Novel carvedilol analogues that suppress store-overload-induced Ca 2+ release

Article

pubs.acs.org/jmc

Novel Carvedilol Analogues That Suppress Store-Overload-Induced

Ca²⁺Release

Chris D. Smith,^†Aixia Wang,^†Kannan Vembaiyan,^†Jingqun Zhang,^§Cuihong Xie,^§Qiang Zhou,^§

Guogen Wu,^§S. R. Wayne Chen,^‡,§and Thomas G. Back*^,†

^†Department of Chemistry, University of Calgary, Calgary, Alberta T2N 1N4, Canada

^‡Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N

4N1, Canada

^§Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois 60612, United States

S

* Supporting Information

ABSTRACT: Carvedilol is a uniquely eﬀective drug for the treat-

ment of cardiac arrhythmias in patients with heart failure. This

activity is in part because of its ability to inhibit store-overload-

induced calcium release (SOICR) through the RyR2 channel. We

describe the synthesis, characterization, and bioassay of ca. 100

compounds based on the carvedilol motif to identify features that

correlate with and optimize SOICR inhibition. A single-cell bio-

assay was employed on the basis of the RyR2-R4496C mutant

HEK-293 cell line in which calcium release from the endoplasmic

reticulum through the defective channel was measured. IC₅₀values

for SOICR inhibition were thus obtained. The compounds inves-

tigated contained modiﬁcations to the three principal subunits of

carvedilol, including the carbazole and catechol moieties, as well as

the linker chain containing the β-amino alcohol functionality. The

SAR results indicate that signiﬁcant alterations are tolerated in each of the three subunits.

suppression of SOICR.³²This suggests that the unique eﬃcacy of

carvedilol in suppressing SOICR occurs independently of its

INTRODUCTION

■

Ventricular arrhythmias are a leading cause of sudden death,

particularly in patients with heart failure. Consequently, a variety

α- and β-blocking activity and its antioxidant properties, and it is

instead principally because of its ability to stabilize Ca²⁺handling

of antiarrhythmic drug therapies have been evaluated in clinical

trials, which revealed only limited survival beneﬁts.¹⁻³Antag-

via the RyR2 channel. Indeed, we recently reported three novel

carvedilol analogues 2−4 (Chart 1) with comparable abilities to

inhibit SOICR to that of the parent compound 1 (ca. 10 μM) but

onists of β-adrenergic receptors (β-blockers) have been of special

interest in these studies, as overstimulation of these receptors can

trigger fatal ventricular arrhythmias.⁴⁻⁶The underlying mech-

with strongly attenuated β-blockade (ca. micromolar compared

anism of this process involves, in part, an overload of Ca²⁺in the

sarcoplasmic reticulum, which results in spontaneous Ca²⁺eﬄux

through the RyR2 Ca²⁺-release channel.^7,8In turn, this store-

overload-induced calcium release (SOICR) through a defective

RyR2⁷⁻¹⁴triggers delayed afterdepolarizations (DADs),¹⁵⁻²¹

which have been implicated in catecholaminergic polymorphic

ventricular tachycardias (CPVTs) as well as in ventricular

tachyarrhythmias and sudden death.^4,5,22,23

The nonselective β-blocker carvedilol (1) and certain

congeners also inhibit the α-adrenergic receptor²⁴and are

reported to display antioxidant activity.^25,26Thus, 1 has proven

uniquely eﬀective in suppressing ventricular arrhythmias in

patients with failing hearts.²⁷⁻³⁰Unfortunately, the beneﬁts of

carvedilol therapy are limited by drug intolerance and excessive

β-blockade, with attendant complications of bradycardia and

hypotension.^2,31More recently, we demonstrated that a variety

of other α- and β-blockers, as well as antioxidants, failed in the

to nanomolar for 1). Compounds 2−4 proved highly eﬀective in

preventing stress-induced ventricular arrhythmias in mice (vide

infra) without the undesired eﬀects of excessive β-blockade.³²

For the purpose of these studies, a convenient single-cell

bioassay was developed for measuring SOICR suppression by

drug candidates, which is based on human embryonic kidney

(HEK 293) cells expressing a mutant RyR2 channel (R4496C).^7,8

This mutation results in spontaneous calcium release from the

endoplasmic reticulum of the cells through the defective channel,

with calcium eﬄux detected by the measurement of ﬂuorescence

from the Ca²⁺-sensitive indicator dye fura 2/AM.

Moreover, the same R4496C mutation in mice renders them

highly susceptible to stress-induced ventricular arrhythmias,

which are easily triggered by stimulants such as caﬀeine and

Received: July 18, 2013

Published: October 14, 2013

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Chart 1. Structures of Carvedilol and Some of Its Analogues

a

Scheme 1

a

(a) LiBr, DME, 50 °C or i-PrOH, reﬂux. (b) Chloroacetyl chloride, Et₃N, CHCl₃, rt. (c) NaH, THF, rt. (d) LiAlH₄, THF, rt. (e) 1,1′-

Carbonyldiimidazole, Et₃N, CH₂Cl₂, rt. (f) BBr₃, CH₂Cl₂, rt. (g) 2 M NaOH, EtOH, reﬂux.

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a

Scheme 2

a

(a) NaH, MeI, THF, rt. (b) (MeO)₂CO, DABCO, DMF, 95 °C. (c) LiOH, EtOH, reﬂux. (d) i-PrOH, reﬂux. (e) NaH, MeI, DMF, rt.

epinephrine. This provides a useful animal model for evaluating

103a with the corresponding amines 104a-l, as shown in Scheme 1.

Cyclization of amino alcohols 1, 6, 7, and 16 with chloroacetyl

chloride aﬀorded lactams 17−20, whereas the use of 1,1′-carbon-

yldiimidazole aﬀorded products 25−27 in Table 2. The reduction of

17−20 with lithium aluminum hydride provided 21−24. The free

phenol 28 was obtained by demethylation of 25 with boron

tribromide, whereas hydrolysis of 28 aﬀorded the amino alcohol 9.

The methylated product 29 in Table 2 was prepared by methyla-

tion of 1 with iodomethane, whereas 30 was obtained from 1 by

cyclization and N-methylation with dimethyl carbonate in one step

followed by hydrolysis (Scheme 2). Compound 31 was produced

from the reaction of epoxide 103b with the N-methyl derivative of

amine 104a followed by O-methylation with iodomethane.

