Bis(1H-2-indolyl)methanones as a novel class of inhibitors of the platelet-derived growth factor receptor kinase

1002

J . Med. Chem. 2002, 45, 1002-1018

Articles

Bis(1H-2-in d olyl)m eth a n on es a s a Novel Cla ss of In h ibitor s of th e

P la telet-Der ived Gr ow th F a ctor Recep tor Kin a se

Siavosh Mahboobi,*^,†,‡Steffen Teller,^†,§Herwig Pongratz,^‡Harald Hufsky,^‡Andreas Sellmer,^‡Alexander Botzki,^‡

Andrea Uecker,^§Thomas Beckers,^||Silke Baasner,^||Christoph Scha¨chtele, Florian U¨ berall,^#

Matthias U. Kassack,^∞Stefan Dove,*^,‡and Frank-D. Bo¨hmer*^,§

Faculty of Chemistry and Pharmacy, Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany;

Research Unit Molecular Cell Biology, Medical Faculty, Friedrich Schiller University, D-07747 J ena, Germany; Department of

Cancer Research, ASTA Medica AG, D-60314 Frankfurt/ Main, Germany; Tumor Biology Center, Institute of Molecular

Medicine, 79106 Freiburg, Germany; Institute of Medicinal Chemistry and Biochemistry, University of Innsbruck,

A 6020 Innsbruck, Austria; and Pharmaceutical Institute, University of Bonn, D-53121 Bonn, Germany

Received J uly 19, 2001

The novel lead bis(1H-2-indolyl)methanone inhibits autophosphorylation of platelet-derived

growth factor (PDGF) receptor tyrosine kinase in intact cells. Various substituents in the 5- or

6-position of one indole ring increase or preserve potency, whereas most modifications of the

ring structures and of the methanone group as well as substitution at both indoles result in

weak or no activity. An ATP binding site model, derived by homology from the FGFR-1 tyrosine

kinase crystal structure suggesting hydrogen bonds of one indole NH and the methanone oxygen

with the backbone carbonyl and amide, respectively, of Cys684, explains why only one indole

moiety is open for substitution and locates groups in the 5- or 6-position outside the pocket.

The hitherto most active derivatives, 39, 53 and 67, inhibit both isoforms of the PDGF receptor

kinase in intact cells, with IC₅₀of 0.1-0.3 µM, and purified PDGFâ-receptor in vitro, with IC₅₀

of 0.09, 0.1, or 0.02 µM, respectively. PDGF-stimulated DNA synthesis is inhibited by these

derivatives with IC₅₀values of 1-3 µM. Kinetic analysis of 53 showed an ATP-competitive

mode of inhibition. The compounds are inactive or weakly active toward a number of other

tyrosine kinases, including the FGF receptor 1, EGF receptor, and c-Src kinase, as well as

toward serine-threonine kinases, including different PKC isoforms and GRK2, and appear

therefore selective for PDGF receptor inhibition.

In tr od u ction

rectly force tumor growth.¹³Also, PDGF seems to be

involved in the regulation of the interstitial tissue

pressure,¹⁴which may be relevant in the context of

conventional chemotherapeutic treatment of tumors.

Therefore, the investigation of different strategies to

block PDGF receptor signaling activity has attracted

much interest. Low molecular weight direct inhibitors

of the PDGF receptor tyrosine kinase activity with

diverse structures have been described, including quino-

lines,^15,16quinoxalines,^17-19pyridopyrimidines,^20,21

phenylaminopyrimidines,²²phenylbenzimidazoles,²³

indolin-2-ones,^24-26leflunomide,²⁷and pyrrolo(3,4)-beta-

carbolinediones.²⁸Many of these compounds suppress

disease-relevant PDGFR signaling in various experi-

mental models. When screening a chemical library for

effects on PDGFR autophosphorylation in a cellular

assay system, we observed a strong inhibition by bis-

(1H-2-indolyl)methanone. This paper presents the syn-

thesis and structure-activity relationships for bis(1H-

2-indolyl)methanone derivatives. Many of the compounds

are rather potent. Inhibition of the PDGFR kinase is

direct, targeted at the ATP-site, and selective when

compared to a panel of tyrosine and serine-threonine

kinases.

Aberrant expression and activity of platelet-derived

growth factors (PDGFs) and their cognate receptors

of the class III receptor tyrosine kinase family (for

reviews, see refs 1-3) have been found in various

disease states, including different cancers, atheroscle-

rosis, and fibrosis.^4-7Examples include the autocrine

activation of resident PDGF receptors by aberrantly

expressed PDGF in human glioma cells^8-10and consti-

tutively active fusion proteins of PDGFâ-receptor in

human chronic myelomonocytic leukemia.^11,12In other

forms of human cancer, tumor-derived PDGF may be

involved in stroma cell stimulation and thereby indi-

* General correspondence and correspondence on chemical aspects

should go to S.M. (Fax: +49-941-943 1737. E-mail: siavosh.mahboobi@

chemie.uni-regensburg.de). Correspondence on modeling should go to

S.D. (E-mail stefan.dove@chemie.uni-regensburg.de). Correspondence

on biological aspects should go to F.D.B. (E-mail: i5frbo@rz.uni-

jena.de).

^†Authors contributed equally to this work.

^‡University Regensburg.

^§Friedrich Schiller University.

^||ASTA Medica AG.

Institute of Molecular Medicine.

#

University of Innsbruck.

^∞University of Bonn.

Published on Web 01/30/2002

Inhibitors of PDGF Receptor Kinase

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 5 1003

Sch em e 1^a

a

(A) THF, -78 °C; (B) PDC/PTFA, CH₂Cl₂, rt, 2 h to 21 d; (C) either 1. NaOH/H₂O/EtOH, reflux, 2 to 12 h, or TBAF/THF, 50 °C, 0.5

to 4 h; (D) THF, -78 °C, CO₂, CH₂Cl₂, 6 M HCl, reflux, 1 h; (E) SOCl₂, reflux, 2 h; F: THF, -78 °C to rt, 12 h.

Ch a r t 1

Resu lts a n d Discu ssion

Syn th esis of Bis(1H-2-in d olyl)m eth a n on e De-

r iva tives a n d Rela ted Com p ou n d s. Bis(1H-2-in-

dolyl)methanone (1) and the corresponding derivatives

11-15 and 40 were synthesized as described²⁹by

coupling of the respective aldehyde 3a , oxidation of the

resulting carbinols 1a , 11a -15a , and 40a and depro-

tection of the N-phenylsulfonated ketones 1b, 11b-15b,

and 40b (Scheme 1, route I). The same reaction se-

quence was used for the preparation of the 2-benzoylin-

doles 20 and 22-25. Additionally, all these ketones as

well as other 2-aroylindole derivatives (21, 26, 27, 29,

and 30) can be prepared by condensation of N-protected

2-lithiated indole 2 with suitable acid chlorides 6 or 3b

(Scheme 1, route II). The necessary methoxyindoles for

the preparation of compounds 11-15 were obtained by

an easy and efficient synthesis, elaborated by Leimgru-

ber and Batcho.³⁴

Sch em e 2^a

a

(G) EDCI·HCl, CH₂Cl₂, rt.

Following the general reaction sequence described in

Scheme 1, route I, we also prepared 1H-2-indolyl(1H-

3-indolyl)methanone (10)^32,33(Chart 1) via the N-pro-

tected carbinol 10a using 1-phenylsulfonyl-1H-indole-

3-carbaldehyde instead of the 2-carbaldehyde of type 3a .

Employing the 2-aldehydes of benzo[b]furan³⁵and ben-

zo[b]thiophene³⁶afforded the O,S-related benzo[b]furan

and benzo[b]thiophene analogues 16 and 17 (Chart 1).

Bisbenzo[b]thiophen-2-ylmethanone (18) was also syn-

thesized in analogy to Scheme 1, route I, by condensing

2-lithiated benzo[b]furan with the respective 2-aldehyde.

Also, various indolylcarboxamide derivatives were

synthesized. Condensation of indole-2-carboxylic acid

with different amines resulted in moderate yields by

using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

hydrochloride (EDCI·HCl) in dry CH₂Cl₂(Scheme 2).

37

Because of the high activity of the 5-methoxyindole

compound 11 (see below), we synthesized the corre-

sponding 5-hydroxy derivative 39 and, in turn, func-

tionalized the 5-hydroxy group. Following literature

procedures, we failed to obtain compound 39 by using

38

benzylthiol/AlCl₃or trimethylchlorosilane/NaI³⁹for

cleaving the ether 11 (Scheme 3). Therefore, we followed

the methodology described in Scheme 1 and prepared

1004 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 5

Mahboobi et al.

Sch em e 3^a

1,2-ethanedione (7)⁵⁰were inactive. The same is true

for bis(1H-3-indolyl)methanone (9) and 1H-2-indolyl(1H-

3-indolyl)methanone (10) as well as for 1H-2-indolyl(5-

methoxy-1H-2-indolyl)methane (19). Taken together,

these results suggest that a carbonyl group bridging the

two indolyl residues in the 2,2′-position is characteristic

of the new pharmacophore.

Methoxy-substitution in the 5- or 6-position increases

the efficacy of inhibition compared to the parent com-

pound 1, whereas substitution in 7-position leads to

inactivity (Table 1). The 5,5′-dimethoxy-substituted

derivative 14 is only weakly active. Also, methyl sub-

stitution in position 5 reduces activity compared to

compound 1. The favorable effect of methoxy substitu-

ents agrees with previous results for quinolines,¹⁶where

a 4-methoxyphenyl group in the 2-position as well as

6,7-dimethoxy substitution has led to the most potent

PDGFRâ inhibitors.

a

(H) R-halide/K₂CO₃, acetone; (I) RCO₂Cl/pyridine, ethyl ac-

etate.

Substitution of the 1′-nitrogen by sulfur or oxygen in

compound 16 and 17, respectively, leads to moderately

or strongly reduced activity in comparison with com-

pound 11. If both nitrogens are exchanged by sulfur, a

completely inactive compound results (18) (Table 1).

Ch a r t 2

Phenyl (20-23, 25-28), naphthyl (29), and pyridyl

(30) replacement of one indolyl ring leads to inactivity

(IC₅₀> 30 µM, data not shown). Only the 4-methox-

yphenyl compound 24 has some residual potency (IC₅₀

) 3-10 µM).

Sch em e 4^a

With the exception of the weakly active compound 33

(IC₅₀) 10-30 µM), all the carboxamides 31, 32, and

34-38 were inactive (IC₅₀> 30 µM).

a

If 1 equiv of each alkyl halide (R-Hal) is employed, the

Derived from the 5-OH compound 39, a series of

diverse ether and ester structures (compounds 40-76,

Table 1) indicates that a certain variability of substit-

uents is tolerated in the 5-position of the lead structure

1. Nevertheless, empirical structure-activity relation-

ships based on some inactive derivatives and on an IC₅₀

range of about 2 orders of magnitude are evident. On

average, esters seem to be more active than ethers. The

5-dimethylaminomethyl ester 53 is the most potent

derivative so far. Unbranched, short alkyl chains are

favorable (41, 50, 52, 54) with decreasing activity from

methyl to n-propyl. Among larger substituents, un-

branched aralkyl (55, 58, 61, 69) and aryl groups (57,

60, 66, 68, 72) are superior to long, ω-iodinated alkyl

chains (44, 47) and cycloalkyl rings (46, 70, 71). Potency

is slightly lowered in substituted phenyl derivatives

(IC₅₀of 60 < 61 < 69 < 56 < 51 < 64). Only bulky

phenoxyphenyl or benzoylphenyl substituents lead to

inactivity (74-76), which also results from nonpolar,

R-branched substituents (48, 73). A polar R-branch,

however, is favorable (59). This striking positive effect

of polarity is even more obvious if nitrogen or oxygen

atoms are introduced in alkyl or cycloalkyl groups

(compare 42 and 49 with 46, 43 and 45 with 44 and 47,

53 with 52, and 67 with 52).

disubstituted (R¹dR²dR) and two monosubstituted derivatives

(R¹dH, R²dR or R¹dR and R²dH) are obtained in a ratio of 2:1:1.

The substitution pattern of the N-alkylated species could be

identified by 2-dimensional NOESY-¹H NMR analysis and ac-

cording to the fragmentation pattern in mass spectrometry.

the ketone 40 starting from 5-benzyloxyindole and

indole-2-carbaldehyde (route I) or indole-2-carboxylic

acid (route II). In the next step, 39 could easily be

obtained by removing the benzyl group with ammonium

formate and Pd/C as described⁴⁰(Scheme 3). As com-

pound 39 showed similar activity as 11, further ana-

logues were prepared according to Scheme 3. Since it

was impossible to remove the benzyl group from the

N-phenylsulfonyl protected derivative of 40, the protect-

ing groups had to be removed before further derivati-

zation.

Bis(1H-3-indolyl)methanone (9)^30,31(Chart 1) and 1,2-

bis(1H-2-indolyl)-1,2-ethandione (7)⁵⁰were obtained by

following described procedures.³⁰

The bis(1H-2-indolyl)methane 19 (Chart 2), in which

the indole moieties are bridged via a methylene group

instead of a carbonyl group, was synthesized by treating

the bisindole 11 with hydrazine hydrate in diethylene

glycol. For preparation of the N-alkylated and benzyl-

ated species 77-85, compound 11 was reacted with the

respective alkyl- and benzyl halides (Scheme 4).

SAR for In h ibition of P DGF R Au top h osp h or yl-

a tion in a Cellu la r Assa y. Bis(1H-2-indolyl)metha-

none (1) caused a strong inhibition of PDGF receptor

activity (IC₅₀1 µM), which was similar to the effect of

the used reference compound, quinoxaline AG1295. The

precursor compounds as well as 1,2-bis(1H-2-indolyl)-

Mod elin g of In h ib it or In t er a ct ion w it h t h e

P DGF Râ Kin a se Dom a in . It is rather difficult to

explain the structure-activity relationships described

so far without structural information about the

PDGFRâ tyrosine kinase domain. Kinetic analysis (see

below) suggests that the bis(1H-2-indolyl)methanones,

as many other tyrosine kinase inhibitors, interact with

the ATP binding site. Recently, we have derived a

Inhibitors of PDGF Receptor Kinase

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 5 1005

Ta ble 1. Inhibition of PDGF Receptor Tyrosine Kinase by Bis(1H-2-indolyl)methanones and Related Compounds

a

IC₅₀were determined by measuring inhibition of PDGF receptor autophosphorylation in intact Swiss 3T3 cells as described¹⁸and

outlined in detail under Experimental.

putative structure of the PDGFRâ tyrosine kinase by

homology modeling (program COMPOSER,⁴¹imple-

mented in SYBYL-6.6, Tripos Inc.), starting from dif-

ferent FGFR-1 tyrosine kinase crystal structures.^42-44

This model was used to dock inhibitors of the bis(1H-

2-indolyl)methanone class and of different other struc-

tural families⁴⁵(to be published in detail elsewhere).

Initially, two alternative docking modes of the bis(1H-

2-indolyl)methanones, both based on a bidentate hy-

drogen-bond donor-acceptor system and on the projec-

tion of one indole ring inside and the other one outside

the catalytic cleft, came into question according to

corresponding binding patterns of inhibitors cocrystal-

lized with FGFR-1 tyrosine kinase (see Figure 1).

1006 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 5

Mahboobi et al.

F igu r e 1. Structures of the FGFR-1 kinase inhibitors SU-

4984, SU-5402,⁴³and PD-173074,⁴⁴with schematic representa-

tion of their binding modes and of important corresponding

PDGFRâ (above) and FGFR-1 kinase residues (below).

The first one, derived from the complexes with SU-

4984 and SU-5402,⁴³contains hydrogen bonds of the

inner indole NH with the oxygen of the Glu682 (FGFR-

1: Glu562) backbone and of the methanone oxygen with

the NH function of Cys684 (FGFR-1: Ala564). The latter

bond is also present in the second mode resembling the

crystal structure with PD-173074⁴⁴(see Figure 2a), but

now the outer indole nitrogen serves as hydrogen donor

for the backbone oxygen of Cys684. Assuming the first

mode would imply closely superimposed indolinone and

indolylmethanone moieties of SU-5402 and 67, respec-

tively. However, the low activity of the 5,5′-dimethoxy

derivative 14 compared to that of the 5-methoxy com-

pound 11 (Table 2) indicates limited space around the

inner indolyl system, contrary to the higher degrees of

freedom for 5- and 6-substitution at the corresponding

moiety of potent indolinone PDGFRâ inhibitors.^24-26

Thus, the inner indole ring of the bis(1H-2-indolyl)-

methanones should penetrate more deeply into the

binding cleft than that of SU-5402, and therefore, the

second binding mode corresponding to that of PD-

173074 must be suggested (see Figure 2). The unsub-

stituted moieties of compounds 16 and 17 are also more

probably inside the pocket due to their 5-methoxyindole

substituents, but they do not provide hydrogen donor

atoms for Glu682. Nevertheless, the modeled distance

of about 3.5 Å between the heteroatoms of the inner

heterocycle and the backbone oxygen of Glu682 might

indicate an electrostatic attraction in the case of bisin-

doles (see Figure 2b) and repulsion in the case of the

less active compounds 16 and 17.

F igu r e 2. Suggested binding mode of bis(1H-2-indolyl)-

methanones to PDGFRâ kinase in comparison with the crystal

structure of FGFR-1 kinase complexed with PD-173074.⁴⁴

Hydrogen bonds are represented as pink dashed lines. Impor-

tant residues are drawn and labeled. (a) PD-173074 (C- and

H-atoms orange) bound to FGFR-1 kinase. (b) Compound 67

(C- and H-atoms green) docked into the PDGFRâ kinase model;

the third interaction between the inner indole-NH and the Glu-

682 oxygen (thin dashed line) is weak and hypothetical.

compound 67 is docked in a propeller-like energy-

minimum conformation with an angle of about 22°

between both indole planes. However, detailed conclu-

sions about the active conformation of the inner indole

ring and about the fine structure of surrounding resi-

dues in the pocket are not possible, despite the highly

homologous catalytic domains of FGFR-1 and PDGFRâ

kinases. The main reason for this uncertainty is the

different conformation of the nucleotide binding loop

between strands â1 and â2 in FGFR-1 kinase crystal

structures. In complex with ATP,⁴²with PD-173074,⁴⁴

and with SU-4984,⁴³this region is poorly ordered, but

with SU-5402,⁴³it is ordered so that the highly con-

served Phe489 caps the hydrophobic pocket in which the

oxindole binds. Thus, it cannot be ruled out that a

specific arrangement of the corresponding loop in the

PDGFRâ kinase narrows the binding site in comparison

to the model in Figure 2b. Nevertheless, the inactivity

All docking calculations were performed with

SYBYL6.6 (Tripos Inc.) on a SGI Indigo²workstation.

