Novel 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines as 5-HT6 agonists and antagonists

Bioorganic & Medicinal Chemistry 15 (2007) 6208–6226

Novel 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines

as 5-HT₆agonists and antagonists

Hassan Elokdah,^a,*David Li,^bGeraldine McFarlane,^bRonald C. Bernotas,^a

Albert J. Robichaud,^bRonald L. Magolda,^bGuo Ming Zhang,^cDeborah Smith^c

and Lee E. Schechter^c

^aChemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA

^bChemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA

^cNeuroscience, Wyeth Research, CN 8000, Princeton, NJ 08543, USA

Received 5 December 2006; revised 17 May 2007; accepted 12 June 2007

Available online 14 June 2007

Abstract—1-Aminoethyl-3-arylsulfonyl-1H-indoles 1 are 5-HT₆receptor ligands with modest activity in a 5-HT₆cyclase assay.

Introduction of an additional nitrogen in the indole ring provides 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 2 with

both enhanced 5-HT₆aﬃnity and cyclase activity, many acting as 5-HT₆agonists. We constrained the basic side chain as part of

a ring to make 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines incorporating a pyrrolidinyl 3 or piperidinyl 4 ring system.

Preparation of compounds 3 and 4 required synthesis of the key intermediates, 1-(pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 7

and 1-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 8, respectively. Intermediates 7 were prepared through alkylation of 7-azaindole

while the intermediates 8 required an alternate synthesis. The compounds of both series 3 and 4 were shown to have high binding

aﬃnities for the 5-HT₆receptor. The in vitro functional activity at the 5-HT₆receptor varied depending on various functionalities

including the selection of the arylsulfonyl, the substitution on the arylsulfonyl group, the ring size, and the substitution on the basic

amine moiety producing either 5-HT₆receptor agonists or antagonists.

1. Introduction

aminoethyl)-3-arylsulfonyl-1H-indoles (1) (Fig. 1) with

modest functional activity at the 5-HT₆receptor (Ta-

ble 1).¹⁵Continuing work expanding the scope led

to a related series of 1-aminoethyl-3-arylsulfonyl-1H-

pyrrolo[2,3-b]pyridines (2) with enhanced 5-HT₆bind-

ing aﬃnity and functional activity (Table 1).^16,17In an

eﬀort to further expand the SAR around structure 2,

we sought to constrain the basic amine side chain as

part of a ring to make 1-(azacyclyl)-3-arylsulfonyl-

1H-pyrrolo[2,3-b]pyridines incorporating either a pyr-

rolidinyl (3) or piperidinyl (4) ring in the side chain

(Fig. 1). The results of these eﬀorts are the subject

of this report.

Identiﬁcation of ligands for the 5-HT₆receptor has

been the focus of several reports in the last dec-

ade.^1–4Ligands for the 5-HT₆receptor may be useful

in the treatment of CNS disorders such as schizophre-

nia, depression, and impairment of learning and mem-

ory in diseases such as Alzheimer’s disease (AD).^5–10

Eﬀorts have led to the discovery of several classes of

selective high aﬃnity 5-HT₆receptor ligands.^11–14

A

common feature in many of these compound classes

is the presence of a basic amine group and a requisite

aryl sulfonyl moiety. As is the case with monoamine

ligands, the necessity of the basic moiety for potent

binding to the receptor was expected. However,

among these classes it has been demonstrated that

the presence of the aryl sulfonyl group was crucial

for selectivity. Earlier we identiﬁed a series of 1-(2-

NR

NR₁R₂

NR

N

SO₂Ar

1

2

3

4

*

Corresponding author. Tel.: +1 484 865 4504; fax: +1 484 865

9398; e-mail: elokdah@wyeth.com

Figure 1. Genesis of leads.

doi:10.1016/j.bmc.2007.06.024

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

6209

Table 1. Biological data for representative leads

hydrochlorides^18,19

1

and 2,

nish 19, a 2-step process in which imine (18) was

preformed followed by a hydride reduction step aﬀorded

the required picoline. Subsequent treatment of 19

(R = benzyl) with n-BuLi followed by DMF¹⁶furnished

piperidinyl 7-azaindole 8 system (R = Bn), albeit in poor

yield due to formylation of the benzyl group. However,

the desired N-ethyl analogs of 8 were obtained from 19

(R = ethyl) in signiﬁcantly better yields under these con-

ditions. Sulfonylation to ﬁnal targets 4 (R = Et) was

readily accomplished as previously described in Scheme

1. Removal of the ethyl using a-chloroethylchlorofor-

mate (ACE–Cl)²⁰furnished the secondary unsubstituted

amine 4 (R = H). Reaction of this free amine 4 (R = H)

with aldehydes or ketones under standard reductive

amination conditions furnished N-substituted analogs

4 (R = alkyl).

Compound Ar R₁R₂5-HT₆

K_i(nM)

5-HT₆cAMP Assay

Agonist

EC₅₀(nM)

Ph Me Me 20 0.2 Weak partial Agonist

Ph Me Me 23 25 94

E_max(%)

1a

2a

2

2. Chemistry

2.1. Synthesis of pyrrolidine analogs (3)

Conversion of N-substituted hydroxypyrrolidines (5,

R = Me or Et) into the chloro derivatives (6a) or the

tosylates (6b) aﬀorded substrates for N-substitution

reactions. Reaction of 7-azaindole with either 6a or 6b

under basic conditions eﬃciently furnished the desired

pyrrolidinyl-7-azaindoles (7). Subsequent sulfonylation

of 7 with sulfonyl chlorides in the presence of a Lewis

acid in nitrobenzene aﬀorded the target analogs 3

(R = Me or Et). In a similar manner, compounds 3

where R = benzyl were prepared. In an eﬀort to prepare

additional analogs, dealkylation of 3 with a-chloroethyl-

chloroformate (ACE–Cl)²⁰yielded secondary amines 3

(R = H) (Scheme 1).

3. Biological data

3.1. 5-HT₆binding studies

All ﬁnal compounds were tested in a standard radioli-

gand binding assay¹⁸using human-cloned 5-HT₆recep-

tors stably transfected in HeLa cells (Tables 2 and 3) to

determine aﬃnity for the 5-HT₆receptor. In pyrrolidinyl

series 3, essentially all the analogs, with the exception of

3q, were high aﬃnity ligands with K_ivalues <10 nM.

This impressive and consistently high aﬃnity shows that

the constrained basic side chain locks the amine in a

conformation that binds favorably to the receptor.

However, within this series, a few subtle diﬀerences

can still be discerned. For example, while a ﬂuoro,

chloro, bromo, or triﬂuoromethyl substitution at any

position on the phenylsulfonyl ring is surprisingly well

tolerated, there is a slight preference for meta-substitu-

tion (3b, 3d, 3f, and 3h). Other sites of variation, how-

ever, had little impact on aﬃnity. For example, both

secondary and tertiary amine analogs (e.g., 3b vs 3k

and 3d vs 3n) had comparable aﬃnities. Interestingly,

certain arylsulfonyl derivatives, in particular 5-chloroth-

ien-2-yl (3t) and 6-Cl-imidazo[2,1-b]thiazol-5-yl (3v, 3w,

3x), were amongst the most potent at the 5-HT₆receptor

with K_ivalues around 1 nM.

2.2. Synthesis of piperidine analogs (4)

To prepare the piperidine analogs (4), we attempted

alkylation of 7-azaindole with either 1-ethyl-3-chloro-

piperidine (11a), 1-benzyl-3-chloro-piperidine (11b), or

the corresponding tosylates (12a and 12b), under the

same conditions used for the preparation of pyrrolidinyl

derivatives (7). Instead of the desired piperidinyl-7-

azaindoles (8), the reactions consistently gave the ring-

contracted products (9) (Fig. 2). It is proposed that this

transformation proceeds through the latent aziridinium

species (10). Nucleophilic attack by the azaindole on

the secondary carbon of the aziridinium system is pre-

ferred to attack on the tertiary center aﬀording the pyr-

rolidinylmethyl derivatives (9). Furthermore, attempted

alkylation of 7-azaindole with halopiperidine derivatives

incapable of forming aziridinium cations (i.e., 13–16)

yielded no detectable alkylation product under similar

reaction conditions, thus supporting the proposed mech-

anism. A variety of other routes were tried but were

unsuccessful in yielding 8. These included reactions of

7-azaindole with 1-benzyl-3-piperidinone under stan-

dard reductive amination conditions and reactions of

7-azaindole with 1-benzyl-3-piperidinol under Mitsun-

obu conditions.

Among the piperidinyl analogs (4), high 5-HT₆aﬃnity

was observed with almost all derivatives as well with

only four compounds (4f–4h and 4u) having K_ivalues

>10 nM. As in the ﬁrst series, a minor preference for

meta-substituted derivatives was observed (4c–4e).

Among the aromatic derivatives, superior aﬃnity for

the receptor was achieved with 4y and 4aa which contain

the bicyclic aromatic 6-Cl-imidazo[2,1-b]thiazol-5-yl

moiety. In general, there was no direct correlation be-

tween the size of substituent on the amine (H, Me, Et,

i-Pr) and the binding aﬃnity (e.g., 4n–4q or 4y, 4z,

4aa, 4ab).

An alternate route was required to access the desired

analogs. The approach we envisioned (Scheme 2) utilizes

conversion of the piperidinyl aminopicoline (19,

R = benzyl), readily available from aminopyridine 17,

to piperidinyl-7-azaindole 8 following the procedure of

Hands and coworkers.²¹Toward that end, reaction of

2-amino-picoline with 1-benzyl-3-piperidinone under

one-pot reductive amination conditions^22,23was at-

tempted. Although the direct conversion failed to fur-

3.2. 5-HT₆functional assays

Functional eﬃcacy of these ligands was determined for

both series in a cAMP RIA in HeLa cells stably

transfected with the h5-HT₆receptor,¹⁹to determine

6210

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

R

N

O

S

O

Ar

N

R

N

a

Cl

N

d

N

c

6a

OH

N

R

b

R

5

7

3

N

R = Alkyl

R = H

e

OTs

6b

Scheme 1. Synthesis of compounds 3. Reagents and conditions: (a) POCl₃, toluene, reﬂux; (b) tosylchloride, Et₃N, CH₂Cl₂; (c) 7-azaindole, Cs₂CO₃,

DMSO, 80 ꢁC; (d) ArSO₂Cl, AgOTf, PhNO₂, 140 ꢁC; (e) i—ACE–Cl, DCE, reﬂux; ii—EtOH, reﬂux.

the correlation between receptor aﬃnity and functional

activity (Tables 2 and 3). Among the derivatives in series

3, meta-substituted phenylsulfonyl compounds such as

3b, 3d, 3f, and 3h were generally partial agonists with

moderate to weak potency in the functional assay. With

the exception of compound 3c, moving the phenyl sub-

stituent to the ortho- or para-positions provided com-

pounds with antagonist eﬃcacy. In addition, while

alkylating the basic amine did not impact binding aﬃn-

ity, it did change the functional activity of the com-

pounds (3j, 3l–3s, 3w, and 3x) from agonist to

antagonist. Among these, compounds 3p, 3t, and 3x

were nearly full antagonists with IC₅₀values of 23, 11,

and 10 nM, respectively. A higher proportion of the

compounds in series 4 demonstrated potent partial

agonism with compounds 4c and 4n being nearly full

agonists with moderate potency (EC₅₀= 50 and

67 nM, respectively). The functional SAR of this series

is diﬃcult to deﬁne, as there are instances of signiﬁcant

diﬀerences in eﬃcacy with relatively small changes in the

substitution pattern. For example, while the 3-ﬂuor-

ophenyl analog 4n is nearly a full agonist, the closely re-

lated 2-ﬂuorophenyl derivative (4m) possesses full

antagonist eﬃcacy with an IC₅₀= 50 nM. In addition,

meta-substituted phenylsulfonyl derivatives were gener-

ally functionally agonists regardless of the substitution

on the basic nitrogen, while the para-substituted analogs

were generally antagonists.

Several of the racemic compounds in each series were

separated into their enantiomers and tested separately

in the binding assays but a signiﬁcant eudismic ratio

was not evident among the corresponding enantiomeric

pairs. Similarly, in the functional assay, the enantiomers

maintained functional activity and potency similar to

that of the corresponding racemate.

4. Conclusions

Two series of 3-arylsulfonyl-7-azaindoles with con-

strained basic amine side chains were prepared. The ba-

sic amine was constrained in a ﬁve-membered ring,

pyrrolidines (3), or six-membered ring, piperidines (4).

Me

NH

Me

N

Me

N

a

b

N

NH₂

N

R

N

X

N

R

17

18

R = Bn or Et

19

R = Bn or Et

8

9

N

R

+

N

X

O

10

Ar

O S

11a, X = Cl, R = Et

11b, X = Cl, R = Bn

12a, X = OTs, R = Et

N

c

d

N

R

12b, X = OTs, R = Bn

N

R

8

4

Bn

N

R = Et

e

f

Bz

Cbz

R = H

R = Alkyl

N

O

Scheme 2. Synthesis of compounds 4. Reagents and conditions: (a) 1-

benzyl-3-piperidinone, TsOH, benzene, reﬂux, 16 h; (b) MeOH,

NaBH₄; (c) n-BuLi, DMF, THF, À78 ꢁC; (d) ArSO₂Cl, AgOTf,

PhNO₂, heat; (e) i—ACE–Cl, DCE, reﬂux; ii—EtOH, reﬂux; (f)

aldehydes or ketones, NaBH(OAc)₃, THF.

Cl

Br

Cl

13

14

15

16

Figure 2. Alkylation of 7-azaindole with 3-piperidinyl halides or

tosylates.

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

Table 2. Biological data for compound 3 hydrochlorides^18,19

6211

Compound

Ar

R

5-HT₆K_i^a(nM)

5-HT₆cAMP assay^a

Agonist

EC₅₀(nM)

Antagonist

IC₅₀(nM) I_max(%)

50

E_max(%)

3a

3b

3c

3d

3e

3f

2-FPh

3-FPh

H

2.0 0.1

2.7 0.1

8.5 0.5

1.5 0.1

5.5 0.4

1.3 0.1

4.3 0.3

1.3 0.1

2.5 0.6

—

44

50

47

—

49

—

41

61

—

54

—

32

—

100

—

94

—

96

—

69

—

85

91

85

98

75

89

93

94

100

—

69

93

H

278

—

4-FPh

3-ClPh

H

1645

1680

—

H

—

4-ClPh

3-BrPh

H

340

—

H

35

3g

3h

3i

4-BrPh

3-CF₃Ph

H

—

135

—

H

520

2035

—

Ph

2-FPh

Me

Et

H

—

3j

5.6

1

186

—

3k

3l

3-FPh

4-FPh

1.4 0.3

5.0 0.1

2.2 0.6

1.5 0.5

4.2 0.3

0.9 0.1

231

—

213

91

3m

3n

3o

3p

3q

3r

3s

3t

2-ClPh

3-ClPh

—

142

95

4-ClPh

3-BrPh

—

23

56

Ph

3-FPh

11

8.3 1.3

3.3

1

—

132

120

11

3-ClPh

5-Cl-thien-2-yl

8-Quinolyl

1

—

1.0 0.1

5.7 0.5

1.0 0.1

0.8 0.2

1.4 0.1

3u

3v

3w

3x

H

—

643

—

6-Cl-imidazo[2,1-b]thiazol-5-yl

H

80

Me

Et

—

26

10

Displacement of [³H]-LSD binding to cloned h5-HT₆receptors stably expressed in HeLa cells.

^aK_i, EC₅₀, IC₅₀, E_max, and I_maxvalues were determined in triplicate.

1

Alkylation of 7-azaindole with 3-chloro-pyrrolidine or

3-tosyl-pyrrolidine furnished pyrrolidinyl-7-azaindoles

(7) that were subsequently elaborated to targets 3. On

the other hand, alkylation of 7-azaindole with 1-ben-

zyl-3-chloro-piperidine proceeded through an aziridini-

and are uncorrected. H NMR spectra were recorded

on a Varian Unity Plus 400 spectrometer. The chemical

shifts (d) are reported in parts per million (ppm) down-

ﬁeld from zero relative to the residual DMSO signal

(2.49 ppm), chloroform (7.26 ppm), or TMS (0 ppm).

Coupling constants are reported in Hertz (Hz). Solvate,

hydrate, and HCl protons are not included. Mass spec-

tra were recorded on either a Hewlett–Packard 5995A, a

Finnigan Trace MS or a Micromass LCT spectrometer.

C,H,N combustion analyses were determined on either a

Perkin-Elmer 2400 analyzer or were performed by Rob-

ertson Microlit (Madison, NJ). All analyzed compounds

are within 0.4% of the theoretical value unless other-

wise indicated. Unless otherwise noted, reagents were

obtained from commercial sources and were used with-

out further puriﬁcation. Solvents for extraction and

chromatography (dichloromethane, ethyl acetate) were

HPLC-grade OmniSolv. Reagents purchased from EM

Science. Chromatographic puriﬁcations were performed

by ﬂash chromatography using Baker 40-lm silica gel.

Analytical high pressure liquid chromatography

(HPLC) was performed on a Prodigy ODS 3 150,

4.6 mm id column using a 0.2% triﬂuoroacetic acid/

water/acetonitrile gradient with a ﬂow rate of 1 mL/

min and UV detection at 215 nm. Chiral HPLC was per-

formed on a Chiracel AD, 0.46 · 25 cm column.

um intermediate to furnish

a

ring-contracted

pyrrolidinylmethyl product 9. An alternate facile syn-

thetic route to the piperidinyl analogs 4 was designed

and successfully utilized in the preparation of the com-

pounds in this novel series.

All analogs were shown to have high binding aﬃnity to

the 5-HT₆receptor. All the analogs in series 3 and 4,

with the exception of ﬁve compounds (90% of the com-

pounds), exhibited high 5-HT₆receptor binding aﬃnity

with K_ivalues <10 nM. Among compounds of the ear-

lier series 2, 17 out of 24 compounds (70%) were high

potency ligands with K_ivalues <10 nM. Most com-

pounds in series 4 functioned as partial agonists, while

the majority of compounds in series 3 were identiﬁed

as antagonists. In both series, meta-substitution on the

phenylsulfonyl generally corresponded with partial

agonism while para-substitution favored antagonism.

Alkylation of the basic nitrogen shifted the functional

activity to antagonism only in series 3.

