Design and synthesis of 3-(2-pyridyl)pyrazolo[1,5-a]pyrimidines as potent CRF1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2004.05.056

A series of 3-(2-pyridyl)pyrazolo[1,5-a]pyrimidines was designed and synthesized as antagonists for the corticotrophin-releasing factor-1 (CRF ₁) receptor. Several compounds such as 20c (K_i=10nM) exhibited good binding affinities at the CRF₁ receptor. In addition, 20c had adequate solubility in water.

Full text of DOI:10.1016/j.bmcl.2004.05.056

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3943–3947
Design and synthesis of 3-(2-pyridyl)pyrazolo[1,5-a]pyrimidines as
potent CRF1 receptor antagonists
Charles Q. Huang,* Keith M. Wilcoxen, Dimitri E. Grigoriadis,
James R. McCarthy and Chen Chen*
Department of Medicinal Chemistry and Department of Pharmacology, Neurocrine Biosciences, Inc.,
10555 Science Center Drive, San Diego, CA 92129, USA
Received 23 February 2004; accepted 24 May 2004
Available online
Abstract—A series of 3-(2-pyridyl)pyrazolo[1,5-a]pyrimidines was designed and synthesized as antagonists for the corticotrophin-
releasing factor-1 (CRF1) receptor. Several compounds such as 20c (Ki ¼ 10 nM) exhibited good binding affinities at the CRF1
receptor. In addition, 20c had adequate solubility in water.
Ó 2004 Elsevier Ltd. All rights reserved.
Corticotropin-releasing factor (CRF), a neuropeptide
isolated from mammalian brain,1 has been implicated as
the mediator for the integrated physiological response to
stress.2 CRF acts via two receptor subtypes, CRF1, and
CRF2, which belong to the Class B G-protein-coupled
receptor superfamily.3 The binding of CRF to CRF1
receptor in the hypothalamus is responsible for the in-
creased release of ACTH and other peptides.4 Inhibition
of CRF1 receptors has been shown to reduce ACTH
levels in plasma of stressed animals.5 Many small mole-
cules from different chemical classes have been identified
as potent CRF1 receptor antagonists (1–9, Fig. 1).6 Al-
though several of them have exhibited brain penetration
and oral activity in anxiety and depression animal mod-
els, many earlier reported CRF1 antagonist compounds,
such as 1–6,7 suffer from high lipophilicity and poor
R
Cl
F
S
N
Cl
H
N
N
N
NH
N
N
N
N
N
N
N
N
N
N
Cl
Cl
O
R =H: CP-124,526 (1)
R=Me: Antalarmin (2)
CRA1000 (5)
DMP904 (4)
NBI 27914 (3)
O
O
O
S
O
N
Cl
NH
2
N
O
N
N
N
Cl
NH
N
N
N
O
Cl
N
N
N
Cl
N
O
Cl
F
CRA 0450 (9)
DMP696 (8)
NBI 30545 (7)
SSR125543A (6)
Figure 1. Some small molecule CRF1 receptor antagonists.
* Corresponding authors. Tel.: +1-858-658-7735; fax: +1-858-658-7601 (C.Q.H.); tel.: +1-858-658-7634; fax: +1-858-658-7619 (C.C.); e-mail
addresses: chuang@neurocrine.com; cchen@neurocrine.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.05.056

3944
C. Q. Huang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3943–3947
Table 1. Calculated log P
lowed by decarboxylation under acidic conditions,
afforded the substituted 3-chloro-5-trifluoromethyl-
pyridin-2-ylacetonitrile (55% yield for two steps), which
was then acetylated with ethyl acetate in the presence of
sodium hydride to afford the ketone 11a in quantitative
yield. Compounds 11b and 11c were synthesized in a
similar manner (13% and 40%, respectively, from 10b
and 10c).15 Alternatively, reaction of 2-chloropyridine
10d or 10e with acetoacetonitrile sodium salt, obtained
from 2-methylisoxazole and sodium ethoxide,16 afforded
the 2-(2-pyridyl)acetoacetonitrile 11d in 61% yield, or
11e in 19% yield. Cyclizations of 11a–e with hydrazine
hydrobromide in a mixture of ethanol–water (10:1) at
reflux gave the corresponding 3-amino-4-(2-pyridyl)-5-
methylpyrazoles 12a–e in good yields (40–65%), which
were subjected to a second cyclization with ethyl aceto-
acetate in refluxing dioxane to give the pyrazolo[1,5-
a]pyrimidinones 13a–e as white solids (18–52% yield).