Products 2 and 33 in Table 3 were prepared from the reactions

of amine 104a with the homologated epoxides 105 and 106,

which were in turn obtained from 4-hydroxycarbazole and the

corresponding homologated haloepoxides. Alternatively, 34 was

produced from 4-hydroxycarbazole and amine 104a via the

monotosylate 109. Compounds 36−38 were obtained from

epoxide 103a and amines 110 and 111a,b, respectively, whereas

product 39, containing transposed alcohol and amine function-

alities, was prepared from the carbazole derivative112 and epoxide

113. These processes are summarized in Scheme 3. Cyclizations

to aﬀord lactams 32, 35, and 40 were eﬀected from the cor-

responding amino alcohols 2, 34, and 39, respectively, with

chloroacetyl chloride, as shown previously for 17−20 in Scheme 1.

Although the products in Tables 1−3 originated from

4-hydroxycarbazole, the syntheses of those in Table 4 were carried

out similarly but by employing 3-hydroxycarbazole, its 6-ﬂuoro

derivative, or 3-aminocarbazole instead, as shown in Scheme 4.

Compound 46 was obtained by alkylation of amine 104a with

bromide 115, which was obtained as a byproduct in the prepara-

tion of epoxide 114b. Similarly, compound 48 was obtained by

alkylation of 104a with chloride 116, which was in turn obtained

from 9-t-Boc-protected 3-aminocarbazole and epichlorohydrin.

Furthermore, the products in Table 5 were obtained by ana-

logous methods, employing 2-hydroxycarbazole, its 6-ﬂuoro or

6,8-diﬂuoro analogues, or 1-hydroxycarbazole as starting materials

potential antiarrhythmic drugs.⁹⁻¹⁴

Our initial eﬀorts that led to the discovery of 2−4 were guided

by the X-ray crystal structure of the complex of the carvedilol

analogue carazolol (5) with the β-adrenergic receptor that had

been previously reported by Stevens, Kobilka, and their co-

workers.³³Their results indicated that the carbazole amino group

participates in hydrogen bonding with residue S203 of the

receptor, whereas multiple hydrogen bonds occur between

the secondary alcohol and the protonated amino group of the

β-amino alcohol moiety with residues D113, Y316, and N312.

Furthermore, a series of hydrophobic interactions were observed

involving the aromatic rings of the carbazole and the N-isopropyl

group of 5 with corresponding hydrophobic pockets in the

receptor. Blocking, modifying, or relocating the key hydrogen-

bonding functionalities and hydrophobic regions of carvedilol

might therefore be expected to disrupt its binding to the

β-adrenergic receptor. Similarly, a catechol moiety is a common

structural motif in many α-blockers,²⁴suggesting that manipu-

lation of this group in 1 could result in diminished α-blockade.

However, such structural changes might also interfere with

binding to RyR2 and SOICR suppression. We now report the

synthesis of a wide range of novel structures, in addition to the

carvedilol analogues 2−4, as part of a SAR investigation to

determine how such structural modiﬁcations would aﬀect the

abilities of these compounds to decrease SOICR in the HEK 293

(R4496C) cell line.

RESULTS

■

The SOICR-suppressing ability of a series of carvedilol ana-

logues, 2−94, 97, and 98, as well as of reference compounds 1,

95, 96, and 99−102 that were included for comparison is shown

in Tables 1−8. All compounds were tested for SOICR inhibition

in the RyR2-R4496C mutant HEK293 cell line, and the IC₅₀

values along with the number of replicates and the total number

of cells employed in the assay are provided in the tables.

Chemistry. The synthesis of compounds 1, 6−8, and 10−16 in

Table 1 was achieved by reacting the commercially available epoxide

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a

Scheme 3

a

(a) LiBr, DME, 60 °C. (b) K₂CO₃, DMF, 100 °C. (c) TBAF, THF, rt. (d) TsCl, Et₃N, CHCl₃, 0 °C. (e) 104a, LiBr, DME, reﬂux. (f) i-PrOH,

reﬂux. (g) LiBr, DME, reﬂux.

(Scheme 5). Lactams 41, 49, and 51 were again obtained by

cyclization of the corresponding amino alcohols 3, 4, and 50,

respectively, with chloroacetyl chloride, whereas cyclizations to

aﬀord 42 and 52 from 3 and 50, respectively, were eﬀected with

bromomethanesulfonyl chloride or 1,1′-carbonyldiimidazole.

The N-acylated carbazole derivatives 59 and 60 in Table 6 were

prepared as shown in Scheme 6. Although 60 was prepared by direct

acylation of 17, compound 59 was more easily obtained by prior

acylation of epoxide 103a followed by ring-opening with amine 104a

in the usual manner. The other compounds in Table 6 were prepared

by alkylating the other indicated phenols or alcohols instead of

4-hydroxycarbazole with the corresponding haloalkyl epoxides

followed by treatment with amine 104a, as indicated in Scheme 6.

Product 62 was obtained by Wolﬀ−Kishner reduction of ketone 63,

whereas desulfurization of 66 with nickel boride³⁴aﬀorded 65.

Products 83−90 and 92 in Table 7 were obtained by treating

epoxides 103a (entries 3, 4, 9, 10, and 12), 105 (entry 5), 114a

(entry 6), 117a (entry 7), or 117c (entry 8) with the corresponding

amines 104a or 118a−f, as shown in Scheme 7. The benzofuran

and benzoxazole derivatives 81 and 82 (entries 1 and 2) were

produced by reductive amination or alkylation of amine 119 with

aldehyde 121 or chloride 122, respectively, followed by

debenzylation of the intermediate benzylamines. Amides 93

and 94 (entries 13 and 14) were formed by amidation of

carboxylic acid 120 with amines 104a or 118f, respectively, using

N-(3-diethylaminopropyl)-N′-ethylcarbodiimide hydrochloride

(EDC hydrochloride) and 1-hydroxybenzotriazole hydrate

(HOBT·H₂O) as coupling reagents.³⁵Product 91 (entry 11)

was prepared by cyclization of 94 with diethylaminosulfur triﬂuoride

(DAST).³⁶

Metoprolol (95) was obtained from commercial sources,

whereas 4,6-dibromo-3-hydroxycarbazole (96) was prepared

by a literature procedure.³⁷The conversion of 96 to 97 and its

further transformation to 98 was achieved via the same

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a

Scheme 4

a

One molar NaOH, DMSO, rt or 40 °C. (b) 104a, i-PrOH, reﬂux. (c) 104a, Et₃N, MeOH, 60 °C. (d) EtOH, reﬂux. (e) 104a, K₂CO₃, cat. KI,

