Disubstituted indazoles as potent antagonists of the integrin α(v)β3

J . Med. Chem. 2000, 43, 41-58

41

Disu bstitu ted In d a zoles a s P oten t An ta gon ists of th e In tegr in r_vâ₃

Douglas G. Batt,* J oseph J . Petraitis, Gregory C. Houghton, Dilip P. Modi, Gary A. Cain, Martha H. Corjay,

Shaker A. Mousa, Peter J . Bouchard, Mark S. Forsythe, Patricia P. Harlow, Frank A. Barbera, Susan M. Spitz,

Ruth R. Wexler, and Prabhakar K. J adhav

DuPont Pharmaceuticals Company, P.O. Box 80500, Wilmington, Delaware 19880-0500

Received J anuary 28, 1999

A new series of indazole-containing R_vâ₃integrin antagonists is described. Starting with lead

compound 18a , variations in a number of structural features were explored with respect to

inhibition of the binding of â₃-transfected 293 cells to fibrinogen and to selectivity for R_vâ₃

over GPIIbIIIa, another RGD-binding integrin. Indazoles attached to a 2-aminopyridine or

2-aminoimidazole by a propylene linker at the indazole 1-position and to a diaminopropionate

derivative via a 5-carboxylate amide provided the best potency with moderate selectivity. Several

differences in the SAR of the diaminopropionate moiety were observed between this series

and a series of isoxazoline-based selective GPIIbIIIa antagonists. Compound 34a (SM256) was

a potent antagonist of R_vâ₃(IC₅₀2.3 nM) with 9-fold selectivity over GPIIbIIIa.

In tr od u ction

quence. Many cyclic peptide and nonpeptide antagonists

of GPIIbIIIa have been reported over the past 10 years.

Structural studies of cyclic peptide antagonists have

offered some insights into differences in the binding

sites. DMP 728 (1), which is selective for GPIIbIIIa,

exists in a rigid conformation where the RGD portion

is extended. A related compound 2 is more flexible but

prefers a different conformation, allowing the guanidine

and carboxyl groups to approach each other more

closely. This change leads to a reversal of selectivity,

with 2 binding preferentially to R_vâ₃.¹⁴A similar effect

was seen with a series of cyclic pentapeptides containing

the RGD sequence.¹⁵

The integrin family of receptors comprises more than

20 heterodimeric cell surface proteins which are in-

volved in cell-cell and cell-matrix adhesion.¹Integrins

are formed by various combinations of at least 16

R-subunits and 8 â-subunits and are very widely dis-

tributed in various tissues and cell types. Different

integrins have varying affinities and specificities for a

multitude of extracellular matrix proteins. The platelet

fibrinogen receptor, R_IIbâ₃or GPIIbIIIa, has received an

enormous amount of attention over the past decade,

since antagonists of GPIIbIIIa have utility in thrombotic

disorders such as unstable angina, myocardial infarc-

tion, transient ischemic attacks, and perhaps athero-

sclerosis and stroke.²

The classical receptor for vitronectin, the R_vâ₃inte-

grin, shares a common â-subunit with GPIIbIIIa. While

GPIIbIIIa is found almost exclusively on platelets, R_vâ₃

is more widely distributed, occurring on osteoclasts,

platelets, endothelial cells, and migrating smooth muscle

cells.³This integrin has recently attracted significant

attention for several possible medical indications. R_vâ₃

is involved in bone resorption by osteoclasts, so antago-

nists may have utility for the treatment of osteoporo-

sis.^4,5This receptor plays a major role in angiogenesis

and vascular remodeling,⁶suggesting possible applica-

tions in combating the growth and metastasis of ma-

lignant tumors^7,8and in suppressing the neovascular-

ization observed in diabetic retinopathy and age-related

macular degeneration, two of the leading causes of

blindness in adults.⁹Coronary restenosis, a serious

complication following angioplasty for the relief of

coronary artery occlusion,¹⁰is reduced by abciximab

(ReoPro), a recombinant chimeric antibody which binds

to both GPIIbIIIa and R_vâ₃.¹¹This benefit is probably

due to R_vâ₃blockade, since selective GPIIbIIIa antago-

nists were not effective in preventing restenosis.^12,13

Both GPIIbIIIa and R_vâ₃bind to extracellular matrix

proteins which contain the Arg-Gly-Asp (RGD) se-

A vast literature of nonpeptide GPIIbIIIa antagonists

exists.²These compounds generally consist of a core

scaffold bearing two side chains with basic and acidic

groups mimicking the guanidine and carboxylate of the

RGD sequence. However, to date only a few nonpeptide

antagonists of R_vâ₃have been reported.^16-20In our

laboratories, structural variation of the potent GPIIbIIIa

antagonist prodrug DMP 754 (3) yielded a series of

isoxazoline-based antagonists derived from 4a , one of

the most potent and selective being 4b.^21,22In searching

for different scaffolds, exploration of 5,6-bicyclic ring

systems bearing appropriate acidic and basic substitu-

* To whom correspondence should be addressed. Tel: 302-992-5000.

Fax: 302-695-1173. E-mail: battdg@a1.lldmpc.umc.dupont.com.

Published on Web 12/16/1999

42 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 1

Batt et al.

Sch em e 2. Preparation of Indazolecarboxylate Esters^a

ents yielded 18a as a lead compound which showed good

binding to R_vâ₃. We here report the synthesis and

structure-activity relationships of this series of inda-

zole-based R_vâ₃antagonists.

a

Reagents: (a) HCl, NH₄BF₄, NaNO₂, H₂O, 0 °C; (b) KOAc,

CHCl₃; (c) Ac₂O, KOAc, CHCl₃; (d) nAmONO, 18-crown-6, CHCl₃,

4; (e) HCl, H₂O, EtOH.

2.²⁹For the large-scale preparation of 12a , the modifica-

tion of Ru¨chardt and Hassmann³⁰allowed easy purifica-

tion of the intermediate 11a by distillation, followed by

acid hydrolysis of the acetyl intermediate.

Basic chain attachment was achieved by one of

several methods. The approach shown in Scheme 3

allowed variation of both the basic chain length and the

positioning of the substituents on the indazole core.

Alkylation of the indazole anion with a phthalimide-

protected bromoalkylamine provided mixtures (ca. 3:2)

of the 1- and 2-alkylated products 13 and 14 in good

overall yields. This lack of selectivity for indazole

alkylation had been reported previously;^31-33fortunately

the 2-alkylated products could be easily removed by

flash chromatography and elaborated separately to

isomeric target compounds 19. Hydrazine removed the

phthalimide protecting group of 13 to give the amine

15, which without purification provided 16 upon reac-

tion with 2-thiomethyl-4,5-dihydroimidazole hydroio-

dide. The ester was saponified, and the crude carboxylic

acid was coupled with 6, followed by deprotection to the

final products 18. These compounds, as well as the other

final products described herein, are amorphous solids

which were generally isolated as trifluoroacetate salts

following preparative reverse-phase HPLC purification

and either lyophilization or ether trituration.

Ch em istr y

Synthesis of the target compounds was accomplished

by attaching the groups bearing the acidic and basic

moieties to an indazolecarboxylic acid. Generally, the

basic chain was elaborated first on the ester-protected

indazolecarboxylate, followed by coupling of the derived

acid with an appropriate amine bearing the target

compound’s carboxylate group, using standard peptide

bond-forming methods. The substituted diaminopropi-

onate derivatives used as amine components were

prepared using literature methods^23-25from either the

commercially available diaminopropionate derivative 5

or (S)-asparagine 7 (Scheme 1). The (R)-enantiomer of

6 was prepared from the commercially available (R)-

isomer of 5. The N-methyl derivative 9 was prepared

from 8 (R ) Me, Ar ) mesityl) using the method of Sakai

and Ohfune.²⁶

Sch em e 1. Preparation of Diaminopropionate

An improved synthesis of the aminopropylindazole

intermediate 21 (15a , with n ) 3 and R ) Et) is shown

in Scheme 4. Conjugate addition of 12a to acrylonitrile

in ethanol with catalytic base provided the nitrile 20,

with no traces of the 2-alkylated isomer detectable, as

reported for indazole itself.³⁴At early times in the

reaction, both isomers were present by TLC, but the

undesired isomer disappeared as the reaction pro-

gressed. This suggests that the reversible nature of the

conjugate addition led to the thermodynamically pre-

ferred product 20, in contrast to the irreversible alky-

lation shown in Scheme 3 which presumably gave a

kinetic mixture. The nitrile was converted to the amine

hydrochloride 21 by catalytic reduction in the presence

of small amounts of HCl generated in situ from chloro-

form.³⁵

Derivatives

Scheme 4 also illustrates the incorporation of the

2-aminopyridine group as the basic moiety. Compound

21 could not be induced to react with 2-chloropyridine

or 2-bromopyridine, but with 2-chloropyridine 1-oxide

in the presence of solid sodium bicarbonate³⁶the N-oxide

22a was obtained in 80% yield. Reduction of the N-oxide

was followed by protection of 22b as the Boc derivative.

The ester was saponified, and 23a was coupled with the

Indazole-6-carboxylic acid^27,28has been reported in the

literature, but other isomers were unknown. The esters

12 were prepared from the corresponding aminoben-

zoate esters 10 using the J acobson method (diazotiza-

tion followed by base treatment) as shown in Scheme

Indazoles as Antagonists of the Integrin R_vâ₃

Sch em e 3. Initial Synthetic Approach^a

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 1 43

a

Reagents: (a) KN(TMS)₂, PhthN(CH₂)_nBr, THF, 4; (b) H₂NNH₂, EtOH; (c) 2-MeS-4,5-dihydroimidazole‚HI, pyridine, 4; (d) NaOH,

H₂O, EtOH, 4, HCl, H₂O; (e) 6, DCC, HOBT, DMF; (f) CF₃COOH, CH₂Cl₂.

Sch em e 4. Preparation of Aminopropyl Intermediate 21 and Aminopyridine Derivatives^a

a

Reagents: (a) CH₂dCHCN, NaN(TMS)₂(cat.), EtOH, 4; (b) H₂, Pd/C, CHCl₃, EtOH; (c) 2-chloropyridine 1-oxide, NaHCO₃, nBuOH,

100 °C; (d) H₂, Pd/C, EtOH; or HCOONH₄, Pd/C, EtOH, 4; (e) Boc₂O, DMAP, CH₂Cl₂; (f) NaOH, H₂O, EtOH, then H₃O⁺; (g) 6, 8, or

related amine, DCC, HOBT, DMF; (h) CF₃COOH, CH₂Cl₂; optionally followed by NaOH in H₂O for methyl esters.

appropriate amine component, after which protecting

group removal provided the final products 24. Protection

of the amino group proved unnecessary, since the

nucleophilicity of the pyridylamine was sufficiently low

that it did not interfere with subsequent coupling of 23b.

Amine 21 could also be used to allow introduction of

basic groups after incorporation of the acidic chain, as

shown in Scheme 5. Protection as the benzyl carbamate

gave 25, but saponification of this compound was

problematic, since the ester was resistant to mild

44 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 1

Batt et al.

Sch em e 5. Variation of the Basic Group Late in the

vided 30 in 55% yield. Acidic deprotection afforded 31

quantitatively. Reductive amination with 1-trityl-2-

aminoimidazole²²or 1-Cbz-3-aminopyrazole³⁷gave 32a

or 32b, respectively. The usual sequence of saponifica-

tion, coupling, and deprotection provided the desired

products. In the case of the trityl-protected aminoimi-

dazole derivatives, trityl removal could be achieved by

heating in trifluoroacetic acid. tert-Butyl esters were

removed in the same step, or methyl esters could be

subsequently cleaved with lithium hydroxide. Alterna-

tively, the trityl group could be removed without affect-

ing the tert-butyl ester by heating in methanol/acetic

acid, followed by removal of the ester with TFA at room

temperature.

Synthesis^a

The imidazole amide 39 was synthesized according

to Scheme 7. In contrast to acrolein, methyl acrylate

underwent conjugate addition with 12a to provide the

bis-ester 36 in quantitative yield. The side chain methyl

ester was selectively saponified with lithium hydroxide,

and 37 was coupled with 2-aminoimidazole giving 38.

Saponification of the remaining ester with sodium

hydroxide, followed by coupling and deprotection, pro-

vided 39.

Variation of the R-substituent (corresponding to the

so-called exosite-binding group in GPIIbIIIa antago-

nists³⁸) was achieved by coupling with the appropriate

diaminopropionate derivative 8 or other amine as il-

lustrated above or more efficiently late in the synthesis

as shown in Scheme 8. (The latter approach has also

been used for R-substituent variation in isoxazoline

GPIIb/IIIa antagonists.^39,40) The appropriate R-Cbz

derivative 40 (B ) 2-pyridyl or 1-trityl-2-imidazolyl) was

deprotected by hydrogenolysis, and the resulting amine

41 was functionalized using an acid or acid chloride,

chloroformate ester, sulfonyl chloride, sulfamoyl chlo-

ride,⁴⁰or isocyanate to give the corresponding amide,

carbamate, sulfonamide, sulfamide, or urea, respec-

tively. Removal of the ester completed the synthesis; in

the imidazole case the trityl and tert-butyl esters were

removed in one step with boiling trifluoroacetic acid.

a

Reagents: (a) BzOOCCl, Et₃N, CH₂Cl₂; (b) LiOH, H₂O, THF;

(c) 8, DCC, HOBT, DMF; (d) Pd(OH)₂, 1,4-cyclohexadiene, MeOH,

4; (e) see Experimental Section; (f) CF₃COOH, CH₂Cl₂.

hydrolysis while harsher conditions caused loss of the

Cbz group. Lithium hydroxide provided 26 in about 50%

yield after several days at room temperature. Coupling

with 8 (R ) tBu, Ar ) mesityl) followed by hydrogenoly-

sis of the Cbz group gave 28, which could be allowed to

react with an electrophilic amidine derivative to give,

after deprotection, 29.

Other basic groups were more easily introduced by

reductive amination of the aldehyde 31 with the ap-

propriate heterocyclic amine, as shown in Scheme 6.

Unfortunately, in contrast to the success achieved with

acrylonitrile, acrolein could not be induced to undergo

conjugate addition with 12a . Therefore, alkylation with

the protected bromoaldehyde followed by removal of the

undesired 2-alkylated product by chromatography pro-

The reversed amide 49 was prepared from 5-nitroin-

dazole 43 (Scheme 9), which was elaborated to 44 using

the same procedures as outlined earlier (Scheme 6) for

the preparation of 31. The aminopyridine group was

introduced by reductive amination of 44. The nitro

Sch em e 6. Basic Group Introduction by Reductive Amination^a

a

Reagents: (a) NaN(TMS)₂, 2-(2-bromoethyl)-1,3-dioxolane, THF, 4; (b) HOAc, H₂O, 4; (c) 1-trityl-2-aminoimidazole, toluene, 4 (-H₂O),

NaBH(OAc)₃(d) 1-Cbz-3-aminopyrazole, NaBH(OAc)₃, ClCH₂CH₂Cl; (e) NaOH, H₂O, EtOH, 4; (f) 6, 8, or related amine, DCC, HOBT,

DMF; (g) see text.

Indazoles as Antagonists of the Integrin R_vâ₃

Sch em e 7. Imidazole Amide Preparation^a

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 1 45

a

Reagents: (a) methyl acrylate, tBuOH, KOtBu, THF, 4; (b) LiOH, H₂O, THF; (c) 2-aminoimidazole sulfate, iPr₂NEt, BOP, DMF,

70 °C; (d) LiOH, H₂O, THF; (e) 8 (R ) tBu, Ar ) mesityl), DCC, HOBT, DMF; (f) CF₃COOH, CH₂Cl₂.

Sch em e 8. Variation of R-Substituent Late in the Synthesis^a

a

Reagents: (a) H₂, Pd/C, EtOH; (b) see Experimental Section; (c) CF₃COOH, CH₂Cl₂.

Sch em e 9. Preparation of Retro-Amide 49^a

Once IC₅₀values fell much below 1 nM, however, this

assay was not useful for distinguishing among different

compounds. A functional R_vâ₃antagonism assay was

used instead, involving adhesion of â₃-transfected 293

cells to fibrinogen (R_vâ₃293â₃).^22,42For assessment of

selectivity with respect to GPIIbIIIa antagonism, inhibi-

tion of aggregation of human gel-purified platelets

(GPIIbIIIa GPP) was used. GPP was preferred over the

more commonly used platelet-rich plasma aggregation

assay since in the latter system differences in plasma

protein binding among different compounds would

complicate SAR analysis. ELISA and GPP results are

based on single determinations; historically these assays

have shown standard errors of about 25% or less. The

293â₃results were averaged from three determinations;

the innately higher variability of such a cell-based

adhesion assay is reflected in the standard errors of

some of these values. For comparison, results for

compound 4b²²are given in Tables 2 and 3.

Initially, the effects of changes in gross structural

features of 18a were studied by varying the length of

the chain bearing the basic moiety and by varying the

relative positions of the acidic and basic chains about

the indazole core (Table 1). In these early studies,

2-aminoimidazoline served as the basic group, since this

was found previously to provide better potency for R_vâ₃

and selectivity over GPIIbIIIa than guanidine itself.^20,22

The 1,5-isomer was much more potent than the 1,6-

isomer and similar to the 1,4-isomer (compare R_vâ₃

ELISA IC₅₀values for 18a , 18b, and 18c). The 1,4- and

a

Reagents: (a) see Scheme 5; (b) Fe, HOAc, 90 °C; (c) DCC,

HOBT, DMF; (d) see Scheme 7.

group of 45 was reduced in 80% yield, and coupling of

46 with commercially available 47 followed by depro-

tection provided 48, which was converted to 49 as

described in Scheme 8.

Resu lts a n d Discu ssion

Early structure-activity studies were guided by a

purified R_vâ₃receptor binding assay (R_vâ₃ELISA).⁴¹

46 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 1

Batt et al.

Ta ble 1. Effect of Substituent Orientation and Basic Chain

Ta ble 2. Effect of Basic Group

Length

a

b

Average of 3 determinations. 1 determination; nd ) not

determined.

good enhancement of the potency of the indazole series

relative to 2-aminoimidazoline, and both of these basic

groups were used in further SAR exploration.

The nature of the acidic chain also had a profound

influence on potency against R_vâ₃as shown in Table 3.

In the aminopyridine series, reversing the amide from

24a to 49 caused a 10-20-fold loss in potency, and

N-methylation of the normal amide (24b) was even

worse. This suggests that the NH of the amide is

important for interaction with the receptor.