After initial optimization of the complexes with the

Kollman all-atom force field, final energy minimizations

of the ligands and the binding site region were per-

formed with the Tripos force field. In Figure 2b,

Inhibitors of PDGF Receptor Kinase

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 5 1007

Ta ble 2. Inhibition of Different Protein Kinases and of Growth

Factor Dependent Cell Proliferation by Selected

Bis(1H-2-indolyl)methanones

attenuate large differences in geometry, dipole mo-

ments, and hydrogen-bonding abilities. Low variability

of FGFR-1 and PDGFRâ kinase inhibition was also

observed on very diversely 2-substituted pyrido[2,3-d]-

pyrimidines.⁴⁷Deriving binding models for these com-

pounds, Trumpp-Kallmeyer et al.²¹also concluded that

large, flexible groups in 2-position extend out of the

binding pocket and are exposed to solvent. On the other

hand, the model in Figure 2 illustrates that bulky

branches in the R-position of the ester substituents and

phenoxy-substituted phenyl groups lead to inactivity,

since they would interfere with the â1 strand and/or the

hinge region. According to the cellular assay, additional

effects due to membrane transport and distribution

cannot be ruled out, but they are not dominant, since

the activity-hydrophobicity correlation is rather in-

verse. As shown by in vitro phosphorylation assays (see

below), hydrolysis of the esters into compound 39 can

also be neglected.

IC₅₀(µM)

50

0.3

39

53

67

0.2

Phosphorylation assays

PDGFR (Swiss 3T3 cells)^a

PDGFâ-R (in vitro, purified

receptor)^b

0.2

0.1

0.07

0.09

0.6

0.1

1.3

0.02

PDGFâ-R (in vitro, Sf9-derived

GST-fusion protein)^c

PDGFâ-R (PAE cells)^d

PDGFR-R (PAE cells)^d

FGFR-1 (PAE cells)^d

EGFR (A431 cells)^d

Src (src-NIH3T3 cells)^d

GRK2 (in vitro)^e

4.9

4.2

0.1

0.2

>10

>30

>100 nt

17.0

>100 >30

0.2

1.0

>10

>30

0.1

>10

>30

0.1

0.3

>10

>30

>100 >100

PKCι (in vitro)^f

>100 15.1

20.4

>100

PKCꢀ ΑΕ (in vitro)^f

DNA synthesis in Swiss 3T3

cells,^gstimulated with

PDGFBB

30

1.7

9.5

1.3

5.1

2.5

4.6

2.6

10-30

EGF

bFGF

FCS

Other:

ca. 10 10-30 10-30 10-30

The proposed binding mode is further supported by

compounds 77-85, some N-mono- and dialkylated and

-benzylated derivatives of the active compound 11

(Scheme 4).

8.8

nt

5.5

3.2

2.1

3.5

10-30

proliferation sis-NIH3T3

nt

(inducible PDGF-B expression)^g

a

Inhibition of autophosphorylation of endogenous PDGF recep-

The hydrogen-donor function of the indole NH is

preserved in the monosubstituted compounds, but ac-

cording to the model, any bulk at the inner indole

nitrogen would interfere with the residues Thr681 and

Glu682. Consequently, all derivatives of this type are

inactive (data not shown).

tors in Swiss 3T3 cells was determined as described.¹⁸Kinase

b

was purified from membranes of PDGFâ receptor overexpressing

cells, and assays were performed as described.^18,19,53^cA consti-

tutively active GST-fusion protein of the cytoplasmic domain of

PDGFâ receptor was expressed in Sf9 cells, and kinase assays with

the isolated fusion protein were performed as in Hofmann et al.⁵⁵

d

Autophosphorylation of the respective kinases in intact cells was

determined by immunoblotting.⁵³^eGRK2 was overexpressed in

293 cells and activity determination was done as in Kassack et

al.⁵⁴^fHis-tagged PKC-isoforms were overexpressed in COS7 cells.

Selectivity of Kin a se In h ibition a n d Effects on

Cell P r olifer a tion . Selected potent compounds were

further characterized. The inhibition of PDGFâ-receptor

kinase purified from a cell line with high level overex-

pression was tested in an in vitro autophosphorylation

assay. The IC₅₀values are equal to or lower than those

in the intact cell test (Table 2), probably mainly due to

higher ATP levels in the Swiss 3T3 fibroblasts. Struc-

ture-activity relationships are slightly different, since

the methoxymethyl derivative 67 is in vitro about five

times more active than compounds 39 and 53. The

autophosphorylation of a GST-fusion protein of the

PDGFâ-receptor cytoplasmic domain expressed in Sf9

cells is also inhibited, but with 1-2 orders of magnitude

higher IC₅₀values compared to those in the purified

receptor test (Table 2, ATP concentration 10 µM in both

assays). The lower susceptibility of the Sf9 cell-derived

PDGFRâ kinase-GST fusion protein may be the con-

sequence of its constitutive activity. Abl tyrosine kinase

has recently been reported to bind the ATP-site directed

inhibitor STI571 preferentially in the inactive kinase

conformation.⁴⁸The reversed structure-activity

relationshipssthe unsubstituted 5-OH derivative 39 is

now most active and compounds 50 and 67 are least

activessuggest that the fringe of the binding site in the

PDGFRâ kinase-GST fusion protein is changed, pos-

sibly due to an active-like, specific conformation of the

â1-â2 loop and/or the hinge region. Taken together, the

inhibition results obtained with purified and with

recombinant kinase demonstrate that compounds of the

bis(1H-2-indolyl)methanone family are direct inhibitors

of the PDGFâ-receptor tyrosine kinase. The selectivity

of the compounds was first investigated by testing the

inhibition of other kinases in cellular phosphorylation

assays (Table 2). Both subtypes of the PDGF receptor,

g

The assays are outlined in the Experimental Section. See Ex-

perimental Section for details on these assays. nt, not tested.

of the bisindolylmethanones as FGFR-1 kinase inhibi-

tors (see Table 2) also supports the suggested binding

mode: The more bulky FGFR-1 kinase residue Val561

replacing Thr681 in the PDGFRâ kinase is far inside

the pocket and should interfere with the phenyl moiety

of the inner indole system.

Figure 2b shows that the 5-substituent of the ester

derivative 67 is projected outside the catalytic cleft,

explaining to a certain extent the high degrees of

freedom for rather different groups in this position

without substantial loss of PDGFRâ inhibition (see

Table 2). However, it becomes obvious that the 5-sub-

stituents are surrounded by short chains of the â1

strand, Arg604 to Ser608 (corresponding to Lys482 to

Glu486 in the FGFR-1 kinase), and of the hinge region,

Arg685 to Asp688 (FGFR-1: Ser565 to Asn568). Among

these residues, the side chain of Leu606 as part of the

hydrophobic pocket perpendicularly interacts with the

outer indole ring. The backbone and side chains, re-

spectively, of the other residues form something like

polar “banks”, which may explain the correlation of

activity with polarity in the 5-position. According to the

low variability of the activity data and to the relatively

high distances, however, specific dipole-dipole interac-

tions and polarization effects should not dominate. An

effect first described by Franks,⁴⁶concluding that the

substituent with its solvent shell somehow “freezes” to

the solvated surface of polar amino acids, is more likely.

Water around various polar groups should then greatly

1008 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 5

Mahboobi et al.

F igu r e 3. Kinetic evaluation of PDGFâ-receptor kinase inhibition by a bis(1H-2-indolyl)methanone. Purified PDGFâ-receptor

kinase was assayed in vitro in the presence of different concentrations of compound 53 with the synthetic peptide KY571 as a

substrate. Assays were performed with a fixed concentration of KY571 and variable concentration of ATP (a) or fixed ATP

concentration and variable KY571 concentration (b). The data are shown in a Lineweaver-Burk representation.

PDGFRR and PDGFRâ, are similarly well inhibited. No

effects up to 30 µM are observed on EGF receptor

kinase, FGF receptor 1-kinase, and Src-kinase (Table

2). G-protein coupled receptor kinase 2 (GRK2), a serine-

threonine kinase, is not affected by any of the com-

pounds up to 100 µM (Table 2). Also an in vitro assay

of PKC isoforms ι and ꢀ measuring exogenous peptide

substrate phosphorylation revealed only weak or no

inhibition by the tested derivatives (Table 2). For

compound 53, the following IC₅₀values were determined

with a panel of different kinase GST-fusion proteins in

vitro: ErbB2, 51.0 µM; IGF1 receptor, 24.0 µM; CDK2/

cyclin E, 28.0 µM; J AK2, 29.0 µM; PKB/Akt, 34.0 µM;

PKCR, 89.0 µM; PKCꢀ, 90 µM; and PKCú, >100 µM.

Compared to the PDGFâ-receptor kinase with 18.5 to

77-fold lower IC₅₀values in the same type of assay, these

Inhibitors of PDGF Receptor Kinase

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 5 1009

kinases are thus markedly less sensitive or even insen-

sitive to inhibition by the bis(1H-2-indolyl)methanone

derivative 53.

the previously described pyrrolo(3,4)-betacarbolinedi-

ones²⁸and the widely used quinoxaline derivative

AG1295,^17-19which was applied as standard throughout

this study. By comparison with published data, the

present bis(1H-2-indolyl)methanone derivatives exhibit

similar potency in cellular assays as 2-phenylaminopy-

rimidines, for example, CGP53716²²and CGP57148/

STI751,⁴⁹and phenylbenzimidazoles.²³They are less

active, but apparently more selective, PDGFRâ kinase

inhibitors than several indoline-2-ones.^24-26PDGF-

mediated cell proliferation can be significantly blocked

by different bis(1H-2-indolyl)methanones. Thus, these

compounds are interesting candidates for application in

disease states with pathological PDGF-receptor signal-

ing as certain cancers and artherosclerosis/restenosis.

All tested compounds inhibit the PDGF-stimulated

DNA synthesis in Swiss 3T3 fibroblasts with an IC₅₀of

about 1 order of magnitude above that for inhibition of

cellular PDGF receptor phosphorylation (Table 2). In-

terestingly, the stimulation with other mitogens results

in different selectivities for individual compounds.

Compound 67 has little effect on DNA synthesis stimu-

lated by bFGF or fetal calf serum, whereas the other

compounds inhibit mitogenesis induced by other agents.

Thus, for these bis(1H-2-indolyl)methanone derivatives,

further targets may exist in mitogenic pathways initi-

ated by different mitogens. Inhibition of PDGF-depend-

ent cell proliferation is also observed in NIH3T3 cells,

engineered to inducibly express PDGF-B (Table 2). All

compounds have additionally been tested in prolifera-

tion assays using the cancer cell lines L1210, MCF7,

SKOV3, and HeLa. Most compounds are inactive in

these assays (data not shown), excluding some general

mechanism of cytostatic/cytotoxic action. As an excep-

tion among the potent kinase inhibitors, compound 11

exhibits toxic effects on fibroblasts upon incubation for

24 h or longer (data not shown), which have also been

observed in other cellular assays with this compound

upon long-term incubation.

Kin etic Eva lu a tion of P DGF Recep tor Kin a se

In h ibition by Com p ou n d 53. The inhibition mecha-

nism of 53 was investigated as described,¹⁹using

purified human PDGFâ-receptor and a synthetic peptide

substrate derived from the sequence around the auto-

phosphorylation site Tyr751 (”KY751”). Inhibition by

different concentrations of 53 was measured by both

varying KY751 concentration at ATP saturation and

ATP concentration at nearly saturation with KY751.

Results are depicted in Figure 3 in a Lineweaver-Burk

representation of the data. The type of inhibition is

competitive with respect to ATP (Figure 3a) and close

to noncompetitive with respect to the peptide substrate

(Figure 3b). Similar to previous observations with other

tyrosine kinase inhibitors, these findings indicate the

ATP-binding region as the main site of interaction of

the bis(1H-2-indolyl)methanone inhibitors with the

PDGF receptor.

Exp er im en ta l Section

Elemental analyses was done by the Analytical Lab at

University Regensburg. Melting points were determined on a

Bu¨chi 512 or a Reichert hot-stage microscope. FT IR spectra

were collectecd with a Nicolet 510. ¹H NMR spectra were

determined with a Bruker 250 (250 MHz). MS data were

collected with a Varian MAT 311A (EI, 70 eV). All reactions

were carried out under nitrogen, dried over self-indicating

silica gel, concentrated H₂SO₄, and KOH.

5-Meth oxy-1-p h en ylsu lfon yl-1H-in d ole. During 20 min,

NaH (1.29 g, 43.0 mmol) (80% in paraffin) was added to a

stirred solution of 5-methoxyindole (6.18 g, 42.0 mmol) in 60

mL of anhydrous DMF at 0 °C. After stirring at room

temperature for 1 h, benzenesulfonyl chloride (4.9 mL, 43.0

mmol) was added slowly. The reaction mixture was stirred for

an additional hour and then poured into 500 mL of 5% aq

NaHCO₃and extracted with ether (3 × 250 mL). The combined

organic layers were dried (Na₂SO₄), and the solvent was

removed under reduced pressure to give a beige solid. Recrys-

tallization from ethanol afforded 9.88 g (82%) of the title

compound as colorless crystals. Mp: 97-98 °C. IR (KBr): ν )

3068, 2842, 1611 cm^-^{1 1}H NMR (DMSO-d₆): δ ) 3.73 (s, 3

.

H), 6.77-6.78 (m, 1H), 6.92-6.97 (m, 1H), 7.11-7.12 (m, 1H),

7.54-7.61 (m, 2H), 7.64-7.71 (m, 1H), 7.75-7.77 (m, 1H),

7.81-7.84 (m, 1H), 7.91-7.95 (m, 2H). EI-MS (70 eV) m/z

(%): 287 (48) [M^+•], 146 (100), 141 (6), 131 (8), 103 (18), 77

(46). Anal. (C₁₅H₁₃NO₃S): C, H, N.

5-Ben zyloxy-1-p h en ylsu lfon yl-1H-in d ole was prepared

in a manner similar to 5-methoxy-1-phenylsulfonyl-1H-indole,

using 5-benzyloxyindole. Yield: 6.13 g (75%) of colorless

crystals. Mp: 79-81 °C. IR (KBr): ν ) 3064, 3035, 2905, 2873,

1601, 1582, 1537 cm^-1. ¹H NMR (DMSO-d₆): δ ) 5.09 (s, 2H),

6.76 (d, J ) 3.5 Hz, 1H), 7.02 (dd, J ) 8.9 Hz, 3.5 Hz, 1 H),

7.20 (d, J ) 3.5 Hz, 1 H), 7.27-7.97 (m, 12 H). EI-MS (70 eV)

m/z (%): 363 (58) [M^+•], 272 (30), 223 (9), 141 (21), 91 (100).

Anal. (C₂₁H₁₇NO₃S): C, H, N.

Con clu sion s

1,2 Bis(1H-2-in d olyl)-1,2-eth a n d ion e (7).⁵⁰

We have identified a novel family of ATP-competitive

PDGF receptor tyrosine kinase inhibitors, bis(1H-2-

indolyl)methanones. The most active compounds are the

5-hydroxyl derivative 39 and its esters 53 and 67. One

unsubstituted moiety (indole, benzofuran, benzothiophen)

is always necessary for sufficient activity. Rather dif-

ferent substituents in the 5- or 6-position of the other

moiety (essentially indole) are possible without sub-

stantial loss of PDGFRâ inhibition. Docking studies

using a molecular model of the PDGFRâ kinase domain

suggest a binding mode of the compounds where the

outer indole NH and the methanone oxygen are hydro-

gen bound with the backbone carbonyl and amide,

respectively, of Cys684 and where groups in the 5- or

6-position are projected outside the catalytic cleft. The

hitherto most active bis(1H-2-indolyl)methanone deriva-

tives are significantly more potent than leflunomide,²⁷

Bis(1H-3-in d olyl)m eth a n on e (9).³⁰

P r oced u r e A (Sch em e 1, R ou t e I): Syn t h esis of t h e

Su bst it u t ed (1-P h en ylsu lfon yl-1H-2-in d olyl)m et h a n ols

1a , 10a -17a , 20a , 22a -25a , a n d 40a a n d of th e An a logu e

Bisben zo[b]th iop h en -2-ylm eth a n e (18a ). n-Butyllithium

(9.9 mL, 15.9 mmol) was added dropwise to a solution of

anhydrous diisopropylamine (2.23 mL, 15.9 mmol) in dry THF

(15 mL) at -78 °C. After stirring for 10 min, the mixture was

allowed to warm to 0 °C, then it was stirred for 30 min. A

solution of the appropriate 1-phenylsulfonylindole (14.0 mmol)

in dry THF (22 mL) was added within 10 min, and the reaction

mixture was kept stirring at 0 °C for an additional 30 min,

before the respective (1-phenylsulfonyl-1H-2-indolyl)lithium 3

so obtained was cooled to -78 °C again.

2-F or m yl-1-p h en ylsu lfon yl-1H-in d ole²⁹2 (4.39 g, 15.4

mmol) (or, depending on the desired product, any other

suitable aldehyde) in dry THF (15 mL) was added slowly. After

warming to room temperature overnight, the mixture was

poured into 1% aq HCl (100 mL), and the organic layer was

1010 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 5

Mahboobi et al.

separated. The water layer was extracted with ethyl acetate

(3 × 50 mL), and the combined organic layers were washed

successively with bicarbonate and brine. After drying (Na₂-

SO₄), the solvent was evaporated under reduced pressure to

leave a foamy solid, which was subjected to column chroma-

tography (SiO₂; ethyl acetate/hexane 4/1) or recrystallized from

ethanol, yielding the product as light yellowish crystals.

Bis(1-p h en ylsu lfon yl-1H-2-in d olyl)m eth a n ol (1a ).²⁹

(1-P h en ylsu lfon yl-1H-2-in d olyl)(1-p h en ylsu lfon yl-1H-

3-in d olyl)m eth a n ol (10a ). Yield: 4.41 g (55%). Mp: 88-90

cm^-1. ¹H NMR (DMSO-d₆): δ ) 6.43-6.44 (m, 1H), 6.93-6.95

(m, 1H), 7.27-7.35 (m, 4H), 7.37-7.38 (m, 2H), 7.76-7.83 (m,

2H), 7.85-7.96 (m, 2H). EI-MS (70 eV) m/z (%): 296 (69) [M^+•],

234 (18), 161 (100), 135 (72), 89 (23). Anal. (C₁₇H₁₀OS₂):

C, H, N.