EtOH, reﬂux. (f) TFA, CH₂Cl₂, rt.

procedure that was employed for the preparation of 1 from

4-hydroxycarbazole and for the cyclization of 1 to 17, as shown in

Scheme 1. Products 99 and its hydrochloride salt 100³⁸as well as

102³⁹were obtained by known procedures. Alternatively, the

regioisomer 101 of 99 was prepared, along with 101, from the

known thiapyrone 123,⁴⁰as shown in Scheme 8.

eﬀect on activity. When the other catechol oxygen atom was

replaced with sulfur or a methylene group (12 and 13, respec-

tively) or when the methoxy group was also absent, as in 14,

slightly higher activity compared to 1 was observed. However,

replacement of the catechol moiety by a 2-pyridyl group (15) or

by a cyclohexyl substituent (16) resulted in a 3- and 2-fold loss of

activity, respectively.

We also investigated whether SOICR inhibition would be

aﬀected by manipulation of the β-amino alcohol moiety in the

linker chain, which plays a critical role in the excessive β-blockade

encountered with carvedilol. Entries 1−12 in Table 2 show

the IC₅₀values for analogues where this functionality was

incorporated into various rings with or without the previous

modiﬁcations to the catechol region of the carvedilol molecule

given in Table 1. In the case of δ-lactams 17−20, there was a

moderate loss of activity compared to 1 when either the intact

catechol moiety was retained (17) or when it was replaced by a

simple cyclohexyl group (20). Moreover, the chlorinated

derivatives 18 and 19 were essentially devoid of activity when

introduced together with lactamization (cf. the relatively active

chlorinated compounds 6 and 7 in Table 1). The morpholine

SOICR Inhibition. The benchmark compound 1 displayed an

IC₅₀of 15.9 μM (Table 1, entry 1) in this assay. We ﬁrst prepared

and assayed several derivatives (6−16) with modiﬁed catechol

groups, as shown in Table 1. Aromatic hydroxylation of the

catechol moiety of carvedilol at the 4′- and 5′-positions is known

to aﬀord phenolic metabolites.⁴¹Modiﬁcation of these sites to

probe their eﬀect on SOICR inhibition was therefore of particular

interest (entries 2−4). The introduction of 4′- and 5′-chloro

substituents in 6 slightly improved SOICR activity, but

replacement of the methoxy group with a third chlorine atom

in 7 diminished the potency signiﬁcantly. Surprisingly, the simple

phenyl derivative 8 proved comparable to 1, whereas replace-

ment of the methoxy substituent of 1 with a hydroxyl group in

derivative 9 lowered the IC₅₀by half. The similar replacement by

methyl or methylthio groups (10 and 11, respectively) had no

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a

Scheme 5

a

(a) One molar NaOH, DMSO, rt or 40 °C. (b) i-PrOH, reﬂux.

analogues 21−24 revealed no consistent pattern of behavior

when compared with the corresponding free β-amino alcohols 1,

6, 7, and 16 and with the corresponding lactams 17−20,

respectively. Although a slight decrease in activity was observed

in 17 and 21 compared to 1, the chlorinated analogues 22 and 23

were intermediate between the corresponding amino alcohols 6

and 7 and the inactive lactams 18 and 19. The cyclohexyl deriv-

ative 24 was devoid of activity, in contrast to the weakly active

amino alcohol 16. The cyclic carbamates 25−27 all showed poor

SOICR inhibition compared to the corresponding amino

alcohols 1, 6, and 16, whereas the free phenol analogue 28 was

comparable to carvedilol but less active than phenol 9 in this

regard. Furthermore, alkylation of the aliphatic secondary amino

group in 29 had little eﬀect, whereas alkylation of the carbazole

nitrogen in 30 resulted in diminished activity. Surprisingly,

exhaustive alkylation of both nitrogens and of the secondary

alcohol group in 31 produced a more strongly SOICR-inhibiting

compound than either 1, 29, or 30.

Attempts to determine the eﬀects of homologation of the

linker chain at various sites upon SOICR inhibition were also

made (Table 3, entries 1−8). Homologation was eﬀected by

insertion of one or more extra methylene units between the

carbazole ether and secondary alcohol of 1 to aﬀord 2, its cyclized

derivative 32, and 33, respectively. Similarly, homologation

between the alcohol and amino group provided 34 and the

corresponding lactam 35, whereas insertion of an extra

methylene unit between the amino group and the catechol

ether and between the catechol ether and aromatic ring aﬀorded

derivatives 36 and 37, respectively. Products 2, 32, 33, 34, 37,

and 38 proved comparable to 1, whereas 36 was slightly less

potent. When homologation was combined with lactamization of

the linker chain of 34 to aﬀord 35, activity diminished more than

6-fold. Removal of the methoxy group from homologue 37 to

give 38 had essentially no eﬀect on the activity. Transposition of

the alcohol and secondary amino groups in the linker chain of 1

and 17 was also investigated (entries 9 and 10). Thus, 39 and its

lactam analogue 40 were prepared and found to have IC₅₀’s ca.

1.7-fold those of 1.

When the point of attachment of the linker was moved from

the 4-position of the carbazole moiety (as in carvedilol) to the

3-position, a series of highly active compounds was obtained

(Table 4, entries 1−7). Thus, compounds 3, 41, 43, and 44 all

proved superior to carvedilol in their inhibition of SOICR.