In agreement with findings in the isoxazoline series

represented by 4a and 4b,^21,22the substituent R to the

carboxylate was also necessary for activity, as shown

by the inactivity of 24c and 34f. In GPIIbIIIa antago-

nists, lipophilic substituents R to the carboxylate were

found to enhance potency and duration of action through

presumed binding to a lipophilic pocket on the receptor,

labeled the “exosite”.³⁸Whereas this substituent was not

absolutely necessary for good GPIIbIIIa binding,³⁹it

appears critical for binding of this series of compounds

to R_vâ₃. The presence of an exosite-binding group is not

sufficient for activity, though, since the aminoimidazole

compound 34e, which bears one of the better R-substit-

uents (see below) but lacks the carboxylate moiety, is

inactive. The stereochemistry of the R-substituted car-

boxylate is important, since the (R)-isomer 34d is 100-

fold less potent than the (S)-isomer 34a .

Moving the exosite-binding group â to the carboxylate,

providing aspartate derivatives such as 24e and 24f,

also led to inactive compounds. This also contrasts to

GPIIbIIIa antagonists such as the series represented

by 3, where aspartate amide or other â-substituted

â-alanine moieties could replace diaminopropionate

derivatives and still give useful binding to the receptor,

although with somewhat reduced potency.³⁹

The nature of the functionality attaching the exosite-

binding group was important for potency against R_vâ₃

(Table 3). While carbamates such as 24d and 24g were

active at 200-300 nM, isosteric amides (24j, 24k ) and

ureas (24i) were at least 3-fold less active. This might

reflect a difference in conformational preference for the

a

b

1 determination. Average of 3 determinations.

1,5-isomers were also compared in a series having an

R-substituent and basic moiety which provided better

potency (see below); in this case (34b vs 34a ) the R_vâ₃

ELISA values were similar but the preference for the

1,5-isomer in the 293â₃assay was clear. The analogues

with the basic chain at the 2-position (19a and 19b),

obtained as minor isomers during attachment of this

chain by alkylation, were active but significantly less

potent than the 1,5-isomer. Changing the length of the

basic chain to either two (18d ) or four (18e) methylenes

greatly reduced activity.

Variation of the guanidine replacement was evaluated

in the 1,5-disubstituted series, with R-mesitylenesulfo-

nylamino as the R-substituent (Table 2). Expanding the

imidazoline ring of 29a to tetrahydropyrimidine 29b

increased potency against R_vâ₃without changing GPI-

IbIIIa potency, leading to some selectivity. Selectivity

was increased by replacement with 2-aminopyridine or

2-aminoimidazole. The aminopyridine 24a maintained

similar potency against R_vâ₃as 29a but reduced GPI-

IbIIIa activity. Aminoimidazole 34a , on the other hand,

dramatically increased R_vâ₃potency.

The 2-aminoimidazole amide 39 was similar to the

2-aminopyridine 24a but was much less potent than

34a , in contrast to the findings in the isoxazoline series

represented by 4b.²²Like 4b, the basic moiety of 39

offered greater selectivity with respect to GPIIbIIIa (70-

fold) than most other indazole derivatives examined.

3-Aminopyrazole 35 was essentially inactive, presum-

ably due to the severely reduced basicity and also

because the tautomer shown in Table 2, with no NH

available on the ring nitrogen corresponding to that in

34a or protonated 24, is the preferred one.⁴³In sum-

mary, 2-aminopyridine and 2-aminoimidazole provide

Indazoles as Antagonists of the Integrin R_vâ₃

Ta ble 3. Effect of Acidic Substituent

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 1 47

a

b

d

2-pyr ) pyrid-2-yl; 2-im ) imidazol-2-yl. Average of 3 determinations. ^c1 determination; nd ) not determined. Descarboxy.

carbamates or might suggest that the ether-type oxygen

of the carbamate is important for binding to the recep-

tor. This finding also contrasts with the SAR observed

for isoxazoline GPIIbIIIa antagonists, where similar

potency was observed for these three types of exosite-

binding groups.³⁹

However, in accordance with findings from GPIIbIIIa

research,⁴⁰aryl sulfonamides (24m , 24a ) and sulfamides

(24s, 24t) provided the same or better potency when

compared to the carbamates. Alkyl (24n , 24q) or benzyl

(24p , 24r ) sulfonamide and sulfamide analogues were

less potent. One possibility for the qualitative similarity

between sulfonamide and carbamate R-substituents

was suggested by examination of molecular models of

N-methyl benzyl carbamate and N-methyl benzene-

sulfonamide (Figure 1: structures were minimized with

MM2, NH protons are shown in purple). Superimposing

the nitrogens and the methyl carbons (used as mimics

for the points of attachment of the nitrogens in 24d

and 24m ) allows both pairs of oxygen atoms to overlap

quite well. Since only these two functional groups, along

with the similar sulfamide, conferred good activity,

perhaps these two oxygens are more important for R_vâ₃

receptor interaction than is the case for GPIIbIIIa. The

differences in potency between carbamate and sulfona-

mide may reflect the differences in positioning of the

aromatic rings relative to the functional groups, seen

in Figure 1.

Since many sulfonyl chlorides are commercially avail-

able or easily prepared, the sulfonamide moiety was

48 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 1

Batt et al.

34h and 34i, 34r and 34s). Additional meta substitution

hardly affected potency (34i vs 34q), and ortho disub-

stitution (34r , 34s) was similar to para monosubstitu-

tion but with differing effects on selectivity over GPI-

IbIIIa. Para substitution and ortho disubstitution were

additive, with very potent compounds resulting (34a ,

34t). Adding the para substituent increased the selec-

tivity relative to the ortho disubstituted cases (34a or

34t vs 34s). Naphthyl derivatives were also potent, with

2-naphthyl 34v more potent and selective than 1-naph-

thyl 34u .

In summary, the indazole ring system provided a

useful scaffold for attaching basic and acidic moieties

to obtain potent, somewhat selective antagonists of the

integrin R_vâ₃. General features of the SARs are similar

to those observed for isoxazoline-based antagonists

represented by 4b, with generally greater potency but

less selectivity with respect to GPIIbIIIa.²²The 1,5-

disubstituted indazole core with a three-carbon tether

attaching the basic moiety was optimal. Groups less

basic than guanidine (2-aminopyridine and especially

2-aminoimidazole) enhanced potency along with show-

ing better selectivity over the related integrin GPIIbIIIa.

The amide bond in the acidic chain was important for

activity, as was the carboxylate group and an R-(S)-

substituent. Aryl sulfonamides gave the best potency

as exosite-binding groups, with the mesitylenesulfona-

mide analogue 34a providing excellent potency and

9-fold selectivity with respect to GPIIbIIIa. This com-

pound (SM256) was selected for further investigation,

the results of which are published elsewhere.^42,44

F igu r e 1. Stereoview of the overlap between N-methyl benzyl

carbamate and N-methyl benzenesulfonamide.

Ta ble 4. Effect of Sulfonamide Aromatic Group

Exp er im en ta l Section

Melting points were determined with a Thomas-Hoover

melting point apparatus and are uncorrected. Reactions were

run at room temperature under an atmosphere of N₂unless

otherwise indicated. Organic phases from aqueous extractions

were dried over MgSO₄or Na₂SO₄, filtered, and concentrated

under reduced pressure. Flash chromatography was performed

on silica gel using the method of Still.⁴⁵Analytical HPLC was

done with a 4.6-mm × 250-mm Dynamax C₁₈column operated

at room temperature, eluting at 1.0 mL/min using a 20-min

linear gradient from 97.5:2.5 to 20:80 water:acetonitrile,

containing 0.05% TFA, with UV detection at 254 nm. Prepara-

tive HPLC separations used the same conditions, but with a

41.4-mm × 250-mm column eluted at 40 mL/min over 35 min.

¹H NMR data were obtained at 300 MHz using a Varian

VXR400 spectrometer and were referenced to TMS. Mass

spectral data were obtained on either VG 70-VSE (FAB, high-

res FAB, high-res DCI) or Finnigan MAT 8230 (DCI) mass

spectrometers. Combustion analyses were performed by Quan-

titative Technologies, Inc., Bound Brook, NJ . Solvents and

reagents were used as purchased from commercial sources

unless otherwise noted. Quoted yields are of isolated material.

Eth yl In d a zole-5-ca r boxyla te (12a ). Ethyl 3-methyl-4-

aminobenzoate⁴⁶(251 g, 1.4 mol), KOAc (143 g, 1.46 mol), Ac₂O

(286 g, 2.8 mol), and CHCl₃(2700 mL) were combined and

stirred. The temperature rose to 40 °C, then started to decline,

at which time no starting material was detected by TLC. 18-

Crown-6 (75 g, 280 mmol) and n-amyl nitrite (365 g, 3.1 mol)

were added and the mixture was heated at reflux overnight.

The cooled mixture was washed with aqueous NaHCO₃and

water, dried, and concentrated. The residue was combined with

that from another batch (711 g total) and distilled through a

10-cm Vigreaux column to provide 11a (576 g, 82%): bp 115-

165 °C (1.0 Torr). This was stirred overnight with HCl (6 N;

2000 mL) and EtOH (2000 mL). The mixture was concen-

trated, and the solid was stirred in H₂O. The pH was adjusted

to 8 with aqueous NH₃, and the mixture was extracted with

a

b

Average of 3 determinations. 1 determination.

chosen for exploring the SAR of the aryl ring. The

results for the aminoimidazole series are shown in Table

4; very similar comparisons were found in the aminopy-

ridine series, although the R_vâ₃potencies were generally

reduced. All aryl sulfonamides evaluated gave 293â₃

IC₅₀values below 200 nM, while potencies against

GPIIbIIIa ranged a bit more widely.

Relative to phenyl (34g), 4-substitution with small

groups increased potency (34h , 34i, 34j), while larger

and more polar groups (34m , 34n ) tended to reduce

activity. p-Biphenyl (34p ) was an exception, showing

greater potency than would be expected for the size of

the substituent. 4-Substitution also generally enhanced

selectivity with respect to GPIIbIIIa, with lipophilic

substituents (34k and 34n ) being more effective. 4-Chlo-

ro (34i) and 3,4-dichloro (34q) substituents provided the

best balance of potency and selectivity. Electronic effects

of ring substituents on potency were minimal (compare

Indazoles as Antagonists of the Integrin R_vâ₃

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 1 49

CH₂Cl₂. The organic phase was dried and concentrated to

provide a solid, which was recrystallized from MeCN to give

12a (281 g, 60%) as a tan solid: mp 122-124 °C; ¹H NMR

(CDCl₃) δ 10.23 (bs, 1H), 8.56 (s, 1H), 8.20 (s, 1H), 8.10 (d, J

) 8.8 Hz, 1H), 7.53 (d, J ) 8.8 Hz, 1H), 4.42 (q, J ) 7.3 Hz,

2H), 1.42 (t, J ) 7.3 Hz, 3H); HRMS (NH₃-CI) m/z 191.0838

[(M + H)⁺calcd for C₁₀H₁₁N₂O₂191.0821]. Anal. (C₁₀H₁₀N₂O₂)

C, H, N.

material, 2-methylthio-4,5-dihydroimidazole hydriodide (2.71

g, 11.1 mmol), and pyridine (125 mL) was heated at 80 °C for

5 h. The mixture was cooled and concentrated, and the residue

was purified by flash chromatography (CH₂Cl₂:MeOH 80:20)

to provide 16a (R ) Et, n ) 3) (3.73 g, 75%) as a gum: ¹H

NMR (DMSO-d₆) δ 8.50 (s, 1H), 8.30 (s, 1H), 8.24 (bs, 1H),

7.98 (d, J ) 8.3 Hz, 1H), 7.75 (d, J ) 8.3 Hz, 1H), 4.49 (t, J )

7.6 Hz, 2H), 4.34 (q, J ) 7.3 Hz, 2H), 3.57 (s, 4H), 3.13 (m,

2H), 2.05 (m, 2H), 1.35 (t, J ) 7.3 Hz, 3H); HRMS (NH₃-CI)

m/z 316.1765 [(M + H)⁺calcd for C₁₆H₂₂N₅O₂316.1774].

Meth yl In d a zole-6-ca r boxyla te (12b). A solution of meth-

yl 4-methyl-3-aminobenzoate (12.39 g, 75 mmol) and NH₄BF₄

(10.48 g, 100 mmol) in water (85 mL) and concentrated HCl

(15 mL) was cooled to 3 °C and treated dropwise over 25 min

with a solution of NaNO₂(5.18 g, 75 mmol) in water (12 mL).

The resulting thick slurry was stirred for 35 min, and the solid

was collected by filtration, rinsed with water, methanol, and

ether, and dried under N₂. The solid was added in one portion

to a stirred mixure of KOAc (8.1 g, 82.5 mmol) and 18-crown-6

(0.5 g, 1.9 mmol) in CHCl₃(170 mL). After 70 min, water (170

mL) was added, and the layers were separated. The aqueous

phase was extracted with CHCl₃. The combined organic phases

were washed with water, dried, and concentrated. The residue

was triturated with hexane and the resulting solid isolated

by filtration to provide 12b (8.85 g, 67%) as a dull yellow

3-[1-[3-(N-4,5-Dih yd r oim id a zol-2-yla m in o)p r op yl]in d a -

zol-5-ylca r bon yla m in o]-2(S)-(ben zyloxyca r bon yla m in o)-

p r op ion ic Acid Tr iflu or oa ceta te (18a ). A mixture of 16a

(R ) Et, n ) 3; 3.39 g, 7.64 mmol), aqueous NaOH (1.0 M; 16

mL, 16 mmol), and EtOH (35 mL) was stirred at reflux for 16

h, then cooled and treated with aqueous HCl (1.0 M; 16 mL,

16 mmol). The solvent was removed under vacuum, benzene

was added, and solvent was again removed. A portion of the

resulting residue (77 mg, 240 µmol) was combined with 6²⁵

(70 mg, 240 µmol), DCC (60 mg, 313 µmol), HOBT (10 mg),

DMF (5 mL), and Et₃N (0.1 mL), and the resulting mixture

was stirred for 16 h. The mixture was concentrated and the

residue was purified by flash chromatography (CH₂Cl₂:MeOH

90:10) to provide 17a (n ) 3; 122 mg, 85%) as a yellow gum:

¹H NMR (DMSO-d₆) δ 8.53 (bm, 1H), 8.30 (s, 1H), 8.24 (s+m,

2H), 7.88 (d, J ) 8.5 Hz, 1H), 7.71 (d, J ) 8.5 Hz, 1H), 7.70

(m, 1H), 7.34 (m, 5H), 5.04 (s, 2H), 4.47 (t, J ) 7.4 Hz, 2H),

4.23 (m, 1H), 3.75-3.50 (m, 2H), 3.55 (s, 4H), 3.12 (q, J ) 7.4

Hz, 2H), 2.06 (m, 2H), 1.33 (s, 9H); HRMS (NH₃-CI) m/z

564.2959 [(M + H)⁺calcd for C₂₉H₃₈N₇O₅564.2934]. A solution

of this material (108 mg, 180 µmol) in CH₂Cl₂(5 mL) and TFA

(0.5 mL) was stirred overnight and concentrated. The residue

was triturated in ether to provide 18a (74 mg, 75%) as a

hygroscopic, off-white amorphous solid: ¹H NMR (DMSO-d₆)

δ 8.57 (bt, 1H), 8.31 (s, 1H), 8.28 (m, 1H), 8.24 (s, 1H), 7.88 (d,

J ) 8.8 Hz, 1H), 7.72 (d, J ) 8.8 Hz, 1H), 7.62 (m, 1H), 7.32

(m, 5H), 5.02 (s, 2H), 4.47 (t, J ) 7.6 Hz, 2H), 4.29 (m, 1H),

3.65 (m, 2H), 3.55 (s, 4H), 3.11 (m, 2H), 2.06 (m, 2H); HRMS

(FAB) m/z 508.2323 [(M + H)⁺calcd for C₂₅H₃₀N₇O₅508.2308].

Anal. (C₂₅H₂₉N₇O₅‚1.4CF₃COOH‚1.2H₂O) C, H, N, F.

1

powder: mp 142-144 °C (MeCN); H NMR (CDCl₃) δ 11.17

(bs, 1H), 8.30 (q, J ) 1.1 Hz, 1H), 8.18 (d, J ) 1.1 Hz, 1H),

7.85 (dd, J ) 8.4, 1.1 Hz, 1H), 7.81 (dd, J ) 8.4, 1.1 Hz, 1H),

3.97 (s, 3H); MS (NH₃-CI) m/z 177 [(M + H)⁺, 100%]. Anal.

(C₉H₈N₂O₂) C, H, N.

Meth yl in d a zole-4-ca r boxyla te (12c) was prepared from

methyl 2-methyl-3-aminobenzoate using the procedure for the

synthesis of 12b, as an orange solid: ¹H NMR (CDCl₃) δ 8.61

(s, 1H), 7.98 (d, J ) 7.3 Hz, 1H), 7.74 (d, J ) 8.4 Hz, 1H), 7.42

(dd, J ) 8.4, 7.3 Hz, 1H), 4.01 (s, 3H); HRMS (NH₃-CI) m/z

177.0669 [(M + H)⁺calcd for C₉H₉N₂O₂177.0664].

Eth yl 1-(3-[1-P h th a lim id o]p r op yl)in d a zole-5-ca r boxy-

la te (13a ; R ) Et, n ) 3) a n d Eth yl 2-(3-[1-P h th a lim id o]-

p r op yl)in d a zole-5-ca r boxyla te (14a ; R ) Et, n ) 3). A

solution of potassium bis(trimethylsilyl)amide (0.5 M in tolu-

ene; 46.6 mL, 23.3 mmol) and 18-crown-6 (100 mg) in THF

(50 mL) was treated with a solution of 12a (4.43 g, 23.3 mmol)

in THF (50 mL), then with a solution of N-(3-bromopropyl)-

phthalimide (6.24 g, 23.3 mmol) in THF (50 mL). The mixture

was heated at reflux for 16 h, then cooled and poured into

water (200 mL). The aqueous layer was extracted with EtOAc,

and the combined organic layers were dried and concentrated.