(5-Meth oxy-1-ph en ylsu lfon yl-1H-2-in dolyl)ph en ylm eth -

a n ol (20a ). Yield: 4.74 g (86%). Mp: 51-52 °C. IR (KBr): ν )

3064, 2834, 1615 cm^-1. ¹H NMR (DMSO-d₆): δ ) 3.72 (s, 3H),

6.15-6.18 (m, 1H), 6.37-6.39 (m, 1H), 6.60 (s, 1H), 6.86-6.91

(m, 1H), 7.06-7.07 (m, 1H), 7.28-7.39 (m, 5H), 7.47-7.53 (m,

2H), 7.60-7.67 (m, 1H), 7.73-7.77 (m, 2H), 7.84-7.87 (m, 1H).

EI-MS (70 eV) m/z (%): 393 (63) [M^+•], 251 (100), 224 (21),

105 (61), 77 (44). Anal. (C₂₂H₁₉NO₄S): C, H, N.

°C. IR (KBr): ν ) 3533, 3064, 1605 cm^-^{1 1}H NMR (DMSO-

.

d₆): δ ) 6.35 (d, J ) 6 Hz, 1H), 6.62 (s, 1H), 6.64 (s, 1H), 7.15-

7.74 (m, H), 7.86-8.04 (m, H). PI-FDMS (CH₂Cl₂) m/z (%): 542

(100) [M^+•]. Anal. (C₂₉H₂₂N₂O₅S₂·0.25ethyl acetate): C, H, N.

(5-Meth oxy-1-p h en ylsu lfon yl-1H-2-in d olyl)(1-p h en yl-

su lfon yl-1H-2-in d olyl)m eth a n ol (11a ). Yield: 6.49 g (81%).

2-Meth oxyp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-

in d olyl)m eth a n ol (22a ). Yield: 2.43 g (41%) of light red

crystals. Mp: 75-76 °C. IR (KBr): ν ) 3068, 2961, 1603 cm^-1

.

¹H NMR (DMSO-d₆): δ ) 3.70 (s, 3H), 3.75 (s, 3H), 6.10-6.12

(m, 1H, exchangeable), 6.68-6.77 (m, 2H), 6.86-6.91 (m, 2H),

6.94-7.05 (m, 3H), 7.45-7.49 (m, 1H), 7.54-7.70 (m, 3H),

7.86-7.95 (m, 3H). EI-MS (70 eV) m/z (%): 423 (27) [M^+•], 281

(35), 135 (100), 77 (34). Anal. (C₂₃H₂₁NO₅S): C, H, N.

Mp: 150-152 °C. IR (KBr): ν ) 3450, 1449, 1368 cm^-^{1 1}H

.

NMR (DMSO-d₆): δ ) 3.73 (s, 3H), 6.57 (s, 2H), 6.70-6.72

(m, 1H), 6.91-6.95 (m, 1H), 7.07-7.08 (m, 1H), 7.20-7.36 (m,

3H), 7.48-7.56 (m, 5H), 7.61-7.68 (m, 2H), 7.87-8.04 (m, 6H).

EI-MS (70 eV) m/z (%): 572 (3) [M^+•], 290 (12), 250 (14), 142

(37), 125 (32), 77 (100). Anal. (C₃₀H₂₄N₂O₆S₂): C, H, N.

(6-Meth oxy-1-p h en ylsu lfon yl-1H-2-in d olyl)(1-p h en yl-

su lfon yl-1H-2-in d olyl)m eth a n ol (12a ). Yield: 6.73 g (84%).

3-Meth oxyp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-

in d olyl)m eth a n ol (23a ). Yield: 4.03 g (68%). Mp: 121-122

°C. IR (KBr): ν ) 3095, 2958, 1605 cm^-^{1 1}H NMR (DMSO-

.

1

Mp: 180 °C. IR (KBr): ν ) 3429, 3066, 2966 cm^-1. H NMR

d₆): δ ) 3.72 (s, 6H), 6.16-6.18 (m, 1H, exchangeable), 6.34-

6.36 (m, 1H), 6.56 (s, 1H), 6.84-6.95 (m, 4H), 7.06-7.07 (m,

1H), 7.23-7.29 (m, 1H), 7.47-7.53 (m, 2H), 7.61-7.67 (m, 1H),

7.79-7.79 (m, 2H), 7.85-7.88 (m, 1H). EI-MS (70 eV) m/z

(%): 423 (72) [M^+•], 266 (100), 250 (23), 135 (45), 77 (27). Anal.

(C₂₃H₂₁NO₅S): C, H, N.

(DMSO-d₆): δ ) 3.82 (s, 3H), 6.50 (s, 1H), 6.62-6.67 (m, 2H),

6.86-6.90 (m, 1H), 7.20-7.43 (m, 4H), 7.49-7.67 (m, 8H),

7.97-8.04 (m, 5H). MS (70 eV) m/z (%): 572 (4) [M^+•], 290 (9),

142 (37), 125 (19), 94 (16), 77 (100). Anal. (C₃₀H₂₄N₂O₆S₂): C,

H, N_.

4-Meth oxyp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-

in d olyl)m eth a n ol (24a ). Yield: 4.57 g (77%) of light red

(7-Meth oxy-1-p h en ylsu lfon yl-1H-2-in d olyl)(1-p h en yl-

su lfon yl-1H-2-in d olyl)m eth a n ol (13a ). Yield: 4.41 g (55%).

crystals. Mp: 78-79 °C. IR (KBr): ν ) 3442, 3068, 2935 cm^-1

.

Mp: 148-150 °C. IR (KBr): ν ) 3543, 3064, 2962 cm^-^{1 1}H

.

¹H NMR (DMSO-d₆): δ ) 3.72 (s, 3H), 3.74 (s, 3H), 6.03-6.05

(m, 1H, exchangeable), 6.31-6.33 (m, 1H), 6.63 (s, 1H), 6.85-

6.90 (m, 3H), 7.06-7.07 (m, 1H), 7.23-7.29 (m, 2H), 7.45-

7.51 (m, 2H), 7.60-7.73 (m, 3H), 7.83-7.87 (m, 1H). EI-MS

(70 eV) m/z (%): 423 (27) [M^+•], 281 (100), 265 (18), 250 (17),

173 (18), 135 (31), 77 (25). Anal. (C₂₃H₂₁NO₅S): C, H, N.

2,4-Dim et h oxyp h en yl-(5-m et h oxy-1-p h en ylsu lfon yl-

1H-2-in d olyl)m eth a n ol (25a ). Yield: 3.88 g (61%), mp 119-

120 °C. IR (KBr): ν ) 3002, 2941, 1591 cm^-1. ¹H NMR (DMSO-

d₆): δ ) 3.69 (s, 3H), 3.73 (s, 3H), 3.78 (s, 3H), 5.75-5.77 (m,

1H, exchangeable), 6.15 (s, 1H), 6.51-6.60 (m, 3H), 6.85-6.89

(m, 1H), 7.00-7.01 (m, 1H), 7.26-7.29 (m, 1H), 7.51-7.68 (m,

3H), 7.84-7.90 (m, 3H). EI-MS (70 eV) m/z (%): 453 (23) [M^+•],

NMR (CDCl₃): δ ) 3.53 (s, 3H), 4.19-4.21 (m, 1H), 6.36 (s,

1H), 6.67-6.70 (m, 1H), 6.94-6.98 (m, H), 7.07-7.13 (m, 1H),

7.21-7.57 (m, 10H), 7.72-7.75 (m, 2H), 8.06-8.14 (m, 3H).

EI-MS (70 eV) m/z (%): 572 (3) [M^+•], 492 (3), 430 (4), 351 (5),

290 (6), 250 (9), 142 (64), 77 (100). Anal. (C₃₀H₂₄N₂O₆S₂): C,

H, N.

Bis(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-in d olyl)m eth a -

n ol (14a ). Yield: 6.41 g (76%). Mp: 104-105 °C. IR (KBr): ν

) 3435, 3092, 2962 cm^-^{1 1}H NMR (DMSO-d₆): δ ) 3.73 (s,

.

6H), 6.53 (s, 2H), 6.68-6.71 (m, 1H), 6.91-6.95 (m, 2H), 7.07-

7.08 (m, 2H), 7.16-7.18 (m, 1H), 7.49-7.55 (m, 4H), 7.61-

7.67 (m, 2H), 7.87-7.91 (m, 2H), 7.95-7.98 (m, 4H). EI-MS

(70 eV) m/z (%): 602 (1) [M^+•], 462 (1), 320 (6), 250 (12), 142

(28), 109 (33), 77 (100). Anal. (C₃₁H₂₆N₂O₇S₂): C, H, N.

(5-Meth yl-1-p h en ylsu lfon yl-1H-2-in d olyl)(1-p h en ylsu l-

fon yl-1H-2-in d olyl)m eth a n ol (15a ). Yield: 5.61 g (72%), mp

311 (60), 284 (25), 173 (67), 165 (100), 77 (39). Anal. (C₂₄H₂₃

NO₆S): C, H, N.

-

(5-Ben zyloxy-1-p h en ylsu lfon yl-1H-2-in d olyl)(1-p h en yl-

su lfon yl-1H-2-in d olyl)m eth a n ol (40a ). Yield: 7.18 g (79%).

1

140-141 °C. IR (KBr): ν ) 3523, 3066, 2921 cm^-1. H NMR

Mp: 94-97 °C. IR (KBr): ν ) 3532, 1611 cm^-^{1 1}H NMR

.

(DMSO-d₆): δ ) 2.33 (s, 3H), 6.57 (d, J ) 4.35 Hz, 1H), 6.71

(d, J ) 5.68 Hz, 1H), 7.12-7.37 (m, 5H), 7.47-7.68 (m, 7H),

7.83-8.07 (m, 6H). PI-FDMS (dichloromethane) m/z (%):556

(100) [M^+•], 557 (32), 558 (12). Anal. (C₃₀H₂₄N₂O₅S₂·0.25ethyl

acetate): C, H, N.

(DMSO-d₆): δ ) 5.07 (s, 2H), 6.54 (s, 1H), 6.58 (s, 1 H), 6.70

(d, J ) 2.7 Hz, 1 H), 7.00 (dd, J ) 1 Hz, 3.6 Hz, 1 H), 7.15-

8.01 (m, 22 H). PI-FDMS (CH₂Cl₂); m/z (%): 648 (100) [M^+•].

Anal. (C₃₆H₂₈N₂O₆S₂): C, H, N.

P r oced u r e B (Sch em e 1, Rou te 1): P r ep a r a tion of th e

(1-P h en ylsu lfon yl-1H -2-in d olyl)m et h a n on es 1b , 10b -

16b, 20b, 22b-25b, 40b a n d of th e An a logu e Bisben zo-

[b]th iop h en -2-ylm eth a n on e (18). PDC (pyridinium dichro-

mate) (11.66 g, 31.0 mmol) and PTFA (pyridinium trifluoro-

acetate) (2.48 g, 155 mmol) were added to a solution of the

respective (1-phenylsulfonyl-1H-2-indolyl)methanol derivative

(6.2 mmol) (1a , 10a -16a , 20a , 22a -25a or 40a , procedure A)

in 40 mL of dry CH₂Cl₂and for the preparation of 18 to a

solution of 18a in 40 mL of dry CH₂Cl₂. When the oxidation

was completed (2 h to 3 weeks, TLC control) solid chromium

waste was removed by filtration through SiO₂. Evaporation

of the solvent left a foamy material, which was purified by

column chromatography on silica gel with CH₂Cl₂/ethyl acetate

as eluent, leading to light yellow cristals.

(Ben zo[b]th iop h en -2-yl)(5-m eth oxy-1-p h en ylsu lfon yl-

1H-2-in d olyl)m eth a n ol (16a ). Yield: 4.47 g (71%). Mp: 71-

73 °C. IR (KBr): ν ) 3433, 3062, 2937 cm^-1. ¹H NMR (DMSO-

d₆): δ ) 3.73 (s, 3H), 6.73-6.77 (m, 2H), 6.85 (s, 1H), 6.89-

6.94 (m, 1H), 7.10-7.11 (m, 1H), 7.30-7.36 (m, 3H), 7.43-

7.49 (m, 2H), 7.58-7.64 (m, 1H), 7.76-7.81 (m, 3H), 7.87-

7.91 (m, 2H). EI-MS (70 eV) m/z (%): 449 (46) [M^+•], 307 (100),

291 (37), 174 (86), 161 (61), 77 (61). Anal. (C₂₄H₁₉NO₄S₂): C,

H, N.

(Ben zo[b]fu r a n -2-yl)(5-m eth oxy-1-p h en ylsu lfon yl-1H-

2-in d olyl)m eth a n ol (17a ). Yield: 5.22 g (86%). Mp: 118-

119 °C. IR (KBr): ν ) 3452, 2836, 1216 cm^-1. ¹H NMR (DMSO-

d₆): δ ) 3.78 (s, 3H), 6.71-6.74 (m, 2H), 6.95-6.99 (m, 2H),

7.05-7.14 (m, 2H), 7.20-7.31 (m, 3H), 7.36-7.40 (m, 1H),

7.44-7.54 (m, 2H), 7.59-7.68 (m, 2H), 7.88-7.92 (m, 2H). EI-

MS (70 eV) m/z (%): 433 (43) [M^+•], 291 (100), 276 (34), 174

(55), 77 (63). Anal. (C₂₄H₁₉NO₅S): C, H, N.

Bis(1-p h en ylsu lfon yl-1H-2-in d olyl)m et h a n on e (1b ).²⁹

(1-P h en ylsu lfon yl-1H-2-in d olyl)(1-p h en ylsu lfon yl-1H-

3-in d olyl)m eth a n on e (10b). Yield: 0.58 g (58%). Mp: 181-

182 °C. IR (KBr): ν ) 3060, 1650, 1607, 1584, 1537, 1480, 1449

Bisben zo[b]th iop h en -2-yl-m eth a n ol (18a ). Yield: 3.69

g (89%) of needles. Mp: 130-131 °C. IR (KBr): ν ) 3475, 1630

Inhibitors of PDGF Receptor Kinase

cm^-1

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 5 1011

.

¹H NMR (DMSO-d₆): δ ).7.37-7.81 (m, 12H); 8.02-

3H), 3.84 (s, 3H), 7.10-7.14 (m, 1H), 7.19-7.22 (m, 2H), 7.29-

7.34 (m, 1H), 7.40-7.64 (m, 5H), 7.69-7.76 (m, 1H), 7.89-

7.96 (m, 3H). EI-MS (70 eV) m/z (%): 421 (72) [M^+•], 280 (100),

265 (20), 249 (31), 135 (20), 77 (49). Anal. (C₂₃H₁₉NO₅S): C,

H, N.

4-Meth oxyp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-

in d olyl)m eth a n on e (24b). Yield: 1.68 g (64%) of beige

crystals. Mp: 129-130 °C. IR (KBr): ν ) 3066, 2937, 1611

cm^-1. ¹H NMR (DMSO-d₆): δ ) 3.77 (s, 3H), 3.80 (s, 3H), 6.16

(s, 1H), 6.88-6.93 (m, 1H), 7.01-7.04 (m, 2H), 7.12-7.40 (m,

7H), 7.55-7.61 (m, 1H), 7.82-7.86 (m, 1H). EI-MS (70 eV) m/z

(%): 421 (72) [M^+•], 357 (22), 280 (100), 252 (32), 173 (42), 135

(56), 77 (57). Anal. (C₂₃H₁₉NO₅S): C, H, N.

2,4-Dim et h oxyp h en yl-(5-m et h oxy-1-p h en ylsu lfon yl-

1H-2-in d olyl)m eth a n on e (25b). Yield: 1.48 g (53%) of

colorless crystals. Mp: 62-64 °C. IR (KBr): ν ) 3046, 2943,

1653 cm^-1. ¹H NMR (DMSO-d₆): δ ) 3.64 (s, 3H), 3.75 (s, 3H),

3.88 (s, 3H), 6.64-6.69 (m, 2H), 6.92 (s, 1H), 7.02-7.07 (m,

1H), 7.13-7.14 (m, 1H), 7.57-7.74 (m, 4H), 7.85-7.95 (m, 3H).

EI-MS (70 eV) m/z (%): 451 (100) [M^+•], 311 (74), 295 (40),

279 (76), 264 (34), 173 (97), 165 (72), 160 (62), 77 (72). Anal.

(C₂₄H₂₁NO₆S): C, H, N.

8.30 (m, 7H), 8.57 (s, 1H). PI-FDMS (CH₂Cl₂); m/z (%): 540

(100) [M^+•]. Anal. (C₂₉H₂₀N₂O₅S₂): C, H, N.

5-Meth oxy-1-p h en ylsu lfon yl-1H-2-in d olyl(1-p h en ylsu l-

fon yl-1H-2-in d olyl)m eth a n on e (11b). Yield: 2.23 g (63%).

Mp: 204-205 °C. IR (KBr): ν ) 3064, 2838, 1652 cm^-^{1 1}H

.

NMR (DMSO-d₆): δ ) 3.80 (s, 3H), 7.19-7.26 (m, 2H), 7.37-

7.43 (m, 1H), 7.51-7.80 (m, 10H), 8.01-8.20 (m, 6H). EI-MS

(70 eV) m/z (%): 570 (39) [M^+•], 429 (40), 365 (15), 288 (100),

245 (37), 77 (83). Anal. (C₃₀H₂₂N₂O₆S₂): C, H, N.

6-Met h oxy-1-p h en ylsu lfon yl-1H -2-in d olyl)(1-p h en yl-

su lfon yl-1H-2-in dolyl)m eth an on e (12b). Yield: 1.49 g (42%)

of light red crystals. Mp: 184-186 °C. IR (KBr): ν ) 3078,

2838, 1613 cm^-1. ¹H NMR (DMSO-d₆): δ ) 3.93 (s, 3H), 7.04-

7.08 (m, 1H), 7.40-7.43 (m, 1H), 7.52-7.83 (m, 12H), 8.05-

8.09 (m, 4H), 8.14-8.18 (m, 1H). EI-MS (70 eV) m/z (%): 570

(42) [M^+•], 430 (39), 290 (35), 288 (94), 273 (37), 245 (22), 77

(100). Anal. (C₃₀H₂₂N₂O₆S₂): C, H, N.

(7-Meth oxy-1-p h en ylsu lfon yl-1H-2-in d olyl)(1-p h en yl-

su lfon yl-1H-2-in dolyl)m eth an on e (13b). Yield: 1.98 g (56%).

Mp: 129-130 °C. IR (KBr): ν ) 3068, 2972, 1663 cm^-^{1 1}H

.

