analogues via Suzuki coupling.
Reagents and conditions: (a) RuHCl(CO)(PPh3), 50 °C, toluene,
95%; (b) SEM-Cl, NaH, THF, 57%; (c) Pd(dppf)Cl2 Æ DCM,
Na2CO3/H2O, dioxane, 120 °C, 72%; (d) 4-(4-methyl-piperazin-1-yl)-
benzene-1,2-diamine, S(0), DMF, 80 °C, 6 h, 50%; (e) 4 M HCl, EtOH,
70 °C, 6 h, 82%.
OMe
OMe
O
I
CO2H
NH
NH2
I
b
N
N
N
N
c
a
I
NH
N
I
N
95%
N
N
H
82%
57%
N
H
SEM
OMe
6
5
4
N
H
N
7
SEM
R1
d
53%
R2
R1
N
R2
R1
R2
Br
OMe
OMe
OMe
R3
R3
R3
N
N
N
N
N
f
to 2a-2f
e
NH
N
N
SEM
g
from 2f to 2g
SEM
N
N
h, f from 9h to 2h
N
N
H
N
8
N
2
SEM
R1 = H, For R2, R3
SEM
9
2a: H,H; 2b: H, Me; 2c: -CH=CH-CH=CH-
2d: CN, H; 2e: OMe, H; 2f; CO2Me, H;
2g: CONHEt, H; 2h: CH2NHEt, H
9h: R1,R3 = H, R2 = CHO
Scheme 1. General synthetic approach to 3-(1H-benzimidazol-2-yl)-4-[2-(heteroaryl)-vinyl]-pyrazole analogues. Reagents and conditions:
(a) 4-methoxy-benzene-1,2-diamine, HATU, DIPEA, DMF, 82%; (b) glacial HOAc, 90 °C, 12 h, 95%; (c) SEM-Cl, NaH, THF, 57%; (d) tributyl
vinyl stannane, Pd(PPh3)4, DMF, 72 °C, 10 h, 53%; (e) Pd(dppf)Cl2.DCM, cat. BHT, DMF, 90 °C, 8 h, 11–28%; (f) 1:1 EtOH/4 M HCl, 80 °C, 12 h,
38–72%; (g) NaOH, MeOH; then EtNH2, HATU, DIPEA, DMF, 45% for two steps; (h) EtNH2, NaBH4, 55%.

R. Lin et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4557–4561
4559
CF3
idine (12) with pinacolborane (13) in the presence of car-
CF3
bonylchlorohydridotris(triphenylphosphine) ruthenium
(II), RuHCl(CO)(PPh3),10 afforded (E)-2-(pyridine-3-
yl)vinyl-boronate 14. Suzuki coupling of 14 with SEM-
protected 4-bromo-1H-pyrazole-3-carboxaldehyde (11,
prepared from 10) gave compound 15 in 72% yield.
Benzimidazole ring formation was achieved by treating
3-carboxaldehyde 15 and 4-(4-methyl-piperazin-1-yl)-
1,2-benzenediamine with sulfur (0) to give compound
16 in 50% yield. Subsequent de-protection of the SEM
group in 16 gave compound 2i in 82% yield.
N
N
N
N
Br
N
b
Br
NH
a
SEM
10
10%
N
19
N
H
18
SEM
c
76%
CF3
CF3
R2
N
R2
N
R3
N
N
N
R3
N
N
SEM
SEM
Br
N
d
To further modify the structure of the benzimidazole
series (2), the bicyclic benzimidazole ring was replaced
with monocyclic imidazole as shown in Scheme 3. For
example, following a literature procedure for imidazole
ring formation,11 aldehyde 15 was treated with dibromo-
trifluoroacetone, sodium acetate, and concentrated
ammonium hydroxide, to give compound 17; which
upon de-protection produced target compound 3a.
Compound 3a was further converted to compound 3b
with ammonium hydroxide in 50% yield.
