Non-hinge-binding pyrazolo[1,5-a]pyrimidines as potent B-Raf kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.10.049

As part of our research effort to discover B-Raf kinase inhibitors, we prepared a series of C-3 substituted N-(3-(pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-3-(trifluoromethyl)benzamides. X-ray crystallography studies revealed that one of the more potent inhibitors (10n) bound to B-Raf kinase without forming a hinge-binding hydrogen bond. With basic amine residues appended to C-3 aryl residues, cellular activity and solubility were enhanced over previously described compounds of this class.

Full text of DOI:10.1016/j.bmcl.2009.10.049

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6519–6523
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Non-hinge-binding pyrazolo[1,5-a]pyrimidines as potent B-Raf kinase inhibitors
a
a
a
a
a
Dan M. Berger a, , Nancy Torres , Minu Dutia , Dennis Powell , Greg Ciszewski , Ariamala Gopalsamy ,
Jeremy I. Levin a, Kyung-Hee Kim a, Weixin Xu b, James Wilhelm b, YongBo Hu b, Karen Collins c,
Larry Feldberg c, Steven Kim c, Eileen Frommer c, Donald Wojciechowicz c, Robert Mallon c
*
a Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA
b Structural Biology and Computational Chemistry, Wyeth Research, Cambridge, MA, USA
c Oncology, Wyeth Research, Pearl River, NY 10965, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
As part of our research effort to discover B-Raf kinase inhibitors, we prepared a series of C-3 substituted
N-(3-(pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-3-(trifluoromethyl)benzamides. X-ray crystallography studies
revealed that one of the more potent inhibitors (10n) bound to B-Raf kinase without forming a hinge-binding
hydrogen bond. With basic amine residues appended to C-3 aryl residues, cellular activity and solubility were
enhanced over previously described compounds of this class.
Received 11 September 2009
Revised 9 October 2009
Accepted 12 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Raf
Kinase
Inhibitor
Pyrazolo[1,5-a]pyrimidine
The Ras-Raf-MEK-ERK signal transduction pathway (ERK path-
way) plays a key role in cellular growth and proliferation. Muta-
tions of either Ras or B-Raf lead to a sustained and constitutive
activation of the ERK pathway, resulting in increased cell division
and cell survival, and are associated with a variety of human can-
cers. Mutant B-Raf (most commonly V600E) is associated with
melanoma1 (66%), colorectal cancer2 (12%), and papillary thyroid
cancers3 (ꢀ45%). B-Raf (mutant and wild-type) inhibitors therefore
have the potential to treat cancers associated with dysregulation of
the ERK pathway. A number of inhibitors of the Ras-Raf-MEK-ERK
pathway have been discovered and some of these have now ad-
vanced into clinical trials.4
In order to improve the aqueous solubility of these compounds, a
number of them were prepared with basic amine water-solubiliz-
ing groups attached.
For all of the target compounds, the optimized trifluorobenza-
mide group was retained at the meta-position of the C-7 phenyl
residue.5 The preparation of intermediates 6a–d were carried out
as outlined in Scheme 1. Coupling of 3-aminoacetophenones 3a–
c with 3-(trifluoromethyl)benzoyl chloride followed by reaction
with N,N-dimethylformamide dimethyl acetal afforded enaminone
intermediates 4a–c. Condensation of 4b and 4c with 5-aminopyra-
zole 5a in refluxing acetic acid afforded pyrazolo[1,5-a]pyrimidines
6a and 6b. Under similar conditions, 6d was prepared from the
reaction of 4a with 5b. A slightly different route was required for
In our effort to discover novel and selective B-Raf kinase inhib-
itors, we have explored the SAR of a series of C-2 and C-3 substi-
tuted pyrazolo[1,5-a] pyrimidines.5–7 As shown in Figure 1, the
initial lead in this series was compound 1 (B-Raf IC50: 1.5
B-Raf mutant cell HT29 and WM266 IC50s: 7.0 M and 6.2
l
l
M,
M,
l
O
N
respectively). We now report additional SAR information for this
pyrazolo[1,5-a]pyrimidine series, focusing on the incorporation of
substituents on the central phenyl ring (Fig. 1, R1) and a survey
of replacements for the ester group on the pyrazole ring (Fig. 1,
R2). Specifically, a series of substituted alkyne, five- and six-mem-
bered aryl and heteroaryl substituents were explored in order to
optimize the B-Raf kinase inhibitory activity of these compounds.