NMR (CDCl₃): δ ) 3.72 (s, 3H), 6.87-6.90 (m, 1H), 7.18-7.33

(m, 4H), 7.35-7.36 (m, 1H), 7.45-7.66 (m, 8H), 8.14-8.18 (m,

1H), 8.28-8.32 (m, 2H), 8.51-8.55 (m, 2H). EI-MS (70 eV) m/z

(%): 570 (19) [M^+•], 430 (37), 289 (100), 144 (20), 77 (58). Anal.

(C₃₀H₂₂N₂O₆S₂): C, H, N.

(5-Ben zyloxy-1-p h en ylsu lfon yl-1H-2-in d olyl)(1-p h en yl-

su lfon yl-1H-2-in dolyl)m eth an on e (40b). Yield: 4.50 g (45%).

Mp: 111-113 °C. IR (KBr): ν ) 3067, 2956, 1655, 1607 cm^-1

.

¹H NMR (DMSO-d₆): δ ) 5.15 (s, 2H), 7.22-8.19 (m, 24 H).

PI-FDMS (CH₂Cl₂); m/z (%): 646 (100) [M^+•]. Anal.

(C₃₆H₂₆N₂O₆S₂): C, H, N.

Bis(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-in d olyl)m eth a -

n on e (14b). Yield: 2.05 g (55%). Mp: 190-191 °C. IR (KBr):

P r ep a r a tion a lso Accor d in g to P r oced u r e F (Sch em e

1, Rou te II).

1

ν ) 3008, 2941, 1657 cm^-1. H NMR (DMSO-d₆): δ ) 3.80 (s,

6H), 7.18-7.26 (m, 4H), 7.44 (s, 2H), 7.68-7.75 (m, 6H), 8.02-

8.08 (m, 6H). EI-MS (70 eV) m/z (%): 600 (20) [M^+•], 536 (6),

460 (55), 395 (13), 319 (100), 147 (36), 77 (77). Anal.

(C₃₁H₂₄N₂O₇S₂): C, H, N.

P r oced u r e C (Sch em e 1, Rou te I): Rem ova l of th e

P h en ylsu lfon yl P r otection Gr ou p To F or m th e (1H-2-

In d olyl)m eth a n on es 1, 10-17, 20-27, 29, 30, a n d 40.

Meth od 1. Some of the N-protected methanone derivatives

prepared by procedure B (21b, 26b) (1.8 mmol) were heated

in ethanol (40 mL) and 10% aq NaOH (20 mL) under reflux

for 12 h. After cooling, the solution was poured into brine (100

mL) and extracted with ethyl acetate (3 × 50 mL). The

combined organic layers were dried (Na₂SO₄) and evaporated

under reduced pressure to leave the crude product, which was

subjected to column chromatography (SiO₂; CH₂Cl₂). The

treatment of 17a with NaOH in refluxing ethanol as described

above resulted in the formation of 17. Thus, Method 1 was

used for the preparation of compounds 17, 21, and 26.

Meth od 2. A mixture of the respective N-protected metha-

none derivative prepared by procedure B (1.8 mmol) and TBAF

(tetrabutylammonium fluoride trihydrate) (0.79 g, 2.5 mmol)

in THF/MeOH 1:1 (20 mL) was gently refluxed. When TLC

indicated that the reaction was completed (30 min to 4 h), part

of the solvent was removed to allow precipitation of the yellow

product. Compounds 1, 10-16, 20, 22-25, 27, 29, 30, and 40

were prepared according to method 2.

(5-Meth yl-1-p h en ylsu lfon yl-1H-2-in d olyl)(1-p h en ylsu l-

fon yl-1H-2-in d olyl)m eth a n on e (15b). Yield: 1.79 g (52%).

Mp: 189-191 °C. IR (KBr): ν ) 3064, 1663, 1605 cm^-^{1 1}H

.

NMR (DMSO-d₆): δ ) 2.40 (s, 3H), 7.33-7.48 (m, 2H), 7.51-

7.75 (m, 11H), 8.02-8.21 (m, 6H). PI-FDMS (dichloromethane)

m/z (%): 554 (100) [M^+•], 555 (31), 556 (13). Anal. (C₃₀H₂₂N₂O₅S₂·

0.25 ethyl acetate): C, H, N.

(Ben zo[b]th iop h en -2-yl)(5-m eth oxy-1-p h en ylsu lfon yl-

1H-2-in d olyl)m eth a n on e (16b). Yield: 1.83 g (66%) of beige

crystals. Mp: 82-83 °C. IR (KBr): ν ) 3066, 2937, 1640 cm^-1

.

¹H NMR (DMSO-d₆): δ ) 3.79 (s, 3H), 7.12-7.17 (m, 1H),

7.22-7.23 (m, 1H), 7.46-7.47 (m, 1H), 7.51-7.55 (m, 1H),

7.57-7.65 (m, 3H), 7.70-7.75 (m, 1H), 7.93-7.99 (m, 3H),

8.09-8.16 (m, 2H), 8.25 (s, 1H). EI-MS (70 eV) m/z (%): 447

(63) [M^+•], 306 (100), 291 (14), 263 (33), 235 (39), 173 (39), 77

(31). Anal. (C₂₄H₁₇NO₄S₂): C, H, N.

Bisben zo[b]th iop h en -2-ylm eth a n on e (18). Yield: 1.39

g (76%). Mp: 161 °C. IR (KBr): ν ) 3054, 1617 cm^-1. ¹H NMR

(DMSO-d₆): δ ) 7.51-7.64 (m, 4H), 8.12-8.16 (m, 4H), 8.62

(s, 2H). EI-MS (70 eV) m/z (%): 294 (100) [M^+•], 266 (9), 161

(52), 133 (21), 89 (21). Anal. (C₁₇H₁₀OS₂): C, H.

Bis(1H-2-in d olyl)m eth a n on e (1).²⁹

1H-2-in d olyl(1H-3-in d olyl)m eth a n on e (10).^32,33

(5-Meth oxy-1H-2-in d olyl)(1H-2-in d olyl)m eth a n on e (11)

was prepared according to method 2. Yield: 0.48 g (91%). Mp:

219-222 °C. IR (KBr): ν ) 3398, 2839, 1615 cm^-1.¹H NMR

(DMSO-d₆): δ ) 3.80 (s, 3H), 6.96-7.00 (m, 1H), 7.09-7.15

(m, 1H), 7.19-7.20 (m, 1H), 7.28-7.34 (m, 1H), 7.40-7.43 (m,

1H), 7.50-7.57 (m, 3H), 7.75-7.78 (m, 1H), 11.85 (s, 1H), 11.96

(s, 1H). EI-MS (70 eV) m/z (%): 290 (95) [M^+•], 173 (100), 158

(26), 147 (42), 117 (20). Anal. (C₁₈H₁₄N₂O₂): C, H, N.

(6-Meth oxy-1H-2-in dolyl)(1H-2-in dolyl)m eth a n on e (12)

was prepared according to method 2. Yield: 0.43 g (82%). Mp:

(5-Meth oxy-1-ph en ylsu lfon yl-1H-2-in dolyl)ph en ylm eth -

a n on e (20b). Yield: 1.48 g (61%) of colorless needles. Mp: 148

°C. IR (KBr): ν ) 3064, 2964, 1663 cm^-^{1 1}H NMR (DMSO-

.

d₆): δ ) 3.77 (s, 3H), 7.09-7.14 (m, 1H), 7.19-7.21 (m, 3H),

7.57-7.65 (m, 4H), 7.68-7.77 (m, 2H), 7.88-7.92 (m, 4H). EI-

MS (70 eV) m/z (%): 391 (82) [M^+•], 250 (100), 207 (20), 179

(25), 105 (32), 77 (51). Anal. (C₂₂H₁₇NO₄S): C, H, N.

2-Met h oxyp h en yl(5-m et h oxy-1-p h en ylsu lfon yl-1H -2-

in d olyl)-1-m eth a n on e (22b). Yield:

1

266-267 °C. IR (KBr): ν ) 3398, 1615, 1545 cm^-1. H NMR

1.54 g (59%) of colorless needles. Mp: 179 °C. IR (KBr): ν

) 3067, 2985, 1648 cm^-^{1 1}H NMR (DMSO-d₆): δ ) 3.67 (s,

.

(DMSO-d₆): δ ) 3.82 (s, 3H), 6.76-6.80 (m, 1H), 6.92-6.93

(m, 1H), 7.08-7.14 (m, 1H), 7.26-7.32 (m, 1H), 7.49-7.57 (m,

3H), 7.62-7.65 (m, 1H), 7.73-7.76 (m, 1H), 11.81 (s, 1H), 11.91

(s, 1H). EI-MS (70 eV) m/z (%): 290 (100) [M^+•], 173 (40), 147

(38), 117 (22), 89 (14). Anal. (C₁₈H₁₄N₂O₂): C, H, N.

3H), 3.75 (s, 3H), 7.01 (s, 1H), 7.06-7.21 (m, 4H), 7.55-7.74

(m, 5H), 7.90-7.96 (m, 3H). EI-MS (70 eV) m/z (%): 421 (100)

[M^+•], 280 (58), 265 (49), 249 (90), 160 (78), 135 (56), 77 (86).

Anal. (C₂₃H₁₉NO₅S): C, H, N.

3-Meth oxyp h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-2-

in d olyl)m eth a n on e (23b). Yield:

(7-Meth oxy-1H-2-in dolyl)(1H-2-in dolyl)m eth a n on e (13)

was prepared according to method 2. Yield: 0.48 (g 91%). Mp:

277 °C. IR (KBr): ν ) 3384, 3072, 1592 cm^-1. ¹H NMR (DMSO-

d₆): δ ) 3.94 (s, 3H), 6.83-6.86 (m, 1H), 7.02-7.15 (m, 2H),

1.75 g (67%) of colorless needles. Mp: 181 °C. IR (KBr): ν

) 3083, 2958, 1663 cm^-^{1 1}H NMR (DMSO-d₆): δ ) 3.77 (s,

.

1012 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 5

Mahboobi et al.

7.28-7.34 (m, 2H), 7.49-7.53 (m, 3H), 7.74-7.77 (m, 1H),

11.79 (s, 1H), 11.94 (s, 1H). EI-MS (70 eV) m/z (%): 290 (100)

[M^+•], 173 (48), 144 (49), 130 (16), 117 (24), 89 (23). Anal.

(C₁₈H₁₄N₂O₂): C, H, N.

Bis(5-m eth oxy-1H-2-in d olyl)m eth a n on e (14) was pre-

pared according to method 2. Yield: 0.47 g (81%). Mp: 202-

204 °C. IR (KBr): ν ) 3305, 2923, 1630 cm^-1. ¹H NMR (DMSO-

d₆): δ ) 3.80 (s, 6H), 6.95-7.00 (m, 2H), 7.19-7.20 (m, 2H),

7.39-7.47 (m, 4H), 11.83 (s, 2H). EI-MS (70 eV) m/z (%): 320

(84) [M^+•], 173 (62), 147 (100), 132 (27), 104 (6). Anal.

(C₁₉H₁₆N₂O₃): C, H, N.

1H), 7.92-7.98 (m, 2H), 11.78 (s, 1H). EI-MS (70 eV) m/z (%):

281 (100) [M^+•], 173 (54), 158 (42), 135 (23), 77 (13). Anal.

(C₁₇H₁₅NO₃): C, H, N.

2,4-Dim eth oxyp h en yl-(5-m eth oxy-1H-2-in d olyl)m eth a -

n on e (25) was prepared according to method 2. Yield: 0.45 g

(81%). Mp: 160-161 °C. IR (KBr): ν ) 3286, 2960, 1623 cm^-1

.

¹H NMR (DMSO-d₆): δ ) 3.74 (s, 3H), 3.75 (s, 3H), 3.86 (s,

3H), 6.61-6.66 (m, 1H), 6.71 (s, 2H), 6.92-6.96 (m, 1H), 7.08-

7.09 (m, 1H), 7.34-7.42 (m, 2H), 11.69 (br. s, 1H). EI-MS (70

eV) m/z (%): 311 (86) [M^+•], 280 (6), 173 (100), 165 (18). Anal.

(C₁₈H₁₇NO₄): C, H, N.

(1H-2-In d olyl)(5-m eth yl-1H-2-in d olyl)m eth a n on e (15)

was prepared according to method 2. Yield: 0.28 g (57%). Mp:

3,4-Dich lor op h en yl-(5-m et h oxy-1H -2-in d olyl)m et h a -

n on e (26) was prepared according to method 1. Yield: 0.53 g

1

184-186 °C. IR (KBr): ν ) 3450, 3297, 1618 cm^-1. H NMR

1

(64%). Mp: 190-192 °C. IR (KBr): ν ) 3316, 1620 cm^-1. H

(DMSO-d₆): δ ) 2.39 (s, 3H), 7.06-7.20 (m, 2H), 7.26-7.62

(m, 6H), 7.71-7.82 (m, 1H), 11.83 (s, 1H), 11.97 (s, 1H). EI-

MS (70 eV) m/z (%): 274 (100) [M^+•], 158 (48), 144 (29), 131

(71), 117 (38). Anal. (C₁₈H₁₄N₂O): C, H, N.

NMR (DMSO-d₆): δ ) 3.80 (s, 3H), 6.93-7.18 (m, 4H), 7.80-

7.92 (m, 2H), 8.03-8.12 (m, 1H), 11.95 (s, 1H). EI-MS (70 eV)

m/z (%): 319 (100) [M^+•], 304 (31), 241 (10), 173 (16), 130 (15).

Anal. (C₁₆H₁₁Cl₂NO₂·0.4 dichloromethane): C, H, N.

(Ben zo[b]t h iop h en -2-yl)(5-m et h oxy-1H -2-in d olyl)-1-

m eth a n on e (16) was prepared according to method 2. Yield:

0.51 g (92%). Mp: 200 °C. IR (KBr): ν ) 3298, 3052, 1592

(5-Meth oxy-1H-2-in dolyl)-2-n itr oph en ylm eth an on e (27)

was prepared according to method 2. Yield: 0.21 g (40%). Mp:

1

185-187 °C. IR (KBr): ν ) 3299, 3072, 1609 cm^-1. H NMR

cm^-^{1 1}H NMR (DMSO-d₆): δ ) 3.80 (s, 3H), 6.99-7.04 (m,

.

(DMSO-d₆): δ ) 3.73 (s, 3H), 6.69 (s, 1H), 7.01 (dd, J ) 2.4,

9.0 Hz, 1H), 7.07-7.08 (m, 1H), 7.40 (d, J ) 9.0 Hz, 1H), 7.79-

7.95 (m, 3H), 8.23-8.27 (m, 1H), 12.04 (br. s, 1H). EI-MS (70

eV) m/z (%): 296 (65) [M^+•], 162 (100), 134 (22), 119 (19), 104

(37), 76 (17). Anal. (C₁₆H₁₂N₂O₄): C, H, N.

1H), 7.19-7.20 (m, 1H), 7.41-7.44 (m, 1H), 7.48-7.61 (m, 3H),

8.10-8.14 (m, 2H), 8.54 (s, 1H), 11.93 (s, 1H). EI-MS (70 eV)

m/z (%): 307 (100) [M^+•], 173 (82), 158 (51), 130 (33). Anal.

(C₁₈H₁₃NO₂S): C, H, N.

(Ben zo[b]fu r a n -2-yl)(5-m et h oxy-1H -2-in d olyl)m et h a -

n on e (17) was prepared according to method 1, the title

compound was synthesized by treating 17a with NaOH in

refluxing ethanol, resulting in oxidation and loss of the

phenylsulfonyl protection group: Yield: 0.09 g (18%). Mp:

231-233 °C. IR (KBr): ν ) 2836, 1098 cm^-1. ¹H NMR (DMSO-

d₆): δ ) 3.80 (s, 3H), 7.03-7.04 (m, 1H), 7.22-7.23 (m, 1H),

7.38-7.44 (m, 2H), 7.56-7.63 (m, 1H), 7.74-7.75 (m, 1H),

7.81-7.90 (m, 2H), 8.00-8.01 (m, 1H), 11.96 (s, 1H). EI-MS

(70 eV) m/z (%): 291 (100) [M^+•], 276 (9), 173 (41), 158 (37),

130 (31). Anal. (C₁₈H₁₃NO₃): C, H, N.

1-Na p h th yl-(5-m eth oxy-1H-2-in d olyl)m eth a n on e (29)

was prepared according to method 2. Yield: 0.58 g (59%). Mp:

1

174-175 °C. IR (KBr): ν ) 3301, 3050, 1611 cm^-1. H NMR

(DMSO-d₆): δ ) 3.72 (s, 3H), 6.76 (s, 1H), 6.98-7.12 (m, 2H),

7.40-7.47 (m, 1H), 7.53-7.70 (m, 3H), 7.82-7.89 (m, 1H),

8.03-8.20 (m, 3H), 12.02 (s, 1H). EI-MS (70 eV) m/z (%): 301

(100) [M^+•], 300 (47), 286 (12), 284 (13), 158 (11), 127 (26). Anal.

(C₂₀H₁₅NO₂): C, H, N.

(5-Meth oxy-1H-2-in dolyl)(2-pyr idyl)m eth an on e (30) was

prepared according to method 2. Yield: 0.30 g (65%). Mp: 201

°C. IR (KBr): ν ) 3328, 3067, 1649 cm^-^{1 1}H NMR (DMSO-

.

(5-Meth oxy-1H-2-in d olyl)p h en ylm eth a n on e (20) was

prepared according to method 2. Yield: 0.41 g (90%) of needles.

d₆): δ ) 3.73 (s, 3H), 7.98-8.04 (m, 1H), 8.12-8.22 (m, 2H),

8.31-8.39 (m, 2H), 8.53-8.60 (m, 1H), 8.69-8.71 (m, 1H),

8.83-8.85 (m, 1H), 11.84 (s, 1H). EI-MS (70 eV) m/z (%): 252

(100) [M^+•], 237 (18), 173 (88), 158 (49), 77 (13). Anal.

(C₁₅H₁₂N₂O₂): C, H, N.

1

Mp: 162 °C. IR (KBr): ν ) 3311, 3008, 1625 cm^-1. H NMR

(DMSO-d₆): δ ) 3.77 (s, 3H), 6.96-7.03 (m, 2H), 7.15-7.16

(m, 1H), 7.39-7.43 (m, 1H), 7.56-7.62 (m, 2H), 7.65-7.72 (m,

1H), 7.90-7.95 (m, 2H), 11.86 (br. s, 1H). EI-MS (70 eV) m/z

(%): 251 (100) [M^+•], 236 (28), 158 (10), 130 (10), 105 (13), 77

(19). Anal. (C₁₆H₁₃NO₂): C, H, N.