Cyclization of 3 to aﬀord lactam 41 retained the high activity

of the parent amino alcohol, and only the sultam moiety of

derivative 42 strongly impeded SOICR inhibition. Furthermore,

homologation of 3 by one, two, or three methylene units between

the carbazole and hydroxyl functions produced the highly active

analogues 43−45, respectively, with the lowest IC₅₀of 4.66 μM

observed for the doubly homologated derivative 44. Single

homologation between the alcohol and amino functions in 46

also produced a more potent product than carvedilol, whereas

the 6-ﬂuoro derivative 47 showed essentially identical activity to

that of the parent compound 3 of this series. Replacement of the

ether oxygen with an amino group at C-3 of the carbazole moiety

in 48 resulted in comparable activity to that of carvedilol.

The 2-substituted carbazole series (Table 5, entries 1−10) was

also investigated and revealed several highly active SOICR

inhibitors. The parent compound 4 as well as its lactam and

homologated counterparts 49 and 50, respectively, proved

similar to carvedilol. In contrast, the homologated lactam 51 and

cyclic carbamate 52 were ineﬀective in SOICR inhibition.

Monoﬂuorination of the 6- position or 6,8-diﬂuorination of the

carbazole had a beneﬁcial eﬀect on activity, leading to the highly

potent analogues 53 and 54. Fluorination of the catechol moiety

in compound 55 or ﬂuoro or triﬂuoromethyl substitution of the

methoxy group in 57 and 56, respectively, had little eﬀect

compared to 1 or 4. Finally, attachment of the linker chain to the

1-position of the carbazole unit in 58 (entry 11) also had little

eﬀect on activity.

It has been suggested that the carbazole moiety of carvedilol

serves to embed the molecule in the lipid bilayer of cell mem-

branes.⁴²Furthermore, it provides a hydrophobic region and a

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a

Scheme 6

a

(a) NaH, THF, 0 °C. (b) 104a, LiBr, DME, 60 °C or i-PrOH, reﬂux. (c) One molar NaOH, DMSO, 40 °C. (d) NH₂NH_2·H₂O, KOH, ethylene

glycol, 100−160 °C. (e) NiCl₂·6H₂O, NaBH₄(Ni₂B), MeOH-THF-H₂O, rt.

hydrogen-bonding functionality that are key for binding to the

β-adrenergic receptor.³³To determine whether these structural

features are also required for SOICR inhibition, we prepared

a variety of analogues containing modiﬁed carbazole units

(Table 6). In entries 1 and 2, amidation of the carbazole nitro-

gens of 1 and 17 with octadecanoic acid aﬀorded 59 and the

lactam derivative 60, respectively. Unlike the N-methylated

derivatives 30 and 31 in Table 2, which showed comparable

activity to carvedilol (1), amides 59 and 60 unfortunately

revealed negligible or signiﬁcantly diminished activity relative to

1 and 17.

Other carbazole modiﬁcations are shown in entries 3−22

of Table 6. The tetrahydrocarbazole 61, the ﬂuorene and

ﬂuorenone analogues 62 and 63, respectively, that lack the

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a

Scheme 7

a

(a) i-PrOH, reﬂux. (b) BnNH₂, i-PrOH, reﬂux. (c) 121, NaBH(OAc)₃, 1,2-dichloroethane or 122, DIPEA, cat. KI, MeCN, 60 °C. (d) H₂, 10%

Pd/C, MeOH. (e) Ethyl bromoacetate, NaOH, DMF, rt. (f) KOH, MeOH-H₂O. (g) 104a or 118f, EDC·HCl, HOBT·H₂O, Et₃N, THF, rt. (h)

DAST, CH₂Cl₂-THF, −78 °C, 1 h; then K₂CO₃, rt, 2 h.

carbazole nitrogen atom, and the diphenylamine 65 all showed

comparable or only slightly lower activity than carvedilol. How-

ever, the dibenzofuran 64 and the phenothiazine 66 were

more strongly active than 1, whereas oxidation of 66 to the

corresponding sulfone 67 decreased activity by more than

10-fold. Replacement of the carbazole with naphthyl residues in

68 and its homologated analogue 69 aﬀorded potent SOICR

inhibitors. The adamantyl residues in 70−72 resulted in less

eﬃcacious compounds, and the quinolinone 73 and partially

reduced quinolinones 74 and 75 were essentially inactive. The

installation of indole (compounds 76 and 77), benzodiazole

(compounds 78 and 79), and benzimidazole (compound 80)

residues in place of the carbazole also produced very weak or

essentially inactive products.

were devoid of activity, but the benzomorpholine 83 proved

more than twice as potent as carvedilol (1). The lactam derivative

84 and homologue 85 were comparable to 1. Repositioning the

linker chain of 85 to the 3- and 2-position of the carbazole moiety

resulted in strong and negligible activities in 86 and 87, respec-

tively. Fluorination of the 6-position of 87 to aﬀord 88 failed to

improve the bioactivity. Piperazines 89 and 90, as well as

dihydrooxazole 91 and diaryl ether 92 displayed weaker activity

than 1. Surprisingly, replacement of the amino alcohol moiety of

1 with amide linkages in 93 and 94 aﬀorded the most potent

SOICR inhibitors of this investigation, with IC₅₀values of ca.

3.6 μM compared with 15.9 μM for carvedilol.

Several other classes of compounds have been reported to

provide salutary eﬀects in the treatment of cardiac arrhythmias.

We therefore measured their SOICR inhibiting properties

in order to compare them with the above carvedilol analogues

(Table 8). The clinically useful β-blocker metoprolol (95) was

devoid of any SOICR-inhibition in the mutant HEK293 single

We also introduced additional heterocyclic groups into the

linker chain or in place of the catechol moiety (Table 7, entries

1−12), as well as amide instead of amino alcohol functionalities

(entries 13−14). The benzofuran and benzoxazoles 81 and 82

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a

Scheme 8

a

(a) Borax, H₂O, rt. (b) MeOH, 2 M NaOH, rt. (c) TFA, TFAA, 60 °C. (d) TMSN₃, TFA, rt. (e) LiAlH₄, THF-Et₂O, reﬂux. (f) Formaldehyde,

NaBH₃CN, MeOH, rt.

cell bioassay. This result is consistent with our previous ﬁnding³²

that carvedilol is unique in the family of β-blocker drugs in

eﬀectively suppressing SOICR in the HEK293 cell line and in the

knock-in mouse model.

metabolic oxidation at those sites and possibly retard clearance.