5. Experimental

5.2. General method for preparation of compounds 3 from

compounds 7

5.1. General methods

A suspension of 7 (R = benzyl, methyl or ethyl)

(4.0 mmol), arylsulfonylchloride (4 mmol) and silver tri-

ﬂuoromethanesulfonate (9.3 mmol) in nitrobenzene

Melting points were determined on a Thomas–Hoover

capillary or an Electrothermal melting point apparatus

6212

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

Table 3. Biological data for compound 4 hydrochlorides^18,19

5-HT₆cAMP assay^a

a

5-HT₆K_i(nM)

Compound

Ar

R

Agonist

EC₅₀(nM)

Antagonist

IC₅₀(nM) I_max(%)

E_max(%)

4a

4b

4c

4d

4e

4f

Ph

H

Et

4.9 0.5

3.6 0.2

3.7 0.3

1.3 0.1

7.6 0.1

11.5 0.5

33.5 0.5

11.1 0.2

4.6 0.4

12 0.1

47

56

26

58

2-ClPh

3-ClPh

H

50

30

84

49

H

4-ClPh

H

682

28

76

63

71

74

Me

Et

4g

4h

4i

4-ClPh

70

338

i-Pr

H

3-CF₃Ph

4-CF₃Ph

273

414

49

65

72

66

49

4j

H

4k

4l

3-CF₃Ph

3-BrPh

Me

H

2.1 0.2

3.8 0.2

2.0 0.1

2.4 0.1

4.7 0.5

4.4 0.1

3.4 0.2

9.4 0.2

6.1 0.2

3.9 0.4

13.5 0.5

1.2 0.1

1.9 0.4

3.2 0.2

0.7 0.2

2.0 0.4

0.7 0.1

1.7 0.1

72

4m

4n

4o

4p

4q

4r

2-FPh

3-FPh

H

50

100

77

H

67

306

60

84

75

63

67

3-FPh

Me

Et

3-FPh

3-BrPh

i-Pr

H

172

492

4s

3,5-diClPh

297

62

56

50

49

62

46

47

68

44

4t

Me

Et

38.7

4u

4v

4w

4x

4y

4z

4aa

4ab

67

98

71

50

66

25

34

5-Cl-thien-2-yl

6-Cl-imidazo[2,1-b]thiazol-5-yl

H

Me

Et

H

Me

Et

i-Pr

8

65

Displacement of [³H]-LSD binding to cloned h5-HT₆receptors stably expressed in HeLa cells.

^aK_i, EC₅₀, IC₅₀, E_max, and I_maxvalues were determined in triplicate.

(2.1 mL) was stirred at 140 ꢁC under nitrogen for 17.5 h.

The mixture was subjected to aqueous work-up and

puriﬁed by ﬂash chromatography or HPLC to aﬀord

compounds 3. a-Chloroethylchloroformate (0.2 mL,

2 mmol) was added to a solution of 3 (R = benzyl)

(0.644 mmol) in 1,2-dichloroethane (6 mL). The reaction

mixture was reﬂuxed under nitrogen for 4.5 h, concen-

trated, and diluted with ethanol (5 mL). The mixture

was reﬂuxed for 1.5 h followed by aqueous work-up

and puriﬁcation by ﬂash chromatography to give 3

(R = H).

column chromatography furnished compounds

4

(R = H) (50–79% yield). An aldehyde or a ketone

(0.35 mmol) was added to 0.1 mmol of 4 (R = H) and

sodium triacetoxyborohydride (0.4 mmol) in acetonitrile

(2.1 mL). The reaction mixture was stirred at room tem-

perature for 3 h. followed by aqueous work-up, organic

phase extraction, and treatment with ethereal HCl.

Compounds 4 (R = alkyl) were obtained as hydrochlo-

ride salts.

5.3.1. 3-(2-Fluoro-benzenesulfonyl)-1-pyrrolidin-3-yl-1H-

pyrrolo[2,3-b]pyridine (3a)

5.3. General method for preparation of compounds 4 from

compound 8

5.3.1.1. Step 1. 1-(1-Benzyl-pyrrolidin-3-yl)-3-(2-ﬂu-

oro-benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine was pre-

pared from 1-(1-benzyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-

b]pyridine (1.7 g, 6.1 mmol), 2-ﬂuorobenzenesulfonyl

chloride (0.79 mL, 6.0 mmol) and silver triﬂuorome-

thanesulfonate (2.9 g, 11 mmol) in nitrobenzene as de-

scribed in Step 1 for compound 3t to give a yellow gum

(0.233 g. 9.0%); mass spectrum (+EI, [M+H]⁺) m/z 436.

¹H NMR (500 MHz, DMSO-d₆): d 8.50 (s, 1H), 8.37

(dd, 1H, J = 4.64 Hz and 1.48 Hz), 8.06-8.10 (m, 2H),

7.65–7.71 (m, 1H), 7.40–7.44 (m, 1H), 7.26–7.36 (m,

6H), 7.18–7.23 (m, 1H), 5.43–5.48 (m, 1H), 3.72 (d, 1H,

J = 13.05 Hz), 3.61 (d, 1H, J = 13.06 Hz), 3.04–3.10 (m,

1H), 2.78–2.81 (m, 1H), 2.66–2.70 (m, 1H), 2.36–2.43

(m, 1H), 1.96–2.04 ppm (m, 1H).

A mixture of 8 (R = Et, 1.74 mmol), arylsulfonylchlo-

ride (1.92 mmol), and silver triﬂuoromethanesulfonate

(3.5 mmol), in nitrobenzene (0.8 mL) was heated at

130 ꢁC for 20 h in a pressure vessel. After cooling, the

mixture was puriﬁed by column chromatography to af-

ford compounds 4 (R = Et). a-Chloroethylchlorofor-

mate (2.2 mmol) was added to a solution of 4 (R = Et,

0.43 mmol) and proton-sponge (0.22 mmol) in 1,2-

dichloroethane (7 mL). The mixture was heated at

100 ꢁC for 8 h. The solvent was evaporated, and 10%

water in dioxane (7 mL) was added and the mixture

was again heated at 100 ꢁC for 5 h. Puriﬁcation by ﬂash

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

6213

5.3.1.2. Step 2. a-Chloroethylchloroformate

(0.13 mL, 1.2 mmol) was added to a solution of 1-(1-

benzyl-pyrrolidin-3-yl)-3-(2-ﬂuoro-benzenesulfonyl)-

1H-pyrrolo[2,3-b]pyridine (0.206 g, 0.473 mmol) in

1,2-dichloroethane (7 mL). The reaction mixture was

reﬂuxed under nitrogen for 40 min. A second portion

of a-chloroethylchloroformate (1.3 mL, 1.2 mmol)

was added, and the mixture was reﬂuxed for 2 h. After

concentrating, adding methylene chloride and concen-

trating, ethanol (7 mL) was added. The reaction

mixture was reﬂuxed under nitrogen for 1.5 h. The

mixture was concentrated. The residue was parti-

tioned in chloroform and aqueous sodium bicarbo-

nate. The organic phase was puriﬁed by ﬂash

chromatography using 5–10% methanol in methylene

chloride and 0.1% ammonium hydroxide/10% metha-

nol in methylene chloride. Concentrating and drying

in vacuo at ambient temperature for 1.5 h yielded

3-(2-ﬂuoro-benzenesulfonyl)-1-pyrrolidin-3-yl-1H-pyrrol-

o[2,3-b]pyridine as a light yellow semi-solid (46.7 mg,

28.7%). Ethanol and ethereal hydrogen chloride were

added. Concentrating and drying in vacuo at 78 ꢁC

for 11 h gave the hydrochloride as a cream solid

(48.9 mg, 24.7%); mass spectrum (+EI, [M+H]⁺) m/z

346. ¹H NMR (500 MHz, DMSO-d₆): d 9.32–9.43

(br, 1H), 9.15–9.25 (br, 1H), 8.69 (s, 1H), 8.40–8.41

(m, 1H), 8.05–8.16 (m, 2H), 7.62–7.73 (m, 1H), 7.38–

7.42 (m, 1H), 7.30–7.36 (m, 2H), 5.55–5.64 (m, 1H),

3.60–3.75 (m, 2H), 3.50–3.58 (m, 1H), 3.27–3.36 (m,

1H), 2.48–2.55 (m, 1H), 2.30–2.40 ppm (m, 1H).

HRMS (C₁₇H₁₆FN₃O₂S), calcd [M+H]⁺346.1025,

found [M+H]⁺346.1032.

Ethanol and ethereal hydrogen chloride were added.

Concentrating and drying in vacuo at 78 ꢁC for 11 h

gave the hydrochloride as

a light brown solid

(20.3 mg, 21.2%); mass spectrum (+EI, [M+H]⁺) m/z

1

346. H NMR (500 MHz, DMSO-d₆): d 9.19–9.33 (m,

br, 2H), 8.66 (s, 1H), 8.41(dd, 1H, J = 4.76 Hz and

1.59 Hz), 8.24 (dd, 1H, J = 7.93 Hz and 1.58 Hz),

7.79–7.86 (m, 2H), 7.59–7.65 (m, 1H), 7.45–7.50 (m,

1H), 7.33–7.36 (m, 1H), 5.51–5.58 (m, 1H), 3.62-3.72

(m, 2H), 3.49–3.57 (m, 1H), 2.33–2.56 ppm (m, 3H).

HRMS (C₁₇H₁₆FN₃O₂S), calcd [M+H]⁺346.1025,

found [M+H]⁺346.1013.

5.3.3. 3-(4-Fluoro-benzenesulfonyl)-1-pyrrolidin-3-yl-1H-

pyrrolo[2,3-b]pyridine (3c)

5.3.3.1. Step 1. 1-(1-Benzyl-pyrrolidin-3-yl)-3-(4-ﬂuo-

ro-benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine was pre-

pared from 1-(1-benzyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-

b]pyridine (1.7 g, 6.1 mmol), silver triﬂuoromethanesulfo-

nate (3.0 g, 12 mmol), and 4-ﬂuorobenzenesulfonyl chlo-

ride (1.34 g, 6.89 mmol) in nitrobenzene as described in

Step 1 for compound 3t. Puriﬁcation furnished a dark

yellow gum (0.667 g, 24.7%); mass spectrum (+EI,

1

[M+H]⁺) m/z 436. H NMR (500 MHz, DMSO-d₆): d

8.47 (s, 1H), 8.35–8.37 (m, 1H), 8.15–8.17 (d and d, 1H,

J = 1.34 Hz and 1.46 Hz), 8.03–8.07 (m, 2H), 7.32–7.41

(m, 2H), 7.26–7.31 (m, 5H), 7.20–7.23 (m, 1H), 5.39–5.43

(m, 1H), 3.66 (dd, 2H, J = 25.62 Hz and 13.05 Hz), 3.02–

3.07 (m, 1H), 2.68–2.78 (m, 2H), 2.01–2.06 ppm (m, 1H).

5.3.3.2. Step 2. a-Chloroethylchloroformate (0.35 mL,

3.2 mmol) was added to a solution of 1-(1-benzyl-pyrro-

lidin-3-yl)-3-(4-ﬂuoro-benzenesulfonyl)-1H-pyrrolo[2,3-

b]pyridine (0.557 g, 1.28 mmol) in 1,2-dichloroethane

(10 mL). The reaction mixture was reﬂuxed under

nitrogen for 1 h. A second portion of a-chloroethyl-

chloroformate (0.35 mL, 3.2 mmol) was added, and

the mixture was reﬂuxed for two more hours. The sol-

vent was evaporated, and methylene chloride was

added and evaporated. Ethanol (10 mL) was then

added to the residue, and it was reﬂuxed under nitrogen

for 1 h. The reaction mixture was concentrated and

partitioned in chloroform and saturated aqueous so-

dium bicarbonate. The organic phase was washed with

water and brine. It was dried with anhydrous magnesium

sulfate, ﬁltered, and concentrated. The residue was puriﬁed

by ﬂash chromatography using 5–10% methanol in meth-

ylene chloride and 1.0% ammonium hydroxide/10% meth-

anol in methylene chloride. After concentrating and

drying, 3-(4-ﬂuoro-benzenesulfonyl)-1-pyrrolidin-3-yl-1H-

pyrrolo[2,3-b]pyridine was obtained as a cream foam

(0.187 g, 42.3%). It was dissolved in chloroform, and ethe-

real hydrogen chloride was added. The mixture was concen-

trated and dried in vacuo for 12 h at 85 ꢁC to yield to

hydrochloride as a cream solid (0.191 g, 35.7%): mp 189–

5.3.2. 3-(3-Fluoro-benzenesulfonyl)-1-pyrrolidin-3-yl-1H-

pyrrolo[2,3-b]pyridine (3b)

5.3.2.1. Step 1. 1-(1-Benzyl-pyrrolidin-3-yl)-3-(3-ﬂuo-

ro-benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine was

prepared from 1-(1-benzyl-pyrrolidin-3-yl)-1H-pyrrolo-

[2,3-b]pyridine (1.7 g, 6.1 mmol), 3-ﬂuorobenzenesulfo-

nyl chloride (0.80 mL, 6.0 mmol) and silver triﬂuorome-

thanesulfonate (2.7 g, 11 mmol) in nitrobenzene as

described in Step 1 for compound 3t to give a yellow

semi-solid (0.100 g. 3.86%)

5.3.2.2. Step 2. a-Chloroethylchloroformate (0.1 mL,

0.9 mmol) was added to a solution of 1-(1-benzyl-pyrro-

lidin-3-yl)-3-(3-ﬂuoro-benzenesulfonyl)-1H-pyrrolo[2,3-

b]pyridine (99.6 mg, 0.229 mmol) in 1,2-dichloroethane

(5 mL). The reaction mixture was reﬂuxed under nitro-

gen for 3.5 h. After concentrating, adding methylene

chloride, and concentrating ethanol (5 mL) was added.

The reaction mixture was reﬂuxed under nitrogen for

1.5 h. The mixture was concentrated, and the residue

was partitioned in chloroform and aqueous sodium

bicarbonate. The organic phase was washed with brine,

dried with anhydrous magnesium sulfate, ﬁltered, and

concentrated. The residue was puriﬁed by ﬂash chroma-

tography using 10% methanol in 1,2-dichloroethane and

10% methanol in chloroform and 0.1% ammonium

hydroxide/10% methanol in chloroform. Concentrating

and drying in in vacuo at 68 ꢁC for 25 min yielded 3-

(3-ﬂuoro-benzenesulfonyl)-1-pyrrolidin-3-yl-1H-pyrrolo

[2,3-b]pyridine as an orange foam (21.9 mg, 27.8%).

1

190 ꢁC (dec); mass spectrum (+EI, [M+H]⁺) m/z 346. H

NMR (500 MHz, DMSO-d₆): d 9.23–9.33 (s, br, 2H), 8.64

(s, 1H), 8.41 (dd, 1H, J = 4.76 Hz and 1.47 Hz), 8.19–8.21

(d and d, 1H, J = 1.59 Hz and 1.47 Hz), 8.02–8.08 (m,

2H), 7.32–7.42 (m, 3H), 5.51–5.58 (m, 1H), 3.60-3.72

(m, 2H), 3.50–3.56 (m, 1H), 3.29-3.35 (m, 1H), 2.48–2.54

(m, 1H), 2.34–2.41 ppm (m, 1H). Anal. (C₁₇H₁₆FN₃O₂SÆH-

ClÆ0.1H₂O) C, H, N.

6214

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

5.3.4. 3-(3-Chloro-benzenesulfonyl)-1-pyrrolidin-3-yl-1H-

pyrrolo[2,3-b]pyridine (3d)

added, and the mixture was reﬂuxed for one more hour.

After concentrating, adding methylene chloride, and

concentrating, ethanol (7 mL) was added. The reaction

mixture was reﬂuxed under nitrogen for 2.5 h and con-

centrated. The residue was partitioned in chloroform

and aqueous sodium bicarbonate. The organic phase

was puriﬁed by ﬂash chromatography using 5–10% meth-

anol in methylene chloride and 0.1% ammonium hydrox-

ide/10% methanol in methylene chloride and 5–7.5%

methanol in 1,2-dichloroethane. Concentrating and dry-

ing in vacuo at 78 ꢁC for 4 h yielded 3-(4-chloro-benze-

nesulfonyl)-1-pyrrolidin-3-yl-1H-pyrrolo[2, 3-b]pyridine

as a light orange foam (58.9 mg, 35.9%). It was dis-

solved in chloroform, and ethereal hydrogen chloride

was added. Concentrating and drying in vacuo at

85 ꢁC for 12 h gave the hydrochloride as a light buﬀ so-

lid (55.7 mg, 28.3%): mp 188–190 ꢁC (dec); mass spec-

trum (+EI, [M+H]⁺) m/z 362. ¹H NMR (500 MHz,

DMSO-d₆): d 9.12–9.30 (br, 2H), 8.64 (s, 1H), 8.41

(dd, 1H, J = 4.76 Hz and 1.46 Hz), 8.19–8.21 (m, 1H),

7.97–8.00 (m, 2H), 7.60–7.64 (m, 2H), 7.33–7.36 (m,

1H), 5.51–5.58 (m, 1H), 3.61–3.71 (m, 2H), 3.50–3.57

(m, 1H), 2.28–2.54 ppm (m^*, 3H). Anal. (C₁₇H₁₆ClN₃

O₂SÆ2.0HCl) C, H, N.

5.3.4.1. Step 1. 1-(1-Benzyl-pyrrolidin-3-yl)-3-(3-

chloro-benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine was

prepared from 1-(1-benzyl-pyrrolidin-3-yl)-1H-pyrrolo-

[2,3-b]pyridine (1.7 g, 6.1 mmol), 3-chloro-

benzenesulfonyl chloride (0.84 mL, 6.0 mmol), and

silver triﬂuoromethanesulfonate (2.8 g, 11 mmol) in

nitrobenzene as described in Step 1 for compound 3t

to give 1-(1-benzyl-pyrrolidin-3-yl)-3-(3-chloro-benze-

nesulfonyl)-1H-pyrrolo[2,3-b]pyridine as a light yellow

semi-solid (76.1 mg. 2.82%). To a solution of this mate-

rial (75.2 mg, 0.166 mmol) in 1,2-dichloroethane (5 mL)

was added a-chloroethylchloroformate (0.1 mL,

0.9 mmol). The reaction mixture was reﬂuxed under

nitrogen for 2 h. After concentrating, adding methylene

chloride, and concentrating, ethanol (5 mL) was added.

The reaction mixture was reﬂuxed under nitrogen for

1 h. The mixture was concentrated. Water was added

to the residue, and it was basiﬁed with solid sodium

bicarbonate. It was extracted with chloroform and con-

centrated. The residue was puriﬁed by ﬂash chromato-

graphy using 10% methanol in chloroform and 0.1%

ammonium hydroxide/10% methanol in chloroform.