(5-Ben zyloxy-1H -2-in d olyl)(1H -2-in d olyl)m et h a n on e

(40) was prepared according to method 2. Yield: 1.51 g (53%).

Mp: 199-201 °C. IR (KBr): ν ) 3458, 3313, 1618, 1582 cm^-1

.

(1H-2-In d olyl)p h en ylm eth a n on e (21) was prepared ac-

cording to method 1. Yield: 0.45 g (73%). Mp: 145-147 °C.

¹H NMR (DMSO-d₆): δ ) 5.14 (s, 2H), 7.04-7.77 (m, 14 H),

11.86 (s, 1H), 11.95 (s, 1H). EI-MS (70 eV) m/z (%): 366 (100)

[M^+•], 275 (83), 158 (47), 144 (9), 130 (18), 91 (75). Anal.

(C₂₄H₁₈N₂O₂): C, H, N.

1

IR (KBr): ν ) 3314, 3081, 1669 cm^-1. H NMR (DMSO-d₆): δ

) 7.08-7.16 (m, 2H), 7.29-7.37 (m, 1H), 7.48-7.75 (m, 5H),

7.91-7.97 (m, 2H), 11.90 (s, 1H). EI-MS (70 eV) m/z (%): 221

(100) [M^+•], 204 (13), 144 (36), 89 (28), 77 (30). Anal. (C₁₅H₁₁

NO): C, H, N.

-

P r ep a r a t ion of 2-Am in op h en yl(5-m et h oxy-1H -2-in -

d olyl)m eth a n on e (28). The title compound was obtained by

reduction of 27 (1.48 g, 5.00 mmol) in 10 mL of dry methanol.⁵¹

Yield: 1.10 g (83%) of needles. Mp: 144-145 °C. IR (KBr): ν

2-Me t h oxyp h e n yl-(5-m e t h oxy-1H -2-in d olyl)m e t h a -

n on e (22) was prepared according to method 2. Yield: 0.44 g

) 3486, 3311, 1615 cm^-^{1 1}H NMR (DMSO-d₆): δ ) 3.76 (s,

.

1

(87%). Mp: 127 °C. IR (KBr): ν ) 3303, 3070, 1620 cm^-1. H

3H), 6.60-6.67 (m, 3H), 6.83-6.96 (m, 3H), 7.15 (m, 1H), 7.26-

7.41 (m, 2H), 7.82-7.86 (m, 1H), 11.69 (br. s, 1H). EI-MS (70

eV) m/z (%): 266 (100) [M^+•], 238 (49), 223 (26), 195 (14), 120

(17), 92 (21), 84 (32). Anal. (C₁₆H₁₄N₂O₂): C, H, N.

NMR (DMSO-d₆): δ ) 3.73 (s, 3H), 3.75 (s, 3H), 6.67 (s, 1H),

6.93-6.98 (m, 1H), 7.04-7.10 (m, 2H), 7.17-7.21 (m, 1H),

7.35-7.41 (m, 2H), 7.50-7.57 (m, 1H), 11.77 (s, 1H). EI-MS

(70 eV) m/z (%): 281 (100) [M^+•], 263 (14), 250 (11), 220 (14),

173 (27), 161 (29), 135 (18), 77 (19). Anal. (C₁₇H₁₅NO₃): C, H,

N.

P r oced u r e D (Sch em e 1, Rou te II): P r ep a r a tion of

1-P h en ylsu lfon yl-1H-2-in d oleca r boxylic Acid s (5). The

appropriate 1-phenylsulfonylindole was lithiated at -78 °C for

1 h, as described above in procedure A. An excess of solid and

dry carbon dioxide was added. The mixture was warmed to

room temperature overnight and the solvent removed under

reduced pressure. To the white solid obtained, were added CH₂-

Cl₂(about 3.0 mL per mmol) and hydrochloric acid (6 N, 1.0

mL/mmol), and the mixture was refluxed for 1 h. The organic

layer was washed with hydrochloric acid (2 N; 1.0 mL/mmol)

and dried (Na₂SO₄). Removing the solvent under reduced

pressure left an oily residue that was crystallized from diethyl

ether. Thus, (1-phenylsulfonyl-1H-2-indolyl)carboxylic acid⁵²

and 5-benzyloxy-1-phenylsulfonyl-1H-indole-2-carboxylic acid

were prepared:

3-Me t h oxyp h e n yl-(5-m e t h oxy-1H -2-in d olyl)m e t h a -

n on e (23) was prepared according to method 2. Yield: 0.43 g

(85%). Mp: 147-148 °C. IR (KBr): ν ) 3294, 3066, 1688 cm^-1

.

¹H NMR (DMSO-d₆): δ ) 3.77 (s, 3H), 3.86 (s, 3H), 6.96-7.01

(m, 1H), 7.05-7.06 (m, 1H), 7.16-7.17 (m, 1H), 7.22-7.27 (m,

1H), 7.38-7.42 (m, 2H), 7.47-7.51 (m, 2H), 11.85 (s, 1H). EI-

MS (70 eV) m/z (%): 281 (100) [M^+•], 266 (23), 250 (8), 158

(19), 130 (14). Anal. (C₁₇H₁₅NO₃): C, H, N.

4-Me t h oxyp h e n yl-(5-m e t h oxy-1H -2-in d olyl)m e t h a -

n on e (24) was prepared according to method 2. Yield: 0.44 g

1

(86%). Mp: 165 °C. IR (KBr): ν ) 3276, 3062, 1625 cm^-1. H

NMR (DMSO-d₆): δ ) 3.77 (s, 3H), 3.88 (s, 3H), 6.94-6.99

(m, 1H), 7.02-7.03 (m, 1H), 7.09-7.16 (m, 3H), 7.39-7.41 (m,

Inhibitors of PDGF Receptor Kinase

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 5 1013

1-P h en ylsu lfon yl-1H-2-in d oleca r boxylic Acid .⁵²

(5-Meth oxy-1-p h en ylsu lfon yl-1H-2-in d olyl)(1-n a p h th -

yl)m eth a n on e (29b) was prepared from 3 and naphthalene-

1-carbonic acid chloride. Yield: 1.06 g (48%) mp 225-228 °C.

5-Ben zyloxy-1-p h en ylsu lfon yl-1H -in d ole-2-ca r b oxyl-

ic Acid . Starting from 5-benzyloxy-1-phenylsulfonyl-1H-indole

(50.0 g, 137.6 mmol), the title compound was obtained as

colorless crystals (43.7 g, 77%). Mp: 175-178 °C. IR (KBr): ν

1

IR (KBr): ν ) 3071, 3008, 1652 cm^-1. H NMR (DMSO-d₆): δ

) 3.75 (s, 3H), 7.11-7.23 (m, 3H), 7.56-7.79 (m, 7H), 7.92-

7.99 (m, 3H), 8.07-8.12 (m, 1H), 8.20-8.27 (m, 1H), 8.60-

8.67 (m, 1H). EI-MS (70 eV) m/z (%): 441 (24) [M^+•], 300 (100),

285 (11), 257 (19), 228 (12). Anal. (C₂₆H₁₉NO₄S): C, H, N.

5-Meth oxy-1-p h en ylsu lfon yl-1H-2-in d olyl(2-p yr id in yl)-

m eth a n on e (30b) was prepared from 3 and 2-pyridinecar-

bonic acid chloride. Yield: 0.98 g (75%) of colorless crystals.

) 1700 cm^-^{1 1}H NMR (DMSO-d₆): δ ) 5.11 (s, 2H), 7.13-

.

7.74 (m, 11 H), 7.90-7.97 (m, 3H), 13.56 (br. s, 1H). EI-MS

(70 eV) m/z (%): 407 (2) [M^+•], 363 (19), 272 (16), 222 (6), 141

(20), 91 (100). Anal. (C₂₂H₁₇NO₅S): C, H, N.

P r oced u r e E (Sch em e 1, R ou t e II): P r ep a r a t ion of

1-P h en ylsu lfon yl-1H-2-in d oleca r boxylic Acid Ch lor id es

(6). The appropriate 1-phenylsulfonyl-1H-2-indolecarboxylic

acid (5.0 mmol) (cf., procedure D, Scheme 1, route II) was

dissolved in thionyl chloride (10.0 mL) and refluxed for 1 h.

Excess thionyl chloride was removed under reduced pressure,

and the acid chloride was dried in vacuo. An analytical sample

could be obtained by column chromatography (SiO₂/CH₂Cl₂)

and crystallization from CH₂Cl₂/hexane. Thus, 1-phenylsulfo-

nyl-1H-2-indolecarboxylic acid chloride and 5-benzyloxy-1-

phenylsulfonyl-1H-2-indolecarboxylic acid chloride were pre-

pared.

1-P h en ylsu lfon yl-1H-2-in d oleca r boxylic a cid ch lor id e:

Yield: quantitative, of colorless crystals. Mp: 122-123 °C. IR

(KBr): ν ) 1760 cm^-1. Anal. (C₁₅H₁₀ClNO₃S): C, H, N.

5-Ben zyloxy-1-p h en ylsu lfon yl-1H-2-in d oleca r b oxylic

Acid Ch lor id e. Yield: quantitative, of light yellowish crystals.

Mp: 130-131 °C. IR (KBr): ν ) 1750 cm^-1. ¹H NMR (CDCl₃):

δ ) 5.11 (s, 2H), 7.10-7.66 (m, 11H), 7.98-8.17 (m, 3H). Anal.

(C₂₂H₁₆ClNO₄S): C, H, N.

P r oced u r e F (Sch em e 1, Rou te II): P r ep a r a tion of (1-

P h en ylsu lfon yl-1H-2-in d olyl)m eth a n on es (1b, 10b-16b,

20b, 22b-25b, 40b ) a n d Ot h er (1-P h en ylsu lfon yl-1H-2-

in d olyl)a r oyl Der iva tives (21b, 26b, 27b, 29b, a n d 30b)

by Rea ction of (1-P h en ylsu lfon yl-1H-in d olyl)-2-lith iu m

3 w ith Ca r boxylic Acid Ch lor id es. At -78 °C a solution of

the respective (1-phenylsulfonyl-1H-indolyl)-2-lithium (3) (5.0

mmol) (cf. Procedure A) was added slowly to the appropriate

1-phenylsulfonyl-1H-indole-2-carboxylic acid chloride 6 (5.5

mmol) (cf. procedure E) or the appropriate benzoic acid chloride

(5.5 mmol) in dry THF (15.0 mL). The mixture was allowed to

warm to room temperature overnight, hydrolyzed with aque-

ous NaHCO₃(300 mL; 2%), and extracted with CH₂Cl₂(3 ×

50 mL), and the combined organic layers were dried (Na₂SO₄).

Column chromatography (SiO₂/CH₂Cl₂) and crystallization

from diethyl ether/light petrol (4:1) afforded the product as

colorless to faintly yellowish crystals. Thus, the title com-

pounds 21b, 26b, 27b, 29b, and 30b were prepared. (For the

preparation of compounds 1b, 10b-16b, 20b, 22b-25b, and

40b, we followed procedures A and B, Scheme 1, route I, as

described above.)

1

Mp: 207 °C. IR (KBr): ν ) 3002, 1671, 1615, cm^-1. H NMR

(DMSO-d₆): δ ) 3.75 (s, 3H), 7.04-7.09 (m, 1H), 7.16-7.17

(m, 1H), 7.27 (s, 1H), 7.53-7.59 (m, 2H), 7.63-7.72 (m, 2H),

7.79-7.85 (m, 3H), 8.05-8.16 (m, 2H), 8.70-8.73 (m, 1H).

EI-MS (70 eV) m/z (%): 492 (9) [M^+•], 251 (100), 208 (11), 179

(9), 77 (15). Anal. (C₂₁H₁₆N₂O₄S): C, H, N.

P r ep a r a tion of 1H-2-In d olyl(5-m eth oxy-1H-2-in d olyl)-

m eth a n e (19). Compound 11 (0.35 g, 1.21 mmol), 0.30 g of

KOH, and 0.15 mL of hydrazine hydrate were dissolved in 12

mL of diethylene glycol and heated to 195 °C within 2 h. After

cooling to room temperature, 10 mL of water was added and

the mixture was extracted with dichloromethane (2 × 10 mL).

The combined extracts were dried over Na₂SO₄, and the solvent

was removed in vacuo. Column chromatography (SiO₂/CH₂-

Cl₂) and crystallization from methanol afforded 0.28 g (84%)

of the product as colorless crystals. Mp: 112 °C. IR (KBr): ν

) 3400, 1620, 1595 cm^-^{1 1}H NMR (DMSO-d₆): δ ) 3.71 (s,

.

3H), 4.18 (s, 2H), 6.14 (d, J ) 1.2 Hz, 1H), 6.20 (d, J ) 1.2 Hz,

1H), 6.65 (dd, J 1 ) 2.5 Hz., J ²) 9.3 Hz, 1H), 6.89-7.40 (m,

3H), 7.17 (d, J ) 9.3 Hz, 1H), 7.29 (d, J ) 7.5 Hz, 1H), 7.42 (d,

J ) 7.5 Hz, 1H), 10.81 (s, 1H), 11.0 (s, 1H). MS (70 eV) m/z

(%): 276 (100) [M^+•], 232 (15), 160 (35), 130 (35), 117 (32). Anal.

(C₁₈H₁₆N₂O): C, H, N.

P r oced u r e G (Sch em e 2): P r ep a r a tion of th e Am id e

Der iva tives 31-38. The appropriate amine (6.2 mmol) was

added to a solution of the indole-2-carboxylic acid (6.2 mmol)

and EDCI·HCl (1.78 g, 9.3 mmol) in 7 mL of dry CH₂Cl₂. This

mixture was stirred for 30 min and poured into 2 N HCl (50

mL). The two-phase system was extracted with CH₂Cl₂(3 ×

50 mL), and the combined organic layers were washed with

NaHCO₃solution and water. After drying (Na₂SO₂), the

solvent was reduced to allow precipitation of the product,

which was washed with ice-cold CH₂Cl₂:

N-P h en yl-1H-2-in d oleca r boxa m id e (31). Yield: 1.22 g

(83%) of colorless crystals. Mp: 192-193 °C. IR (KBr): ν )

3425, 3344, 1646 cm^-^{1 1}H NMR (DMSO-d₆): δ ) 7.04-7.14

.

(m, 2H), 7.19-7.26 (m, 1H), 7.34-7.49 (m, 4H), 7.66-7.70 (m,

1H), 7.80-7.83 (m, 2H), 10.20 (s, 1H), 11.74 (s, 1H). EI-MS

(70 eV) m/z (%): 236 (70) [M^+•], 144 (100), 116 (14), 93 (36),

89 (43). Anal. (C₁₅H₁₂N₂O): C, H, N.

(1-P h en ylsu lfon yl-1H-2-in dolyl)ph en ylm eth an on e (21b):

From 3 and benzoic acid chloride. 1.17 g (65%). Mp: 142-143

N-P h en yl-5-m et h oxy-1H -2-in d oleca r b oxa m id e (32).

Yield: 1.44 g (87%) of green crystals. Mp: 197 °C. IR (KBr):

°C. IR (KBr): ν ) 3071, 1661, 1599 cm^-^{1 1}H NMR (DMSO-

.

1

ν ) 3384, 3289, 1656 cm^-1. H NMR (DMSO-d₆): δ ) 3.78 (s,

d₆): δ ) 7.29-7.41 (m, 2H), 7.49-7.80 (m, 8H), 7.91-8.09 (m,

5H). EI-MS (70 eV) m/z (%): 361 (68) [M^+•], 297 (37), 220 (100),

192 (30), 165 (34), 105(39), 77 (95). Anal. (C₂₁H₁₅NO₃S): C, H,

N.

3H), 6.86-6.90 (m, 1H), 7.07-7.14 (m, 2H), 7.33-7.40 (m, 4H),

7.79-7.82 (m, 2H), 10.14 (br. s, 1H), 11.58 (br. s, 1H). EI-MS

(70 eV) m/z (%): 266 (66) [M^+•], 173 (100), 146 (14), 119 (27).

Anal. (C₁₆H₁₄N₂O₂): C, H, N.

3,4-Dich lor op h en yl-(5-m eth oxy-1-p h en ylsu lfon yl-1H-

2-in d olyl)m eth a n on e (26b) was prepared from 3 and 3,4-

dichloro-benzoic acid chloride. 1.66 g (72%). Mp: 141-144 °C.

N-3-Tr iflu or om eth ylp h en yl-1H-2-in d oleca r boxa m id e

(33). Yield: 1.47 g (78%) of light yellow crystals. Mp: 160 °C

1

(dec). IR (KBr): ν ) 3375, 3325, 1681 cm^-1. H NMR (DMSO-

1

IR (KBr): ν ) 3091, 2929, 1663 cm^-1. H NMR (DMSO-d₆): δ

d₆): δ ) 7.06-7.12 (m, 1H), 7.21-7.28 (m, 1H), 7.44-7.50 (m,

3H), 7.59-7.72 (m, 2H), 8.10-8.13 (m, 1H), 8.25 (br. s, 1H),

10.50 (br. s, 1H), 11.79 (br. s, 1H). EI-MS (70 eV) m/z (%): 304

(39) [M^+•], 144 (100), 116 (15), 89 (42). Anal. (C₁₆H₁₁N₂OF₃):

C, H, N.

) 3.78 (s, 3H), 7.10-7.21 (m, 2H), 7.33 (s, 1H), 7.56-7.75 (m,

3H), 7.80-7.98 (m, 5H), 8.04 (d, J ) 1.8 Hz, 1H). EI-MS (70

eV) m/z (%): 459 (58) [M^+•], 395 (9), 318 (27), 283 (100), 268

(27), 173 (26). Anal. (C₂₂H₁₅Cl₂NO₄S): C, H, N.

(5-Met h oxy-1-p h en ylsu lfon yl-1-H -2-in d olyl)-2-n it r o-

p h en ylm eth a n on e (27b) was prepared from 3 and 2-ni-

trobenzoic acid chloride. Yield: 1.27 g (47%) of beige crystals.

N-3-Tr iflu or om et h ylp h en yl-5-m et h oxy-1H -2-in d ole-

ca r boxa m id e (34). Yield: 1.53 g (74%) of light green crystals.

1

Mp: 203 °C. IR (KBr): ν ) 3369, 3305, 1702 cm^-1. H NMR

Mp: 190-191 °C. IR (KBr): ν ) 3070, 1673, 1650 cm^-1

.

