Pyrazolo[1,5-α]pyrimidines: Estrogen receptor ligands possessing estrogen receptor β antagonist activity

5872

J. Med. Chem. 2004, 47, 5872-5893

Pyrazolo[1,5-a]pyrimidines: Estrogen Receptor Ligands Possessing Estrogen

Receptor â Antagonist Activity

Dennis R. Compton,^†Shubin Sheng,^‡Kathryn E. Carlson,^†Natalie A. Rebacz,^†In Young Lee,^†

Benita S. Katzenellenbogen,^‡and John A. Katzenellenbogen*^,†

Department of Chemistry and Department of Molecular and Integrative Physiology, University of Illinois,

600 South Matthews Avenue, Urbana, Illinois 61801

Received May 19, 2004

In our search for novel subtype-selective estrogen receptor (ER) ligands, we have examined

various heterocyclic units as core structural elements. Here, we have investigated the fused,

bicyclic pyrazolo[1,5-a]pyrimidine core, which is a system that allows for analogues to be readily

assembled in a library-like fashion. This series of pyrazolo[1,5-a]pyrimidine ER ligands provided

us with a new pharmacological profile for an ER ligand: compounds that are passive on both

ERs, with a distinct potency selectivity in favor of ERâ. The most distinctive ligand in this

series, 2-phenyl-3-(4-hydroxyphenyl)-5,7-bis(trifluoromethyl)-pyrazolo[1,5-a]pyrimidine, was 36-

fold selective for ERâ in binding. Curiously, on the basis of molecular modeling, the ERâ binding

selectivity of compounds in this series appears to be derived from differing orientations that

they adapt in the ligand binding pockets of ERR vs ERâ. In transcription assays this

pyrazolopyrimidine was fully effective as an ERâ antagonist while exhibiting no significant

activity on ERR. Thus, this ligand functions as a potency- and efficacy-selective ERâ antagonist

that would abrogate estrogen action through ERâ with minimal effects on its activity through

ERR; as such, it could be used to study the biological function of ERâ.

Introduction

benzoxazole^24,25and benzothiazole^25,26ERâ-selective

ligands. The majority of these fused heterocycles contain

only a single heteroatom.

The estrogen receptor (ER)^1,2is a member of the

superfamily of ligand-regulated nuclear transcription

factors that mediates the action of estrogens and has

as its primary endogenous ligand 17â-OH estradiol (E2).

The ER is widely distributed throughout the body, being

found in reproductive tissues (uterus and breast) but

also in bone, brain, and the cardiovascular system. The

ER is a pharmaceutical target of interest for the

prevention and treatment of breast cancer, as well as

for hormone replacement therapy to prevent osteoporo-

sis and mitigate menopausal symptoms.^3-5The term

selective estrogen receptor modulators (SERMs) has

been coined to describe ER ligands that show a desirable

balance of tissue-selective effects, being agonists in the

brain, liver, bone, and cardiovascular system and being

antagonists in the breast and uterus.^1,2,6,7The ability

to optimally target the ER is complicated by the pres-

ence of two receptor subtypes, ERR and ERâ, themselves

having differing tissue distributions.^8,9These subtypes

share high sequence homology in the binding pocket,

with 24 of the 26 amino acid residues being identical

and the two differences being conservative.¹⁰

To extend the structural scope of ER ligands, we are

exploring fused bicyclic systems that contain multiple

heteroatoms. In this search, we sought to design a

ligand core structure that could be varied in size and

would embody multiple nitrogen atoms to have some

polarity while still being largely hydrophobic. To this

end, we began exploring pyrazolo[1,5-a]pyrimidines as

a core scaffold onto which additional substituents could

be attached to produce ER ligands. Although a few

examples of pyrazolo[1,5-a]pyrimidine pharmaceuticals

can be found in the literature,^27-30the substituents thus

far described are not appropriate for ER ligands.

Figure 1 illustrates the numbering system used for

pyrazolo[1,5-a]pyrimidines and our vision of how the

pyrazolo[1,5-a]pyrimidine system might act as a scaffold

for the construction of an ER ligand. Originally, we

imagined that it might be possible for the pyrimidine

ring of a 6-hydroxypyrazolo[1,5-a]pyrimidine to function

as the A-ring mimic of estradiol, in a fashion that would

be geometrically congruent with the orientation of other

[6,5]-fused bicyclic heterocyclic core ER ligands such as

raloxifene. However, on the basis of our initial work on

this system, described elsewhere, we believe that this

is unlikely.³¹Thus, we have pursued an alternative

approach, substituting the pyrazolo[1,5-a]pyrimidine

core with aromatic rings at the 2 and 3 positions. By

making at least one of these aromatic rings a phenol,

we would provide a functionality that is capable of

hydrogen-bonding that can potentially act as an A-ring

mimic of the natural ligand E2, in a “pendant phenol”

orientation thought to be adopted by certain other fused

heterocyclic systems^32-34and illustrated in certain

The ER is able to accept a wide variety of structurally

distinct ligands into its binding pocket, a topic that has

recently been reviewed by Anstead,¹¹Gao,¹²and Mee-

gan.¹³Among these diverse systems are numerous

heterocycles^14-17including fused bicyclic systems such

as benzothiophenes,^18,19indoles,²⁰benzofurans,²¹and

indolizines^22,23(Figure 1), as well as recently reported

* To whom correspondence should be addressed. Phone: 217 333

6310. Fax: 217 333 7325. E-mail: jkatzene@uiuc.edu.

^†Department of Chemistry.

^‡Department of Molecular and Integrative Physiology.

Published on Web 10/15/2004

Pyrazolo[1,5-a]pyrimidines

Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 5873

Figure 1. Fused heterocyclic systems as ER ligands. Numbering system of pyrazolo[1,5-a]pyrimidine rings and structural design

for use as an ER ligand.

Scheme 1

crystal structures, at least in ERâ.^10,35In addition to

orienting the phenolic hydroxyl group para to the

heterocyclic core, we wanted to examine systems with

two para hydroxyl groups, as well as systems having

one para and one meta hydroxyl group. Changing the

size of the substituents at the 5 and 7 positions would

vary the hydrophobicity and the size of the system,

which might lead to improved binding. The pyrazolo-

[1,5-a]pyrimidine core itself would act as a hydrophobic,

although somewhat polar, portion of the ligand to assist

in filling the central space within the binding pocket.

In this study we evaluated the ERR and ERâ binding

affinities of 44 pyrazolo[1,5-a]pyrimidines and studied

the transcriptional efficacy of 11 of the most interesting

of these. In this series, we have observed compounds

having binding affinities as high as 2% that of E₂, as

well as ligands that exhibited an ERR binding selectivity

as high as 41-fold and an ERâ binding selectivity as high

as 36-fold. The latter of these compounds is fully

effective as an ERâ antagonist while exhibiting no

significant activity on ERR, a pharmacological profile

that might be useful in evaluating the role of ERâ in

mediating the diverse biological effects of estrogens.

Scheme 2

Results and Discussion

1. Chemistry. The desired pyrazolo[1,5-a]pyrimidine

systems 1 can be readily assembled in just a few steps

from simple starting materials. The retrosynthetic

analysis in Scheme 1 shows how pyrazolo[1,5-a]pyrimi-

dine 1 can be formed by the condensation of 3-amino-

4,5-diarylpyrazole 2 and a diketone 3, the key 3-ami-

nopyrazole intermediate 2 then being produced by a

condensation of a 2,3-diaryl-3-oxopropiontirile 4 and

hydrazine 5. Utilizing pyrazole 2 and a series of com-

mercially available diketones, we were able to prepare

a library of compounds for screening.

As shown in Scheme 2, a Claisen condensation

between a methyl benzoate 6a-c and a benzyl cyanide

7a-c gave the 4,5-diaryl-3-oxopropionitriles³⁶8a-f.

These systems were then reacted with excess hydrazine

to yield the diaryl-3-aminopyrazoles 9a-f. We found

that the hydrazine condensation worked best with the

addition of a small amount of concentrated hydrochloric

acid³⁷to facilitate proton transfer and dehydration. With

5874 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24

Compton et al.

Scheme 3

Scheme 4

Scheme 5

could be incorporated onto the pyrazolopyrimidine core.

When the more hindered diketones 18a,b where reacted

with 9c in acetic acid (Scheme 5), however, we found

that the pyrazolo[1,5-a]pyrimidines did not form; start-

ing material was recovered, even when the reaction

times were extended to 48 h. To overcome these limita-

tions, we examined new reaction conditions, but we

encountered some difficulty because of the poor solubil-

ity of the 3-aminopyrazoles in simple aromatic solvents

such as benzene and toluene. The 3-aminopyrazoles

were found to be soluble in anhydrous o-dichlorobenzene

above 100 °C. Thus, reaction of diketones 18a,b with

the 3-aminopyrazoles 9a-e using 1.2 equiv of p-tolu-

enesulfonic acid in o-dichlorobenzene (Scheme 6) pro-

vided good yields of the pyrazolo[1,5-a]pyrimidines

19a-e and 20a-e containing the larger substituents.

This alternative synthesis allowed us to examine a

larger, more diverse library of ligands, allowing us to

explore the effect of size of the substituents at the 5 and

7 positions on ER binding.

The final step to yield testable compounds requires

their conversion from the methyl ethers to the corre-

sponding free phenols (Scheme 7). Although there are

many possible methods for this transformation, the use

of boron trifluoride/methyl sulfide complex was chosen

as a mild deprotection agent. After all deprotections

were performed, a library of 44 compounds 11f-14f and

21a-e through 28a-e was obtained, and their relative

binding affinities were measured.

2. Estrogen Receptor Binding Affinity. The rela-

tive binding affinities (RBAs) of the pyrazolo[1,5-a]-

pyrimidine systems were measured in purified full-

length human ERR and ERâ receptors using a competi-

tive radiometric binding assay, according to our pub-

lished procedure.⁴¹The RBA values are listed in Table

1; E2 has a RBA of 100%.

The first trend to note in the series is the RBA of

compounds 11f-14f. These compounds contain only the

unsubstituted phenyl rings at the 2 and 3 positions, and

as might have been predicted, they show no measurable

binding to the receptor because they lack the hydroxyl

group that is believed to be a necessary hydrogen-

bonding partner for the ER. The low affinity of these

this intermediate available, we were able to assemble

a library of pyrazolo[1,5-a]pyrimidines.

Historically, the pyrazolo[1,5-a]pyrimidines have been

formed by reacting 3-aminopyrazoles with diketones or

R,â-unsaturated ketones under acidic conditions.^38-40As

shown in Scheme 3, a series of commercially available

diketones 10a-e were reacted with the 3-aminopyra-

zoles 9a-f to yield the pyrazolo[1,5-a]pyrimidines con-

taining a variety of alkyl substituents at the 5 and 7

positions. To determine the most suitable reaction

conditions, the first systems we chose for examination

where those utilizing 1,3-propanedial 10a. Because this

simple dialdehyde (10a) is not stable, we used the

tetramethyl bis-acetal as a the synthetic equivalent for

1,3-propanedial. The generation of 10a in situ, by

deprotection of the acetal, gave material for reaction

with the 3-aminopyrazoles 9a-f. Since acetals are

sensitive to acidic conditions, acetic acid was chosen as

the solvent; it is sufficiently acidic to generate the 1,3-

propanedial and sufficiently polar to dissolve the 3-ami-

nopyrazoles, which are quite polar. Once this method

was found to be successful, it was then extended to

diketones 10b-f with good success to produce an initial

library of 29 compounds that are substituted with alkyl

groups at the C-5 and C-7 positions (Scheme 3).

In addition to examining the effects of increasing the

size of the C-5 and C-7 substituents, we prepared a

smaller series of pyrazolo[1,5-a]pyrimidines containing

a substituent at C-6 by reacting 9a-e with 3-methyl-

2,4-pentanedione 16 (Scheme 4). These reactions were

found to proceed well in acetic acid to give five additional

pyrazolo[1,5-a]pyrimidines with methyl substituents at

positions 5, 6, and 7.

After the initial binding affinity studies (see below)

indicated that the heterocycles were binding to the ER,

we wanted to investigate how large of a group would

be tolerated at the 5 and 7 positions. We wished to

incorporate tert-butyl and phenyl substituents, which

would allow us to determine how large of a substitution

Pyrazolo[1,5-a]pyrimidines

Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 5875

Scheme 6

selective for ERâ over ERR. This is not universally the

case, however, because 27a showed 41-fold selectivity

for ERR over ERâ. Although neither 24b nor 27a is the

highest binding ligand, they did show very good affinity

selectivity for ERâ and ERR, respectively.

In addition to examination of substituents at the 5

and 7 positions, a smaller series of compounds was

developed with an additional methyl substituent at the

6 position (26a-e). The binding data for this system

are best understood when compared to the data of the

dimethyl-substituted compounds 22a-e. When a third

methyl substituent was placed at the 6 position (26a-

e), there was a significant decrease in the RBA com-

pared to that of the corresponding dimethyl-substituted

analogues (22a-e), in all cases where the RBA was

measurable. Because substitution of a 6-hydrogen with

a 6-methyl group is not well tolerated, we chose not to

explore other systems substituted with larger alkyl

groups at the 6 position.

One can compare the two monophenol series to

determine whether there is a preference for the p-

hydroxyphenyl at position 2 (Ar¹) or 3 (Ar²) to act as

the A-ring mimic of E2 (series 21a-28a vs 21b-28b).

The overall trend indicates that a p-hydroxyphenyl at

position 2 is the preferred A-ring mimic; however, a

comparison of 24a to 24b indicates an interesting

interaction. While 24a shows a higher affinity than 24b,

there is a greater change in the ERR values than that

of the ERâ values; in ERR there was a 40-fold decrease

in RBA when going from a 4-hydroxyphenyl at C-2 (24a)

to a 4-hydroxyphenyl at C-3 (24b), whereas there is only

a 12% decrease in the ERâ RBA. This seems to indicate

that when binding to ERâ, 24b is able to compensate

for the loss of the preferred A-ring mimic; however,

because this compensation does not occur in ERR, 24b

is a compound that has a 36-fold affinity preference for

ERâ over ERR.

In further attempts to increase the RBA, one of the

hydroxyl groups was moved from the para to the meta

position while the other hydroxyl was left in the para

position (24d,e and 28d,e). This led, however, to a loss

of binding affinity, with compounds 24d,e being the only

systems to have measurable RBAs. The diphenols

24c-e were compared, and additional support for Ar¹

(i.e., at C-2) being the A-ring mimic was found. When

the p-hydroxyl remains on Ar¹(24d), the RBA for both

ERR and ERâ is higher than for 24e, where Ar¹has a

m-hydroxyl group. Although both 24d and 24e have

significantly lower affinity than the initial diphenol 24c,

the information obtained still supports a 4-hydroxy-

phenyl at the C-2 position as being the A-ring mimic of

estradiol.

compounds is consistent with the low affinity of 3-deoxy-

estradiol¹¹and that of other ligands in which the

hydroxyl group is removed from the phenol that mimics

the A-ring of estradiol.^12,42This indicates that the ER

binding found in the rest of the series is due to the

appropriate placement of the hydroxyl groups to enable

hydrogen-bonding in the binding pocket, with the pyra-

zolo[1,5-a]pyrimidine system acting as a hydrophobic

core unit to occupy space in the pocket. It was found

that the addition of hydroxyl groups in appropriate

orientations, as well as the addition of substituents at

the 5 and 7 positions, did lead to ligands having good

binding affinity to the ERs, with pyrazolo[1,5-a]pyrimi-

dine 24c having the highest overall RBA for ERR and

ERâ, 1.9% and 1.7%, respectively.

The nature of the substituent at the 5 and 7 positions

proved to be very important for binding. Compounds

24a-e showed the highest overall binding to the recep-

tor, and comparison with other analogues suggests a

beneficial effect of the trifluoromethyl group for receptor

interaction that may be derived from factors other than

its hydrophobic character. For example, when substit-

uents of comparable size are examined (25a-e and

27a-e), only 27a has an RBA on ERR comparable to

that of the series 24a-e. When 25c is compared to 27c,

a greater than 2-fold increase in binding affinity is

observed for 27c on ERâ and 27a shows a 6-fold increase

over 25a for ERR. These results were not anticipated

because the larger tert-butyl substituent was expected

to reduce the binding affinity of the ligands, especially

for ERâ with its smaller binding pocket.¹⁰

The general trends in RBAs indicate that within a

subset of R groups, the systems with p-hydroxyphenyls

at both positions 2 and 3 were superior to those with

other hydroxyl substitution patterns. Two notable ex-

ceptions are 25a and 27a, both of which show signifi-

cantly higher ERR binding over the corresponding

diphenols 25c and 27c, respectively. The majority of

systems were shown to be ERâ selective or to have no

significant preference for either receptor. Again, 27a

proved to be a noticeable exception, being 40-fold more

selective for ERR. Despite the modest binding affinity

Although 24c was found to have the highest RBA of

the series, it showed no selectivity between ERR and

ERâ. Nonetheless, with this series there seems to be

an overall preference for ERâ, with 24b being 36-fold

5876 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24

Compton et al.

Scheme 7

of the pyrazolo[1,5-a]pyrimidines, we were able to study

meaningful structure-affinity relationships.

3.3. C-2 and C-3 Diphenolic Pyrazolopyrim-

idines. The diphenolic systems (i.e., 2,3-bis(4-hydroxy-

phenyl)pyrazolo[1,5-a]pyrimidines), 21c, 22c, 23c, 24c,

25c, and 27c (Figure 2, panels A, C, D, G, I, and K),

were all found to act as antagonists on both ERR and

ERâ. The addition of a single hydroxyl transformed

compounds that were partial agonists on ERR (22a, 24a,

and 25a) into full ERR antagonists (22c, 24c, and 25c).

Although at the concentrations examined compounds

22c and 25c did not reach full ERR antagonism, they

did not show any agonism on ERR. It is of note that

compounds 22c, 24c, and 25c, in particular, also

represent a novel pharmacological class of for estrogenss

ERâ potency-selective antagonists.

3.4. General Discussion of Transactivation Re-

sults. The transactivation assays provided us with

results that were unexpected in two respects. Although

the ligands possessed only low to modest RBAs, they

proved to have a very significant effect on the receptors;

in addition, the ligands proved to share significant

degrees of antagonism on both ERR and ERâ. It is of

particular note that several were antagonists on both

ERs even though they do not contain the basic amine

side chain (BSC) or additional bulky groups generally

associated with imparting estrogen antagonism; this

phenomenon has been termed “passive antagonism” by

Shiau and co-workers.⁴³

The pyrazolo[1,5-a]pyrimidine ER ligands illustrate

multiple pharmacological classes within the same struc-

tural series; some pyrazolo[1,5-a]pyrimidine systems

were found to be ERâ-selective passive antagonists

while showing ERR binding selectivity (23c, 25a, and

25c) or no significant subtype selectivity (24a, 24c, and

27c). This is similar to the profile exhibited by the 1,1-

diarylethlene systems developed by Muthyala⁴⁴and the

tetrahydrochrysenes (THCs) developed by Meyers.⁴⁵

Additional systems represent an entirely new pharma-

cological classes of estrogen receptor ligands: ERâ

potency-selective antagonists (22c, 24c, and 25c) and

ERâ potency- and efficacy-selective antagonist (24b).

In addition to this already interesting activity, several

compounds were found to act as ERR antagonists (21c,

22c, 23c, and 24c), though with lower potency than as

ERâ antagonists. Nevertheless, these compounds rep-

resent the first ER ligands that we know of that act as

ERR passive antagonists.⁴³Thus, although the pyrazolo-

[1,5-a]pyrimidines possess only modest binding affini-

3. Activity of Selected Pyrazolo[1,5-a]pyrim-

idines on Gene Transcription. Eleven compounds

that showed good relative binding affinities or interest-

ing selectivity between ERR and ERâ (21c, 22a, 22c,

23c, 24a-c, 25a, 25c, 27a, and 27c) were tested for

their agonistic or antagonistic character as regulators

of transcription by cotransfection assays in human

endometrial cancer cells (HEC-1), using expression

plasmids for either ERR or ERâ and an estrogen-

responsive reporter gene. The agonist activity of the

compounds was examined using a four-point dose

response curve at 10^-8, 10^-7, 10^-6, and 10^-5M; antago-

nist activity was assayed at the same four concentra-

tions in the presence of 10^-9M E₂. The transcriptional

activity is expressed relative to that obtained with 10^-9

M E₂, which is set at 100%. The results are shown in

Figure 2.

3.1. C-2 Monophenolic Pyrazolopyrimidines. Com-

pounds 22a, 24a, and 25a (Figure 2, panels B, E, and H,

respectively) are all C-2 monophenols (i.e., 2-(4-hydroxy-

phenyl)-3-phenylpyrazolo[1,5-a]pyrimidines), and they

all possess varying degrees of partial activation of ERR,

with little or no activation of ERâ (solid lines). When

these same compounds are tested as antagonists (in the

presence of 1 nM estradiol), they inhibited estradiol

partially on ERR and fully on ERâ (dashed lines). Thus,

these ligands would be classified as partial agonists on

ERR and full antagonists on ERâ. Although compound

27a (Figure 2, panel J) possessed the same 2-(4-hy-

droxyphenyl)-3-phenylpyrazolo[1,5-a]pyrimidine pat-

tern, it showed very little activity as an agonist or an

antagonist on either receptor. This was somewhat

unexpected because it exhibited one of the highest RBA

values for ERR.

3.2. C-3 Monophenolic Pyrazolopyrimidines. The

only C-3 monophenolic system of interest (i.e., a 2-(phen-

yl)-3-(4-hydroxyphenyl)pyrazolo[1,5-a]pyrimidine) was

24b (Figure 2, graph F) because it showed an RBA that

was 36-fold selective for ERâ. As expected, the low ERR

binding affinity of compound 24b (0.01%) correlated

with its low potency in the ERR transfection assay.

Notably, this compound showed full antagonism on ERâ,

with minimal effect on ERR. Thus, it represents a novel

pharmacological class for estrogenssERâ potency- and

efficacy-selective antagonists.

Pyrazolo[1,5-a]pyrimidines

Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 5877

Table 1. Relative Binding Affinity (RBA) of 2,3-Diaryl-5,7-dialkylpyrazolo[1,5-a]pyrimidines for Estrogen Receptors R and â,

Deterimined by a Competitive Radiometric Binding Assay with [³H]estradiol and Full-Length Human ERR and ERâ, Using Methods

Described in the Experimental Section^a

a

b

c

d

e

f

Ar¹) 4-HOPh

Ar²) Ph

Ar¹) Ph

Ar¹) 4-HOPh

Ar²) 4-HOPh

Ar¹) 4-HOPh

Ar²) 3-HOPh

Ar¹) 3-HOPh

Ar²) 4-HOPh

Ar¹) Ph

Ar²) Ph

Ar²) 4-HOPh

11

12

13

14

21

22

23

24

25

26

27

28

R¹) H

R²) H

ERR

ERâ

â/R

<0.01

R¹) Me

R²) H

ERR

ERâ

â/R

<0.01

R¹) Et

R²) H

ERR

ERâ

â/R

<0.01

R¹) CF₃

R²) H

ERR

ERâ

â/R

<0.01

R¹) H

R²) H

ERR

ERâ

â/R

<0.01

0.01 ( 0.001

0.05 ( 0.001

5

<0.01

0.023 ( 0.004

0.10 ( 0.002

R¹) Me

R²) H

ERR

ERâ

â/R

0.02 ( 0.004

0.11 ( 0.001

5.5

0.01 ( 0.002

0.05 ( 0.004

5

0.04 ( 0.003

0.07 ( 0.01

1.8

<0.01

R¹) Et

R²) H

ERR

ERâ

â/R

0.13 ( 0.02

0.06 ( 0.004

0.5

0.02 ( 0.003

0.05 ( 0.006

5

0.16 ( 0.01

0.07 ( 0.01

0.18

<0.01

R¹) CF₃

R²) H

ERR

ERâ

â/R

0.39 ( 0.03

0.41 ( 0.09

1.1

0.01 ( 0.003

0.05 ( 0.006

36

1.9 ( 0.3

1.7 ( 0.06

0.9

0.04 ( 0.004

0.08 ( 0.02

2

0.01 ( 0.00

0.04 ( 0.00

4

R¹) i-Pr

R²) H

ERR

ERâ

â/R

0.14 ( 0.04

0.06 ( 0.02

0.4

0.01 ( 0.004

0.05 ( 0.002

5

0.10 ( 0.02

0.07 ( 0.006

0.7

0.01 ( 0.001

<0.01

0.01 ( 0.002

R¹) Me

R²) Me

ERR

ERâ

â/R

0.01 ( 0.001

0.02 ( 0.001

2

<0.01

0.01 ( 0.004

0.01 ( 0.003

0.01 ( 0.00

1

<0.01

R¹) t-Bu

R²) Me

ERR

ERâ

â/R

0.83 ( 0.07

0.02 ( 0.002

0.02

<0.01

0.01 ( 0.002

0.13 ( 0.003

0.16 ( 0.04

1.1

0.02 ( 0.005

0.01 ( 0.001

0.5

<0.01

R¹) Ph

R²) H

ERR

ERâ

â/R

<0.01

0.02 ( 0.06

0.03 ( 0.04

1.5

<0.01

^aThe RBA of estradiol is set to 100%. Where error bars are indicated, values represent the average ( range or SD of two to three

independent determinations. The RBA is not reported when it was <0.01. The K_dof estradiol is 0.2 nM (ERR) and 0.5 nM (ERâ) Because

the â/R selectivity values are calculated from the RBA values, determined in competitive binding assays with tritiated esradiol, they

favor ERâ by 2.5-fold, which is the ratio of estradiol binding affinity for the two ER subtypes.

ties, they have provided us with new pharmacological

classes of ER ligands, and they offer new insights that

can be used to influence design of future ligands.

The most distinctive compound in the whole series

was the C-3 monophenolic bis(trifluoromethyl)pyrazolo-

[1,5-a]pyrazole 24b. In binding, it was 36-fold selective

for ERâ, and it was fully effective as an ERâ antagonist

while exhibiting no significant agonism on ERR or ERâ.

Thus, as an ERâ potency- and efficacy-selective antago-

nist, this ligand could be used to abrogate estrogen

action through ERâ with minimal effect on its activity

through ERR. A compound with this activity could prove

to be useful in evaluating the biological activity of ERâ.

4. Molecular Modeling. The ability of the ligands

to act as antagonists on ERâ is not too surprising

because it is known that the ERâ binding pocket is

approximately 100 Å³smaller in size than that of ERR.¹⁰

We were surprised, however, by the ability of some

members of the pyrazolo[1,5-a]pyrimidine system to act

as antagonists on ERR without having the prototypical

antagonist basic amine side chain. The larger size of

the ERR pocket would suggest that the ligands should

5878 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24

Compton et al.