O
N
CF3
CF3
NH
N
NH
R1
7
N
6
5
2
N
N
3
R2
CO2Et
2
1
* Corresponding author.
E-mail address: bergerd@wyeth.com (D.M. Berger).
Figure 1. B-Raf inhibitors.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.10.049

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D. M. Berger et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6519–6523
intermediate 12. Reductive amination of aldehyde 12 with pyrrol-
idine and N-ethylpiperidine provided target compounds 10y and
10z, respectively.
The in vitro activity of the 30 compounds prepared is shown in
Tables 1 and 2. Several trends are evident from the data presented.
The C-3 alkyne substituted analogs 10a and 10b were modest
H
N
NH2
CF3
O
R1
N
N
a, b
R1
HN
H2N
+
O
O
R2
4a: R1 = H
4b: R1 = F
3a: R1 = H
3b: R1 = F
3c: R1 = Cl
5a: R2 = H
5b: R2 = Br
B-Raf kinase inhibitors (IC50s 0.552
tively), in contrast to C-3 aryl substituted analogs such as 10p
(B-Raf IC50: 0.038 M). Of the compounds lacking strongly basic
lM and 0.842 lM, respec-
4c: R1 = Cl
l
c
amine substituents on the C-3 phenyl group listed in Table 1, the
meta-amide-substituted analog 10e and pyrazole-substituted 10v
were the most potent (B-Raf IC50s: 0.057 lM and 0.084 lM, respec-
tively), raising the possibility of an additional interaction with the
protein. Molecular modeling of these two analogs (not shown)
indicates that both can potentially act as hydrogen bond donors
to the hinge region Cys532 backbone carbonyl group. Consistent
with this postulate, the substituted pyrazole analog 10w was a
H
N
NO2
e, f, a
CF3
NO2
d
O
R1
O
N
F
N
N
O
O
N
R2
7
8
modest B-Raf enzyme inhibitor (B-Raf IC50: 0.393
lM) in compar-
6a: R1 = F, R2 = H
6b: R1 = Cl, R2 = H
6c: R1 = OMe, R2 = H
6d: R1 = H, R2 = Br
ison to 10v. Despite the good enzyme activity of 10e and 10v, cel-
lular activity for these compounds was modest (10e: WM266 IC50
:
:
3.7
2.8
l
l
M, HT29 IC50: 3.2 lM, 10v: WM266 IC50: 3.7 lM, HT29 IC50
M). The para-phenylsulfonamide-substituted compound 10d
was a significantly weaker B-Raf kinase inhibitor (B-Raf IC50
>10 M).
The impact of a basic amine moiety on in vitro activity was
demonstrated by comparing compounds 10f and 10g. Thus, com-
pound 10g was approximately 3.6-fold more potent than 10f
:
Scheme 1. Reagents and conditions: (a) 3-(trifluoromethyl)benzoyl chloride, Et3N,
CH2Cl2, 0 °C to rt, 2–12 h, 80–95%; (b) DMF–DMA, reflux, 6–12 h, 90–100%; (c)
acetic acid, 80 °C, 12–24 h, 60–85%; (d) DMF–DMA, reflux, 12 h, 70%; (e) 5a, acetic
acid, 80 °C, 12 h, 82%; (f) H2, 10% Pd/C, EtOAc, rt, 48 h, 96%.
l
against B-Raf enzyme (IC50s 0.034
and had submicromolar activity in the cellular assays (WM266
IC50: 0.88 M, HT29 IC50: 0.77 M). A small decrease in activity
lM vs 0.139 lM, respectively),
the synthesis of the methoxy substituted analog 6c. Thus, reaction
of 3-nitro-6-fluoro-acetophenone 7 with N,N-dimethylformamide
dimethyl acetal produced the methoxy substituted aromatic
enaminone 8. Condensation of 8 with 5-aminopyrazole 5a, fol-
lowed by hydrogenation over 10% palladium on carbon and subse-
quent acylation with 3-(trifluoromethyl)benzoyl chloride gave 6c.