Conversion of 13 to the corresponding 7-chloropyraz-
olo[1,5-a]pyrimidines 14a–e was accomplished in 80–
91% yields with POCl3 in refluxing acetonitrile. Finally,
the target compounds 15–19 were obtained by the
reaction of chloropyrimidines 14 with an alkylamine in
refluxing acetonitrile in excellent yields (80–90%).
Compound
C log Pa
1
2
3
4
5
6
7
8
9
8.43
8.89
9.71
4.80
5.98
7.75
2.65
3.32
3.89
a ACD/LogP software.
water solubility.8 These undesirable properties make it
more difficult to develop these compounds into phar-
maceutical agents. For example, CP-124,526 exhibits a
very long half-life associated with high volume distribu-
tion in rats.9 Recent efforts on discovery of more
hydrophilic CRF1 antagonists have generated com-
pounds such as 7–9 with more suitable physicochemical
properties.10 By using ACD/LogP software,11 we calcu-
lated C log P values of 1–9 (Table 1) to assess the relative
lipophilicities of these compounds. C log P values of
compounds 1–3, 5, and 6 are P 6, much higher than that
of compounds 7–9, which have C log P values of <4. In
our efforts to identify potent CRF1 antagonists with
desirable physicochemical properties, we synthesized
NBI 30545 (7)10a by incorporation of polar alkoxy groups
into the 3-phenylpyrazolo[1,5-a]pyrimidine molecules.12
The calculated log P of 7 was 3.18, a very desirable value
for a CNS agent.13 As an alternative, replacement of the
lipophilic 3-phenyl group of the 3-phenylpyrazolo[1,5-
a]pyrimidine with a weakly basic and hydrophilic pyr-
idine moiety should also decrease the lipophilicity of this
class of compounds. In addition, alternation of substit-
uents on the pyridine ring will change the basicity and
hydrophilicity. Here we report the synthesis and struc-
ture–activity relationships of the 3-(2-pyridyl)pyraz-
olo[1,5-a]pyrimidines as CRF1 receptor antagonists.
Compounds 18 and 19 were further modified as shown in
Schemes 2 and 3, respectively. Palladium-catalyzed
hydrogenation of 18 gave the corresponding amino
analog 20a, which was further elaborated to various
derivatives. Alkylation of 20a with a standard reductive
amination protocol gave 5-methylamino (20b), dimethyl-
amino (20c), diethylamino (20d) and piperidin-1-yl
compound (20e), respectively, with the corresponding
aldehyde. 20a was also subjected to a Sandmeyer chlo-
rination protocol to afford the chlorinated compound
20g, a nitroso by-product 20f was isolated under these
conditions. 5-Fluoro- (20h) and 5-iodopyridine (20i)
were synthesized in a similar manner. Diazotization of
compound 20a, followed by methanol treatment, affor-
ded the desired 5-methoxy analog (20j), along with a
5-hydroxypyridyl compound 20k and a reduced by-
product 20l from this reaction.