Concentrating and drying in vacuo at 58 ꢁC for 20 min

yielded 3-(3-chloro-benzenesulfonyl)-1-pyrrolidin-3-yl-

5.3.6. 3-(3-Bromo-benzenesulfonyl)-1-pyrrolidin-3-yl-1H-

pyrrolo[2,3-b]pyridine (3f)

1H-pyrrolo[2,3-b]pyridine as

a

cream semi-solid

(38.2 mg, 63.5%). It was dissolved in ethanol, and ethe-

real hydrogen chloride was added. Concentrating and

drying in vacuo at 78 ꢁC for 12 h gave the hydrochloride

as an oﬀ-white solid (38.8 mg, 53.7%); mass spectrum

5.3.6.1. Step 1. 1-(1-Benzyl-pyrrolidin-3-yl)-3-(3-bro-

mo-benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine was pre-

pared from 1-(1-benzyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-

b]pyridine (1.7 g, 6.1 mmol), 3-bromobenzenesulfonyl

chloride (0.86 mL, 6.0 mmol), and silver triﬂuoro-

methanesulfonate (2.9 g, 11 mmol) in nitrobenzene as

described in Step 1 for compound 3t. Puriﬁcation using

ﬂash chromatography using 100% methylene chloride

and 100% ethyl acetate and by HPLC using a gradient

of (methylene chloride and methanol) in hexane/TEA

1

(+EI, [M+H]⁺) m/z 362. H NMR (500 MHz, DMSO-

d₆): d 9.17–9.38 (br, 2H), 8.67 (s, 1H), 8.40–8.42 (m,

1H), 8.24 (dd, 1H, J = 8.05 Hz and 1.58 Hz), 7.96–7.99

(m, 2H), 7.67–7.70 (m, 1H), 7.59 (t, 1H, J = 7.93 Hz),

7.34–7.37 (m, 1H), 5.51–5.58 (m, 1H), 3.62–3.72 (m,

2H), 3.51–3.56 (m, 1H), 2.34–2.56 ppm (m, 3H). Anal.

(C₁₇H₁₆ClN₃O₂SÆ1.0 HClÆ1.2H₂O) C, H, N.

yielded

zenesulfonyl)-1H-pyrrolo[2,3-b]pyridine

3.7%) as yellow semi-solid. To this material

1-(1-benzyl-pyrrolidin-3-yl)-3-(3-bromo-ben-

(0.110 g.

5.3.5. 3-(4-Chloro-benzenesulfonyl)-1-pyrrolidin-3-yl-1H-

pyrrolo[2,3-b]pyridine (3e)

a

(0.109 g, 0.220 mmol) in 1,2-dichloroethane (5 mL)

was added a-chloroethylchloroformate (0.12 mL,

1.1 mmol). The reaction mixture was reﬂuxed under

nitrogen for 50 min. A second portion of a-chloroethyl-

chloroformate (0.1 mL, 0.9 mmol) was added, and this

mixture was reﬂuxed for 30 min. After concentrating,

adding methylene chloride, and evaporating, ethanol

(5 mL) was added. The reaction mixture was reﬂuxed

under nitrogen for 55 min. The mixture was concen-

trated. The residue was puriﬁed by ﬂash chromatogra-

phy using 0.1% ammonium hydroxide/10% methanol in

methylene chloride and 10% methanol in methylene

chloride. Concentrating and drying in vacuo at

ambient temperature for 70 min yielded 3-(3-bromo-

benzenesulfonyl)-1-pyrrolidin-3-yl-1H-pyrrolo[2,3-b]pyri-

dine as a beige gum (67.5 mg, 75.5%). It was dissolved in

chloroform, and ethereal hydrogen chloride was added.

Concentrating and drying in vacuo at 85 ꢁC for 12 h

gave the hydrochloride as a beige solid (69.2 mg,

65.9%): mp 173–175 ꢁC (dec); mass spectrum (+EI,

5.3.5.1. Step 1. 1-(1-Benzyl-pyrrolidin-3-yl)-3-(4-

chloro-benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine was

prepared from 1-(1-benzyl-pyrrolidin-3-yl)-1H-pyrrolo-

[2,3-b]pyridine

(1.16 g,

4.18 mmol),

4-chloro-

benzenesulfonyl chloride (0.891 g, 4.22 mmol), and

silver triﬂuoromethanesulfonate (2.14 g, 8.33 mmol) as

described in Step 1 for compound 3t to give a yellow

gum (0.130 g. 6.88%); ¹H NMR (400 MHz, DMSO-

d₆): d 8.51 (s, 1H), 8.39 (dd, 1H, J = 4.64 Hz and

1.39 Hz), 8.17–8.19 (d and d, 1H, J = 1.39 Hz and

1.50 Hz), 7.99–8.02 (m, 2H), 7.63–7.65 (m, 2H), 7.22–

7.33 (m, 6H), 5.41–5.45 (m, 1H), 3.62–3.72 (m, 2H),

3.04–3.08 (m, 1H), 2.69–2.80 (m, 2H), 2.39–2.45 (m,

2H), 2.03–2.10 ppm (m, 1H).

5.3.5.2. Step 2. a-Chloroethylchloroformate (0.12 mL,

1.1 mmol) was added to a solution of 1-(1-benzyl-

pyrrolidin-3-yl)-3-(4-chloro-benzenesulfonyl)-1H-pyrrolo-

[2,3-b]pyridine (0.205 g, 0.454 mmol) in 1,2-dichloro-

ethane (8 mL). The reaction mixture was reﬂuxed

1

[M+H]⁺) m/z 406. H NMR (500 MHz, DMSO-d₆): d

under nitrogen for 2 h.

a-chloroethylchloroformate (0.12 mL, 1.1 mmol) was

A

second portion of

9.24–9.35 (br, m, 2H), 8.68 (s, 1H), 8.42 (dd, 1H,

J = 4.76 Hz and 1.46 Hz), 8.24 (dd, 1H, J = 8.05 Hz

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

6215

and 1.46 Hz), 8.10 (t, 1H, J = 1.83 Hz), 8.00–8.02 (m,

1H), 7.80–7.83 (m, 1H), 7.50–7.54 (m, 1H), 7.36 (dd,

1H, J = 8.05 Hz and 4.76 Hz), 5.50–5.57 (m, 1H),

3.64–3.72 (m, 2H), 3.50–3.56 (m, 1H), 2.47–2.56 (m,

1H), 2.34–2.43 ppm (m, 2H). Anal. (C₁₇H₁₆BrN₃O₂SÆ1.5

HCl) C, H, N.

nyl)-1H-pyrrolo[2,3-b]pyridine as a yellow gum (53.3 mg,

1.84%) which was dissolved in 1,2-dichloroethane (5 mL)

and to the resulting solution was added a-chloroethylchlo-

roformate (0.1 mL, 0.9 mmol). The reaction mixture was

reﬂuxed under nitrogen for 2 h. After concentrating,

adding methylene chloride, and concentrating ethanol

(5 mL) wasadded. The reaction mixturewas reﬂuxedunder

nitrogen for 2 h. The mixture was concentrated and

partitioned in chloroform and aqueous sodium bicarbon-

ate. The organic phase was puriﬁed by ﬂash chromatogra-

phy using 7.5–10% methanol in methylene chloride.

Concentrating and drying in vacuo at ambient temperature

for 70 min yielded 1-pyrrolidin-3-yl-3-(3-triﬂuoromethyl-

benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridineasalightbeige

semi-solid (28.4 mg, 65.4%). Ethanol and ethereal hydro-

gen chloride were added. Concentrating and drying in

vacuo at 78 ꢁC for 11 h gave the hydrochloride as a white

solid (29.3 mg, 56.9%); mass spectrum (+EI, [M+H]⁺) m/z

5.3.7. 3-(4-Bromo-benzenesulfonyl)-1-pyrrolidin-3-yl-1H-

pyrrolo[2,3-b]pyridine (3g)

5.3.7.1. Step 1. 1-(1-Benzyl-pyrrolidin-3-yl)-3-(4-bro-

mo-benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine was pre-

pared from 1-(1-benzyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-

b]pyridine (1.7 g, 6.1 mmol), 4-bromobenzenesulfonyl

chloride (1.5 g, 5.9 mmol), and silver triﬂuoromethane-

sulfonate (2.9 g, 11 mmol) in nitrobenzene as described

in Step 1 for compound 3t. The compound was obtained

as a yellow semi-solid (0.172 g. 5.9%); mass spectrum

1

(+EI, [M+H]⁺) m/z 496. H NMR (500 MHz, DMSO-

1

d₆): d 8.48 (s, 1H), 8.36–8.37 (m, 1H), 8.15 (dd, 1H,

J = 8.06 Hz and 1.59 Hz), 7.89–7.92 (m, 2H), 7.74–7.77 (m,

2H), 7.26–7.30 (m, 5H), 7.19–7.23 (m, 1H), 5.40–5.43 (m,

1H), 3.66 (dd, 2H, J = 25.01 Hz and 13.06 Hz), 3.02–

3.06 (m, 1H), 2.68–2.78 (m, 2H), 2.01–2.06 ppm (m, 1H).

396. H NMR (500 MHz, DMSO-d₆): d 9.18–9.32 (br,

2H), 8.73 (s, 1H), 8.41–8.42 (m, 1H), 8.24–8.33 (m,

3H), 8.01 (d, 1H, J = 7.93 Hz), 7.80–7.83 (m, 1H),

7.35–7.38 (m, 1H), 5.50–5.57 (m, 1H), 3.62–3.72 (m,

2H), 3.49–3.56 (m, 1H), 2.48–2.56 (m, 1H),

2.34–2.43 ppm (m, 1H). Anal. (C₁₈H₁₆F₃N₃O₂SÆ1.

5HClÆ0.5H₂O) C, H, N.

5.3.7.2. Step 2. a-Chloroethylchloroformate (0.17 mL,

1.6 mmol) was added to a solution of 1-(1-benzyl-pyrroli-

din-3-yl)-3-(4-bromo-benzenesulfonyl)-1H-pyrrolo[2,3-

b]pyridine (0.155 g, 0.312 mmol) in 1,2-dichloroethane

(6 mL). The reaction mixture was reﬂuxed under

nitrogen for 45 min. A second portion of a-chloroethyl-

chloroformate (0.1 mL, 0.9 mmol) and a few mL of

ethanol were added, and the mixture was reﬂuxed for

45 min. After concentrating, adding methylene chloride,

and concentrating, the residue was partitioned in chloro-

form and aqueous sodium bicarbonate. The organic

phase was mostly concentrated and puriﬁed by ﬂash chro-

matography using 10% methanol in methylene chloride.

Concentrating and drying in vacuo at 55 ꢁC for 30 min

yielded 3-(4-bromo-benzenesulfonyl)-1-pyrrolidin-3-yl-

1H-pyrrolo[2,3-b]pyridine as a buﬀ semi-solid (53.0 mg,

41.7%). It was dissolved in chloroform, and ethereal

hydrogen chloride was added. Concentrating and drying

in vacuo at 85 ꢁC for 12 h gave the hydrochloride as a buﬀ

semi-solid (54.8 mg, 36.5%); mass spectrum (+EI,

5.3.9. 3-Benzenesulfonyl-1-(1-methyl-pyrrolidin-3-yl)-1H-

pyrrolo[2,3-b]pyridine (3i). A thick suspension of 1-(1-

methyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine (0.930

g, 4.62 mmol), benzenesulfonyl chloride (0.71 mL,

5.5 mmol), and silver triﬂuoromethanesulfonate (2.33 g,

9.07 mmol) in nitrobenzene (4.6 mL) was vigorously stir-

red at 125 ꢁC for 9.5 h. After cooling to ambient temper-

ature, saturated aqueous potassium carbonate and ethyl

acetate were added to the reaction mixture, and it was

stirred for several min. The layers were separated, and

the aqueous layer was further extracted with ethyl ace-

tate. The organic phase was washed with brine, dried with

anhydrous magnesium sulfate, ﬁltered, and concentrated.

The residue was puriﬁed by ﬂash chromatography using

100% ethyl acetate and by HPLC using (8:2 methylene

chloride/methanol/0.1% TEA) in hexane/0.1% TEA.

Concentrating and drying in vacuo at 80 ꢁC for 20 min

yielded 3-benzenesulfonyl-1-(1-methyl-pyrrolidin-3-yl)-

1H-pyrrolo[2,3-b]pyridine as a pale yellow gum (0.622 g,

39.4%). A small amount (about 100 mg) was dissolved in

ethyl acetate, and ethereal hydrogen chloride was added.

Concentrating and drying in vacuo at 78 ꢁC for 11 h

yielded the hydrochloride as a cream foam (121 mg); mass

1

[M+H]⁺) m/z 406. H NMR (500 MHz, DMSO-d₆): d

9.20–9.32 (br, m, 2H), 8.64 (s, 1H), 8.41 (dd, 1H,

J = 4.76 and 1.46 Hz), 8.18–8.21 (d and d, 1H,

J = 1.59 Hz and 1.47 Hz), 7.89–7.92 (m, 2H), 7.75–7.78

(m, 2H), 7.33–7.36 (m, 1H), 5.51–5.58 (m, 1H), 3.60–

3.71 (m, 2H), 3.50–3.56 (m, 1H), 3.29–3.35 (m, 1H),

2.28–2.56 ppm (m, 2H). Anal. (C₁₇H₁₆BrN₃O₂SÆ1.4

HCl) C, H, N.

1

spectrum (+EI, [M+H]⁺) m/z 342. H NMR (500 MHz,

DMSO-d₆): d 10.57–10.93 (m, 1H), 8.69–8.71 (m, 1H),

8.40–8.41 (m, 1H), 8.20 (d, 1H, J = 8.05 Hz), 7.97–7.99

(m, 2H), 7.53–7.62 (m, 3H), 7.32–7.36 (m, 1H), 5.55–5.75

(m, 1H), 3.81–4.04 (m, 2H), 3.46–3.68 (m, 2H), 2.87–2.90

(m, 3H), 2.28–2.75 ppm (m, 2H). Anal. (C₁₈H₁₉N₃O₂SÆ1.0

HClÆ1.4H₂O) C, H, N.

5.3.8. 1-Pyrrolidin-3-yl-3-(3-triﬂuoromethyl-benzenesulfo-

nyl)-1H-pyrrolo[2,3-b]pyridine (3h)

5.3.8.1. Step 1. 1-(1-Benzyl-pyrrolidin-3-yl)-3-(3-tri-

ﬂuoromethyl-benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine

was prepared from 1-(1-benzyl-pyrrolidin-3-yl)-1H-pyr-

rolo[2,3-b]pyridine (1.7 g, 6.1 mmol), 3-triﬂuoromethyl-

benzenesulfonyl chloride (0.96 mL, 6.0 mmol), and silver

triﬂuoromethanesulfonate (2.7 g, 11 mmol) in nitroben-

zene as described in Step 1 for compound 3t to give 1-(1-

benzyl-pyrrolidin-3-yl)-3-(3-triﬂuoromethyl-benzenesulfo-

5.3.10. 3-(2-Fluoro-benzenesulfonyl)-1-(1-methyl-pyrroli-

din-3-yl)-1H-pyrrolo[2,3-b]pyridine (3j). A thick suspen-

sion of 1-(1-methyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-

b]pyridine (1.24 g, 6.16 mmol), 2-ﬂuorobenzenesulfonyl

chloride (0.99 mL, 7.5 mmol), and silver triﬂuorome-

thanesulfonate (3.19 g, 12.4 mmol) in nitrobenzene

6216

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

(6.2 mL) was vigorously stirred at 125 ꢁC for 9.5 h. After

cooling to ambient temperature, saturated aqueous

potassium carbonate and ethyl acetate were added to

the reaction mixture, and it was stirred for several

min. The layers were separated, and the aqueous layer

was further extracted with ethyl acetate. The organic

phase was washed with brine, dried with anhydrous

magnesium sulfate, ﬁltered, and concentrated. The resi-

due was puriﬁed by ﬂash chromatography using 100%

ethyl acetate and by HPLC using a gradient of (methy-

lene chloride/methanol) in hexane with 0.1% TEA. Con-

centrating and drying in vacuo at 80 ꢁC for 20 min

yielded 3-(2-ﬂuoro-benzenesulfonyl)-1-(1-methyl-pyrro-

lidin-3-yl)-1H-pyrrolo[2,3-b]pyridine as a pale yellow

gum (0.483 g, 21.9%). It was dissolved in ethyl acetate,

and ethereal hydrogen chloride was added. The precipi-

tate was ﬁltered and dried in vacuo at 78 ꢁC for 14 h to

yield the hydrochloride as an oﬀ-white solid (0.335 g,

12.6%): mp 177–180 ꢁC (dec); mass spectrum (+EI,

nyl chloride (0.905 g, 4.65 mmol), and silver triﬂuoro-

methanesulfonate (2.29 g, 8.91 mmol) in nitrobenzene

(4.2 mL) was vigorously stirred at 125 ꢁC for 14.5 h.

After cooling to ambient temperature, saturated aque-

ous potassium carbonate and chloroform were added

to the reaction mixture, and it was stirred for several

min. The layers were separated, and the aqueous layer

was further extracted with chloroform. The organic

phase was washed with brine, dried with anhydrous

magnesium sulfate, ﬁltered, and concentrated. The resi-

due was puriﬁed by ﬂash chromatography using 100%

ethyl acetate. Concentrating and drying in vacuo at

80 ꢁC for 20 min yielded 3-(4-ﬂuoro-benzenesulfonyl)-

1-(1-methyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine

as a yellow gum (0.622 g, 41.5%). It was dissolved in

ether, and ethereal hydrochloride was added. Filtering

and drying in vacuo for 12 h at 72 ꢁC gave the hydro-

chloride as a light yellow solid (0.615 g, 34.2%): mp

150 ꢁC (dec); mass spectrum (+EI, [M+H]⁺) m/z 360.

¹H NMR (500 MHz, DMSO-d₆): d 10.68–10.99 (m,

1H), 8.70–8.73 (m, 1H), 8.40–8.42 (m, 1H), 8.20 (d,

1H, J = 7.81 Hz), 8.04–8.08 (m, 2H), 7.33–7.41 (m,

3H), 5.55–5.73 (m, 1H), 3.83–4.04 (m, 2H), 3.59–3.69

(m, 1H), 3.46–3.56 (m, 1H), 3.16–3.36 (m, 1H), 2.88–

2.90 (m, 3H), 2.28–2.75 ppm (m, 2H). Anal.

(C₁₈H₁₈FN₃O₂SÆ1.0 HClÆ0.25H₂O) C, H, N.

1

[M+H]⁺) m/z 360. H NMR (500 MHz, DMSO-d₆): d

10.35–10.85 (m, 1H), 8.73 (s, br, 1H), 8.42 (dd, 1H,

J = 4.76 Hz and 1.59 Hz), 8.05–8.15 (m, 2H), 7.65–7.71

(m, 1H), 7.31–7.44 (m, 3H), 5.58–5.78 (m, 1H), 3.48–

4.02 (m, 3H), 2.90 (s, br, 3H), 2.27–2.75 ppm (m, 1H).

Anal. (C₁₈H₁₈FN₃O₂SÆ1.0 HClÆ1.2H₂O) C, H, N.