The 2′-methoxy group can be replaced by H, OH, Me or MeS

substituents (compounds 8, 9, 10 and 11) and the 1′-ether

oxygen can be replaced by S (compound 12) or CH₂

(compounds 13 and 14) without deleterious eﬀects on SOICR

inhibition. Remarkably, the simple phenyl derivative 14 is

roughly twice as potent as 1, whereas even the pyridyl and

cyclohexyl analogues 15 and 16 show only a three- or 2-fold loss

of activity. This suggests that the compounds in Table 1 may

prove good candidates as SOICR inhibitors.

The β-amino alcohol functionality plays a key role in

mediating β-adrenergic blockade via multiple hydrogen-bonding

interactions with the β-receptor.³³In order to determine whether

or not this functionality plays a similar role in SOICR inhibi-

tion, we investigated the alkylation of these key groups via

incorporation into cyclic structures or by simple methylation.

However, Table 2 indicates mixed results with respect to the

SOICR inhibition shown by such compounds. Although the

lactam and morpholine derivatives of carvedilol (17 and 21,

respectively), as well as the O- and N-methylated compounds

29-31 showed similar or slightly lower SOICR inhibition

compared to 1; further alteration of these structures was

generally accompanied by severe or total loss of activity.

The variously homologated analogues in Table 3 (2, 32−34,

and 36−38) and the compounds with transposed amino alcohol

linkers (39 and 40) all showed strong SOICR suppression in

the mutant HEK293 cells. Similarly, relocation of the point of

attachment of the linker chain from the 4-position (as in 1) to

the 3-, 2-, or 1-positions of the carbazole subunit generally had

a salutary eﬀect on the compounds in Tables 4 and 5, except

for the sultam derivative 42, the lactam 51, and the cyclic carba-

mate 52.

Furthermore, compound 96 has been reported to inhibit Ca²⁺-

induced Ca²⁺release (CICR) in skeletal muscle sarcoplasmic

reticulum.³⁷In the RyR2-R4496C mutant HEK293 cell assay it

exhibited negligible activity, which improved substantially when

its structure was incorporated into the novel carvedilol derivative

97, whereas further lactamization of the amino alcohol in 98

resulted in complete loss of activity. The thiazepine compounds

99³⁸and 102³⁹have been reported to suppress ventricular

arrhythmias and sudden death in mice through enhanced binding

of the 12.6 kDa FK506 binding protein (FKBP12.6) to the RyR2

channel. However, neither 99, its hydrochloride salt 100, nor its

isomer 101 displayed any measurable activity in the present

assay. On the other hand, the amide derivative 102 showed

activity about one-half that of 1.

DISCUSSION

■

These results demonstrate that considerable variation in the

structure of carvedilol is possible while retaining strong SOICR-

suppressing activity in the RyR2-R4496C mutant HEK293 single

cell assay. Thus, 34 of the above compounds (3, 6, 9, 10, 12−14,

31−34, 37, 38, 41, 43−47, 50, 53−56, 58, 64, 66, 68, 69, 83, 84,

86, 93 and 94) proved equal or superior to carvedilol (1) in

this assay. This subset of highly potent analogues reveals that

signiﬁcant changes can be tolerated in the catechol, linker and

carbazole moieties without loss of activity relative to the clinically

useful drug 1. All of the compounds in Table 1, where modiﬁca-

tions to the catechol subunit are listed, show signiﬁcant activity.

Beneﬁcial catechol modiﬁcations include chlorination of the

4′- and 5′-positions (compound 6), which is expected to block

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Table 1. SOICR Inhibition by Modiﬁed Catechol Analogues of 1

The alterations to the carbazole moiety shown in Table 6

produced mixed results. The relatively strong activity of several

analogues lacking the carbazole nitrogen or other hydrogen-

bonding functionalities is noteworthy. Thus, the ﬂuorenyl deriv-

ative 62, naphthyl derivatives 68 and 69, and the weaker but still

signiﬁcantly active adamantyl analogues 70−72 demonstrate that

the hydrogen-bonding carbazole NH functionality that partic-

ipates in binding to the β-receptor is not required for SOICR

inhibition. However, N-acylation of the carbazole nitrogen

suppressed activity (compounds 59 and 60), whereas other

heterocyclic groups displayed IC₅₀’s ranging from 5.7 μM

(compound 66) to a complete loss of activity. The more

extensive structural modiﬁcations to the compounds listed in

Table 7 also had varied eﬀects on SOICR suppression. Of special

interest are the benzomorpholine derivative 83 and the amides

93 and 94, with IC₅₀’s ranging from 3.55 to 5.76 μM compared to

15.9 μM for 1.

Finally, we note the striking contrast between the most active

SOICR inhibitors described above and the SOICR-suppressing

abilities of several conventional β-blockers and antiarrhythmic

agents shown in Table 8. The complete absence of such activity

in the case of metoprolol (95), the dibromocarbazole derivatives

96 and 98, and the thiazepine derivatives 99−101 strongly

suggest that the latter compounds express their antiarrhythmic

eﬀects through diﬀerent mechanisms than the active compounds

described in Tables 1−7. Only the carvedilol-resembling

analogue 97 and the thiazepine 102 exhibited any measurable

eﬀect on SOICR suppression.

CONCLUSIONS

■

It was recently demonstrated that the eﬀectiveness of carvedilol

as an antiarrhythmic therapy for patients with heart failure was

due in part to its ability to suppress SOICR by regulating calcium

eﬄux through the RyR2 channel.³²As a continuation of this

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Table 2. SOICR Inhibition by Compounds with Cyclized or Alkylated Linker Chains

investigation, we screened ca. 100 mostly novel compounds for their

SOICR-suppressing eﬀects on the RyR2-R4496C mutant HEK293

cell line. The wide variety of modiﬁcations that are tolerated suggests

that RyR2 is a promiscuous channel that accommodates a broad

range of ligands, including ones with structural changes to the

carbazole, linker chain, and catechol moieties of carvedilol.