A general synthetic route14 for the preparation of 3-(2-
pyridyl)-7-alkylaminopyrazolo[1,5-a]pyrimidines 15–19
was developed as outlined in Scheme 1. Reaction of 2,3-
dichloro-5-trifluoromethylpyridine 10a with tert-butyl
cyanoacetate in the presence of sodium hydride, fol-
Similarly, 3-nitropyridine 19 was reduced to give the
corresponding 3-amino analog 21a, which was further
O
2
2
2
2
N
N
R
R
R
R
OH
NH
NH
N
Cl
c
d
a or b
CN
N
N
N
N
N
1
2
1
1
1
R
R
R
R
10a-e
11a-e
13a-e
12a-e
1
2
a: R = CF , R = Cl;
3
2
3
R
2
3
1
N
N
2
R
4
b: R = R = Cl;
N
N
R
R
Cl
e
f
N
1
2
4
c: R = Cl, R = H
N12
N
1
5
N
1
2
N
1
R
d: R = NO , R = Me;
6
2
R
1
2
e: R = Me, R = NO ;
2
15-19
14a-e
Scheme 1. Synthesis of the 3-(2-pyridyl)pyrazolo[1,5-a]pyridimidines: (a) MeC(ONa) ¼ CHCN/DMSO; (b) (i) NCCH2COOBu-t/t-BuOK/THF, (ii)
TFA, (iii) NaH/EtOAc/THF; (c) NH2NH2HBr/H2O/EtOH; (d) ethyl acetoacetate/dioxane/reflux; (e) POCl3/reflux; (f) R3R4NH/acetonitrile/reflux.

C. Q. Huang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3943–3947
3945
NPr2
N
NPr2
N
NPr2
N
NPr2
N
N
N
N
N
N
N
N
N
+
N
N
N
N
I
ON
Cl
F
20h
20i
20f
20g
e
c
d
NPr2
NPr2
N
NPr2
N
N
N
N
N
N
N
a
b
N
N
N
N
1
1
20b: R = NHMe;
H2N
R
O N
2
1
20c: R = N Me ;
18
20a
2
1
20d: R = NEt ;
2
f
1
20e: R =
N
NPr
N
NPr
NPr
2
2
2
N
N
N
N
N
N
+
+
N
N
N
N
N
MeO
HO
20l
20j
20k
Scheme 2. Chemical modification of the 5-position of the pyridine: (a) H2/Pd–C/EtOH; (b) RCHO/NaCNBH3/AcOH; (c) NaNO2/HCl/CuCl;
(d) NaNO2/HBF4; (e) NaNO2/HCl/CuI; (f) NaNO2/HCl/MeOH.
NPr
N
NPr
N
NPr
2
2
2
N
N
N
N
N
N
a
b
N
2
N
N
N
NO
NH
R
2
2
2
21a
19
21b: R = NHMe;
2
21c: R =NMe
2
c
d
NPr
NPr
N
NPr
2
NPr
2
2
2
N
N
N
N
N
N
N
N
+
+
N
OMe
N
NO
N
OH
N
N
N
N
Cl
21d
21g
21e
21f
Scheme 3. Chemical modification of the 3-position of the pyridine: (a) H2/Pd–C/EtOH; (b) aq CH2O/NaCNBH3/AcOH; (c) NaNO2/HCl/MeOH;
(d) NaNO2/HCl/CuCl.
modified as showed in Scheme 3. Methylation of 21a with
a standard reductive amination protocol gave the 3-
methylamino (21b) and 3-dimethylamino analog (21c).
Compound 21a was converted to the corresponding 3-
methoxy analog 21d by diazotization, followed by meth-
anol treatment. Sandmeyer chlorination of 21a provided
the 3-chloro analog 21e, 3-nitroso (21f) and 3-hydroxy
compound (21g) were obtained as two by-products.
ranging from 1 nM to 10 lM. The structure–activity rela-
tionships of these compounds are summarized in Tables 2
and 3. Selected compounds were also measured for their
abilities to inhibit CRF-stimulated c-AMP production in
cells expressing the human CRF1 receptor to assess their
functional antagonism in a manner similar to that previ-
ously reported.18 Antalarmin (2), which was utilized as a
positive control, demonstrated potent binding and func-
tion activities (Ki ¼ 2:6 nM and c-AMP IC50 ¼ 16 nM).