5.3.11. 3-(3-Fluoro-benzenesulfonyl)-1-(1-methyl-pyrroli-

din-3-yl)-1H-pyrrolo[2,3-b]pyridine (3k). A thick suspen-

sion of 1-(1-methyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-

b]pyridine (1.01 g, 5.02 mmol), 3-ﬂuorobenzenesulfonyl

chloride hydrochloride (0.80 mL, 6.0 mmol), and silver

triﬂuoromethanesulfonate (2.60 g, 10.1 mmol) in nitro-

benzene (5.0 mL) was vigorously stirred at 125 ꢁC for

14.5 h. After cooling to ambient temperature, saturated

aqueous potassium carbonate and ethyl acetate were

added to the reaction mixture, and it was stirred for sev-

eral min. The layers were separated, and the aqueous layer

was further extracted with ethyl acetate. The organic

phase was washed with brine, dried with anhydrous mag-

nesium sulfate, ﬁltered, and concentrated. The residue

was puriﬁed by ﬂash chromatography using 100% ethyl

acetate and by HPLC using (8:2, methylene chloride/

methanol/0.1% TEA) in hexane/0.1% TEA. Concentrat-

ing and drying in vacuo at 80 ꢁC for 20 min yielded 3-(3-

ﬂuoro-benzenesulfonyl)-1-(1-methyl-pyrrolidin-3-yl)-1H-

pyrrolo[2,3-b]pyridine as a pale yellow gum (0.337 g,

18.7%). It was dissolved in ethyl acetate, and ethereal

hydrogen chloride was added. The precipitate was ﬁl-

tered, rinsed with ether, and dried in vacuo at 78 ꢁC for

14 h to yield the hydrochloride as a white solid (0.241 g,

11.1%): mp 135 ꢁC (dec); mass spectrum (+EI, [M+H]⁺)

m/z 360. ¹H NMR (500 MHz, DMSO-d₆): d 10.52–10.82

(m, 1H), 8.73 (s, 1H), 8.42 (dd, 1H, J = 4.76 Hz and

1.47 Hz), 8.23–8.25 (d and d, 1H, J = 1.46 Hz and

1.58 Hz), 7.78–7.85 (m, 2H), 7.59–7.64 (m, 1H), 7.45–

7.50 (m, 1H), 7.33–7.37 (m, 1H), 5.55–5.72 (m, 1H),

3.49–4.02 (m, 3H), 2.89 (s, br, 3H), 2.28–2.75 ppm (m,

2H). Anal. (C₁₈H₁₈FN₃O₂SÆ1.0 HClÆ1.1H₂O) C, H, N.

5.3.13. 3-(2-Chloro-benzenesulfonyl)-1-(1-methyl-pyrroli-

din-3-yl)-1H-pyrrolo[2,3-b]pyridine (3m). A thick suspen-

sion of 1-(1-methyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-

b]pyridine (0.889 g, 4.41 mmol), 2-chlorobenzenesulfo-

nyl chloride (0.72 mL, 5.3 mmol), and silver triﬂuorom-

ethanesulfonate (2.32 g, 9.03 mmol) in nitrobenzene

(4.4 mL) was vigorously stirred at 125 ꢁC for 9.5 h. After

cooling to ambient temperature, saturated aqueous

potassium carbonate and ethyl acetate were added to

the reaction mixture, and it was stirred for several

min. The layers were separated, and the aqueous layer

was further extracted with ethyl acetate. The organic

phase was washed with brine, dried with anhydrous

magnesium sulfate, ﬁltered, and concentrated. The resi-

due was puriﬁed by ﬂash chromatography using 100%

ethyl acetate and 10% methanol in ethyl acetate. Con-

centrating and drying in vacuo at 80 ꢁC for 40 min

yielded 3-(2-chloro-benzenesulfonyl)-1-(1-methyl-pyrro-

lidin-3-yl)-1H-pyrrolo[2,3-b]pyridine as a yellow foam

(0.610 g, 36.7%). A small amount was dissolved in ethyl

acetate, and ethereal hydrochloride was added. The mix-

ture was concentrated and dried in vacuo at 76 ꢁC for

12 h to yield the hydrochloride as a pale yellow solid

(120 mg): mp 135 ꢁC; mass spectrum (+EI, [M+H]⁺)

m/z 376. ¹H NMR (500 MHz, DMSO-d₆): d 10.44–

10.70 (m, 1H), 8.83 (d, 1H, J = 9.88 Hz), 8.39–8.41 (d

and d, 1H, J = 1.58 Hz and 1.47 Hz), 8.31–8.33 (d and

d, 1H, J = 1.83 and 1.95 Hz), 8.01–8.05 (m, 1H), 7.54–

7.65 (m, 3H), 7.28–7.32 (m, 1H), 5.61–5.82 (m, 1H),

3.82–4.08 (m, 2H), 3.61–3.74 (m, 1H), 3.50–3.60 (m,

1H), 2.88–2.96 (m, 3H), 2.28–2.78 ppm (m, 2H). Anal.

(C₁₈H₁₈ClN₃O₂SÆ1.5 HClÆ0.5H₂O) C, H, N.

5.3.12. 3-(4-Fluoro-benzenesulfonyl)-1-(1-methyl-pyrroli-

din-3-yl)-1H-pyrrolo[2,3-b]pyridine (3l). A thick suspen-

sion of 1-(1-methyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-

b]pyridine (0.837 g, 4.16 mmol), 4-ﬂuorobenzenesulfo-

5.3.14. 3-(3-Chloro-benzenesulfonyl)-1-(1-methyl-pyrroli-

din-3-yl)-1H-pyrrolo[2,3-b]pyridine (3n). A thick suspen-

sion of 1-(1-methyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

6217

b]pyridine (0.754 g, 3.75 mmol), 3-chlorobenzenesulfo-

nyl chloride (0.63 mL, 4.5 mmol), and silver triﬂuorom-

ethanesulfonate (2.02 g, 7.86 mmol) in nitrobenzene

(3.8 mL) was vigorously stirred at 125 ꢁC for 14.5 h.

After cooling to ambient temperature, saturated aque-

ous sodium bicarbonate and ethyl acetate were added

to the reaction mixture, and it was stirred for several

minutes. The layers were separated, and the aqueous

layer was further extracted with ethyl acetate. The or-

ganic phase was washed with brine, dried with anhy-

drous magnesium sulfate, ﬁltered, and concentrated.

The residue was puriﬁed by ﬂash chromatography using

100% ethyl acetate. Concentrating and drying in vacuo

at 80 ꢁC for 20 min yielded 3-(3-chloro-benzenesulfo-

nyl)-1-(1-methyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyri-

dine as a light yellow foam (0.529 g, 37.5%). It was

dissolved in ethyl acetate, and ethereal hydrogen chlo-

ride was added. The precipitate was ﬁltered and rinsed

with ethyl acetate and ether. It was then dried in vacuo

at 75 ꢁC for 14 h to yield the hydrochloride as a cream-

colored solid (0.429 g, 25.5%): mp 147–150 ꢁC (dec);

mobenzenesulfonyl chloride (0.85 mL, 5.9 mmol), and

silver triﬂuoromethanesulfonate (2.53 g, 9.85 mmol) in

nitrobenzene (4.9 mL) as described for compound 3o.

Following work-up, the residue was puriﬁed by ﬂash

chromatography using 100% ethyl acetate and by HPLC

(Luna CN column) using (8:2, methylene chloride/meth-

anol/TEA) in hexane/TEA. Concentrating and drying in

vacuo yielded a yellow gum (0.258 g, 12.5%). About

78 mg was dissolved in ethyl acetate, and ethereal hydro-

gen chloride was added. Concentrating and drying in va-

cuo furnished the hydrochloride salt as an oﬀ-white

solid (76.2 mg): mp 145 ꢁC (dec); mass spectrum (+EI,

1

[M+H]⁺) m/z 420. H NMR (500 MHz, DMSO-d₆): d

10.45–10.85 (m, 1H), 8.73 (s, 1H), 8.41–8.43 (m, 1H),

8.24 (dd, 1H, J = 8.06 Hz and 1.47 Hz), 8.10 (t, 1H,

J = 1.83 Hz), 8.00–8.02 (m, 1H), 7.80–7.83 (m, 1H),

7.50–7.54 (m, 1H), 7.35–7.38 (m, 1H), 5.51–5.74 (m,

1H), 3.47–4.02 (m, 3H), 2.89 (s, br, 3H), 2.34–

2.75 ppm (m, 1H). Anal. (C₁₈H₁₈BrN₃O₂SÆ1.5HClÆ1.0-

H₂O) C, H, N.

1

mass spectrum (+EI, [M+H]⁺) m/z 376. H NMR (500

5.3.17. 3-Benzenesulfonyl-1-(1-ethyl-pyrrolidin-3-yl)-1H-

pyrrolo[2,3-b]pyridine (3q). A thick suspension of 1-(1-

ethyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine (1.30 g,

6.04 mmol), benzenesulfonyl chloride (0.92 mL,

7.3 mmol), and silver triﬂuoromethanesulfonate (3.22 g,

12.5 mmol) in nitrobenzene (6.0 mL) was vigorously stir-

red at 125 ꢁC for 16.5 h. After cooling to ambient temper-

ature, saturated aqueous potassium carbonate and ethyl

acetate were added to the reaction mixture, and it was stir-

red for several minutes. The layers were separated, and the

aqueous layer was further extracted with ethyl acetate.

The organic phase was washed with brine, dried with

anhydrous magnesium sulfate, ﬁltered, and concentrated.

The residue was puriﬁed by ﬂash chromatography using

100% ethyl acetate. Concentrating and drying in vacuo

at 80 ꢁC for 20 min gave 3-benzenesulfonyl-1-(1-ethyl-

pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine as a light yel-

low semi-solid (0.888 g, 41.3%). It was dissolved in ethyl

acetate, and ethereal hydrogen chloride was added. The

precipitate was ﬁltered, rinsed with ethyl acetate, and

dried in vacuo at 74 ꢁC for 14 h. The hydrochloride was

obtained as a light buﬀ solid (0.670 g, 25.9%): mp 152–

155 ꢁC (dec); Mass spectrum (+EI, [M+H]⁺) m/z 356.

¹H NMR (500 MHz, DMSO-d₆): d 10.75–11.15 (m,

1H), 8.69–8.77 (s and s, 1H), 8.41 (dd, 1H, J = 4.76 Hz

and 1.34 Hz), 8.19–8.22 (m, 1H), 7.97–8.01 (m, 2H),

7.53–7.61 (m, 3H), 7.32–7.36 (m, 1H), 5.52–5.78 (m,

1H), 3.87–4.04 (m, 1H), 3.48–3.86 (m, 2H), 3.18–3.30

(m, 3H), 2.48–2.73 (m, 1H), 2.28–2.42 (m, 1H), 1.22–

1.26 ppm (m, 3H). Anal. (C₁₉H₂₁N₃O₂S) C, N. H, calcd

4.95; found: 4.54.

MHz, DMSO-d₆): d 10.70–11.10 (m, 1H), 8.73–8.78

(m, 1H), 8.41–8.43 (m, 1H), 8.24 (d, 1H, J = 8.24 Hz),

7.96–7.99 (m, 2H), 7.69 (d, 1H, J = 7.57 Hz), 7.57–7.61

(m, 1H), 7.35–7.38 (m, 1H), 5.53–5.76 (m, 1H), 3.93–

4.05 (m, 1H), 3.17–3.84 (m, 3H), 2.87–2.91 (m, 3H),

2.28–2.76 ppm (m, 2H). HRMS (C₂₀H₁₈ClN₄O₂S), calcd

[M+H]⁺376.0886, found [M+H]⁺376.0890.

5.3.15. 3-(4-Chloro-benzenesulfonyl)-1-(1-methyl-pyrroli-

din-3-yl)-1H-pyrrolo[2,3-b]pyridine (3o). A thick suspen-

sion of 1-(1-methyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-

b]pyridine (1.10 g, 5.47 mmol), 4-chlorobenzenesulfonyl

chloride (1.27 g, 6.02 mmol), and silver triﬂuorome-

thanesulfonate (2.89 g, 11.2 mmol) in nitrobenzene

(5 mL) was vigorously stirred at 125 ꢁC for 17 h. After

cooling to ambient temperature, saturated aqueous so-

dium bicarbonate and ethyl acetate were added to the

reaction mixture, and it was stirred for several min.

The layers were separated, and the aqueous layer was

further extracted with ethyl acetate. The organic phase

was washed with brine, dried with anhydrous magne-

sium sulfate, ﬁltered, and concentrated. The residue

was puriﬁed by ﬂash chromatography using 100% ethyl

acetate. After concentration, it was recrystallized from

ethyl acetate and dried in vacuo at 75 ꢁC for 5 h. 3-(4-

Chloro-benzenesulfonyl)-1-(1-methyl-pyrrolidin-3-yl)-

1H-pyrrolo[2,3-b]pyridine was obtained as an oﬀ-white

solid (0.333 g, 16.2%): mp 136–138 ꢁC; mass spectrum

1

(+EI, [M+H]⁺) m/z 376. H NMR (500 MHz, DMSO-

d₆): d 8.43 (s, 1H), 8.37–8.39 (m, 1H), 8.14 (dd, 1H,

J = 8.05 Hz and 1.59 Hz), 7.98–8.01 (m, 2H), 7.58–7.62

(m, 2H), 7.28–7.31 (m, 1H), 5.39–5.45 (m, 1H), 2.99–

3.04 (m, 1H), 2.86–2.89 (m, 1H), 2.62 (dd, 1H,

J = 10.13 Hz and 6.59 Hz), 2.31 (s, 3H), 1.92–2.00 ppm

(m, 1H). Anal. (C₁₈H₁₈ClN₃O₂SÆ1.5 HClÆ0.5H₂O) C,

H, N.

5.3.18. 1-(1-Ethyl-pyrrolidin-3-yl)-3-(3-ﬂuoro-benzenesulfo-

nyl)-1H-pyrrolo[2,3-b]pyridine (3r). A thick suspension of

1-(1-ethyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine (0.890

g, 4.13 mmol), 3-ﬂuorobenzenesulfonyl chloride (0.62

mL, 4.7 mmol), and silver triﬂuoromethanesulfonate

(2.35 g, 9.15 mmol) in nitrobenzene (4.1 mL) was vigor-

ously stirred at 125 ꢁC for 18 h. After cooling to ambient

temperature, saturated aqueous sodium bicarbonate and

ethyl acetate were added to the reaction mixture, and it

was stirred for several min. The layers were separated,

5.3.16. 3-(3-Bromo-benzenesulfonyl)-1-(1-methyl-pyrroli-

din-3-yl)-1H-pyrrolo[2,3-b]pyridine (3p). The title com-

pound was prepared from 1-(1-methyl-pyrrolidin-3-yl)-

1H-pyrrolo[2,3-b]pyridine (0.993 g, 4.93 mmol), 3-bro-

6218

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

and the aqueous layer was further extracted with ethyl

acetate. The organic phase was washed with brine, dried

with anhydrous magnesium sulfate, ﬁltered, and concen-

trated. The residue was puriﬁed by ﬂash chromatography

using 100% ethyl acetate. Concentrating and drying in va-

cuo at 80 ꢁC for 30 min gave 1-(1-ethyl-pyrrolidin-3-yl)-3-

(3-ﬂuoro-benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine as a

yellow semi-solid (0.474 g, 30.8%). It was dissolved in

ethyl acetate, and ethereal hydrogen chloride was added.

The precipitate was ﬁltered, rinsed with ether, and dried

in vacuo at 75 ꢁC for 15.5 h. The hydrochloride was ob-

tained as a white solid (0.405 g, 22.0%): mp 200–202 ꢁC

ture, the reaction mixture was diluted with ethyl acetate,

and ﬁltered. The ﬁltrate was washed with aqueous

potassium carbonate and brine. The organic phase was

dried with anhydrous magnesium sulfate, ﬁltered,

and concentrated. The residue was puriﬁed by ﬂash

chromatography twice using 100% methylene chloride,

and 100% ethyl acetate and by HPLC using 2–15%

(8:2 methylene chloride/methanol/TEA) in hexane/

TEA. Concentrating and drying in vacuo at 62 ꢁC for

35 min yielded 1-(1-benzyl-pyrrolidin-3-yl)-3-(5-chloro-

thiophene-2-sulfonyl)-1H-pyrrolo[2,3-b]pyridine as

dark yellow gum (0.357 g, 19.8%); Mass spectrum

a

1

(dec); mass spectrum (+EI, [M+H]⁺) m/z 374. H NMR

(+EI, [M+H]⁺) m/z 458. H NMR (500 MHz, DMSO-

(500 MHz, DMSO-d₆): d 10.75–11.15 (m, 1H), 8.72–8.81

(s and s, 1H), 8.42 (dd, 1H, J = 4.64 Hz and 1.35 Hz),

8.23–8.25 (d and d, 1H, J = 1.34 Hz and 1.47 Hz), 7.79–

7.87 (m, 2H), 7.59–7.64 (m, 1H), 7.45–7.50 (m, 1H),

7.33–7.37 (m, 1H), 5.52–5.78 (m, 1H), 3.89–4.06 (m,

1H), 3.79–3.88 (m, 1H), 3.47–3.58 (m, 1H), 3.16–3.31

(m, 3H), 2.32–2.74 (m, 2H), 1.22–1.26 ppm (m, 3H). Anal.

(C₁₉H₂₀FN₃O₂SÆ2.5 HCl) C, H, N.

d₆): d 8.48 (s, 1H), 8.39–8.41 (m, 1H), 8.17–8.19 (d and

d, 1H, J = 1.46 Hz and 1.59 Hz), 7.73 (d, 1H,

J = 4.15 Hz), 7.16–7.34 (m, 7H), 5.40–5.46 (m, 1H),

3.70 (d, 1H, J = 13.17 Hz), 3.62 (d, 1H, J = 13.05 Hz),

3.04–3.09 (m, 1H), 2.77 (dd, 1H, J = 9.89 Hz and

2.69 Hz), 2.67–2.71 (m, 1H), 2.37–2.43 (m, 2H), 2.01–

2.08 ppm (m, 1H).