¹H

(DMSO-d₆): δ ) 3.79 (s, 3H), 6.88-6.92 (m, 1H), 7.15-7.16

(m, 1H), 7.35-7.39 (m, 2H), 7.43-7.47 (m, 1H), 7.59-7.65 (m,

1H), 8.09-8.13 (m, 1H), 8.24 (br. s, 1H), 10.45 (br. s, 1H), 11.64

(br. s, 1H). EI-MS (70 eV) m/z (%): 334 (71) [M^+•], 315 (5), 173

(100), 146 (16), 119 (25). Anal. (C₁₇H₁₃N₂O₂F₃): C, H, N.

NMR (DMSO-d₆): δ ) 3.77 (s, 3H), 7.19-7.24 (m, 3H), 7.64-

7.80 (m, 4H), 7.86-7.94 (m, 2H), 8.05-8.13 (m, 3H), 8.16-

8.23 (m, 1H). EI-MS (70 eV) m/z (%): 436 (24) [M^+•], 134 (100),

104 (57), 77 (41). Anal. (C₂₂H₁₆N₂O₆S): C, H, N.

1014 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 5

Mahboobi et al.

N-4-Tr iflu or om et h ylp h en yl-5-m et h oxy-1H -2-in d ole-

1H-2-In d olyl-[5-(3-d im eth yla m in op r op yloxy)-1H-2-in -

d olyl]m eth a n on e (43). Yield: 0.18 g (50%). Mp: 163-166 °C.

ca r boxa m id e (35). Yield: 1.60 g (77%) of light green crystals.

Mp: 262-264 °C. IR (KBr): ν ) 3379, 3365, 1702 cm^-1

.

¹H

IR (KBr): ν ) 3278, 2952, 1736 cm^-1. H NMR (DMSO-d₆): δ

1

NMR (DMSO-d₆): δ ) 3.78 (s, 3H), 6.87-6.92 (m, 1H), 7.15-

7.16 (m, 1H), 7.35-7.38 (m, 2H), 7.72-7.76 (m, 2H), 8.02-

8.06 (m, 2H), 10.47 (br. s, 1H), 11.66 (br. s, 1H). EI-MS (70

eV) m/z (%): 334 (77) [M^+•], 315 (5), 173 (100), 146 (17), 119

(27). Anal. (C₁₇H₁₃N₂O₂F₃): C, H, N.

) 2.00 (q, J ) 2.7 Hz, 2H), 2.36 (s, 6H), 2.65 (t, J ) 2.7 Hz,

2H), 4.03 (t, J ) 2.7 Hz, 2H), 6.96-7.77 (m, 9H), 11.84 (s, 1H),

11.96 (s, 1H). EI-MS (70 eV) m/z (%): 361 (8) [M^+•], 86 (22),

58 (100). Anal. (C₂₂H₂₃N₃O₂·2.25dichloromethane): C, H, N.

5-(4-Iod ob u t oxy-1H -2-in d olyl)(1H -2-in d olyl)m e t h a -

n on e (44). Yield: 0.22 g (47%). Mp: 110-113 °C. IR (KBr): ν

N-2-Naph th yl-5-m eth oxy-1H-2-in dolecar boxam ide (36).

Yield: 1.69 g (86%) of yellow crystals. Mp: 210-211 °C. IR

) 3455, 3291, 1661, 1618 cm^-^{1 1}H NMR (DMSO-d₆): δ )

.

1

(KBr): ν ) 3380, 3258, 1646 cm^-1. H NMR (DMSO-d₆): δ )

1.78-2.03 (m, 4H), 3.38 (t, J ) 2.7 Hz, 2H), 4.02 (t, J ) 2.5

Hz, 2H), 6.95-8.99 (m, 9H), 11.84 (s, 1H), 11.95 (s, 1H). EI-

MS (70 eV) m/z (%): 458 (20) [M^+•], 330 (26), 276 (18), 183

(100), 55 (97). Anal. (C₂₁H₁₉IN₂O₂): C, H, N.

1H-2-In dolyl-[5-(2-dim eth ylam in oeth oxy)-1H-2-in dolyl]-

m eth a n on e (45). Yield: 0.13 g (38%). Mp: 143-145 °C. IR

(KBr): ν ) 3235, 2950, 1605, 1593 cm^-1. ¹H NMR (DMSO-d₆):

δ ) 2.37 (s, 6H), 2.84 (t, J ) 2.2 Hz, 2H), 4.13 (t, J ) 2.3 Hz,

2H), 6.97-7.77 (m, 9H), 11.86 (s, 1H), 11.96 (s, 1H). EI-MS

(70 eV) m/z (%): 347 (9) [M^+•], 72 (14), 58 (100). Anal.

(C₂₁H₂₁N₃O₂·2.0dichloromethane): C, H, N.

3.79 (s, 3H), 6.87-6.91 (m, 1H), 7.15-7.16 (m, 1H), 7.36-7.39

(m, 1H), 7.43-7.44 (m, 1H), 7.54-7.66 (m, 4H), 7.87-7.90 (m,

1H), 7.96-8.04 (m, 2H), 10.38 (br. s, 1H), 11.61 (br. s, 1H).

EI-MS (70 eV) m/z (%): 316 (44) [M^+•], 174 (30), 143 (100),

119 (19). Anal. (C₂₀H₁₆N₂O₂): C, H, N.

N-4-(1,5-Dim eth yl-2-ph en yl-2,3-dih ydr o-1H-3-pyr azolyl)-

1H-2-in d oleca r boxa m id e (37). Yield: 1.59 g (74%) of light

yellow crystals. Mp: 283 °C. IR (KBr): ν ) 3419, 3309, 1696,

1648 cm^-1. ¹H NMR (DMSO-d₆): δ ) 2.20 (s, 3H), 3.11 (s, 3H),

7.02-7.09 (m, 1H), 7.17-7.24 (m, 1H), 7.31-7.56 (m, 7H),

7.64-7.66 (m, 1H), 9.58 (s, 1H), 11.65 (s, 1H). EI-MS (70 eV)

m/z (%): 346 (2) [M^+•], 286 (100), 143 (52), 115 (64), 88 (14).

Anal. (C₂₀H₁₈N₄O₂): C, H, N.

(5-Cycloh exylm eth oxy-1H-2-in dolyl)(1H-2-in dolyl)m eth -

a n on e (46). Yield: 0.19 g (52%). Mp: 185 °C (dec). IR (KBr):

ν ) 3457, 3293, 1676, 1620 cm^-^{1 1}H NMR (DMSO-d₆): δ )

.

1.00-1.35 (m, 5H), 1.66-1.99 (m, 6H), 3.80 (d, J ) 2.5 Hz,

2H), 6.95-7.78 (m, 9H), 11.82 (s, 1H), 11.95 (s, 1H). EI-MS

(70 eV) m/z (%): 372 (79) [M^+•], 276 (100), 159 (68), 117 (42).

Anal. (C₂₄H₂₄N₂O₂): C, H, N.

N-4-(1,5-Dim eth yl-2-ph en yl-2,3-dih ydr o-1H-3-pyr azolyl)-

5-m eth oxy-1H-2-i n d oleca r boxa m id e (38). Yield: 1.52 g

(69%) of colorless crystals. Mp: 259-260 °C. IR (KBr): ν )

3423, 3267, 1648 cm^-1. ¹H NMR (DMSO-d₆): δ ) 2.20 (s, 3H),

3.11 (s, 3H), 3.77 (s, 3H), 8.84-6.88 (m, 1H), 7.11-7.12 (m,

1H), 7.26 (m, 1H), 7.30-7.41 (m, 4H), 7.50-7.53 (m, 2H), 9.52

(s, 1H), 11.50 (s, 1H). EI-MS (70 eV) m/z (%): 376 (47) [M^+•],

203 (35), 174 (33), 119 (31), 84 (35), 56 (100). Anal.

(C₂₁H₂₀N₄O₃): C, H, N.

P r epar ation of (5-Hydr oxy-1H-2-in dolyl)(1H-2-in dolyl)-

m eth a n on e (39) (Sch em e 3). A mixture of 40 (4.00 g, 10.92

mmol), ammonium formate (12.00 g, 188.80 mmol), and Pd/C

(2.0 g) in methanol/THF (1/1 v/v) (200 mL) was stirred at 40

°C for 4 h. After removal of the catalyst, the solvent was

evaporated to leave an oily material. Ethyl acetate (200 mL)

and water (100 mL) were added. The organic layer was washed

with water and dried (Na₂SO₄), and the solvent was evapo-

rated. Treatment of the residue with a little diethyl ether

results in crystallization of 39, which was washed with ether:

Yield: 1.95 g (65%) of yellow crystals. Mp: 249-251 °C. IR

(KBr): ν ) 3457, 3320, 1707, 1618 cm^-1. ¹H NMR (DMSO-d₆):

δ ) 6.84-7.76 (m, 9H), 8.93 (s, 1H), 11.68 (s, 1H), 11.92 (s,

1H). EI-MS (70 eV) m/z (%): 276 (100) [M^+•], 159 (63), 144

(26), 133 (27), 117 (31), 105 (10). Anal. (C₁₇H₁₂N₂O₂·0.2ethyl

acetate): C, H, N.

5-(5-Iod op en t h oxy-1H -2-in d olyl)-1H -2-in d olylm et h a -

n on e (47). Yield: 0.19 g (41%). Mp: 127-130 °C. IR (KBr): ν

) 3422, 3287, 1721, 1618 cm^-^{1 1}H NMR (DMSO-d₆): δ )

.

1.52-1.67 (m, 2H), 1.72-1.99 (m, 4H), 3.39 (t, J ) 2.6 Hz, 2H),

4.04 (t, J ) 2.6 Hz, 2H), 6.95-7.78 (m, 9H), 11.83 (s, 1H), 11.95

(s, 1H). EI-MS (70 eV) m/z (%): 472 (100) [M^+•], 344 (30), 276

(47), 197 (44), 159 (93). Anal. (C₂₂H₂₁IN₂O₂): C, H, N.

1H-2-In d olyl-[5-(1-p h en yleth oxy)-1H-2-in d olyl]m eth a -

n on e (48). Yield: 0.20 g (52%). Mp: 151-153 °C. IR (KBr): ν

) 3457, 3299, 1713, 1620 cm^-1. ¹H NMR (DMSO-d₆): δ ) 1.57

(d, J ) 2.6 Hz, 3H), 5.48 (q, J ) 2.6 Hz, 1H), 6.89-7.75 (m,

14H), 11.79 (s, 1H), 11.91 (s, 1H). EI-MS (70 eV) m/z (%): 380

(19) [M^+•], 276 (100), 159 (38), 144 (17), 117 (22), 105 (88). Anal.

(C₂₅H₂₀N₂O₂): C, H, N.

1H-2-In d olyl-[5-(2-p ip er id in -1-yleth oxy)-1H-2-in d olyl]-

m eth a n on e (49). Yield: 0.14 g (36%). Mp: 104-106 °C. IR

1

(KBr): ν ) 3286, 1742, 1591 cm^-1. H NMR (DMSO-d₆): δ )

1.32-1.57 (m, 6H), 2.40-2.48 (m, 4H), 2.70 (t, J ) 5.9 Hz, 2H),

4.06 (t, J ) 5.9 Hz, 2H), 6.95-7.01 (m, 1H), 7.08-7.58 (m, 7H),

7.73-7.79 (m, 1H). EI-MS (70 eV) m/z (%): 387 (5) [M^+•], 276

(4), 98 (100). Anal. (C₂₄H₂₅N₃O₂·0.66ethyl acetate): C, H, N.

P r oced u r e I: P r ep a r a tion of th e Ester Der iva tives

50-76 (Sch em e 3). The appropriate acid chloride (3.0 mmol)

was added to a solution of 39 (0.28 g, 1.0 mmol) in ethyl acetate

(10 mL)/pyridine (2 mL) and stirred for 20 h. After pouring

the mixture into ice-water (100 mL) and extraction with ethyl

acetate, the organic layer was dried (Na₂SO₄). Removing the

solvent in vacuo left the crude product, which was crystallized

from ethyl acetate/dichloromethane, yielding the respective

compound as yellow crystals.

P r oced u r e H: P r ep a r a tion of th e Alk yl Der iva tives

41-49 (Sch em e 3). The respective alkyl halide (5.50 mmol)

was added together with K₂CO₃(0.70 g, 5.00 mmol) to a

solution of 39 (0.28 g, 1.00 mmol) in acetone (40 mL). The

mixture was heated at reflux for 70 h. After removal of the

acetone, the mixture was poured into ice-water (100 mL) and

extracted with ethyl acetate. The organic layer was dried (Na₂-

SO₄) and the solvent removed in vacuo. The crude product was

crystallized from ethyl acetate/dichloromethane to yield the

compounds as yellow crystals.

[2-(1H-2-in d olylca r bon yl)-1H-5-in d olyl]eth a n oa te (50).

Yield: 0.19 g (60%). Mp: 223-224 °C. IR (KBr): ν ) 3424,

3330, 1750 cm^-1. ¹H NMR (DMSO-d₆): δ ) 2.30 (s, 3H), 7.05-

7.78 (m, 9H), 11.99 (s, 1H), 12.07 (s, 1H). EI-MS (70 eV) m/z

(%): 318 (58) [M^+•], 276 (100), 159 (60), 144 (24), 133 (24), 117

(34). Anal. (C₁₉H₁₄N₂O₃·0.25ethyl acetate): C, H, N.

[2-(1H-2-In dolylcar bon yl)-1H-5-in dolyl]-4-m eth oxyben z-

oa te (51). Yield: 0.24 g (58%). Mp: 262-264 °C. IR (KBr): ν

) 3411, 3334, 1717, 1603 cm^-1. ¹H NMR (DMSO-d₆): δ ) 3.90

(s, 3H), 7.10-8.15 (m, 13H), 12.00 (s, 1H), 12.11 (s, 1H). EI-

MS (70 eV) m/z (%): 410 (11) [M^+•], 135 (100). Anal. (C₂₅H₁₈N₂O₄·

0.5ethyl acetate): C, H, N.

(5-Eth oxy-1H-2-in d olyl)(1H-2-in d olyl)m eth a n on e (41).

Yield: 0.13 g (44%). Mp: 168-169 °C. IR (KBr): ν ) 3451,

1

3291, 1655, 1618 cm^-1. H NMR (DMSO-d₆): δ ) 1.36 (t, J )

2.8 Hz, 3H), 1.36 (q, J ) 2.8 Hz, 2H), 6.94-7.78 (m, 9H), 11.82

(s, 1H), 11.95 (s, 1H). EI-MS (70 eV) m/z (%): 304 (100) [M^+•],

275 (19), 187 (49), 158 (38), 144 (15), 130 (28). Anal.

(C₁₉H₁₆N₂O₂): C, H, N.

1H-2-In dolyl-[5-(2-(m or ph olin -1-yl)eth oxy)-1H-2-in dolyl]-

m eth a n on e (42). Yield: 0.16 g (40%). Mp: 98-101 °C. IR

1

(KBr): ν ) 3289, 3062, 1599 cm^-1. H NMR (DMSO-d₆): δ )

2.45-2.58 (m, 4H), 2.72 (t, J ) 5.8 Hz, 2H), 3.56-3.63 (m, 4H),

4.12 (t, J ) 5.8 Hz, 2H), 6.95-7.01 (m, 1H), 7.08-7.22 (m, 2H),

7.27-7.58 (m, 5H), 7.73-7.78 (m, 1H), 11.83 (s, 1H), 11.98 (s,

1H). EI-MS (70 eV) m/z (%): 389 (9) [M^+•], 114 (14), 100 (100).

Anal. (C₂₃H₂₃N₃O₃·0.33ethyl acetate): C, H, N.

[2-(1H-2-In d olylca r bon yl)-1H-5-in d olyl]bu ta n oa te (52).

Yield: 0.22 g (64%). Mp: 201-204 °C. IR (KBr): ν ) 3422,

1

3334, 1746, 1620 cm^-1. H NMR (DMSO-d₆): δ ) 1.00 (t, J )

2.9 Hz, 3H), 1.67 (sext., J ) 2.9 Hz, 2H), 2.58 (t, J ) 2.9 Hz,

Inhibitors of PDGF Receptor Kinase

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 5 1015

2H), 7.04-7.84 (m, 9H), 12.00 (s, 1H), 12.07 (s, 1H). EI-MS

(70 eV) m/z (%): 346 (25) [M^+•], 276 (100), 159 (44), 144 (20),

117 (28). Anal. (C₂₁H₁₈N₂O₃·0.15ethyl acetate): C, H, N.

[2-(1H-2-In d olylca r bon yl)-1H-5-in d olyl]d im eth yla m i-

n oeth a n oa te (53). Yield: 0.15 g (41%). Mp: 215-217 °C. IR

m/z (%): 414 (17) [M^+•], 276 (4), 158 (9), 141 (33), 139 (100),

111 (13). Anal. (C₂₄H₁₅ClN₂O₃·0.25ethyl acetate): C, H, N.

[2-(1H -2-In d olylca r b on yl)-1H -5-in d olyl]-4-n it r ob en z-

oa te (63). Yield: 0.18 g (43%). Mp: 274-276 °C. IR (KBr): ν

) 3429, 3338, 1737, 1618 cm^-^{1 1}H NMR (DMSO-d₆): δ )

.

1

(KBr): ν ) 3374, 1761, 1620, cm^-1. H NMR (DMSO-d₆): δ )

7.10-7.15 (m, 1H), 7.26-7.35 (m, 2H), 7.50-7.78 (m, 6H),

8.38-8.46 (m, 4H), 12.01 (s, 1H), 12.16 (s, 1H). EI-MS (70 eV)

m/z (%): 425 (32) [M^+•], 276 (100), 159 (68), 150 (52), 133 (31),

117 (46). Anal. (C₂₄H₁₅N₃O₅·0.25ethyl acetate): C, H, N.

[2-(1H-2-Indolylcarbonyl)-1H-5-indolyl]-3,4,5-trimethoxy-

ben zoa te (64). Yield: 0.24 g (51%). Mp: 216-219 °C. IR

2.36 (s, 6H), 3.49 (s, 2H), 7.06-7.78 (m, 9H), 12.00 (s, 1H),

12.09 (s, 1H). EI-MS (70 eV) m/z (%): 361 (1) [M^+•], 333 (4),

276 (5), 58 (100). Anal. (C₂₁H₁₉N₃O₃·0.25ethyl acetate): C, H,

N.

[2-(1H -2-In d olylca r b on yl)-1H -5-in d olyl]p r op a n oa t e

(54): 0.21 g (62%). Mp: 236-238 °C. IR (KBr): ν ) 3426, 3330,

1

(KBr): ν ) 3467, 3292, 1732 cm^-1. H NMR (DMSO-d₆): δ )

1748, 1620 cm^-1

.