These compounds were tested for their binding affinities at
the cloned human CRF1 receptor in a competition binding
assay as described,17 and the Ki values were determined
from concentration–response curves using concentrations
Results from a quick survey at the 7-position of the
3-(2-pyridyl)pyrazolo[1,5-a]pyrimidine on 15 and 16
using the preferred dialkylamine side-chains of the

3946
C. Q. Huang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3943–3947
Table 2. SAR of the 7-amino group of 3-(2-pyridyl)pyrazolopyrimidines (15–19)
3
R
2
N
4
R
N
R
N
N
N
1
15-19
R
Compound
R1
R2
R3NR4
Ki (nM)a
C log Pb
15a
15b
15c
15d
15e
15f
16a
16b
16c
16d
17
CF3
CF3
CF3
CF3
CF3
CF3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
NPr2
PrNCH2Pr-c
PrNBu-n
1.2
0.8
1.2
1.7
1.1
12
5.91
5.75
6.44
6.74
6.98
3.62
5.18
5.01
4.03
2.88
4.44
3.81
3.74
PrNCH2Ph
N(Bu-n)2
N(CH2CH2OMe)2
NPr2
3.2
3.9
3.2
78
Cl
Cl
PrNCH2Pr-c
PrNCH2CH2OMe
N(CH2CH2OMe)2
NPr2
Cl
Cl
88
18
19
NO2
Me
Me
NO2
NPr2
NPr2
9.1
14
a Ki values were average of at least two independent measurements.
b ACD/LogP software.
Table 3. SAR of modified pyridine analogs (20 and 21)
The structure–activity relationship study of the pyridine
ring was performed on the 7-dipropylaminopyraz-
olo[1,5-a]pyrimidine. The 3,5-dichloropyridin-2-yl com-
pound 16a (Ki ¼ 3:2 nM) was 27-fold better in binding
affinity than the 5-chloropyridin-2-yl analog 17
(Ki ¼ 88 nM), and this again implies the importance of
the orthogonal relationship between the pyridyl ring and
the bicyclic core for high CRF1 receptor binding.7b;19
Since the nitrogen atom of a pyridine is smaller than a
CH moiety of a phenyl group, an ‘ortho’-substituted
pyridine is expected to be required for it to achieve this
orthogonal conformation. The binding affinity was
further improved when a more lipophilic trifluoromethyl
group was incorporated at the 5-position of the pyridine
(15a, Ki ¼ 1:2 nM).
2
N
R
N
N
N
N
1
20, 21
Ki (nM)a
R
Compound R1
R2
C log Pb
20a
20b
20c
20d
20e
20f
20g
20h
20i
NH2
Me
Me
Me
Me
85
40
3.41
3.29
4.76
5.82
5.27
4.90
3.97
4.00
5.13
4.33
3.95
4.08
3.32
2.98
4.76
4.81
5.08
4.18
3.69
NHMe
NMe2
NEt2
10
13
N(CH2)5-c Me
17
NO
Cl
Me
Me
Me
Me
Me
Me
Me
100
6.7
19
F
I
6.6
10
20j
OMe
OH
H
Further SAR studies on the 3- and 5-substituted-pyridyl
compounds are summarized in Table 3. The 3-methyl-5-
nitropyridin-2-yl compound 18 exhibited good binding
to the receptor (Ki ¼ 9:1 nM), while the more hydro-
philic amino-analog 20a (Ki ¼ 85 nM) was almost 10-
times lower in binding affinity. Compound 20a could be
rescued by methylation (20c, Ki ¼ 10 nM) or ethylation
(20d, Ki ¼ 13 nM) of the NH2 moiety. A group as large
as a piperidine was tolerated at this position (20e,
Ki ¼ 17 nM), although 20c was the preferred compound
since its lipophilicity was lower than the other two (the
C log P value was 4.76 for 20c). Among the halogenated
pyridine analogs (20g–i), the two more lipophilic 5-
chloro and 5-iodo-derivatives 20g and 20i exhibited
better binding than the 5-fluoro analog 20h. The 5-
methoxypyridin-2-yl analog 20j also possessed good
binding affinity (Ki ¼ 10 nM) and desirable hydrophi-
licity (C log P ¼ 4:33). However, the 5-hydroxy pyridine
(20k, Ki ¼ 530 nM) had lower binding affinity than the
unsubstituted pyridine 20l (Ki ¼ 110 nM).