EXPERIMENTAL SECTION

■

All compounds subjected to bioassay for which elemental analyses were

not provided were of >95% purity as determined by HPLC analysis

employing the following conditions: Novapak C₁₈reversed-phase

column, 3.9 × 150 mm; solvent: acetonitrile/water, 70:30, 0.8 mL/min;

UV detector: 254 nm. ¹H NMR spectra were obtained at 300 or

400 MHz. ¹³C NMR spectra were obtained at 75 or 101 MHz. ¹⁹F NMR

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Table 3. Eﬀects of Homologation and Transposition of Linker Chain on SOICR Inhibition

spectra were obtained at 376 MHz with hexaﬂuorobenzene (−164 ppm)

as the external standard relative to trichloroﬂuoromethane (0.00 ppm).

Products 2−4 were prepared as described previously in the Supporting

Information of ref 32.

m/z (relative intensity): 475 [M + 1]⁺. HRMS (EI) calcd for

C₂₄H₂₄³⁵Cl₂N₂O₄[M⁺], 474.1113; found, 474.1123.

Compounds 7 and 8 and 10−16 were prepared similarly.

1-(9H-Carbazol-4-yloxy)-3-{[2-(2,4,5-trichlorophenoxy)-

ethyl]amino}-2-propanol (7).⁴³Yield: 66%, white solid. mp 146−

148 °C. IR (ﬁlm): 3285, 1452, 1095 cm⁻¹. ¹H NMR (300 MHz, CDCl₃)

δ 8.24 (d, J = 7.8 Hz, 1H), 8.07 (s, 1H), 7.44−7.35 (m, 3H), 7.32 (dd, J =

8.0, 8.1 Hz, 1H), 7.20 (ddd, J = 1.6, 6.7, 8.1 Hz, 1H), 7.06 (dd, J = 0.5, 8.1

Hz, 1H), 6.96 (s, 1H), 6.68 (d, J = 7.6 Hz, 1H), 4.38−4.24 (m, 3H),

4.15−4.07 (m, 2H), 3.20−3.11 (m, 3H), 3.06 (dd, J = 6.9, 12.2 Hz, 1H).

¹³C NMR (75 MHz, CDCl₃) δ 154.9, 153.2, 141.4, 139.1, 131.1, 130.7,

126.3, 124.6, 124.3, 122.5, 122.1, 118.8, 114.9, 112.3, 110.1, 104.1, 100.4,

70.1, 68.6, 68.4, 52.2, 48.0. MS (EI) m/z (relative intensity): 478 (4)

[M⁺], 184 (14), 183 (100). HRMS (EI) calcd for C₂₃H₂₁³⁵Cl₃N₂O₃

[M]⁺, 478.0618; found, 478.0619.

Typical Procedure for the Preparation of Compounds 6−16.

Preparation of 1-(9H-Carbazol-4-yloxy)-3-{[2-(4,5-dichloro-2-

methoxyphenoxy)ethyl]amino}-2-propanol (6).⁴³Epoxide 103a

(169 mg, 0.706 mmol) and amine 104b (250 mg, 1.06 mmol) were

reﬂuxed for 2 h in isopropanol (4 mL). The solvent was then removed

under vacuum, and the residue was puriﬁed by ﬂash chromatography

over silica gel (methanol/dichloromethane) to obtain 208 mg (62%) of

product 6 as a white solid. mp 149−151 °C. IR (ﬁlm): 3294, 1544, 1258,

1092 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 8.21 (d, J = 7.7 Hz, 1H), 8.06

(s, 1H), 7.46−7.14 (m, 4H), 7.06 (d, J = 7.7 Hz, 1H), 6.87 (s, 1H), 6.75

(s, 1H), 6.64 (d, J = 7.7 Hz, 1H), 4.29−3.91 (m, 5H), 3.57 (s, 3H),

3.30−3.12 (m, 4H). ¹³C NMR (101 MHz, CDCl₃) δ 155.2, 149.0, 147.5,

141.1, 138.8, 126.8, 125.2, 124.2, 123.5, 123.0, 122.6, 119.8, 115.3, 113.4,

112.8, 110.2, 104.0, 101.4, 70.4, 69.2, 68.5, 56.3, 52.1, 48.6. MS (ESI)

1-(9H-Carbazol-4-yloxy)-3-[2-(phenoxyethyl)amino]-2-prop-

anol (8).^44,45Yield: 76%, white solid. mp 109−111 °C. IR (ﬁlm) 3407,

3244, 3055, 2924, 2873, 1597, 1506, 1453, 1242, 1095, 750, 725 cm⁻¹.

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Table 4. SOICR Inhibition by 3-Carbazolyl Analogues

¹H NMR (400 MHz, CDCl₃) δ 8.27 (d, J = 7.8 Hz, 1H), 8.07 (br s, 1H),

141.1, 138.8, 127.9, 126.7, 125.8 (2 signals), 125.1, 123.0, 122.6, 121.8,

119.8, 112.9, 112.0, 110.1, 103.9, 101.4, 70.3, 68.6, 68.4, 51.9, 48.7, 14.5.

MS (EI) m/z (relative intensity): 422 (20) [M⁺], 196 (66), 182 (100),

153 (38). HRMS (EI) calcd for C₂₄H₂₆N₂O₃S [M]⁺, 422.1664; found,

422.1676.

1-(9H-Carbazol-4-yloxy)-3-{[2-[(2-methoxyphenylthio)-

ethyl]amino}-2-propanol (12).⁴⁵Yield: 69%, white solid. mp 48−49 °C.

IR (ﬁlm) 3407, 2930, 2833, 1603, 1581, 1456, 1098, 910, 750, 725 cm⁻¹.

¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J = 7.8 Hz, 1H), 8.08 (s, 1H),

7.19−7.44 (m, 6H), 7.07 (d, J = 7.7 Hz, 1H), 6.95 (dd, J = 10.5, 4.2 Hz,

1H), 6.90 (dd, J = 8.7, 1.0 Hz, 2H), 6.68 (d, J = 7.9 Hz, 1H), 4.38−4.20

(m, 3H), 4.12 (t, J = 5.2 Hz, 2H), 3.19−3.10 (m, 3H), 3.05 (dd, J = 12.3,

7.3 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 158.9, 155.3, 141.1, 138.9,

129.6, 126.8, 125.2, 123.1, 122.7, 121.1, 119.9, 114.7, 112.9, 110.2, 104.0,

101.5, 70.5, 68.7, 67.3, 52.1, 49.0. MS (ESI) m/z (relative intensity):

377 (100) [M + H]⁺. HRMS (ESI) calcd for C₂₃H₂₅N₂O₃[M + H]⁺,

377.1860; found, 377.1856.