¹H NMR (DMSO-d₆): δ ) 1.16 (t, J ) 3.0

3.79 (s, 3H), 3.90 (s, 6H), 7.10-7.35 (m, 3H), 7.45-7.64 (m,

6H), 7.76-7.78 (m, 1H), 12.01 (s, 1H), 12.13 (s, 1H). EI-MS

(70 eV) m/z (%): 470 (9) [M^+•], 276 (21), 195 (100), 159 (14),

133 (6), 117 (10). Anal. (C₂₇H₂₂N₂O₆·0.33ethyl acetate):

C, H, N.

Hz, 3H), 2.62 (q, J ) 3.0 Hz, 2H), 7.04-7.78 (m, 9H), 11.99 (s,

1H), 12.07 (s, 1H). EI-MS (70 eV) m/z (%): 332 (35) [M^+•], 276

(100), 159 (51), 144 (20), 117 (26). Anal. (C₂₀H₁₆N₂O₃·

0.25dichloromethane): C, H, N.

[2-(1H-2-In d olylca r bon yl)-1H-5-in d olyl]-2-th iop h en yl-

eth a n oa te (55). Yield: 0.19 g (48%). Mp: 224-226 °C. IR

(KBr): ν ) 3432, 3320, 1757, 1620 cm^-1. ¹H NMR (DMSO-d₆):

δ ) 4.26 (s, 2H), 7.02-7.78 (m, 12H), 12.00 (s, 1H), 12.10 (s,

1H). EI-MS (70 eV) m/z (%): 400 (22) [M^+•], 276 (100), 159

(50), 97 (91). Anal. (C₂₃H₁₆N₂O₃S·0.25ethyl acetate): C, H, N.

[2-(1H -2-In d olylca r b on yl)-1H -5-in d olyl]-O-a cet ylsa li-

cyla te (56). Yield: 0.24 g (55%). Mp: 133-135 °C. IR (KBr):

[2-(1H-2-In dolylcar bon yl)-1H-5-in dolyl]cin n am ate (65).

Yield: 0.15 g (36%). Mp: 226-228 °C. IR (KBr): ν ) 3409,

3328, 1769, 1715 cm^-^{1 1}H NMR (DMSO-d₆): δ ) 6.81-6.97

.

(m, 1H), 7.09-7.18 (m, 2H), 7.24-7.35 (m, 1H), 7.43-7.63 (m,

8H), 7.75-7.96 (m, 4H), 12.00 (s, 1H), 12.11 (s, 1H). EI-MS

(70 eV) m/z (%): 406 (17) [M^+•], 276 (22), 159 (15), 131 (100),

103 (26). Anal. (C₂₆H₁₈N₂O₃): C, H, N.

[2-(1H-2-In dolylcar bon yl)-1H-5-in dolyl]-2-fu r an car box-

yla te (66). Yield: 0.21 g (58%). Mp: 245-246 °C. IR (KBr): ν

) 3446, 3314, 1740 cm^-1. ¹H NMR (DMSO-d₆): δ ) 6.81-6.83

(m, 1H), 7.09-7.35 (m, 3H), 7.50-7.63 (m, 6H), 7.76-7.78 (m,

1H), 8.11-8.12 (m, 1H), 12.01 (s, 1H), 12.14 (s, 1H). EI-MS

(70 eV) m/z (%): 370 (28) [M^+•], 276 (6), 158 (11), 117 (9), 95

(100). Anal. (C₂₂H₁₄N₂O₄·0.25ethyl acetate): C, H, N.

[2-(1H-2-In d olylca r bon yl)-1H-5-in d olyl]m eth oxyeth a -

n oa te (67). Yield: 0.23 g (67%). Mp: 202-203 °C. IR (KBr):

1

ν ) 3303, 1744, 1735 cm^-1. H NMR (DMSO-d₆): δ ) 2.27 (s,

3H), 7.10-7.19 (m, 2H), 7.29-7.36 (m, 2H), 7.49-7.66 (m, 6H),

7.75-7.82 (m, 2H), 8.19-8.21 (m, 1H), 12.05 (d, J ) 0.5 Hz,

1H), 12.14 (d, J ) 0.5 Hz, 1H). EI-MS (70 eV) m/z (%): 438 (5)

[M^+•], 396 (15), 318 (19), 276 (100). Anal. (C₂₆H₁₈N₂O₅·1.0ethyl

acetate): C, H, N.

[2-(1H-2-In d olylca r bon yl)-1H-5-in d olyl]-4-p h en ylben z-

oa te (57). Yield: 0.27 g (59%). Mp: 286 °C (dec). IR (KBr): ν

) 3413, 3336, 1717 cm^-1. ¹H NMR (DMSO-d₆): δ ) 7.05-7.15

(m, 1H), 7.24-7.39 (m, 2H), 7.42-7.82 (m, 11H), 7.93, 8.25

(AA′BB′, 4H), 12.02 (s, 1H), 12.14 (s, 1H). EI-MS (70 eV) m/z

(%): 456 (21) [M^+•], 276 (11), 181 (100), 152(19). Anal.

(C₃₀H₂₀N₂O₃·0.5ethyl acetate): C, H, N.

1

ν ) 3428, 3328, 1771 cm^-1. H NMR (DMSO-d₆): δ ) 3.40 (s,

3H), 4.35 (s, 2H), 7.08-7.16 (m, 2H), 7.28-7.36 (m, 1H), 4.49-

7.63 (m, 5H), 7.74-7.80 (m, 1H), 12.00 (s, 1H), 12.10 (s. 1H).

EI-MS (70 eV) m/z (%): 348 (15) [M^+•], 320 (10), 275 (10), 158

(22), 130 (24), 45 (100). Anal. (C₂₀H₁₆N₂O₄): C, H, N.

[2-(1H-2-In d olylca r bon yl)-1H-5-in d olyl]-2-p h en ylp r o-

p a n oa te (58). Yield: 0.27 g (66%). Mp: 211-213 °C. IR

(KBr): ν ) 3426, 3326, 1748, 1620 cm^-1. ¹H NMR (DMSO-d₆):

δ ) 2.98 (m, 4H), 6.96-7.00 (m, 1H), 7.10-7.14 (m, 1H), 7.23-

7.40 (m, 7H), 7.48-7.53 (m, 2H), 7.60 (bs, 2H), 7.74-7.78 (m,

1H), 12.00 (s, 1H), 12.07 (s, 1H). EI-MS (70 eV) m/z (%): 408

(15) [M^+•], 276 (100), 159 (39), 144 (17), 117 (21). Anal.

(C₂₆H₂₀N₂O₃·0.25ethyl acetate): C, H, N.

[2-(1H -2-In d olylca r b on yl)-1H -5-in d olyl]-2-q u in olin e-

ca r boxyla te (68). Yield: 0.14 g (33%). Mp: 286-288 °C. IR

1

(KBr): ν ) 3469, 3301, 1744 cm^-1. H NMR (DMSO-d₆): δ )

7.09-7.18 (m, 1H), 7.28-7.37 (m, 2H), 7.49-7.85 (m, 7H),

7.89-7.98 (m, 1H), 8.13-8.37 (m, 3H), 8.67-8.68 (m, 1H),

12.02 (s, 1H), 12.16 (s, 1H). EI-MS (70 eV) m/z (%): 431 (8)

[M^+•], 387 (15), 276 (100), 159 (94), 144 (41), 128 (58). Anal.

(C₂₇H₁₇N₃O₃·0.5dichloromethane): C, H, N.

D,L-[2-(1H-2-In d olylca r bon yl)-1H-5-in d olyl]-r-a cetoxy-

[2-(1H-2-In d olylca r bon yl)-1H-5-in d olyl]-4-eth oxyben z-

oa te (69). Yield: 0.18 g (42%). Mp: 254-256 °C. IR (KBr): ν

r-p h en yleth a n oa te (59). Yield: 0.22 g (49%). Mp: 194-196

°C. IR (KBr): ν ) 3401, 3313, 1759, 1740 cm^-1

.

¹H NMR

) 3444, 3313, 1721 cm^-1. H NMR (DMSO-d₆): δ ) 1.38 (t, J

1

(DMSO-d₆): δ ) 2.21 (s, 3H), 6.24 (s, 1H), 6.90-6.92 (m, 1H),

7.11-7.13 (m, 1H), 7.28-7.67 (m, 11H), 7.74-7.76 (m, 1H),

11.99 (s, 1H), 12.12 (s, 1H). EI-MS (70 eV) m/z (%): 452 (13)

[M^+•], 276 (100), 159 (35), 144 (15), 117 (21). Anal. (C₂₇H₂₀N₂O₅·

0.25ethyl acetate): C, H, N.

) 6.7 Hz, 3H), 4.16 (q, J ) 6.7 Hz, 2H), 7.10-7.19 (m, 2H),

7.12, 7.81 (AB, J ) 8.7 Hz, 4H), 7.21-7.35 (m, 1H), 7.50-7.63

(m, 5H), 7.75-7.78 (m, 1H), 12.00 (s, 1H), 12.11 (s, 1H). EI-

MS (70 eV) m/z (%): 424 (13) [M^+•], 149 (100). Anal.

(C₂₆H₂₀N₂O₄): C, H, N.

[2-(1H-2-In d olylca r bon yl)-1H-5-in d olyl]ben zoa te (60).

Yield: 0.23 g (61%). Mp: 257-260 °C. IR (KBr): ν ) 3425,

[2-(1H -2-In d olylca r b on yl)-1H -5-in d olyl]cyclop r op yl-

ca r boxyla te (70). Yield: 0.22 g (63%). Mp: 268-270 °C. IR

1

3316, 1726, 1620 cm^-1

.

¹H NMR (DMSO-d₆): δ ) 7.10-7.32

(KBr): ν ) 3422, 3345, 1735 cm^-1. H NMR (DMSO-d₆): δ )

(m, 3H), 7.51-7.68 (m, 7H), 7.74-7.80 (m, 2H), 8.16-8.19 (m,

2H), 12.01 (s, 1H), 12.14 (s, 1H). EI-MS (70 eV) m/z (%): 380

(20) [M^+•], 276 (3), 158 (5), 105 (100), 77 (25). Anal. (C₂₄H₁₆N₂O₃·

0.25ethyl acetate): C, H, N.

1.00-1.10 (m, 4H), 1.87-1.99 (m, 1H), 7.05-7.16 (m, 2H),

7.28-7.33 (m, 1H), 7.46-7.63 (m, 5H), 7.74-7.79 (m, 1H),

12.00 (s, 1H), 12.10 (s, 1H). EI-MS (70 eV) m/z (%): 344 (58)

[M^+•], 276 (100), 159 (31), 144 (14), 69 (86), 41 (49). Anal.

(C₂₁H₁₆N₂O₃·0.25dichloromethane): C, H, N.

[2-(1H-2-In dolylcar bon yl)-1H-5-in dolyl]-3-m eth oxyph e-

n yleth a n oa te (61). Yield: 0.28 g (67%). Mp: 212-215 °C.

[2-(1H -2-In d olylca r b on yl)-1H -5-in d olyl]cyclob u t a n e-

ca r boxyla te (71). Yield: 0.24 g (67%). Mp: 238-240 °C. IR

IR (KBr): ν ) 3424, 3328, 3054, 2836, 1752 cm^-^{1 1}H NMR

.

1

(DMSO-d₆): δ ) 3.78 (s, 3H), 3.96 (s, 2H), 6.86-7.15 (m, 5H),

7.27-7.35 (m, 2H), 7.46-7.60 (m, 5H), 7.75-7.77 (m, 1H),

12.00 (s, 1H), 12.09 (s, 1H). EI-MS (70 eV) m/z (%): 424 (10)

[M^+•], 276 (100), 159 (56), 144 (24), 117 (28). Anal.

(C₂₆H₂₀N₂O₄): C, H, N.

(KBr): ν ) 3423, 3336, 1740 cm^-1. H NMR (DMSO-d₆): δ )

1.83-2.12 (m, 2H), 2.22-2.43 (m, 4H), 3.39-3.53 (m, 1H),

7.03-7.16 (m, 2H), 7.28-7.35 (m, 1H), 7.45-7.63 (m, 5H),

7.74-7.80 (m, 1H), 11.95 (s, 1H), 12.05 (s, 1H). EI-MS (70 eV)

m/z (%): 358 (27) [M^+•], 276 (100), 159 (25), 117 (20), 55 (58).

Anal. (C₂₂H₁₈N₂O₃): C, H, N.

[2-(1H-2-In d olylca r bon yl)-1H-5-in d olyl]-2-ch lor oben z-

oa te (62). Yield: 0.24 g (57%). Mp: 252-254 °C. IR (KBr): ν

[2-(1H-2-In d olylca r bon yl)-1H-5-in d olyl]-3-p yr id in eca r -

boxyla te (72). Yield: 0.18 g (48%). Mp: 248-250 °C. IR

) 3456, 3322, 1740, 1618 cm^-^{1 1}H NMR (DMSO-d₆): δ )

.

1

7.10-7.16 (m, 1H), 7.24-7.35 (m, 2H), 7.50-7.79 (m, 9H),

8.10-8.13 (m, 1H), 12.02 (s, 1H), 12.16 (s, 1H). EI-MS (70 eV)

(KBr): ν ) 3065, 1730, 1595 cm^-1. H NMR (DMSO-d₆): δ )

7.09-7.17 (m, 1H), 7.26-7.41 (m, 2H), 7.49-7.71 (m, 6H),

1016 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 5

Mahboobi et al.

7.73-7.79 (m, 1H), 8.45-8.60 (m, 1H), 8.86-8.95 (m, 1H),

9.27-9.33 (m, 1H), 12.00 (s, 1H), 12.15 (s, 1H). EI-MS (70 eV)

m/z (%): 381 (45) [M^+•], 276 (17), 159 (12), 117 (15), 106 (100),

78 (34). Anal. (C₂₃H₁₅N₃O₃·0.25ethyl acetate): C, H, N.

[2-(1H-2-In d olylca r bon yl)-1H-5-in d olyl]d ip h en yleth a -

n oa te (73). Yield: 0.28 g (60%). Mp: 289-290 °C. IR (KBr):

7.73-7.76 (m, 1H). EI-MS (70 eV) m/z (%): 346 (100) [M^+•],

202 (29), 144 (28). Anal. (C₂₂H₂₂N₂O₂): C, H, N.

(1H-2-In d olyl)(1-eth yl-5-m eth oxy-1H-2-in d olyl)m eth a -

n on e (81). Yield: 0.08 g (17%). Mp: 142-143 °C. IR (KBr):

ν ) 3355, 1594 cm^-^{1 1}H NMR (DMSO-d₆): δ ) 1.33 (t, J )

.

7.0 Hz, 3H), 3.80 (s, 3H), 4.54 (q, J ) 7.0 Hz, 2H), 7.02-7.15

(m, 2H), 7.23-7.24 (m, 1H), 7.28-7.35 (m, 3H), 7.49-7.59 (m,

2H), 7.73-7.76 (m, 1H), 11.96 (s, 1H). EI-MS (70 eV) m/z (%):

318 (100) [M^+•], 303 (29), 174 (19), 158 (20), 130 (36). Anal.

(C₂₀H₁₈N₂O₂): C, H, N.

1

ν ) 3463, 3332, 1742 cm^-1. H NMR (DMSO-d₆): δ ) 5.57 (s,

1H), 6.98-7.18 (m, 2H), 7.27-7.62 (m, 16H), 7.73-7.78 (m,

1H), 12.00 (s, 1H), 12.10 (s, 1H). EI-MS (70 eV) m/z (%): 470

(5) [M^+•], 276 (75), 194 (59), 167 (98), 165 (100). Anal.

(C₃₁H₂₂N₂O₃·0.25ethyl acetate): C, H, N..

(1-Eth yl-1H-2-in d olyl)(5-m eth oxy-1H-2-in d olyl)m eth a -

n on e (82). Yield: 0.09 g (20%). Mp: 101-102 °C. IR (KBr):

[2-(1H-2-In dolylcar bon yl)-1H-5-in dolyl]-2-ph en oxyben z-

oa te (74). Yield: 0.18 g (39%). Mp: 252-260 °C. IR (KBr) ν )

1

ν ) 3355, 1602 cm^-1. H NMR (DMSO-d₆): δ ) 1.35 (t, J ) 7

3436, 3324, 1711 cm^-^{1 1}H NMR (DMSO-d₆): δ ) 6.96-7.04

.

Hz, 3H), 3.78 (s, 3H), 4.57 (q, J ) 7 Hz, 2H), 6.96-7.01 (m,

1H), 7.15-7.21 (m, 2H), 7.24-7.25 (m, 1H), 7.36-7.43 (m, 3H),

7.63-7.67 (m, 1H), 7.76-7.79 (m, 1H), 11.85 (br. s, 1H). EI-

MS (70 eV) m/z (%): 318 (100) [M^+•], 303 (25), 173 (28), 160

(13), 158 (11), 145 (33), 130 (38). Anal. (C₂₀H₁₈N₂O₂): C, H, N.

(1-Ben zyl-1H -2-in d olyl)(1-b en zyl-5-m et h oxy-1H -2-in -

d olyl)m eth a n on e (83). Yield: 0.24 g (36%). Mp: 132 °C. IR

(m, 3H), 7.08-7.20 (m, 3H), 7.27-7.54 (m, 7H), 7.57-7.63 (m,

2H), 7.68-7.80 (m, 2H), 8.07-8.13 (m, 1H), 11.98 (s, 1H), 12.08

(s, 1H); EI-MS (70 eV) m/z (%): 472 [M⁺] (39). Anal.

(C₃₀H₂₀N₂O₄): C, H, N.

[2-(1H-2-In dolylcar bon yl)-1H-5-in dolyl]-3-ph en oxyben z-

oa te (75). Yield: 0.19 g (40%). Mp: 242-245 °C. IR (KBr) ν )

3439, 3331, 1708 cm^-^{1 1}H NMR (DMSO-d₆): δ ) 7.08-7.35

.

1

(KBr): ν ) 1621 cm^-1. H NMR (DMSO-d₆): δ ) 3.78 (s, 3H),

(m, 6H), 7.39-7.66 (m, 10H), 7.68-7.78 (m, 1H), 7.92-7.96

(m, 1H), 11.99 (s, 1H), 12.11 (s, 1H). EI-MS (70 eV) m/z (%):

472 [M⁺] (28), 197 (100). Anal. (C₃₀H₂₀N₂O₄): C, H, N.