Figure 2. Transcription activation through ERR and ERâ in response to selected compounds with a pyrazolo[1,5-a]pyrimidine

core. Human endometrial cancer cells (HEC-1) were transfected with expression vectors for ERR or ERâ and the estrogen responsive

receptor gene 2ERE-pS2-Luc and were incubated with the indicated concentrations of ligands 21c, 22a, 23c, 24a-c, 25a, 27a,

and 27c (solid lines) for 24 h. Antagonistic activity was assayed in the presence of 1 nM E2 (dashed lines). The values given are

the mean ( SD of two or more experiments and are expressed as a percent of the ERR or ERâ response with 10^-9M E2.

be able to fill the space inside the pocket without

inducing antagonism. The fact that the ligands are

causing partial or complete antagonism on ERR would

suggest that they are binding to the receptor in a unique

fashion. To gain insight into the activity of the system,

we docked compound 24c into the binding pockets of

ERR and ERâ to study the potential binding orienta-

tions.

Initial molecular modeling studies of the diarylpyra-

zolo[1,5-a]pyrimidines showed that the system could

function as an ER ligand and that it should be possible

to place additional small substituents at the 5, 6, and 7

positions (not shown). After the RBA results for the

series were obtained, ligand 24c (which has the highest

overall RBA and acts as an antagonist on both ER

subtypes) was selected to be modeled into the crystal

structures of ERR-E2 (1ERE) and ERâ-genistein

(1QKM) using Sybyl 6.9. We hoped to understand why

this ligand had the highest binding affinities for both

ERR and ERâ and if there were protein-ligand interac-

tions that might be used to rationalize the antagonistic

character of 24c. After learning that the systems are

antagonistic, we also studied the antagonistic ERR-4-

hydroxytamoxifen (3ERT) crystal structure and found

that 24c minimized into the same orientation as in

1ERE (not shown), thus offering no additional insight

into why the ligands act as ERR antagonists.

When the ligands in the crystal structure were

examined, it is important to note the key interactions

of the endogenous ligand estradiol (Figure 3A). In the

diarylpyrazolo[1,5-a]pyrimidines, there are two possible

phenols that can act as the A-ring mimic of E2 and form

a hydrogen bond with Glu353 and Arg394. In addition,

there are two possible orientations for the remainder

of the ligand structure, producing four possible binding

modes to be examined by modeling (Figure 3B).

In binding modes I and II, the C-2 phenol acts as the

estradiol A-ring mimic, with the second phenol being

oriented either in the 11â direction relative to E2 (mode

I) or in roughly the 7R direction (mode II). In either of

these orientations there is potential for the fluorines on

the trifluoromethyl substituents to hydrogen-bond with

the His524. In modes III and IV, the C-3 phenol mimics

the A-ring of estradiol. In the first of these cases (mode

III), the second phenol is oriented in the 11â direction

(as in mode I), but the pyrimidine portion of the core is

Pyrazolo[1,5-a]pyrimidines

Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 5879

The results from our modeling (Figure 4) showed that

compound 24c interacts differently between the two

subtypes. Binding mode II (Figure 4A) appears to be

the orientation of ligand 24c in ERR, whereas in ERâ,

binding mode I (Figure 4B) appears to be the preferred

orientation. This is not the first instance where molec-

ular modeling studies of multiply phenolic ER ligands

indicated a preference for the same A-ring mimic but

different binding modes between ERR and ERâ for the

remainder of the ligand core. Nishiguchi and co-work-

ers⁴⁶observed similar modeling results while studying

diaryldialkylpyrazoles as ER ligands, as did Wolohan⁴⁷

studying triarylalkylpyrazoles.

As shown in Figure 4A, ligand 24c is oriented in a

fashion that would allow it to hydrogen-bond with

Glu353 and His524, thus maximizing the strong hydro-

gen-bonding interactions with the receptor. This orien-

tation also suggests that it is the ability of the fluorines

to hydrogen-bond with His524 that leads to the in-

creased RBA values found not only for 24c but with the

whole series of trifluoromethyl-substituted compounds

24a-e. Although no hydrogen-bonding interactions

were found between Thr347, the only other polar

residue in the ERR ligand binding pocket, the trifluoro-

methyl group is close enough that it is possible for this

third hydrogen-bonding pair to exist.

The orientation of 24c in the binding pocket of ERR

(Figure 4A) offers no clear insight of why the compounds

act as antagonists or partial antagonists on this ER

subtype. The orientation of 24c in ERâ (Figure 4B),

however, does suggest why most of these ligands are

antagonistic on this ER subtype. The aromatic ring at

the C-3 position is oriented in the direction that a basic

amine side chain would align to form the salt bridge

with Asp303 and induce antagonism because ERâ has

a smaller ligand binding pocket;¹⁰the basic side chain

may not be required to disrupt the ERâ structure

sufficiently to engender antagonist character, as has

been noted with the ERâ-selective passive antagonist

R,R-diethyltetrahydrochrysene.⁴⁵In Figure 4B, ligand

24c was found to have fewer hydrogen-bonding pairs;

the hydrogen bond distance to His475 is 4.8 Å and the

distance to Thr299 was >5 Å, both distances where

hydrogen bonding would not occur. Since the RBA is

comparable between ERR and ERâ, it is possible that

in solution His475 (which corresponds to His524 in ERR)

moves closer, enabling an additional hydrogen-bonding

interaction.

Figure 3. (A) Estradiol (E2) and its hydrogen-bonding pat-

terns in ERR. (B) Two-dimensional illustration of the four

possible binding modes for 24c.

displaced more toward the 7R direction (instead of

toward the back of the pocket, as in mode I). In this

orientation it appears that greater reorganization of the

receptor is required for hydrogen bonding to occur

between the fluorine and the His524. Mode IV switches

the orientation of the second phenol and the pyrimidine

but still requires greater reorganization to achieve the

proper orientation for hydrogen bonding between the

fluorines and His524.

From the RBA data of the individual monophenols

24a and 24b, we believe that the most likely binding

orientation for our pyrazolo[1,5-a]pyrimidines is mode

I or its 180° rotation mode II, i.e., with the C-2 phenol

A-ring mimic of E2. Binding modes III and IV, however,

cannot be fully excluded because these orientations

might account for the observed antagonistic character;

thus, they were also examined during our modeling

studies.

The modeling has shown that it is the ability of 24c

to form additional hydrogen-bonding pairs through the

trifluoromethyl groups that has led to the ligands within

this series having RBA values higher than compounds

having just hydrophobic groups of similar size. The

difference between the receptor subtypes has also been

emphasized, showing not only that the same ligand is

able to have multiple binding modes but that the ER

subtypes may prefer different binding orientations of

the same ligand.

The desired binding mode was studied by modeling

by first overlapping the desired phenol with the A-ring

of estradiol (ERR) or the A-ring mimic in genistein (ERâ)

and orienting the pyrazolo[1,5-a]pyrimidine core in the

desired orientation. An initial minimization was per-

formed by allowing the ligand to move while maintain-

ing the protein in a fixed orientation. The ligand and

amino acids within the binding pocket were allowed to

rotate and reach a minimum energy. Finally, the ligand

and the entire protein were allowed to minimize. As

detailed below, good structures were obtained with

compound 24c in both modes I and II, whereas when

binding modes III and IV were used to dock ligand 24c

into ERR and ERâ, the ligand was found to reorient to

give binding mode I or II (ERâ and ERR, respectively)

or to be ejected from the pocket.

Conclusion

Estrogen receptor ligands built on the pyrazolo[1,5-

a]pyrimidine core have been shown to exhibit unique

profiles when binding to the ER. While having only

modest binding affinities that typically exhibited affinity

5880 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24

Compton et al.

Figure 4. (A) Minimized docking structure of 24c into the binding pocket of ERR showing hydrogen-bonding interactions and

distances. (B) Minimized docking structure of 24c into the binding pocket of ERâ showing hydrogen-bonding interactions and

distances. Selected binding pocket residues are shown and are in homologous positions in ERR and ERâ.

Microanalytical Service Laboratory at the University of Illinois

on an Exter Analytical CE440 analyzer.

selectivity for ERâ, they had a significant effect in the

receptor transactivation assays. The ligands were found

to act as passive antagonists on both ERR and ERâ, with

some showing pronounced selective antagonism on ERâ.

While multiple examples of ERâ passive antagonists are

reported,^44,45these are the first systems that have been

found to act as passive antagonists on ERR. Thus, the

pyrazolo[1,5-a]pyrimidine core has provided us with new

pharmacological profiles of ERâ-selective antagonists

and ERR passive antagonists. Although the modeling

studies provide no definitive answer to the mechanism

of antagonism, we were able to learn from them that

the ligands are likely presenting themselves differently

to each receptor subtype and that this may have some

influence on the antagonistic character. The pyrazolo-

[1,5-a]pyrimidine core has offered new insights into the

interaction between the estrogen receptor and novel

ligand systems. Furthermore, it has furnished a com-

pound that effectively antagonizes ERâ with minimal

effect on ERR. This compound (2-phenyl-3-(4-hydroxy-

phenyl)-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimi-

dine, 24b) could prove to be useful in evaluating the

biological activity of ERâ.

General Procedure A for the Synthesis of 2,3-Diaryl-

3-oxopropionitriles. To a suspension of 60% sodium hydride

(33.6 mmol) in THF was added the benzyl cyanide (15.5 mmol)

and methyl benzoate (17.1 mmol). The mixture was stirred at

60 °C for 48 h. Water (10 mL) was added, and the mixture

was concentrated by rotary evaporation. An additional 20 mL

of water was added and extracted (3 × 50 mL) with CH₂Cl₂.

The organic phases were combined and discarded, and the

aqueous portion was acidified with 3 M HCl until no more

precipitate formed. The aqueous solution was then extracted

(3 × 50 mL) with CH₂Cl₂, and the organic phases were

combined. The combined organic phase was washed (2 × 25

mL) with a saturated NaCl solution and dried with Na₂SO₄.

The dichloromethane was then removed by rotary evaporation.

The resulting 2,3-diaryl-3-oxopropionitriles were carried on to

the next step without further purification.

2-(4-Methoxyphenyl)-3-oxo-3-phenylpropionitrile (8a).

Following general procedure A, methyl benzoate 6c and benzyl

cyanide 7a were coupled to yield propionitrile 8a. Yield 60%;

¹H NMR (500 MHz, CDCl₃) δ 3.78 (s, 3H, Ar-OCH₃), 5.57 (s,

1H, CdOCHCN), 6.90 (AA′XX′, 2H, Ar-H), 7.35 (AA′XX′, 2H,

Ar-H), 7.45 (m, 2H, Ar-H), 7.58 (m, 1H, Ar-H), 7.94 (m, 2H,

Ar-H); ¹³C NMR (125 MHz, CDCl₃) δ 46.09 (CdOCHCN),

55.50 (Ar-OCH₃), 115.23 (2C, Ar-C), 116.98 (CdOCHCN),

122.28 (Ar-C), 129.16 (Ar-C), 129.41 (2C, Ar-C), 129.67 (2C,

Ar-C), 133.77 (Ar-C), 134.51 (Ar-C), 160.26 (Ar-COCH₃),

189.27 (CdO); LRMS m/z 251.1; HRMS (C₁₆H₁₃NO₂) calcd

251.0954, found 251.0946.

3-(4-Methoxyphenyl)-3-oxo-2-phenylpropionitrile (8b).

Following general procedure A, methyl benzoate 6a and benzyl

cyanide 7c were coupled to yield propionitrile 8b. Yield 68%;

¹H NMR (500 MHz, CDCl₃) δ 3.84 (s, 3H, Ar-OCH₃), 5.56 (s,

1H, CdOCHCN), 6.92 (AA′XX′, 2H, Ar-H), 7.37 (m, 3H Ar-

H), 7.44 (m, 2H, Ar-H), 7.94 (AA′XX′, 2H, Ar-H); ¹³C NMR

(125 MHz, CDCl₃) δ 46.54 (CdOCHCN), 55.77 (Ar-OCH₃),

114.42 (2C, Ar-C), 117.01 (CdOCHCN), 126.51 (Ar-C),

128.31 (2C, Ar-C), 129.17 (Ar-C), 129.76 (2C, Ar-C), 130.94

(Ar-C), 131.95 (2C, Ar-C), 164.66 (Ar-COCH₃), 187.45 (Cd

O); LRMS m/z 251.1; HRMS (C₁₆H₁₃NO₂) calcd 251.0944, found

251.0946.

2,3-Bis(4-methoxyphenyl)-3-oxopropionitrile (8c). Fol-

lowing general procedure A, methyl benzoate 6a and benzyl

cyanide 7a were coupled to yield propionitrile 8c. Yield 79%;

¹H NMR (500 MHz, CDCl₃) δ 3.77 (3H, s, OCH₃), 3.84 (3H, s,

OCH₃), 5.53 (1H, s, CdOCHCN), 6.90 (4H, m, ArH), 7.34 (2H,

AA′XX′, ArH), 7.92 (2H, AA′XX′, ArH); ¹³C NMR (125 MHz,

CDCl₃) δ 45.76 (CdOCHCN), 55.44 (Ar-OCH₃), 55.72 (Ar-

Experimental Section

Materials and Methods. All reagents and solvents were

purchased from Aldrich, Acros, or Fisher. Methylene chloride

and tetrahydrofuran were obtained immediately prior to use

from a solvent-dispensing system (SDS) built by J. C. Meyer

on the basis of a design developed by Pangborn et al.⁴⁸The

reaction samples were kept under a nitrogen atmosphere

unless otherwise noted. Reactions were monitored by thin-

layer chromatography (TLC) with 0.25 mm silica gel plastic

plates containing F₂₅₄indicator. Visualization was obtained

using a UV lamp. Column chromatography was performed

using Woelm 32-63 µm silica gel packing. Melting points were

obtained on a Thomas-Hoover capillary melting point ap-

1

paratus and are uncorrected. H NMR spectra were obtained

on Varian Unity 500 MHz spectrometer. ¹³C NMR spectra were

obtained at 125 MHz. Chemical shifts are reported downfield

in parts per million from TMS utilizing the solvent peaks as

the reference. Mass spectra were recorded under electron

impact (EI) conditions at 70 eV by the Mass Spectrometry

Laboratory at the University of Illinois. Elemental analysis

of carbon, hydrogen, and nitrogen was performed by the

Pyrazolo[1,5-a]pyrimidines

Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 5881

OCH₃), 114.36 (2Ar-C), 115.11 (2Ar-C), 117.27 (CN), 122.78

(Ar-C), 126.50 (Ar-C), 129.53 (2Ar-C), 131.85 (2Ar-C),

160.12 (Ar-COCH₃), 164.55 (Ar-COCH₃), 187.72 (CdO);

LRMS m/z 281.1; HRMS (C₁₇H₁₅NO₃) calcd 281.1054, found

281.1051.

114.59, 126.66, 129.38, 129.54, 130.26, 134.29, 160.23 (Ar-

COCH₃); LRMS m/z 265.1; HRMS (C₁₆H₁₅N₃O) 265.1215, found

265.1215.

3-Amino-4,5-bis(4-methoxyphenyl)pyrazole (9c). Fol-

lowing general procedure B, 8c was reacted with 5 to yield

9c. Isolated yield 80%; white solid; mp 169-172 °C; ¹H NMR

(400 MHz, (CD₃)₂CO) δ 3.74 (s, 3H, OCH₃), 3.78 (s, 3H, OCH₃),

4.27 (bs, 2H, NH₂), 6.83 (AA′XX′, 2H Ar-H), 6.90 (AA′XX′, 2H,

Ar-H), 7.18 (AA′XX′, 2H, Ar-H), 7.31 (AA′XX′, 2H, Ar-H);

¹³C NMR (100 MHz, (CD₃)₂CO) δ 55.34 (Ar-OCH₃), 55.40 (Ar-

OCH₃), 114.52, 126.73, 129.32, 131.47, 158.89 (Ar-COCH₃),

160.05 (Ar-COCH₃); LRMS m/z 295.1; HRMS (C₁₇H₁₇N₃O₂)

calcd 295.1318, found 295.1321.

2-(4-Methoxyphenyl)-3-(3-methoxyphenyl)-3-oxopro-

pionitrile (8d). Following general procedure A, methyl ben-

zoate 6b and benzyl cyanide 7a were coupled to yield pro-

pionitrile 8d. Yield 53%; ¹H NMR (500 MHz, CDCl₃) δ 3.77

(s, 3H, Ar-OCH₃), 3.81 (s, 3H, Ar-OCH₃), 5.55 (s, 1H,

CdOCHCN), 6.99 (AA′XX′, 2H, Ar-H), 7.11 (ddd, 1H, J ) 8.4,

2.8, 0.9 Hz, Ar-H), 7.34 (m, 3H, Ar-H), 7.44 (dd, 1H, J ) 2.4,

1.7 Hz, Ar-H), 7.49 (ddd, 1H, J ) 7.7, 1.5, 0.9 Hz); ¹³C NMR

(125 MHz, CDCl₃) δ 46.16 (CdOCHCN), 55.48 (Ar-OCH₃),

55.62 (Ar-OCH₃), 113.68 (Ar-C), 115.22 (2C, Ar-C), 116.97

(CdOCHCN), 121.00 (Ar-C), 121.82 (Ar-C), 122.37 (Ar-C),

129.64 (2C, Ar-C), 130.07 (Ar-C), 135.08 (Ar-C), 160.26 (2C,

Ar-COCH₃), 189.16 (CdOCHCN); LRMS m/z 281.1.

2-(3-Methoxyphenyl)-3-(4-methoxyphenyl)-3-oxopro-

pionitrile (8e). Following general procedure A, methyl ben-

zoate 6a and benzyl cyanide 7b were coupled to yield pro-

pionitrile 8e. Yield 58%; ¹H NMR (500 MHz, CDCl₃) δ 3.77

(s, 3H, Ar-OCH₃), 3.84 (s, 3H, Ar-OCH₃), 5.54 (s, 1H,

CdOCHCN), 6.86 (dd, 1H, J ) 8.4, 2.6 Hz, Ar-H), 6.90

(AA′XX′, 2H, Ar-H), 6.97 (dd, 1H, J ) 2.4, 1.7 Hz, Ar-H),

7.00 (dd, 1H, J ) 7.7, 0.9 Hz, Ar-H), 7.29 (t, 1H, J ) 7.9 Hz,

Ar-H), 7.93 (AA′XX′, 2H, Ar-H); ¹³C NMR (125 MHz, CDCl₃)

δ 46.53 (CdOCHCN), 55.48 (Ar-OCH₃), 55.73 (Ar-OCH₃),

113.87 (Ar-C), 114.39 (2C, Ar-C), 114.65 (Ar-C), 116.95 (Cd

OCHCN), 120.52 (Ar-C), 126.52 (Ar-C), 130.75 (Ar-C),

131.90 (2C, Ar-C), 132.48 (Ar-C), 160.49 (Ar-COCH₃), 164.64

(Ar-COCH₃), 187.39 (CdOCHCN); LRMS m/z 281.1

2,3-Diphenyl-3-oxopropionitrile (8f). Following general

procedure A, methyl benzoate 6c and benzyl cyanide 7c were

coupled to yield propionitrile 8f. Yield 63%; ¹H NMR (500 MHz,

CDCl₃) δ 5.65 (s, 1H, CdOCHCN), 7.42 (m, 7H, Ar-H), 7.59

(m, 1H, Ar-H), 7.96 (m, 2H, Ar-H); ¹³C NMR (125 MHz,

CDCl₃) δ 46.76 (CdOCHCN), 116.78 (CN), 128.41 (2C, Ar-

C), 129.16 (2C, Ar-C), 129.28 (Ar-C), 129.41 (2C, Ar-C),

129.80 (2C, Ar-C), 130.49 (Ar-C), 133.70 (Ar-C), 134.60 (Ar-

C), 189.12 (CdO); LRMS m/z 221.1.

General Procedure B for the Synthesis of 3-Amino-

4,5-diarylpyrazoles. The 2,3-diaryl-3-ketopropionitriles were

dissolved in 60 mL of absolute EtOH, and 3 mL of concentrated

HCl was added. The mixture was brought to reflux, at which

time a 5- to 7-fold excess of a solution of hydrazine hydrate 5

was added slowly over several minutes. The reaction mixture

was stirred at reflux for an additional 9 h. The solution was

condensed to approximately 15 mL by rotary evaporation, and

10 mL of water was added. A solution of saturated NaHCO₃

was added until a slightly basic pH was obtained. The solution

was then extracted (3 × 50 mL) with ethyl acetate, and the

organic layers were combined. The combined organic layers

were washed (2 × 25 mL) with a saturated NaCl solution and

dried with Na₂SO₄. The ethyl acetate was removed by rotary

evaporation. The remaining material was purified by flash

chromatography on silica gel using a 10% MeOH/90% CHCl₃

as the solvent.

3-Amino-4-(4-methoxyphenyl)-5-(3-methoxyphenyl)-

pyrazole (9d). Following general procedure B, 8d was reacted

with 5 to yield 9d. Isolated yield 86%; white solid; mp 51-55

1

°C; H NMR (500 MHz, (CD₃)₂CO) δ 3.66 (s, 3H, Ar-OCH₃),

3.79 (s, 3H, Ar-OCH₃), 4.19 (bs, 2H, -NH₂), 6.81 (dd, 1H, J

) 7.7, 2.4 Hz, Ar-H), 6.92 (AA′XX′, 2H, Ar-H), 6.96 (m, 2H,

Ar-H), 7.18 (m, 3H, Ar-H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ

55.25 (Ar-OCH₃), 55.43 (Ar-OCH₃), 113.28, 114.06, 114.91,

120.23, 126.80, 130.20, 131.72, 159.18 (Ar-COCH₃), 160.55

(Ar-COCH₃); LRMS m/z 295.2; HRMS (C₁₇H₁₇N₃O₂) calcd

295.1320, found 295.1321.

3-Amino-4-(3-methoxyphenyl)-5-(4-methoxyphenyl)-

pyrazole (9e). Following general procedure B, 8e was reacted

with 5 to yield 9e. Isolated yield 55%; white solid; mp 58-62

1

°C; H NMR (500 MHz, CD₃CO₂D) δ 3.72 (s, 3H, Ar-OCH₃),

3.77 (s, 3H, Ar-OCH₃), 6.87 (m, 5H, Ar-H), 7.28 (dd, 1H, J )

8.2, 7.9 Hz, Ar-H), 7.35 (AA′XX′, 2H, Ar-H); ¹³C NMR (125

MHz, CD₃CO₂D) δ 55.49 (Ar-OCH₃), 55.68 (Ar-OCH₃), 105.26

(pyrazole-C), 113.96 (Ar-C), 115.11 (2C, Ar-C), 116.32 (Ar-

C), 121.62 (Ar-C), 123.10 (Ar-C), 130.89 (2C, Ar-C), 131.08

(Ar-C), 133.14 (Ar-C), 144.17 (pyrazole-C), 150.95 (pyra-

zole-C), 161.17 (Ar-COCH₃), 161.77 (Ar-COCH₃); LRMS m/z

295.1; HRMS (C₁₇H₁₇N₃O₂) calcd 295.1323, found 295.1321.

3-Amino-4,5-diphenylpyrazole (9f). Following general

procedure B, 8f was reacted with 5 to yield 9f. Isolated yield

88%; white solid; mp 143-146 °C; ¹H NMR (500 MHz, (CD₃)₂-

CO) δ 4.32 (bs, 2H, NH₂), 7.21 (m, 1H, Ar-H), 7.29 (m, 7H,

Ar-H), 7.38 (m, 2H, Ar-H), 11.36 (bs, 1H, NH); ¹³C NMR (125

MHz, (CD₃)₂CO) δ 126.77, 128.26, 128.40, 129.17, 129.41,

130.31, 134.81; LRMS m/z 235.1; HRMS (C₁₅H₁₃N₃) calcd

235.1112, found 235.1109.

General Procedure C for the Synthesis of Pyrazolo-

[1,5-a]pyrimidines Using Acetic Acid. The desired 3-amino-

4,5-diarylpyrazoles (0.5 mmol) were dissolved in 10 mL of

acetic acid. To this solution 0.75 mmol of the dicarbonyl

compound was added, and the mixture was heated to 110 °C

for 1.5 h. The acetic acid was then removed by rotary

evaporation. The pyrazolo[1,5-a]pyrimidine was obtained by

dissolving the solid mixture in hot ethanol and allowing it to

cool. The resulting solid was filtered, and the mother liquor

was discarded.

2-(4-Methoxyphenyl)-3-phenylpyrazolo[1,5-a]pyrimi-

dine (11a). Following general procedure C, 9a was reacted

with 1,1,3,3-tetramethoxypropane 10a to yield 11a. Isolated

1

yield 70%; white solid; mp 138-140 °C; H NMR (500 MHz,

CDCl₃) δ 3.83 (s, 3H, OCH₃), 6.81 (dd, 1H, J ) 6.9, 4.1,

pyrimidine-H), 6.90 (AA′XX′, 2H, Ar-H), 7.31 m, 1H, Ar-

H), 7.40 (m, 2H, Ar-H), 7.54 (m, 2H, Ar-H), 7.60 (AA′XX′,

2H, Ar-H), 8.48 (dd, 1H, J ) 3.9, 1.7 Hz, pyrimidine-H), 8.68

(dd, 1H, J ) 6.9, 1.7 Hz, pyrimidine-H); ¹³C NMR (125 MHz,

CDCl₃) δ 55.40 (Ar-C), 108.21 (pyrimidine-C), 108.89 (pyra-

zole-C), 114.10 (2C, Ar-C), 125.46 (Ar-C), 126.96 (Ar-C),

128.71 (2C, Ar-C), 130.08 (2C, Ar-C), 130.37 (2C, Ar-C),

132.04 (Ar-C), 134.79 (pyrimidine-C), 147.03 (pyrazole-C),

149.41 (pyrimidine-C), 154.09 (pyrazole-C), 160.17 (Ar-

COCH₃); LRMS m/z 301.1; HRMS (C₁₉H₁₅N₃O) calcd 301.1213,

found 301.1215.

3-Amino-4-(4-methoxyphenyl)-5-phenylpyrazole (9a).

Following general procedure B, 8a was reacted with 5 to yield

9a. Isolated yield 78%; white solid; mp 87-89 °C; ¹H NMR

(500 MHz, (CD₃)₂CO) δ 3.78 (s, 3H, Ar-OCH₃), 4.30 (bs, 2H,

NH₂), 6.90 (AA′XX′, 2H, Ar-H), 7.17 (AA′XX′, 2H, Ar-H), 7.26

(m, 3H, Ar-H), 7.40 (m, 2H, Ar-H); ¹³C NMR (125 MHz,

(CD₃)₂CO) δ 55.37 (Ar-OCH₃), 114.88, 126.67, 128.06, 128.30,

129.16, 131.55, 159.05 (Ar-COCH₃); LRMS m/z 265.1; HRMS

(C₁₆H₁₅N₃O) calcd 265.1211, found 265.1215.

3-Amino-5-(4-methoxyphenyl)-4-phenylpyrazole (9b).