5.3.20.2. Step 2. a-Chloroethylchloroformate (0.2 mL,

2 mmol) was added to a solution of 1-(1-benzyl-pyrroli-

din-3-yl)-3-(5-chloro-thiophene-2-sulfonyl)-1H-pyrrol-

o[2,3-b]pyridine (0.295 g, 0.644 mmol) in 1,2-dichloro-

ethane (6 mL). The reaction mixture was reﬂuxed under

nitrogen for 4.5 h. After concentrating, adding methy-

lene chloride and concentrating, ethanol (5 mL) was

added. The reaction mixture was reﬂuxed under nitrogen

for 1.5 h. The mixture was concentrated. Aqueous

sodium bicarbonate was added, and the mixture was

extracted with chloroform. The organic phase was

concentrated and was puriﬁed by ﬂash chromatography

using 10% methanol in chloroform and 0.1% ammonium

hydroxide/10% methanol in chloroform. Concentrating

and drying in vacuo at 60 ꢁC for 1 h, 40 min yielded

3-(5-chloro-thiophene-2-sulfonyl)-1-pyrrolidin-3-yl-1H-

pyrrolo[2,3-b]pyridine as a light brown gum (112 mg,

47.3%). Ethanol and ethereal hydrogen chloride were

added. Concentrating and drying in vacuo at 80 ꢁC for

12 h gave the hydrochloride as a beige solid (124 mg,

43.7%); mass spectrum (+EI, [M+H]⁺) m/z 368. ¹H

NMR (500 MHz, DMSO-d₆): d 9.33–9.44 (br, 1H),

9.19–9.31 (br, 1H), 8.66 (s, 1H), 8.44 (dd, 1H, J = 4.64

and 1.47 Hz), 8.22–8.24 (d and d, 1H, J = 1.59 and

1.47 Hz), 7.74 (d, 1H, J = 4.15 Hz), 7.38 (dd, 1H,

J = 8.06 and 4.76 Hz), 7.22 (d, 1H, J = 4.15 Hz), 5.53–

5.61 (m, 1H), 3.61–3.70 (m, 2H), 3.28–3.34 (m, 1H),

2.34–2.54 ppm (m, 3H). Anal. (C₁₅H₁₄ClN₃O₂S₂Æ1.5HCl)

C, H, N.

5.3.19. 3-(3-Chloro-benzenesulfonyl)-1-(1-ethyl-pyrroli-

din-3-yl)-1H-pyrrolo[2,3-b]pyridine (3s). A thick suspen-

sion

of

1-(1-ethyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-

b]pyridine (0.879 g, 4.08 mmol), 3-chlorobenzenesulfo-

nyl chloride (0.69 mL, 4.9 mmol), and silver triﬂuoro-

methanesulfonate (2.11 g, 8.21 mmol) in nitrobenzene

(4.1 mL) was vigorously stirred at 125 ꢁC for 16 h. After

cooling to ambient temperature, saturated aqueous so-

dium bicarbonate and ethyl acetate were added to the

reaction mixture, and it was stirred for several min.

The layers were separated, and the aqueous layer was

further extracted with ethyl acetate. The organic phase

was washed with brine, dried with anhydrous magne-

sium sulfate, ﬁltered, and concentrated. The residue

was puriﬁed by ﬂash chromatography using 100% ethyl

acetate. Concentrating and drying in vacuo at 80 ꢁC for

25 min gave 3-(3-chloro-benzenesulfonyl)-1-(1-ethyl-

pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine as a yellow

foam (0.540 g, 34.0%). It was dissolved in ethyl acetate,

and ethereal hydrogen chloride was added. The precipi-

tate was ﬁltered, rinsed with ethyl acetate and dried in

vacuo at 75 ꢁC for 12.5 h. The hydrochloride was ob-

tained as a cream solid (0.491 g, 27.0%): mp 166–

168 ꢁC (dec); Mass spectrum (+EI, [M+H]⁺) m/z 390.

¹H NMR (500 MHz, DMSO-d₆): d 11.00–11.40 (m,

1H), 8.73–8.86 (s and s, 1H), 8.41–8.43 (m, 1H), 8.22–

8.25 (d and d, 1H, J = 1.34 Hz and 1.46 Hz) 7.95–8.00

(m, 2H), 7.67–7.70 (m, 1H), 7.56–7.61 (m, 1H), 7.34–

7.37 (m, 1H), 5.53–5.78 (m, 1H), 3.87–4.05 (m, 1H),

3.48–3.82 (m, 2H), 3.19–3.28 (m, 3H), 2.33–2.73 (m,

2H), 1.22–1.26 ppm (m, 3H). Anal. (C₁₉H₂₀ClN₃O_2-

SÆ2.0HClÆ0.75H₂O) C, H, N.

5.3.21. 8-(1-Pyrrolidin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-

sulfonyl)-quinoline (3u)

5.3.21.1. Step 1. 8-[1-(1-Benzyl-pyrrolidin-3-yl)-1H-

pyrrolo[2,3-b]pyridine-3-sulfonyl]-quinoline was pre-

pared from 1-(1-benzyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-

b]pyridine (1.7 g, 6.1 mmol), quinoline-8-sulfonyl chlo-

ride (1.36 g, 6.0 mmol), and silver triﬂuoromethanesulf-

onate (2.44 g, 9.50 mmol) in nitrobenzene as described

in Step 1 for compound 3t to give a yellow semi-solid

(0.108 g. 3.86%); ¹H NMR (400 MHz, DMSO-d₆): d

8.78–8.80 (m, 1H), 8.75 (s, 1H), 8.62–8.65 (m, 1H),

8.42–8.44 (m, 1H), 8.25–8.31 (m, 3H), 7.78–7.82 (m,

5.3.20. 3-(5-Chloro-thiophene-2-sulfonyl)-1-pyrrolidin-3-

yl-1H-pyrrolo[2,3-b]pyridine (3t)

5.3.20.1. Step 1. A suspension of 1-(1-benzyl-pyrroli-

din-3-yl)-1H-pyrrolo[2,3-b]pyridine (1.1 g, 4.0 mmol), 5-

chloro-thiophene-2-sulfonyl chloride (0.9 g, 4 mmol)

and silver triﬂuoromethanesulfonate (2.4 g, 9.3 mmol)

in nitrobenzene (2.1 mL) was stirred at 140 ꢁC under

nitrogen for 17.5 h. After cooling to ambient tempera-

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

6219

1H), 7.55–7.58 (m, 1H), 7.23–7.36 (m, 6H), 5.43–5.45

(m, 1H), 3.67–3.76 (d and d, 2H, J = 12.64 Hz and

13.22 Hz), 3.09–3.18 (m, 1H), 2.80–2.83 (m, 1H), 2.70–

2.74 (m, 1H), 1.89–1.97 ppm (m, 1H).

(5 mL) was added. The reaction mixture was reﬂuxed un-

der nitrogen for 1 h. The mixture was concentrated, and

the residue was partitioned in chloroform and aqueous

sodium bicarbonate. The organic phase was concentrated

and puriﬁed by ﬂash chromatography using 7.5–10%

methanol in chloroform. Concentrating and drying in va-

cuo at 70 ꢁC for 20 min yielded 3-(6-chloro-imidazo[2,1-

b]thiazole-5-sulfonyl)-1-pyrrolidin-3-yl-1H-pyrrolo[2,3-

b]pyridine as a light yellow semi-solid (61.6 mg, 57.6%).

Ethanol and ethereal hydrogen chloride were added.

Concentrating and drying in vacuo at 78 ꢁC for 11 h gave

the hydrochloride as a yellow semi-solid (58.2 mg,

46.2%); mass spectrum (+EI, [M+H]⁺) m/z 408. ¹H

NMR (500 MHz, DMSO-d₆): d 9.28–9.34 (br, 2H), 8.86

(s, 1H), 8.42 (dd, 1H, J = 4.64 Hz and 1.59 Hz), 8.28 (d,

1H, J = 4.52 Hz), 8.24 (dd, 1H, J = 8.06 Hz and

1.59 Hz), 7.63 (d, 1H, J = 4.51 Hz), 7.36–7.39 (m, 1H),

5.51–5.58 (m, 1H), 3.59–3.75 (m, 2H), 3.29–3.56 (m^*,

2H), 2.48–2.56 (m, 1H), 2.32–2.42 ppm (m, 1H). HRMS

(C₁₆H₁₄ClN₅O₂S₂), calcd [M+H]⁺408.0355, found

[M+H]⁺408.0349.

5.3.21.2. Step 2. a-Chloroethylchloroformate (0.1 mL,

0.9 mmol) was added to a solution of 8-[1-(1-benzyl-pyrr-

olidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl]-quin-

oline (0.107 g, 0.228 mmol) in 1,2-dichloroethane (5 mL).

The reaction mixture was reﬂuxed under nitrogen for

2 h, 45 min. A second portion of a-chloroethylchloro-

formate (0.1 mL, 0.9 mmol) was added, and the mix-

ture was reﬂuxed for 45 min. After concentrating,

adding methylene chloride, and concentrating, ethanol

(5 mL) was added. The reaction mixture was reﬂuxed

under nitrogen for 45 min. The mixture was concen-

trated. Water and solid sodium bicarbonate were

added to the residue, and it was extracted with chloro-

form and concentrated. The residue was puriﬁed by

ﬂash chromatography using 10% methanol in chloro-

form and 0.1% ammonium hydroxide/10% methanol

in chloroform. Concentrating and drying in vacuo at

58 ꢁC for 20 min yielded 8-(1-pyrrolidin-3-yl-1H-pyrrolo-

[2,3-b]pyridine-3-sulfonyl)-quinoline as a brown-orange

gum (32.7 mg, 37.8%). Methanol, ethanol, and ethereal

hydrogen chloride were added. Concentrating and dry-

ing in vacuo at 78 ꢁC for 12 h gave the hydrochloride

as a light brown semi-solid (32.4 mg, 29.2%); mass

spectrum (+EI, [M+H]⁺) m/z 379. ¹H NMR

(500 MHz, DMSO-d₆): d 9.20–9.37 (br, m, 2H), 8.95–

8.98 (m, 1H), 8.83 (s, 1H), 8.60–8.63 (m, 1H), 8.42–

8.46 (m, 1H), 8.31–8.33 (m, 2H), 8.25–8.29 (m, 1H),

7.75–7.82 (m, 1H), 7.57–7.62 (m, 1H), 7.28–7.32 (m,

1H), 5.56–5.63 (m, 1H), 3.65–3.74 (m, 1H), 3.50–3.62

(m, 2H), 3.26–3.36 (m, 1H), 2.27–2.37 ppm (m, 1H).

HRMS (C₂₀H₁₈N₄O₂S), calcd [M+H]⁺379.1236, found

[M+H]⁺379.1228.

5.3.23. 3-(6-Chloro-imidazo[2,1-b]thiazole-5-sulfonyl)-1-

(1-methyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine (3w).

A thick suspension of 1-(1-methyl-pyrrolidin-3-yl)-1H-

pyrrolo[2,3-b]pyridine (1.02 g, 5.07 mmol), 6-chloro-imi-

dazo[2,1-b]thiazole-5-sulfonyl chloride (1.56 g, 6.08

mmol), and silver triﬂuoromethanesulfonate (2.66 g,

10.4 mmol) in nitrobenzene (5.1 mL) was vigorously

stirred at 125 ꢁC for 14.5 h. After cooling to ambient

temperature, saturated aqueous potassium carbonate

and ethyl acetate were added to the reaction mixture,

and it was stirred for several minutes. The layers were

separated, and the aqueous layer was further extracted

with ethyl acetate. The organic phase was washed with

brine, dried with anhydrous magnesium sulfate, ﬁltered,

and concentrated. The residue was puriﬁed by ﬂash

chromatography using 100% ethyl acetate and 10%

methanol in ethyl acetate and by HPLC using (8:2,

methylene chloride/methanol/TEA) in hexane/TEA.

Concentrating and drying in vacuo at 80 ꢁC for

20 min yielded 3-(6-chloro-imidazo[2,1-b]thiazole-5-sul-

fonyl)-1-(1-methyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyr-

idine as a light yellow solid (0.143 g, 6.68%). It was

dissolved in chloroform, and ethereal hydrogen chlo-

ride was added. Concentrating and drying in vacuo

at 78 ꢁC for 13 h yielded the hydrochloride as a pale

yellow solid (0.163 g): MP: 158–160 ꢁC (dec); mass

spectrum (+EI, [M+H]⁺) m/z 422. ¹H NMR

(500 MHz, DMSO-d₆): d 10.65–10.80 (m, 1H), 8.88–

8.97 (m, 1H), 8.42 (dd, 1H, J = 4.76 Hz and

1.59 Hz), 8.21–8.29 (m, 2H), 7.61–7.64 (d and d, 1H,

J = 4.39 Hz and 4.52 Hz), 7.35–7.39 (m, 1H), 5.54–

5.73 (m, 1H), 3.82–4.09 (m, 2H), 3.48–3.72 (m, 2H),

2.90 (dd, 3H, J = 12.20 Hz and 4.88 Hz), 2.28–

2.77 ppm (m, 2H). Anal. (C₁₇H₁₆ClN₅O₂S₂) C, H, N.

5.3.22. 3-(6-Chloro-imidazo[2,1-b]thiazole-5-sulfonyl)-1-

pyrrolidin-3-yl-1H-pyrrolo[2,3-b]pyridine (3v)

5.3.22.1. Step 1. 1-(1-Benzyl-pyrrolidin-3-yl)-3-(6-

chloro-imidazo[2,1-b]thiazole-5-sulfonyl)-1H-pyrrolo[2,3-

b]pyridine was prepared from 1-(1-benzyl-pyrrolidin-3-

yl)-1H-pyrrolo[2,3-b]pyridine (1.1 g, 4.0 mmol), 6-chloro-

imidazo[2,1-b]thiazole-5-sulfonyl chloride (1.03 g, 4.01

mmol), and silver triﬂuoromethanesulfonate (2.9 g, 11

mmol) in nitrobenzene as described in Step 1 for com-

pound 3t to give a yellow foam (0.140 g, 7.0%); ¹H

NMR (400 MHz, DMSO-d₆): d 8.65 (s, 1H), 8.37 (dd,

1H, J = 4.64 Hz and 1.51 Hz), 8.26 (d, 1H, J = 4.41 Hz),

8.18 (dd, 1H, J = 8.00 Hz and 1.51 Hz), 7.59–7.61 (m,

1H), 7.19–7.32 (m, 6H), 5.40–5.43 (m, 1H), 3.65 (dd,

2H, J = 30.02 Hz and 12.99 Hz), 3.04–3.08 (m, 1H),

2.77–2.80 (m, 1H), 2.69–2.73 (m, 1H), 2.01–2.08 ppm

(m, 1H).

5.3.22.2. Step 2. a-Chloroethylchloroformate (0.1 mL,

0.9 mmol) was added to a solution of 1-(1-benzyl-pyrroli-

din-3-yl)-3-(6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl)-

1H-pyrrolo[2,3-b]pyridine (0.131 g, 0.263 mmol) in 1,

2-dichloroethane (5 mL). The reaction mixture was

reﬂuxed under nitrogen for 4.5 h. After concentrating,

adding methylene chloride, and concentrating, ethanol

5.3.24. 3-(6-Chloro-imidazo[2,1-b]thiazole-5-sulfonyl)-1-

(1-ethyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine (3x).

A thick suspension of 1-(1-ethyl-pyrrolidin-3-yl)-1H-

pyrrolo[2,3-b]pyridine (1.03 g, 4.78 mmol), 6-chloroimi-

dazo[2,1-b]thiazole-5-sulfonyl

5.26 mmol), and silver triﬂuoromethanesulfonate

chloride

(1.35 g,

6220

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

(2.52 g, 9.81 mmol) in nitrobenzene (4.7 mL) was vigor-

ously stirred at 125 ꢁC for 18 h. After cooling to ambient

temperature, saturated aqueous potassium carbonate

and ethyl acetate were added to the reaction mixture,

and it was stirred for several min. The layers were sepa-

rated, and the aqueous layer was further extracted with

ethyl acetate. The organic phase was washed with brine,

dried with anhydrous magnesium sulfate, ﬁltered, and

concentrated. The residue was puriﬁed by ﬂash chroma-

tography using 100% ethyl acetate. Concentrating and

drying in vacuo at 80 ꢁC for 30 min gave 3-(6-chloro-

imidazo[2,1-b]thiazole-5-sulfonyl)-1-(1-ethyl-pyrrolidin-3-

yl)-1H-pyrrolo[2,3-b]pyridine as a light buﬀ foam (0.704 g,

33.8%). Ethyl acetate, ethanol, chloroform, and ethereal

hydrogen chloride were added. The mixture was concen-

trated and recrystallized from isopropanol. It was then

dried in vacuo at 72 ꢁC for 12 h. The hydrochloride was

obtained as a cream solid (0.360 g, 13.8%): mp 160 ꢁC

ride was prepared from 1-(1-ethylpiperidin-3-yl)-1H-

pyrrolo[2,3-b]pyridine and 2-chlorobenzenesulfonyl

chloride in substantially the same manner, as described

for compound 4p. The product was obtained as a light

yellow solid, hydrochloride salt, mp 152–153 ꢁC. Mass

1

spectrum (ES, [M+H]⁺) m/z 404. H NMR (400 MHz,

DMSO-d₆) d 10.51 (s, 1H), 8.71 (s, 1H), 8.41 (d, 1H,

J = 4.04 Hz), 8.34 (d, 1H, J = 7.83 Hz), 8.01 (d, 1H,

J = 7.68 Hz), 7.61 (m, 3H), 7.30 (dd, 1H, J = 7.93 and

4.63 Hz), 5.27 (m, 1H), 3.68 (m, 1H), 3.53 (m, 2H),

3.12 (m, 2H), 2.88 (m, 1H), 2.15 (m, 1H), 2.06 (m,

3H), and 1.21 ppm (t, 3H, J = 7.32 Hz). Anal.

(C₂₀H₂₂ClN₃O₂SÆ2.0HClÆ0.2Et₂O) C, H, N.

5.3.27.2. Step 2. 1-(1-ethylpiperidin-3-yl)-3-[(2-chloro-

phenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine was converted

to the title compound in substantially the same manner,

as described for the preparation of compound 4n. The

product was obtained as a light brown solid, hydrochlo-

ride salt, mp 129–130 ꢁC. Mass spectrum (ES, [M+H]⁺)

m/z 376. ¹H NMR (400 MHz, DMSO-d₆) d 9.40 (m,

1H), 9.11 (m, 1H), 8.75 (s, 1H), 8.64 (m, 2H), 8.00 (d,

1H, J = 7.81 Hz), 7.55 (m, 3H), 5.20 (m, 1H), 3.52 (m,

3H), 2.84 (m, 1H), 2.20 (m, 1H), 2.00 (m, 2H), and

1.85 ppm (m, 1H).

1

(dec); mass spectrum (+EI, [M+H]⁺) m/z 436. H NMR

(500 MHz, DMSO-d₆): d 11.00–11.10 (m, 1H), 8.88–9.09

(s and s, 1H), 8.42–8.43 (m, 1H), 8.21–8.34 (m, 2H),

7.60–7.65 (d and d, 1H, J = 4.51 Hz and 4.39 Hz), 7.35–

7.39 (m, 1H), 5.52–5.76 (m, 1H), 3.808–4.02 (m, 2H),

3.48–3.74 (m, 2H), 3.17–3.25 (m, 2H), 2.36–2.70 (m,

2H), 1.21–1.26 ppm (m, 3H). Anal. (C₁₈H₁₈ClN₅O_2-

S₂Æ1.5HClÆ0.5H₂O) C, H calcd 3.82, found, 3.18. N, calcd

16.60, found, 16.19.

Anal. (C₁₈H₁₈ClN₃O₂SÆ2.8HClÆ0.05Et₂O) C, H, N.