[2-(1H-2-In dolylcar bon yl)-1H-5-in dolyl]-2-ben zoylben z-

oa te (76). Yield: 0.15 g (31%). Mp: 250-258 °C. IR (KBr) ν

) 3436, 3322, 1725 cm^-1. ¹H NMR (DMSO-d₆): δ ) 6.78-6.81

(m, 1H), 7.08-7.15 (m, 1H), 7.23-7.24 (m, 1H), 7.28-7.34 (m,

2H), 7.42-7.91 (m, 13H), 8.21-8.25 (m, 1H), 11.97 (s, 1H),

12.07 (s, 1H). EI-MS (70 eV) m/z (%): 484 [M⁺] (22), 209 (100).

Anal. (C₃₁H₂₀N₂O₄): C, H, N.

P r oced u r e J : P r ep a r a tion of N-Su bstitu ted Der iva -

tives 77-85 (Sch em e 4). At 0 °C sodium hydride (60%

suspension in paraffin) (0.16 g, 4.0 mmol) was added to 11

(0.40 g, 1.4 mmol) in 10 mL of anhydrous THF. After 30 min,

the respective alkyl iodide was added to benzyl bromide (1.4

mmol), and the reaction mixture was stirred for 10 h. At room

temperature, water was carefully added and the mixture was

poured into sat. NaHCO₃solution (50 mL). The organic layer

was separated, the aqueous layer was extracted with ether (3

× 15 mL), and the combined organic layers were dried (Na₂-

SO₄). Removal of the solvent resulted in yellow crystals, which

were subjected to flash chromatography (SiO₂; CH₂Cl₂). The

two different N-monoalkylated and the N-dialkylated com-

pounds could be isolated as yellow crystals in a 1:1:2 ratio [77

(0.18 g, 43%), 78 (0.09 g, 20%) and 79 (0.09 g, 20%)].

5.81 (s, 2H), 5.84 (s, 2H), 6.99-7.06 (m, 5H), 7.14-7.38 (m,

11H), 7.50-7.54 (m, 1H), 7.60-7.63 (m, 1H), 7.76-7.79 (m,

1H). EI-MS (70 eV) m/z (%): 470 (81) [M^+•], 379 (55), 236 (65),

206 (70), 91 (100). Anal. (C₃₂H₂₆N₂O₂): C, H, N.

(1H-2-In d olyl)(1-ben zyl-5-m eth oxy-1H-2-in d olyl)m eth -

a n on e (84). Yield: 0.12 g (23%). Mp: 171 °C. IR (KBr): ν )

1

3334, 1596 cm^-1. H NMR (DMSO-d₆): δ ) 3.80 (s, 3H), 5.84

(s, 2H), 6.99-7.34 (m, 10H), 7.46-7.54 (m, 3H), 7.73-7.76 (m,

1H), 11.96 (br. s, 1H). EI-MS (70 eV) m/z (%): 380 (100) [M^+•],

303 (21), 206 (21), 190 (71). Anal. (C₂₅H₂₀N₂O₂): C, H, N.

(1-Be n zyl-1H -2-in d olyl)(5-m e t h oxy-1H -2-in d olyl)-1-

m eth a n on e (85). Yield: 0.11 g (21%). Mp: 170 °C. IR (KBr):

1

ν ) 3355, 3031, 2831 cm^-1. H NMR (DMSO-d₆): δ ) 3.79 (s,

3H), 5.87 (s, 2H), 6.96-7.00 (m, 1H), 7.06-7.09 (m, 2H), 7.14-

7.27 (m, 6H), 7.32-7.40 (m, 2H), 7.51 (s, 1H), 7.60-7.64 (m,

1H), 7.79-7.82 (m, 1H), 11.85 (s, 1H). EI-MS (70 eV) m/z (%):

380 (100) [M^+•], 303 (15), 236 (20), 190 (65). Anal.

(C₂₅H₂₀N₂O₂): C, H, N.

Bioch em ica l a n d Biologica l Assa ys.

Kin a se Assa ys. Swiss 3T3 fibroblasts (ATCC CCL 92) were

cultivated in DMEM/10% FCS (Life Technologies). The effect

on PDGF-stimulated tyrosine phosphorylation was measured

by subjecting quiescent cultures in 24-well plates (NUNC) to

a medium change into serum-free DMEM (0.4 mL per well)

and treating them with the test compounds in DMSO (final

DMSO concentration 1%) or solvent for 2 h. The cells were

subsequently stimulated with 100 ng/mL human recombinant

PDGF-BB (TEBU/Peprotech) or with the corresponding solvent

for 10 min at room temperature, washed twice with PBS, and

extracted with lysis buffer containing Hepes, pH 7.5, 1% Triton

(1-Met h yl-1H-2-in d olyl)(1-m et h yl-5-m et h oxy-1H-2-in -

d olyl)m eth a n on e (77). Yield: 0.18 g (43%). Mp: 148-149 °C.

IR (KBr): ν ) 1611 cm^-^{1 1}H NMR (DMSO-d₆): δ ) 3.79 (s,

.

3H), 4.01 (s, 3H), 4.03 (s, 3H), 7.04-7.09 (m, 1H), 7.14-7.24

(m, 4H), 7.37-7.44 (m, 1H), 7.54-7.58 (m, 1H), 7.62-7.65 (m,

1H), 7.73-7.76 (m, 1H). EI-MS (70 eV) m/z (%): 318 (100)

[M^+•], 174 (33), 144 (39), 130 (15), 89 (18). Anal. (C₂₀H₁₈N₂O₂):

C, H, N.

X-100, phosphatase, and protease inhibitors as described.¹⁸

A

10 µg sample of protein of identically treated cell extracts was

subjected to SDS-PAGE with 7.5% gels and immunoblotting

with anti-phosphotyrosine antibodies. Quantification of IC₅₀

values was based on the intensity of the signal for autophos-

phorylated PDGF receptor. Titration was done using four to

eight inhibitor concentrations within a range of 2 orders of

magnitude, which was selected on the basis of preliminary

experiments. IC₅₀values were obtained by curve-fitting of the

results using the program Sigma Plot 2.0 (J andel Corp.). With

three independent experiments, SEM were in the range of

(50%. Quinoxaline AG1295 served as a reference compound

for these determinations.¹⁸Porcine aortic endothelial (PAE)

cells expressing human PDGFR- or â-receptors and human

FGF receptor-1 were kindly provided by Dr. L. Claesson-Welsh

(Uppsala). Testing inhibition of the respective receptor kinases

in these cells was done as described.⁵³To measure effects on

EGF receptor phosphorylation, A431 cells (ATCC CRL 1555)

were starved overnight in serum-free medium, treated for 2 h

with the compounds, thereafter stimulated with 100 ng/mL

EGF (TEBU/Peprotech) for 10 min, and subjected to extraction

and immunoblotting as described above. In vitro kinase

reactions with purified PDGFâ-receptor were performed as

(1H-2-In d olyl)(1-m eth yl-5-m eth oxy-1H-2-in d olyl)m eth -

a n on e (78). Yield: 0.09 g (20%). Mp: 190 °C. IR (KBr): ν )

1

3326, 1602 cm^-1. H NMR (DMSO-d₆): δ ) 3.80 (s, 3H), 4.00

(s, 3H), 7.03-7.15 (m, 2H), 7.22-7.23 (m, 1H), 7.29-7.34 (m,

3H), 7.50-7.57 (m, 2H), 7.73-7.76 (m, 1H), 11.96 (br. s, 1H).

EI-MS (70 eV) m/z (%): 340 (100) [M^+•], 161 (27), 146 (15),

130 (22), 89 (14). Anal. (C₁₉H₁₆N₂O₂): C, H, N.

(1-Meth yl-1H-2-in d olyl)(5-m eth oxy-1H-2-in d olyl)m eth -

a n on e (79). Yield: 0.09 g (20%). Mp: 176-177 °C. IR (KBr):

1

ν ) 3317, 1609 cm^-1. H NMR (DMSO-d₆): δ ) 3.78 (s, 3H),

4.02 (s, 3H), 6.96-7.01 (m, 1H), 7.15-7.21 (m, 2H), 7.25-7.26

(m, 1H), 7.37-7.43 (m, 3H), 7.61-7.65 (m, 1H), 7.76-7.79 (m,

1H), 11.85 (br. s, 1H). EI-MS (70 eV) m/z (%): 304 (100) [M^+•],

173 (43), 160 (15), 131 (47), 89 (17). Anal. (C₁₉H₁₆N₂O₂): C, H,

N.

(1-Eth yl-1H-2-in dolyl)(1-eth yl-5-m eth oxy-1H-2-in dolyl)-

m eth a n on e (80). Yield: 0.20 g (43%). Mp: 99-100 °C. IR

(KBr): ν ) 1611 cm^-1. ¹H NMR (DMSO-d₆): δ ) 1.35 (m, 6H),

3.79 (s, 3H), 4.56 (m, 4H), 7.03-7.08 (m, 1H), 7.14-7.21 (m,

4H), 7.36-7.43 (m, 1H), 7.56-7.60 (m, 1H), 7.65-7.68 (m, 1H),

Inhibitors of PDGF Receptor Kinase

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 5 1017

described^18,19,53. Src-dependent tyrosine phosphorylation in src-

transformed NIH3T3 fibroblasts was determined as de-

scribed.⁵³

GRK2 activity was measured in vitro by employing lysates

of GRK2-overexpressing 293 cells as the source of kinase and

rhodopsin purified from bovine rod outer segments as de-

scribed.⁵⁴

(5) Banai, S.; Wolf, Y.; Golomb, G.; Pearle, A.; Waltenberger, J .

PDGF-Receptor Tyrosine Kinase Blocker AG1295 Selectively

Attenuates Smooth-Muscle Cell-Growth in-vitro and Reduces

Neointimal Formation after Balloon Angioplasty in Swine.

Circulation 1998, 97, 1960-1969.

(6) Rutherford, C.; Martin, W.; Salame, M.; Carrier, M.; Anggard,

E.; et al. Substantial Inhibition of Neointimal Response to

Balloon Injury in the Rat Carotid-Artery Using a Combination

of Antibodies to Platelet-Derived Growth Factor-BB and Basic

Fibroblast Growth-Factor. Atherosclerosis 1997, 130, 45-51.

(7) Abe, J .; Deguchi, J .; Matsumoto, T.; Takuwa, N.; Noda, M.; et

al. Stimulated activation of platelet-derived growth-factor recep-

tor in-vivo in balloon-injured arteriessA link between angio-

tensin-II and intimal thickening. Circulation 1997, 96, 1906-

1913.

(8) Guha, A.; Dashner, K.; Black, P. M.; Wagner, J . A.; Stiles, C. D.

Expression of PDGF and PDGF receptors in human astrocytoma

operation specimens supports the existence of an autocrine loop.

Int. J . Cancer 1995, 60, 168-173.

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L.; et al. Inhibition of Glioma Cell Growth by a Truncated

Platelet-Derived Growth Factor-beta Receptor. J . Biol. Chem.

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Westermark, B.; et al. Activated Platelet-Derived Growth Factor

Autocrine Pathway Drives the Transformed Phenotype of a

Human Glioblastoma Cell Line. J . Cell Physiol. 1994, 158, 381-

389.

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of PDGF Receptor beta to a Novel ETS-Like Gene, TEL, in

Chronic Myelomonocytic Leukemia with T(512) Chromosomal

Translocation. Cell 1994, 77, 307-316.

(12) J ousset, C.; Carron, C.; Boureux, A.; Quang, C. T.; Oury, C.; et

al. A Domain of TEL Conserved in a Subset of ETS Proteins

Defines a Specific Oligomerization Interface Essential to the

Mitogenic Properties of the TEL-PDGFR-beta Oncoprotein.

EMBO J . 1997, 16(N1), 69-82.

(13) Kawai, T.; Hiroi, S.; Torikata, C. Expression in Lung Carcinomas

of Platelet-Derived Growth-Factor and its Receptors. Laboratory

Invest. 1997, 77, 431-436.

For PKC assays, COS-7 cells were transiently transfected

with expression plasmids for the different RGS-HIS6-tagged

PKC isoforms. Cells were scraped off from the dishes in PBS

and centrifuged for 5 min at 1000g. The pellet was resus-

pended in 500 µL of lysis buffer containing 150 mM NaCl, 50

mM HEPES pH 7.5, 1% Nonidet P-40, 50 µg/mL leupeptin,

50 µg/mL aprotinine, and 1 mM phenylmethylsulfonyl fluoride

(PMSF) and incubated for 10 min on ice. Cell lysates were

centrifuged at 10000g for 10 min, and the supernatant was

transferred to a fresh tube. Equilibrated Ni²⁺-NTA agarose

(100 µL) (Qiagen) was added, and the tubes were rotated for

1 h to allow binding of Ni²⁺-agarose to the RGS-His6-tagged

PKCs. The beads with bound PKCs were then washed four

times with lysis buffer supplemented with 50 mM imidazole,

and the purified PKCs were eluted with 500 mM imidazole in

20 mM tris(hydroxymethyl)aminomethane (Tris)-HCl, pH 7.5.

About 100 ng of purified PKC were added to 100 µL of assay

buffer containing 20 mM Tris-HCl, pH 7.5, 20 mM MgCl₂, 50

µM substrate peptide PKCR-19-31/Ser25 (ALEXIS), 40 µM

ATP, and 1 µCi [γ-³³P]-ATP (NEN). In addition, for measure-

ment of PKC-ꢀ, 10 µM sonified phosphatidylserine and 10 µM

12-O-tetradecanoylphorbol-13-acetate (TPA) were added. The

reaction was incubated for 10 min at 30 °C and stopped on

ice. A portion of the reaction mix (50 µL) was transferred to

phosphocellulose disk sheets (GIBCO BRL). The phosphocel-

lulose sheets were washed three times with 1% phosphoric acid

and twice with distilled water and transferred to scintillation

vials containing 4 mL of liquid scintillation fluid, and the

radioactivity was measured in a liquid scintillation counter.

(14) Heuchel, R.; Berg, A.; Tallquist, M.; Ahlen, K.; Reed, R. K.; et

al. Platelet-derived growth factor beta receptor regulates inter-

stitial fluid homeostasis through phosphatidylinositol-3′ kinase

signaling. Proc Natl Acad Sci U.S.A. 1999, 96, 11410-11415.

(15) Dolle, R. E.; Dunn, J . A.; Bobko, M.; Singh, B.; Kuster, J . E.; et

al. 5,7-Dimethoxy-3-(4-pyridinyl)quinoline is a potent and selec-

tive inhibitor of human vascular beta-type platelet-derived

growth factor receptor tyrosine kinase. Can J Physiol Pharmacol

1995, 73, 805-811.

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Zilberstein, A. A new series of PDGF receptor tyrosine kinase

inhibitors: 3-Substituted quinoline derivatives. J . Med. Chem.

1994, 37, 2129-2137.

In vitro assays with Sf9-derived kinase GST-fusion proteins

were performed as described in Hofman et al.⁵⁵

Kinetic experiments with purified human PDGFâ-receptor

were performed as described.¹⁹The concentration of ATP was

varied from 25 to 400 µM, and with the concentration of KY751

substrate peptide fixed at 3 mM, the concentration of the

peptide KY751 was varied from 0.1 to 3 mM with the ATP

concentration fixed at 400 µM.

Cell Gr ow th P a r a m eter s. DNA synthesis in Swiss 3T3

fibroblasts stimulated by different agents was determined in

24-well plates by incorporation of methyl-[³H]thymidine, as

described.¹⁸Alternatively, Swiss 3T3 cells were grown in 96-

well plates to confluency. The medium was changed for serum-

free DMEM and inhibitors (final DMSO concentration 1%) and

growth factors were added as desired. DNA synthesis was

measured by incorporation of BrdU with an ELISA kit (Roche)

exactly according to the instructions of the manufacturer.

NIH3T3 cell lines expressing the gene for human PDGF-B

chain in an inducible manner were generated as described

earlier for other oncogenes⁵⁶and were kept in DMEM,

supplemented with 10% donor calf serum (DCS), previously

tested for absence of tetracycline. In DMEM with 2% DCS the

growth of these cells requires induction of PDGF-B expression.

Inhibitors were tested under these conditions, and the effect

on proliferation was evaluated after 48 h by an XTT prolifera-

tion assay using a cell proliferation kit (Roche, Mannheim)

according to the instructions of the manufacturer.

(17) Gazit, A.; App, H.; Mcmahon, G.; Chen, J .; Levitzki, A.; et al.

Tyrphostins. 5. Potent Inhibitors of Platelet-Derived Growth-

Factor Receptor Tyrosine KinasesStructure-Activity Relation-

ships in Quinoxalines, Quinolines, and Indole Tyrphostins. J .

Med. Chem. 1996, 39(N11), 2170-2177.

(18) Kovalenko, M.; Gazit, A.; Bo¨hmer, A.; Rorsman, C.; Ro¨nnstrand,

L.; et al. Selective Platelet-Derived Growth Factor Receptor

Kinase Blockers Reverse sis-Transformation. Cancer Res. 1994,

54, 6106-6114.

(19) Kovalenko, M.; Ro¨nnstrand, L.; Heldin, C. H.; Loubtchenkov,

M.; Gazit, A.; et al. Phosphorylation Site-Specific Inhibition of

Platelet-Derived Growth-Factor beta-Receptor Autophosphory-

lation by the Receptor Blocking Tyrphostin AG1296. Biochem-

istry 1997, 36, 6260-6269.

(20) Hamby, J . M.; Connolly, C. J .; Schroeder, M. C.; Winters, R. T.;

Showalter, H. D.; et al. Structure-activity relationships for a

novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors.

J . Med. Chem. 1997, 40, 2296-2303.

(21) Trumpp-Kallmeyer, S.; Rubin, J . R.; Humblet, C.; Hamby, J . M.;

Hollis Showalter, H. D. Development of a binding model to

protein tyrosine kinases for substituted pyrido[2,3-d]pyrimidine

inhibitors. J . Med. Chem. 1998, 41, 5457-5465.

(22) Buchdunger, E.; Zimmermann, J .; Mett, H.; Meyer, T.; Mu¨ller,

M.; et al. Selective inhibition of the platelet-derived growth factor

signal transduction pathway by a protein-tyrosine kinase inhibi-

tor of the 2-phenylaminopyrimidine class. Proc. Natl. Acad. Sci.

U.S.A. 1995, 92, 2558-2562.

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A. M.; et al. Structure-activity relationships for 1-phenylben-

zimidazoles as selective ATP site inhibitors of the platelet-

derived growth factor receptor. J . Med. Chem 1999, 42, 1803-

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J M010988N

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Bis(1H-2-indolyl)methanones as a novel class of inhibitors of the platelet-derived growth factor receptor kinase

DOI: 10.1021/jm010988n

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