Following general procedure B, 8b was reacted with 5 to yield

9b. Isolated yield 76%; white solid; mp 101-103 °C; ¹H NMR

(500 MHz, (CD₃)₂CO) δ 3.76 (s, 3H, OCH₃), 4.31 (bs, 2H, NH₂),

6.83 (AA′XX′, 2H, Ar-H), 7.21 (m, 1H, Ar-H) 7.28 (m, 6H,

Ar-H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 55.46 (Ar-OCH₃),

3-(4-Methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimi-

dine (11b). Following general procedure C, 9b was reacted

with 1,1,3,3-tetramethoxypropane 10a to yield 11b. Isolated

1

yield 66%; yellow solid; mp 171-172 °C; H NMR (500 MHz,

5882 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24

Compton et al.

CDCl₃) δ 3.83 (s, 3H, OCH₃), 6.80 (dd, 1H, J ) 6.9, 4.1 Hz,

pyrimidine-H), 6.95 (AA′XX′, 2H, Ar-H), 738 (m, 3H, Ar-

H), 7.47 (AA′XX′, 2H, Ar-H), 7.68 (m, 2H, Ar-H), 8.48 (dd,

1H, J ) 4.1, 1.7 Hz, pyrimidine-H), 8.68 (dd, 1H, J ) 6.9, 1.5

Hz pyrimidine-H); ¹³C NMR (125 MHz, CDCl₃) δ 55.38 (Ar-

OCH₃), 108.28 (pyrimidine-C), 109.09 (pyrazole-C), 114.24

(2C, Ar-C), 124.08 (Ar-C), 128.71 (2C, Ar-C), 129.01 (2C,

Ar-C), 131.16 (2C, Ar-C), 133.14 (2C, Ar-C), 134.80 (pyrim-

idine-C), 146.88 (pyrazole-C), 149.25 (pyrimidine-C), 153.91

(pyrazole-C); LRMS (EI, 70 eV) m/z 301.1; HRMS (C₁₉H₁₅N₃O)

301.1216, found 301.1215.

2,3-Bis(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine

(11c). Following general procedure C, 9c was reacted with

1,1,3,3-tetramethoxypropane 10a to yield 11c. Isolated yield

79%; yellow solid; mp 175-177 °C; ¹H NMR (500 MHz, CDCl₃)

δ 3.83 (s, 3H, OCH₃), 3.84 (s, 3H, OCH₃), 6.80 (dd, 1H, J )

7.1, 4.1 Hz, pyrimidine-H), 6.90 (AA′XX′, 2H, Ar-H), 6.96

(AA′XX′, 2H, Ar-H), 7.46 (AA′XX′, 2H, Ar-H), 7.61 (AA′XX′,

2H, Ar-H), 8.46 (dd,1H, J ) 4.1, 1.7 Hz, pyrimidine-H), 8.67

(dd, 1H, J ) 4.1, 1.7 Hz, pyrimidine-H); ¹³C NMR δ (125 MHz,

CDCl₃) δ 55.49 (Ar-OCH₃), 55.50 (Ar-OCH₃), 108.15 (pyrim-

idine-C), 108.64 (pyrazole-C), 114.18 (2C, Ar-C), 114.37 (2C,

Ar-C), 124.38 (Ar-C), 125.65 (Ar-C), 130.35 (2C, Ar-C),

131.29 (2C, Ar-C), 134.82 (pyrimidine-C), 147.07 (pyrazole-

C), 149.27 (pyrimidine-C), 153.91 (pyrazole-C), 158.79 (Ar-

COCH₃), 160.19 (Ar-COCH₃); LRMS m/z 331.2; HRMS

(C₂₀H₁₇N₃O₂) 331.1319, found 331.1321.

dine-C), 154.06 (pyrazole-C); LRMS m/z 271.1; HRMS

(C₁₈H₁₃N₃) calcd 271.1111, found 271.1109. Anal. (C₁₈H₁₃N₃)

C, H, N calcd: 79.68% C, 4.83% H, 15.49% N. Found: 79.53%

C, 4.90% H, 15.32% N.

2-(4-Methoxyphenyl)-5,7-dimethyl-3-phenylpyrazolo-

[1,5-a]pyrimidine (12a). Following general procedure C, 9a

was reacted with 2,4-pentandione 10b to yield 12a. Isolated

1

yield 64%; white solid; mp 139-140 °C; H NMR (500 MHz,

CDCl₃) δ 2.56 (s, 3H, pyrimidine-CH₃), 2.78 (s, 3H, pyrimi-

dine-CH₃), 3.83 (s, 3H, Ar-OCH₃), 6.55 (s, 1H, pyrimidine-

H), 6.91 (AA′XX′, 2H, Ar-H), 7.28 (m, 1H, Ar-H), 7.38 (m,

2H, Ar-H), 7.60 (m, 4H, Ar-H); ¹³C NMR (125 MHz, CDCl₃)

δ 17.12 (pyrimidine-CH₃), 24.93 (pyrimidine-CH₃), 55.35

(Ar-OCH₃) 107.70 (pyrazole-C), 108.82 (pyrimidine-C), 113.96

(2C, Ar-C), 126.20 (Ar-C), 126.45 (Ar-C), 128.42 (2C, Ar-

C), 130.14 (2C, Ar-C), 130.45 (2C, Ar-C), 132.64 (Ar-C),

144.92 (pyrimidine-CCH₃), 146.83 (pyrazole-C), 153.43 (pyra-

zole-C), 158.74 (pyrimidine-CCH₃), 159.90 (Ar-COCH₃);

LRMS m/z 329.1; HRMS (C₂₁H₁₉N₃O) calcd 329.1524, found

329.1528.

3-(4-Methoxyphenyl)-5,7-dimethyl-2-phenylpyrazolo-

[1,5-a]pyrimidine (12b). Following general procedure C, 9b

was reacted with 2,4-pentandione 10b to yield 12b. Isolated

1

yield 72%; white solid; mp 182-183 °C; H NMR (500 MHz,

CDCl₃) δ 2.57 (s, 3H, pyrimidine-CH₃), 2.79 (d, 3H, J ) 0.4

Hz, pyrimidine-CH₃), 3.84 (s, 3H, Ar-OCH₃), 6.57 (q, 1H, J

) 0.9 Hz, pyrimidine-H), 6.93 (AA′XX′, 2H, Ar-H), 7.37 (m,

3H, Ar-H), 7.47 (AA′XX′, 2H, Ar-H), 7.67 (m, 2H, Ar-H);

¹³C NMR (125 MHz, CDCl₃) δ 17.18 (pyrimidine-CH₃), 25.04

(pyrimidine-CH₃), 55.40 (Ar-OCH₃), 107.94 (pyrazole-C),

108.94 (pyrimidine-C), 114.09 (2C, Ar-C), 124.86 (Ar-C),

128.41 (Ar-C), 128.56 (2C, Ar-C), 129.22 (2C, Ar-C), 131.27

(2C, Ar-C), 133.93 (Ar-C), 144.99 (pyrimidine-CCH₃), 146.80

(pyrazole-C), 153.41 (pyrazole-C), 158.47 (Ar-COCH₃), 158.64

(pyrimidine-CCH₃); LRMS m/z 329.1; HRMS (C₂₁H₁₉N₃O)

calcd 329.1530, found 329.1528.

2-(4-Methoxyphenyl)-3-(3-methoxyphenyl)pyrazolo-

[1,5-a]pyrimidine (11d). Following general procedure C, 9d

was reacted with 1,1,3,3-tetramethoxypropane 10a to yield

1

11d. Isolated yield 68%; off-white solid; mp 120-122 °C; H

NMR (500 MHz, CDCl₃) δ 3.74 (s, 3H, Ar-OCH₃), 3.81 (s, 3H,

Ar-OCH₃), 6.77 (dd, 1H, J ) 6.9, 3.9 Hz, pyrimidine-H), 6.85

(ddd, 1H, J ) 8.4, 2.6, 0.9 Hz, Ar-H), 6.90 (AA′XX′, 2H, Ar-

H), 7.11 (dd, 1H, J ) 2.4, 1,5 Hz, Ar-H), 7.14 (dt, 1H, J ) 7.5,

1.1 Hz, Ar-H), 7.31 (t, 1H, J ) 7.9 Hz, Ar-H), 7.61 (AA′XX′,

2H, Ar-H), 8.46 (dd, 1H, J ) 4.1, 1.9 Hz, pyrimidine-H), 8.66

(dd, 1H, J ) 7.1, 1.9 Hz, pyrimidine-H); ¹³C NMR (125 MHz,

CDCl₃) δ 55.22 (Ar-OCH₃), 55.34 (Ar-OCH₃), 108.15 (pyrim-

idine-C), 108.64 (pyrazole-C), 112.69 (Ar-C), 14.01 (2C, Ar-

C), 115.47 (2C, Ar-C), 122.50 (Ar-C), 125.38 (Ar-C), 129.60

(Ar-C), 130.34 (2C, Ar-C), 133.29 (Ar-C), 134.70 (pyrimi-

dine-C), 146.95 (pyrazole-C), 149.35 (pyrimidine-C), 154.02

(pyrazole-C), 159.70 (Ar-COCH₃), 160.12 (Ar-COCH₃); LRMS

m/z 331.1; HRMS (C₂₀H₁₇N₃O₂) calcd 331.1321, found 331.1321.

2,3-Bis(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]-

pyrimidine (12c). Following general procedure C, 9c was

reacted with 2,4-pentandione 10b to yield 12c. Isolated yield

1

74%; light-yellow solid; mp 171-172 °C; H NMR (500 MHz,

CDCl₃) δ 2.55 (s, 3H, pyrimidine-CH₃), 2.77 (d, 3H, J ) 0.9

Hz, pyrimidine-CH₃), 3.82 (s, 3H, Ar-OCH₃), 3.83 (s, 3H, Ar-

OCH₃), 6.53 (q, 1H, J ) 0.9 Hz, pyrimidine-H), 6.90 (AA′XX′,

2H, Ar-H), 6.93 (AA′XX′, 2H, Ar-H), 7.47 (AA′XX′, 2H, Ar-

H), 7.61 (AA′XX′, 2H, Ar-H); ¹³C NMR (125 MHz, CDCl₃) δ

17.11 (pyrimidine-CH₃), 24.89 (pyrimidine-CH₃), 55.35 (2C,

Ar-OCH₃), 107.45 (pyrazole-C), 108.70 (pyrimidine-C), 113.96

(2C, Ar-C), 114.04 (2C, Ar-C), 124.97 (Ar-C), 126.28 (Ar-

C), 130.37 (2C, Ar-C), 131.29 (2C, Ar-C), 144.90 (pyrimidine-

CCH₃), 146.76 (pyrazole-C), 153.91 (pyrazole-C), 158.40 (Ar-

COCH₃), 158.50 (pyrimidine-CCH₃), 159.85 (Ar-COCH₃);

LRMS m/z 359.2; HRMS (C₂2H₂₁N₃O₂) calcd 359.1640, found

359.1631.

2-(3-Methoxyphenyl)-3-(4-methoxyphenyl)pyrazolo-

[1,5-a]pyrimidine (11e). Following general procedure C, 9e

was reacted with 1,1,3,3-tetramethoxypropane 10a to yield

11e. Isolated yield 85%; orange solid; mp 159-161 °C; ¹H NMR

(500 MHz, CDCl₃) δ 3.71 (s, 3H, Ar-OCH₃), 3.81 (s, 3H, Ar-

OCH₃), 6.77 (dd, 1H, J ) 6.9, 3.9 Hz, pyrimidine-H), 6.88 (dt,

1H, J ) 7.3, 2.4 Hz, Ar-H), 6.93 (AA′XX′, 2H, Ar-H), 7.23

(m, 3H, Ar-H), 7.43 (AA′XX′, 2H, Ar-H), 8.44 (dd, 1H, J )

4.1, 1.7 Hz, pyrimidine-H), 8.65 (dd, 1H, J ) 7.1, 1.7 Hz,

pyrimidine-H); ¹³C NMR (125 MHz, CDCl₃) δ 55.30 (Ar-

OCH₃), 55.40 (Ar-OCH₃), 108.31 (pyrimidine-C), 109.24

(pyrazole-C), 113.82 (Ar-C), 114.23 (2C, Ar-C), 115.06 (Ar-

C), 121.48 (Ar-C), 124.07 (Ar-C), 129.65 (Ar-C), 131.27 (2C,

Ar-C), 134.41 (Ar-C), 134.79 (pyrimidine-C), 146.91 (pyra-

zole-C), 149.26 (pyrimidine-C), 153.72 (pyrazole-C), 158.78

(Ar-COCH₃), 159.71 (Ar-COCH₃); LRMS m/z 331.2; HRMS

(C₂₀H₁₇N₃O₂) calcd 331.1324, found 331.1321.

2-(4-Methoxyphenyl)-3-(3-methoxyphenyl)-5,7-dimeth-

ylpyrazolo[1,5-a]pyrimidine (12d). Following general pro-

cedure C, 9d was reacted with 2,4-pentandione 10b to yield

12d. Isolated yield 87%; white solid; mp 142-143 °C; ¹H NMR

(500 MHz, CDCl₃) δ 2.57 (s, 3H, pyrimidine-CH₃), 2.78 (d,

3H, J ) 0.64 Hz, pyrimidine-CH₃), 3.75 (s, 3H, Ar-OCH₃),

3.83 (s, 3H, Ar-OCH₃), 6.57 (q, 1H, J ) 0.9 Hz, pyrimidine-

H), 6.82 (ddd, 1H, J ) 8.2, 2.6, 0.9 Hz, Ar-H), 6.91 (AA′XX′,

2H, Ar-H), 7.15 (dt, 1H, J ) 7.5, 1.2 Hz, Ar-H), 7.18 (dd, 1H

J ) 2.4, 1.3 Hz, Ar-H), 7.27 (t, 1H, J ) 7.9 Hz, Ar-H), 7.60

(AA′XX′, 2H, Ar-H); ¹³C NMR (125 MHz, CDCl₃) δ 17.19

(pyrimidine-CH₃), 25.04 (pyrimidine-CH₃), 55.29 (Ar-OCH₃),

55.43 (Ar-OCH₃), 107.57 (pyrazole-C), 108.87 (pyrimidine-

C), 112.42 (Ar-C), 114.01 (2C, Ar-C), 115.44 (Ar-C), 122.67

(Ar-C), 126.26 (Ar-C), 129.40 (Ar-C), 130.56 (2C, Ar-C),

133.98 (Ar-C), 145.00 (pyrimidine-CCH₃), 146.87 (pyrazole-

C), 153.58 (pyrazole-C), 158.82 (Ar-COCH₃), 159.64 (Ar-

COCH₃), 159.99 (pyrimidine-CCH₃); LRMS m/z 359.2; HRMS

(C₂₂H₂₁N₃O₂) calcd 359.1627, found 359.1634.

2,3-Diphenylpyrazolo[1,5-a]pyrimidine (11f). Following

general procedure C, 9f was reacted with 1,1,3,3-tetramethoxy-

propane 10a to yield 11f. Isolated yield 90%; yellow solid; mp

1

127-129 °C; H NMR (500 MHz, CDCl₃) δ 6.76 (dd, 1H, J )

6.9, 3.9 Hz, Ar-H), 7.31 (m, 1H, pyrimidine-H), 7.39 (m, 5H,

Ar-H), 7.57 (m, 2H, Ar-H), 7.68 (m, 2H, Ar-H), 8.47 (dd,

1H, J ) 3.9, 1.7 Hz, pyrimidine-H), 8.68 (dd, 1H, J ) 6.9, 1.7

Hz, pyrimidine-H); ¹³C NMR (125 MHz, CDCl₃) δ 108.31

(pyrimidine-C), 109.21 (pyrazole-C), 126.88 (Ar-C), 128.53

(2C, Ar-C), 128.57 (2C, Ar-C), 128.69 (Ar-C), 129.02 (2C,

Ar-C), 129.95 (2C, Ar-C), 131.72 (Ar-C), 132.97 (Ar-C),

134.75 (pyrimidine-C), 146.80 (pyrazole-C), 149.37 (pyrimi-

2-(3-Methoxyphenyl)-3-(4-methoxyphenyl)-5,7-dimeth-

ylpyrazolo[1,5-a]pyrimidine (12e). Following general pro-

Pyrazolo[1,5-a]pyrimidines

Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 5883

cedure C, 9e was reacted with 2,4-pentandione 10b to yield

H), 6.92 (m, 4H, Ar-H), 7.45 (AA′XX′, 2H, Ar-H), 7.58

(AA′XX′, 2H, Ar-H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 10.66

(-CH₂CH₃), 13.07 (-CH₂CH₃), 23.99 (pyrimidine-CH₂CH₃),

31.88 (pyrimidine-CH₂CH₃), 55.41 (Ar-OCH₃), 55.52 (Ar-

OCH₃), 106.45 (pyrimidine-H), 107.65 (pyrazole-C), 114.39

(2C, Ar-C), 114.47 (2C, Ar-C), 126.04 (Ar-C), 127.33 (Ar-

C), 130.88 (2C, Ar-C), 131.93 (2C, Ar-C), 147.48 (pyrazole-

C), 150.67 (pyrimidine-CCH₂CH₃), 153.19 (pyrazole-C), 159.22

(Ar-COCH₃), 160.77 (Ar-COCH₃), 163.98 (pyrimidine-CCH₂-

CH₃); LRMS m/z 387.3; HRMS (C₂₄H₂₅N₃O₂) calcd 387.1945,

found 387.1947.

1

12e. Isolated yield 72%; off-white solid; mp 128-131 °C; H

NMR (500 MHz, CDCl₃) δ 2.56 (s, 3H, pyrimidine-CH₃), 2.79

(s, 3H, pyrimidine-CH₃), 3.74 (Ar-OCH₃), 3.83 (Ar-OCH₃),

6.56 (s, 1H, pyrimidine-H), 6.92 (m, 3H, Ar-H), 7.26 (m, 3H,

Ar-H), 7.49 (AA′XX′, 2H, Ar-H); ¹³C NMR (125 MHz, CDCl₃)

δ 17.12 (pyrimidine-CH₃), 25.00 (pyrimidine-CH₃), 55.29

(Ar-OCH₃), 55.38 (Ar-OCH₃), 108.01 (pyrazole-C), 108.95

(pyrimidine-C), 114.04 (2C, Ar-C), 114.12 (Ar-C), 114.61

(Ar-C), 121.68 (Ar-C), 124.81 (Ar-C), 129.55 (Ar-C), 131.33

(2C, Ar-C), 135.16 (Ar-C), 144.96 (pyrimidine-CCH₃), 146.77

(pyrazole-C), 153.14 (pyrazole-C), 158.49 (Ar-COCH₃), 158.63

(Ar-COCH₃), 159.66 (pyrimidine-CCH₃); LRMS m/z 359.3;

HRMS (C₂₂H₂₁N₃O) calcd 359.1637, found 359.1634.

5,7-Dimethyl-2,3-diphenylpyrazolo[1,5-a]pyrimidine

(12f). Following general procedure C, 9f was reacted with 2,4-

pentandione 10b to yield 12f. Isolated yield 86%; peach solid;

mp 170-171 °C; ¹H NMR (500 MHz, CDCl₃) δ 2.58 (s, 3H,

pyrimidine-CH₃), 2.81 (d, 3H, J ) 0.9 Hz, pyrimidine-CH₃),

6.59 (q, 1H, J ) 0.9 Hz, pyrimidine-H), 7.28 (m, 1H, Ar-H),

7.37 (m, 5H, Ar-H), 7.57 (m, 2H, Ar-H), 7.67 (m, 2H, Ar-

H); ¹³C NMR (125 MHz, CDCl₃) δ 17.19 (pyrimidine-CH₃),

25.05 (pyrimidine-CH₃), 108.20 (pyrazole-C), 126.53 (Ar-C),

128.48 (3C, Ar-C), 128.56 (2C, Ar-C), 129.30 (2C, Ar-C),

130.16 (2C, Ar-C), 132.50 (Ar-C), 133.84 (Ar-C), 145.07

(pyrimidine-CCH₃), 146.86 (pyrazole-C), 153.70 (pyrazole-

C), 158.90 (pyrimidine-CCH₃); LRMS m/z 299.2; HRMS

(C₂₀H₁₇N₃) calcd 299.1423, found 299.1422. Anal. (C₂₀H₁₇N₃)

C, H, N calcd: 80.24% C, 5.72% H, 14.04% N. Found: 79.93%

C, 5.64% H, 13.94% N.

5,7-Diethyl-2-(4-methoxyphenyl)-3-phenylpyrazolo[1,5-

a]pyrimidine (13a). Following general procedure C, 9a was

reacted with 3,5-heptanedione 10c to yield 13a. Isolated yield

81%; white solid; mp 123-125 °C; ¹H NMR (500 MHz, CDCl₃)

δ 1.38 (t, 3H, J ) 7.5 Hz, -CH₂CH₃), 1.49 (t, 3H, J ) 7.5 Hz,

-CH₂CH₃), 2.87 (q, 2H, J ) 7.6 Hz, pyrimidine-CH₂CH₃), 3.26

(q, 2H, J ) 7.5 Hz, pyrimidine-CH₂CH₃), 3.84 (s, 3H, Ar-

OCH₃), 6.59 (s, 1H, pyrimidine-H), 6.93 (AA′XX′, 2H, Ar-

H), 7.28 (m, 1H, Ar-H), 7.39 (m, 2H, Ar-H), 7.63 (m, 4H, Ar-

H); ¹³C NMR (125 MHz, CDCl₃) δ 10.41 (-CH₂CH₃), 13.10

(-CH₂CH₃), 23.54 (pyrimidine-CH₂CH₃), 31.69 (pyrimidine-

CH₂CH₃), 55.35 (Ar-OCH₃), 105.48 (pyrimidine-H), 107.54

(pyrazole-C), 113.96 (2C, Ar-C), 126.26 (Ar-C), 126.45 (Ar-

C), 128.34 (2C, Ar-C), 130.06 (2C, Ar-C), 130.50 (2C, Ar-

C), 132.81 (Ar-C), 146.87 (pyrazole-C), 149.97 (pyrimdine-

CCH₂CH₃), 153.29 (pyrazole-C), 159.88 (Ar-COCH₃), 163.57

(pyrimidine-CCH₂CH₃); LRMS m/z 357.2; HRMS (C₂₃H₂₃N₃O)

calcd 357.1834, found 357.1841.

5,7-Diethyl-2-(4-methoxyphenyl)-3-(3-methoxyphenyl)-

pyrazolo[1,5-a]pyrimidine (13d). Following general proce-

dure C, 9d was reacted with 3,5-heptanedione 10c to yield 13d.

1

Isolated yield 79%; white solid; mp 85-88 °C; H NMR (500

MHz, CDCl₃) δ 1.36 (t, 3H, J ) 7.6 Hz -CH₂CH₃), 1.47 (t, 3H,

J ) 7.5 Hz, -CH₂CH₃), 2.86 (q, 2H, J ) 7.6 Hz, pyrimidine-

CH₂CH₃), 3.23 (q, 2H, J ) 7.5 Hz, pyrimidine-CH₂CH₃), 3.76

(s, 3H, Ar-OCH₃), 3.83 (s, 3H, Ar-OCH₃), 6.58 (s, 1H,

pyrimidine-H), 6.82 (ddd, 1H, J ) 8.2, 2.6, 1.1 Hz, Ar-H),

6.91 (AA′XX′, 2H, Ar-H), 7.17 (dd, 1H, J ) 7.5, 0.9 Hz, Ar-

H), 7.25 (m, 2H, Ar-H), 7.61 (AA′XX′, 2H. Ar-H); ¹³C NMR

(125 MHz, CDCl₃) δ 10.45 (-CH₂CH₃), 13.02 (-CH₂CH₃), 23.57

(pyrimidine-CH₂CH₃), 31.68 (pyrimidine-CH₂CH₃), 55.24

(Ar-OCH₃), 55.42 (Ar-OCH₃), 105.57 (pyrimidine-C), 107.36

(pyrazole-C), 112.43 (Ar-C), 113.98 (2C, Ar-C), 115.11 (Ar-

C), 122.50 (Ar-C), 126.47 (Ar-C), 129.25 (2C, Ar-C), 130.61

(2C, Ar-C), 134.11 (Ar-C), 146.86 (pyrazole-C), 150.02

(pyrimidine-CCH₂CH₃), 153.42 (pyrazole-C), 159.56 (Ar-

COCH₃), 159.94 (Ar-COCH₃), 163.60 (pyrimidine-CCH₂CH₃);

LRMS m/z 387.3; HRMS (C₂₄H₂₅N₃O₂) calcd 387.1944, found

387.1947.

5,7-Diethyl-2-(3-methoxyphenyl)-3-(4-methoxyphenyl)-

pyrazolo[1,5-a]pyrimidine (13e). Following general proce-

dure C, 9e was reacted with 3,5-heptanedione 10c to yield 13e.

Isolated yield 91%; yellow solid; mp 100-101 °C; ¹H NMR (500

MHz, CDCl₃) δ 1.34 (t, 3H, J ) 7.6 Hz, -CH₂CH₃), 1.46 (t,

3H, J ) 7.5 Hz, -CH₂CH₃), 2.84 (q, 2H, J ) 7.6 Hz,

pyrimidine-CH₂CH₃), 3.23 (q, 2H, J ) 7.4 Hz, pyrimidine-

CH₂CH₃), 3.73 (s, 3H, Ar-OCH₃), 3.82 (s, 3H, Ar-OCH₃), 6.57

(s, 1H, pyrimidine-H), 6.90 (m, 3H, Ar-H), 7.25 (m, 3H, Ar-

H), 7.50 (AA′XX′, 2H, Ar-H); ¹³C NMR (125 MHz, CDCl₃) δ

10.44 (-CH₂CH₃), 13.17 (-CH₂CH₃), 23.53 (pyrimidine-CH₂-

CH₃), 31.73 (pyrimidine-CH₂CH₃), 55.30 (Ar-OCH₃), 55.37

(Ar-OCH₃), 105.59 (pyrimidine-H), 107.87 (pyrazole-C),

113.95 (2C, Ar-C), 114.28 (Ar-C), 114.48 (Ar-C), 121.76 (Ar-

C), 124.95 (Ar-C), 129.54 (Ar-C), 131.26 (2C, Ar-C), 135.59

(Ar-C), 146.75 (pyrazole-C), 150.04 (pyrimidine-CCH₂CH₃),

152.98 (pyrimidine-CCH₂CH₃), 158.36 (Ar-COCH₃), 159.66

(Ar-COCH₃), 163.49 (pyrimidine-CCH₂CH₃); LRMS m/z 387.3;

HRMS (C₂₄H₂₅N₃O₂) calcd 387.1942, found 387.1947.

5,7-Diethyl-3-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-

a]pyrimidine (13b). Following general procedure C, 9b was

reacted with 3,5-heptanedione 10c to yield 13b. Isolated yield

1

82%; light-yellow solid; mp 111-113 °C; H NMR (500 MHz,

5,7-Diethyl-2,3-diphenylpyrazolo[1,5-a]pyrimidine (13f).