The residue was purified by flash chromatography (hexanes:

EtOAc 50:50) to provide 13a (R ) Et, n ) 3) (4.25 g, 48%) as

a yellow solid: mp 122-124 °C; ¹H NMR (CDCl₃) δ 8.48 (s,

1H), 8.06 (s, 1H), 8.04 (d, J ) 8.5 Hz, 1H), 7.82 (m, 2H), 7.71

(m, 2H), 7.42 (d, J ) 8.5 Hz, 1H), 4.44 (t, J ) 7.5 Hz, 2H),

4.40 (q, J ) 7.2 Hz, 2H), 3.80 (t, J ) 7.5 Hz, 2H), 2.40 (m,

2H), 1.42 (t, J ) 7.2 Hz, 3H); HRMS (NH₃-CI) m/z 378.1430

[(M + H)⁺calcd for C₂₁H₂₀N₃O₄378.1454]. Anal. (C₂₁H₁₉N₃O₄‚

0.25H₂O) C, H, N. Also obtained (as a more polar material)

was 14a (R ) Et, n ) 3) (2.75 g, 31%) as a yellow solid: mp

133-135 °C; ¹H NMR (CDCl₃) δ 8.48 (s, 1H), 8.25 (s, 1H), 7.85

(d, J ) 8.4 Hz, 1H), 7.81 (m, 2H), 7.70 (m, 2H), 7.61 (d, J )

8.4 Hz, 1H), 4.50 (t, J ) 7.5 Hz, 2H), 4.40 (q, J ) 7.2 Hz, 2H),

3.78 (t, J ) 7.5 Hz, 2H), 2.47 (m, 2H), 1.43 (t, J ) 7.2 Hz, 3H);

HRMS (NH₃-CI) m/z 378.1430 [(M + H)⁺calcd for C₂₁H₂₀N₃O₄

378.1454]. Anal. (C₂₁H₁₉N₃O₄‚0.1H₂O) C, H, N.

Eth yl 1-(3-[N-4,5-Dih yd r oim id a zol-2-yla m in o]p r op yl)-

in d a zole-5-ca r boxyla te (16a ; R ) Et, n ) 3). A mixture of

13a (R ) Et, n ) 3; 4.20 g, 11.1 mmol), EtOH (75 mL), THF

(75 mL), and anhydrous H₂NNH₂(1.5 mL) was stirred for 16

h. THF (100 mL) was added, the mixture was filtered, and

the filtrate was concentrated to provide 15a (R ) Et, n ) 3)

as an orange syrup, which was used without purification: ¹H

NMR (CDCl₃) δ 8.51 (s, 1H), 8.10 (s, 1H), 8.06 (d, J ) 8.5 Hz,

1H), 7.46 (d, J ) 8.5 Hz, 1H), 4.52 (t, J ) 7.5 Hz, 2H), 4.41 (q,

J ) 7.2 Hz, 2H), 2.68 (t, J ) 7.5 Hz, 2H), 2.06 (m, 2H), 1.47

(bs, 2H), 1.43 (t, J ) 7.2 Hz, 3H); HRMS (NH₃-CI) m/z 248.2392

[(M + H)⁺calcd for C₁₃H₁₈N₃O₂248.1399]. A mixture of this

Using the procedures described for preparing 18a via 13a

and 16a , the following compounds were prepared.

3-[1-[3-(N-4,5-Dih yd r oim id a zol-2-yla m in o)p r op yl]in d a -

zol-6-ylca r bon yla m in o]-2(S)-(ben zyloxyca r bon yla m in o)-

p r op ion ic a cid tr iflu or oa ceta te (18b): from 12b, as an off-

white amorphous solid; ¹H NMR (MeOH-d₄) δ 8.12 (s, 1H), 8.01

(s, 1H), 7.82 (d, J ) 8.8 Hz, 1H), 7.54 (d, J ) 8.8 Hz, 1H),

7.3-7.1 (5H), 5.06 (ab, J ) 12.5 Hz, 2H), 4.6-4.5 (m, 3H), 3.88

(dd, J ) 13.7, 4.6 Hz, 1H), 3.72 (dd, J ) 13.7, 8.3 Hz, 1H),

3.57 (s, 4H), 3.10 (t, J ) 6.6 Hz, 2H), 2.18 (m, 2H); HRMS

(FAB) m/z 508.2324 [(M + H)⁺calcd for C₂₅H₃₀N₇O₅508.2308].

Anal. (C₂₅H₂₉N₇O₅‚CF₃COOH) C, H, N, F.

3-[1-[3-(N-4,5-Dih yd r oim id a zol-2-yla m in o)p r op yl]in d a -

zol-4-ylca r bon yla m in o]-2(S)-(ben zyloxyca r bon yla m in o)-

p r op ion ic a cid tr iflu or oa ceta te (18c): from 12c, as a

1

hygroscopic, off-white amorphous solid; H NMR (MeOH-d₄)

δ 8.38 (s, 1H), 7.75 (d, J ) 8.1 Hz, 1H), 7.50 (m, 2H), 7.3-7.2

(m, 5H), 5.06 (ab, J ) 12.5 Hz, 2H), 4.46 (m, 1H), 4.53 (t, J )

6.6 Hz, 2H), 3.90 (m, 1H), 3.73 (m, 1H), 3.60 (s, 4H), 3.14 (t, J

) 6.6 Hz, 2H), 2.17 (m, 2H); HRMS (FAB) m/z 508.2313 [(M

+ H)⁺calcd for C₂₅H₃₀N₇O₅508.2308]. Anal. (C₂₅H₂₉N₇O₅‚1.4CF₃-

COOH) C, H, N, F.

3-[1-[2-(N-4,5-Dih yd r oim id a zol-2-yla m in o)eth yl]in d a -

zol-5-ylca r bon yla m in o]-2(S)-(ben zyloxyca r bon yla m in o)-

p r op ion ic a cid tr iflu or oa ceta te (18d ): from 12a and N-(2-

bromoethyl)phthalimide, as a white amorphous solid; ¹H NMR

(MeOH-d₄) δ 8.25 (s, 1H), 8.18 (s, 1H), 7.88 (d, J ) 8.8 Hz,

1H), 7.59 (d, J ) 8.8 Hz, 1H), 7.3-7.2 (5H), 5.06 (ab, J ) 12.5

Hz, 2H), 4.59 (t, J ) 5.5 Hz, 2H), 4.50 (dd, J ) 8.3, 4.6 Hz,

1H), 3.87 (dd, J ) 13.8, 4.6 Hz, 1H), 3.70 (m, 3H), 3.47 (s, 4H);

MS (ESI) m/z 494.3 (100%, M + H)⁺; HRMS (FAB) m/z

494.2133 [(M + H)⁺calcd for C₂₄H₂₈N₇O₅494.2152]. Anal.

(C₂₄H₂₇N₇O₅‚1.15CF₃COOH‚H₂O) C, H, N, F.

50 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 1

Batt et al.

3-[1-[4-(N-4,5-Dih yd r oim id a zol-2-yla m in o)bu tyl]in d a -

zol-5-ylca r bon yla m in o]-2(S)-(ben zyloxyca r bon yla m in o)-

p r op ion ic a cid tr iflu or oa ceta te (18e): from 12a and N-(4-

bromobutyl)phthalimide, as a white amorphous solid; ¹H NMR

(MeOH-d₄) δ 8.24 (s, 1H), 8.12 (s, 1H), 7.85 (d, J ) 8.8 Hz,

1H), 7.62 (d, J ) 8.8 Hz, 1H), 7.3-7.2 (5H), 5.06 (ab, J ) 12.8

Hz, 2H), 4.5 (m, 3H), 3.86 (dd, J ) 13.7, 4.6 Hz, 1H), 3.71 (dd,

J ) 13.7, 8.4 Hz, 1H), 3.62 (s, 4H), 3.15 (t, J ) 6.6 Hz, 2H),

1.95 (m, 2H), 1.52 (m, 2H); HRMS (FAB) m/z 522.2479 [(M +

H)⁺calcd for C₂₆H₃₂N₇O₅522.2465]. Anal. (C₂₆H₃₁N₇O₅‚1.15CF₃-

COOH‚H₂O) C, H, N, F.

3-[2-[3-(N-4,5-Dih yd r oim id a zol-2-yla m in o)p r op yl]in d a -

zol-5-ylca r bon yla m in o]-2(S)-(ben zyloxyca r bon yla m in o)-

p r op ion ic a cid tr iflu or oa ceta te (19a ): from 14a (R ) Et,

n ) 3), as a white amorphous solid; ¹H NMR (MeOH-d₄) δ 8.39

(s, 1H), 8.24 (s, 1H), 7.69 (d, J ) 8.8 Hz, 1H), 7.63 (d, J ) 8.8

Hz, 1H), 7.3-7.2 (5H), 5.06 (ab, J ) 12.5 Hz, 2H), 4.55 (t, J )

6.6 Hz, 2H), 4.50 (dd, J ) 8.4, 4.8 Hz, 1H), 3.85 (dd, J ) 13.8,

4.8 Hz, 1H), 3.71 (dd, J ) 13.8, 8.4 Hz, 1H), 3.67 (s, 4H), 3.22

(t, J ) 6.6 Hz, 2H), 2.25 (m, 2H); HRMS (FAB) m/z 508.2308

[(M + H)⁺calcd for C₂₅H₃₀N₇O₅508.2308]. Anal. (C₂₅H₂₉N₇O₅‚

1.2CF₃COOH‚0.8H₂O) C, H, N, F.

3-[2-[3-(N-4,5-Dih yd r oim id a zol-2-yla m in o)p r op yl]in d a -

zol-6-ylca r bon yla m in o]-2(S)-(ben zyloxyca r bon yla m in o)-

p r op ion ic a cid tr iflu or oa ceta te (19b): from 12b via 14b,

as a white amorphous solid; ¹H NMR (MeOH-d₄) δ 8.30 (s, 1H),

8.11 (s, 1H), 7.76 (d, J ) 8.8 Hz, 1H), 7.46 (d, J ) 8.8 Hz, 1H),

7.3-7.1 (m, 5H), 5.06 (ab, J ) 12.5 Hz, 1H), 4.56 (t, J ) 6.6

Hz, 2H), 4.52 (dd, J ) 8.1, 4.8 Hz, 1H), 3.86 (dd, J ) 13.9, 4.8

Hz, 1H), 3.72 (dd, J ) 13.9, 8.2 Hz, 1H), 3.66 (s, 4H), 3.21 (t,

J ) 6.6 Hz, 2H), 2.25 (m, 2H); HRMS (FAB) m/z 508.2285 [(M

+ H)⁺calcd for C₂₅H₃₀N₇O₅508.2308]. Anal. (C₂₅H₂₉N₇O₅‚1.5CF₃-

COOH) C, H, N, F.

Eth yl 1-(2-Cya n oeth yl)in d a zole-5-ca r boxyla te (20). A

solution of 12a (76 g, 400 mmol), acrylonitrile (158 mL, 2.4

mol), and sodium bis(trimethylsilyl)amide (1.0 M in THF; 20.0

mL, 20.0 mmol) in EtOH (800 mL) was heated to reflux. After

2 h the solution was cooled and treated with HCl (1.0 M; 30

mL, 30 mmol). Partial concentration under vacuum provided

a solid. Water (2000 mL) was added and the solid was collected

by filtration, rinsed with water, and dried to provide 20 (87.6

g, 90%) as a pale yellow fluffy solid: mp 106-109 °C; ¹H NMR

(CDCl₃) δ 8.54 (s, 1H), 8.16 (s, 1H), 8.13 (d, J ) 9.1 Hz, 1H),

7.48 (d, J ) 9.1 Hz, 1H), 4.70 (t, J ) 6.6 Hz, 2H), 4.42 (q, J )

7.0 Hz, 2H), 3.03 (t, J ) 6.6 Hz, 2H), 1.43 (t, J ) 7.0 Hz, 3H);

HRMS (NH₃-CI) m/z 244.1070 [(M + H)⁺calcd for C₁₃H₁₄N₃O₂

244.1086]. Anal. (C₁₃H₁₃N₃O₂) C, H, N.

Eth yl 1-(3-Am in op r op yl)in d a zole-5-ca r boxyla te Hy-

d r och lor id e (21). A mixture of 20 (60 g, 260 mmol), PtO₂(6.0

g), EtOH (1600 mL), and CHCl₃(200 mL) was shaken in a

pressure bottle under H₂(40 psig) for 19 h. The mixture was

filtered through Celite and the solids were washed with EtOH.

The filtrate was concentrated and the residue was dissolved

in aqueous NaHCO₃and washed with EtOAc. The aqueous

phase was acidified with HCl and concentrated to provide

crude 21 in quantitative yield. This was recrystallized (EtOH)

to provide a white solid (36.6 g, 57%): mp 198-200 °C; ¹H

NMR (DMSO-d₆) δ 8.49 (s, 1H), 8.32 (s, 1H), 8.07 (bs, 3H),

7.98 (d, J ) 8.8 Hz, 1H), 7.85 (d, J ) 8.8 Hz, 1H), 4.58 (t, J )

6.8 Hz, 2H), 4.34 (q, J ) 7.0 Hz, 2H), 2.80 (bm, 2H), 2.14 (m,

2H), 1.34 (t, J ) 7.0 Hz, 3H); HRMS (NH₃-CI) m/z 248.1396

[(M + H)⁺calcd for C₁₃H₁₈N₃O₂248.1399]. Anal. (C₁₃H₁₇N₃O₂‚

1.05HCl) C, H, N, Cl.

Eth yl 1-(3-[N-(1-Oxid o-2-p yr id yl)a m in o]p r op yl)in d a -

zole-5-ca r boxyla te (22a ). A mixture of 21 (600 mg, 2.4

mmol), 2-chloropyridine 1-oxide hydrochloride (806 mg, 4.9

mmol), NaHCO₃(816 mg, 9.7 mmol), and nBuOH (7 mL) was

stirred at 100 °C for 21 h, then was cooled and filtered. The

filtrate was concentrated and the residue was purified by flash

chromatography (CH₂Cl₂:MeOH 95:5) to provide 22a (675 mg,

81%) as a pale yellow solid: mp 87-89 °C; ¹H NMR (CDCl₃) δ

8.52 (s, 1H), 8.15 (s, 1H), 8.13 (dd, J ) 6.6, 1.1 Hz, 1H), 8.03

(dd, J ) 8.8, 1.5 Hz, 1H), 7.39 (d, J ) 8.8 Hz, 1H), 7.10 (t, J )

7.3 Hz, 1H), 6.93 (bm, 1H), 6.56 (t, J ) 6.6 Hz, 1H), 6.41 (dd,

J ) 8.4, 1.5 Hz, 1H), 4.57 (t, J ) 6.6 Hz, 2H), 4.40 (q, J ) 7.0

Hz, 2H), 3.24 (q, J ) 6.6 Hz, 2H), 2.38 (m, 2H), 1.40 (t, J )

7.0 Hz, 3H); HRMS (NH₃-CI) m/z 341.1622 [(M + H)⁺calcd

for C₁₈H₂₁N₄O₃341.1614]. Anal. (C₁₈H₂₀N₄O₃) C, H, N.

Eth yl 1-(3-[N-(2-P yr id yl)a m in o]p r op yl)in d a zole-5-ca r -

boxyla te (22b). 22a (2.90 g, 8.5 mmol), 10% Pd on charcoal

(580 mg), and EtOH (50 mL) were shaken under H₂(60 psig)

for 60 h. The mixture was filtered through Celite and the solids

were rinsed with EtOH. Concentration provided 22b (2.40 g,

88%) as a glass: ¹H NMR (CDCl₃) δ 8.52 (s, 1H), 8.12 (s, 1H),

8.06 (m, 2H), 7.38 (m, 2H), 6.55 (m, 1H), 6.32 (m, 1H), 4.70

(bm, 1H), 4.53 (t, J ) 6.6 Hz, 2H), 4.40 (q, J ) 7.3 Hz, 2H),

3.30 (m, 2H), 2.24 (m, 2H), 1.42 (t, J ) 7.3 Hz, 3H); HRMS

(NH₃-CI) m/z 325.1659 [(M + H)⁺calcd for C₁₈H₂₁N₄O₂

325.1665].

1-(3-[N-(2-P yr id yl)-N-ter t-b u t oxyca r b on yla m in o]p r o-

p yl)in d a zole-5-ca r boxylic Acid (23a ). A solution of 22b

(2.25 g, 6.9 mmol), CH₂Cl₂(75 mL), Et₃N (1.5 mL), and N,N-

dimethylaminopyridine (225 mg) was stirred at 0 °C. Di-tert-

butyl dicarbonate (2.26 g, 10.3 mmol) was added and the

mixture was stirred for 16 h. Concentration and purification

by flash chromatography (hexanes:EtOAc 65:35) gave the Boc-

protected amine (1.92 g, 65%) as a clear oil: ¹H NMR (CDCl₃)

δ 8.50 (d, J ) 1.5 Hz, 1H), 8.28 (m, 1H), 8.08 (s, 1H), 8.04 (dd,

J ) 8.8, 1.5 Hz, 1H), 7.60 (m, 2H), 7.37 (d, J ) 8.8 Hz, 1H),

6.99 (m, 1H), 4.46 (t, J ) 7.3 Hz, 2H), 4.41 (q, J ) 7.0 Hz,

2H), 4.02 (m, 2H), 2.34 (m, 2H), 1.42 (t, J ) 7.0 Hz, 3H), 1.42

(s, 9H); HRMS (NH₃-CI) m/z 425.2193 [(M + H)⁺calcd for

C₂₃H₂₉N₄O₄425.2189]. A mixture of this material (1.8 g, 4.2

mmol), water (25 mL), EtOH (25 mL), and aqueous NaOH (1.0

M; 9 mL, 9 mmol) was heated at reflux for 16 h. The mixture

was cooled and acidified with HCl (1.0 M; 10 mL, 10 mmol) to

give a gum. The liquid was decanted and the residue was

triturated several times with hexane to provide 23a (1.27 g,

1

75%) as a solid: mp 129-131 °C; H NMR (CDCl₃) δ 8.59 (s,

1H), 8.30 (m, 1H), 8.12 (s, 1H), 8.07 (d, J ) 8.8 Hz, 1H), 7.61

(m, 2H), 7.41 (d, J ) 8.8 Hz, 1H), 7.00 (m, 1H), 4.46 (t, J ) 7.2

Hz, 2H), 4.01 (t, J ) 7.2 Hz, 2H), 2.34 (m, 2H), 1.42 (s, 9H);

HRMS (NH₃-CI) m/z 397.1878 [(M + H)⁺calcd for C₂₁H₂₅N₄O₄

397.1876]. Anal. (C₂₁H₂₄N₄O₄) C, H, N.