20k
20l
530
110
40
21a
21b
21c
21d
21e
21f
21g
Me
Me
Me
Me
Me
Me
Me
NH2
NHMe
NMe2
OMe
Cl
13
23
25
6.2
>10,000
>10,000
NO
OH
a Ki values were average of at least two independent measurements.
b ACD/LogP software.
corresponding 3-phenylpyrazolo[1,5-a]pyrimidines sug-
gested the dipropylamino moiety was one of the best
groups at this position for high CRF1 receptor binding
affinity (Table 2). The N-propyl-N-2-methoxyethyl-
amine derivative 16c (Ki ¼ 3:2 nM) possessed similar
binding affinity as the corresponding dipropylamine 16a
(Ki ¼ 3:2 nM). However, the calculated log P value of
16c was a log unit lower than that of 16a. These results
certainly offers a possible alternative to design analogs
with lower lipophilicity from this series.
Substitution at the 3-position of the pyridine ring was
studied on derivatives from the 3-nitropyridine 19,
which possessed a Ki of 14 nM. Interestingly, among the

C. Q. Huang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3943–3947
3947
5. Hernandez, J.-F.; Kornreich, W.; Rivier, C.; Miranda, A.;
Yamamoto, G.; Andrews, J.; Tache, Y.; Vale, W.; Rivier,
J. J. Med. Chem. 1993, 36, 2860.
6. For a recent review, see: Grigoriadis, D. E.; Haddach, M.;
Ling, N.; Saunders, J. Current Med. Chem. 2001, 1,
63.
3-aminopyridin-2-yl analogs (21a–c), the N,N-dimeth-
ylamino derivative (21c, Ki ¼ 23 nM) was not superior
in binding to the corresponding mono-methyl analog
(21b, Ki ¼ 13 nM). On the other hand, a chloro-substi-
tution at this 3-position gave a compound (21e) with
high binding affinity (Ki ¼ 6:2 nM). In comparison, a
methoxy group at this position was less favored and 21d
(Ki ¼ 25 nM) was 4-fold less active than 21e. A hydroxy
group at this position completely abolished the binding
of 21g to the receptor (Ki > 10 lM).
7. (a) Schulz, D. W.; Mansbach, R. S.; Sprouse, J.; Braselton,
J. P.; Collins, J.; Corman, M.; Dunaiskis, A.; Faraci, S.;
Schmidt, A. W.; Seeger, T.; Seymour, P.; Tingley, F. D.,
III; Winston, E. N.; Chen, Y.; Heym, J. Proc. Natl. Acad.
Sci. U.S.A. 1996, 93, 10477; (b) Chen, C.; Dagnino, R., Jr.;
De Souza, E. B.; Grigoriadis, D. E.; Huang, C. Q.; Kim,
K. I.; Liu, Z.; Moran, T.; Webb, T. R.; Whitten, J. P.; Xie,
Y. F.; McCarthy, J. R. J. Med. Chem. 1996, 39, 4358; (c)
Gilligan, P. J.; Baldauf, C.; Cocuzza, A.; Chidester, D.;
Zaczek, R.; Fitzgerald, L. W.; McElroy, J.; Smith, M. A.;
Shen, H. L.; Saye, J. A.; Christ, D.; Trainor, G.;
Robertson, D. W.; Hartig, P. Bioorg. Med. Chem. 2000,
8, 181; (d) Arai, K.; Ohata, H.; Shibasaki, T. Neurosci.