7.47−7.29 (m, 4H), 7.26−7.18 (m, 2H), 7.06 (d, J = 8.0 Hz, 1H), 6.90

(td, J = 7.5, 1.1 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 7.9 Hz,

1H), 4.40−4.15 (m, 3H), 3.88 (s, 3H), 3.14−3.01 (m, 3H), 2.99−2.85

(m, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 158.1, 155.1, 141.0, 138.8,

131.3, 128.1, 126.7, 125.1, 123.2, 123.0, 122.6, 121.2, 119.8, 112.8, 110.8,

110.1, 104.0, 101.3, 70.3, 68.5, 55.9, 51.7, 48.2, 33.0. MS (EI) m/z

(relative intensity): 422 (45) [M⁺], 269 (100), 195 (50), 182 (68), 153

(52), 120 (50). HRMS (EI) calcd for C₂₄H₂₆N₂O₃S [M]⁺, 422.1664;

found, 422.1658.

1-(9H-Carbazol-4-yloxy)-3-{[3-(2-methoxyphenyl)propyl]-

amino}-2-propanol (13).⁴⁵Yield: 64%, white solid. mp 104−105 °C.

IR (ﬁlm) 3407, 2933, 2836, 1603, 1503, 1456, 1239, 1098, 907, 750,

719 cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J = 7.8 Hz, 1H), 8.09

(s, 1H), 7.47−7.35 (m, 2H), 7.32 (t, J = 8.0 Hz, 1H), 7.22 (ddd, J = 8.0,

6.6, 1.6 Hz, 1H), 7.17 (td, J = 8.0, 1.7 Hz, 1H), 7.12 (dd, J = 7.3, 1.5 Hz,

1H), 7.06 (d, J = 8.0 Hz, 1H), 6.88 (td, J = 7.4, 1.0 Hz, 1H), 6.84 (d, J =

8.1 Hz, 1H), 6.67 (d, J = 7.9 Hz, 1H), 4.47−4.09 (m, 3H), 3.80 (s, 3H),

3.06 (dd, J = 12.2, 3.5 Hz, 1H), 2.96 (dd, J = 12.2, 7.6 Hz, 1H), 2.86−

2.61 (m, 4H), 1.81−1.91 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ

157.6, 155.3, 141.1, 138.9, 130.4, 130.0, 127.2, 126.8, 125.1, 123.0, 122.7,

120.6, 119.8, 112.9, 110.4, 110.1, 104.0, 101.4, 70.6, 68.4, 55.4, 52.1,

49.5, 30.2, 27.8. MS (EI) m/z (relative intensity): 404 (40), 182 (100),

1-(9H-Carbazol-4-yloxy)-3-{[2-(2-methylphenoxy)ethyl]-

amino}-2-propanol (10).^44,45Yield: 76%, white solid. mp 118−119 °C.

IR (ﬁlm) 3407, 3306, 3055, 2924, 1606, 1497, 1453, 1242, 1098, 750,

719 cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J = 7.7 Hz, 1H), 8.07

(br s, 1H), 7.36−7.44 (m, 2H), 7.32 (dd, J = 8.0, 7.9 Hz, 1H), 7.21 (ddd,

J = 8.1, 6.5, 1.8 Hz, 1H), 7.04−7.17 (m, 3H), 6.91−6.79 (m, 2H), 6.68

(d, J = 7.9 Hz, 1H), 4.40−4.20 (m, 3H), 4.12 (t, J = 5.1 Hz, 2H), 3.22−

3.12 (m, 3H), 3.06 (dd, J = 12.3, 7.1 Hz, 1H), 2.20 (s, 3H). ¹³C NMR

(101 MHz, CDCl₃) δ 156.9, 155.2, 141.1, 138.8, 130.8, 127.0, 126.9,

126.8, 125.1, 123.0, 122.6, 120.7, 119.8, 112.9, 111.3, 110.1, 104.0, 101.4,

70.5, 68.6, 67.4, 52.0, 49.0, 16.3. MS (ESI) m/z (relative intensity): 391

(100) [M + H]⁺. HRMS (ESI) calcd for C₂₄H₂₇N₂O₃[M + H]⁺,

391.2012; found, 391.2016.

1-(9H-Carbazol-4-yloxy)-3-{[2-(2-methylthiophenoxy)ethyl]-

amino}-2-propanol (11).⁴⁵Yield: 65%, white solid. mp 103−104 °C.

IR (ﬁlm) 3407, 3297, 2917, 1606, 1456, 1435, 1236, 1095, 756, 722

cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 8.27 (d, J = 7.8 Hz, 1H), 8.08 (br s,

1H), 7.35−7.46 (m, 2H), 7.32 (dd, J = 8.0, 8.0 Hz, 1H), 7.21 (ddd,

J = 8.0, 6.7, 1.6 Hz, 1H), 7.08−7.15 (m, 2H), 7.06 (d, J = 8.0 Hz, 1H),

6.97 (ddd, J = 7.6, 7.4, 1.2 Hz, 1H), 6.81−6.88 (m, 1H), 6.69 (d, J = 7.9

Hz, 1H), 4.15−4.39 (m, 5H), 3.14−3.22 (m, 3H), 3.06 (dd, J = 12.3, 7.0

Hz, 1H), 2.36 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.3, 155.2,

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Table 5. SOICR Inhibition by 2- and 1-Carbazolyl Analogues

178 (88), 153 (50). HRMS (EI+) m/z calcd for C₂₅H₂₈N₂O₃[M]⁺,

404.2100; found, 404.2101.

δ 163.8, 155.2, 146.9, 141.1, 138.8, 138.8, 126.8, 125.2, 123.1,

122.6, 119.9, 117.1, 112.9, 111.2, 110.1, 104.0, 101.4, 70.4, 68.5,

65.3, 52.1, 49.0. MS (ESI) m/z (relative intensity): 378 (100)

[M + H]⁺. HRMS (EI) calcd for C₂₂H₂₃N₃O₃[M]⁺, 377.1739;

found, 377.1742.