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon yla m in o]-2(S)-(b en zyloxyca r b on yla m in o)p r op ion ic

Acid Tr iflu or oa ceta te (24d ). A mixture of 23a (1.19 g, 3.0

mmol), 6 (880 mg, 3.0 mmol), HOBT (410 mg, 3.0 mmol), and

THF (20 mL) was treated with DCC (660 mg, 3.2 mmol) and

stirred for 24 h. The mixture was filtered, the filtrate concen-

trated and the residue purified by flash chromatography

(hexanes:EtOAc 50:50) to provide the amide (1.81 g, 89%) as

a glass: ¹H NMR (CDCl₃) δ 8.28 (d, J ) 5.1 Hz, 1H), 8.17 (s,

1H), 8.04 (s, 1H), 7.77 (d, J ) 8.8 Hz, 1H), 7.60 (m, 2H), 7.4-

7.25 (m, 6H), 6.98 (m, 2H), 5.88 (bm, 1H), 5.13 (s, 2H), 4.47

(bm, 1H), 4.46 (t, J ) 7.2 Hz, 2H), 4.01 (t, J ) 7.0 Hz, 2H),

3.87 (m, 2H), 2.31 (m, 2H), 1.48 (s, 9H), 1.43 (s, 9H); HRMS

(NH₃-CI) m/z 673.3324 [(M + H)⁺calcd for C₃₆H₄₄N₆O₇

673.3350]. This material (32 mg, 47 µmol) was dissolved in

CH₂Cl₂(5 mL) and TFA (300 µL) and stirred for 16 h. The

solution was concentrated and the residue was triturated with

ether to provide 24d (25 mg, 83%) as a hygroscopic white

solid: ¹H NMR (MeOH-d₄) δ 8.23 (s, 1H), 8.14 (s, 1H), 7.8 (m,

2H), 7.72 (d, J ) 5.5 Hz, 1H), 7.58 (d, J ) 8.8 Hz, 1H), 7.3-

7.2 (m, 5H), 6.91 (d, J ) 9.2 Hz, 1H), 6.80 (t, J ) 7.0 Hz, 1H),

5.02 (ab, J ) 12.5 Hz, 2H), 4.58 (t, J ) 6.6 Hz, 2H), 4.50 (dd,

J ) 8.1, 4.9 Hz, 1H), 3.86 (dd, J ) 13.7, 4.9 Hz, 1H), 3.71 (dd,

J ) 13.7, 8.1 Hz, 1H), 3.30 (t, J ) 6.6 Hz, 2H), 2.30 (m, 2H);

HRMS (FAB) m/z 517.2213 [(M + H)⁺calcd for C₂₇H₂₉N₆O₅

517.2199]. Anal. (C₂₇H₂₈N₆O₅‚1.1CF₃COOH) C, H, N.

3-[N-Met h yl-N-[1-[3-(N-p yr id in -2-yla m in o)p r op yl]in -

d a zol-5-ylca r bon yl]a m in o]-2(S)-(2,4,6-tr im eth ylben zen e-

su lfon yla m in o)p r op ion ic Acid Tr iflu or oa ceta te (24b).

23a (61 mg, 153 µmol) and 9 (48 mg, 153 µmol) were coupled

using the procedure described for 24d to give a colorless glass

(106 mg, 100%): ¹H NMR (CDCl₃) δ 8.30 (m, 1H), 8.02 (s, 1H),

7.83 (s, 1H), 7.61 (m, 2H), 7.46 (m, 1H), 7.38 (m, 1H), 6.98 (m,

1H), 6.95 (s, 2H), 6.05 (bm, 1H), 4.47 (t, J ) 7.0 Hz, 2H), 4.30

Indazoles as Antagonists of the Integrin R_vâ₃

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 1 51

(bm, 1H), 4.01 (t, J ) 7.0 Hz, 2H), 3.97 (bm, 1H), 3.73 (dd, J

) 13.6, 4.8 Hz, 1H), 3.54 (s, 3H), 3.10 (s, 3H), 2.66 (s, 6H),

2.31 (m, 2H), 2.28 (s, 3H), 1.43 (s, 9H); HRMS (FAB) m/z

693.3045 [(M + H)⁺calcd for C₃₅H₄₅N₆O₇S 693.3070]. This

material was dissolved in THF (1.5 mL) and water (1.5 mL)

and treated with LiOH (1.0 M; 160 µL, 160 µmol). After 19 h,

HCl (1.0 M; 160 µL) was added and the mixture was concen-

trated. The residue was stirred in CH₂Cl₂(2 mL) with

trifluoroacetic acid (2 mL) for 4.5 h. The mixture was concen-

trated and purifed by HPLC to provide 24b (65 mg, 74%) as a

white powder after lyophilization: ¹H NMR (DMSO-d₆) δ 8.78

(bm, 1H), 8.22 (bm, 1H), 8.18 (s, 1H), 7.87 (m, 2H), 7.70 (m,

2H), 7.31 (d, J ) 10.3 Hz, 1H), 7.02 (m, 1H), 7.00 (s, 2H), 6.84

(t, J ) 6.6 Hz, 1H), 4.56 (t, J ) 6.6 Hz, 2H), 4.19 (m, 1H), 3.93

(m, 1H), 3.35 (m, 1H), 3.28 (m, 2H), 2.92 (s, 3H), 2.58 (s, 6H),

2.23 (s, 3H), 2.19 (m, 2H); HRMS (FAB) m/z 579.2392 [(M +

H)⁺calcd for C₂₉H₃₅N₆O₅S 579.2390]. Anal. (C₂₉H₃₄N₆O₅S‚

2.2CF₃COOH) C, H, N.

dried and concentrated to provide 26 (1.6 g, 56%) as a sticky

solid: ¹H NMR (DMSO-d₆) δ 8.44 (s, 1H), 8.25 (s, 1H), 7.93 (d,

J ) 8.8 Hz, 1H), 7.72 (d, J ) 8.8 Hz, 1H), 7.35 (m, 5H), 5.00

(s, 2H), 4.46 (t, J ) 7.0 Hz, 2H), 3.01 (q, J ) 7.0 Hz, 2H), 1.98

(m, 2H). This acid (100 mg, 283 µmol) was coupled with 8 (R

) tert-butyl, Ar ) mesityl) (107 mg, 283 µmol) using DCC as

described for the preparation of 24d to give 27 (130 mg, 68%)

as a yellowish solid: ¹H NMR (CDCl₃) δ 8.24 (s, 1H), 8.09 (s,

1H), 7.85 (d, J ) 8.8 Hz, 1H), 7.42 (d, J ) 8.8 Hz, 1H), 7.36

(m, 5H), 6.93 (s, 2H), 6.83 (m, 1H), 5.78 (d, J ) 7.3 Hz, 1H),

5.09 (s, 2H), 4.47 (t, J ) 6.6 Hz, 2H), 4.02 (m, 1H), 3.84 (m,

1H), 3.62 (m, 1H), 3.46 (m, 1H), 3.18 (m, 2H), 2.66 (s, 6H),

2.26 (s, 3H), 2.15 (m, 2H), 1.21 (s, 9H); MS (ESI) m/z 678.4

[(M + H)⁺, 100%].

ter t-Bu tyl 3-(1-[3-Am in op r op yl]in d a zol-5-ylca r bon yl-

am in o)-2(S)-(2,4,6-tr im eth ylben zen esu lfon ylam in o)pr opio-

n a te (28). A mixture of 27 (50 mg, 74 µmol), Pd(OH)₂on

charcoal (15 mg), 1,4-cyclohexadiene (1 mL), and MeOH (2 mL)

was heated at reflux for 4 h. The mixture was cooled and

filtered through Celite, and the solids were rinsed with MeOH.

The filtrate was concentrated to provide 28 (34 mg, 85%) as a

solid which was used without purification: ¹H NMR (CDCl₃)

δ 8.03 (s, 1H), 7.80-7.65 (m, 3H), 7.31 (d, J ) 8.8 Hz, 1H),

6.84 (s,H), 4.40 (m, 2H), 4.02 (m, 1H), 3.78 (m, 2H), 3.06 (m,

2H), 2.63 (m, 1H), 2.59 (s, 6H), 2.27 (m, 2H), 2.19 (s, 3H), 1.23

(s, 9H); MS (ESI) m/z 544.5 [(M + H)⁺, 100%].

3-[1-[3-(N-4,5-Dih yd r oim id a zol-2-yla m in o)p r op yl]in d a -

zol-5-ylcar bon ylam in o]-2(S)-(2,4,6-tr im eth ylben zen esu lfo-

n yla m in o)p r op ion ic Acid Tr iflu or oa ceta te (29a ). A mix-

ture of 28 (60 mg, 110 µmol), 2-methylthio-4,5-dihydroimidazole

hydroiodide (32 mg, 130 µmol), and pyridine (5 mL) was heated

at 120 °C for 18 h. After concentration, the residue was purified

by flash chromatography (CH₂Cl₂:MeOH 90:10), deprotected

by treatment with TFA (1 mL) and CH₂Cl₂(2 mL), and purified

by HPLC to provide 29a (15 mg, 22%) as an amorphous white

solid: ¹H NMR (MeOH-d₄) δ 8.18 (s, 2H), 7.80 (d, J ) 8.8, 1.5

Hz, 1H), 7.58 (d, J ) 8.8 Hz, 1H), 6.79 (s, 2H), 4.54 (t, J ) 6.6

Hz, 2H), 4.16 (dd, J ) 9.2, 4.8 Hz, 1H), 3.78 (dd, J ) 13.6, 4.8

Hz, 1H), 3.60 (s, 4H), 3.48 (dd, J ) 13.6, 9.2 Hz, 1H), 3.18 (t,

J ) 6.6 Hz, 2H), 2.58 (s, 6H), 2.25 (m, 2H), 2.02 (s, 3H); HRMS

(FAB) m/z 556.2343 [(M + H)⁺calcd for C₂₆H₃₄N₇O₅S 556.2342].

Anal. (C₂₆H₃₃N₇O₅S‚0.9CF₃COOH‚0.8H₂O) C, H, N.

3-[1-[3-(N-(3,4,5,6-Tet r a h yd r op yr im id in -2-yl)a m in o)-

p r op yl]in d a zol-5-ylca r bon yla m in o]-2(S)-(2,4,6-tr im eth yl-

ben zen esu lfon yla m in o)p r op ion ic Acid Tr iflu or oa ceta te

(29b). Using the same procedure, 28 and 2-methylthio-3,4,5,6-

tetrahydropyrimidine hydroiodide were converted to 29b as

an amorphous solid after HPLC purification: ¹H NMR (DMSO-

d₆) δ 8.47 (m, 1H), 8.25 (s, 1H), 8.19 (s, 1H), 8.06 (d, J ) 9.5

Hz, 2H), 7.80 (d, J ) 9.5 Hz, 2H), 7.32 (m, 1H), 6.84 (s, 1H),

4.47 (t, J ) 13.6 Hz, 2H), 4.02 (dd, J ) 9.2, 4.8 Hz, 1H), 3.58

(m, 2H), 3.20 (m, 4H), 3.03 (m, 2H), 2.55 (s, 6H), 2.17 (s, 3H),

2.07 (m, 2H), 1.78 (m, 2H); HRMS (FAB) m/z 570.2509 [(M +

H)⁺calcd for C₂₇H₃₆N₇O₅S 570.2498]. Anal. (C₂₇H₃₆N₇O₅S‚

2.3CF₃COOH‚H₂O) C, H, N.

Using the procedures described for preparing 24d , the

following compounds were prepared from 23a .

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon yla m in o]p r op ion ic a cid tr iflu or oa ceta te (24c): from

â-alanine tert-butyl ester, as as an amorphous white solid; ¹H

NMR (MeOH-d₄) δ 8.24 (s, 1H), 8.14 (s, 1H), 7.83 (m, 2H), 7.73

(d, J ) 5.5 Hz, 1H), 7.58 (d, J ) 8.8 Hz, 1H), 6.94 (d, J ) 9.2

Hz, 1H), 6.82 (t, J ) 6.6 Hz, 1H), 4.57 (t, J ) 6.6 Hz, 2H), 3.63

(t, J ) 6.6 Hz, 2H), 3.30 (m, 2H), 2.57 (t, J ) 7.0 Hz, 2H), 2.30

(m, 2H); HRMS (FAB) m/z 368.1721 [(M + H)⁺calcd for

C₁₉H₂₂N₅O₃368.1722]. Anal. (C₁₉H₂₁N₅O₃‚2.6CF₃COOH‚1.3CH₃-

CN) C, H, N.

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon yla m in o]-3(S)-(2-p h en ylet h yla m in oca r bon yl)p r op i-

on ic a cid tr iflu or oa ceta te (24e): from (S)-aspartic acid

1-phenethylamide 4-tert-butyl ester, as as an amorphous white

solid; ¹H NMR (DMSO-d₆) δ 8.37 (s, 1H), 8.27 (s, 1H), 8.00

(m, 1H), 7.89 (m, 1H), 7.82 (m, 1H), 7.75 (m, 1H), 7.20 (m,

5H), 6.95 (d, J ) 8.8 Hz, 1H), 6.80 (t, J ) 6.6 Hz, 1H), 4.79

(m, 1H), 4.57 (t, J ) 6.6 Hz, 2H), 2.7 (m, 4H), 2.18 (m, 2H);

MS (ESI) m/z 515.4 (100%, M + H)⁺; HRMS (FAB) m/z

515.2433 [(M + H)⁺calcd for C₂₈H₃₁N₆O₄515.2406]. Anal.

(C₂₈H₃₀N₆O₄‚1.43CF₃COOH‚2.5CH₃CN) C, H, N.

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon ylam in o]-3(S)-(2,4,6-tr im eth ylph en ylam in ocar bon yl)-

p r op ion ic a cid tr iflu or oa ceta te (24f): from (S)-aspartic

acid 1-(2,4,6-trimethylphenylamide) 4-tert-butyl ester, as as

an amorphous white solid; ¹H NMR (MeOH-d₄) δ 8.31 (s, 1H),

8.16 (s, 1H), 7.83 (m, 2H), 7.71 (d, J ) 6.2 Hz, 1H), 7.60 (d, J

) 8.8 Hz, 1H), 6.94 (m, 3H), 6.80 (t, J ) 6.3 Hz, 1H), 4.79 (t,

J ) 6.2 Hz, 2H), 4.56 (t, J ) 6.6, 2H), 3.28 (m, 2H), 3.26 (m,

2H), 2.27 (m, 8H), 2.06 (s, 3H); HRMS (FAB) m/z 529.2551

[(M + H)⁺calcd for C₂₉H₃₃N₆O₄529.2563]. Anal. (C₂₉H₃₂N₆O₄‚

1.2CF₃COOH) C, H, N.

Eth yl 1-(3-Ben zyloxyca r bon yla m in op r op yl)in d a zole-

5-ca r boxyla te (25). A solution of 21 (5.0 g, 18 mmol) and Et₃N

(7.5 mL, 19 mmol) in CH₂Cl₂(100 mL) was cooled on ice,

treated with benzyl chloroformate (2.7 mL, 19 mmol), and

stirred for 16 h. After concentration, the residue was dissolved

in CH₂Cl₂, washed with water, dried, and concentrated to

provide 25 (3.4 g, 49%) as a white solid. While this material

was suitable for further use, it could be purified by flash

chromatography (CH₂Cl₂:MeOH 95:5): ¹H NMR (CDCl₃) δ 8.50

(s, 1H), 8.06 (m, 2H), 7.38 (m, 6H), 5.20 (bm, 1H), 5.02 (s, 2H),

4.42 (m, 4H), 3.18 (m, 2H), 2.18 (m, 2H), 1.40 (t, J ) 7.2 Hz,

3H); MS (ESI) m/z 382.5 [(M + H)⁺, 100%].

Eth yl 1-[2-(1,3-Dioxola n -2-yl)eth yl]in d a zole-5-ca r boxy-

la te (30). A solution of 12a (74.5 g, 397 mmol) in THF (1000

mL) was treated with sodium bis(trimethylsilyl)amide (1.0 M

in THF; 430 mL, 430 mmol), 18-crown-6 (1.5 g), and 2-(2-

bromoethyl)-1,3-dioxolane (90 g, 496 mmol). The solution was

heated at reflux for 20 h, cooled, and concentrated. The residue

was partitioned between toluene and water. The aqueous

phase was further extracted with toluene, and the combined

organic phases were washed with water and brine, then dried

and concentrated. The resulting oil was chromatographed

(toluene, then 185:15 toluene-EtOAc) to provide 30 (71.0 g,

55%): ¹H NMR (CDCl₃) δ 8.49 (s, 1H), 8.10 (s, 1H), 8.06 (d, J

) 9.2 Hz, 1H), 7.46 (d, J ) 9.2 Hz, 1H), 4.84 (t, J ) 4.4 Hz,

1H), 4.55 (t, J ) 7.0 Hz, 2H), 4.41 (q, J ) 7.0 Hz, 2H), 3.90

(m, 4H), 2.31 (m, 2H), 1.42 (t, J ) 7.0 Hz, 3H); HRMS (NH₃-

CI) m/z 291.1328 [(M + H)⁺calcd for C₁₅H₁₉N₂O₄291.1345].

ter t-Bu t yl 3-(1-[3-Ben zyloxyca r b on yla m in op r op yl]-

in d a zol-5-ylca r bon yla m in o)-2(S)-(2,4,6-tr im eth ylben ze-

n esu lfon yla m in o)p r op ion a te (27). 25 (3.08 g, 8.07 mmol)

was dissolved in EtOH (160 mL) and water (40 mL) and

treated with LiOH (678 mg, 16.2 mmol). THF was added until

the mixture was homogeneous, then stirring was continued

for 5 days. After concentration, the residue was taken up in

water and washed with EtOAc, and the aqueous phase was

acidified to pH 4-5 with aqueous HCl (1.0 M). The resulting

mixture was extracted with EtOAc, and the organic phase was

Eth yl 1-[3-Oxop r op yl]in d a zole-5-ca r boxyla te (31). A

mixture of 30 (73.0 g, 256 mmol), HOAc (365 g), and water

(1020 mL) was heated at 70 °C for 20 h, cooled, and extracted

52 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 1

Batt et al.

with CH₂Cl₂(5 × 500 mL). The extract was washed cautiously

with aqueous NaHCO₃until no more gas was evolved, then

with water and brine, then was dried and concentrated to give

31 (60.9 g, 98%) as a light yellow solid: ¹H NMR (CDCl₃) δ

9.87 (s, 1H), 8.50 (s, 1H), 8.10 (d, J ) 8.8 Hz, 1H), 8.10 (s,

1H), 7.51 (d, J ) 8.8 Hz, 1H), 4.70 (t, J ) 6.2 Hz, 2H), 4.41 (q,

J ) 7.2 Hz, 2H), 3.19 (t, J ) 6.2 Hz, 2H), 1.42 (t, J ) 7.2 Hz,

3H); HRMS (NH₃-CI) m/z 247.1068 [(M + H)⁺calcd for

C₁₃H₁₅N₂O₃247.1083].