Following general procedure C, 9f was reacted with 3,5-

heptanedione 10c to yield 13f. Isolated yield 79%; off-white

CDCl₃) δ 1.38 (t, 3H, J ) 7.5 Hz, -CH₂CH₃), 1.50 (t, 3H, J )

7.5 Hz, -CH₂CH₃), 2.87 (q, 2H, J ) 7.6 Hz, pyrimidine-CH₂-

CH₃), 3.26 (q, 2H, J ) 7.43 Hz, pyrimidine-CH₂CH₃), 3.85 (s,

3H, Ar-OCH₃), 6.60 (s, 1H, pyrimidine-H), 6.96 (AA′XX′, 2H,

Ar-H), 7.38 (m, 3H, Ar-H), 7.54 (AA′XX′, 2H, Ar-H), 7.71

(m, 2H, Ar-H); ¹³C NMR (125 MHz, CDCl₃) δ 10.41 (-CH₂CH₃),

13.13 (-CH₂CH₃), 23.51 (pyrimidine-CH₂CH₃), 31.70 (pyrim-

idine-CH₂CH₃), 55.31 (Ar-OCH₃), 105.52 (pyrimidine-H),

107.71 (pyrazole-C), 113.93 (2C, Ar-C), 124.96 (Ar-C), 128.28

(Ar-C), 128.48 (2C, Ar-C), 129.23 (2C, Ar-C), 131.15 (2C,

Ar-C), 134.10 (Ar-C), 146.72 (pyrazole-C), 149.98 (pyrimi-

dine-CCH₂CH₃), 153.16 (pyrazole-C), 158.29 (Ar-COCH₃),

163.41 (pyrimidine-CCH₂CH₃); LRMS m/z 357.2; HRMS

(C₂₃H₂₄N₃O) calcd 357.1843, found 357.1841.

1

solid; mp 143-144 °C; H NMR (500 MHz, CDCl₃) δ 1.39 (t,

3H, J ) 7.6 Hz, -CH₂CH₃), 1.51 (t, 3H, J ) 7.50 Hz,

-CH₂CH₃), 2.88 (q, 2H, J ) 7.6 Hz, -CH₂CH₃), 3.27 (qd 2H,

J ) 7.5, 0.6 Hz, -CH₂CH₃), 6.62 (t, 1H, J ) 0.6 Hz, pyrimi-

dine-H), 7.28 (m, 1H, Ar-H), 7.38 (m, 5H, Ar-H), 7.63 (m,

2H, Ar-H), 7.69 (m, 2H, Ar-H); ¹³C NMR (125 MHz, CDCl₃)

δ 10.43 (-CH₂CH₃), 13.10 (-CH₂CH₃), 23.57 (pyrimidine-CH₂-

CH₃), 31.73 (pyrimidine-CH₂CH₃), 105.71 (pyrimidine-C),

108.01 (pyrazole-C), 126.33 (Ar-C), 128.35 (2C, Ar-C), 128.39

(Ar-C), 128.51 (2C, Ar-C), 129.33 (2C, Ar-C), 130.08 (2C,

Ar-C), 132.61 (Ar-C), 134.02 (Ar-C), 146.84 (pyrazole-C),

150.09 (pyrimidine-CCH₂CH₃), 153.51 (pyrazole-C), 163.71

(pyrimidine-CCH₂CH₃); LRMS m/z 327.2; HRMS (C₂₂H₂₁N₃)

calcd 327.1729, found 327.1735. Anal. (C₂₂H₂₁N₃) C, H, N

calcd: 80.70% C, 6.46% H, 12.83% N. Found: 80.38% C, 6.42%

H, 12.77% N.

5,7-Diethyl-2,3-bis(4-methoxyphenyl)pyrazolo[1,5-a]-

pyrimidine (13c). Following general procedure C, 9c was

reacted with 3,5-heptanedione 10c to yield 13c. Isolated yield

1

88%; light-yellow solid; mp 129-131 °C; H NMR (500 MHz,

(CD₃)₂CO) δ 1.29 (t, 3H, J ) 7.6 Hz, -CH₂CH₃), 1.43 (t, 3H, J

) 7.5 Hz, -CH₂CH₃), 2.79 (q, 2H, J ) 7.6 Hz, pyrimidine-

CH₂CH₃), 3.18 (qd, 2H, J ) 7.5, 0.6 Hz, pyrimidine-CH₂CH₃),

3.81 (s, 6H, Ar-OCH₃), 6.78 (t, 1H, J ) 0.64 Hz, pyrimidine-

2-(4-Methoxyphenyl)-3-phenyl-5,7-bis(trifluoromethyl)-

pyrazolo[1,5-a]pyrimidine (14a). Following general proce-

dure C, 9a was reacted with 1,1,1,5,5,5-hexfluoro-2,4-penta-

dione 10d to yield 14a. Isolated yield 60%; yellow solid; mp

5884 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24

Compton et al.

1

159-161 °C; H NMR (500 MHz, CDCl₃) δ 3.85 (s, 3H, Ar-

C), 135.13 (q, J ) 37.8 Hz, pyrimidine-CCF₃), 145.25 (q, J )

37.8 Hz, pyrimidine-CCF₃), 146.48 (pyrazole-C), 156.45

(pyrazole-C), 159.56 (Ar-COCH₃), 159.84 (Ar-COCH₃); LRMS

m/z 467.2; HRMS (C₂₂H₁₅F₆N₃O₂) calcd 467.1064, found

467.1068.

OCH₃), 6.93 (AA′XX′, 2H, Ar-H), 7.41 (m, 1H, Ar-H), 7.47

(m, 3H, Ar-H, pyrimidine-H), 7.59 (m, 2H, Ar-H), 7.69

(AA′XX′, 2H, Ar-H); ¹³C NMR (125 MHz, CDCl₃) δ 55.40 (Ar-

OCH₃), 102.28 (m, pyrimidine-C), 112.31 (pyrazole-C), 114.25

(2C, Ar-C), 119.32 (q, J ) 275.3 Hz, -CF₃), 120.46 (q, J )

275.3 Hz, -CF₃), 124.17 (Ar-C), 127.97 (Ar-C), 128.82 (Ar-

C), 130.25 (2C, Ar-C), 130.28 (2C, Ar-C), 134.90 (2C, Ar-

C), 135.06 (q, J ) 37.8 Hz, pyrimidine-CCF₃), 145.46 (q, J )

37.8 Hz, pyrimidine-CCF₃), 146.73 (pyrazole-C), 156.77

(pyrazole-C), 160.87 (Ar-COCH₃); LRMS m/z 437.2; HRMS

(C₂₁F₁₃F₆N₃O) calcd 437.0963, found 437.0963;

2,3-Diphenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]-

pyrimidine (14f). Following general procedure C, 9f was

reacted with 1,1,1,5,5,5-hexfluoro-2,4-pentadione 10d to yield

14f. Isolated yield 73%; yellow solid; mp 177-179 °C; ¹H NMR

(500 MHz, CDCl₃) δ 7.44 (m, 6H, Ar-H), 7.50 (s, 1H, Ar-H),

7.59 (m, 2H, Ar-H), 7.75 (m, 2H, Ar-H); ¹³C NMR (125 MHz,

CDCl₃) δ 102.59 (m, pyrimidine-C), 112.99 (pyrazole-C),

119.27 (q, J ) 275.3 Hz, -CF₃), 120.42 (q, J ) 275.3 Hz, -CF₃),

128.06 (Ar-C), 128.83 (2C, Ar-C), 128.85 (Ar-C), 129.47 (2C,

Ar-C), 129.67 (2C, Ar-C), 130.03 (2C, Ar-C), 131.82 (Ar-

C), 135.27 (q, J ) 37.8 Hz, pyrimidine-CCF₃), 145.60 (q, J )

37.8 Hz, pyrimidine-CCF₃), 146.61 (pyrazole-C), 156.98

(pyrazole-C); LRMS m/z 407.2; HRMS (C₂₀H₁₁F₆N₃) calcd

407.0853, found 407.0853. Anal. (C₂₀H₁₁F₆N₃‚0.1H₂O) C, H, N

calcd: 58.72% C, 2.76% H, 10.27% N. Found: 58.44% C, 2.68%

H, 10.00% N.

2-(4-Methoxyphenyl)-3-phenyl-5,7-diisopropylpyrazolo-

[1,5-a]pyrimidine (15a). Following general procedure C, 9a

was reacted with 2,6-dimethyl-3,5-heptanedione 10e to yield

15a. Isolated yield 73%; white solid; mp 118-120 °C; ¹H NMR

(500 MHz, CDCl₃) δ 1.37 (d, 6H, J ) 6.9 Hz, -CH(CH₃)₂), 1.51

(d, 6H, J ) 6.9 Hz, -CH(CH₃)₂), 3.12 (sept, 1H, J ) 6.9 Hz,

pyrimidine-CH(CH₃)₂), 3.99 (sept, 1H, J ) 6.9 Hz, pyrimi-

dine-CH(CH₃)₂), 3.85 (s, 3H, Ar-OCH₃), 6.61 (s, 1H, pyrimi-

dine-H), 6.93 (AA′XX′, 2H, Ar-H), 7.28 (m, 1H, Ar-H), 7.38

(m, 2H, Ar-H), 7.66 (m, 4H, Ar-H); ¹³C NMR (125 MHz,

CDCl₃) δ 20.12 (2C, -CH(CH₃)₂), 22.12 (2C, -CH(CH₃)₂), 28.48

(pyrimidine-CH(CH₃)₂), 36.85 (pyrimidine-CH(CH₃)₂), 55.40

(Ar-OCH₃), 102.24 (pyrimidine-C), 107.38 (pyrazole-C),

113.98 (2C, Ar-C), 126.10 (Ar-C), 126.68 (Ar-C), 128.26 (2C,

Ar-C), 130.02 (2C, Ar-C), 130.59 (2C, Ar-C), 132.96 (Ar-

C), 146.90 (pyrazole-C), 153.20 (pyrazole-C), 154.45 (pyrim-

idine-CCH(CH₃)₂), 159.88 (Ar-COCH₃), 167.34 (pyrimidine-

CCH(CH₃)₂); LRMS m/z 385.3; HRMS (C₂₅H₂₇N₃O) calcd

385.2155, found 385.2154.

3-(4-Methoxyphenyl)-2-phenyl-5,7-bis(trifluoromethyl)-

pyrazolo[1,5-a]pyrimidine (14b). Following general proce-

dure C, 9b was reacted with 1,1,1,5,5,5-hexfluoro-2,4-penta-

dione 10d to yield 14b. Isolated yield 76%; yellow solid; mp

1

149-151 °C; H NMR (500 MHz, CDCl₃) δ 3.87 (s, 3H, Ar-

OCH₃), 6.99 (AA′XX′, 2H, Ar-H), 7.41 (m, 3H, Ar-H), 7.47

(s, 1H, pyrimidine-H), 7.50 (AA′XX′, 2H, Ar-H), 7.75 (m, 2H,

Ar-H); ¹³C NMR (125 MHz, CDCl₃) δ 55.47 (Ar-OCH₃), 102.51

(m, pyrimidine-C), 112.85 (pyrazole-C), 114.44 (2C, Ar-C),

119.37 (q, J ) 275.3 Hz, -CF₃), 120.53 (q, J ) 275.3 Hz, -CF₃),

122.24 (Ar-C), 128.88 (2C, Ar-C), 129.46 (2C, Ar-C), 129.64

(Ar-C), 131.47 (2C, Ar-C), 132.95 (Ar-C), 135.31 (q, J ) 37.8

Hz, pyrimidine-CCF₃), 145.37 (q, J ) 37.8 Hz, pyrimidine-

CCF₃), 146.54 (pyrazole-C), 156.75 (pyrazole-C), 159.61 (Ar-

COCH₃); LRMS m/z 437.3; HRMS (C₂₂H₁₅F₆N₃O) calcd 437.0957,

found 437.0959.

2,3-Bis(4-methoxyphenyl)-5,7-bis(trifluoromethyl)pyra-

zolo[1,5-a]pyrimidine (14c). Following general procedure C,

9c was reacted with 1,1,1,5,5,5-hexfluoro-2,4-pentadione 10d

to yield 14c. Isolated yield 84%; orange solid; mp 160-161 °C;

¹H NMR (500 MHz, (CD₃)₂CO) δ 3.83 (s, 3H, Ar-OCH₃), 3.85

(s, 3H, Ar-OCH₃), 6.96 (AA′XX′, 2H, Ar-H), 7.02 (AA′XX′, 2H,

Ar-H), 7.45 (AA′XX′, 2H, Ar-H), 7.64 (AA′XX′, 2H, Ar-H),

7.85 (s, 1H, pyrimidine-H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ

55.56 (Ar-OCH₃), 55.64 (Ar-OCH₃), 103.98 (m, pyrimidine-

C), 112.37 (pyrazole-C), 114.89 (2C, Ar-C), 114.97 (2C, Ar-

C), 120.40 (q, J ) 274.3, CF₃), 121.52 (q, J ) 274.3, CF₃),

123.30 (Ar-C), 125.11 (Ar-C), 131.09 (2C, Ar-C), 132.15 (2C,

Ar-C), 135.35 (q, J ) 37.8, pyrimidine-CCF₃), 145.86 (q, J )

37.8, pyrimidine-CCF₃), 147.55 (pyrazole-C), 156.53 (pyra-

zole-C), 160.41 (Ar-COCH₃), 161.68 (Ar-COCH₃); LRMS m/z

467.3; HRMS (C₂₂H₁₅F₆N₃O₂) calcd 467.1063, found 467.1068.

3-(4-Methoxyphenyl)-3-phenyl-5,7-diisopropylpyrazolo-

[1,5-a]pyrimidine (15b). Following general procedure C, 9b

was reacted with 2,6-dimethyl-3,5-heptanedione 10e to yield

1

15b. Isolated yield 83%; off-white solid; mp 147-148 °C; H

3-(3-Methoxyphenyl)-2-(4-methoxyphenyl)-5,7-bis(tri-

fluoromethyl)pyrazolo[1,5-a]pyrimidine (14d). Following

general procedure C, 9d was reacted with 1,1,1,5,5,5-hexfluoro-

2,4-pentadione 10d to yield 14d. Isolated yield 87%; yellow

NMR (500 MHz, CDCl₃) δ 1.36 (d, 6H, J ) 7.1 Hz, -CH(CH₃)₂),

1.51 (d, 6H, J ) 6.9 Hz, -CH(CH₃)₂), 3.11 (sept, 1H, J ) 6.9

Hz, pyrimidine-CH(CH₃)₂), 3.98 (sept, 1H, J ) 6.9 Hz,

pyrimidine-CH(CH₃)₂), 6.93 (s, 1H, pyrimidine-H), 7.39

(AA′XX′, 2H, Ar-H), 7.39 (m, 3H, Ar-H), 7.55 (AA′XX′, 2H,

Ar-H), 7.69 (m, 2H, Ar-H); ¹³C NMR (125 MHz, CDCl₃) δ

20.33 (2C, -CH(CH₃)₂), 22.14 (2C, -CH(CH₃)₂), 28.48 (pyrim-

idine-CH(CH₃)₂), 36.86 (pyrimidine-CH(CH₃)₂), 55.35 (Ar-

OCH₃), 102.26 (pyrimidine-C), 107.57 (pyrazole-C), 113.85

(2C, Ar-C), 125.14 (Ar-C), 128.29 (Ar-C), 128.51 (2C, Ar-

C), 129.35 (2C, Ar-C), 131.13 (2C, Ar-C), 134.34 (Ar-C),

146.72 (pyrazole-C), 153.09 (pyrazole-C), 154.51 (pyrimi-

dine-CCH(CH₃)₂), 158.19 (Ar-COCH₃), 167.19 (pyrimidine-

CCH(CH₃)₂); LRMS m/z 385.2; HRMS (C₂₅H₂₇N₃O) calcd

385.2153, found 385.2154.

2,3-Bis(4-methoxyphenyl)-5,7-diisopropylpyrazolo[1,5-

a]pyrimidine (15c). Following general procedure C, 9c was

reacted with 2,6-dimethyl-3,5-heptanedione 10e to yield 15c.

Isolated yield 89%; off-white solid; 108-110 °C; ¹H NMR (500

MHz, CDCl₃) δ 1.34 (d, 6H, J ) 6.9 Hz, -CH(CH₃)₂), 1.48 (d,

6H, J ) 6.9 Hz, -CH(CH₃)₂), 3.09 (sept, 1H, J ) 6.9 Hz,

-CH(CH₃)₂), 3.95 (sept, 1H, J ) 6.9 Hz, -CH(CH₃)₂), 3.84 (s,

3H, Ar-OCH₃), 3.85 (s, 3H, Ar-OCH₃), 6.57 (s, 1H, pyrimi-

dine-H), 6.92 (m, 4H, Ar-H), 7.54 (AA′XX′, 2H, Ar-H), 7.61

(AA′XX′, 2H, Ar-H); ¹³C NMR (125 MHz, CDCl₃) δ 20.23 (2C,

-CH(CH₃)₂), 22.15 (2C, -CH(CH₃)₂), 28.46 (pyrimidine-CH-

(CH₃)₂), 36.86 (pyrimidine-CH(CH₃)₂), 55.35 (Ar-OCH₃),

55.42 (Ar-OCH₃), 102.02 (pyrimidine-C), 107.11 (pyrazole-

C), 113.85 (2C, Ar-C), 113.98 (2C, Ar-C), 125.33 (Ar-C),

126.80 (2C, Ar-C), 130.53 (2C, Ar-C), 131.11 (2C, Ar-C),

1

solid; mp 137-140 °C; H NMR (500 MHz, CDCl₃) δ 3.79 (s,

3H, Ar-OCH₃), 3.85 (s, 3H, Ar-OCH₃), 6.93 (m, 3H, Ar-H),

7.12 (dt, 1H, J ) 7.7, 1.1 Hz, Ar-H), 7.15 (dd, 1H, J ) 2.6, 1.5

Hz, Ar-H), 7.34 (dd, 1H, J ) 8.2, 7.7 Hz, Ar-H), 7.44 (s, 1H,

pyrimidine-H), 7.68 (AA′XX′, 2H, Ar-H); ¹³C NMR (125 MHz,

CDCl₃) δ 55.42 (Ar-OCH₃), 55.52 (Ar-OCH₃), 102.30 (m,

pyrimidine-C), 112.19 (pyrazole-C), 114.01 (2C, Ar-C),

114.31 (2C, Ar-C), 115.55 (Ar-C), 119.32 (q, J ) 275.3 Hz,

-CF₃), 120.46 (q, J ) 275.3 Hz, -CF₃), 122.65 (Ar-C), 124.20

(Ar-C), 129.86 (Ar-C), 130.87 (2C, Ar-C), 135.12 (q, J ) 38.7

Hz, pyrimidine-CCF₃), 145.52 (q, J ) 37.8 Hz, pyrimidine-

CCF₃), 146.74 (pyrazole-C), 156.88 (pyrazole-C), 159.91 (Ar-

COCH₃), 160.96 (Ar-COCH₃); LRMS m/z 467.2; HRMS (C₂₂H₁₅-

N₃O₂) calcd 467.1063, found 467.1068.

2-(3-Methoxyphenyl)-3-(4-methoxyphenyl)-5,7-bis(tri-

fluoromethyl)pyrazolo[1,5-a]pyrimidine (14e). Following

general procedure C, 9e was reacted with 1,1,1,5,5,5-hexfluoro-

2,4-pentadione 10d to yield 14e. Isolated yield 93%; light-

1

orange solid; mp 142-143 °C; H NMR (500 MHz, CDCl₃) δ

3.76 (s, 3H, Ar-OCH₃), 3.86 (s, 3H, Ar-OCH₃), 6.98 (m, 3H,

Ar-H), 7.31 (m, 3H, Ar-H), 7.47 (s, 1H, pyrimidine-H), 7.50

(AA′XX′, 2H, Ar-H); ¹³C NMR (125 MHz, CDCl₃) δ 55.35 (Ar-

OCH₃), 55.40 (Ar-OCH₃), 102.47 (m, pyrimidine-C), 112.88

(pyrazole-C), 114.34 (2C, Ar-C), 114.50 (Ar-C), 115.53 (Ar-

C), 119.28 (q, J ) 275.3 Hz, -CF₃) 120.45 (q, J ) 275.3, -CF₃),

121.81 (Ar-C), 122.14 (Ar-C), 129.85 (Ar-C), 131.46 (2C, Ar-

Pyrazolo[1,5-a]pyrimidines

Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 5885

146.76 (pyrazole-C), 152.89 (pyrazole-C), 154.39 (pyrimi-

dine-CCH(CH₃)₂), 158.13 (Ar-COCH₃), 159.82 (Ar-COCH₃),

167.08 (pyrimidine-CCH(CH₃)₂); LRMS m/z 415.3; HRMS

(C₂₆H₂₉N₃O₂) calcd 415.2260, found 415.2260.

Ar-C), 134.316 (pyrimidine-CCH₃), 142.09 (pyrimidine-

CCH₃), 145.10 (pyrazole-C), 152.30 (pyrazole-C), 158.39 (Ar-

COCH₃); LRMS m/z 343.2; HRMS (C₂₂H₂₁N₃O) calcd 343.1679,

found 343.1685.

2,3-Bis(4-methoxyphenyl)-5,6,7-trimethylpyrazolo[1,5-

a]pyrimidine (17c). Following general procedure C, 9c was

reacted with 3-methyl-2,4-pentanedione 16 to yield 17c.

3-(3-Methoxyphenyl)-2-(4-methoxyphenyl)-5,7-diiso-

propylpyrazolo[1,5-a]pyrimidine (15d). Following general

procedure C, 9d was reacted with 2,6-dimethyl-3,5-heptanedi-

one 10e to yield 15d. Isolated yield 82%; off-white solid; mp

1

Isolated yield 81%; off-white solid; mp 201-203 °C; H NMR

1

(500 MHz, CDCl₃) δ 2.29 (s, 3H, pyrimidine-CH₃), 2.55 (s, 3H,

pyrimidine-CH₃), 2.82 (s, 3H, pyrimidine-CH₃), 3.82 (s, 3H,

Ar-OCH₃), 3.83 (s, 3H, Ar-OCH₃), 6.90 (AA′XX′, 2H, Ar-H),

6.93 (AA′XX′, 2H, Ar-H), 7.49 (AA′XX′, 2H, Ar-H), 7.61

(AA′XX′, 2H, Ar-H); ¹³C NMR (125 MHz, CDCl₃) δ 13.65

(pyrimidine-CH₃), 14.10 (pyrimidine-CH₃), 24.43 (pyrimi-

dine-CH₃), 55.35 (2C, Ar-OCH₃), 107.01 (pyrazole-C), 113.94

(2C, Ar-C), 114.00 (2C, Ar-C), 114.53 (pyrimidine-CCH₃),

125.23 (Ar-C), 126.61 (Ar-C), 130.33 (2C, Ar-C), 131.19 (2C,

Ar-C), 141.86 (pyrimidine-CCH₃), 145.15 (pyrazole-C), 152.00

(pyrazole-C), 158.27 (pyrimidine-CCH₃), 158.45 (Ar-COCH₃),

159.74 (Ar-COCH₃); LRMS m/z 373.2; HRMS (C₂₃H₂₃N₃O₂)

calcd 373.1795, found 373.1790.

3-(3-Methoxyphenyl)-2-(4-methoxyphenyl)-5,6,7-tri-

methylpyrazolo[1,5-a]pyrimidine (17d). Following general

procedure C, 9d was reacted with 3-methyl-2,4-pentanedione

16 to yield 17d. Isolated yield 78%; white solid; mp 143-145

°C; ¹H NMR (500 MHz, CDCl₃) δ 2.29 (s, 3H, pyrimidine-CH₃),

2.56 (s, 3H, pyrimidine-CH₃), 2.81 (s, 3H, pyrimidine-CH₃),

3.75 (s, 3H, Ar-OCH₃), 3.83 (s, 3H, Ar-OCH₃), 6.81 (ddd, 1H,

J ) 8.2, 2.6, 0.9 Hz, Ar-H), 6.91 (AA′XX′, 2H, Ar-H), 7.17

(dt, 1H, J ) 7.5, 0.9 Hz, Ar-H), 7.21 (d, 1H, J ) 1.3 Hz, Ar-

H), 7.27 (t, 1H, J ) 7.9 Hz, Ar-H), 7.62 (AA′XX′, 2H, Ar-H);

¹³C NMR (125 MHz, CDCl₃) δ 13.86 (pyrimidine-CH₃), 14.08

(pyrimidine-CH₃), 24.47 (pyrimidine-CH₃), 55.22 (Ar-OCH₃),

55.37 (Ar-OCH₃), 107.04 (pyrazole-C), 112.17 (Ar-C), 113.93

(2C, Ar-C), 114.72 (pyrimidine-CCH₃), 115.27 (Ar-C), 122.52

(Ar-C), 126.49 (Ar-C), 129.28 (Ar-C), 130.48 (2C, Ar-C),

134.15 (Ar-C), 141.95 (pyrimidine-CCH₃), 145.16 (pyrazole-

C), 152.37 (pyrazole-C), 158.73 (pyrimidine-CCH₃), 159.56

(Ar-COCH₃), 159.82 (Ar-COCH₃); LRMS m/z 373.2; HRMS

(C₂₃H₂₃N₃O₂) calcd 373.1794, found 373.1790.

2-(3-Methoxyphenyl)-3-(4-methoxyphenyl)-5,6,7-tri-

methylpyrazolo[1,5-a]pyrimidine (17e). Following general

procedure C, 17e was reacted with 3-methyl-2,4-pentanedione

16 to yield 17e. Isolated yield 83%; off-white solid; mp 160-

162 °C; ¹H NMR (500 MHz, CDCl₃) δ 2.28 (s, 3H, pyrimidine-

CH₃), 2.54 (s, 3H, pyrimidine-CH₃), 2.80 (s, 3H, pyrimidine-

CH₃), 3.72 (s, 3H, Ar-OCH₃), 3.81 (s, 3H, Ar-OCH₃), 6.89 (m,

3H, Ar-H), 7.24 (m, 3H, Ar-H), 7.47 (AA′XX′, 2H, Ar-H);

¹³C NMR (125 MHz, CDCl₃) δ 13.66 (pyrimidine-CH₃), 14.14

(pyrimidine-CH₃), 24.48 (pyrimidine-CH₃), 55.30 (Ar-OCH₃),

55.39 (Ar-OCH₃), 107.60 (pyrazole-C), 114.02 (2C, Ar-C),

114.09 (Ar-C), 114.44 (Ar-C), 114.83 (pyrimidine-CCH₃),

121.66 (Ar-C), 125.03 (Ar-C), 129.51 (Ar-C), 131.27 (2C, Ar-

C), 135.43 (Ar-C), 141.93 (pyrimidine-CCH₃), 145.14 (pyra-

zole-C), 151.96 (pyrazole-C), 158.37 (Ar-COCH₃), 158.62

(pyrimidine-CCH₃), 159.65 (Ar-COCH₃); LRMS m/z 373.2;

HRMS (C₂₃H₂₃N₃O₂) calcd 373.1791, found 373.1790.