Intermediates 9a–c were prepared through the reaction of 6a–c
with N-iodosuccinimide, as shown in Scheme 2.
Final products 10a and 10b were prepared by Sonogashira
et al.8 coupling of 6d with substituted alkynes. The preparation
of the majority of the target compounds 10c–e, 10i–v, 10x,
10aa–dd (Scheme 3) was carried out by Suzuki9 chemistry, where
the appropriately substituted boronic acids or esters were coupled
with 6d, 9a–c. For certain analogs, it was desirable to further elab-
orate the C-3 substituents after the coupling reaction (Scheme 3).
Thus, following the preparation of 11a and 11b under Suzuki cou-
pling conditions, the resulting anilines were converted to the
amide-substituted targets 10f–h in the presence of benzotriazol-
1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (Pybop).
Additional target compounds were prepared as shown in
Scheme 4. Compound 10v was converted to 10w by reaction with
1-(2-chloroethyl)pyrrolidine under basic conditions. The reaction
of 6d with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan-
2-carbaldehyde under microwave conditions provided aldehyde
l
l
was observed for the meta-phenyl-substituted analog 10h com-
pared to 10g, demonstrating that para-substitution on the C-3 aryl
residue provided optimal potency. This was further confirmed by
preparation of analogs 10i–n, wherein the best potency is observed
for the para-substituted compounds 10k and 10n, with slightly de-
creased activity for the corresponding meta-substituted analogs
10j and 10m. A more significant loss in activity is seen for the
ortho-substituted compounds 10i and 10l. Similar activity was ob-
served for the pyrrolidine and methylpiperazine substituted 10o
and 10p as compared to the dimethylamine-substituted 10n.
The C-3 pyridine substituted analogs 10s and 10t, with water-
solubilizing groups, have activity comparable to the corresponding
phenyl-substituted analogs 10n–p. The HT29 cellular potencies of
10s and 10t are particularly noteworthy, with IC50s of 0.46
lM and
0.31 M, respectively. In contrast, the 3-pyridyl substituted ana-
l
logs 10q and 10r, which lack strongly basic amine substituents,
were less active in both enzyme and cellular assays. The morpho-
line-substituted pyrimidyl analog 10u was modestly active in the
enzyme assay (B-Raf IC50: 0.941 lM).
The 3-furyl analog 10x, and substituted 3-furyl analogs 10y and
10z all had modest activity against B-Raf. It appears that com-
pounds containing five-membered ring linkers to the water-solubi-
lizing groups (10w, 10y, and 10z) were generally less potent than
the corresponding six-membered ring analogs. This decrease in
activity is most likely due to a reduction in hydrophobic contact
with the enzyme when compared to the six-membered ring ana-
logs, as the C-3 meta- and para-substituted phenyl compounds
were potent enzyme inhibitors.
H
N
H
N
CF3
a
CF3
O
O
R1
R1
N
N
N
N
In Table 2 is listed a set of compounds exploring R1 substitution
on the central phenyl ring. It is noteworthy that both the fluoro and
chloro substituted compounds 10aa and 10bb, had better enzyme
activity than the parent 10v, while the methoxy substituted com-
pound 10cc was somewhat less active than 10v. The fluoro analog
10aa was an 18 nM inhibitor of B-Raf kinase and the most active of
the compounds in the pyrazolo[1,5-a]pyrimidine series. However,
the cellular activities of both 10aa and 10bb did not show a corre-
N
N
H
I
9a: R1 = F
6a-c
9b: R1 = Cl
9c: R1 = OMe
Scheme 2. Reagents and conditions: (a) N-iodosuccinimide, CH2Cl2, rt, 12–24 h,
45–60%.