(1 mL) was stirred for 1 h, concentrated, and purified by HPLC

to provide 34a (121 mg, 82%) as an amorphous white solid

after lyophilization: ¹H NMR (MeOH-d₄) δ 8.12 (s, 2H), 7.72

(dd, J ) 8.8, 1.5 Hz, 1H), 7.54 (d, J ) 8.8 Hz, 1H), 6.76 (s,

2H), 6.73 (s, 2H), 4.53 (t, J ) 6.6 Hz, 2H), 4.16 (dd, J ) 9.2,

4.8 Hz, 1H), 3.76 (dd, J ) 13.6, 4.8 Hz, 1H), 3.49 (dd, J ) 13.6,

9.2 Hz, 1H), 3.23 (t, J ) 6.6 Hz, 2H), 2.56 (s, 6H), 2.22 (m,

2H), 1.98 (s, 3H); HRMS (FAB) m/z 554.2196 [(M + H)⁺calcd

for C₂₆H₃₂N₇O₅S 554.2186]. Anal. (C₂₆H₃₁N₇O₅S‚0.9CF₃COOH)

C, H, N, S, F.

Eth yl 1-[3-(N-(1-Tr ip h en ylm eth ylim id a zol-2-yla m in o)-

p r op yl]in d a zole-5-ca r boxyla te (32a ). A mixture of 31 (10.0

g, 40.6 mmol), 1-triphenylmethyl-2-aminoimidazole²²(13.2 g,

40.6 mmol), and toluene (500 mL) was heated at reflux under

a Dean-Stark trap. Toluene (300 mL) was removed while

adding an equivalent amount; the mixture was then heated

further for 20 h, when NMR analysis of an aliquot showed the

absence of aldehyde. The mixture was cooled, NaBH(OAc)₃

(34.42 g, 162.4 mmol) was added, stirring was continued for

20 h, and the reaction was poured into water. The layers were

separated and the aqueous phase was extracted with EtOAc.

The combined extracts were washed with aqueous NaHCO₃,

water, and brine, then were dried and concentrated to provide

a crude product (25.0 g). This was purified by flash chroma-

tography (toluene:EtOAc, step gradient from 90:10 to 50:50)

to provide 32a (11.2 g, 52%) as an oil which slowly solidified:

¹H NMR (CDCl₃) δ 8.45 (s, 1H), 7.97 (s, 1H), 7.93 (d, J ) 8.8

Hz, 1H), 7.33 (m, 9H), 7.21 (m, 6H), 6.99 (d, J ) 8.8 Hz, 1H),

6.67 (d, J ) 1.8 Hz, 1H), 6.41 (d, J ) 1.8 Hz, 1H), 4.41 (q, J )

7.2 Hz, 2H), 4.06 (t, J ) 6.6 Hz, 2H), 2.98 (m, 3H), 1.81 (m,

2H), 1.42 (t, J ) 7.2 Hz, 3H); HRMS (FAB) m/z 556.2725 [(M

+ H)⁺calcd for C₃₅H₃₄N₅O₂556.2713].

1-[3-(N-(1-Tr iph en ylm eth ylim idazol-2-yl)am in o)pr opyl]-

in d a zole-5-ca r boxylic Acid (33a ). A mixture of 32a (10.5

g, 18.9 mmol), EtOH (300 mL), and aqueous NaOH (1.0 M;

105 mL, 105 mmol) was heated at reflux for 4 h. The solution

was cooled and concentrated to remove the EtOH. The pH of

the aqueous residue was adjusted to 4, the mixture was

extracted with CH₂Cl₂, and the organic phases were dried (Na₂-

SO₄). The mixture was filtered and the solids were washed

with DMF to recover precipitated product. The combined

filtrates were concentrated, and the residue was washed with

EtOH and dried to provide 33a (8.5 g, 85%) as a white solid:

¹H NMR (DMSO-d₆) δ 8.39 (s, 1H), 8.13 (s, 1H), 7.87 (d, J )

8.8 Hz, 1H), 7.36 (m, 10H), 7.12 (d, J ) 8.8 Hz, 6H), 6.51 (d,

J ) 1.8 Hz, 1H), 6.28 (d, J ) 1.8 Hz, 1H), 4.05 (t, J ) 6.7 Hz,

2H), 2.84 (m, 2H), 1.63 (m, 2H); HRMS (FAB) m/z 528.2418

[(M + H)⁺calcd for C₃₃H₃₀N₅O₂528.2400]. Anal. (C₃₃H₂₉N₅O₂‚

0.2H₂O) C, H, N.

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-4-ylca r -

bon ylam in o]-2(S)-(2,4,6-tr im eth ylben zen esu lfon ylam in o)-

p r op ion ic Acid Tr iflu or oa ceta te (34b). This compound was

prepared as described for 33a and 34a from 12c as an

amorphous white solid: ¹H NMR (MeOH-d₄) δ 8.36 (m, 2H),

7.70 (d, J ) 8.0 Hz, 1H), 7.37 (m, 2H), 6.75 (s, 2H), 6.72 (s,

2H), 4.52 (t, J ) 6.2 Hz, 2H), 4.20 (m, 1H), 3.80 (dd, J ) 13.5,

4.7 Hz, 1H), 3.52 (dd, J ) 13.5, 9.1 Hz, 1H), 3.21 (t, J ) 6.6

Hz, 2H), 2.55 (s, 6H), 2.19 (m, 2H), 2.04 (s, 3H); HRMS (FAB)

m/z 554.2192 [(M + H)⁺calcd for C₂₆H₃₂N₇O₅S 554.2185]. Anal.

(C₂₆H₃₁N₇O₅S‚CF₃COOH) C, H, N.

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-5-ylca r -

b on yla m in o]-2(S)-(b en zyloxyca r bon yla m in o)p r op ion ic

Acid Tr iflu or oa ceta te (34c). This compound was prepared

by coupling 33a and 6 as described for the preparation of 34a .

Both the trityl and tert-butyl protecting groups were removed

by heating at reflux in TFA for 4 h, followed by concentration

and purification by HPLC, to provide 34c in 45% overall yield

as an amorphous white solid: ¹H NMR (MeOH-d₄) δ 8.23 (s,

1H), 8.22 (s, 1H), 7.79 (d, J ) 8.8 Hz, 1H), 7.55 (d, J ) 8.8 Hz,

1H), 7.23 (m, 5H), 6.76 (s, 2H), 5.02 (m, 2H), 4.52 (m, 3H),

3.86 (dd, J ) 13.6, 4.8 Hz, 1H), 3.72 (dd, J ) 13.9, 8.0 Hz,

1H), 3.22 (t, J ) 13.9 Hz, 2H), 2.1 (m, 2H); HRMS (FAB) m/z

506.2166 [(M + H)⁺calcd for C₂₅H₂₈N₇O₅506.2152]. Anal.

(C₂₅H₂₇N₇O₅‚1.2CF₃COOH‚1.5H₂O) C, H, N.

Using the procedures described for preparing 34a and 34c,

the following compounds were prepared from 33a .

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon ylam in o]-2(R)-(2,4,6-tr im eth ylben zen esu lfon ylam in o)-

p r op ion ic a cid tr iflu or oa ceta te (34d ): from the enanti-

omer of 8 (R ) tert-butyl, Ar ) mesityl), as an amorphous white

solid; ¹H NMR (MeOH-d₄) δ 8.14 (m, 2H), 7.75 (d, J ) 9.1 Hz,

1H), 7.56 (d, J ) 8.8 Hz, 1H), 6.77 (m, 4H), 4.55 (t, J ) 6.3

Hz, 2H), 4.18 (m, 1H), 3.75 (dd, J ) 13.6, 4.8 Hz, 1H), 3.48

(dd, J ) 13.5, 9.1 Hz, 1H), 3.23 (t, J ) 6.6 Hz, 2H), 2.57 (s,

6H), 2.23 (m, 2H) 2.01 (s, 3H); HRMS (FAB) m/z 554.2191 [(M

+ H)⁺calcd for C₂₆H₃₂N₇O₅S 554.2186]. Anal. (C₂₆H₃₁N₇O₅S‚CF₃-

COOH) C, H, N.

N -[1-[3-(N -I m id a zo l-2-y la m in o )p r o p y l]in d a zo l-5-

ylca r b on yl]-N′-(2,4,6-t r im et h ylb en zen esu lfon yl)et h yl-

en ed ia m in e tr iflu or oa ceta te (34e): from 51, as a white

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon ylam in o]-2(S)-(2,4,6-tr im eth ylben zen esu lfon ylam in o)-

p r op ion ic Acid Tr iflu or oa ceta te (34a ). A solution of 33a

(215 mg, 407 µmol), 8 (R ) tert-butyl, Ar ) mesityl) (140 mg,

407 µmol), DCC (87 mg, 407 µmol), and HOBT (57 mg, 407

µmol) in DMF (5 mL) was stirred for 24 h and poured into

water. The mixture was extracted with EtOAc, and the extract

was dried and concentrated. Purification by flash chromatog-

raphy (toluene:EtOAc 70:30) provided the coupled product (261

mg, 75%) as a soft solid: ¹H NMR (CDCl₃) δ 8.17 (s, 1H), 7.97

(s, 1H), 7.73 (d, J ) 8.8 Hz, 1H), 7.4-7.1 (15H), 6.99 (d, J )

8.8 Hz, 1H), 6.94 (s, 2H), 6.85 (bm, 1H), 6.68 (d, J ) 1.8 Hz,

1H), 6.42 (d, J ) 1.8 Hz, 1H), 5.82 (bm, 1H), 4.07 (t, J ) 7.0

Hz, 2H), 3.93 (m, 1H), 3.83 (m, 1H), 3.62 (m, 1H), 3.04 (m,

1H), 2.97 (m, 2H), 2.65 (s, 6H), 2.26 (s, 3H), 1.82 (m, 2H), 1.32

(s, 9H); MS (ESI) m/z 852.4 [(M + H)⁺,100%]. A solution of

this material (250 mg, 294 µmol) in MeOH (8 mL) and HOAc

(1 mL) was heated at reflux overnight, cooled, and concen-

trated. The residue was flash chromatographed (CHCl₃:MeOH:

aqueous NH₃90:10:1) to provide the detritylated product (145

mg, 81%) as a glassy foam: ¹H NMR (MeOH-d₄) δ 8.17 (s, 1H),

8.13 (s, 1H), 7.76 (d, J ) 8.8 Hz, 1H), 7.57 (d, J ) 8.8 Hz, 1H),

6.85 (s, 2H), 6.51 (s, 2H), 4.53 (t, J ) 7.0 Hz, 2H), 4.06 (m,

1H), 3.70 (m, 1H), 3.50 (m, 1H), 3.17 (t, J ) 7.0 Hz, 2H), 2.59

(s, 6H), 2.16 (m, 2H), 2.10 (s, 3H), 1.22 (s, 9H). A solution of

this material (135 mg, 222 µmol) in CH₂Cl₂(6 mL) and TFA

1

powder; H NMR (MeOH-d₄) δ 8.22 (s, 1H), 8.16 (s, 1H), 7.82

(d, J ) 9.2 Hz, 1H), 7.59 (d, J ) 9.2 Hz, 1H), 6.91 (s, 2H), 6.80

(s, 2H), 4.56 (m, 2H), 3.43 (m, 2H), 3.24 (m, 2H), 3.08 (m, 2H),

2.59 (s, 6H), 2.24 (m, 2 H), 2.17 (s, 3H); HRMS (FAB) m/z

510.2310 [(M + H)⁺calcd for C₂₅H₃₂N₇O₃S 510.2287]. Anal.

(C₂₅H₃₁N₇O₃S‚1.2CF₃COOH) C, H, N, S, F.

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon yla m in o]p r op ion ic a cid tr iflu or oa ceta te (34f): from

â-alanine tert-butyl ester, as an amorphous white solid; ¹H

NMR (MeOH-d₄) δ 8.26 (s, 1H), 8.15 (s, 1H), 7.84 (d, J ) 8.8

Hz, 1H), 7.59 (d, J ) 8.8 Hz, 1H), 6.78 (s, 2H), 4.55 (t, J ) 6.6

Hz, 2H), 3.63 (t, J ) 6.6 Hz, 2H), 3.23 (t, J ) 6.6 Hz, 2H), 2.64

(t, J ) 6.6 Hz, 2H), 2.23 (m, 2H); HRMS (FAB) m/z 357.1683

[(M + H)⁺calcd for C₁₇H₂₁N₆O₃357.1675]. Anal. (C₁₇H₂₀N₆O₃‚

1.06CF₃COOH) C, H, F; N: calcd, 17.61; found, 17.15.

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon ylam in o]-2(S)- (ben zen esu lfon ylam in o)pr opion ic acid

tr iflu or oa ceta te (34g): from 8 (R ) tert-butyl, Ar ) phenyl),

1

as an amorphous white solid; H NMR (MeOH-d₄) δ 8.21 (s,

1H), 8.15 (s, 1H), 7.80 (m, 3H), 7.56 (d, J ) 9.2 Hz, 1H), 7.40

(m, 3H), 4.55 (t, J ) 6.6 Hz, 2H), 4.23 (m, 1H), 3.77 (dd, J )

13.5, 5.1 Hz, 1H), 3.50 (dd, J ) 13.6, 8.8 Hz, 1H), 3.21 (t, J )

6.6 Hz, 2H), 2.23 (m, 2H); HRMS (FAB) m/z 512.1718 [(M +

Indazoles as Antagonists of the Integrin R_vâ₃

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 1 53

H)⁺calcd for C₂₃H₂₇N₇O₅S 512.1716]. Anal. (C₂₃H₂₆N₇O₅S‚

(s, 1H), 8.10 (s, 1H), 8.03 (d, J ) 8.8 Hz, 1H), 7.84 (d, J ) 2.9

Hz, 1H), 7.5-7.3 (m, 6H), 5.73 (d, J ) 2.9 Hz, 1H), 5.39 (s,

2H), 4.52 (t, J ) 6.2 Hz, 2H), 4.41 (q, J ) 7.0 Hz, 2H), 4.26

(bm, 1H), 3.24 (q, J ) 6.4 Hz, 2H), 2.23 (m, 2H), 1.43 (t, J )

6.4 Hz, 3H); HRMS (FAB) m/z 448.1971 [(M + H)⁺calcd for

C₂₄H₂₆N₅O₄448.1985]. A solution of 32b (217 mg, 485 µmol)

in EtOH (2.5 mL) was treated with LiOH (1.0 N; 1.5 mL, 1.5

mmol). After 22 h, HCl (1.0 N, 1.5 mL) was added and the

mixture was concentrated. The residue was coupled with 8 (R

) tert-butyl, Ar ) 2,4,6-trimethylphenyl) according to the

method for the preparation of 34a to give the product (111

mg, 38%) as a glassy foam: ¹H NMR (CDCl₃) δ 8.20 (s, 1H),

8.08 (s, 1H), 7.79 (d, J ) 8.8 Hz, 1H), 7.42 (d, J ) 8.8 Hz, 1H),

7.33 (d, J ) 2.6 Hz, 1H), 6.93 (s, 2H), 7.0-6.9 (m, 2H), 6.06

(bs, 1H), 5.56 (d, J ) 2.2 Hz, 1H), 4.53 (t, J ) 6.6 Hz, 2H),

4.0-3.6 (m, 4H), 3.15 (t, J ) 6.6 Hz, 2H), 2.65 (s, 6H), 2.26 (s,

3H), 2.23 (m, 2H), 1.30 (s, 9H); HRMS (FAB) m/z 610.2824

[(M + H)⁺calcd for C₃₀H₄₀N₇O₅S 610.2812]. This material (95

mg, 156 µmol) was deprotected with TFA (3 mL) in CH₂Cl₂(3

mL) for 6 h and purified by HPLC to provide 35 (54 mg, 54%)

as a white solid after lyophilization: ¹H NMR (DMSO-d₆) δ

8.44 (t, J ) 5.7 Hz, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.06 (d, J )

9.5 Hz, 1H), 7.80 (s, 1H), 7.76 (d, J ) 8.8 Hz, 1H), 7.69 (d, J

) 8.8 Hz, 1H), 6.82 (s, 2H), 4.53 (t, J ) 7 Hz, 2H), 4.01 (m,

1H), 3.57 (m, 1H), 3.40 (m, 1H), 3.10 (t, J ) 7 Hz, 2H), 2.53 (s,

6H), 2.10 (m, 2H), 2.05 (s, 3H); HRMS (FAB) m/z 554.2192

[(M + H)⁺calcd for C₂₆H₃₂N₇O₅S 554.2186]. Anal. (C₂₆H₃₁N₇-

O₅S‚1.4CF₃COOH) C, H, N, S, F.

1.1CF₃COOH) C, H, N.

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon yla m in o]-2(S)-(4-p h en ylben zen esu lfon yla m in o)p r o-

p ion ic a cid tr iflu or oa ceta te (34p ): from 8 (R ) methyl,

Ar ) 4-biphenyl), as an amorphous white solid; ¹H NMR

(MeOH-d₄) δ 8.14 (s, 1H), 8.06 (s, 1H), 7.83 (d, J ) 8.4 Hz,

2H), 7.71 (d, J ) 8.7 Hz, 1H), 7.53 (d, J ) 8.8 Hz, 2H), 7.34

(m, 6H), 6.77 (s, 2H), 4.42 (t, J ) 6.6 Hz, 2H), 4.29 (m, 1H),

3.79 (dd, J ) 13.5, 4.4 Hz, 1H), 3.49 (dd, J ) 13.5, 9.1 Hz,

1H), 3.19 (t, J ) 6.5 Hz, 2H), 2.16 (m, 2H); HRMS (FAB) m/z

588.2026 [(M + H)⁺calcd for C₂₉H₃₀N₇O₅S 588.2029]. Anal.

(C₂₉H₂₉N₇O₅S‚CF₃COOH) C, H, N.

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon yla m in o]-2(S)-(2,6-d ich lor oben zen esu lfon yla m in o)-

p r op ion ic a cid tr iflu or oa ceta te (34r ): from 8 (R ) methyl,

Ar ) 2,6-dichlorophenyl), as an amorphous white solid; ¹H

NMR (MeOH-d₄) δ 8.20 (s, 1H), 8.15 (s, 1H), 7.79 (d, J ) 8.8

Hz, 1H), 7.56 (d, J ) 8.8 Hz, 2H), 7.36 (d, J ) 7.7 Hz, 1H),

7.22 (m, 1H), 6.76 (s, 1H), 4.56 (t, J ) 6.6 Hz, 2H), 4.42 (m,

1H), 3.84 (dd, J ) 13.5, 4.4 Hz, 1H), 3.58 (dd, J ) 14.0, 9.2

Hz, 1H), 3.21 (t, J ) 6.6 Hz, 2H), 2.34 (m, 2H); HRMS (FAB)

m/z 580.0935 [(M + H)⁺calcd for C₂₃H₂₄Cl₂N₇O₅S 580.0937].