General Procedure D for the Synthesis of Pyrazolo-

[1,5-a]pyrimidines Using p-Toluenesulfonic Acid. The

desired 3-amino-4,5-diarylpyrazole (0.5 mmol) was dissolved

in 10 mL of dichlorobenzene. The diketone (0.7 mmol) and

p-toluenesulfonic acid (0.7 mmol) were added, and the mixture

was heated to 130 °C for 24 h. The dichlorobenzene was

removed by rotary evaporation, and the resulting solid was

purified by flash chromatography with 30% EtOAc/70% hex-

ane.

125-126 °C; H NMR (500 MHz, CDCl₃) δ 1.39 (d, 6H, J )

6.9 Hz, -CH(CH₃)₂), 1.51 (d, 6H, J ) 6.9 Hz, -CH(CH₃)₂), 3.13

(sept, 1H, pyrimidine-CH(CH₃)₂), 3.80 (s, 3H, Ar-OCH₃), 3.86

(s, 3H, Ar-OCH₃), 3.98 (sept, 1H, pyrimidine-CH(CH₃)₂), 6.62

(s, 1H, pyrimidine-H), 6.84 (ddd, 1H, J ) 8.2, 2.6, 0.9 Hz,

Ar-H), 6.96 (AA′XX′, 2H, Ar-H), 7.12 (dt, 1H, J ) 7.7, 1.2

Hz, Ar-H), 7.28 (dd, 1H, J ) 8.2, 7.5 Hz, Ar-H), 7.37 (dd,

1H, J ) 2.6, 1.5 Hz, Ar-H), 7.66 (AA′XX′, 2H, Ar-H); ¹³C NMR

(125 MHz, CDCl₃) δ 20.21 (2C, -CH(CH₃)₂), 22.09 (2C, -CH-

(CH₃)₂), 28.47 (pyrimidine-CH(CH₃)₂), 36.77 (pyrimidine-CH-

(CH₃)₂), 55.21 (Ar-OCH₃), 55.41 (Ar-OCH₃), 102.39 (pyrim-

idine-C), 107.14 (pyrazole-C), 112.43 (Ar-C), 113.97 (2C,

Ar-C), 114.83 (Ar-C), 122.36 (Ar-C), 126.67 (Ar-C), 129.11

(Ar-C), 130.67 (2C, Ar-C), 134.23 (Ar-C), 146.86 (pyrazole-

C), 153.33 (pyrazole-C), 154.47 (pyrimidine-CCH(CH₃)₂),

159.49 (Ar-COCH₃), 159.92 (Ar-COCH₃), 167.34 (pyrimi-

dine-CCH(CH₃)₂); LRMS m/z 415.2; HRMS (C₂₆H₂₉N₃O₂) calcd

415.2261, found 415.2260.

2-(3-Methoxyphenyl)-3-(4-methoxyphenyl)-5,7-diiso-

propylpyrazolo[1,5-a]pyrimidine (15e). Following general

procedure C, 9e was reacted with 2,6-dimethyl-3,5-heptanedi-

one 10e to yield 15e. Isolated yield 89%; white solid; mp 118-

120 °C; ¹H NMR (500 MHz, CDCl₃) δ 1.35 (d, 6H, J ) 6.9 Hz,

-CH(CH₃)₂), 1.48 (d, 6H, J ) 7.1 Hz, -CH(CH₃)₂), 3.10 (sept,

1H, J ) 6.9 Hz, pyrimidine-CH(CH₃)₂), 3.76 (s, 3H, Ar-

OCH₃), 3.84 (s, 3H, Ar-OCH₃), 3.96 (sept, 1H, J ) 6.9 Hz,

pyrimidine-CH(CH₃)₂), 6.59 (s, 1H, pyrimidine-H), 6.92 (m,

3H, Ar-H), 7.27 (m, 3H, Ar-H), 7.55 (AA′XX′, 2H, Ar-H);

¹³C NMR (125 MHz, CDCl₃) δ 20.24 (2C, -CH(CH₃)₂), 22.13

(2C, -CH(CH₃)₂), 28.45 (pyrimidine-CH(CH₃)₂), 36.86 (pyrim-

idine-CH(CH₃)₂), 55.32 (Ar-OCH₃), 55.36 (Ar-OCH₃), 102.30

(pyrimidine-C), 107.67 (pyrazole-C), 113.83 (2C, Ar-C),

114.32 (Ar-C), 114.45 (Ar-C), 121.84 (Ar-C), 125.09 (Ar-

C), 129.53 (Ar-C), 131.19 (2C, Ar-C), 135.62 (Ar-C), 146.71

(pyrazole-C), 152.85 (pyrazole-C), 154.50 (pyrimidine-CCH-

(CH₃)₂), 158.22 (Ar-COCH₃), 159.66 (Ar-COCH₃), 167.21

(pyrimidine-CCH(CH₃)₂); LRMS m/z 415.3; HRMS (C₂₆H₂₉N₃O₂)

calcd 415.2261, found 415.2260.

2-(4-Methoxyphenyl)-5,6,7-trimethyl-3-phenylpyrazolo-

[1,5-a]pyrimidine (17a). Following general procedure C, 9a

was reacted with 3-methyl-2,4-pentanedione 16 to yield 17a.

Isolated yield 87%; white solid; mp 189-190 °C; ¹H NMR (500

MHz, CDCl₃) δ 2.31 (s, 3H, pyrimidine-CH₃), 2.57 (s, 3H,

pyrimidine-CH₃), 2.83 (s, 3H, pyrimidine-CH₃), 3.83 (s, 3H,

Ar-OCH₃), 6.90 (AA′XX′, 2H, Ar-H), 7.26 (m. 1H, ArH), 7.37

(m, 2H, Ar-H), 7.60 (m, 4H, Ar-H); ¹³C NMR (125 MHz,

CDCl₃) δ 13.71 (pyrimidine-CH₃), 14.14 (pyrimidine-CH₃),

24.50 (pyrimidine-CH₃), 55.40 (Ar-OCH₃), 107.31 (pyrazole-

C), 113.98 (2C, Ar-C), 114.72 (pyrimidine-CCH₃), 126.28

(Ar-C), 126.55 (Ar-C), 128.42 (2C, Ar-C), 130.09 (2C, Ar-

C), 130.46 (2C, Ar-C), 132.88 (Ar-C), 141.99 (pyrimidine-

CCH₃), 145.33 (pyrazole-C), 152.36 (pyrazole-C), 158.72

(pyrimidine-CCH₃), 159.84 (Ar-COCH₃); LRMS m/z 343.2;

HRMS (C₂₂H₂₁N₂O) calcd 343.1682, found 343.1685.

3-(4-Methoxyphenyl)-5,6,7-trimethyl-2-phenylpyrazolo-

[1,5-a]pyrimidine (17b). Following general procedure C, 9b

was reacted with 3-methyl-2,4-pentanedione 16 to yield 17b.

Isolated yield 81%; white solid; mp 182-184 °C; ¹H NMR (500

MHz, CDCl₃) δ 2.32 (s, 3H, pyrimidine-CH₃), 2.52 (s, 3H,

pyrimidine-CH₃), 2.84 (s, 3H, pyrimidine-CH₃), 3.83 (s, 3H,

Ar-OCH₃), 6.92 (AA′XX′, 2H, Ar-H), 7.35 (m, 3H, Ar-H), 7.48

(AA′XX′, 2H, Ar-H), 7.67 (m, 2H, Ar-H); ¹³C NMR (125 MHz,

CDCl₃) δ 13.76 (pyrimidine-CH₃), 14.21 (pyrimidine-CH₃),

24.51 (pyrimidine-CH₃), 55.43 (Ar-OCH₃), 107.56 (pyrazole-

C), 114.07 (2C, Ar-C), 114.82 (pyrimidine-CCH₃), 125.05

(Ar-C), 128.26 (2C, Ar-C), 129.22 (2C, Ar-C), 131.24 (2C,

5,7-Di-tert-butyl-2-(4-methoxyphenyl)-3-phenylpyrazolo-

[1,5-a]pyrimidine (19a). Following general procedure D, 9a

was reacted with 2,2,6,6-tetramethyl-3,5-heptanedione 18a to

yield 19a. Isolated yield 42%; light-yellow solid; mp 195-197

°C; ¹H NMR (500 MHz, CDCl₃) δ 1.41 (s, 9H, -C(CH₃)₃), 1.70

(s, 9H, -C(CH₃)₃), 3.86 (s, 3H, Ar-OCH₃), 6.79 (s, 1H,

pyrimidine-H), 6.94 (AA′XX′, 2H, Ar-H), 7.26 (m, 1H, Ar-

H), 7.38 (m, 2H, Ar-H), 7.68 (m, 4H, Ar-H); ¹³C NMR (125

5886 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24

Compton et al.

MHz, CDCl₃) δ 27.35 (3C, -C(CH₃)₃), 29.84 (3C, -C(CH₃)₃),

36.34 (pyrimidine-C(CH₃)₃), 38.44 (pyrimidine-C(CH₃)₃), 55.42

(Ar-OCH₃), 101.62 (pyrimidine-C), 106.56 (pyrazole-C),

113.90 (2C, Ar-C), 125.93 (Ar-C), 126.95 (Ar-C), 128.12 (2C,

Ar-C), 130.08 (2C, Ar-C), 130.59 (2C, Ar-C), 133.17 (Ar-

C), 147.54 (pyrazole-C), 152.02 (pyrazole-C), 155.14 (pyrim-

idine-CC(CH₃)₃), 159.82 (Ar-COCH₃), 168.90 (pyrimidine-

CC(CH₃)₃); LRMS m/z 413.2; HRMS (C₂₇H₃₁N₃O) calcd 413.2473,

found 413.2467.

5,7-Di-tert-butyl-3-(4-methoxyphenyl)-2-phenylpyrazolo-

[1,5-a]pyrimidine (19b). Following general procedure D, 9b

was reacted with 2,2,6,6-tetramethyl-3,5-heptanedione 18a to

yield 19b. Isolated yield 59%; off-white solid; mp 180-182 °C;

¹H NMR (500 MHz, CDCl₃) δ 1.42 (s, 9H, -C(CH₃)₃), 1.71 (s,

9H, -C(CH₃)₃), 3.86 (s, 3H, Ar-OCH₃), 6.80 (s, 1H, pyrimi-

dine-H), 6.94 (AA′XX′, 2H, Ar-H), 7.40 (m, 3H, Ar-H), 7.60

(AA′XX′, 2H, Ar-H), 7.75 (m, 2H, Ar-H); ¹³C NMR (125 MHz,

CDCl₃) δ 27.34 (3C, -C(CH₃)₃), 29.84 (3C, -C(CH₃)₃), 36.33

(pyrimidine-C(CH₃)₃), 38.42 (pyrimidine-C(CH₃)₃), 55.33 (Ar-

OCH₃), 101.67 (pyrimidine-C), 106.78 (pyrazole-C), 113.68

(2C, Ar-C), 125.36 (Ar-C), 128.17 (Ar-C), 128.42 (2C, Ar-

C), 129.34 (2C, Ar-C), 131.16 (2C, Ar-C), 134.60 (Ar-C),

147.35 (pyrazole-C), 151.88 (pyrazole-C), 155.14 (pyrimi-

dine-CC(CH₃)₃), 158.04 (Ar-COCH₃), 168.68 (pyrimidine-

CC(CH₃)₃); LRMS m/z 413.3; HRMS (C₂₇H₃₁N₃O) calcd 413.2472,

found 413.2467.

5,7-Di-tert-butyl-2,3-bis(4-methoxyphenyl)pyrazolo-

[1,5-a]pyrimidine (19c). Following general procedure D, 9c

was reacted with 2,2,6,6-tetramethyl-3,5-heptanedione 18a to

yield 19c. Isolated yield 84%; light-yellow solid; mp 158-161

°C; ¹H NMR (500 MHz, CDCl₃) δ 1.41 (s, 9H, -C(CH₃)₃), 1.70

(s, 9H, -C(CH₃)₃), 3.86 (s, 6H, Ar-OCH₃), 6.77 (s, 1H,

pyrimidine-H), 6.94 (m, 2H, Ar-H), 7.60 (AA′XX′, 2H, Ar-

H), 7.68 (AA′XX′, 2H, Ar-H); ¹³C NMR (125 MHz, CDCl₃) δ

27.33 (3C, -C(CH₃)₃), 29.84 (3C, -C(CH₃)₃), 36.31 (pyrimi-

dine-C(CH₃)₃), 38.39 (pyrimidine-C(CH₃)₃), 55.34 (Ar-OCH₃),

55.41 (Ar-OCH₃), 101.45 (pyrimidine-C), 106.29 (pyrazole-

C), 113.67 (2C, Ar-C), 113.89 (2C, Ar-C), 125.55 (Ar-C),

127.08 (Ar-C), 130.51 (2C, Ar-C), 131.14 (2C, Ar-C), 147.38

(pyrazole-C), 151.70 (pyrazole-C), 155.03 (pyrimidine-CC-

(CH₃)₃), 157.99 (Ar-COCH₃), 159.76 (Ar-COCH₃), 168.57

(pyrimidine-CC(CH₃)₃); LRMS m/z 443.3; HRMS (C₂₈H₃₃N₃O₂)

calcd 443.2568, found 443.2573.

5,7-Di-tert-butyl-3-(3-methoxyphenyl)-2-(4-methoxyphen-

yl)pyrazolo[1,5-a]pyrimidine (19d). Following general pro-

cedure D, 9d was reacted with 2,2,6,6-tetramethyl-3,5-hep-

tanedione 18a to yield 19d. Isolated yield 62%; white solid;

mp 146-148 °C; ¹H NMR (500 MHz, CDCl₃) δ 1.43 (s, 9H,

-C(CH₃)₃), 1.70 (s, 9H, -C(CH₃)₃), 3.81 (s, 3H, Ar-OCH₃), 3.86

(s, 3H, Ar-OCH₃), 6.80 (s, 1H, pyrimidine-H), 6.83 (dd, 1H,

J ) 7.9, 1.3 Hz, Ar-H), 6.94 (AA′XX′, 2H, Ar-H), 7.23 (m,

2H, Ar-H), 7.43 (m, 1H, Ar-H), 7.69 (AA′XX′, 2H, Ar-H);

¹³C NMR (125 MHz, CDCl₃) δ 27.33 (3C, -C(CH₃)₃), 29.85 (3C,

-C(CH₃)₃), 36.34 (pyrimidine-C(CH₃)₃), 38.45 (pyrimidine-

C(CH₃)₃), 55.27 (Ar-OCH₃), 55.42 (Ar-OCH₃), 101.65 (pyrim-

idine-C), 106.35 (pyrazole-C), 112.58 (Ar-C), 113.88 (Ar-

C), 114.61 (Ar-C), 122.39 (Ar-C), 126.92 (Ar-C), 127.90 (Ar-

C), 128.96 (Ar-C), 130.69 (2C, Ar-C), 134.44 (Ar-C), 147.49

(pyrazole-C), 152.18 (pyrazole-C), 155.20 (pyrimidine-CC-

(CH₃)₃), 159.45 (Ar-COCH₃), 159.86 (Ar-COCH₃), 168.94

(pyrimidine-CC(CH₃)₃); LRMS m/z 443.3; HRMS (C₂₈H₃₃N₃O₂)

calcd 443.2569, found 443.2573.

(Ar-C), 114.61 (Ar-C), 121.85 (Ar-C), 125.30 (Ar-C), 129.42

(Ar-C), 131.25 (2C, Ar-C), 135.90 (Ar-C), 147.35 (pyrazole-

C), 151.64 (pyrazole-C), 155.14 (pyrimidine-CC(CH₃)₃), 158.09

(Ar-COCH₃), 159.58 (Ar-COCH₃), 168.72 (pyrimidine-CC-

(CH₃)₃); LRMS m/z 443.3; HRMS (C₂₈H₃₃N₃O₂) calcd 443.2576,

found 443.2573.

2-(4-Methoxyphenyl)-3,5,7-triphenylpyrazolo[1,5-a]py-

rimidine (20a). Following general procedure D, 9a was

reacted with dibenzoylmethane 18b to yield 20a. Isolated yield

93%; yellow solid; mp 191-193 °C; ¹H NMR (500 MHz, CDCl₃)

δ 3.84 (s, 3H, Ar-OCH₃), 6.90 (AA′XX′, 2H, Ar-H), 7.32 (m,

1H, Ar-H), 7.44 (m, 2H, Ar-H), 7.51 (m, 3H, Ar-H), 7.60 (m,

3H, Ar-H), 7.65 (AA′XX′, 2H, Ar-H), 7.73 (m, 2H, Ar-H),

8.21 (m, 4H, Ar-H); ¹³C NMR (125 MHz, CDCl₃) δ 55.43 (Ar-

OCH₃), 105.26 (pyrimidine-C), 108.74 (pyrazole-C), 113.98

(2C, Ar-C), 126.18 (Ar-C), 126.52 (Ar-C), 127.43 (2C, Ar-

C), 128.44 (2C, Ar-C), 128.81 (2C, Ar-C), 129.02 (2C, Ar-

C), 129.68 (2C, Ar-C), 130.31 (2C, Ar-C), 130.37 (Ar-C),

130.64 (2C, Ar-C), 131.09 (Ar-C), 131.75 (Ar-C), 132.75 (Ar-

C), 137.72 (Ar-C), 146.37 (pyrazole-C), 148.18 (pyrimidine-

CPh), 154.18 (pyrazole-C), 155.85 (pyrimidine-CPh), 160.08

(Ar-COCH₃); LRMS m/z 453.2; HRMS (C₃₁H₂₃N₃O) calcd

453.1847, found 453.1841.

3-(4-Methoxyphenyl)-2,5,7-triphenylpyrazolo[1,5-a]py-

rimidine (20b). Following general procedure D, 9b was

reacted with dibenzoylmethane 18b to yield 20b. Isolated yield

1

67%; orange solid; mp 220-223 °C dec; H NMR (500 MHz,

CDCl₃) δ 3.88 (s, 3H, Ar-OCH₃), 6.99 (AA′XX′, 2H, Ar-H),

7.37 (m, 3H, Ar-H), 7.41 (s, 1H, pyrimidine-H), 7.51 (m, 3H,

Ar-H), 7.60 (m, 5H, Ar-H), 7.73 (m, 2H, Ar-H), 8.21 (m, 4H,

Ar-H); ¹³C NMR (125 MHz, CDCl₃) δ 55.46 (Ar-OCH₃), 105.33

(pyrimidine-C), 109.07 (pyrazole-C), 114.07 (2C, Ar-C),

124.98 (Ar-C), 127.38 (Ar-C), 127.45 (2C, Ar-C), 128.51 (2C,

Ar-C), 128.81 (2C, Ar-C), 128.88 (Ar-C), 129.03 (2C, Ar-

C), 129.38 (2C, Ar-C), 129.69 (2C, Ar-C), 130.34 (Ar-C),

131.08 (Ar-C), 131.44 (2C, Ar-C), 131.82 (Ar-C), 137.83 (Ar-

C), 146.44 (pyrazole-C), 148.08 (pyrimidine-CPh), 154.11

(pyrazole-C), 155.72 (pyrimidine-CPh), 158.61 (Ar-COCH₃);

LRMS m/z 453.1; HRMS (C₃₁H₂₃N₃O) calcd 453.1839, found

453.1841.

2,3-Bis(4-methoxyphenyl)-5,7-diphenylpyrazolo[1,5-a]-

pyrimidine (20c). Following general procedure D, 9c was

reacted with dibenzoylmethane 18b to yield 20c. Isolated yield

77%; orange solid; mp 206-208; ¹H NMR (500 MHz, CDCl₃) δ

3.83 (s, 3H, Ar-OCH₃), 3.88 (s, 3H, Ar-OCH₃), 6.90 (AA′XX′,

2H, Ar-H), 6.99 (AA′XX′, 2H, Ar-H), 7.39 (s, 1H, pyrimidine-

H), 7.50 (m, 3H, Ar-H), 7.63 (m, 7H, Ar-H), 8.18 (m, 2H, Ar-

H), 8.22 (m, 2H, Ar-H); ¹³C NMR (125 MHz, CDCl₃) δ 55.45

(2C, Ar-OCH₃), 105.15 (pyrimidine-C), 108.50 (pyrazole-C),

113.98 (2C, Ar-C), 114.03 (2C, Ar-C), 125.08 (Ar-C), 126.31

(Ar-C), 127.41 (2C, Ar-C), 128.81 (2C, Ar-C), 129.02 (2C,

Ar-C), 129.66 (3C, Ar-C), 130.31 (Ar-C), 130.56 (2C, Ar-

C), 131.06 (Ar-C), 131.40 (2C, Ar-C), 131.82 (Ar-C), 137.81

(2C, Ar-C), 146.29 (pyrazole-C), 149.07 (pyrimidine-CPh),

153.90 (pyrazole-C), 155.61 (pyrimidine-CPh), 158.47 (Ar-

COCH₃), 160.02 (Ar-COCH₃); LRMS m/z 483.2; HRMS

(C₃₂H₂₅N₃O₂) calcd 483.1944, found 483.1947.

3-(3-Methoxyphenyl)-2-(4-methoxyphenyl)-5,7-diphen-

ylpyrazolo[1,5-a]pyrimidine (20d). Following general pro-

cedure D, 9d was reacted with dibenzoylmethane 18b to yield

20d. Isolated yield 92%; yellow solid; mp 202-203 °C; ¹H NMR

(500 MHz, CDCl₃) δ 3.81 (s, 3H, Ar-OCH₃), 3.84 (s, 3H, Ar-

OCH₃), 6.88 (ddd, 1H, J ) 7.9, 2.6, 1.1 Hz), 6.92 (AA′XX′, 2H,

Ar-H), 7.29 (dt, 1H, J ) 7.5, 1.3 Hz, Ar-H), 7.33 (dd, 1H, J

) 7.9, 7.7 Hz, Ar-H), 7.36 (dd, 1H, J ) 2.6, 1.5 Hz), 7.41 (s,

1H, Ar-H), 7.51 (m, 3H, Ar-H), 7.60 (m, 3H, Ar-H), 7.67

(AA′XX′, 2H, Ar-H), 8.21 (m, 4H, Ar-H); ¹³C NMR (125 MHz,

CDCl₃) δ 55.36 (Ar-OCH₃), 55.45 (Ar-OCH₃), 105.25 (pyrim-

idine-C), 108.53 (pyrazole-C), 112.74 (Ar-C), 113.97 (2C,

Ar-C), 115.28 (Ar-C), 122.75 (Ar-C), 126.16 (Ar-C), 127.41

(2C, Ar-C), 128.81 (2C, Ar-C), 129.02 (2C, Ar-C), 129.35

(Ar-C), 129.68 (2C, Ar-C), 130.38 (Ar-C), 130.71 (2C, Ar-

C), 131.11 (Ar-C), 131.72 (Ar-C), 134.02 (Ar-C), 137.71 (Ar-

C), 146.40 (pyrazole-C), 148.14 (pyrimidine-CPh), 154.27

5,7-Di-tert-butyl-2-(3-methoxyphenyl)-3-(4-methoxyphen-

yl)pyrazolo[1,5-a]pyrimidine (19e). Following general pro-

cedure D, 9e was reacted with 2,2,6,6-tetramethyl-3,5-hep-

tanedione 18a to yield 19e. Isolated yield 63%; light-yellow

1

solid; mp 144-145 °C; H NMR (500 MHz, CDCl₃) δ 1.40 (s,

9H, -C(CH₃)₃), 1.69 (s, 9H, -C(CH₃)₃), 3.77 (s, 3H, Ar-OCH₃),

3.85 (s, 3H, Ar-OCH₃), 6.78 (s, 1H, pyrimidine-H), 6.92 (m,

3H, Ar-H), 7.30 (m, 3H, Ar-H), 7.59 (AA′XX′, 2H, Ar-H);

¹³C NMR (125 MHz, CDCl₃) δ 27.34 (3C, -C(CH₃)₃), 29.83 (3C,

-C(CH₃)₃), 36.33 (pyrimidine-C(CH₃)₃), 38.42 (pyrimidine-

C(CH₃)₃), 55.34 (Ar-OCH₃), 55.36 (Ar-OCH₃), 101.73 (pyrim-

idine-C), 106.91 (pyrazole-C), 113.65 (2C, Ar-C), 113.99

Pyrazolo[1,5-a]pyrimidines

Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 5887

(pyrazole-C), 155.85 (pyrimidine-CPh), 159.65 (Ar-COCH₃),

160.11 (Ar-COCH₃); LRMS m/z 483.2; HRMS (C₃₂H₂₅N₃O₂)

calcd 483.1949, found 483.1947.

2,3-Bis(4-hydroxyphenyl)pyrazolo[1,5-a]pyrimidine

(21c). Following general procedure E, 11c was deprotected to

yield 21c. Isolated yield 79%; yellow solid; mp >260 °C; ¹H

NMR (500 MHz, (CD₃)₂CO) δ 6.85 (m, 4H, Ar-H), 6.98 (dd,

1H, J ) 6.9, 3.9 Hz, pyrimidine-H), 7.35 (AA′XX′, 2H, Ar-

H), 7.52 (AA′XX′, 2H, Ar-H), 8.37 (s, 1H, Ar-OH), 8.46 (dd,

1H, J ) 4.1, 1.7 Hz, pyrimidine-H), 8.58 (s, 1H, Ar-OH), 8.88

(dd, 1H, J ) 6.9, 1.7 Hz, pyrimidine-H); ¹³C NMR δ 108.07

(pyrimidine-C), 108.46 (pyrazole-C), 115.31 (2C, Ar-C),

115.36 (2C, Ar-C), 123.64 (Ar-C), 125.06 (Ar-C), 130.33 (2C,

Ar-C), 131.42 (2C, Ar-C), 135.12 (pyrimidine-C), 146.87

(pyrazole-C), 149.28 (pyrimidine-C), 153.45 (pyrazole-C),

156.48 (Ar-COH), 158.06 (Ar-COH); LRMS m/z 303.1; HRMS

(C₁₈H₁₃N₃O₂) calcd 303.1002, found 303.1008.

2-(3-Methoxyphenyl)-3-(4-methoxyphenyl)-5,7-diphen-

ylpyrazolo[1,5-a]pyrimidine (20e). Following general pro-

cedure D, 9e was reacted with dibenzoylmethane 18b to yield

20e. Isolated yield 86%; orange solid; mp 190-191 °C dec; ¹H

NMR (500 MHz, CDCl₃) δ 3.75 (s, 3H, Ar-OCH₃), 3.88 (s, 3H,

Ar-OCH₃), 6.92 (ddd, 1H, J ) 7.7, 2.6, 1.3 Hz, Ar-H), 7.00

(AA′XX′, 2H, Ar-H), 7.30 (m, 3H, Ar-H), 7.41 (s, 1H, Ar-H),

7.50 (m, 3H, Ar-H), 7.60 (m, 3H, Ar-H), 7.65 (AA′XX′, 2H,

Ar-H), 8.19 (m, 2H, Ar-H), 8.22 (m, 2H, Ar-H); ¹³C NMR

(125 MHz, CDCl₃) δ 55.36 (Ar-OCH₃), 55.43 (Ar-OCH₃),

105.38 (pyrimidine-C), 109.09 (pyrazole-C), 113.98 (2C, Ar-

C), 114.49 (2C, Ar-C), 121.86 (Ar-C), 124.82 (Ar-C), 127.39

(2C, Ar-C), 128.79 (2C, Ar-C), 129.00 (2C, Ar-C), 129.52

(Ar-C), 129.64 (2C, Ar-C), 130.34 (Ar-C), 131.08 (Ar-C),

131.45 (2C, Ar-C), 131.67 (Ar-C), 135.11 (Ar-C), 137.68 (Ar-

C), 146.36 (pyrimidine-CPh), 147.99 (pyrazole-C), 153.79

(pyrazole-C), 155.69 (pyrimidine-CPh), 158.53 (Ar-COCH₃),

159.63 (Ar-COCH₃); LRMS m/z 483.2; HRMS (C₃₂H₂₅N₃O₂)

calcd 483.1942, found 483.1947.