5.3.25. 3-(Phenylsulfonyl)sulfonyl]-1-piperidin-3-yl-1H-

pyrrolo[2,3-b]pyridine, hydrochloride (4a). The title com-

pound was prepared from 1-(1-ethylpiperidin-3-yl)-3-

(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine in substan-

tially the same manner, as described for compound 4n.

The product was obtained as a light brown solid, hydro-

5.3.28. 3-[(3-Chlorophenyl)sulfonyl]-1-piperidin-3-yl-1H-

pyrrolo[2,3-b]pyridine, hydrochloride (4d)

5.3.28.1. Step 1. 1-(1-Ethylpiperidin-3-yl)-3-[(3-chloro-

phenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine was prepared

from 1-(1-ethylpiperidin-3-yl)-1H-pyrrolo[2,3-b]pyridine

and 3-chlorobenzenesulfonyl chloride in substantially

the same manner, as described for compound 4p. The

product was obtained as a light brown solid, hydrochlo-

ride salt, mp 115 ꢁC (dec). Mass spectrum (ES, [M+H]⁺)

m/z 404. ¹H NMR (400 MHz, DMSO-d₆) d 10.03 (s, 1H),

8.60 (s, 1H), 8.43 (dd, 1H, J = 4.64 and 1.47 Hz), 8.25

(dd, 1H, J = 7.93 and 1.47 Hz), 7.98 (m, 2H), 7.70 (d,

1H, J = 8.59 Hz), 7.60 (dd, 1H, J = 7.80 and 7.93 Hz),

7.37 (dd, 1H, J = 8.05 and 4.75 Hz), 5.21 (m, 1H), 3.70

(m, 1H), 3.53 (m, 2H), 3.12 (m, 2H), 2.88 (m, 1H), 2.15

(m, 1H), 2.06 (m, 3H), and 1.21 ppm (t, 3H, J = 7.3 Hz).

1

chloride salt. Mass spectrum (ES, [M+H]⁺) m/z 342. H

NMR (400 MHz, DMSO-d₆) d 8.59 (s, 1H), 8.38 (dd,

1H, J = 4.76 and 1.46 Hz), 8.17 (dd, 1H, J = 8.05 and

1.58 Hz), 7.97 (d, 2H, J = 6.83 Hz), 7.56 (m, 3H), 7.42

(dd, 1H, J = 8.05 and 7.93 Hz), 4.92 (m, 1H), 3.45 (m,

1H), 3.15 (m, 1H), 3.05 (m, 1H), 2.66 (m, 1H), 2.10

(m, 1H), 2.00 (m, 1H), 1.80 (m, 1H), and 1.65 ppm (m,

1H). Anal. (C₁₈H₁₉N₃O₂SÆ0.7HClÆ0.2Dioxane) C, H, N.

5.3.26. 1-(1-Ethylpiperidin-3-yl)-3-(phenylsulfonyl)-1H-

pyrrolo[2,3-b]pyridine, hydrochloride (4b). The title com-

pound was prepared from 1-(1-ethylpiperidin-3-yl)-1H-

pyrrolo[2,3-b]pyridine and 4-bromobenzenesulfonyl

chloride in substantially the same manner, as described

for compound 4p. The product was obtained as a light

brown solid, hydrochloride salt, mp 147–148 ꢁC. Mass

5.3.28.2. Step 2. 1-(1-Ethylpiperidin-3-yl)-3-[(3-chloro-

phenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine was converted

to the title compound in substantially the same manner, as

described for compound 4n. The product was obtained as

a white solid, hydrochloride salt, mp 181–182 ꢁC. Mass

1

spectrum (ES, [M+H]⁺) m/z 370. H NMR (400 MHz,

spectrum (ES, [M+H]⁺) m/z 376. H NMR (400 MHz,

DMSO-d₆) d 10.24 (s, 1H), 8.56 (s, 1H), 8.42 (d, 1H,

J = 3.42 Hz), 8.21 (d, 1H, J = 6.71 Hz), 7.98 (d, 1H,

J = 6.85 Hz), 7.58 (m, 2H), 7.34 (dd, 1H, J = 7.81 and

4.64 Hz), 5.22 (m, 1H), 3.71 (m, 1H), 3.51 (m, 1H),

3.12 (m, 2H), 2.88 (m, 1H), 2.17 (m, 1H), 2.07 (m,

1H), 1.90 (m, 1H), and 1.21 ppm (t, 3H, J = 7.72 Hz).

Anal. (C₂₀H₂₃N₃O₂SÆ2.2HCl) C, H, N.

DMSO-d₆) d 9.15 (m, 1H), 8.93 (m, 1H), 8.64 (s, 1H), 8.42

(d, 1H, J = 4.76 Hz), 8.24 (d, 1H, J = 8.05 Hz), 7.97 (m,

2H), 7.68 (d, 1H, J = 8.29 Hz), J = 7.60 (dd, 1H, J = 7.80

and 7.06 Hz), J = 7.35 (dd, 1H, J = 7.81 and 4.76 Hz),

5.13 (m, 1H), 3.50 (m, 1H), 3.45 (m, 1H), 3.32 (m, 1H),

2.85 (m, 1H), 2.18 (m, 1H), 2.10 (m, 1H), 1.95 (m, 1H),

and 1.82 ppm (m, 1H). Anal. (C₁₈H₁₈ClN₃O₂SÆ1.5 HCl)

C, H, N.

5.3.27. 3-[(2-Chlorophenyl)sulfonyl]-1-piperidin-3-yl-1H-

pyrrolo[2,3-b]pyridine, hydrochloride (4c)

5.3.27.1. Step 1. 1-(1-Ethylpiperidin-3-yl)-3-[(2-chloro-

phenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine, hydrochlo-

5.3.29. 3-[(4-Chlorophenyl)sulfonyl]-1-piperidin-3-yl-1H-

pyrrolo[2,3-b]pyridine, hydrochloride (4e). The title com-

pound was prepared from 1-(1-ethylpiperidin-3-yl)-3-

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

6221

[(4-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine in

substantially the same manner, as described for com-

pound 4n. The product was obtained as a white solid,

hydrochloride salt, mp 166–167 ꢁC. Mass spectrum

5.3.33. 3-{[3-(Triﬂuoromethyl)phenyl]sulfonyl}-1-piperi-

din-3-yl-1H-pyrrolo[2,3-b]pyridine, hydrochloride (4i)

5.3.33.1. Step 1. 1-(1-Ethylpiperidin-3-yl)-3-{[3-(tri-

ﬂuoromethyl)phenyl]sulfonyl}-1H-pyrrolo[2,3-b]pyridine,

hydrochloride was prepared from 1-(1-ethylpiperidin-3-

yl)-1H-pyrrolo[2,3-b]pyridine and 3-(triﬂuorometh-

yl)benzenesulfonyl chloride in substantially the same

manner, as described for compound 4p. The product

was obtained as a light brown solid, hydrochloride salt,

mp 146–147 ꢁC. Mass spectrum (ES, [M+H]⁺) m/z 438.

NMR (400 MHz, DMSO-d₆) d 10.15 (s, 1H), 8.66 (s,

1H), 8.44 (m, 1H), 8.30 (m, 2H), 8.23 (s, 1H), 8.02 (d,

1H, J = 7.93 Hz), 7.82 (t, 1H, J = 7.81 Hz), 7.39 (m,

1H), 5.22 (m, 1H), 3.70 (m, 1H), 3.51 (m, 1H), 3.12

(m, 2H), 2.88 (m, 1H), 2.17 (m, 1H), 2.07 (m, 1H),

1.91 (m, 1H), and 1.21 ppm (t, 3H, J = 7.32 Hz). Anal.

(C₂₁H₂₂F₃N₃O₂SÆ1.3HClÆ0.2 H₂O) C, H, N.

1

(ES, [M+H]⁺) m/z 376. H NMR (400 MHz, DMSO-

d₆) d 9.15 (m, 1H), 8.85 (m, 1H), 8.61 (s, 1H), 8.41

(dd, 1H, J = 4.64 and 1.47 Hz), 8.20 (dd, 1H, J = 8.05

and 1.47 Hz), 7.98 (d, 2H, J = 8.67 Hz), 7.63 (d, 2H,

J = 8.76 Hz), 7.35 (dd, 1H, J = 8.06 and 4.63 Hz), 5.13

(m, 1H), 3.48 (m, 2H), 3.31 (m, 1H), 2.85 (m, 1H),

2.17 (m, 1H), 2.06 (m, 1H), 1.90 (m, 1H), and

1.82 ppm (m, 1H). Anal. (C₁₈H₁₈ClN₃O₂SÆ2.5 HCl) C,

H, N.

5.3.30. 3-[(4-Chlorophenyl)sulfonyl]-1-(1-methylpiperidin-

3-yl)-1H-pyrrolo[2,3-b]pyridine, hydrochloride (4f). The

title compound was prepared from 3-[(4-chlorophe-

nyl)sulfonyl]-1-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine

and formaldehyde in substantially the same manner, as

described for compound 4o. The product was obtained

as a yellow solid, hydrochloride salt, mp 176–176 ꢁC.

5.3.33.2. Step 2. The title compound was prepared

from 1-(1-ethylpiperidin-3-yl)-3-{[3-(triﬂuoromethyl)-

phenyl]sulfonyl}- 1H-pyrrolo[2,3-b]pyridine in substan-

tially the same manner, as described for compound 4n.

The product was obtained as a light brown solid, hydro-

chloride salt, mp 172–173 ꢁC. Mass spectrum (ES,

1

Mass spectrum (ES, [M+H]⁺) m/z 390. H NMR (400

MHz, DMSO-d₆) d 10.48 (s, 1H), 8.56 (s, 1H), 8.42 (d,

1H, J = 4.64 Hz), 8.22 (dd, 1H, J = 8.05 and 1.58 Hz),

7.98 (d, 1H, J = 8.54 Hz), 7.63 (d, 1H, J = 8.54 Hz),

7.35 (dd, 1H, J = 7.93 and 4.75 Hz), 5.25 (m, 1H), 3.60

(m, 1H), 3.45 (m, 2H), 2.90 (m, 1H), 2.79 (s, 3H),

2.05 ppm (m, 3H). Anal. (C₁₉H₂₀ClN₃O₂SÆ2.0HClÆ0.15-

H₂O) C, H, N.

1

[M+H]⁺) m/z 410. H NMR (400 MHz, DMSO-d₆) d

9.23 (m, 1H), 8.95 (m, 1H), 8.70 (s, 1H), 8.43 (d, 1H,

J = 4.75 Hz), 8.24 (m, 3H), 8.01 (d, 1H, J = 7.56 Hz),

7.82 (dd, 1H, J = 7.81 and 7.93 Hz), J = 7.36 (dd, 1H,

J = 4.76 and 4.76 Hz), 5.14 (m, 1H), 3.50 (m, 2H), 3.22

(m, 1H), 2.85 (m, 1H), 2.19 (m, 1H), 2.07 (m, 1H), 1.95

(m, 1H), and 1.82 ppm (m, 1H). Anal. (C₁₉H₁₈F₃N₃O_2-

SÆ1.5HCl) C, H, N.

5.3.31. 1-(1-Ethylpiperidin-3-yl)-3-[(4-chlorophenyl)sulfo-

nyl]-1H-pyrrolo[2,3-b]pyridine, hydrochloride (4g). The

title compound was prepared from 1-(1-ethylpiperidin-

3-yl)-1H-pyrrolo[2,3-b]pyridine

and

4-chloro-

5.3.34. 3-{[4-(Triﬂuoromethyl)phenyl]sulfonyl}-1-piperi-

din-3-yl-1H-pyrrolo[2,3-b]pyridine, hydrochloride (4j)

5.3.34.1. Step 1. 1-(1-Ethylpiperidin-3-yl)-3-{[4-(tri-

ﬂuoromethyl)phenyl]sulfonyl}-1H-pyrrolo[2,3-b]pyridine,

hydrochloride was prepared from 1-(1-ethylpiperidin-3-

yl)-1H-pyrrolo[2,3-b]pyridine and 4-(triﬂuoromethyl)ben-

zenesulfonyl chloride in substantially the same manner,

as described for compound 4p. The product was ob-

tained as a light brown solid, hydrochloride salt, mp

benzenesulfonyl chloride in substantially the same man-

ner, as described for compound 4p. The product was

obtained as a light brown solid, hydrochloride salt, mp

142-143 ꢁC. Mass spectrum (ES, [M+H]⁺) m/z 404. H

1

NMR (400 MHz, DMSO-d₆) d 10.05 (s, 1H), 8.57 (s,

1H), 8.43 (dd, 1H, J = 4.75 and 1.46 Hz), 8.21 (dd,

1H, J = 7.93 and 1.47 Hz), 7.98 (dd, 2H, J = 8.66 and

1.95 Hz), 7.64 (dd, 2H, J = 8.79 and 1.96 Hz), 7.36

(dd, 1H, J = 7.93 and 4.75 Hz), 5.22 (m, 1H), 3.68 (m,

1H), 3.50 (m, 2H), 3.12 (m, 2H), 2.88 (m, 1H), 2.15

(m, 1H), 2.06 (m, 2H), 1.90 (m, 1H), and 1.21 ppm (t,

3H, J = 6.65). Anal. (C₂₀H₂₂ClN₃O₂SÆ2.0HClÆ0.1H₂O)

C, H, N.

1

145–146 ꢁC. Mass spectrum (ES, [M+H]⁺) m/z 438. H

NMR (400 MHz, DMSO-d₆) d 10.40 (s, 1H), 8.63 (s,

1H), 8.44 (d, 1H, J = 3.42 Hz), 8.20 (m, 3H), 7.94 (d,

2H, J = 8.17 Hz), 7.37 (m, 1H), 5.22 (m, 1H), 3.70 (m,

1H), 3.51 (m, 1H), 3.12 (m, 2H), 2.88 (m, 1H), 2.17

(m, 1H), 2.07 (m, 1H), 1.91 (m, 1H), and 1.21 ppm (t,

3H, J = 7.2 Hz). Anal. (C₂₁H₂₂F₃N₃O₂SÆ2.5 HCl) C,

H, N.

5.3.32. 3-[(3-Fluorophenyl)sulfonyl]-1-(1-isopropylpiperi-

din-3-yl)-1H-pyrrolo[2,3-b]pyridine, hydrochloride (4h).

The title compound was prepared from 3-[(4-chlorophe-

nyl)sulfonyl]-1-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine

and acetone in substantially the same manner, as de-

scribed for compound 4o. The product was obtained

as a yellow solid, hydrochloride salt, mp 185–186 ꢁC.

5.3.34.2. Step 2. The title compound was prepared

from 1-(1-ethylpiperidin-3-yl)-3-{[4-(triﬂuoromethyl)-

phenyl]sulfonyl}-1H-pyrrolo[2,3-b]pyridine in substan-

tially the same manner, as described for compound 4n.

The product was obtained as a light brown solid,

hydrochloride salt, mp 136–137 ꢁC. Mass spectrum

Mass spectrum (ES, [M+H]⁺) m/z 418. H NMR (400

1

MHz, DMSO-d₆) d 10.36 (s, 1H), 8.64 (s, 1H), 8.43 (d,

1H, J = 3.79 Hz), 8.20 (d, 1H, J = 7.07 Hz), 7.98 (d,

2H, J = 8.42 Hz), 7.64 (d, 2H, J = 8.41 Hz), 7.35 (dd,

1H, J = 7.93 and 4.75 Hz), 5.38 (m, 1H), 3.55 (m, 3H),

3.40 (m, 1H), 2.95 (m, 1H), 2.10 (m, 2H), 2.00 (m,

2H), and 1.25 ppm (m, 6H). Anal. (C₂₁H₂₄ClN₃O_2-

SÆ1.7HClÆ0.2Et₂O) C, H, N.

1

(ES, [M+H]⁺) m/z 410. H NMR (400 MHz, DMSO-

d₆) d 9.33 (m, 1H), 9.06 (m, 1H), 8.67 (s, 1H), 8.41 (d,

1H, J = 3.90 Hz), 8.22 (d, 1H, J = 7.57 Hz), 8.18 (d,

2H, J = 7.93 Hz), 7.93 (d, 2H, J = 8.05 Hz), 7.35

(m,1H), 5.15 (m, 1H), 3.31 (m, 1H), 2.82 (m, 1H), 2.17

(m, 1H), 2.06 (m, 1H), 1.90 (m, 1H), and 1.82 ppm

6222

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

(m, 1H). Anal. (C₁₉H₁₈F₃N₃O₂SÆ2.6 HClÆ0.15Et₂O) C,

H, N.

J = 8.41 and 7.81 Hz), 7.34 (m, 2H), 5.19 (m, 1H), 3.52

(m, 2H), 2.86 (m, 1H), 2.49 (m, 1H), 2.19 (m, 1H),

2.05 (m, 1H), 1.95 (m, 1H), and 1.82 ppm (m, 1H). Anal.

(C₁₈H₁₈FN₃O₂SÆ1.5HCl) C, H, N.

5.3.35. 3-{[3-(Triﬂuoromethyl)phenyl]sulfonyl}-1-(1- meth-

ylpiperidin-3-yl)-1H-pyrrolo[2,3-b]pyridine, hydrochloride

(4k). The title compound was prepared from 3-{[3-(triﬂuo-

romethyl)phenyl]sulfonyl}-1-piperidin-3-yl-1H-pyrrolo-

[2,3-b]pyridine and formaldehyde in substantially the same

manner, as described for compound 4o. The product was

obtained as a light green solid, hydrochloride salt, mp

5.3.38. 3-[(3-Fluorophenyl)sulfonyl]-1-piperidin-3-yl-1H-

pyrrolo[2,3-b]pyridine, hydrochloride (4n). a-Chloroeth-

ylchloroformate (0.24 mL, 2.2 mmol) was added to a

stirred solution of 4p (0.167 g, 0.43 mmol) and proton-

sponge (0.047 g, 0.22 mmol) in 1,2-dichloroethane

(7 mL) under a nitrogen atmosphere at room tempera-

ture. The mixture was stirred while heating at 100 ꢁC

and monitored by TLC. After no starting material was

detected (8 h), the solvents were evaporated in vacuo.

The residue was dissolved in 10% water in dioxane

(7 mL) and the mixture was stirred at 100 ꢁC for 5 h.

The solvents were evaporated in vacuo and the residue

was puriﬁed by ﬂash column chromatography using

10% methanol in dichloromethane as an eluant to give

a semi-solid, 123 mg, (79% yield). The semi-solid was

converted to HCl salt using ethereal hydrogen chloride

to give an oﬀ-white solid, mp 190–191 ꢁC. Mass spec-

trum (ES, [M+H]⁺) m/z 360. ¹H NMR (400 MHz,

DMSO-d₆) d 9.25 (m, 1H), 8.96 (m, 1H), 8.63 (s, 1H),

8.42 (dd, 1H, J = 4.64 and 1.35 Hz), 8.24 (dd, 1H,

J = 8.04 and 1.47 Hz), 7.82 (m, 2H), 7.62 (m, 1H), 7.48

(m, 1H), J = 7.35 (dd, 1H, J = 8.05 and 4.63 Hz), 5.14

(m, 1H), 3.50 (m, 2H), 3.32 (m, 1H), 2.83 (m, 1H),

2.22 (m, 1H), 2.07 (m, 1H), 1.95 (m, 1H), and

1.82 ppm (m, 1H). Anal. (C₁₈H₁₈FN₃O₂SÆ1.3HCl) C,

H, N.