Anal. (C₂₃H₂₃Cl₂N₇O₅S‚CF₃COOH‚0.5CH₃CN) C, H, N.

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon yla m in o]-2(S)-(2,6-d im eth ylben zen esu lfon yla m in o)-

p r op ion ic a cid tr iflu or oa ceta te (34s): from 8 (R ) methyl,

Ar ) 2,6-dimethylphenyl), as an amorphous white solid; ¹H

NMR (MeOH-d₄) δ 8.12 (s, 1H), 8.11 (s, 1H), 7.73 (d, J ) 8.8

Hz, 1H), 7.52 (d, J ) 8.7 Hz, 1H), 6.96 (d, J ) 7.7 Hz, 2H),

6.75 (s, 2H), 4.52 (t, J ) 6.6 Hz, 2H), 4.17 (m, 1H), 3.76 (dd, J

) 13.6, 4.8 Hz, 1H), 3.52 (dd, J ) 13.5, 8.7 Hz, 1H), 3.21 (t, J

) 6.6 Hz, 2H), 2.60 (s, 6H), 2.21 (m, 2H); HRMS (FAB) m/z

540.2024 [(M + H)⁺calcd for C₂₅H₃₃N₆O₄S 540.2029]. Anal.

(C₂₅H₃₂N₆O₄S‚1.43CF₃COOH) C, H, N.

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-5-ylca r -

b on yla m in o]-2(S)-(4-p h en yl-2,6-d im et h ylb en zen esu lfo-

n yla m in o)p r op ion ic a cid tr iflu or oa ceta te (34t): from 8

(R ) tert-butyl, Ar ) 4-phenyl-2,6-dimethylphenyl), as an

amorphous white solid; ¹H NMR (MeOH-d₄) δ 8.06 (s, 1H), 7.95

(s, 1H), 7.63 (d, J ) 9.1 Hz, 2H), 7.29 (m, 6H), 7.10 (s, 2H),

4.34 (t, J ) 6.3 Hz, 2H), 4.27 (m, 1H), 3.77 (dd, J ) 13.5, 4.4

Hz, 1H), 3.50 (dd, J ) 13.51, 9.9 Hz, 1H), 3.17 (t, J ) 6.6 Hz,

2H), 2.66 (s, 6H), 2.11 (m, 2H); HRMS (FAB) m/z 616.2323

[(M + H)⁺calcd for C₃₁H₃₄N₇O₅S 616.2342]. Anal. (C₃₁H₃₃N₇-

O₅S‚CF₃COOH) C, H, N.

Eth yl 1-(2-Meth oxyca r bon yleth yl)in d a zole-5-ca r boxy-

la te (36). A solution of 12a (3.80 g, 20 mmol), methyl acrylate

(1.8 mL, 20 mmol), and tBuOH (1.91 mL, 20 mmol) in THF

(400 mL) was treated with KOtBu (1.0 M in THF; 1.0 mL, 1.0

mmol), heated at reflux for 45 min, cooled, treated with HCl

(1.0 N; 2 mL), and concentrated to provide crude 36 (5.40 g,

97%) which was used without further purification: ¹H NMR

(CDCl₃) δ 8.51 (s, 1H), 8.10 (s, 1H), 8.08 (d, J ) 9.2 Hz, 1H),

7.51 (d, J ) 9.2 Hz, 1H), 4.68 (t, J ) 6.6 Hz, 2H), 4.41 (q, J )

7.3 Hz, 2H), 3.63 (s, 3H), 3.01 (t, J ) 6.6 Hz, 2H), 1.42 (t, J )

7.3 Hz, 3H); MS (NH₃-CI) m/z 277.2 [(M + H)⁺, 100%].

Eth yl 1-(2-Ca r boxyeth yl)in d a zole-5-ca r boxyla te (37).

A solution of 36 (1.00 g, 3.62 mmol) in THF (7 mL) was treated

with a solution of LiOH (304 mg, 7.24 mmol) in water (7 mL)

and stirred vigorously for 5 min. HCl (1.0 N, 8 mL) was added,

followed by additional water (10 mL). The THF was removed

under vacuum and the resulting solid was isolated by filtration

to give 37 (820 mg, 86%) as an off-white solid: mp 102-110

1

°C; H NMR (CDCl₃) δ 8.50 (s, 1H), 8.12 (s, 1H), 8.08 (d, J )

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-5-ylca r -

b on yla m in o]-2(S)-(1-n a p h t h a len esu lfon yla m in o)p r op i-

on ic Acid Tr iflu or oa ceta te (34u ). 33a was coupled with 8

(R ) methyl, Ar ) 1-naphthyl) as described for the synthesis

of 34a . A solution of this product (216 mg, 260 µmol) in EtOH

(7 mL) was treated with NaOH (1.0 N; 1.3 mL, 1.3 mmol) and

heated at reflux for 5 h. The solution was cooled, treated with

aqueous HCl (1.0 N, 1.5 mL), and concentrated. The residue

was heated at reflux in TFA (2.5 mL) for 1.5 h, then

concentrated and purified by HPLC to provide 34u (118 mg,

67%) as an amorphous white solid: ¹H NMR (MeOH-d₄) δ 8.63

(d, J ) 8.8 Hz, 1H), 8.15 (d, J ) 7.3 Hz, 1H), 8.07 (s, 1H), 7.85

(m, 2H), 7.63 (d, J ) 8.1 Hz, 1H), 7.54 (m, 2H), 7.32-7.45 (3H),

6.76 (s, 2H), 4.52 (t, J ) 6.6 Hz, 2H), 4.22 (m, 1H), 3.50 (dd, J

) 13.6, 4.8 Hz, 1H), 3.22 (dd, J ) 13.6, 9.2 Hz, 1H), 3.22 (t, J

) 6.6 Hz, 2H), 2.21 (m, 2H); HRMS (FAB) m/z 562.1860 [(M

+ H)⁺calcd for C₂₇H₂₈N₇O₅S 562.1872]. Anal. (C₂₇H₂₇N₇O₅S‚CF₃-

COOH) C, H, N.

9.2 Hz, 1H), 7.48 (d, J ) 9.2 Hz, 1H), 4.67 (t, J ) 6.6 Hz, 2H),

4.41 (q, J ) 7.0 Hz, 2H), 3.05 (t, J ) 6.6 Hz, 2H), 1.41 (t, J )

7.0 Hz, 3H); MS (NH₃-CI) m/z 191.2 [(M + H - acrylic acid)⁺,

100%]. Anal. (C₁₃H₁₄N₂O₄) C, H, N.

Eth yl 1-(2-[N-Im id a zol-2-yla m in oca r bon yl]eth yl)in d a -

zole-5-ca r boxya te (38). A mixture of 37 (352 mg, 1.34 mmol),

2-aminoimidazole sulfate (0.55 g, 4.15 mmol), iPr₂NEt (1.17

mL, 6.7 mL), and DMF (7 mL) was treated with BOP reagent

(891 mg, 2.0 mmol) and warmed to 70 °C. After 18 h the

mixture was cooled and diluted with water. The resulting

precipitate was collected by filtration to provide 38 (310 mg,

71%) which was used without further purification: ¹H NMR

(CDCl₃) δ 8.49 (s, 1H), 8.11 (s, 1H), 8.07 (d, J ) 8.8 Hz, 1H),

7.55 (d, J ) 8.8 Hz, 1H), 4.75 (t, J ) 7.0 Hz, 2H), 4.41 (q, J )

7.3 Hz, 2H), 3.01 (t, J ) 7.0 Hz, 2H), 1.42 (t, J ) 7.3 Hz, 3H);

HRMS (NH₃-CI) m/z 328.1030 [(M + H)⁺calcd for C₁₆H₁₈N₅O₃

328.1046].

3-[1-[3-(N-P yr a zol-3-yla m in o)p r op yl]in d a zol-5-ylca r -

bon ylam in o]-2(S)-(2,4,6-tr im eth ylben zen esu lfon ylam in o)-

p r op ion ic Acid Tr iflu or oa ceta te (35). A solution of 1-Cbz-

3-aminopyrazole³⁷(282 mg, 1.3 mmol) and 31 (246 mg, 1.0

mmol) in 1,2-dichloroethane (5 mL) was treated with NaBH-

(OAc)₃(424 mg, 2.0 mmol). After 21 h, the mixture was treated

with aqueous NaHCO₃and extracted with CH₂Cl₂. The extract

was dried and concentrated, and the residue was purified by

flash chromatography (toluene:EtOAc 60:40) to provide 32b

(249 mg, 56%) as a pale yellow glass: ¹H NMR (CDCl₃) δ 8.51

3-[1-[2-(N-Im id a zol-2-yla m in oca r bon yl)eth yl]in d a zol-

5-ylca r b on yla m in o]-2(S)-(2,4,6-t r im et h ylb en zen esu lfo-

n yla m in o)p r op ion ic Acid Tr iflu or oa ceta te (39). A solu-

tion of 38 (145 mg, 443 µmol) in THF (2 mL) and water (2

mL) was treated with LiOH (1.0 M; 0.56 mL, 560 µmol). After

21 h the reaction was incomplete by TLC so additional LiOH

(1.35 mL) was added in four portions over the next 8 h. After

16 h more, the reaction was acidified with HCl (1.0 M) and

concentrated. The residue was partitioned between water and

CH₂Cl₂, and the organic phase was dried and concentrated to

54 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 1

Batt et al.

provide the acid (49 mg, 37%): ¹H NMR (DMSO-d₆) δ 8.41 (s,

1H), 8.24 (s, 1H), 7.94 (d, J ) 8.8 Hz, 1H), 7.76 (d, J ) 8.8 Hz,

1H), 6.67 (s, 2H), 4.73 (t, J ) 6.6 Hz, 2H), 3.00 (t, J ) 6.6 Hz,

2H); HRMS (NH₃-CI) m/z 300.1097 [(M + H)⁺calcd for

C₁₄H₁₄N₅O₃300.1097]. This material (48 mg, 160 µmol) was

coupled with 8 (R ) tert-butyl, Ar ) 2,4,6-trimethylphenyl)

according to the method for the preparation of 34a , deprotected

with TFA in CH₂Cl₂, and purified by HPLC to provide 39 (28

mg, 31%) as an amorphous white solid: ¹H NMR (MeOH-d₄)

δ 8.11 (s, 1H), 8.09 (s, 1H), 7.77 (d, J ) 10.6 Hz, 1H), 7.68 (d,

J ) 8.8 Hz, 1H), 7.10 (s, 2H), 6.73 (s, 2H), 4.81 (t, J ) 6.2 Hz,

2H), 4.14 (m, 1H), 3.74 (dd, J ) 13.6, 4.8 Hz, 1H), 3.46 (dd, J

) 13.5, 9.1 Hz, 1H), 3.19 (t, J ) 6.3 Hz, 2H), 2.56 (s, 6H), 1.97

(s, 3H); HRMS (FAB) m/z 568.1971 [(M + H)⁺calcd for

C₂₆H₃₀N₇O₆S 568.1978].

ter t-Bu tyl 3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a -

zol-5-ylca r bon yla m in o]-2(S)-(ben zyloxyca r bon yla m in o)-

p r op ion a te (40a ). A mixture of 22b (1.2 g, 3.7 mmol), aqueous

NaOH (1.0 M; 15 mL, 15 mmol), and EtOH (15 mL) was heated

for 24 h at reflux. The pH of the cooled solution was adjusted

to ca. 6.5 with aqueous HCl (1.0 M) and the precipitate

collected by filtration to provide 23b as a white solid: ¹H NMR

(DMSO-d₆) δ 8.44 (s, 1H), 8.25 (s, 1H), 7.93 (m, 1H), 7.91 (d,

J ) 1.5 Hz, 1H), 7.74 (d, J ) 8.8 Hz, 1H), 7.34 (m, 1H), 6.57

(bt, J ) 5.2 Hz, 1H), 6.45 (m, 2H), 4.53 (t, J ) 7.0 Hz, 2H),

3.20 (m, 2H), 2.10 (m, 2H). This material (740 mg, 2.5 mmol)

was coupled with 6 using the procedure of 24d to provide 40a

(700 mg, 56%) as a glass: ¹H NMR (CDCl₃) δ 8.19 (s, 1H),

8.09 (s, 1H), 8.05 (d, J ) 5.0 Hz, 1H), 7.78 (d, J ) 8.8 Hz, 1H),

7.4-7.25 (m, 8H), 7.01 (m, 1H), 6.56 (m, 1H), 6.32 (d, J ) 8.4

Hz, 1H), 5.90 (m, 1H), 5.13 (s, 2H), 4.53 (t, J ) 6.6 Hz, 2H),

4.05 (m, 1H), 3.85 (m, 2H), 3.28 (m, 2H), 2.26 (m, 2H), 1.48 (s,

9H); MS (FAB) m/z 573 [(M + H)⁺, 100%].

ter t-Bu tyl 3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a -

zol-5-ylca r bon yla m in o]-2(S)- a m in op r op ion a te (41a ). A

mixture of 40a (1.60 g, 2.33 mmol), 10% Pd on charcoal (160

mg), and EtOH (30 mL) was stirred under H₂(1 atm). After 5

h, the mixture was filtered through Celite, the solids were

rinsed with EtOH, and the filtrate was concentrated to provide

41a (1.24 g, 97%) as a glass: ¹H NMR (CDCl₃) δ 8.28 (m, 1H),

8.19 (s, 1H), 8.06 (s, 1H), 7.82 (d, J ) 8.8 Hz, 1H), 7.60 (m,

2H), 7.38 (d, J ) 8.8 Hz, 1H), 6.98 (m, 1H), 6.93 (bt, J ) 5.1

Hz, 1H), 4.45 (t, J ) 7.3 Hz, 2H), 4.00 (t, J ) 7.0 Hz, 2H), 3.88

(m, 1H), 3.66 (m, 1H), 3.56 (m, 1H), 2.51 (m, 2H), 1.70 (bs,

2H), 1.48 (s, 9H), 1.42 (s, 9H); HRMS (NH₃-CI) m/z 539.2998

[(M + H)⁺calcd for C₂₈H₃₉N₆O₅539.2982]. Anal. (C₂₈H₃₈N₆O₅)

C, H, N.

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-ylca r -

b on yla m in o]-2(S )-(isob u t yloxyca r b on yla m in o)p r op i-

on ic Acid Tr iflu or oa ceta te (24g). A solution of 41a (100

mg, 187 µmol), pyridine (15 µL, 205 µmol), and 4-(dimethy-

lamino)pyridine (10 mg, 82 µmol) in DMF (5 mL) was treated

with isobutyl chloroformate (27 µL, 205 µmol) and stirred for

18 h. The mixture was concentrated and purified by flash

chromatography (hexanes:EtOAc 60:40) to provide 42a (R )

isobutyloxycarbonyl; 106 mg, 89%) as a gum: ¹H NMR (DMSO-

d₆) δ 8.52 (m, 2H), 8.28 (s, 1H), 8.21 (s, 1H), 7.95 (s, 1H), 7.90-

7.65 (3H), 7.53 (d, J ) 8.00 Hz, 1H), 7.10 (m, 1H), 6.47 (m,

1H), 4.45 (t, J ) 6.6 Hz, 2H), 4.21 (m, 1H), 3.83 (m, 2H), 3.75

(d, J ) 7.00 Hz, 2H), 3.70 (m, 1H), 3.58 (m, 1H), 2.14 (m, 2H),

1.83 (m, 1H), 1.33 (s, 9H), 1.30 (s, 9H), 0.88 (d, J ) 7.00 Hz,

6H); HRMS (FAB) m/z 639.3506 [(M + H)⁺calcd for C₃₃H₄₇N₆O₇

639.3480]. This material (106 mg, 166 µmol) was treated with

TFA (1.0 mL) in CH₂Cl₂(3 mL) to provide 24g (76 mg, 76%)

as an amorphous white solid: ¹H NMR (DMSO-d₆) δ 8.56 (m,

2H), 8.30 (s, 1H), 8.25 (s, 1H), 7.89-7.75 (4H), 7.43 (d, J )

8.00 Hz, 1H), 6.95 (d, J ) 8.00 Hz, 1H), 6.80 (t, J ) 6.2 Hz,

1H), 4.54 (t, J ) 6.6 Hz, 2H), 4.16 (m, 1H), 3.78 (d, J ) 7.00

Hz, 2H), 3.60 (m, 2H), 3.28 (br, 2H), 3.18 (t, J ) 6.6 Hz, 2H),

1.80 (m, 1H), 0.86 (d, J ) 7.00 Hz, 6H); HRMS (FAB) m/z

483.2355 [(M + H)⁺calcd for C₂₄H₃₁N₆O₅483.2348]. Anal.

(C₂₄H₃₀N₆O₅‚CF₃COOH) C, H, N.

prepared as described for 24g from 41a and mesitylenesulfonyl

chloride as a white solid: ¹H NMR (DMSO-d₆) δ 8.78 (bs, 1H),

8.44 (bt, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 8.03 (d, J ) 9.5 Hz,

1H), 7.88 (d, J ) 5.9 Hz, 1H), 7.80 (t, J ) 7.9 Hz, 1H), 7.70

(m, 2H), 6.96 (d, J ) 8.8 Hz, 1H), 6.80 (s, 2H), 4.53 (t, J ) 6.4

Hz, 2H), 4.00 (dd, J ) 15.3, 7.5 Hz, 1H), 3.52 (m, 1H), 3.38

(m, 1H), 3.28 (m, 2H), 2.49 (s, 6H), 2.15 (m, 2H), 2.00 (s, 3H);

HRMS (FAB) m/z 565.2222 [(M + H)⁺calcd for C₂₈H₃₃N₆O₅S

565.2233]. Anal. (C₂₈H₃₂N₆O₅S‚CF₃COOH) C, H, N, S, F.

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-ylca r -

b on yla m in o]-2(S)-(p h en yla m in oca r b on yla m in o)p r op i-

on ic Acid Tr iflu or oa ceta te (24h ). A solution of 41a (105

mg, 195 µmol) and iPr₂NEt (69 µL, 374 µmol) in CH₂Cl₂(5

mL) was treated with phenyl isocyanate (60 µL, 552 µmol).