General Procedure E for the Deprotection of Pyra-

zolo[1,5-a]pyrimidines. The methoxyphenylpyrazolo[1,5-a]-

pyrimidine (0.3 mmol) was dissolved in 5 mL of dry CH₂Cl₂

and cooled to 0 °C. A solution of BF₃‚SMe₂(1.8 mmol/methoxy)

was added dropwise to the mixture. The solution was allowed

to slowly warm to room temperature and stirred for a total of

18 h. The reaction was stopped by the addition of 2 mL of water

and 8 mL of methanol. The mixture was placed under a

nitrogen stream for 2 h to blow off the SMe₂. An additional 10

mL of water was added, and the solution was extracted with

EtOAc (3 × 15 mL). The combined organic phases were washed

with saturated NaCl (2 × 10 mL) and dried with Na₂SO₄. The

resulting solid was purified by preparatory thin-layer chro-

matography. After isolation the sample was dried under

vacuum in an Aberhalden apparatus in refluxing benzene for

24-48 h. Even after this process some samples still contained

water in the crystals. This was confirmed by ¹H NMR, and

suitable corrections are made for this water in evaluation of

combustion microanalysis data.

2-(4-Hydroxyphenyl)-3-(3-hydroxyphenyl)pyrazolo[1,5-

a]pyrimidine (21d). Following general procedure E, 11d was

deprotected to yield 21d. Isolated yield 67%; light-yellow solid;

1

mp >260 °C; H NMR (500 MHz, (CD₃)₂CO) δ 6.77 (ddd, 1H,

J ) 8.2, 2.6, 1.1 Hz, Ar-H), 6.85 (AA′XX′, 2H, Ar-H), 6.99

(ddd, 1H, J ) 7.7, 1.5, 1.1 Hz, Ar-H), 7.01 (dd, 1H, J ) 6.9,

4.1 Hz, pyrimidine-H), 7.06 (dd, 1H, J ) 2.6, 1.7 Hz, Ar-H),

7.19 (t, 1H, J ) 7.93 Hz, Ar-H), 7.51 (AA′XX′, 2H, Ar-H),

8.28 (s, 1H, Ar-OH), 8.49 (dd, 1H, J ) 3.9, 1.7 Hz, pyrimi-

dine-H), 8.59 (s, 1H, Ar-OH), 8.90 (dd, 1H, J ) 6.9, 1.7 Hz,

pyrimidine-H); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 108.67

(pyrazole-C), 109.31 (pyrimidine-C), 114.40 (Ar-C), 116.04

(2C, Ar-C), 117.78 (Ar-C), 122.19 (Ar-C), 125.54 (Ar-C),

129.94 (Ar-C), 131.12 (2C, Ar-C), 134.60 (Ar-C), 135.88

(pyrimidine-C), 147.63 (pyrazole-C), 150.25 (pyrimidine-C),

154.45 (pyrazole-C), 158.15 (Ar-COH), 158.80 (Ar-COH);

LRMS m/z 303.1; HRMS (C₁₈H₁₃N₃O₂) calcd 303.0999, found

303.1008.

2-(3-Hydroxyphenyl)-3-(4-hydroxyphenyl)pyrazolo[1,5-

a]pyrimidine (21e). Following general procedure E, 11e was

deprotected to yield 21e. Isolated yield 59%; yellow solid; mp

1

>260 °C; H NMR (500 MHz, (CD₃)₂SO) δ 6.77 (m, 3H, Ar-

H), 6.97 (dt, 1H, J ) 7.7, 1.3 Hz, Ar-H), 7.03 (dd, 1H, J ) 2.4,

1.5 Hz, Ar-H), 7.05 (dd, 1H, J ) 7.1, 4.1 Hz, pyrimidine-H),

7.16 (t, 1H, J ) 7.8 Hz, Ar-H), 7.23 (AA′XX′, 2H, Ar-H), 8.51

(dd, 1H, J ) 3.9, 1.7 Hz, pyrimidine-H), 9.11 (dd, 1H, J )

7.1, 1.7 Hz, pyrimidine-H), 9.43 (s, 1H, Ar-OH), 9.48 (dd,

1H, Ar-OH); ¹³C NMR (125 MHz, (CD₃)₂SO) δ 108.01 (pyra-

zole-C), 108.89 (pyrimidine-C), 115.20 (2C, Ar-C), 115.29

(Ar-C), 115.49 (Ar-C), 119.29 (Ar-C), 122.03 (Ar-C), 129.41

(Ar-C), 130.91 (2C, Ar-C), 134.26 (Ar-C), 135.56 (pyrimi-

dine-C), 145.99 (pyrazole-C), 149.77 (pyrimidine-C), 152.42

(pyrazole-C), 156.24 (Ar-COH), 157.30 (Ar-COH); LRMS m/z

303.1; HRMS (C₂₀H₁₃N₃O₂) calcd 303.1007, found 303.1008.

2-(4-Hydroxyphenyl)-3-phenylpyrazolo[1,5-a]pyrimi-

dine (21a). Following general procedure E, 11a was depro-

tected to yield 21a. Isolated yield 82%; light-yellow solid; mp

1

188-189 °C; H NMR (500 MHz, (CD₃)₂CO) δ 6.85 (AA′XX′,

2H, Ar-H), 6.97 (dd, 1H, J ) 7.1, 4.1 Hz, pyrimidine-H), 7.27

(m, 1H, Ar-H), 7.36 (m, 2H, Ar-H), 7.49 (AA′XX′, 2H, Ar-

H), 7.54 (m, 2H, Ar-H), 8.47 (dd, 1H, J ) 4.1, 1.7 Hz,

pyrimidine-H), 8.89 (dd, 1H, J ) 7.1, 1.7 Hz, pyrimidine-

H); ¹³C NMR (125 MHz, (CD₃)₃CO) δ 108.55 (pyrazole-C),

109.31 (pyrimidine-C), 116.04 (2C, Ar-C), 125.30 (Ar-C),

127.22 (Ar-C), 128.92 (2C, Ar-C), 130.79 (2C, Ar-C), 131.08

(2C, Ar-C), 133.24 (Ar-C), 135.84 (pyrimidine-C), 147.81

(pyrazole-C), 150.35 (pyrimidine-C), 154.37 (pyrazole-C),

158.77 (Ar-COH); LRMS m/z 287.1; HRMS (C₁₈H₁₃N₃O) calcd

287.1056, found 287.1059. Anal. (C₁₈H₁₃N₃O‚0.1H₂O) C, H, N

calcd: 74.78% C, 4.60% H, 14.53% N. Found: 74.87% C, 4.63%

H, 14.12% N.

2-(4-Hydroxyphenyl)-5,7-dimethyl-3-phenylpyrazolo-

[1,5-a]pyrimidine (22a). Following general procedure E, 12a

was deprotected to yield 22a. Isolated yield 52%; white solid;

1

mp 213-216 °C; H NMR (500 MHz, (CD₃)₂CO) δ 2.48 (s, 3H,

pyrimidine-CH₃), 2.73 (d, 3H, J ) 0.9 Hz, pyrimidine-CH₃),

6.77 (q, 1H, J ) 0.9 Hz, pyrimidine-H), 6.83 (AA′XX′, 2H, Ar-

H), 7.25 (m, 1H, Ar-H), 7.35 (m, 2H, Ar-H), 7.48 (AA′XX′,

2H, Ar-H), 7.53 (m, 2H, Ar-H), 8.59 (s, 1H, Ar-OH); ¹³C

NMR (125 MHz, (CD₃)₂CO) δ 16.78 (pyrimidine-CH₃), 24.64

(pyrimidine-CH₃), 107.65 (pyrazole-C), 109.44 (pyrimidine-

C), 115.95 (2C, Ar-C), 126.01 (Ar-C), 126.91 (Ar-C), 128.85

(2C, Ar-C), 130.88 (2C, Ar-C), 131.06 (2C, Ar-C), 134.01

(Ar-C), 145.84 (pyrimidine-CCH₃), 147.47 (pyrazole-C),

153.80 (pyrazole-C), 158.64 (Ar-COH), 159.41 (pyrimidine-

CCH₃); LRMS m/z 315.2; HRMS (C₂₀H₁₇N₃O) calcd 315.1372,

found 315.1372. Anal. (C₂₀H₁₇N₃O‚0.1H₂O) C, H, N calcd:

75.74% C, 5.47% H, 13.25% N. Found: 75.65% C, 5.45% H,

12.90% N.

3-(4-Hydroxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimi-

dine (21b). Following general procedure E, 11b was depro-

tected to yield 21b. Isolated yield 89%; yellow solid; mp 219-

221 °C; ¹H NMR (500 MHz, (CD₃)₂CO) δ 6.87 (AA′XX′, 2H,

Ar-H), 7.03 (dd, 1H, J ) 7.1, 4.1 Hz, pyrimidine-H), 7.34

(AA′XX′, 2H, Ar-H), 7.39 (m, 3H, Ar-H), 7.67 (m, 2H, Ar-

H), 8.50 (dd, 1H, J ) 3.9, 1.7 Hz, pyrimidine-H), 8.93 (dd,

1H, J ) 7.1, 1.9 Hz, pyrimidine-H); ¹³C NMR (125 MHz,

(CD₃)₂CO) δ 109.44 (pyrazole-C), 109.51 (pyrimidine-C),

115.99 (2C, Ar-C), 123.96 (Ar-C), 129.13 (2C, Ar-C), 129.19

(2C, Ar-C), 129.63 (2C, Ar-C), 132.07 (Ar-C), 135.95 (pyrim-

idine-C), 147.47 (pyrazole-C), 150.19 (pyrimidine-C), 153.87

(pyrazole-C), 157.23 (Ar-COH); LRMS m/z 287.1; HRMS

(C₁₈H₁₃N₃O) calcd 287.1055, found 287.1058. Anal. (C₁₈H₁₃N₃O‚

0.1H₂O) C, H, N calcd: 74.78% C, 4.60% H, 14.53% N. Found:

74.85% C, 4.57% H, 14.17% N.

3-(4-Hydroxyphenyl)-5,7-dimethyl-2-phenylpyrazolo-

[1,5-a]pyrimidine (22b). Following general procedure E, 12b

was deprotected to yield 22b. Isolated yield 23%; white solid;

mp 253-255 °C; ¹H NMR (500 MHz, (CD₃)₂CO) δ 2.49 (s, 3H,

pyrimidine-CH₃), 2.75 (d, 3H, J ) 0.9 Hz, pyrimidine-CH₃),

6.81 (q, 1H, J ) 1.1 Hz, pyrimidine-H), 6.85 (AA′XX′, 2H, Ar-

H), 7.32 (AA′XX′, 2H, Ar-H), 7.37 (m, 3H, Ar-H), 7.66 (m,

2H, Ar-H), 8.35 (s, 1H, Ar-OH); ¹³C NMR (125 MHz, (CD₃)₂-

5888 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24

Compton et al.

CO), δ 16.75 (pyrimidine-CH₃), 24.66 (pyrimidine-CH₃),

109.57 (pyrimidine-C), 115.84 (pyrazole-C), 115.93 (2C, Ar-

C), 124.64 (Ar-C), 128.85 (Ar-C), 129.04 (2C, Ar-C), 129.65

(2C, Ar-C), 132.13 (2C, Ar-C), 135.11 (Ar-C), 145.85 (pyrim-

idine-CCH₃), 147.39 (pyrazole-C), 153.28 (pyrazole-C), 158.15

(pyrimidine-CCH₃), 159.21 (Ar-COH); LRMS m/z 315.2;

HRMS (C₂₀H₁₇N₃O) calcd 315.1372, found 315.1372. Anal.

(C₂₀H₁₇N₃O‚0.1H₂O) C, H, N calcd: 75.74% C, 5.47% H, 13.25%

N. Found: 75.40% C, 5.35% H, 13.02% N.

CH₂CH₃), 31.47 (pyrimidine-CH₂CH₃), 106.19 (pyrimidine-

H), 107.26 (pyrazole-C), 115.58 (2C, Ar-C), 125.72 (Ar-C),

126.44 (Ar-C), 128.43 (2C, Ar-C), 130.40 (2C, Ar-C), 130.74

(2C, Ar-C), 133.64 (Ar-C), 147.16 (pyrazole-C), 150.39

(pyrimidine-CCH₂CH₃), 153.41 (pyrazole-C), 158.24 (Ar-

COH), 163.90 (pyrimidine-CCH₂CH₃); LRMS m/z 343.2; HRMS

(C₂₂H₂₁N₃O) calcd 343.1686, found 343.1685. Anal. (C₂₂H₂₁N₃O‚

0.2H₂O) C, H, N calcd: 76.14% C, 6.22% H, 12.11% N. Found:

76.09% C, 6.08% H, 11.96% N.

2,3-Bis(4-hydroxyphenyl)-5,7-dimethylpyrazolo[1,5-a]-

pyrimidine (22c). Following general procedure E, 12c was

deprotected to yield 22c. Isolated yield 50%; light-yellow solid;

mp 261-264 °C; ¹H NMR (500 MHz, (CD₃)₂CO) δ 2.47 (s, 3H,

pyrimidine-CH₃), 2.73 (d, 3H, J ) 0.9 Hz, pyrimidine-CH₃),

6.75 (q, 1H, J ) 1.1 Hz, pyrimidine-H), 6.84 (m, 4H, Ar-H),

7.33 (AA′XX′, 2H, Ar-H), 7.52 (AA′XX′, 2H, Ar-H), 8.32 (s,

1H, Ar-OH), 8.53 (s, 1H, Ar-OH); ¹³C NMR (125 MHz, (CD₃)₂-

CO) δ 16.75 (pyrimidine-CH₃), 24.62 (pyrimidine-CH₃),

107.81 (pyrazole-C), 109.16 (pyrimidine-C), 115.87 (2C, Ar-

C), 115.91 (2C, Ar-C), 124.96 (Ar-C), 126.28 (Ar-C), 130.96

(2C, Ar-C), 132.12 (2C, Ar-C), 145.67 (pyrimidine-CCH₃),

147.39 (pyrazole-C), 153.49 (pyrazole-C), 156.91 (pyrimi-

dine-CCH₃), 158.53 (Ar-COH), 158.89 (Ar-COH); LRMS m/z

331.1; HRMS (C₂₀H₁₇N₃O₂) calcd 331.1325, found 331.1321.

Anal. (C₂₀H₁₇N₃O₂‚0.4H₂O) C, H, N calcd: 70.95% C, 5.30%

H, 12.41% N. Found: 70.77% C, 5.14% H, 12.02% N.

5,7-Diethyl-3-(4-hydroxyphenyl)-2-phenylpyrazolo[1,5-

a]pyrimidine (23b). Following general procedure E, 13b was

deprotected to yield 23b. Isolated yield 46%; off-white solid;

1

mp 200 201 °C; H NMR (500 MHz, (CD₃)₂CO) δ 1.31 (t, 3H,

J ) 7.5 Hz, -CH₂CH₃), 1.45 (t, 3H, J ) 7.4 Hz, -CH₂CH₃),

2.82 (q, 2H, J ) 7.6 Hz, pyrimidine-CH₂CH₃), 3.20 (qd, 2H, J

) 7.5, 0.9 Hz, pyrimidine-CH₂CH₃), 6.82 (t, 1H, J ) 0.9 Hz,

pyrimidine-H), 6.85 (AA′XX′, 2H, Ar-H), 7.37 (m, 5H, Ar-

H), 7.66 (m, 2H, Ar-H), 8.33 (s, 1H, Ar-OH); ¹³C NMR (125

MHz, (CD₃)₂CO) δ 10.67 (-CHCH₃), 13.07 (-CH₂CH₃), 23.99

(pyrimidine-CH₂CH₃), 31.87 (pyrimidine-CH₂CH₃), 106.68

(pyrimidine-C), 108.47 (pyrazole-C), 115.90 (2C, Ar-C),

124.67 (Ar-C), 128.93 (2C, Ar-C), 129.02 (Ar-C), 129.71 (2C,

Ar-C), 132.04 (2C, Ar-C), 135.17 (Ar-C), 147.41 (pyrazole-

C), 150.75 (pyrimidine-CCH₂CH₃), 153.22 (pyrazole-C), 156.95

(Ar-COH), 164.05 (pyrimidine-CCH₂CH₃); LRMS m/z 343.2;

HRMS (C₂₂H₂₁N₃O) calcd 343.1687, found 343.1685. Anal.

(C₂₂H₂₁N₃O) C, H, N calcd: 76.94% C, 6.16% H, 12.24% N.

Found: 76.64% C, 6.16% H, 12.11% N.

5,7-Diethyl-2,3-bis(4-hydroxyphenyl)pyrazolo[1,5-a]-

pyrimidine (23c). Following general procedure E, 13c was

deprotected to yield 23c. Isolated yield 56%; yellow solid; mp

148-152 °C; ¹H NMR (500 MHz, (CD₃)₂SO) δ 1.23 (t, 3H, J )

7.5, -CH₂CH₃), 1.37 (t, 3H, J ) 7.5 Hz, -CH₂CH₃), 2.75 (q,

2H, J ) 7.6 Hz, pyrimidine-CH₂CH₃), 3.11 (q, 2H, J ) 7.5

Hz, pyrimidine-CH₂CH₃), 6.76 (m, 4H, Ar-H), 6.83 (s, 1H,

pyrimidine-H), 7.22 (AA′XX′, 2H, Ar-H), 7.38 (AA′XX′, 2H,

Ar-H), 9.38 (s, 1H, Ar-OH), 9.62 (s, 1H, Ar-H); ¹³C NMR

(125 MHz, (CD₃)₂SO) δ 10.23 (-CH₂CH₃), 12.79 (-CH₂CH₃),

22.91 (pyrimidine-CH₂CH₃), 30.72 (pyrimidine-CH₂CH₃),

105.66 (pyrimidine-C), 106.51 (pyrazole-C), 115.13 (2C, Ar-

C), 115.17 (2C, Ar-C), 122.97 (Ar-C), 124.22 (Ar-C), 129.79

(2C, Ar-C), 130.88 (2C, Ar-C), 145.99 (pyrazole-C), 149.48

(pyrimidine-CCH₂CH₃), 152.08 (pyrazole-C), 155.93 (Ar-

COH), 157.64 (Ar-COH), 162.89 (pyrimidine-CCH₂CH₃);

LRMS m/z 359.2; HRMS (C₂₂H₂₁N₃O₂) calcd 359.1630, found

359.1634.

2-(4-Hydroxyphenyl)-3-(3-hydroxyphenyl)-5,7-dimeth-

ylpyrazolo[1,5-a]pyrimidine (22d). Following general pro-

cedure E, 12d was deprotected to yield 22d. Isolated yield 43%;

1

off-white solid; mp 252-255 °C; H NMR (500 MHz, (CD₃)₂-

CO) δ 2.48 (s, 3H, pyrimidine-CH₃), 2.72 (d, 3H, J ) 0.6 Hz,

pyrimidine-CH₃), 6.75 (ddd, 1H, J ) 8.2, 2.6, 0.9 Hz, Ar-H),

6.77 (q, 1H, J ) 0.9 Hz, pyrimidine-H), 6.84 (AA′XX′, 2H, Ar-

H), 6.99 (dt, 1H, J ) 7.5, 1.1 Hz, Ar-H), 7.06 (dd, 1H, J ) 2.6,

1.6 Hz, Ar-H), 7.17 (t, 1H, J ) 7.8 Hz, Ar-H), 7.51 (AA′XX′,

2H, Ar-H), 8.25 (s, 1H, Ar-OH), 8.54 (s, 1H, Ar-OH); ¹³C

NMR (125 MHz, (CD₃)₂CO) δ 16.78 (pyrimidine-CH₃), 24.65

(pyrimidine-CH₃), 107.76 (pyrazole-C), 109.38 (pyrimidine-

C), 114.09 (Ar-C), 115.93 (2C, Ar-C), 117.87 (Ar-C), 122.31

(Ar-C), 126.10 (Ar-C), 129.81 (Ar-C), 131.08 (2C, Ar-C),

135.25 (Ar-C), 145.80 (pyrimidine-CCH₃), 147.49 (pyrazole-

C), 153.78 (pyrazole-C), 158.06 (Ar-COH), 158.59 (Ar-COH),

159.28 (pyrimidine-CCH₃); LRMS m/z 331.1; HRMS (C₂₀H₁₇-

N₃O₂) calcd 331.1324, found 331.1321. Anal. (C₂₀H₁₇N₃O₂‚

0.1H₂O) C, H, N calcd: 72.10% C, 5.20% H, 12.61% N. Found:

71.79% C, 5.11% H, 12.61% N.

2-(3-Hydroxyphenyl)-3-(4-hydroxyphenyl)-5,7-dimeth-

ylpyrazolo[1,5-a]pyrimidine (22e). Following general pro-

cedure E, 12e was deprotected to yield 22e. Isolated yield 73%;

light-yellow solid; mp 202-205 °C; ¹H NMR (500 MHz, (CD₃)₂-

CO) δ 2.48 (s, 3H, pyrimidine-CH₃), 2.72 (d, 3H, J ) 0.9 Hz,

pyrimidine-CH₃), 6.76 (q, 1H, J ) 1.1 Hz, pyrimidine-H), 6.84

(m, 3H, Ar-H), 7.13 (dt, 1H, J ) 7.7, 1.3 Hz, Ar-H), 7.19 (m,

2H, Ar-H), 7.34 (AA′XX′, 2H, Ar-H), 8.32 (s, 1H, Ar-OH),

8.37 (s, 1H, Ar-OH); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 16.74

(pyrimidine-CH₃), 24.64 (pyrimidine-CH₃), 108.46 (pyrazole-

C), 109.49 (pyrimidine-C), 115.87 (2C, Ar-C), 116.00 (Ar-

C), 116.53 (Ar-C), 121.00 (Ar-C), 124.68 (Ar-C), 130.05 (Ar-

C), 132.12 (2C, Ar-C), 136.36 (Ar-C), 145.77 (pyrimdine-

CCH₃), 147.31 (pyrazole-C), 153.27 (pyrazole-C), 156.92

(pyrimidine-CCH₃), 158.13 (Ar-COH), 159.10 (Ar-COH);

LRMS m/z 331.1; HRMS (C₂₀H₁₇N₃O₂) calcd 331.1320, found

331.1320.

5,7-Diethyl-2-(4-hydroxyphenyl)-3-(3-hydroxyphenyl)-

pyrazolo[1,5-a]pyrimidine (23d). Following general proce-

dure E, 13d was deprotected to yield 23d. Isolated yield 63%;

light-yellow solid; mp 218-219 °C; ¹H NMR (500 MHz, (CD₃)₂-

CO) δ 1.29 (t, 3H, J ) 7.6 Hz, -CH₂CH₃), 1.45 (t, 3H, J ) 7.5

Hz, -CH₂CH₃), 2.81 (q, 2H, J ) 7.6 Hz, pyrimidine-CH₂CH₃),

3.19 (qd, 2H, J ) 7.5. 0.9 Hz, pyrimidine-CH₂CH₃), 6.75 (ddd,

1H, J ) 8.2, 2.6, 1.1 Hz, Ar-H), 6.81 (q, 1H, J ) 0.9 Hz,

pyrimidine-H), 6.84 (AA′XX′, 2H, Ar-H), 7.02 (dt, 1H, J )

7.7, 1.1 Hz, Ar-H), 7.10 (dd, 1H, J ) 2.1, 1.7 Hz, Ar-H), 7.17

(t, 1H, J ) 7.2 Hz, Ar-H), 7.52 (AA′XX′, 2H, Ar-H), 8.28 (s,

1H, Ar-OH), 8.58 (s, 1H, Ar-OH); ¹³C NMR (125 MHz, (CD₃)₂-

CO) δ 10.69 (-CH₂CH₃), 13.13 (-CH₂CH₃), 24.03 (pyrimidine-

CH₂CH₃), 31.89 (pyrimidine-CH₂CH₃), 106.50 (pyrimidine-

C), 107.74 (pyrazole-C), 114.01 (Ar-C), 115.93 (2C, Ar-C),

117.79 (Ar-C), 122.21 (Ar-C), 126.17 (Ar-C), 129.76 (Ar-

C), 131.14 (2C, Ar-C), 135.25 (Ar-C), 147.55 (pyrazole-C),

150.74 (pyrimidine-CCH₂CH₃), 153.79 (pyrazole-C), 158.08

(Ar-COH), 158.61 (Ar-COH), 164.19 (pyrimidine-CCH₂CH₃);

LRMS m/z 359.3; HRMS (C₂₂H₂₁N₃O₂) calcd 359.1632, found

359.1634. Anal. (C₂₂H₂₁N₃O₂‚0.2H₂O) calcd 72.79% C, 5.94%

H, 11.57% N. Found: 72.42% C, 6.01% H, 11.74% N.