1

127–128 ꢁC. Mass spectrum (ES, [M+H]⁺) m/z 424. H

NMR (400 MHz, DMSO-d₆) d 10.39 (s, 1H), 8.64 (s,

1H), 8.43 (m, 1H), 8.29 (m, 2H), 8.23 (s, 1H), 8.02 (d,

1H, J = 7.56 Hz), 7.82 (t, 1H, J = 8.05), 7.37 (m, 1H),

5.20 (m, 1H), 3.65 (m, 1H), 3.50 (m, 1H), 2.90 (m, 1H),

2.79 (s, 3H), 2.11 (m, 2H), 1.90 ppm (m, 1H). Anal.

(C₂₀H₂₀F₃N₃O₂SÆ1.9HCl) C, H, N.

5.3.36. 3-[(3-Bromophenyl)sulfonyl]-1-piperidin-3-yl-1H-

pyrrolo[2,3-b]pyridine, hydrochloride (4l)

5.3.36.1. Step 1. 1-(1-Ethylpiperidin-3-yl)-3-[(3-bromo-

phenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine, hydrochloride

was

pyrrolo[2,3-b]pyridine

prepared

from

and

1-(1-ethylpiperidin-3-yl)-1H-

3-bromobenzenesulfonyl

chloride in substantially the same manner, as described

for compound 4p. The product was obtained as a yellow

solid, hydrochloride salt, mp >155 ꢁC (dec). Mass spec-

trum (ES, [M+H]⁺) m/z 448. ¹H NMR (400 MHz,

DMSO-d₆) d 10.14 (s, 1H), 8.72 (s, 1H), 8.38 (m, 2H),

7.99 (dd, 1H, J = 8.01 and 1.46 Hz), 7.74 (d, 1H,

J = 8.05 Hz), 7.65 (t, 1H, J = 6.96 Hz), 7.52 (t, 1H,

J = 7.81 Hz), 7.29 (m, 1H), 5.25 (m, 1H), 3.52 (m, 2H),

3.12 (m, 2H), 2.88 (m, 1H), 2.19 (m, 1H), 2.06 (m, 2H),

1.92 (m, 1H), and 1.21 ppm (t, 3H, J = 7.19 Hz). Anal.

(C₂₀H₂₂BrN₃O₂SÆ1.4HCl) C, H, N.

5.3.39. 3-[(3-Fluorophenyl)sulfonyl]-1-(1-methylpiperidin-

3-yl)-1H-pyrrolo[2,3-b]pyridine, hydrochloride (4o). Fom-

aldehyde (0.0095 mL, 0.35 mmol) was added dropwise

at room temperature to a stirred solution of 4n

(0.033 g, 0.1 mmol) and sodium triacetoxyborohydride

(0.09 g, 0.4 mmol) in acetonitrile (2.1 mL) under a nitro-

gen atmosphere. The reaction mixture was stirred at

room temperature for 3 h. then quenched with water

and extracted with methylene chloride. The organic

layer was separated, washed with water and brine, dried

with anhydrous magnesium sulfate, ﬁltered, and solvent

evaporation to give a solid, 33 mg, (90% yield). The solid

was converted to HCl salt using ethereal hydrogen chlo-

ride. The title compound was obtained as a yellow solid,

mp 147–148 ꢁC. Mass spectrum (ES, [M+H]⁺) m/z 374.

¹H NMR (400 MHz, DMSO-d₆) d 10.57 (s, 1H), 8.58

(s, 1H), 8.43 (d, 1H, J = 3.42 Hz), 8.25 (dd, 1H,

J = 8.06 and 1.22 Hz), 7.81 (m, 2H), 7.63 (m, 1H), 7.48

(m, 1H), 7.36 (m, 1H), 5.23 (m, 1H), 3.60 (m, 2H),

2.90 (m, 1H), 2.79 (s, 3H), 2.05 ppm (m, 3H). Anal.

(C₁₉H₂₀FN₃O₂SÆ1.8HClÆ0.1H₂O) C, H, N.

5.3.36.2. Step 2. The title compound was prepared

from 1-(1-ethylpiperidin-3-yl)-3-[(3-bromophenyl)sulfo-

nyl]-1H-pyrrolo[2,3-b]pyridine in substantially the same

manner, as described for compound 4n. The product

was obtained as an oﬀ-white solid, hydrochloride salt,

mp 184–185 ꢁC. Mass spectrum (ES, [M+H]⁺) m/z 420.

¹H NMR (400 MHz, DMSO-d₆) d 9.15 (m, 1H), 8.90

(m, 1H), 8.77 (s, 1H), 8.40 (m, 2H), 7.89 (dd, 1H,

J = 7.94 and 1.47 Hz), 7.73 (d, 1H, J = 7.81 Hz), 7.65

(t, 1H, J = 7.07), 7.52 (t, 1H, J = 7.68), 7.28 (dd, 1H,

J = 8.03 and 4.64 Hz), 5.19 (m, 1H), 3.50 (m, 2H), 3.32

(m, 1H), 2.85 (m, 1H), 2.21 (m, 1H), 2.07 (m, 1H),

1.95 (m, 1H), and 1.82 ppm (m, 1H). Anal.

(C₁₈H₁₈BrN₃O₂SÆ1.3HClÆ0.1H₂O) C, H, N.

5.3.37. 3-[(2-Fluorophenyl)sulfonyl]-1-piperidin-3-yl-1H-

pyrrolo[2,3-b]pyridine, hydrochloride (4m). The title com-

pound was prepared from 1-(1-ethylpiperidin-3-yl)-3-

[(2-ﬂuorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine in

substantially the same manner, as described for the

preparation of compound 4n. The product was obtained

as a light brown solid, hydrochloride salt, mp 165–

166 ꢁC. Mass spectrum (ES, [M+H]⁺) m/z 360. ¹H

NMR (400 MHz, DMSO-d₆) d 9.24 (m, 1H), 8.95 (m,

1H), 8.67 (s, 1H), 8.42 (dd, 1H, J = 4.67 and 1.59 Hz),

8.12 (dd, 1H, J = 8.18 and 1.34 Hz), 8.08 (dd, 1H,

J = 7.68 and 1.70 Hz), 7.74 (m, 1H), 7.42 (dd, 1H,

5.3.40. 1-(1-Ethylpiperidin-3-yl)-3-[(3-ﬂuorophenyl)sulfo-

A

nyl]-1H-pyrrolo[2,3-b]pyridine, hydrochloride (4p).

mixture of 1-(1-ethylpiperidin-3-yl)-1H-pyrrolo[2,3-

b]pyridine (0.4 g, 1.74 mmol), 3-ﬂuorobenzenesulfonyl

chloride (0.381 g, 1.92 mmol), and silver triﬂuorome-

thanesulfonate (0.9 g, 3.5 mmol) in nitrobenzene

(0.8 mL) was heated at 130 ꢁC for 20 hr in a pressure

vessel. The reaction mixture was cooled down and puri-

ﬁed by ﬂash column chromatography using 0–7% meth-

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

6223

anol in methylene chloride as an eluant to give an oil,

242 mg, (36% yield). The product was converted to

HCl salt using ethereal hydrogen chloride to give a gray

solid, mp 180–181 ꢁC. Mass spectrum (ES, [M+H]⁺) m/z

idine and formaldehyde in substantially the same

manner, as described for compound 4o. The product

was obtained as a yellow solid, hydrochloride salt, mp

1

162–163 ꢁC. Mass spectrum (ES, [M+H]⁺) m/z 424. H

1

388. H NMR (400 MHz, DMSO-d₆) d 10.17 (s, 1H),

NMR (400 MHz, DMSO-d₆) d 10.58 (s, 1H), 8.62 (s,

1H), 8.44 (dd, 1H, J = 5.46 and 1.47 Hz), 8.32 (dd, 1H,

J = 7.93 and 1.10 Hz), 8.00 (s, 2H), 7.92 (s, 1H), 7.37

(dd, 1H, J = 8.05 and 3.64 Hz), 5.20 (m, 1H), 3.65 (m,

1H), 3.50 (m, 1H), 2.90 (m, 1H), 2.79 (s, 3H), 2.05 ppm

(m, 3H). Anal. (C₁₉H₁₉Cl₂N₃O₂SÆ1.6HClÆ0.1 H₂O) C,

H, N.

8.59 (s, 1H), 8.43 (dd, 1H, J = 4.63 and 1.34 Hz), 8.25

(dd, 1H, J = 7.97 and 1.34 Hz), 7.82 (m, 2H), 7.63 (m,

1H), 7.48 (m, 1H), 7.36 (m, 1H), 5.22 (m, 1H), 3.71

(m, 1H), 3.45 (m, 2H), 3.13 (q, 2H), 2.88 (m, 1H), 2.15

(m, 1H), 2.09 (m, 2H), 1.91 (m, 1H), and 1.22 ppm (t,

3H, J = 7.26 Hz). Anal. (C₂₀H₂₂FN₃O₂SÆ1.0HClÆ0.8-

H₂O) C, H, N.

5.3.45. 1-(1-Ethylpiperidin-3-yl)-3-[(3,5-dichlorophenyl)-

sulfonyl]-1H-pyrrolo[2,3-b]pyridine, hydrochloride (4u).

The title compound was prepared from 1-(1-ethylpiperi-

din-3-yl)-1H-pyrrolo[2,3-b]pyridine and 3-(3,5-dichloro-

phenyl)sulfonyl chloride in substantially the same

manner, as described for compound 4p. The product

was obtained as a light brown solid, hydrochloride salt,

mp 153–154 ꢁC. Mass spectrum (ES, [M+H]⁺) m/z 438.

¹H NMR (400 MHz, DMSO-d₆) d 8.63 (s, 1H), 8.44

(dd, 1H, J = 4.76 and 1.47 Hz), 8.32 (dd, 1H, J = 7.93

and 1.46 Hz), 8.00 (s, 2H), 7.92 (s, 1H), 7.37 (dd, 1H,

J = 7.93 and 4.64 Hz), 5.22 (m, 1H), 3.71 (m, 1H), 3.51

(m, 1H), 3.12 (m, 2H), 2.88 (m, 1H), 2.17 (m, 1H),

2.07 (m, 1H), 1.91 (m, 1H), and 1.21 ppm (t, 3H,

J = 7.32). Anal. (C₂₀H₂₁Cl₂N₃O₂SÆ2.0HCl) C, H, N.

5.3.41. 3-[(3-Fluorophenyl)sulfonyl]-1-(1-isopropylpiperi-

din-3-yl)-1H-pyrrolo[2,3-b]pyridine, hydrochloride (4q).

The title compound was prepared from 3-[(3-ﬂuorophe-

nyl)sulfonyl]-1-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine and

acetone in substantially the same manner, as described

for compound 4o. The product was obtained as a yellow

solid, hydrochloride salt, mp 155–156 ꢁC. Mass spec-

trum (ES, [M+H]⁺) m/z 402. ¹H NMR (400 MHz,

DMSO-d₆) d 10.28 (s, 1H), 8.66 (s, 1H), 8.43 (d, 1H,

J = 4.02 Hz), 8.24 (d, 1H, J = 7.32 Hz), 7.82 (m, 2H),

7.63 (m, 1H), 7.47 (m, 1H), 7.36 (m, 1H), 5.33 (m,

1H), 3.55 (m, 3H), 3.40 (m, 1H), 2.95 (m, 1H), 2.10

(m, 2H), 2.00 (m, 2H), and 1.25 ppm (m, 6H). Anal.

(C₂₁H₂₄FN₃O₂SÆ2.0HCl) C, H, N.

5.3.42. 3-[(3-Bromophenyl)sulfonyl]-1-(1-isopropylpiperi-

din-3-yl)-1H-pyrrolo[2,3-b]pyridine, hydrochloride (4r).

The title compound was prepared from 3-[(3-bromophe-

nyl)sulfonyl]-1-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine and

acetone in substantially the same manner, as described

for compound 4o. The product was obtained as a yellow

solid, hydrochloride salt, mp 178–179 ꢁC. Mass spec-

trum (ES, [M+H]⁺) m/z 462. ¹H NMR (400 MHz,

DMSO-d₆) d 10.15 (s, 1H), 8.82 (s, 1H), 8.39 (m, 2H),

7.98 (d, 1H, J = 7.69 Hz), 7.74 (d, 1H, J = 7.80 Hz),

7.65 (t, 1H, J = 7.56 Hz), 7.52 (t, 1H, J = 7.57 Hz), 7.29

(m, 1H), 5.40 (m, 1H), 3.55 (m, 3H), 3.40 (m, 1H), 2.95

(m, 1H), 2.15 (m, 1H), 2.05 (m, 3H), and 1.27 ppm (m,

6H). Anal. (C₂₁H₂₄BrN₃O₂SÆ2.2HCl) C, H, N.

5.3.46. 3-[(5-Chlorothien-2-yl)sulfonyl]-1-piperidin-3-yl-

1H-pyrrolo[2,3-b]pyridine, hydrochloride (4v). The title

compound was prepared from 1-(1-ethylpiperidin-3-yl)-

3-[(5-chlorothien-2-yl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine

in substantially the same manner, as described for com-

pound 4n. The product was obtained as a light brown so-

lid, hydrochloride salt, mp 175–176 ꢁC. Mass spectrum

1

(ES, [M+H]⁺) m/z 382. H NMR (400 MHz, DMSO-

d₆) d 9.33 (m, 1H), 9.05 (m, 1H), 8.63 (s, 1H), 8.42 (dd,

1H, J = 4.64 and 1.47 Hz), 8.23 (dd, 1H, J = 8.05 and

1.58 Hz), 7.75 (d, 1H, J = 6.14 Hz), 7.37 (dd, 1H,

J = 8.01 and 7.93 Hz), 7.22 (d, 1H, J = 4.15 Hz), 5.16

(m, 1H), 3.48 (m, 2H), 3.40 (m, 1H), 2.85 (m, 1H), 2.19

(m, 1H), 2.06 (m, 1H), 1.95 (m, 1H), and 1.84 ppm (m,

1H). Anal. (C₁₆H₁₆ClN₃O₂S₂Æ1.2HCl) C, H, N.

5.3.43. 3-[(3,5-Dichlorophenyl)sulfonyl]-1-piperidin-3-yl-

1H-pyrrolo[2,3-b]pyridine, hydrochloride (4s). The title

compound was prepared from 1-(1-ethylpiperidin-3-yl)-

3-[(3,5-dichlorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine

in substantially the same manner, as described for

compound 4n. The product was obtained as an oﬀ-white

solid, hydrochloride salt, mp 171–172 ꢁC. Mass spec-

trum (ES, [M+H]⁺) m/z 410. ¹H NMR (400 MHz,

DMSO-d₆) d 9.30 (m, 1H), 9.06 (m, 1H), 8.67 (s, 1H),

8.43 (d, 1H, J = 4.63 Hz), 8.30 (dd, 1H, J = 8.05 and

1.46 Hz), 7.99 (s, 2H), 7.91 (s, 1H), 7.37 (dd, 1H,

J = 8.06 and 4.76 Hz), 5.14 (m, 1H), 3.50 (m, 1H), 3.42

(m, 1H), 3.30 (m, 1H), 2.82 (m, 1H), 2.19 (m, 1H),

2.07 (m, 1H), 1.95 (m, 1H), and 1.82 ppm (m, 1H). Anal.

(C₁₈H₁₇Cl₂N₃O₂SÆ1.5HCl) C, H, N.

5.3.47. 3-[(5-Chlorothien-2-yl)sulfonyl]-1-(1-methylpiperi-

din-3-yl)-1H-pyrrolo[2,3-b]pyridine, hydrochloride (4w).

The title compound was prepared from 3-[(5-chloroth-

ien-2-yl)sulfonyl]-1-piperidin-3-yl-1H-pyrrolo[2,3-b]pyr-

idine and formaldehyde in substantially the same manner,

as described for compound 4o. The product was obtained

as a yellow solid, hydrochloride salt, mp 165–166 ꢁC. Mass

1

spectrum (ES, [M+H]⁺) m/z 396. H NMR (400 MHz,

DMSO-d₆) d 10.40 (s, 1H), 8.57 (s, 1H), 8.45 (dd, 1H,

J = 4.63 and 1.46 Hz), 8.24 (dd, 1H, J = 7.93 and

1.34 Hz), 7.75 (d, 1H, J = 4.03 Hz), 7.39 (dd, 1H,

J = 8.05 and 4.76 Hz), 7.22 (d, 1H, J = 4.15 Hz), 5.20 (m,

1H), 3.65 (m, 1H), 3.50 (m, 1H), 2.90 (m, 1H), 2.79 (s,

3H), 2.18 (m, 1H), 2.05 (m, 1H), 1.90 ppm (m, 1H). Anal.

(C₁₇H₁₈ClN₃O₂S₂Æ1.7HCl) C, H, N.

5.3.44. 3-[(3,5-Dichlorophenyl)sulfonyl]-1-(1-methylpiperi-

din-3-yl)-1H-pyrrolo[2,3-b]pyridine, hydrochloride (4t).

The title compound was prepared from 3-[(3,5-dichloro-

phenyl)sulfonyl]-1-piperidin-3-yl-1H-pyrrolo[2,3-b]pyr-

5.3.48. 1-(1-Ethylpiperidin-3-yl)-3-[(5-chlorothien-2-yl)-

sulfonyl]-1H-pyrrolo[2,3-b]pyridine, hydrochloride (4x).