After 60 min, the mixture was concentrated and purified by

flash chromatography (hexanes:EtOAc 50:50) to provide 42a

(R ) phenylaminocarbonyl) (72 mg, 56%): ¹H NMR (CDCl₃) δ

8.25 (d, J ) 4.8 Hz, 1H), 8.19 (s, 1H), 7.97 (m, 1H), 7.86 (s,

1H), 7.74 (m, 2H), 7.58 (m, 2H), 7.17 (m, 2H), 7.13 (m, 2H),

6.94 (m, 2H), 6.63 (m, 1H), 4.79 (m, 1H), 4.35 (t, J ) 7.0 Hz,

2H), 3.96 (t, J ) 7.0 Hz, 2H), 3.80 (m, 2H), 2.25 (m, 2H), 1.46

(s, 9H), 1.40 (s, 9H); MS (FAB) m/z 658.5 [(M + H)⁺, 100%].

This material was treated with TFA (0.8 mL) in CH₂Cl₂(4 mL)

for 3 h, concentrated, and purified by HPLC to provide 24h

(44 mg, 68%) as an amorphous white solid: ¹H NMR (MeOH-

d₄) δ 8.24 (s, 1H), 8.09 (s, 1H), 7.78 (m, 2H), 7.68 (d, J ) 6.2

Hz, 1H), 7.54 (d, J ) 8.8 Hz, 1H), 7.30 (d, J ) 8.4 Hz, 2H),

7.17 (t, J ) 7.8 Hz, 2H), 6.91 (m, 2H), 6.80 (t, J ) 6.2 Hz, 1H),

4.65 (m, 1H), 4.54 (t, J ) 6.2 Hz, 2H), 3.80 (m, 2H), 3.31 (m,

2H), 2.30 (m, 2H); HRMS (FAB) m/z 502.2196 [(M + H)⁺calcd

for C₂₆H₂₈N₇O₄502.2202]. Anal. (C₂₆H₂₇N₇O₄‚CF₃COOH) C, H,

N.

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon yla m in o]-2(S)-(p h en ylm eth yla m in oca r bon yla m in o)-

p r op ion ic Acid Tr iflu or oa ceta te (24i). This compound was

prepared as described for 24h from 41a and benzyl isocyanate

as an amorphous white solid: ¹H NMR (MeOH-d₄) δ 8.24 (s,

1H), 8.13 (s, 1H), 7.80 (m, 2H), 7.67 (m, 1H), 7.57 (d, J ) 9.1

Hz, 1H), 7.15 (m, 1H), 6.70 (m, 3H), 4.86 (m, 1H), 4.57 (t, J )

6.6 Hz, 2H), 4.27 (m, 2H), 3.62 (m, 2H), 3.28 (m, 2H), 3.27 (m,

2H); HRMS (FAB) m/z 516.2365 [(M + H)⁺calcd for C₂₇H₃₀N₇O₄

516.2359]. Anal. (C₂₇H₂₉N₇O₄‚CF₃COOH) C, H, N.

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-ylca r -

b on yla m in o]-2(S)-(3-p h en ylp r op ion yla m in o)p r op ion ic

Acid Tr iflu or oa ceta te (24j). A mixture of 41a (100 mg, 186

µmol), hydrocinnamic acid (28 mg, 186 µmol), DCC (39 mg,

186 µmol), HOBT (25 mg, 186 µmol), and THF (5 mL) was

stirred overnight and concentrated. The residue was purified

by flash chromatography (hexanes:EtOAc 60:40) to provide 42a

(R ) hydrocinnamoyl) as a sticky solid, which was stirred with

TFA (1 mL) in CH₂Cl₂(3 mL) for 4 h, concentrated, and

triturated with ether to provide 24j (104 mg, 89%) as an

amorphous white solid: ¹H NMR (DMSO-d₆) δ 8.56 (m, 1H),

8.30 (s, 1H), 8.25 (m, 2H), 7.89-7.75 (m, 4H), 7.18 (m, 5H),

6.95 (d, J ) 8.00 Hz, 1H), 6.80 (t, J ) 6.2 Hz, 1H), 4.54 (t, J

) 6.6 Hz, 2H), 4.50 (m, 2H), 3.62(m, 2H), 3.40 (m, 1H), 3.22

(br, 1H), 2.80 (t, J ) 9.0 Hz, 2H), 2.40 (t, J ) 9.0 Hz, 1H), 2.20

(m, 2H); HRMS (FAB) m/z 515.2403 [(M + H)⁺calcd for

C

N.

₂₈H₃₁N₆O₄515.2406]. Anal. (C₂₈H₃₀N₆O₆‚1.2CF₃COOH) C, H,

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-ylca r -

b on yla m in o]-2(S)-(4-m et h ylp en t a n oyla m in o)p r op ion ic

Acid Tr iflu or oa ceta te (24k ). This compound was prepared

as described for 24j from 41a and 4-methylvaleric acid as an

amorphous white solid: ¹H NMR (MeOH-d₄) δ 8.55 (m, 2H),

8.29 (s, 1H), 8.24 (s, 1H), 8.14 (m, 1H), 7.80 (m, 2H), 6.96 (m,

1H), 6.80 (m, 1H), 4.70 (m, 1H), 4.60 (t, J ) 7.0 Hz, 2H), 4.45

(m, 2H), 3.60 (m, 2H), 3.30 (m, 2H), 3.06 (m, 1H), 2.15 (m,

4H), 0.80 (d, J ) 6.6 Hz, 6H); HRMS (FAB) m/z 481.2559 [(M

+ H)⁺calcd for C₂₅H₃₃N₆O₄481.2563]. Anal. (C₂₅H₃₂N₆O₄‚1.4CF₃-

COOH‚0.2H₂O) C, H, N.

Using the procedure described for preparing 24g, the

following compounds were prepared from 41a .

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon ylam in o]-2(S)-(ben zen esu lfon ylam in o)pr opion ic acid

tr iflu or oa ceta te (24m ): from benzenesulfonyl chloride, as

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon ylam in o]-2(S)-(2,4,6-tr im eth ylben zen esu lfon ylam in o)-

p r op ion ic Acid Tr iflu or oa ceta te (24a ). This compound was

Indazoles as Antagonists of the Integrin R_vâ₃

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 1 55

an amorphous white solid; ¹H NMR (MeOH-d₄) δ 8.21 (s, 1H),

8.16 (s, 1H), 7.83 (m, 4H), 7.70 (d, J ) 6.6 Hz, 1H), 7.57 (d, J

) 8.7 Hz, 1H), 7.42 (m, 3H), 6.92 (d, J ) 9.1 Hz, 1H), 6.83 (t,

J ) 6.6 Hz, 1H), 4.59 (t, J ) 6.4 Hz, 2H), 4.23 (dd, J ) 8.8, 4.8

Hz, 1H), 3.78 (dd, J ) 13.6, 4.8 Hz, 1H), 3.49 (dd, J ) 13.6,

8.8 Hz, 1H), 3.30 (m, 2H), 2.32 (m, 2H); HRMS (FAB) m/z

523.1763 [(M + H)⁺calcd for C₂₅H₂₇N₆O₅S 523.1764]. Anal.

(C₂₅H₂₇N₆O₅S‚CF₃COOH) C, H, N, S, F.

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon ylam in o]-2(S)-(1-bu tan esu lfon ylam in o)pr opion ic acid

tr iflu or oa ceta te (24n ): from 1-butanesulfonyl chloride, as

an amorphous white solid; ¹H NMR (MeOH-d₄) δ 8.28 (s, 1H),

8.15 (s, 1H), 7.8-7.1 (m, 3H), 6.87 (d, J ) 9.1 Hz, 1H), 6.80 (d,

J ) 6.2 Hz, 1H), 4.58 (t, J ) 6.2 Hz, 2H), 4.30(m, 1h), 3.86

(dd, J ) 13.6, 4.8 Hz, 1H), 3.56 (dd, J ) 13.5, 8.8 Hz, 1H),

3.26 (m, 2H), 3.03 (t, J ) 8.0 Hz, 2H); HRMS (FAB) m/z

503.2076 [(M + H)⁺calcd for C₂₃H₂₉N₆O₅S 503.2062]. Anal.

(C₂₃H₂₈N₆O₅S‚1.1CF₃COOH) C, H, N.

ter t-Bu tyl 3-[1-[3-(N-1-Tr ip h en ylm eth ylim id a zol-2-yl-

a m in o)p r op yl]in d a zol-5-ylca r b on yla m in o]-2(S)-a m in o-

p r op ion a te (41b). Using the procedure described for 34a , 33

and 6 were coupled to provide 40b in 95% yield: ¹H NMR

(CDCl₃) δ 8.11 (s, 1H), 7.93 (s, 1H), 7.70 (d, J ) 8.8 Hz, 1H),

7.40-7.15 (m, 20H), 7.04 (m, 1H), 6.99 (d, J ) 8.8 Hz, 1H),

6.68 (d, J ) 1.5 Hz, 1H), 6.41 (d, J ) 1.5 Hz, 1H), 5.94 (bd, J

) 6.6 Hz, 1H), 5.12 (s, 2H), 4.48 (m, 1H), 4.05 (t, J ) 7.0 Hz,

2H), 3.85 (m, 2H), 3.10-2.90 (m, 3H), 1.80 (m, 2H), 1.47 (s,

9H); HRMS (FAB) m/z 804.3874 [(M + H)⁺calcd for C₄₈H₅₀N₇O₅

804.3873]. Using the procedure described for 41a , this material

was converted to 41b in 74% yield: ¹H NMR (CDCl₃) δ 8.14

(s, 1H), 7.94 (s, 1H), 7.73 (d, J ) 8.8 Hz, 1H), 7.32 (m, 9H),

7.22 (m, 6H), 7.02 (d, J ) 8.8 Hz, 1H), 6.93 (bt, J ) 5.5, 1H),

6.68 (d, J ) 1.8 Hz, 1H), 6.41 (d, J ) 1.8 Hz, 1H), 4.06 (m,

2H), 3.85 (m, 1H), 3.63 (m, 1H), 3.51 (m, 1H), 3.05 (m, 1H),

2.97 (m, 2H), 1.83 (m, 4H), 1.49 (s, 9H); HRMS (FAB) m/z

670.3509 [(M + H)⁺calcd for C₄₀H₄₄N₇O₃670.3506]. Anal.

(C₄₀H₄₃N₇O₃‚0.3H₂O) C, H, N.

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-ylca r -

b on yla m in o]-2(S)-(p h en ylm et h a n esu lfon yla m in o)p r o-

p ion ic a cid tr iflu or oa ceta te (24p ): from phenylmethane-

sulfonyl chloride as an amorphous white solid; ¹H NMR

(MeOH-d₄) δ 8.25 (s, 1H), 8.13 (s, 1H), 7.67-7.8 (3H), 7.53 (d,

J ) 8.8 Hz, 1H), 7.40 (m, 2H), 7.30 (m, 3H), 6.82 (d, J ) 9.2

Hz, 1H), 6.75 (t, J ) 6.2 Hz, 1H), 4.56 (t, J ) 6.6 Hz, 2H), 4.37

(s, 2H), 4.21 (m, 1H), 3.80 (dd, J ) 13.6, 4.8 Hz, 1H), 3.57 (dd,

J ) 13.6, 8.4 Hz, 1H), 3.24 (t, J ) 6.6 Hz, 2H), 2.29 (m, 2H);

HRMS (FAB) m/z 537.1899 [(M + H) ⁺calcd for C₂₆H₂₉N₆O₅S

537.1920]. Anal. (C₂₆H₂₈N₆O₅S‚1.2CF₃COOH) C, H, N.

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon yla m in o]-2(S)-(3-m eth ylp r op a n esu lfon yla m in o)p r o-

p ion ic a cid tr iflu or oa ceta te (24q): from 2-methylpropane-

sulfamyl chloride, as an amorphous white solid; ¹H NMR

(DMSO-d₆) 8.72 (bs, 1H), 8.55 (m, 1H), 8.33 (s, 1H), 8.25 (s,

1H), 7.90 (m, 3H), 7.75 (d, J ) 8.8 Hz, 1H), 7.22 (d, J ) 8.8

Hz, 1H), 6.99 (d, J ) 8.8 Hz, 1H), 6.92 (t, J ) 5.9 Hz, 1H),

6.82 (t, J ) 6.2 Hz, 1H), 4.58 (t, J ) 6.2 Hz, 2H), 3.99 (m, 1H),

3.70 (m, 1H), 3.40 (m, 2H), 3.26 (m, 2H), 2.58 (m, 2H), 2.18

(m, 2H), 1.59 (m, 1H), 0.83 (t, J ) 8.0 Hz, 6H); HRMS (FAB)

m/z 518.2203 [(M + H)⁺calcd for C₂₃H₃₂N₇O₅S 518.2185]. Anal.

(C₂₃H₃₁N₇O₅S‚0.93CF₃COOH) C, H, N.

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon yla m in o]-2(S)-(p h en ylm eth yla m in osu lfon yla m in o)-

pr opion ic acid tr iflu or oacetate (24r ): from phenylmethane-

sulfamyl chloride as an amorphous white solid; ¹H NMR

(MeOH-d₄) δ 8.56 (m, 2H), 8.33 (s, 1H), 8.24 (s, 1H), 7.90 (m,

3H), 7.74 (d, J ) 8.8, 1H), 7.46 (m, 2H), 7.23 (m, 5H), 7.00 (t,

J ) 9.1 Hz, 1H), 4.56 (t, J ) 6.6, 2H), 4.00 (m, 3H), 3.57 (m,

2H), 2.18 (m, 2H); HRMS (FAB) m/z 552.2042 [(M + H)⁺calcd

for C₂₆H₃₀N₇O₅S 552.2029]. Anal. (C₂₆H₂₉N₇O₅S‚CF₃COOH‚

H₂O) C, H, N.

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon yla m in o]-2(S)-(4-m eth ylben zen esu lfon yla m in o)p r o-

p ion ic Acid Tr iflu or oa ceta te (34h ). Using the procedure

described for the preparation of 24g, 41b was reacted with

p-toluenesulfonyl chloride, and the intermediate was heated

at reflux with TFA for 5 h; then the warm mixture was treated

with water, cooled, concentrated, and purified by HPLC to

provide 34h (69% overall) as an amorphous white solid: ¹H

NMR (MeOH-d₄) δ 8.19 (s, 1H), 8.15 (s, 1H), 7.78 (d, J ) 8.7

Hz, 1H), 7.66 (d, J ) 7.7 Hz, 2H), 7.56 (d, J ) 8.8 Hz, 1H),

7.16 (d, J ) 8.4 Hz, 2H), 4.56 (t, J ) 6.2 Hz, 2H), 4.20 (m,

1H), 3.76 (dd, J ) 13.5, 5.1 Hz, 1H), 3.47 (dd, J ) 13.5, 8.8

Hz, 1H), 3.22 (t, J ) 6.6 Hz, 2H), 2.24 (m, 2H), 2.18 (s, 3H);

HRMS (FAB) m/z 526.1875 [(M + H) ⁺calcd for C₂₄H₂₈N₇O₅S

526.1873]. Anal. (C₂₄H₂₇N₇O₅S‚CF₃COOH) C, H, N.

Using the procedure described for preparing 34h , the

following compounds were prepared from 41b.

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-5-ylca r -

b on yla m in o]-2(S)-(4-ch lor ob en zen esu lfon yla m in o)p r o-

p ion ic a cid tr iflu or oa ceta te (34I): from 4-chlorobenzene-

sulfonyl chloride, as an amorphous white solid; ¹H NMR

(MeOH-d₄) δ 8.18 (s, 1H), 8.15 (s, 1H), 7.60 (m, 4H), 7.56 (d, J

) 8.8 Hz, 1H), 7.55 (d, J ) 8.7 Hz, 2H), 6.77 (s, 2H), 4.55 (t, J

) 6.6 Hz, 2H), 4.26 (m, 1H), 3.78 (dd, J ) 14.0, 5.2 Hz, 1H),

3.48 (dd, J ) 13.6, 9.2 Hz, 1H), 3.23 (t, J ) 6.6 Hz, 2H), 2.24

(m, 2H); HRMS (FAB) m/z 546.1320 [(M + H)⁺calcd for C₂₃H₂₅

-

ClN₇O₅S 546.1326]. Anal. (C₂₃H₂₄ClN₇O₅S‚CF₃COOH) C, H,

N.

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-5-ylca r -

b on yla m in o]-2(S)-(4-m et h oxyb en zen esu lfon yla m in o)-

p r op ion ic a cid tr iflu or oa ceta te (34j): from 4-methoxyben-

1

zenesulfonyl chloride, as an amorphous white solid; H NMR

(MeOH-d₄) δ 8.16 (s, 1H), 8.13 (s, 1H), 7.75 (d, J ) 8.8 Hz,

1H), 7.70 (d, J ) 8.8 Hz, 2H), 7.54 (d, J ) 8.8 Hz, 1H), 6.81 (d,

J ) 8.8 Hz, 2H), 6.76 (s, 2H), 4.54 (t, J ) 6.6 Hz, 2H), 4.20

(dd, J ) 9.2, 5.1 Hz, 1H), 3.77 (dd, J ) 13.6, 4.8 Hz, 1H), 3.62

(s, 3H), 3.48 (dd, J ) 13.6, 8.8 Hz, 1H), 3.23 (t, J ) 6.6 Hz,

2H), 2.22 (m, 2H); HRMS (FAB) m/z 568.2348 [(M + H)⁺calcd

for C₂₄H₂₈N₇O₆S 568.2342]. Anal. (C₂₄H₂₈N₇O₆S‚CF₃COOH) C,

H, N.

3-[1-[3-(N -Im id a zol-2-yla m in o)p r op yl]in d a zol-5-yl-

ca r bon yla m in o]-2(S)-(4-tr iflu or om eth ylben zen esu lfon yl-

a m in o)p r op ion ic a cid tr iflu or oa ceta te (34k ): from 4-tri-

fluoromethylbenzenesulfonyl chloride, as an amorphous white

solid; ¹H NMR (MeOH-d₄) δ 8.20 (s, 1H), 8.13 (s, 1H), 7.98 (d,

J ) 8.4 Hz, 2H), 7.76 (m, 2H), 7.66 (m, 1H), 6.77 (s, 2H), 4.54

(t, J ) 6.2 Hz, 2H), 4.32 (m, 1H), 3.80 (dd, J ) 13.5, 4.7 Hz,

1H), 3.51 (dd, J ) 13.5, 8.8 Hz, 1H), 3.23 (t, J ) 6.6 Hz, 2H),

2.23 (m, 2H); HRMS (FAB) m/z 580.1605 [(M + H)⁺calcd for

C₂₄H₂₅F₃N₇O₅S 580.1590]. Anal. (C₂₄H₂₄F₃N₇O₅S‚0.9CF₃COOH‚

0.3CH₃CN) C, H, N.