5,7-Diethyl-2-(4-hydroxyphenyl)-3-phenylpyrazolo[1,5-

a]pyrimidine (23a). Following general procedure E, 13a was

deprotected to yield 23a. Isolated yield 60%; peach solid; mp

1

92-95 °C; H NMR (500 MHz, (CD₃)₂CO) δ 1.30 (t, 3H, J )

7.6 Hz, -CH₂CH₃), 1.45 (t, 3H, J ) 7.5 Hz, -CH₂CH₃), 2.81

(q, 2H, J ) 7.6 Hz, pyrimidine-CH₂CH₃), 3.20 (q, 2H, J )

7.5, 0.9 Hz, pyrimidine-CH₂CH₃), 6.82 (t, 1H, J ) 0.9 Hz,

pyrimidine-H), 6.85 (AA′XX′, 2H, Ar-H), 7.25 (m, 1H, Ar-

H), 7.35 (m, 2H, Ar-H), 7.49 (AA′XX′, 2H, Ar-H), 7.57 (m,

2H, Ar-H), 8.55 (s, 1H, Ar-OH); ¹³C NMR (125 MHz, (CD₃)₂-

CO) δ 10.29 (-CH₂CH₃), 12.65 (-CH₂CH₃), 23.63 (pyrimidine-

5,7-Diethyl-2-(3-hydroxyphenyl)-3-(4-hydroxyphenyl)-

pyrazolo[1,5-a]pyrimidine (23e). Following general proce-

dure E, 13e was deprotected to yield 23e. Isolated yield 61%;

light-yellow solid; mp 190 °C dec; ¹H NMR (500 MHz, (CD₃)₂-

CO) δ 1.29 (t, 3H, J ) 7.6 Hz, -CH₂CH₃), 1.45 (t, 3H, J ) 7.4

Hz, -CH₂CH₃), 2.81 (q, 2H, J ) 7.6 Hz, pyrimidine-CH₂CH₃),

Pyrazolo[1,5-a]pyrimidines

Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 5889

3.19 (qd, 2H, J ) 7.5, 0.9 Hz, pyrimidine-CH₂CH₃), 6.81 (t,

1H, J ) 0.9 Hz, pyrimidine-H), 6.84 (m, 3H, Ar-H), 7.13 (dt,

1H, J ) 7.7, 1.3 Hz, Ar-H), 7.19 (m, 2H, Ar-H), 7.38 (AA′XX′,

2H, Ar-H), 8.31 (s, 1H, Ar-OH), 8.36 (s, 1H, Ar-OH); ¹³C

NMR (125 MHz, (CD₃)₂CO) δ 10.69 (-CH₂CH₃), 13.07 (-CH₂-

CH₃), 24.00 (pyrimidine-CH₂CH₃), 31.87 (pyrimidine-CH₂-

CH₃), 106.64 (pyrimidine-C), 108.45 (pyrazole-C), 115.84 (2C,

Ar-C), 115.98 (Ar-C), 116.59 (Ar-C), 121.05 (Ar-C), 124.71

(Ar-C), 130.06 (Ar-C), 132.04 (2C, Ar-C), 136.45 (Ar-C),

147.36 (pyrazole-C), 150.72 (pyrimidine-CCH₂CH₃), 153.24

(pyrazole-C), 156.87 (Ar-COH), 158.15 (Ar-COH), 163.98

(pyrimidine-CCH₂CH₃); LRMS m/z 359.2; HRMS (C₂₂H₂₁N₃O₂)

calcd 359.1638, found 359.1634. Anal. (C₂₂H₂₁N₃O₂‚0.4H₂O) C,

H, N calcd: 72.07% C, 5.90% H, 11.46% N. Found: 71.71% C,

5.90% H, 11.22% N.

117.84 (Ar-C), 120.39 (q, J ) 274.3 Hz, -CF₃), 121.51 (q, J )

274.3 Hz, -CF₃), 122.23 (Ar-C), 123.96 (Ar-C), 130.52 (Ar-

C), 131.34 (2C, Ar-C), 132.70 (Ar-C), 135.27 (q, J ) 37.8 Hz,

pyrimidine-CCF₃), 145.89 (q, J ) 37.8 Hz, pyrimidine-CCF₃),

147.60 (pyrazole-C), 156.98 (pyrazole-C), 158.45 (Ar-COH),

159.63 (Ar-COH); LRMS m/z 439.1; HRMS (C₂₀H₁₁F₆N₃O₂)

calcd 439.0756, found 439.0755. Anal. (C₂₀H₁₁F₆N₃O₂) C, H,

N calcd: 54.68% C, 2.52% H, 9.57% N. Found: 54.32% C,

2.30% H, 9.29% N.

2-(3-Hydroxyphenyl)-3-(4-hydroxyphenyl)-5,7-bis(tri-

fluoromethyl)pyrazolo[1,5-a]pyrimidine (24e). Following

general procedure E, 14e was deprotected to yield 24e. Isolated

yield 68%; yellow solid; mp >260 °C; ¹H NMR (500 MHz,

(CD₃)₂CO) δ 6.93 (m, 3H, Ar-H), 7.17 (dt, 1H, J ) 7.7, 1.1

Hz, Ar-H), 7.25 (m, 2H, Ar-H), 7.38 (AA′XX′, 2H, Ar-H), 7.87

(s, 1H, pyrimidine-H), 8.59 (s, 1H, Ar-OH), 8.65 (s, 1H, Ar-

OH); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 104.22 (m, pyrimidine-

C), 113.29 (pyrazole-C), 116.39 (2C, Ar-C), 116.54 (Ar-C),

117.23 (Ar-C), 120.37 (q, J ) 274.3 Hz, -CF₃), 121.03 (Ar-

C), 121.50 (q, J ) 274.3 Hz, -CF₃), 121.96 (Ar-C), 130.53 (Ar-

C), 132.23 (2C, Ar-C), 134.25 (Ar-C), 135.42 (q, J ) 37.8 Hz,

pyrimidine-CCF₃), 145.84 (q, J ) 37.8 Hz, pyrimidine-CCF₃),

147.35 (pyrazole-C), 156.49 (pyrazole-C), 158.18 (Ar-COH),

158.42 (Ar-COH); LRMS m/z 439.1; HRMS (C₂₀H₁₁F₆N₃O₂)

calcd 439.0767, found 439.0755. Anal. (C₂₀H₁₁F₆N₃O₂) C, H,

N calcd: 54.68% C, 2.52% H, 9.57% N. Found: 54.55% C,

2.46% H, 9.48% N.

2-(4-Hydroxyphenyl)-3-phenyl-5,7-diisopropylpyrazolo-

[1,5-a]pyrimidine (25a). Following general procedure E, 15a

was deprotected to yield 25a. Isolated yield 56%; peach solid;

mp 190-193 °C; ¹H NMR (500 MHz, (CD₃)₂CO) δ 1.31 (d, 6H,

J ) 6.9 Hz, -CH(CH₃)₂), 1.48 (d, 6H, J ) 6.9 Hz, -CH(CH₃)₂),

3.10 (sept, 1H, J ) 6.9 Hz, pyrimidine-CH(CH₃)₂), 3.89 (sept,

1H, J ) 6.9 Hz, pyrimidine-CH(CH₃)₂), 6.85 (m, 3H, Ar-H

(2H), pyrimidine-H (1H)), 7.24 (m, 1H, Ar-H), 7.35 (m, 2H,

Ar-H), 7.49 (AA′XX′, 2H, Ar-H), 7.59 (m, 2H, Ar-H), 8.55

(s, 1H, Ar-OH); ¹³C NMR (500 MHz, (CD₃)₂CO) δ 20.06 (2C,

-CH(CH₃)₂), 22.06 (2C, -CH(CH₃)₂), 29.27 (pyrimidine-

C(CH₃)₂), 37.17 (pyrimidine-CH(CH₃)₂), 103.65 (pyrimidine-

C), 107.63 (pyrazole-C), 116.01 (2C, Ar-C), 126.18 (Ar-C),

126.79 (Ar-C), 128.83 (2C, Ar-C), 130.72 (2C, Ar-C), 131.19

(2C, Ar-C), 134.02 (Ar-C), 147.57 (pyrazole-C), 153.84

(pyrazole-C), 155.08 (pyrimidine-CCH(CH₃)₂), 158.67 (Ar-

COH), 168.13 (pyrimidine-CCH(CH₃)₂); LRMS m/z 371.2;

HRMS (C₂₄H₂₅N₃O) calcd 371.1998, found 371.1998. Anal.

(C₂₄H₂₅N₃O‚0.2H₂O) C, H, N calcd: 76.85% C, 6.83% H, 11.20%

N. Found: 76.86% C, 6.81% H, 10.97% N.

2-(4-Hydroxyphenyl)-3-phenyl-5,7-bis(trifluoromethyl)-

pyrazolo[1,5-a]pyrimidine (24a). Following general proce-

dure E, 14a was deprotected to yield 24a. Isolated yield 69%;

1

yellow solid; mp 195-197 °C; H NMR (500 MHz, (CD₃)₂CO)

δ 6.88 (AA′XX′, 2H, Ar-H), 7.41 (m, 1H, Ar-H), 7.46 (m, 2H,

Ar-C), 7.55 (m, 4H, Ar-H), 7.87 (s, 1H, pyrimidine-H), 8.78

(s, 1H, Ar-OH); ¹³C NMR (125 MHz, (CD₃)₂CO), δ 104.06 (m,

pyrimidine-C), 112.29 (pyrazole-C), 116.39 (2C, Ar-C),

120.39 (q, J ) 274.3 Hz, -CF₃), 121.50 (q, J ) 274.3 Hz, -CF₃),

123.90 (Ar-C), 128.59 (Ar-C), 129.46 (2C, Ar-C), 130.99 (2C,

Ar-C), 131.33 (2C, Ar-C), 131.54 (Ar-C), 135.30 (q, J ) 37.8

Hz, pyrimidine-CCF₃), 146.23 (q, J ) 37.8 Hz, pyrimidine-

CCF₃), 147.65 (pyrazole-C), 157.03 (pyrazole-C), 159.68 (Ar-

COH); LRMS m/z 423.1; HRMS (C₂₀H₁₁F₆N₃O) calcd 423.0810,

found 423.0806. Anal. (C₂₀H₁₁F₆N₃O) C, H, N calcd: 56.75%

C, 2.62% H, 9.93% N. Found: 56.71% C, 2.55% H, 9.58% N.

3-(4-Hydroxyphenyl)-2-phenyl-5,7-bis(trifluoromethyl)-

pyrazolo[1,5-a]pyrimidine (24b). Following general proce-

dure E, 14b was deprotected to yield 24b. Isolated yield 79%;

1

orange solid; mp 206-208 °C; H NMR (500 MHz, (CD₃)₂CO)

δ 6.93 (AA′XX′, 2H, Ar-H), 7.36 (AA′XX′, 2H, Ar-H), 7.44 (m,

3H, Ar-H), 7.72 (m, 2H, Ar-H), 7.88 (s, 1H, pyrimidine-H),

8.60 (s, 1H, Ar-OH); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 104.30

(m, pyrimidine-C), 113.32 (pyrazole-C), 116.45 (2C, Ar-C),

120.39 (q, J ) 274.3 Hz, -CF₃), 121.50 (q, J ) 274.3 Hz, -CF₃),

121.94 (Ar-C), 129.45 (2C, Ar-C), 129.77 (Ar-C), 130.16 (2C,

Ar-C), 132.33 (2C, Ar-C), 133.06 (Ar-C), 135.54 (q, J ) 37.8

Hz, pyrimidine-CCF₃), 145.99 (q, J ) 37.8 Hz, pyrimidine-

CCF₃), 147.38 (pyrazole-C), 156.52 (pyrazole-C), 158.25 (Ar-

COH); LRMS m/z 423.1; HRMS (C₂₀H₁₁F₆N₃O) calcd 423.0809,

found 423.0808. Anal. (C₂₀H₁₁F₆N₃O) C, H, N calcd: 56.75%

C, 2.62% H, 9.93% N. Found: 56.45% C, 2.42% H, 9.68% N.

2,3-Bis(4-hydroxyphenyl)-5,7-bis(trifluoromethyl)pyra-

zolo[1,5-a]pyrimidine (24c). Following general procedure E,

14c was deprotected to yield 24c. Isolated yield 90%; orange

3-(4-Hydroxyphenyl)-3-phenyl-5,7-diisopropylpyrazolo-

[1,5-a]pyrimidine (25b). Following general procedure E, 15b

was deprotected to yield 25b. Isolated yield 81%; white solid;

mp 201-202 °C; ¹H NMR (500 MHz, CD₃OD) δ 1.31 (d, 6H, J

) 7.1 Hz, -CH(CH₃)₂), 1.46 (d, 6H, J ) 7.1 Hz, -CH(CH₃)₂),

3.06 (sept, 1H, J ) 6.9 Hz, -CH(CH₃)₂), 3.85 (sept, 1H, J )

6.9 Hz, -CH(CH₃)₂), 6.77 (m, 3H, Ar-H and pyrimidine-H),

7.27 (AA′XX′, 2H, Ar-H), 7.31 (m, 3H, Ar-H), 7.58 (m, 2H,

Ar-H); ¹³C NMR (125 MHz, CD₃OD) δ 20.25 (2C, -CH(CH₃)₂),

22.21 (2C, -CH(CH₃)₂), 29.66 (pyrimidine-CH(CH₃)₂), 37.70

(pyrimidine-CH(CH₃)₂), 103.59 (pyrimidine-C), 109.22 (pyra-

zole-C), 116.10 (2C, Ar-C), 124.75 (Ar-C), 129.24 (2C, Ar-

C), 129.30 (Ar-C), 130.17 (2C, Ar-C), 132.42 (2C, Ar-C),

135.20 (Ar-C), 147.74 (pyrazole-C), 154.28 (pyrazole-C),

156.01 (pyrimidine-CCH(CH₃)₂), 157.30 (Ar-COH), 168.95

(pyrimidine-CCH(CH₃)₂); LRMS m/z 371.2; HRMS (C₂₄H₂₅N₃O)

calcd 371.1996, found 371.1998. Anal. (C₂₄H₂₅N₃O) C, H, N

calcd: 77.60% C, 6.78% N, 11.31% N. Found: 77.42% C, 6.75%

H, 11.68% N.

2,3-Bis(4-hydroxyphenyl)-5,7-diisopropylpyrazolo[1,5-

a]pyrimidine (25c). Following general procedure E, 15c was

deprotected to yield 25c. Isolated yield 68%; light-yellow solid;

mp 235-238 °C; ¹H NMR (500 MHz, (CD₃)₂CO) δ 1.30 (d, 6H,

J ) 6.9 Hz, -CH(CH₃)₂), 1.47 (d, 6H, J ) 6.9 Hz, -CH(CH₃)₂),

3.07 (sept, 1H, J ) 6.9 Hz, pyrimidine-CH(CH₃)₂), 3.87 (septd,

1H, J ) 6.9, 0.4 Hz, pyrimidine-CH(CH₃)₂), 6.81 (t, 1H, J )

0.4 Hz, pyrimidine-H), 6.85 (m, 4H, Ar-H), 7.40 (AA′XX′, 2H,

1

solid; mp 223-226 °C; H NMR (500 MHz, (CD₃)₂CO) δ 6.89

(AA′XX′, 2H, Ar-H), 6.94 (AA′XX′, 2H, Ar-H), 7.37 (AA′XX′,

2H, Ar-H), 7.59 (AA′XX′, 2H, Ar-H), 7.82 (s, 1H, pyrimidine-

H), 8.59 (s, 1H, Ar-OH), 8.77 (s, 1H, Ar-OH); ¹³C NMR (125

MHz, (CD₃)₂CO) δ 103.73 (m, pyrimidine-C), 112.47 (pyra-

zole-C), 116.33 (2C, Ar-C), 116.42 (2C, Ar-C), 120.41 (q, CF₃,

J ) 274.3 Hz), 121.54 (q, CF₃, J ) 274.3 Hz), 122.25 (Ar-C),

124.13 (Ar-C), 131.22 (2C, Ar-C), 132.22 (2C, Ar-C), 135.25

(q, J ) 37.8 Hz, pyrimidine-CCF₃), 145.76 (q, J ) 37.8 Hz,

pyrimidine-CCF₃), 147.46 (pyrazole-C), 156.78 (pyrazole-

C), 158.14 (Ar-COH), 159.57 (Ar-COH); LRMS m/z 439.2;

HRMS (C₂₀H₁₁F₆N₃O₂) calcd 439.0748, found 439.0744. Anal.

(C₂₀H₁₁F₆N₃O₂‚0.1H₂O) C, H, N calcd: 54.46% C, 2.562% H,

9.53% N. Found: 54.23% C, 2.40% H, 9.24% N.

3-(3-Hydroxyphenyl)-2-(4-hydroxyphenyl)-5,7-bis(tri-

fluoromethyl)pyrazolo[1,5-a]pyrimidine (24d). Following

general procedure E, 14d was deprotected to yield 24d.

Isolated yield 76%; orange solid; mp 229-231 °C; ¹H NMR (500

MHz, (CD₃)₂CO) δ 6.88 (m, 3H, Ar-H), 7.00 (ddd, 1H, J ) 7.5,

1.1, 0.4 Hz, Ar-H), 7.05 (dd, 1H, J ) 2.04, 0.43 Hz), 7.28 (dd,

1H, J ) 8.2, 7.5 Hz, Ar-H), 7.59 (AA′XX′, 2H, Ar-H), 7.86 (s,

1H, pyrimidine-H), 8.48 (s, 1H, Ar-OH), 8.77 (s, 1H, Ar-

OH); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 103.98 (m, pyrimidine-

C), 112.32 (pyrazole-C), 115.70 (Ar-C), 116.35 (2C, Ar-C),

5890 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24

Compton et al.

Ar-H), 7.52 (AA′XX′, 2H, Ar-H), 8.30 (s, 1H, Ar-OH), 8.52

(s, 1H, Ar-OH); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 20.06 (2C,

-CH(CH₃)₂), 22.08 (2C, -CH(CH₃)₂), 29.21 (-CH(CH₃)₂), 37.15

(-CH(CH₃)₂), 103.29 (pyrimidine-C), 107.77 (pyrazole-C),

115.84 (2C, Ar-C), 115.93 (2C, Ar-C), 124.98 (Ar-C), 126.41

(Ar-C), 131.07 (2C, Ar-C), 131.95 (2C, Ar-C), 147.41 (pyra-

zole-C), 153.43 (pyrazole-C), 154.88 (pyrimidine-CCH-

(CH₃)₂), 156.78 (Ar-COH), 158.53 (Ar-COH), 167.58 (pyrim-

idine-CCH(CH₃)₂); LRMS m/z 387.2; HRMS (C₂₄H₂₅N₃O₂)

calcd 387.1941, found 387.1947.

pyrimidine-CH₃), 2.47 (s, 3H, pyrimidine-CH₃), 2.74 (s, 3H,

pyrimidine-CH₃), 6.76 (AA′XX′, 2H, Ar-H), 7.20 (AA′XX′, 2H,

Ar-H), 7.35 (m, 3H, Ar-H), 7.56 (m, 2H, Ar-H), 9.40 (s, 1H,

Ar-OH); ¹³C NMR (125 MHz, (CD₃)₂SO) δ 13.17 (pyrimidine-

CH₃), 13.58 (pyrimidine-CH₃), 23.88 (pyrimidine-CH₃), 106.97

(pyrazole-C), 115.10 (pyrimidine-CCH₃), 115.18 (2C, Ar-C),

122.78 (Ar-C), 128.09 (Ar-C), 128.31 (2C, Ar-C), 128.37 (2C,

Ar-C), 133.71 (Ar-C), 141.65 (pyrimidine-CCH₃), 144.35

(pyrazole-C), 150.64 (pyrazole-C), 156.03 (pyrimidine-

CCH₃), 158.48 (Ar-COH); LRMS m/z 329.1; HRMS (C₂₁H₁₉N₃O)

calcd 329.1525, found 329.1528. Anal. (C₂₁H₁₉N₃O) C, H, N

calcd: 76.57% C, 5.81% H, 12.76% N. Found: 76.08% C, 5.96%

H, 13.23% N.

2,3-Bis(4-hydroxyphenyl)-5,6,7-trimethylpyrazolo[1,5-

a]pyrimidine (26c). Following general procedure E, 17c was

deprotected to yield 26c. Isolated yield 52%; white solid; mp

>260 °C; ¹H NMR (500 MHz, (CD₃)₂CO) δ 2.29 (s, 3H,

pyrimidine-CH₃), 2.48 (s, 3H, pyrimidine-CH₃), 2.75 (s, 3H,

pyrimdine-CH₃), 6.83 (m, 4H, Ar-H), 7.35 (AA′XX′, 2H, Ar-

H), 7.52 (AA′XX′, 2H, Ar-H), 8.29 (s, 1H, Ar-OH), 8.49 (s,

1H, Ar-OH); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 13.37 (pyrimi-

dine-CH₃), 13.87 (pyrimidine-CH₃), 24.14 (pyrimidine-CH₃),

107.42 (pyrazole-C), 115.38 (pyrimidine-CCH₃), 115.84 (2C,

Ar-C), 115.87 (2C, Ar-C), 125.15 (Ar-C), 126.53 (Ar-C),

130.89 (2C, Ar-C), 132.04 (2C, Ar-C), 142.43 (pyrimidine-

CCH₃), 145.73 (pyrazole-C), 152.34 (pyrazole-C), 156.78

(pyrimidine-CCH₃), 158.37 (Ar-COH), 158.82 (Ar-COH);

LRMS m/z 345.2; HRMS (C₂₁H₁₉N₃O₂) calcd 345.1479, found

345.1477. Anal. (C₂₁H₁₉N₃O₂‚0.8H₂O) C, H, N calcd: 70.10%

C, 5.77% H, 11.68% N. Found: 70.09% C, 5.85% H, 11.16% N.

3-(3-Hydroxyphenyl)-2-(4-hydroxyphenyl)-5,6,7-tri-

methylpyrazolo[1,5-a]pyrimidine (26d). Following general

procedure E, 17d was deprotected to yield 26d. Isolated yield

43%; off-white solid; mp >260 °C; ¹H NMR (500 MHz, (CD₃)₂-

SO) δ 2.26 (s, 3H, pyrimidine-CH₃), 2.48 (s, 3H, pyrimidine-

CH₃), 2.73 (s, 3H, pyrimidine-CH₃), 6.65 (d, 1H, J ) 7.9 Hz),

6.75 (AA′XX, 2H, Ar-H), 6.81 (d, 1H, J ) 7.5 Hz, Ar-H), 6.89

(d, 1H, J ) 1.5 Hz, Ar-H), 7.14 (t, 1H, 7.8 Hz, Ar-H), 7.38

(AA′XX′, 2H, Ar-H), 9.30 (s, 1H, Ar-OH), 9.60 (s, 1H, Ar-

OH); ¹³C NMR (125 MHz, (CD₃)₂SO) δ 13.20 (pyrimidine-

CH₃), 13.54 (pyrimidine-CH₃), 23.87 (pyrimidine-CH₃), 106.12

(pyrazole-C), 113.22 (pyrimidine-CCH₃), 114.86 (Ar-C),

115.16 (2C, Ar-C), 116.69 (Ar-C), 120.66 (Ar-C), 124.20 (Ar-

C), 129.03 (Ar-C), 129.80 (2C, Ar-C), 133.87 (Ar-C), 141.67

(pyrimidine-CCH₃), 144.41 (pyrazole-C), 151.30 (pyrazole-

C), 157.11 (pyrimidine-CCH₃), 157.59 (Ar-COH), 158.51 (Ar-

COH); LRMS m/z 345.2; HRMS (C₂₁H₁₉N₃O₂) calcd 345.1473,

found 345.1477.

2-(3-Hydroxyphenyl)-3-(4-hydroxyphenyl)-5,6,7-tri-

methylpyrazolo[1,5-a]pyrimidine (26e). Following general

procedure E, 17e was deprotected to yield 26e. Isolated yield

73%; white solid; mp 252-254 °C; ¹H NMR (500 MHz, (CD₃)₂-

CO) δ 2.29 (s, 3H, pyrimidine-CH₃), 2.48 (s, 3H, pyrimidine-

CH₃), 2.75 (s, 3H, pyrimidine-CH₃), 6.83 (m, 3H, Ar-H), 7.14

(dt, 1H, J ) 7.7, 1.3 Hz, Ar-H), 7.17 (t, 1H, J ) 7.7 Hz, Ar-

H), 7.20 (dd, 1H, J ) 2.5, 0.9 Hz, Ar-H), 7.35 (AA′XX′, 2H,

Ar-H), 8.30 (s, 1H, Ar-OH), 8.35 (s, 1H, Ar-OH); ¹³C NMR

(125 MHz, (CD₃)₂CO) δ 13.37 (pyrimidine-CH₃), 13.89 (pyrim-

idine-CH₃), 24.17 (pyrimidine-CH₃), 108.09 (pyrazole-C),

115.75 (pyrimidine-CCH₃), 115.81 (Ar-C), 115.84 (2C, Ar-

C), 116.48 (Ar-C), 120.96 (Ar-C), 124.87 (Ar-C), 130.01 (Ar-

C), 132.05 (2C, Ar-C), 136.61 (Ar-C), 142.49 (pyrimidine-

CCH₃), 145.66 (pyrazole-C), 152.12 (pyrazole-C), 156.80

(pyrimidine-CCH₃), 158.11 (Ar-COH), 159.05 (Ar-COH);

LRMS m/z 345.2; HRMS (C₂₁H₁₉N₃O₂) calcd 345.1470, found

345.1477. Anal. (C₂₁H₁₉N₃O₂‚0.5H₂O) C, H, N calcd: 71.01%

C, 5.69% H, 11.86% N. Found: 71.06% C, 5.51% H, 11.72% N.

3-(3-Hydroxyphenyl)-2-(4-hydroxyphenyl)-5,7-diiso-

propylpyrazolo[1,5-a]pyrimidine (25d). Following general

procedure E, 15d was deprotected to yield 25d. Isolated yield

1

77%; white solid; mp 224-227 °C; H NMR (500 MHz, CD₃-

OD) δ 1.32 (d, 6H, J ) 6.9 Hz, -CH(CH₃)₂), 1.46 (d, 6H, J )

6.9 Hz, -CH(CH₃)₂), 3.06 (sept, 1H, J ) 6.9 Hz, pyrimidine-

CH(CH₃)₂), 3.86 (sept, 1H, J ) 6.9 Hz, pyrimidine-CH(CH₃)₂),

6.69 (ddd, 1H, J ) 8.2, 2.6, 1.1 Hz, Ar-H), 6.77 (m, 3H, Ar-H

and pyrimidine-H), 6.95 (dt, 1H, J ) 7.5, 1.1 Hz, Ar-H), 6.99

(dd, 1H, J ) 2.6, 1.3 Hz, Ar-H), 7.14 (t, 1H, J ) 7.7 Hz, Ar-

H), 7.43 (AA′XX′, 2H, Ar-H); ¹³C NMR (125 MHz, CD₃OD) δ

20.27 (-CH(CH₃)₂), 22.24 (-CH(CH₃)₂), 29.65 (2C, pyrimi-

dine-CH(CH₃)₂), 37.74 (2C, pyrimidine-CH(CH₃)₂), 103.40

(pyrimidine-C), 108.57 (pyrazole-C), 114.36 (Ar-C), 116.11

(2C, Ar-C), 118.13 (Ar-C), 122.77 (Ar-C), 126.09 (Ar-C),

130.11 (Ar-C), 131.57 (2C, Ar-C), 135.27 (Ar-C), 147.88

(pyrazole-C), 154.85 (pyrazole-C), 156 (pyrimidine-CCH-

(CH₃)₂), 158.22 (Ar-COH), 159.10 (Ar-COH), 169.17 (pyrim-

idine-CCH(CH₃)₂); LRMS m/z 387.2; HRMS (C₂₄H₂₅N₃O₂)

calcd 387.1943, found 387.1947. Anal. (C₂₄H₂₅N₃O₂‚0.2H₂O) C,

H, N calcd: 73.71% C, 6.55% H, 10.74% N. Found: 73.44% C,

6.19% H, 10.52% N.