D. M. Berger et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6519–6523
6521
a
O
H
N
H
N
CF3
CF3
R
B
O
O
R1
O
R1
H
or
B(OH)2
R
N
N
N
N
or
N
Het(CH2)3
N
R2
X
10a-e, 10i-v, 10x, 10aa-dd
6d, 9a-c
H
N
H
N
CF3
CF3
b
O
O
N
N
N
a
N
6d
B(OH)2
N
N
O
N
NH2
NH2
R
H
10f: R = 4-NHC(O)CH2O(CH2)2OCH3
10g: R = 4-NHC(O)CH2N(CH3)2
10h: R = 3-NHC(O)CH2N(CH3)2
11a: 4-NH2
11b: 3-NH2
Scheme 3. Reagents and conditions: (a) Pd(PPh3)4 or Pd(dppf)Cl2, Na2CO3, aq DME, lW, 175 °C, 1000–2000 s, 10–54%, or DME, 80–100 °C, 24 h, 15–18%, or CuI, (PPh3)2PdCl2,
Et3N, PPh3, NMP, 80 °C, 3 h, 18% (10a), 25% (10b); (b) Pybop, diisopropylethylamine, DMF, 25 °C, 15 h, 66–80%.
that appropriate R1 substituents can boost the B-Raf enzyme activ-
ity of certain pyrazolo[1,5-a]pyrimidine analogs, possibly by form-
ing favorable interaction within hydrophobic pocket.
Unfortunately, this did not provide a corresponding improvement
in cellular potency for the analogs prepared.
H
N
H
N
CF3
CF3
a
a
O
O
N
N
N
a
N
While most of the compounds lacking a basic amine substituent
were insoluble in a pH 7.4 aqueous buffer (e.g., solubility of 10d,
N
N
10r, and 10u: 0
hanced solubility. For example, the C-3 phenyl-substituted 10m
was slightly soluble in pH 7.4 aqueous buffer (4 g/mL). The C-3 al-
kyne substituted analog 10b was somewhat more soluble (8 g/mL
lg/mL), the basic amine groups modestly en-
N
N
N
10v
10w
N
l
H
l
N
at pH 7.4), but far less potent in vitro. Thus, while a significant
amount of ligand–protein hydrophobic contact is required to pro-
vide the observed level of potency, this considerably reduces the
aqueous solubility of these inhibitors, even with attached basic
amine residues. An issue generally encountered with analogs
substituted with dimethylamine or N-methylpiperazine groups
was poor microsomal stability (for example, rat microsome t1/2
for 10b, 10n, and 10p was 3, 6, and 3 min, respectively). In contrast,
analogs substituted with cyclic amines morpholine or pyrrolidine
were considerably more stable (rat microsome t1/2 for 10a, 10o,
and 10w was >30, 27, and 26 min, respectively).