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-ylca r -

b on yla m in o]-2(S)-(p h en yla m in osu lfon yla m in o)p r op i-

on ic a cid tr iflu or oa ceta te (24s): from benzenesulfamyl

1

chloride as an amorphous white solid; H NMR (MeOH-d₄) δ

8.12 (s, 1H), 8.10 (s, 1H), 7.81 (m, 1H), 7.71 (m, 2H), 7.16-

7.06 (m, 4H), 6.92 (d, J ) 9.2 Hz, 1H), 6.82 (t, J ) 6.3 Hz,

2H), 4.57 (t, J ) 6.3 Hz, 2H), 4.25 (dd, J ) 8.0, 4.7 Hz, 1H),

3.72 (dd, J ) 13.6, 5.2 Hz, 1H), 3.52 (dd, J ) 13.5, 8.4 Hz,

1H), 3.30 (m, 2H), 2.30 (m, 2H); HRMS (ESI) m/z 538.1887

[(M + H)⁺calcd for C₂₅H₂₈N₇O₅S 538.1873]. Anal. (C₂₅H₂₇N₇-

O₅S‚1.1CF₃COOH) C, H, N.

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon yla m in o]-2(S)-(2,4,6-t r im et h ylp h en yla m in osu lfon y-

la m in o)p r op ion ic a cid tr iflu or oa ceta te (24t): from mes-

itylenesulfamyl chloride as an amorphous white solid; ¹H NMR

(MeOH-d₄) δ 8.24 (s, 1H), 8.13 (s, 1H), 7.78 (m, 2H), 7.66 (d, J

) 5.9 Hz, 1H), 7.541 (d, J ) 8.8 Hz, 1H), 6.89 (d, J ) 9.1 Hz,

1H), 6.80 (m, 3H), 4.56 (t, J ) 6.6 Hz, 2H), 4.42 (m, 1H), 3.88

(dd, J ) 13.9, 5.1 Hz, 1H), 3.68 (dd, J ) 13.6, 7.7 Hz, 1H),

3.26 (t, J ) 6.6 Hz, 2H), 2.34 (s, 6H), 2.29 (m, 2H), 2.17 (s,

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon yla m in o]-2(S)-(4-a ceta m id oben zen esu lfon yla m in o)-

p r op ion ic a cid tr iflu or oa ceta te (34m ): from 4-acetamido-

benzenesulfonyl chloride, as an amorphous white solid; ¹H

3H); HRMS (FAB) m/z 580.2334 [(M + H)⁺calcd for C₂₈H₃₄

N₇O₅S 580.2342]. Anal. (C₂₈H₃₃N₇O₅S‚CF₃COOH) C, H, N.

-

56 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 1

Batt et al.

NMR (MeOH-d₄) δ 8.11 (s, 1H), 8.10 (s, 1H), 7.72 (m, 3H), 7.51

(m, 3H), 6.76 (s, 2H), 4.53 (t, J ) 6.2 Hz, 2H), 4.23 (m, 1H),

3.77 (dd, J ) 13.6, 4.8 Hz, 1H), 3.47 (dd, J ) 13.9, 8.0 Hz,

1H), 3.22 (t, J ) 6.6 Hz, 2H), 2.22 (m, 2H), 2.02 (s, 3H); HRMS

(FAB) m/z 569.1943 [(M + H)⁺calcd for C₂₅H₂₉N₈O₆S 569.1931].

Anal. (C₂₅H₂₈N₈O₆S‚CF₃COOH) C, H, N.

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-5-ylca r -

b on yla m in o]-2(S)-(4-ter t-b u t ylb en zen esu lfon yla m in o)-

p r op ion ic a cid tr iflu or oa ceta te (34n ): from 4-tert-butyl-

benzenesulfonyl chloride, as an amorphous white solid; ¹H

NMR (MeOH-d₄) δ 8.25 (s, 1H), 8.17 (s, 1H), 7.82 (d, J ) 10.6

Hz, 1H), 7.73 (d, J ) 8.4 Hz, 1H), 7.58 (d, J ) 8.8 Hz, 1H),

7.42 (d, J ) 8.7 Hz, 2H), 6.78 (s, 2H), 4.56 (t, J ) 6.6 Hz, 2H),

4.20 (m, 1H), 3.76 (dd, J ) 13.5, 4.7 Hz, 1H), 3.50 (dd, J )

13.6, 8.8 Hz, 1H), 3.23 (t, J ) 6.6 Hz, 2H), 2.24 (m, 2H), 1.20

(s, 9H); HRMS (FAB) m/z 568.2348 [(M + H)⁺calcd for

J ) 6.6 Hz, 2H), 2.21 (m, 2H); HRMS (NH₃-CI) m/z 268.1576

[(M + H)⁺calcd for C₁₅H₁₈N₅268.1562].

ter t-Bu tyl 3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a -

zol-5-yla m in oca r bon yl]-2(S)-(ben zyloxyca r bon yla m in o)-

p r op ion a te (48). A mixture of 46 (109 mg, 407 µmol), N-Cbz-

aspartic acid 1-tert-butyl ester dicyclohexylamine salt (216 mg,

428 µmol), DCC (93 mg, 449 µmol), and HOBT (61 mg, 449

µmol) in DMF (3 mL) was stirred for 72 h and concentrated.

The residue was purified by flash chromatography (CHCl₃:

iPrOH 95:5) to give 48 (202 mg, 87%) as a white glassy foam:

¹H NMR (CDCl₃) δ 8.07 (m, 1H), 7.96 (m, 2H), 7.63 (bm, 1H),

7.4-7.3 (m, 8H), 6.56 (m, 1H), 6.32 (m, 1H), 6.00 (bm, 1H),

5.13 (s, 2H), 4.70 (bt, J ) 7.0 Hz, 1H), 4.55 (m, 1H), 4.48 (t, J

) 6.6 Hz, 2h), 3.25 (q, J ) 6.6 Hz, 2H), 3.07 (m, 1H), 2.92 (m,

1H), 2.23 (m, 2H), 1.46 (s, 9H); HRMS (FAB) m/z 573.2843

[(M + H)⁺calcd for C₃₁H₃₇N₆O₅573.2825].

3-[1-[3-(N-P yr id in -2-yla m in o)p r op yl]in d a zol-5-yla m i-

n ocar bon yl]-2(S)-(2,4,6-tr im eth ylben zen esu lfon ylam in o)-

p r op ion ic Acid Tr iflu or oa ceta te (49). Using the procedure

described for the preparation of 24n , 48 was converted into

49 as a white powder after ether trituration: ¹H NMR (MeOH-

d₄) δ 7.98 (s, 1H), 7.91 (s, 1H), 7.82 (m, 1H), 7.72 (d, J ) 6.6

Hz, 1H), 7.46 (d, J ) 8.8 Hz, 1H), 7.32 (d, J ) 8.8 Hz, 1H),

6.93 (d, J ) 6.6 Hz, 1H), 6.88 (s, 2H), 6.83 (m, 1H), 4.54 (t, J

) 6.4 Hz, 2H), 4.23 (dd, J ) 7.2, 5.5 Hz, 1H), 3.28 (m, 2H),

2.83 (dd, J ) 15.2, 5.3 Hz, 1H), 2.72 (dd, J ) 15.2, 7.1 Hz,

1H), 2.61 (s, 6H), 2.29 (m, 2H), 2.15 (s, 3H); HRMS (FAB) m/z

565.2214 [(M + H)⁺calcd for C₂₈H₃₃N₆O₅S 565.2233]. Anal.

(C₂₈H₃₂N₆O₅S‚0.95CF₃COOH) C, H, N, S, F.

C

₂₇H₃₄N₇O₅S 568.2342]. Anal. (C₂₇H₃₄N₇O₅S‚1.3CF₃COOH) C,

H, N.

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-5-ylca r -

bon yla m in o]-2(S)-(3,4-d ich lor oben zen esu lfon yla m in o)-

p r op ion ic a cid tr iflu or oa ceta te (34q): from 3,4-dichlo-

1

robenzenesulfonyl chloride, as an amorphous white solid; H

NMR (MeOH-d₄) δ 8.15 (s, 1H), 8.13 (s, 1H), 7.86 (m, 1H), 7.66

(m, 2H), 7.50 (m, 1H), 7.40 (m, 2H), 6.77 (s, 2H), 4.32 (m, 1H),

3.80 (dd, J ) 13.5, 4.7 Hz, 1H), 3.48 (dd, J ) 13.6, 9.5 Hz,

1H), 3.23 (t, J ) 6.6 Hz, 2H), 2.23 (m, 2H); HRMS (FAB) m/z

580.0940 [(M + H)⁺calcd for C₂₃H₂₄Cl₂N₇O₅S 580.0937]. Anal.

(C₂₃H₂₃Cl₂N₇O₅S‚CF₃COOH) C, H; N: calcd, 14.12; found,

13.50.

3-[1-[3-(N-Im id a zol-2-yla m in o)p r op yl]in d a zol-5-ylca r -

b on yla m in o]-2(S)-(2-n a p h t h a len esu lfon yla m in o)p r op i-

on ic a cid tr iflu or oa ceta te (34v): from 2-naphthalenesulfo-

N-Mesitylen esu lfon yl-N′-ter t-bu tyloxyca r bon yleth yl-

en ed ia m in e (50). A solution of N-Boc-ethylenediamine⁴⁷(409

mg, 2.6 mmol) and Et₃N (395 µL, 2.8 mmol) in THF (15 mL)

was treated at 0 °C with a solution of mesitylenesulfonyl

chloride (614 mg, 2.8 mmol) in THF (4 mL) and warmed to

room temperature. After 19 h, the mixture was diluted with

water and extracted with CH₂Cl₂, and the extract was dried

and concentrated. The residue was purified by flash chroma-

tography (hexanes:EtOAc 75:25) to provide 50 (592 mg, 68%)

as a white solid: mp 91-94 °C; ¹H NMR (CDCl₃) δ 6.96 (s,

2H), 5.22 (bs, 1H), 4.82 (bs, 1H), 3.22 (q, J ) 5.5 Hz, 2H), 3.01

(q, J ) 5.5 Hz, 2H), 2.63 (s, 6H), 2.30 (s, 3H), 1.43. (s, 9H);

HRMS (NH₃-CI) m/z 343.1674 [(M + H)⁺calcd for C₁₆H₂₇N₂O₄S

343.1692]. Anal. (C₁₆H₂₆N₂O₄S) C, H, N, S.

1

nyl chloride as an amorphous white solid; H NMR (MeOH-

d₄) δ 7.99 (s, 1H), 7.97 (s, 1H), 7.73 (m, 3H), 7.56 (m, 2H), 7.35

(m, 3H), 6.75 (s, 2H), 4.47 (t, J ) 6.2 Hz, 2H), 4.36 (m, 1H),

3.79 (dd, J ) 13.5, 4.7 Hz, 1H), 3.48 (dd, J ) 13.6, 9.6 Hz,

1H), 3.20 (t, J ) 6.6 Hz, 2H), 2.20 (m, 2H); HRMS (FAB) m/z

562.1872 [(M + H)⁺calcd for C₂₇H₂₈N₇O₅S 562.1873]. Anal.

(C₂₇H₂₇N₇O₅S‚0.8CF₃COOH) C, H, N.

1-(3-Oxop r op yl)-5-n itr oin d a zole (44). Using the proce-

dures used to prepare 30 and 31, 5-nitroindazole was converted

into 44 in 23% overall yield as a pale yellow solid: ¹H NMR

(CDCl₃) δ 9.85 (s, 1H), 8.71 (d, J ) 2.2 Hz, 1H), 8.30 (dd, J )

9.2, 2.2 Hz, 1H), 8.21 (s, 1H), 7.62 (d, J ) 9.2 Hz, 1H), 4.73 (t,

J ) 6.2 Hz, 2H), 3.24 (t, J ) 6.2 Hz, 2H); HRMS (NH₃-CI) m/z

220.0732 [(M + H)⁺calcd for C₁₀H₁₀N₃O₃220.0722]. Anal.

(C₁₀H₉N₃O₃) C, H, N.

N-Mesitylen esu lfon yleth ylen ed ia m in e Tr iflu or oa ce-

ta te. A solution of 50 (444 mg, 1.3 mmol) in CH₂Cl₂(4 mL)

and TFA (4 mL) was stirred for 3 h and concentrated, and the

residue was triturated in ether to provide 51 (460 mg, 100%)

as a white solid: ¹H NMR (DMSO-d₆) δ 7.81 (bs, 3H), 7.63 (t,

J ) 5.9 Hz, 1H), 7.07 (s, 2H), 2.91 (m, 2H), 2.84 (bm, 2H),

2.57 (s, 6H), 2.28 (s, 3H). Anal. (C₁₁H₁₈N₂O₂S‚CF₃COOH) C,

H, N, S, F.

1-(3-[N-P yr idin -2-ylam in o]pr opyl)-5-n itr oin dazole (45).

A solution of 44 (329 mg, 1.50 mmol) and 2-aminopyridine (282

mg, 3.0 mmol) in 1,2-dichloroethane (6 mL) was treated with

NaBH(OAc)₃(636 mg, 3.0 mmol) and stirred for 24 h. Aqueous

NaHCO₃was added, the mixture was extracted with CH₂Cl₂,

and the extracts were dried and concentrated. The residue was

purified by flash chromatography to provide 45 (414 mg, 92%)

as a yellow solid: ¹H NMR (CDCl₃) δ 8.73 (d, J ) 1.5 Hz, 1H),

8.24 (m, 2H), 8.16 (m, 1H), 7.45 (d, J ) 9.2 Hz, 1H), 7.37 (m,

1H), 6.58 (m, 1H), 6.31 (d, J ) 8.0 Hz, 1H), 4.61 (t, J ) 6.5

Hz, 1H), 4.56 (t, J ) 6.6 Hz, 2H), 3.32 (q, J ) 6.2 Hz, 2H),

2.29 (m, 2H); HRMS (NH₃-CI) m/z 298.1289 [(M + H)⁺calcd

for C₁₅H₁₆N₅O₂298.1304].

Ad h esion of â₃-Tr a n sfected 293 Cells to F ibr in ogen

(r_vâ₃293â₃a ssa y). This assay has been described in detail.^22,42

Briefly, polystyrene EIA plates were coated with fibrinogen,

blocked with bovine serum albumin in PBS, and washed. 293

human embryonic kidney cells expressing the human â₃

integrin subunit were preincubated for 15 min at 37 °C in

either the presence or absence of test compound. The cell

suspension was then added to the fibrinogen-coated plates and

incubated for 60 min. The nonadherent cells were removed,

the plates were washed with PBS, and the adherent cells were

lysed. Aliquots were assayed for â-galactosidase activity, and

IC₅₀values were determined by using standard curves and

appropriate controls.

1-(3-[N-P yr idin -2-ylam in o]pr opyl)-5-am in oin dazole (46).

A mixture of 45 (209 mg, 703 µmol), Fe powder (236 mg, 4.2

mmol), and HOAc (5 mL) was heated at 90 °C for 45 min,

cooled, and poured cautiously into aqueous NaHCO₃. The

mixture was stirred with EtOAc and filtered, and the solids

were washed with EtOAc. The filtrate was extracted with

EtOAc, and the extracts were dried and concentrated. The

residue was purified by flash chromatography (CHCl₃: PrOH

92:8) to provide 46 (132 mg, 70%) as an off-white solid: ¹H

NMR (CDCl₃) δ 8.06 (m, 1H), 7.80 (s, 1H), 7.37 (m, 1H), 7.25

(d, J ) 8.8 Hz, 1H), 6.94 (d, J ) 1.5 Hz, 1H), 6.85 (dd, J ) 8.8,

1.5 Hz, 1H), 6.56 (m, 1H), 6.32 (d, J ) 8.4 Hz, 1H), 4.74 (bt, J

) 7.5 Hz, 1H), 4.44 (t, J ) 6.6 Hz, 2H), 3.60 (bm, 2H), 3.26 (q,

Aggr ega tion of Gel-P u r ified P la telets (GP IIbIIIa GP P

a ssa y). Human platelet-rich plasma obtained from healthy

volunteers was applied to a sepharose column to prepare gel-

purified platelets as previously described.⁴⁸Aliquots of gel-

purified platelets (2 × 10⁸platelets/mL) along with 1 mM

CaCl₂and 1 mg/mL fibrinogen, with or without the test

compounds at different concentrations, were assayed for

aggregation as previously described for platelet-rich plasma,⁴⁸

and IC₅₀values were calculated.

Indazoles as Antagonists of the Integrin R_vâ₃

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 1 57

(18) Keenan, R. M.; Lago, M. A.; Miller, W. H.; Ali, F. E.; Cousins,

R. D.; Hall, L. B.; Hwang, S.-M.; J akas, D. R.; Kwon, C.; Louden,

C.; Nguyen, T. T.; Ohlstein, E. H.; Rieman, D. J .; Ross, S. T.;

Samanen, J . M.; Smith, B. R.; Stadel, J .; Takata, D. T.; Vickery,

L.; Yuan, C. C. K.; Yue, T.-L. Discovery of an Imidazopyridine-

Containing 1,4-Benzodiazepine Nonpeptide Vitronectin Receptor

(R_vâ₃) Antagonist With Efficacy in a Restenosis Model. Bioorg.

Med. Chem. Lett. 1998, 8, 3171-3176.

(19) Carron, C. P.; Meyer, D. M.; Pegg, J . A.; Engleman, V. W.;

Nickols, M. A.; Settle, S. L.; Westlin, W. F.; Ruminski, P. G.;

Nickols, G. A. A Peptidomimetic Antagonist of the Integrin R_vâ₃

Inhibits Leydig Cell Tumor Growth and the Development of

Hypercalcemia of Malignancy. Cancer Res. 1998, 58, 1930-1935.

(20) Duggan, M. E.; Fisher, J . E.; Gentile, M. A.; Hartman, G. D.;

Hoffman, W. F.; Huff, J . R.; Ihle, N. C.; Krause, A. E.; Leu, T.

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Ack n ow led gm en t. We thank Yvonne B. Bethel,

Edward R. Holler, Todd W. Leathers, and Walter E.

Meredith for providing large quantities of important

intermediates; Gillian Phillips for preparing 18c; Mark

C. Guzman for the procedure used to prepare 36; Karl

F. Blom, Robert F. Carney, Michael J . Haas, and Carl

Schwartz for providing mass spectral data; and Mau-

reen A. Kearney for technical assistance in performing

in vitro studies.

1

Su p p or tin g In for m a tion Ava ila ble: 300-MHz H NMR

spectra and reverse-phase HPLC chromatograms of 34f, 34q,

and 39. This material is available free of charge via the

Internet at http://pubs.acs.org.

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J M990049J

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Disubstituted indazoles as potent antagonists of the integrin α(v)β3

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