2-(3-Hydroxyphenyl)-3-(4-hydroxyphenyl)-5,7-diiso-

propylpyrazolo[1,5-a]pyrimidine (25e). Following general

procedure E, 15e was deprotected to yield 25e. Isolated yield

73%; white solid; mp 189-190 °C; ¹H NMR (500 MHz, (CD₃)₂-

CO) δ 1.31 (d, 6H, J ) 6.9 Hz, -CH(CH₃)₂), 1.47 (d, 6H, J )

7.1 Hz, -CH(CH₃)₂), 3.08 (sept, 1H, J ) 6.9 Hz, pyrimidine-

CH(CH₃)₂), 3.88 (sept, 1H, J ) 6.9 Hz, pyrimidine-CH(CH₃)₂),

6.85 (m, 4H, Ar-H), 7.13 (dt, 1H, J ) 7.9, 1.1 Hz, Ar-H), 7.20

(m, 2H, Ar-H), 7.40 (AA′XX, 2H, Ar-H), 8.33 (s, 1H, Ar-OH),

8.40 (s, 1H, Ar-OH); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 20.04

(2C, -CH(CH₃)₂), 22.06 (2C, -CH(CH₃)₂), 29.23 (pyrimidine-

CH(CH₃)₂), 37.16 (pyrimidine-CH(CH₃)₂), 103.67 (pyrimi-

dine-C), 108.39 (pyrazole-C), 115.83 (2C, Ar-C), 115.98 (Ar-

C), 116.64 (Ar-C), 121.10 (Ar-C), 124.68 (Ar-C), 130.08 (Ar-

C), 131.95 (2C, Ar-C), 136.50 (Ar-C), 147.32 (pyrazole-C),

153.24 (pyrazole-C), 154.97 (pyrimidine-CCH(CH₃)₂), 156.82

(Ar-COH), 158.16 (Ar-COH), 167.76 (pyrimidine-CCH-

(CH₃)₂); LRMS m/z 387.2; HRMS (C₂₄H₂₅N₃O₂) calcd 387.1951,

found 387.1947. Anal. (C₂₄H₂₅N₃O₂‚0.2H₂O) C, H, N calcd:

73.71% C, 6.55% H, 10.74% N. Found: 73.41% C, 6.25%,

10.41% N.

2-(4-Hydroxyphenyl)-5,6,7-trimethyl-3-phenylpyrazolo-

[1,5-a]pyrimidine (26a). Following general procedure E, 17a

was deprotected to yield 26a. Isolated yield 59%; white solid;

1

mp 218-221 °C; H NMR (500 MHz, CD₃OD) δ 2.25 (s, 3H,

pyrimidine-CH₃), 2.48 (s, 3H, pyrimidine-CH₃), 2.73 (s, 3H,

pyrimidine-CH₃), 6.72 (AA′XX′, 2H, Ar-H), 7.23 (m, 1H, Ar-

H), 7.31 (m, 2H, Ar-H), 7.35 (AA′XX′, 2H, Ar-H), 7.42 (m,

2H, Ar-H); ¹³C NMR (125 MHz, CD₃OD) δ 13.66 (pyrimidine-

CH₃), 13.95 (pyrimidine-CH₃), 23.80 (pyrimidine-CH₃), 108.22

(pyrazole-C), 116.10 (2C, Ar-C), 116.43 (pyrimidine-C),

125.96 (Ar-C), 127.39 (Ar-C), 129.25 (2C, Ar-C), 131.34 (2C,

Ar-C), 131.43 (2C, Ar-C), 133.99 (Ar-C), 143.58 (pyrimi-

dine-CCH₃), 146.05 (pyrazole-C), 153.96 (pyrazole-C), 159.05

(Ar-COH), 160.61 (pyrimidine-CCH₃); LRMS m/z 329.2;

HRMS (C₂₁H₁₉N₃O) calcd 329.1524, found 329.1528. Anal.

(C₂₁H₁₉N₃O‚0.1H₂O) C, H, N calcd: 76.16% C, 5.84% H, 12.69%

N. Found: 75.84% C, 5.83% H, 12.40% N.

5,7-Di-tert-butyl-2-(4-hydroxyphenyl)-3-phenylpyrazolo-

[1,5-a]pyrimidine (27a). Following general procedure E, 19a

was deprotected to yield 27a. Isolated yield 49%; white solid;

mp 220-222 °C; ¹H NMR (500 MHz, (CD₃)₂CO) δ 1.39 (s, 9H,

-C(CH₃)₃), 1.70 (s, 9H, -C(CH₃)₃), 6.87 (AA′XX′, 2H, Ar-H),

6.99 (s, 1H, pyrimidine-H), 7.23 (m, 1H, Ar-H), 7.35 (m, 2H,

Ar-H), 7.51 (AA′XX′, 2H, Ar-H), 7.61 (m, 2H, Ar-H), 8.58

3-(4-Hydroxyphenyl)-5,6,7-trimethyl-2-phenylpyrazolo-

[1,5-a]pyrimidine (26b). Following general procedure E, 17b

was deprotected to yield 26b. Isolated yield 49%; white solid;

mp 219-221 °C; ¹H NMR (500 MHz, (CD₃)₂SO) δ 2.26 (s, 3H,

Pyrazolo[1,5-a]pyrimidines

Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24 5891

(s, 1H, Ar-OH); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 27.30 (3C,

-C(CH₃)₃), 29.80 (3C, -C(CH₃), 36.85 (pyrimidine-C(CH₃)₃),

38.88 (pyrimidine-C(CH₃)₃), 102.66 (pyrimidine-C), 107.13

(pyrazole-C), 116.05 (2C, Ar-C), 126.17 (Ar-C), 126.75 (Ar-

C), 128.78 (2C, Ar-C), 130.69 (2C, Ar-C), 131.15 (Ar-C),

133.98 (Ar-C), 148.11 (pyrazole-C), 153.06 (pyrazole-C),

155.86 (pyrimidine-CC(CH₃)₃), 158.69 (Ar-COH), 169.82

(pyrimidine-CC(CH₃)₃); LRMS m/z 399.3; HRMS (C₂₆H₂₉N₃O)

calcd 399.2309, found 399.2311.

5,7-Di-tert-butyl-3-(4-hydroxyphenyl)-2-phenylpyrazolo-

[1,5-a]pyrimidine (27b). Following general procedure E, 19b

was deprotected to yield 27b. Isolated yield 82%; white solid;

mp 241-244 °C; ¹H NMR (500 MHz, (CD₃)₂CO) δ 1.39 (s, 9H,

-C(CH₃)₃), 1.70 (s, 9H, -C(CH₃)₃), 6.86 (AA′XX′, 2H, Ar-H),

6.99 (s, 1H, pyrimidine-H), 7.39 (m, 5H, Ar-H), 7.69 (m, 2H,

Ar-H), 8.31 (s, 1H, Ar-OH); ¹³C NMR (125 MHz, (CD₃)₂CO)

δ 27.29 (3C, -C(CH₃)₃), 29.80 (3C, -C(CH₃)₃), 36.84 (pyrimi-

dine-C(CH₃)₃), 38.88 (pyrimidine-C(CH₃)₃), 102.77 (pyrimi-

dine-C), 107.97 (pyrazole-C), 115.85 (2C, Ar-C), 124.62 (Ar-

C), 128.96 (2C, Ar-C), 129.11 (2C, Ar-C), 129.74 (2C, Ar-

C), 131.95 (Ar-C), 135.26 (Ar-C), 147.93 (pyrazole-C), 152.45

(pyrazole-C), 155.82 (pyrimidine-CC(CH₃)₃), 156.87 (Ar-

COH), 169.53 (pyrimidine-CC(CH₃)₃); LRMS m/z 399.2; HRMS

(C₂₆H₂₉N₃O) calcd 399.2310, found 399.2311. Anal. (C₂₆H₂₉N₃O‚

0.3H₂O) C, H, N calcd: 77.12% C, 7.37% H, 10.38% N. Found:

76.96% C, 7.37% H, 10.15% N.

5,7-Di-tert-butyl-2,3-bis(4-hydroxyphenyl)pyrazolo[1,5-

a]pyrimidine (27c). Following general procedure E, 19c was

deprotected to yield 27c. Isolated yield 91%; yellow solid; mp

265-267 °C; ¹H NMR (500 MHz, (CD₃)₂CO) δ 1.38 (s, 9H,

-C(CH₃)₃), 1.69 (s, 9H, -C(CH₃)₃), 6.86 (m, 4H, Ar-H), 6.95

(s, 1H, pyrimidine-H), 7.42 (AA′XX′, 2H, Ar-H), 7.55 (AA′XX′,

2H, Ar-H), 8.28 (s, 1H, Ar-OH), 8.52 (s, 1H, Ar-H); ¹³C NMR

(125 MHz, (CD₃)₂CO) δ 27.30 (3C, -C(CH₃)₃), 29.82 (3C,

-C(CH₃)₃), 36.81 (pyrimidine-C(CH₃)₃), 38.83 (pyrimidine-

C(CH₃)₃), 102.35 (pyrimidine-C), 107.28 (pyrazole-C), 115.81

(2C, Ar-C), 116.00 (2C, Ar-C), 124.97 (Ar-C), 126.45 (Ar-

C), 131.04 (2C, Ar-C), 131.93 (2C, Ar-C), 147.95 (pyrazole-

C), 152.65 (pyrazole-C), 155.66 (pyrimidine-CC(CH₃)₃), 156.75

(Ar-COH), 158.56 (Ar-COH), 169.27; LRMS m/z 415.2;

HRMS (C₂₆H₂₉N₃O₂) calcd 415.2265, found 415.2260. Anal.

(C₂₆H₂₉N₃O₂‚0.5H₂O) C, H, N calcd: 73.56% C, 7.12% H, 9.90%

N. Found: 73.45% C, 6.94% H, 9.64% N.

116.06 (Ar-C), 116.68 (Ar-C), 121.14 (Ar-C), 124.78 (Ar-

C), 130.15 (Ar-C), 132.00 (2C, Ar-C), 136.62 (Ar-C), 147.96

(pyrazole-C), 152.55 (pyrazole-C), 155.85 (pyrimidine-CC-

(CH₃)₃), 156.84 (Ar-COH), 158.28 (Ar-COH), 169.49 (pyrim-

idine-CC(CH₃)₃); LRMS m/z 415.3; HRMS (C₂₆H₂₉N₃O₂) calcd

415.2253, found 415.2260.

2-(4-Hydroxyphenyl)-3,5,7-triphenylpyrazolo[1,5-a]py-

rimidine (28a). Following general procedure E, 20a was

deprotected to yield 28a. Isolated yield 68%; yellow solid; mp

198-200 °C dec; ¹H NMR (500 MHz, (CD₃)₂CO) δ 6.84 (AA′XX′,

2H, Ar-H), 7.31 (m, 1H, Ar-H), 7.41 (m, 2H, Ar-H), 7.49 (m,

5H, Ar-H), 7.60 (m, 2H, Ar-H), 7.67 (m, 3H, Ar-H and

pyrimidine-H), 8.30 (m, 4H, Ar-H), 8.58 (s, 1H, Ar-OH); ¹³

C

NMR (125 MHz, (CD₃)₂CO) δ 105.58 (pyrimidine-C), 108.89

(pyrazole-C), 116.03 (2C, Ar-C), 125.76 (Ar-C), 127.14 (Ar-

C), 128.08 (2C, Ar-C), 128.99 (2C, Ar-C), 129.22 (2C, Ar-

C), 129.58 (2C, Ar-C), 130.64 (2C, Ar-C), 130.94 (2C, Ar-

C), 131.20 (2C, Ar-C), 131.65 (Ar-C), 132.42 (Ar-C), 133.76

(Ar-C), 138.27 (Ar-C), 146.98 (pyrazole-C), 148.68 (pyrimi-

dine-CPh), 154.70 (pyrazole-C), 156.38 (Ar-COH), 158.81

(pyrimidine-CPh); LRMS m/z 439.1; HRMS (C₃₀H₂₁N₃O) calcd

439.1680, found 439.1685. Anal. (C₃₀H₂₁N₃O) C, H, N calcd:

81.98% C, 4.82% H, 9.56% N. Found: 81.68% C, 4.85% H,

9.52% N.

3-(4-Hydroxyphenyl)-2,5,7-triphenylpyrazolo[1,5-a]py-

rimidine (28b). Following general procedure E, 20b was

deprotected to yield 28b. Isolated yield 72%; orange solid; mp

1

237-240 °C; H NMR (500 MHz, (CD₃)₂CO) δ 6.92 (AA′XX′,

2H, Ar-H), 7.37 (m, 3H, Ar-H), 7.49 (m, 5H, Ar-H), 7.61 (m,

3H, Ar-H), 7.67 (m, 2H, Ar-H), 7.70 (s, 1H, pyrimidine-H),

8.31 (m, 4H, Ar-H), 8.41 (s, 1H, Ar-OH); ¹³C NMR (125 MHz,

(CD₃)₂CO) δ 106.00 (pyrimidine-C), 109.77 (pyrazole-C),

116.06 (2C, Ar-C), 124.72 (Ar-C), 128.10 (2C, Ar-C), 129.09

(2C, Ar-C), 129.13 (Ar-C), 129.24 (2C, Ar-C), 129.61 (2C,

Ar-C), 129.74 (2C, Ar-C), 130.64 (2C, Ar-C), 131.03 (Ar-

C), 131.67 (Ar-C), 132.18 (2C, Ar-C), 132.41 (Ar-C), 134.83

(Ar-C), 138.31 (Ar-C), 147.02 (pyrazole-C), 148.53 (pyrimi-

dine-CPh), 154.13 (pyrazole-C), 156.20 (pyrimidine-CPh),

157.19 (Ar-COH); LRMS m/z 439.3; HRMS (C₃₀H₂₁N₃O) calcd

439.1682, found 439.1685. Anal. (C₃₀H₂₁N₃O‚0.7H₂O) C, H, N

calcd: 79.70% C, 4.99% H, 9.29% N. Found: 79.55% C, 4.64%

H, 9.10% N.

2,3-Bis(4-hydroxyphenyl)-5,7-diphenylpyrazolo[1,5-a]-

pyrimidine (28c). Following general procedure E, 20c was

deprotected to yield 28c. Isolated yield 75%; orange solid; mp

5,7-Di-tert-butyl-3-(3-hydroxyphenyl)-2-(4-hydroxyphen-

yl)pyrazolo[1,5-a]pyrimidine (27d). Following general pro-

cedure E, 19d was deprotected to yield 27d. Isolated yield 77%;

1

139-141 °C; H NMR (500 MHz, (CD₃)₂CO) δ 6.84 (AA′XX′,

1

yellow solid; mp 227-230 °C; H NMR (500 MHz, (CD₃)₂CO)

2H, Ar-H), 6.93 (AA′XX′, 6.93 Ar-H), 7.48 (m, 5H, Ar-H),

7.55 (AA′XX′, 2H, Ar-H), 7.61 (m, 3H, Ar-H), 7.66 (s, 1H,

pyrimidine-H), 8.31 (m, 4H, Ar-H), 8.40 (s, 1H, Ar-OH), 8.57

(s, 1H, Ar-OH); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 105.60

(pyrimidine-C), 109.08 (pyrazole-C), 115.98 (2C, Ar-C),

116.02 (2C, Ar-C), 124.69 (Ar-C), 125.98 (Ar-C), 128.04 (2C,

Ar-C), 129.21 (2C, Ar-C), 129.58 (2C, Ar-C), 130.61 (2C, Ar-

C),130.93 (Ar-C), 131.08 (2C, Ar-C), 131.60 (Ar-C), 132.17

(2C, Ar-C), 132.52 (Ar-C), 138.39 (Ar-C), 146.83 (pyrazole-

C), 154.36 (pyrazole-C), 155.94 (pyrimidine-CPh), 157.08 (2C,

Ar-COH), 158.70 (pyrimidine-CPh); LRMS m/z 455.2; HRMS

(C₃₀H₂₁N₃O₂) calcd 455.1625, found 455.1634.

δ 1.40 (s, 9H, -C(CH₃)₃), 1.69 (s, 9H, -C(CH₃)₃), 6.74 (ddd,

1H, J ) 8.2, 2.6, 1.1 Hz, Ar-H), 6.87 (AA′XX′, 2H, Ar-H),

6.97 (s, 1H, pyrimidine-H), 7.08 (dt, 1H, J ) 7.7, 1.5 Hz, Ar-

H), 7.16 (dd, 1H, J ) 2.6, 1.9 Hz, Ar-H), 7.18 (t, 1H, J ) 7.9

Hz, Ar-H), 7.54 (AA′XX′, 2H, Ar-H), 8.21 (s, 1H, Ar-OH),

8.52 (s, 1H, Ar-OH); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 27.39

(3C, -C(CH₃)₃), 29.89 (3C, -C(CH₃)₃), 36.88 (pyrimidine-

C(CH₃)₃), 38.92 (pyrimidine-C(CH₃)₃), 102.55 (pyrimidine-

C), 107.30 (pyrazole-C), 113.98 (Ar-C), 116.06 (2C, Ar-C),

117.79 (Ar-C), 122.22 (Ar-C), 126.39 (Ar-C), 129.69 (Ar-

C), 131.22 (2C, Ar-C), 135.30 (Ar-C), 148.20 (pyrazole-C),

153.14 (pyrazole-C), 155.87 (pyrimidine-CC(CH₃)₃), 158.09

(Ar-COH), 158.67 (Ar-COH), 169.74 (pyrimidine-CC(CH₃)₃);

LRMS m/z 415.2; HRMS (C₂₆H₂₉N₃O₂) calcd 415.2264, found

415.2260. Anal. (C₂₆H₂₉N₃O₂‚0.5H₂O) C, H, N calcd: 73.56%

C, 7.12% H, 9.90% N. Found: 73.32% C, 6.87% H, 9.61% N.

3-(3-Hydroxyphenyl)-2-(4-hydroxyphenyl)-5,7-diphen-

ylpyrazolo[1,5-a]pyrimidine (28d). Following general pro-

cedure E, 20d was deprotected to yield 28d. Isolated yield 83%;

1

orange solid; mp 151-152 °C; H NMR (500 MHz, (CD₃)₂CO)

δ 6.81 (ddd, 1H, J ) 7.7, 1.9, 0.9 Hz, Ar-H), 6.86 (AA′XX′,

2H, Ar-H), 7.15 (d, 1H, J ) 7.5 Hz, Ar-H), 7.24 (m, 2H, Ar-

H), 7.49 (m, 3H, Ar-H), 7.54 (AA′XX′, 2H, Ar-H), 7.60 (m,

3H, Ar-H), 7.67 (pyrimidine-H), 8.29 (m, 4H, Ar-H), 8.34

(s, 1H, Ar-OH), 8.58 (s, 1H, Ar-OH); ¹³C NMR (125 MHz,

(CD₃)₂CO) δ 105.82 (pyrimidine-C), 108.94 (pyrazole-C),

114.30 (Ar-C), 115.98 (2C, Ar-C), 117.84 (Ar-C), 122.29 (Ar-

C), 125.82 (Ar-C), 128.11 (2C, Ar-C), 129.19 (2C, Ar-C),

129.57 (2C, Ar-C), 129.95 (Ar-C), 130.62 (2C, Ar-C), 131.01

(Ar-C), 131.21 (2C, Ar-C), 131.62 (Ar-C), 132.43 (Ar-C),

134.96 (Ar-C), 138.31 (Ar-C), 146.94 (pyrazole-C), 148.65

(pyrimidine-CPh), 154.70 (pyrazole-C), 156.31 (pyrimidine-

5,7-Di-tert-butyl-2-(3-hydroxyphenyl)-3-(4-hydroxyphen-

yl)pyrazolo[1,5-a]pyrimidine (27e). Following general pro-

cedure E, 19e was deprotected to yield 27e. Isolated yield 60%;

white solid; mp 232-236 °C; ¹H NMR (500 MHz, (CD₃)₂CO) δ

1.39 (s, 9H, -C(CH₃)₃), 1.69 (s, 9H, -C(CH₃)₃), 6.85 (m, 3H,

Ar-H), 6.98 (s, 1H, pyrimidine-H), 7.15 (dt, 1H, J ) 7.7, 1.2

Hz, Ar-H), 7.22 (m, 1H, Ar-H), 7.43 (AA′XX′, 2H, Ar-H), 8.28

(s, 1H, Ar-OH), 8.39 (s, 1H, Ar-OH); ¹³C NMR (125 MHz,

(CD₃)₂CO) δ 27.37 (3C, -C(CH₃)₃), 29.84 (3C, -C(CH₃)₃), 36.87

(pyrimidine-C(CH₃)₃), 38.90 (pyrimidine-C(CH₃)₃), 102.69

(pyrimidine-C), 108.01 (pyrazole-C), 115.85 (2C, Ar-C),

5892 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24

Compton et al.

CPh), 158.16 (Ar-COH), 158.74 (Ar-COH); LRMS m/z 455.2;

HMRS (C₃₀H₂₁N₃O₂) calcd 455.1629, found 455.1634. Anal.

(C₃₀H₂₁N₃O₂‚0.5%H₂O) C, H, N calcd: 77.57% C, 4.77% H,

9.05% N. Found: 77.34%C, 4.60% H, 8.97% N.

ligand/receptor complex was minimized with the anneal com-

mand, utilizing a hot radius of 8 Å and an interesting radius

of 16 Å. All minimizations used the MMFF94 force field with

the Powell gradient (final rms less than 0.1 kcal mol^-1Å^-1).

2-(3-Hydroxyphenyl)-3-(4-hydroxyphenyl)-5,7-diphen-

ylpyrazolo[1,5-a]pyrimidine (28e). Following general pro-

cedure E, 20e was deprotected to yield 28e. Isolated yield 49%;

orange solid; mp 190-191 °C dec; ¹H NMR (500 MHz, (CD₃)₂-

CO) δ 6.85 (ddd, 1H, J ) 7.7, 2.4, 1.1 Hz, Ar-H), 6.92 (AA′XX′,

2H, Ar-H), 7.15 (dt, 1H, J ) 7.5, 1.3 Hz, Ar-H), 7.20 (m, 2H,

Ar-H), 7.50 (m, 5H, Ar-H), 7.62 (m, 3H, Ar-H), 7.70 (s, 1H,

pyrimidine-H), 8.31 (m, 4H, Ar-H), 8.38 (s, 1H, Ar-OH), 8.39

(s, 1H, Ar-OH); ¹³C NMR (125 MHz, (CD₃)₂CO) δ 105.98

(pyrimidine-C), 109.85 (pyrazole-C), 116.07 (2C, Ar-C),

116.25 (Ar-C), 116.68 (Ar-C), 121.16 (Ar-C), 124.53 (Ar-

C), 128.14 (2C, Ar-C), 129.27 (2C, Ar-C), 129.64 (2C, Ar-

C), 130.15 (Ar-C), 130.67 (2C, Ar-C), 131.03 (Ar-C), 131.68

(Ar-C), 132.23 (2C, Ar-C), 132.53 (Ar-C), 136.18 (Ar-C),

138.44 (Ar-C), 147.07 (pyrazole-C), 148.58 (pyrimidine-

CPh), 154.26 (pyrazole-C), 156.22 (pyrimidine-CPh), 157.17

(Ar-COH), 158.23 (Ar-COH); LRMS (EI, 70 eV) m/z 455.1;

HMRS (C₃₀H₂₁N₃O₂) calcd 455.1628, found 455.1634. Anal.

(C₃₀H₂₁N₃O₂‚0.9H₂O) C, H, N calcd: 76.38% C, 4.87% H, 8.91%

N. Found: 76.25% C, 4.61% H, 8.79% N.

Estrogen Receptor Binding Affinity Assays. Relative

binding affinities were determined by a competitive radiomet-

ric binding assay as previously described,^41,49using 10 nM [³H]-

estradiol as tracer ([6,7-³H]estra-1,3,5(10)triene-3,17-â-diol,

51-53 Ci/mmol, Amersham Biosciences, Piscataway, NJ) and

purified full-length human ERR and ERâ receptors purchased

from Pan Vera (Madison, WI). Incubations were for 18-24 h

at 0 °C. Hydroxyapatite (BioRad, Hercules, CA) was used to

absorb the receptor/ligand complexes, and free ligand was

washed away. The binding affinities are expressed as relative

binding affinity (RBA) values with the RBA of estradiol set to

100%. The values given are the average ( range or SD of two

to three independent determinations. Estradiol binds to ERR

with a K_dof 0.2 nM and to ERâ with a K_dof 0.5 nM.

Cell Culture and Transient Transfections. Human

endometrial cancer (HEC-1) cells were maintained in mini-

mum essential medium (MEM) plus phenol red supplemented

with 5% calf serum and 5% fetal calf serum. Cells were plated

in phenol-red-free improved MEM and 5% charcoal dextran-

treated calf serum (CDCS) and were given fresh medium 24 h

before transfection. Transfection assays were performed in 24-

well plates using a mixture of 0.35 mL of serum-free improved

MEM medium and 0.15 mL of Hank’s balanced salt solution

containing 5 µL of lipofectin (Life Technologies, Inc., Gaith-

ersburg, MD), 1.6 µg of transferrin (Sigma, St. Louis, MO),

0.5 µg of pCMV â-galactosidase as internal control, 1 µg of

2ERE-pS2-Luc, and 100 ng of ER expression vector per well.

The cells were incubated at 37 °C in a 5% CO₂-containing

incubator for 5 h. The medium was then replaced with fresh

improved MEM supplemented with 5% CDCS plus the desired

concentrations of ligands. Cells were harvested 24 h later.

Luciferase and â-galactosidase activity was assayed as de-

scribed.⁵⁰

Molecular Modeling. Small-molecule geometry optimiza-

tion and modeling of ligand/protein complexes were carried

out in Sybyl (version 6.7, Tripos). For ERR, the estradiol-ERR

ligand binding domain (1ERE) crystal structure was used. For

ERâ, the genistein-ERâ ligand binding domain (1QKM)

crystal structure was used. The ligand 24c was prepositioned

by overlaying a p-hydroxyphenyl ring with the A-ring of

estradiol or genistein. Estradiol or genistein was then deleted,

and ligand 24c was merged into its place. The rotatable bonds

of ligand 24c were set, and the 24c was then allowed to

reposition itself in the binding pocket while the protein

remained fixed. The best docked ligand/receptor complexes

were then subjected to a three-part minimization process. In

the first step, the torsional bonds were minimized using the

torsmin command. In the second step, the ligand 24c and

amino acids within 8 Å of the ligand were minimized while

holding the protein backbone fixed. In the final step, the

Acknowledgment. We are grateful for support of

this research through grants from the National Insti-

tutes of Health (Grants PHS 5R37 DK15556 [J.A.K] and

5R01 CA19118 [B.S.K]). We also offer a special thanks

to Kathryn Carlson for performing the numerous rela-

tive binding assays.

Supporting Information Available: Elemental analysis

results, HPLC results, and HPLC spectra. This material is

available free of charge via the Internet at http://pubs.acs.org.

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JM049631K

Article Doi

Pyrazolo[1,5-α]pyrimidines: Estrogen receptor ligands possessing estrogen receptor β antagonist activity

DOI: 10.1021/jm049631k

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