Several attempts were made to co-crystallize these analogs
with B-Raf wild-type enzyme. Of the compounds examined, 10n
was successfully co-crystallized with B-Raf at a resolution of
2.9 Å (PDB code: 3II5). A depiction of 10n bound to B-Raf, based
on the crystallographic coordinates is shown in Figure 2. As shown,
compound 10n is bound to the inactive (DFG-out) conformation of
the enzyme. Two hydrogen bonds are formed, one from the amide
carbonyl of 10n to Asp593, the other from the amide NH group to
Glu500. There is no hydrogen bond to the hinge region. Hydropho-
bic binding interactions of the trifluoromethylbenzamide moiety
with the enzyme appear to contribute significantly to overall bind-
ing affinity of this analog, since it fits well in a hydrophobic pocket
consisting of Ile 512, Leu 566, His 573, and Ile 591. Additionally, the
C-3 phenyl ring makes significant hydrophobic interactions with
the residues of Ile 462 and Leu 596 of the enzyme. The information
H
H
N
N
CF3
CF3
O
O
N
c
b
N
N
N
6d
N
N
12
NR1R2
10y: NR1R2 = pyrrolidine
10z: NR1R2 = N-ethylpiperidine
O
O
O
Scheme 4. Reagents and conditions: (a) 1-(2-chloroethyl)pyrrolidineÁHCl, Cs2CO3,
Bu4NI, DMF, 65 °C, 24 h, 43%; (b) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)furan-2-carbaldehyde, Pd(PPh3)4, Na2CO3, DME,
lW, 175 °C, 1000 s, 33%; (c)
NHR1R2, Na(OAc)3BH, HOAc, NMP, CH2Cl2, 25 °C, 15 h, 38% (10y), 89% (10z).
sponding improvement over compound 10v. Based on the
enhanced enzyme activity of the C-7 fluorophenyl-substituted
10aa versus phenyl-substituted 10v, compound 10dd was pre-
pared in an effort to further boost B-Raf activity versus the rela-
tively potent compound 10t. In this case, both compounds had
comparable activity in both enzyme and cellular assays. It appears

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D. M. Berger et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6519–6523
Table 1
B-Raf kinase and cellular activity of pyrazolopyrimidine analogs 1, 10a–z
H
N
CF3
O
N
N
N
R2
R2
B-Raf IC50
(lM)
WM 266-4 IC50
(
lM)
HT29 IC50 (lM)
a,b
a
a
Compd
1
CO2Et
1.50
6.2
7.0
10a
10b
10c
10d
10e
10f
10g
10h
10i
C„C(CH2)3-morpholine
C„C(CH2)3-N-methylpiperazine
4-Ph-N(CH3)2
4-Ph-SO2N(CH3)2
3-Ph-CONH2
4-Ph-NHC(O)CH2OCH2CH2OCH3
4-Ph-NHC(O)CH2N(CH3)2
3-Ph-NHC(O)CH2N(CH3)2
2-Ph-CH2CH2–N(CH3)2
3-Ph-CH2CH2–N(CH3)2
4-Ph-CH2CH2–N(CH3)2
2-Ph-CH2–N(CH3)2
3-Ph-CH2–N(CH3)2
4-Ph-CH2–N(CH3)2
4-Ph-CH2-pyrrolidine
4-Ph-CH2-N-methylpiperazine
3-Pyridyl
0.552
0.842
0.308
>10
5.5
1.4
>10
ND
3.7
>10
0.88
2.46
2.6
0.74
0.74
2.9
1.3
0.92
2.1
0.82
3.7
3.4
0.92
0.74
ND
3.7
3.3
ND
3.2
3.5
2.6
ND
ND
3.2
3.9
0.77
0.8
0.84
0.65
0.73
2.9
0.057
0.139
0.034
0.040
0.318
0.041
0.026
0.117
0.044
0.024
0.020
0.038
0.113
0.112
0.030
0.044
0.941
0.084
0.393
0.326
0.362
0.219
10j
10k
10l
10m
10n
10o
10p
10q
10r
10s
10t
10u
10v
10w
10x
10y
10z
0.8
0.78
0.65
0.7
ND
2.4
0.46
0.31
ND
2.8
3-Pyridinyl-6-NH2
3-Pyridinyl-6-NHCH2CH2N(CH3)2
3-Pyridinyl-6-N-methylpiperazine
5-Pyrimidyl-2-morpholine
4-Pyrazolyl
4-Pyrazolyl-1-CH2CH2-pyrrolidine
3-Furyl
2.8
ND
2.2
3-Furyl-5-CH2-pyrrolidine
3-Furyl-5-CH2-N-ethylpiperazine
2.9
1.7
a
Values are averages of more than two experiments (ND = not done).