N
N
20
SEM
f from 21b
SEM
21a, R2,R3 = -CH=CH-CH=CH-
21b, R2 = CHO, R3 = H
N
CF3
65%
EtHN
N
N
e from 21a
60%
SEM
N
CF3
N
N
22
SEM
N
NH
g
73%
N
CF3
N
N
H
3c
Complementary to this approach, the imidazole series
could be assembled from the right to left side as shown
in Scheme 4. Imidazole ring formation from aldehyde 10
followed by SEM protection on both imidazole and pyr-
azole rings gave bromide 19, which underwent Stille
coupling with tributyl vinyl stannane to give compound
20. The resultant 4-vinyl pyrazole 20 then proceeded via
Heck reaction with a heteroaryl bromide to give the cor-
responding compound 21. For example, Heck coupling
of 20 with 4-bromoisoquinoline afforded 21a, and subse-
quent SEM-de-protection of 21a gave compound 3c.
Similarly, Heck coupling of 20 with 5-(4,4,5,5-tetra-
methyl-[1,3,2]dioxaborolan-2-yl)-pyridine-3-carboxalde-
hyde to 21b was followed by reductive amination of the
resultant 21b to give 22, and subsequent de-protection
gave compound 3d.
EtHN
N
NH
N
N
H
3d
Scheme 4. Synthetic approach to 3-(1H-imidazol-2-yl)-4[2-(heteroa-
ryl)vinyl]-pyrazole analogues via Stille and Heck coupling. Reagents
and conditions: (a) HATU, DIPEA, DMF; (b) SEM-Cl, NaH, THF,
10% for (a and b); (c) tributyl vinyl stannane, Pd(PPh3)4, DMF, 72 °C,
10 h, 76%. (d) Pd(dppf)Cl2 Æ DCM, cat. BHT, DMF, 90 °C, 8 h, 11–
32%; (e) 1:1 EtOH/4 M HCl, 80 °C, 12 h, 60%; (f) NaBH4, EtNH2,
65%; (g) 1:1 EtOH/4 M HCl, 73%.
zimidazol-2-yl)-4-[2-(pyridin-3-yl)-vinyl]-pyrazoles (2)
and the 3-(imidazol-2-yl)-4-[2-(pyridin-3-yl)-vinyl]-pyr-
azoles (3), show modest to potent CDK1 inhibition,
with IC50 values ranging from about 1 lM to single digit
nM. In general, these two series are slightly less potent
CDK1 inhibitors compared to the previously reported
3-benzimidazol-2-yl pyrazolo[3,4-b]pyridine analogues
(1).9 In the benzimidazole series (2), electron donating
groups on the pyridine ring (e.g., compound 2e with
methoxy) seem to render more potent CDK1 activity
compared to electron withdrawing groups (e.g., com-
pounds 2d with cyano and 2f with methoxycarbonyl
substituents). Also, in the benzimidazole series the
monocyclic pyridine ring confers fivefold higher potency
than isoquinoline bicycle (compound 2a vs compound
2c, IC50 = 0.033 vs 0.15 lM). On the other hand, in
the imidazole series (3) the monocyclic pyridine ring
leads to a fivefold drop in potency compared to the iso-
quinoline bicycle (compound 3a vs compound 3c,
IC50 = 0.48 vs 0.11 lM). Similar to the parent pyrazol-
o[3,4-b]pyridine series (1), the 3-ethylamino methyl sub-
stituent in compound 2h confers very favorable CDK1
potency (IC50 = 4.6 nM), compared to the unsubstituted
(2a), methyl (2b), and other substituted compounds.
Comparison of 2h with corresponding amide compound
2g is also striking (IC50 0.0046 vs 0.11 lM). In addition,
Table 1 shows the inhibitory activities for the two series
of 3,4-disubstituted pyrazole analogues against CDK1
and three other kinases (HER2, VEGF-R2, and Aur-
ora-A kinases). Analogues in both series, the 3-(ben-
CF3
NH
N
N
N
CHO
a
N
N
N
55%
N
17
SEM
SEM
15
100%
b
CF3
NH
CN
NH
N
N
N
N
N
c
50%
N
N
H
N
H
3b
3a
Scheme 3. Synthesis of 3-(1H-imidazol-2-yl)-4-[2-(pyridine-3-yl)-
vinyl]-pyrazole analogues. Reagents and conditions: (a) CF3COC-
HBr2, NaOAc, NH4OH, EtOH, 55%; (b) 4 M HCl, EtOH, 80 °C, 16 h,
100%; (c) 5% NH4OH/H2O, 60 °C, 2 h, 50%.