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berg, R.; Jung, M.; Gully, D.; Roger, P.; Geslin, M.;
Scatton, B.; Maffrand, J.-P.; Soubrie, P. J. Pharmacol.
Exp. Ther. 2002, 301, 333.
Several compounds from this 3-(2-pyridyl)pyrazolo[1,5-
a]pyrimidine series were identified to possess low
nanomolar binding affinities (20c, 20g, 20j, 21b, and
21e). One advantage of using a pyridine ring to replace
the 3-phenyl group is to increase hydrophilicity of this
series of compounds. The calculated log P values for
many of these pyridine derivatives were around 4
(Tables 2 and 3), which is about one log unit lower than
the corresponding phenyl analogs. For example, 20c
(C log P ¼ 4:76), 20j (C log P ¼ 4:33), 21b (C log P ¼
2:98) and 21e (C log P ¼ 4:81) could be considered as
possessing suitable lipophilicity.
8. Hsin, L.-W.; Tian, X.; Webster, E. L.; Coop, A.; Caldwell,
T. M.; Jacobson, A. E.; Chrousos, G. P.; Gold, P. W.;
Habib, K. E.; Ayala, A.; Eckelman, W. C.; Contoreggi, C.;
Rice, K. C. Bioorg. Med. Chem. 2002, 10, 175.
Selected compounds from this series demonstrated their
functional antagonism by dose-dependent inhibition of
CRF-stimulated c-AMP release from cells expressing
the CRF1 receptor.18 For example, 16a, 18 and 20c
exhibited IC50 values of 49, 180, and 150 nM, respec-
tively, in this assay. Importantly, the hydrochloride salt
of 20c had >2 mg/mL of solubility in water, which
should be adequate for further pharmaceutical devel-
opment.
9. Keller, C.; Bruelisauer, A.; Lemaire, M.; Enz, A. Drug
Metab. Dispos. 2002, 30, 173.
10. (a) Wilcoxen, K.; Chen, C.; Huang, C.; Haddach, M.; Xie,
Y.; Wing, L.; Grigoriadis, D. E.; De Souza E. B.;
McCarthy, J. R. 217th ACS National Meeting, Anaheim,
CA, 21–25 March, 1999; Book of Abstract: MEDI 002; (b)
Li, Y.; Hill, G.; Wong, H.; Kelly, N.; Ward, K.;
Pierdomenico, M.; Ren, S.; Gilligan, P.; Grossman, S.;
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Steckler, T. Eur. J. Pharmacol. 2004, 485, 145.
In conclusion, we designed and synthesized a series of
3-(2-pyridyl)pyrazolo[1,5-a]pyrimidines to address the
high lipophilicity and poor water solubility of some
analogs from this series reported earlier.12 Calculation
of lipophilicity using ACD/LogP software suggests that
many of the pyridine compounds possess adequate
lipophilicity/hydrophilicity. Several compounds bearing
a substituted pyridine ring exhibited good binding
affinities at the CRF1 receptor. For example, compound
20c had a C log P value of 4.76, and as a CRF1 receptor
antagonist, it had a Ki value of 10 nM in a competition
binding assay and an IC50 of 150 nM in inhibition of
CRF-stimulated c-AMP production. In addition, 20c
also had relatively good solubility in water.
11. Advanced Chemistry Development, 90 Adelaide Street
West, Toronto, Ontario, M5H 3V9, Canada.
12. (a) Wustrow, D. J.; Capiris, T.; Rubin, R.; Knobelsdorf, J.
A.; Akunne, H.; Davis, M. D.; MacKenzie, R.; Pugsley, T.
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McCarthy, J. R.; Moran, T. J.; Wilcoxen, K. M. WO
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