B-Raf IC50s were determined as previously described.5
b
Table 2
B-Raf kinase and cellular activity of pyrazolopyrimidine analogs 10v, 10aa–dd
O
CF3
NH
R1
N
N
N
R2
Compd R1
R2
B-Raf
IC50
Ma,b
WM 266-4
HT29
IC50
Ma
,
IC50
,
l
Ma
,
l
l
10v
H
F
Cl
4-Pyrazolyl
4-Pyrazolyl
4-Pyrazolyl
0.084
0.018
0.042
0.098
0.030
3.7
6.6
ND
ND
2.8
2.8
2.9
2.9
Figure 2. Representation of compound 10n bound to wild-type B-Raf based on the
crystallographic data obtained at 2.9 Å resolution.
10aa
10bb
10cc
10dd
OMe 4-Pyrazolyl
3-Pyridinyl-6-N-
methylpiperazine
F
0.81
0.63
greater activity versus the ortho-substituted analogs. Thus, the ob-
served binding mode of 10n is consistent with the SAR of this class
of compounds.
a
Values are averages of more than two experiments (ND = not done).
B-Raf IC50s were determined as previously described.5
b
Having determined the nature of the key interactions of com-
pound 10n with B-Raf kinase through the crystallographic data,
this compound was profiled against a panel of 16 additional ki-
provided by this crystal structure indicates that the meta- and
para-basic amine substituted C-3 aromatics can readily reach the
aqueous environment around the enzyme, accounting for their
nases. Compound 10n was equipotent against c-Raf (IC50
:
0.025 M) Moderate selectivity was observed for compound 10n
l

D. M. Berger et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6519–6523
6523
versus p38
high selectivity was observed versus CDK2, CDK4, PKC
JNK1, MK2, PKA, Src, MKK6, PLK1, p70S6K, PI3 K , and PDK1
(IC50s: >2 M).
a
(IC50: 0.216
l
M) and CAMKII (IC50: 0.822
l
M), while
References and notes
a, IKKb,
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a
l
In conclusion, a series of pyrazolo[1,5-a]pyrimidines was pre-
pared that showed good activity as B-Raf inhibitors, despite lacking
a hinge-binding interaction. Optimization of these compounds pro-
vided potent analogs 10s and 10t, which effectively inhibited pro-
liferation of HT29 cells at submicromolar concentrations. It is
noteworthy that the potency achieved for this series is similar to
that observed for pyrazolo[1,5-a]pyrimidine analogs with hinge re-
gion binding residues.6 Further optimization of B-Raf inhibitory
activity could potentially be achieved by incorporating hinge-bind-
ing groups into these structures to enhance potency. Our continued
efforts to enhance the binding potencies and physical properties of
these B-Raf inhibitors will be described in future publications.
3. Xing, M. Endocr. Relat. Cancer 2005, 12, 245.
4. McCubrey, J. A.; Milella, M.; Tafuri, A.; Martelli, A. M.; Lunghi, P.; Bonati, A.;
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Collins, K.; Wojciechowicz, D.; Mallon, R. Bioorg. Med. Chem. Lett. 2009, 19, 2735.
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Frommer, E.; Kim, S.; Collins, K.; Wojciechowicz, D.; Mallon, R. Abstracts of
Papers, 235th ACS National Meeting, New Orleans, LA, United States, April 6–10,
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Acknowledgments
7. Ciszewski, G.; Gopalsamy, A.; Levin, J. I.; Kim, K.-H.; Hu, Y.; Lee, F.; Feldberg, L.;
Frommer, E.; Kim, S.; Collins, K.; Wojciechowicz, D.; Mallon, R. Abstracts of
Papers, 235th ACS National Meeting, New Orleans, LA, United States, April 6–10,
2008; MEDI-080.
8. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.
9. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 50, 4467.
We thank Drs. Tarek Mansour and Robert Abraham for their sup-
port of this work. We also thank the members of the Wyeth Chemical
Technologies group for analytical and spectral determination.