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R. Lin et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4557–4561
Table 1. CDK1 and other kinase inhibitory activities of the two series
of 3,4-disubstituted pyrazole analogues (2a–i, 3a–d)
Table 2. In vitro cellular anti-proliferative activity of the two series of
3,4-disubstituted pyrazole analogues (2a–i, 3a–d) on human tumor
cells
a
Compound
IC50 (lM)
a
Compound
IC50 (lM)
CDK1/cyclin B HER2
VEGF-R2 Aurora-A
A375
HCT-116
HeLa
2a
2b
2c
2d
2e
2f
0.033
0.16
0.15
>10
0.97
0.76
0.61
1.7
0.51
0.55
0.53
4.20
0.40
>10
>100
>100
12
2a
2b
2c
2e
2f
2.5
4.3
3.0
2.2
3.2
1.8
2.8
2.8
>1
2.7
0.047
0.89
0.11
0.65
1.28
1.35
0.82
0.29
0.91
3.1
0.75
3.1
0.89
4.4
>100
37
>100
>100
0.59
>10
0.12
>10
0.30
>10
2g
2h
2i
2g
2h
2i
3.6
2.5
3.7
0.0046
0.029
0.48
3.03
9.3
>100
>100
32.73
>100
0.55
0.86
0.19
0.19
24
0.62
0.46
3a
3b
3c
3d
29
>10
3.06
ꢀ10
3a
3b
3c
3d
47
>10
5.6
7.4
>10
>10
3.6
3.2
0.70
0.11
70.7
2.9
0.018
1.7
a Values are means of at least two experiments and are rounded up to
two significant figures. IC50 values listed as >10 or >100 indicate no
observed 50% inhibition at the highest dose tested, nor was an
inhibition maximum observed.
a Values are means of at least two experiments and are rounded up to
two significant figures. IC50 values listed as >10 indicate no observed
50% inhibition at the highest dose tested, nor was an inhibition
maximum observed.
examination of substitution on the benzimidazole group
revealed that the bulky and polar 4-methyl-piperazine
analogue 2i has CDK1 potency comparable to the
methoxy analogue 2e.
group on the pyrazole ring. Representative compounds
showed potent CDK1 inhibitory activities and inhibited
in vitro cellular proliferation in HeLa, HCT116, and
A375 human tumor cell lines.
Comparison of CDK1 activity with inhibition of the
other three protein kinases, HER2, VEGF-R2, and
Aurora-A kinase, revealed that pyrazole analogues 2
and 3 are generally selective toward CDK1. Selectivity
toward CDK1 inhibition versus the receptor tyrosine
kinases HER2 and VEGF-R2 was commonly seen in
the range of 5- to 10-fold, while selectivity versus
Aurora-A, which is a member of the same family of ser-
ine–threonine protein kinases as CDK1, was lower.
Acknowledgments
We thank Drs. Bill Murray, Filip De Corte, and Paul
Martin for reviewing the manuscript. R. Lin thanks
Drs. Gilles Bignan, Shenlin Huang, Terry Hughes, and
Steve Middleton for helpful discussions.
References and notes
Table 2 shows the in vitro anti-proliferative activities in
cultured human tumor cells for representative com-
pounds. The selected compounds proved to be active
in vitro as anti-proliferatives in various human tumor
cell lines, such as HeLa (cervical carcinoma), HCT116
(colon carcinoma), and A375 (melanoma), although
potencies were slightly lower than comparable com-
pounds from the parent 3-benzimidazoy-2-yl pyrazol-
o[3,4-b]pyridine series (1). The lead CDK1 inhibitors
showed potent cellular proliferative inhibition with
IC50 values ranging from low lM to sub-lM among
the tumor cell lines tested. Notable exceptions were
compounds 3a and 3b, which were significantly less
potent anti-proliferatives than other analogues.
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3,4-disubstituted pyrazole analogues, 3-(benzimidazol-
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