The title compound was prepared from 1-(1-ethylpiperi-

6224

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

din-3-yl)-1H-pyrrolo[2,3-b]pyridine and 3-(5-chloroth-

ien-2-yl)sulfonyl chloride in substantially the same man-

ner, as described for compound 4p. The product was

obtained as a gray solid, hydrochloride salt, mp 166–

167 ꢁC. Mass spectrum (ES, [M+H]⁺) m/z 410. ¹H

NMR (400 MHz, DMSO-d₆) d 10.34 (s, 1H), 8.59 (s,

1H), 8.45 (dd, 1H, J = 4.63 and 1.46 Hz), 8.24 (dd,

1H, J = 8.05 and 1.59 Hz), 7.75 (d, 1H, J = 4.15 Hz),

7.39 (dd, 1H, J = 8.05 and 4.76 Hz), 7.22 (d,

1H, J = 4.15 Hz), 5.25 (m, 1H), 3.68 (m, 1H), 3.51 (m,

1H), 3.12 (m, 2H), 2.88 (m, 1H), 2.17 (m, 1H), 2.07

(m, 1H), 1.94 (m, 1H), and 1.21 ppm (t, 3H,

5.3.52. 3-[(6-Chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfo-

nyl]-1-(1-isopropylpiperidin-3-yl)-1H-pyrrolo[2,3-b]pyridine,

hydrochloride (4ab). The title compound was prepared

from 3-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-

1-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine and acetone in

substantially the same manner, as described for com-

pound 4o. The product was obtained as a yellow solid,

hydrochloride salt, mp 176–177 ꢁC. Mass spectrum (ES,

[M+H]⁺) m/z 464. ¹H NMR (400 MHz, DMSO-d₆) d

10.22 (s, 1H), 8.84 (s, 1H), 8.44 (d, 1H, J = 4.63 Hz),

8.23 (s, 2H), 7.65 (d, 1H, J = 4.39 Hz), 7.36 (dd, 1H,

J = 7.93 and 4.63 Hz), 5.35 (m, 1H), 3.55 (m, 4H), 2.95

(m, 1H), 2.10 (m, 4H), and 1.25 ppm (m, 6H). Anal.

(C₂₀H₂₂ClN₅O₂S₂Æ2.0HCl) C, H, N.

J = 7.02 Hz).

0.67Et₂O).

Anal.

(C₁₈H₂₀ClN₃O₂S₂Æ1.4HClÆ

5.3.49. 3-[(6-Chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfo-

nyl]-1-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine, hydrochlo-

ride (4y). The title compound was prepared from 3-[(6-

chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-1-(1-ethyl-

piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridine in substantially

the same manner, as described for compound 4n. The

product was obtained as an oﬀ-white solid, hydrochloride

salt, mp 221–222 ꢁC. Mass spectrum (ES, [M+H]⁺)

5.3.53. 1-Benzyl-3-chloro-pyrrolidine (6a, R = benzyl).

Phosphorus oxychloride (43 mL, 460 mmol) was added

to

a solution of 1-benzyl-pyrrolidin-3-ol (19.8 g,

112 mmol) in toluene (200 mL). The reaction mixture

was reﬂuxed under nitrogen for 2 h. About 150 mL of sol-

vent was evaporated, and the remaining mixture was

poured into ice-water. Solid potassium carbonate was

added until basic. It was extracted with ethyl acetate and

washed with brine. The organic phase was dried with

anhydrous magnesium sulfate, ﬁltered, and concentrated.

Dryingat80 ꢁCinvacuofor30 minresultedin1-benzyl-3-

chloro-pyrrolidine as a dark brown oil (18.7 g, 85.4%); ¹H

NMR (400 MHz, DMSO-d₆): d 7.20–7.32 (m, 5H), 4.48–

4.53 (m, 1H), 3.60 (dd, 2H, J = 20.88 Hz and 13.11 Hz),

2.91 (dd, 1H, J = 10.68 Hz and 6.15 Hz), 2.64–2.73 (m,

2H), 2.32–2.46 (m, 2H), 1.87–1.95 ppm (m, 1H).

1

m/z 422. H NMR (400 MHz, DMSO-d₆) d 9.05 (m,

1H), 8.82 (s, 1H), 8.42 (d, 1H, J = 4.76 Hz), 8.25 (d, 1H,

J = 4.52 Hz), 8.23 (d, 1H, J = 8.06), 7.64 (d, 1H,

J = 4.51 Hz), 7.36 (m, 1H), 5.14 (m, 1H), 3.48 (m, 2H),

3.40 (m, 1H), 2.85 (m, 1H), 2.19 (m, 1H), 2.06 (m, 1H),

1.95 (m, 1H), and 1.84 ppm (m, 1H). Anal. (C₁₇H₁₆ClN₅

O₂S₂Æ1.5HCl) C, H, N.

5.3.50. 3-[(6-Chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfo-

nyl]-1-(1-methylpiperidin-3-yl)-1H-pyrrolo[2,3-b]pyridine,

hydrochloride (4z). The title compound was prepared

from 3-[(6-Chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-

1-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine and formal-

dehyde in substantially the same manner, as described

for compound 4o. The product was obtained as a yellow

solid, hydrochloride salt, mp 190-191 ꢁC. Mass spectrum

(ES, [M+H]⁺) m/z 436. ¹H NMR (400 MHz, DMSO-d₆)

d 8.75 (s, 1H), 8.44 (dd, 1H, J = 4.64 and 1.34 Hz), 8.24

(s, 2H), 7.65 (d, 1H, J = 4.52 Hz), 7.39 (dd, 1H, J = 7.93

and 4.63 Hz), 5.20 (m, 1H), 3.65 (m, 1H), 3.49 (m, 1H),

2.90 (m, 1H), 2.79 (s, 3H), 2.18 (m, 1H), 2.05 (m, 1H),

1.90 ppm (m, 1H). Anal. (C₁₈H₁₈ClN₅O₂S₂Æ2.0HClÆ0.1

H₂O) C, H, N.

5.3.54. Toluene-4-sulfonic acid 1-methyl-pyrrolidin-3-yl

ester (6b, R = Me). p-Toluenesulfonyl chloride (11.5 g,

60.3 mmol) was added to a solution of 1-methyl-3-pyr-

rolidinol (6.1 g, 60 mmol) in methylene chloride

(60 mL). Triethylamine (8.4 mL, 60 mmol) was then

added to the reaction mixture. After stirring at ambient

temperature for 5 h, the mixture was puriﬁed by ﬂash

chromatography using 10% methanol in chloroform.

Concentrating and drying in vacuo at 60 ꢁC for 20 min

gave toluene-4-sulfonic acid 1-methyl-pyrrolidin-3-yl es-

1

ter as a golden-yellow syrup (10.1 g, 66.0%); H NMR

(400 MHz, DMSO-d₆): d 7.76 (dd, 2H, J = 6.61 Hz

and 1.74 Hz), 7.46 (d, 2H, J = 8.01 Hz), 4.89–4.94 (m,

1H), 2.59–2.64 (m, 1H), 2.50–2.56 (m, 1H), 2.42–2.46

(m, 1H), 2.40 (s, 3H), 2.15 (s, 3H), 2.00–2.13 (m, 2H),

1.67–1.72 ppm (m, 1H).

5.3.51. 3-[(6-Chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfo-

nyl]-1-(1-ethylpiperidin-3-yl)-1H-pyrrolo[2,3-b]pyridine,

hydrochloride (4aa). The title compound was prepared

from 1-(1-ethylpiperidin-3-yl)-1H-pyrrolo[2,3-b]pyridine

and 3-(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl

chloride in substantially the same manner, as described

for compound 4p. The product was obtained as a white

solid, hydrochloride salt, mp >167 ꢁC (dec). Mass spec-

trum (ES, [M+H]⁺) m/z 450. ¹H NMR (400 MHz,

DMSO-d₆) d 8.77 (s, 1H), 8.44 (dd, 1H, J = 4.63 and

1.46 Hz), 8.23 (s, 2H), 7.65 (d, 1H, J = 4.52 Hz), 7.39

(dd, 1H, J = 7.93 and 4.63 Hz), 5.21 (m, 1H), 3.68 (m,

1H), 3.51 (m, 1H), 3.12 (m, 2H), 2.88 (m, 1H), 2.17

(m, 1H), 2.07 (m, 1H), 1.94 (m, 1H), and 1.21 ppm (t,

3H, J = 7.02 Hz). Anal. (C₁₉H₂₀ClN₅O₂S₂Æ1.5HClÆ0.2

H₂O) C, H, N.

5.3.55. Toluene-4-sulfonic acid 1-ethyl-pyrrolidin-3-yl

ester (6b, R = Et). Triethylamine (3.1 mL, 22 mmol)

was added to a solution of 1-ethyl-3-pyrrolidinol

(2.52 g, 21.9 mmol) in methylene chloride (25 mL).

p-Toluenesulfonyl chloride (4.21 g, 22.1 mmol) was then

added to the reaction mixture. After stirring at ambient

temperature for 1.5 h, a second portion of triethylamine

(3.1 mL, 22 mmol) was added to the reaction mixture,

and it was stirred for 1.5 h. The mixture was concen-

trated, and puriﬁed by ﬂash chromatography using

100% ethyl acetate. Concentrating and drying in vacuo

at 80 ꢁC for 20 min gave toluene-4-sulfonic acid 1-

ethyl-pyrrolidin-3-yl ester as a light brown-yellow oil

(4.42 g, 74.9%); mass spectrum (+EI, [M+H]⁺) m/z

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

6225

1

360. H NMR (400 MHz, DMSO-d₆): d 7.75–7.78 (m,

J = 7.77 Hz and 1.63 Hz), 7.64 (d, 1H, J = 3.59 Hz),

7.01–7.04 (m, 1H), 6.44 (d, 1H, J = 3.59 Hz), 5.38–5.44

(m, 1H), 2.91–2.96 (m, 1H), 2.73 (d, 2H, J = 5.68 Hz),

2.34–2.44 (m, 3H), 1.84–1.93 (m, 1H), 1.02 ppm (t, 3H,

J = 7.19 Hz).

2H), 7.45–7.47 (m, 2H), 4.89–4.94 (m, 1H), 2.58–2.68

(m, 2H), 2.43–2.45 (m, 1H), 2.40 (s, 3H), 2.32–2.35 (m,

2H), 2.12–2.17 (m, 1H), 2.00–2.07 (m, 1H), 1.64–1.71

(m, 1H), 0.93 ppm (t, 3H, J = 7.19 Hz).

5.3.56. 1-(1-Benzyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyr-

idine (7, R = benzyl). A mixture of 1-benzyl-3-chloro-pyr-

rolidine (9.2 g, 42 mmol), 7-azaindole (5.44 g,

46.0 mmol), and cesium carbonate (46.0 g, 141 mmol) in

DMSO (100 mL) was heated at 80 ꢁC under nitrogen

for 16 h. After cooling to ambient temperature, the reac-

tion mixture was poured into excess water. It was then ex-

tracted with ethyl acetate and washed with brine. The

organic phase was dried with anhydrous magnesium sul-

fate, ﬁltered, and concentrated. The residue was puriﬁed

by ﬂash chromatography using 10–25% tert-butyl methyl

ether in hexane. Concentrating and drying at 80 ꢁC for

35 min yielded 1-(1-benzyl-pyrrolidin-3-yl)-1H-pyrrolo-

5.3.59. 1-(1-Ethylpiperidin-3-yl)-1H-pyrrolo[2,3-b]pyri-

dine (8, R = Et). A solution of n-butyllithium (2.16 M,

titrated, 124 mL) in hexane was added dropwise to a

solution of N-(1-ethylpiperidin-3-yl)-3-methylpyridin-2-

amine (14.54 g, 66.3 mmol) in THF (217 mL) while stir-

ring at 0 ꢁC over a period of 45 min. After the addition

completed, the reaction mixture was stirred at 0 ꢁC for

1 h, then warmed up to 20 ꢁC and stirred at this temper-

ature for 45 min. The reaction mixture was then re-

cooled to 0 ꢁC and stirred at 0 ꢁC for 5 h. Distilled

DMF (40.3 mL, 298 mmol) was added dropwise over a

period of 5 min. The mixture was stirred at 20 ꢁC for

3 h. then kept at À5 to 0 ꢁC overnight. The mixture

was transferred, over 1 h, into cooled 5.5 M HCl

(150 mL) at such a rate that the temperature was main-

tained at <15 ꢁC. The mixture was then stirred at 20 ꢁC

for 0.5 h before basiﬁed with 30% aqueous NaOH to pH

12 at <15 ꢁC. The mixture was extracted with methylene

chloride. The organic layer was separated and washed

with water, aqueous ammonium chloride, water, and

brine, and then evaporated to give an oil. This crude

oil was puriﬁed by ﬂash column chromatography using

10–20% methanol in methylene chloride as an eluant

to provide the title compound as an oil, 7.5 g, (49%

yield). Mass spectrum (ES, [M+H]⁺) m/z 230. ¹H

NMR (400 MHz, DMSO-d₆) d 8.20 (dd, 1H, J = 4.63

and 1.59 Hz), 7.91 (dd, 1H, J = 7.80 and 1.59 Hz), 7.67

(d, 1H, J = 3.57 Hz), 7.03 (dd, 1H, J = 7.81 and

4.64 Hz), 6.43 (d, 1H, J = 3.54 Hz), 4.81 (m, 1H), 2.90

(m, 1H), 2.75 (m, 1H), 2.32 (m, 2H), 2.27 (m, 1H),

2.01 (m, 1H), 1.86 (m, 2H), 1.75 (m, 1H), 1.61 (m,

1H), and 0.96 ppm (t, 3H, J = 7.20 Hz).

1

[2,3-b]pyridine as a yellow gum (6.9 g, 53%); H NMR

(400 MHz, DMSO-d₆): d 8.19–8.20 (m, 1H), 7.91–7.93

(m, 1H), 7.70 (d, 1H, J = 3.60 Hz), 7.28–7.35 (m, 4H),

7.19–7.24 (m, 1H), 7.03–7.06 (m, 1H), 6.48 (d, 1H,

J = 3.59 Hz), 5.42–5.48 (m, 1H), 3.61-3.69 (m, 2H),

2.94–3.00 (m, 1H), 2.70–2.80 (m, 2H), 2.40–2.45 (m,

2H), 1.90–1.97 ppm (m, 1H).

5.3.57. 1-(1-Methyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyri-

dine (7, R = Me). A suspension of 7-azaindole (0.428 g,

3.62 mmol), toluene-4-sulfonic acid 1-methyl-pyrrolidin-

3-yl ester (0.893 g, 3.50 mmol), and cesium carbonate

(2.38 g, 7.30 mmol) in DMSO (10 mL) was heated at

80 ꢁC for 17 h. The reaction mixture was then allowed

to cool to ambient temperature. It was then diluted with

ethyl acetate and poured into excess water. The organic

phase was washed with brine, dried with anhydrous mag-

nesium sulfate, ﬁltered, concentrated, and dried in vacuo

at 80 ꢁC for 20 min to give 1-(1-methyl-pyrrolidin-3-yl)-

1H-pyrrolo[2,3-b]pyridine as a light brown gum (0.480

1

g, 68.1%); H NMR (400 MHz, DMSO-d₆): d 8.18 (dd,

5.3.60.

amine (19, R = Et). A mixture of 2-amino-3-picoline

(10 g, 88 mmol), 1-ethyl-3-piperidinone hydrate

N-(1-Ethylpiperidin-3-yl)-3-methylpyridin-2-

1H, J = 4.64 Hz and 1.51 Hz), 7.89-7.91 (m, 1H), 7.63

(d, 1H, J = 3.60 Hz), 7.03 (dd, 1H, J = 7.77 Hz and

4.64 Hz), 6.44 (d, 1H, J = 3.59 Hz), 5.39–5.44 (m, 1H),

2.88–2.93 (m, 1H), 2.70 (d, 2H, J = 5.68 Hz), 2.32–2.43

(m, 2H), 2.28 (s, 3H), 1.86–1.93 ppm (m, 1H).

(14.85 g, 88 mmol), para-toluenesulfonic acid hydrate

(3.2 g), and benzene (600 mL) was heated to reﬂux (oil

bath temperature: 100 ꢁC) overnight in a ﬂask equipped

with a Dean Stark Trap (water removal). Solvents were

evaporated from reaction mixture to yield an oily resi-

due. This oil was dissolved in methanol (600 mL) and

sodium borohydride was added portionwise at room

temperature (water bath was used to keep the reaction

temperature around room temperature) over a period

of 30 min. The reaction mixture was then stirred at room

temperature for 2 h then quenched with water and ex-

tracted with chloroform. The organic layer was sepa-

rated and washed with water, aqueous ammonium

chloride, and brine. Puriﬁcation by ﬂash column chro-

matography using 5–15% methanol in methylene chlo-

ride as an eluant provided the title compound as an

oil, 3.6 g, (36% yield). Mass spectrum (ES, [M+H]⁺)

5.3.58. 1-(1-Ethyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyri-

dine (7, R = Et). A suspension of 7-azaindole (2.50 g,

21.2 mmol), toluene-4-sulfonic acid 1-ethyl-pyrrolidin-

3-yl ester (5.6 g, 21 mmol) and cesium carbonate

(15.6 g, 47.9 mmol) in DMSO (60 mL) was heated at

80 ꢁC for 16 h. The reaction mixture was then allowed

to cool to ambient temperature. It was then poured into

excess water and extracted with ethyl acetate. The or-

ganic phase was washed with brine, dried with anhy-

drous magnesium sulfate, ﬁltered, and concentrated.

The residue was puriﬁed by ﬂash chromatography using

75% ethyl acetate in hexane, 100% ethyl acetate, and

10% methanol in chloroform. It was concentrated and

dried in vacuo at 80 ꢁC for 20 min to give 1-(1-ethyl-

pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine as a dark yel-

low oil (2.51 g, 55.5%); ¹H NMR (400 MHz, DMSO-d₆):

d 8.19 (dd, 1H, J = 4.64 Hz and 1.51 Hz), 7.90 (dd, 1H,

1

m/z 220. H NMR (400 MHz, DMSO-d₆) d 7.81 (dd,

1H, J = 6.47 and 1.47 Hz), 7.16 (dd, 1H, J = 6.22 and

1.71 Hz), 7.40 (dd, 1H, J = 7.08 and 7.08 Hz), 5.26 (d,

1H, J = 5.80 Hz), 4.04 (m, 1H), 2.81 (m, 1H), 2.63 (m,

6226

H. Elokdah et al. / Bioorg. Med. Chem. 15 (2007) 6208–6226

6. Minabe, Y.; Shirayama, Y.; Hashimoto, K.; Routledge,

C.; Hagan, J. J.; Ashby, C. R., Jr. Synapse 2004, 52, 20.

7. Lacroix, L. P.; Dawson, L. A.; Hagan, J. J.; Heidbreder,

C. A. Synapse 2004, 51, 158.

1H), 2.30 (q, 2H), 1.98 (s, 3H), 1.90 (m, 2H), 1.73 (m,

1H), 1.63 (m, 1H), 1.46 (m, 1H), 1.36 (m, 1H), and

0.95 ppm (t, 3H, J = 7.19 Hz).

8. King, M. V.; Sleight, A. J.; Woolley, M. L.; Topham, I.

A.; Marsden, C. A.; Fone, K. C. Neuropharmacology 2004,

47, 195.

Acknowledgments

9. Woolley, M. L.; Marsden, C. A.; Sleight, A. J.; Fone, K.

C. Psychopharmacology (Berlin) 2003, 170, 358.

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The authors thank the members of the Wyeth Discovery

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the structural conﬁrmation of the compounds described

in this manuscript.

Supplementary data

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Supplementary data associated with this article can be

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j.bmc.2007.06.024.

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Article Doi

Novel 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines as 5-HT6 agonists and antagonists

DOI: 10.1016/j.bmc.2007.06.024

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