1-(9H-Carbazol-4-yloxy)-3-{2-[(cyclohexyloxy)ethyl]amino}-

2-propanol (16).⁴³Yield: 68%, viscous oil. IR (neat) 3401, 3280, 3051,

1450, 1094 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 8.28 (d, J = 7.7 Hz,

1H), 8.14 (s, 1H), 7.41−7.22 (m, 4H), 7.06 (d, J = 7.7 Hz, 1H), 6.68 (d,

J = 7.7 Hz, 1H), 4.32−4.22 (m, 3H), 3.62−3.59 (m, 2H), 3.27−3.24 (m,

1H), 3.12−3.07 (m, 1H), 3.01- 2.78 (m, 4H), 2.00−1.89 (m, 2H), 1.72−

1.71 (m, 2H), 1.54−1.49 (m, 1H), 1.39−1.19 (m, 5H). ¹³C NMR (75

MHz, CDCl₃) δ 155.2, 141.1, 138.9, 126.8, 125.1, 123.1, 122.7, 119.8,

112.83, 110.2, 104.0, 101.4, 78.1, 70.4, 68.3, 66.6, 52.1, 49.6, 32.4, 25.9,

24.3. MS (EI) m/z (relative intensity): 382 (4) [M⁺], 269 (18), 183

(100). HRMS (EI) calcd for C₂₃H₃₀N₂O₃[M]⁺, 382.2256; found,

382.2270.

1-(9H-Carbazol-4-yloxy)-3-[3-(phenylpropyl)amino]-2-propanol

(14).⁴⁵Yield: 64%, white solid. mp 110−111 °C. IR (ﬁlm) 3407, 3084,

2917, 1603, 1450, 1095, 756, 716 cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ

8.26 (d, J = 7.8 Hz, 1H), 8.08 (s, 1H), 7.48−7.36 (m, 2H), 7.32 (dd, J =

8.0, 8.0 Hz, 1H), 7.29−7.13 (m, 6H), 7.06 (d, J = 7.9 Hz, 1H), 6.67 (d,

J = 7.9 Hz, 1H), 4.36−4.17 (m, 3H), 3.04 (dd, J = 12.2, 3.5 Hz, 1H),

3.00−2.89 (m, 1H), 2.85−2.61 (m, 4H), 1.87 (p, J = 7.2 Hz, 2H). ¹³C

NMR (101 MHz, CDCl₃) δ 155.2, 142.1, 141.1, 138.9, 128.5 (2C),

126.8, 125.9, 125.1, 123.0, 122.6, 119.8, 112.8, 110.2, 104.0, 101.4, 70.5,

68.5, 52.2, 49.5, 33.6, 31.7. MS (EI) m/z (relative intensity): 374 (18)

[M⁺], 183 (100). HRMS (EI) calcd for C₂₄H₂₆N₂O₂[M]⁺, 374.1994;

found, 374.1994.

1-(9H-Carbazol-4-yloxy)-3-{2-(2-pyridyloxy)ethyl]amino}-2-

propanol (15). Yield: 54%, white solid. mp 122−123 °C. IR (ﬁlm)

3396, 3291, 2916, 1589, 1432, 1286, 1094, 783, 751, 720 cm⁻¹. ¹H NMR

(400 MHz, CDCl₃) δ 8.26 (d, J = 8.0 Hz, 1H), 8.14 (ddd, J = 5.0, 2.0, 0.8

Hz, 1H), 8.08 (s, 1H), 7.55 (ddd, J = 8.3, 7.1, 2.0 Hz, 1H), 7.34−7.43 (m,

2H), 7.32 (dd, J = 8.0, 8.0 Hz, 1H), 7.21 (ddd, J = 8.1, 6.8, 1.4 Hz, 1H),

7.06 (dd, J = 8.1, 0.5 Hz, 1H), 6.86 (ddd, J = 7.1, 5.1, 0.9 Hz, 1H), 6.72

(dt, J = 8.4, 0.9 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 4.43−4.52 (m, 2H),

4.20−4.38 (m, 3H), 2.98−3.25 (m, 5H). ¹³C NMR (101 MHz, CDCl₃)

Typical Procedure for the Preparation of Compounds 17−20.

Preparation of 6-[(9H-Carbazol-4-yloxy)methyl]-4-[2-(2-

methoxyphenoxy)ethyl]-3-morpholinone (17).⁴³Chloroacetyl

chloride (113 mg, 1.00 mmol) was added to an ice-cooled solution of

carvedilol (1) (406 mg, 1.00 mmol) and triethylamine (152 mg, 1.50 mmol)

in chloroform. The reaction mixture was warmed to room temperature

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Table 6. Eﬀect of Carbazole Modiﬁcation or Replacement on SOICR Inhibition

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Table 6. continued

and stirred for 6 h. It was then quenched with water (10 mL) and

extracted with chloroform. The combined organic layers were washed

with saturated NH₄Cl solution (25 mL), dried over Na₂SO₄, and

evaporated under reduced pressure. The residue was puriﬁed by ﬂash

chromatography over silica gel (methanol/dichloromethane) to aﬀord

the corresponding chloroacetyl derivative. A suspension of NaH

(1.1 mmol) in anhydrous THF was cooled to 0 °C. The above product

was dissolved in THF and was added to the NaH mixture. The reaction

mixture was stirred for 12 h at room temperature, quenched cautiously

with water (10 mL), and extracted with ethyl acetate. The combined

organic layers were washed with sat. NH₄Cl solution, dried over

Na₂SO₄, and evaporated under reduced pressure. Flash chromatography

of the residue over silica gel aﬀorded 321 mg (72%) of 17 as a viscous oil.

IR (neat): 3270, 1652, 1504, 1252 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ

8.28−8.19 (m, 2H), 7.44−7.06 (m, 6H), 7.01−6.81 (m, 3H), 6.65 (d, J =

7.7 Hz, 1H), 4.45−4.21 (m, 7H), 3.96−3.79 (m, 4H), 3.69 (s, 3H). ¹³C

NMR (75 MHz, CDCl₃) δ 167.1, 154.9, 149.8, 148.1, 141.2, 138.9,

126.7, 125.3, 123.1, 122.5, 122.0, 121.0, 119.9, 114.1, 113.0, 112.0,

110.2, 104.4, 101.3, 72.2, 68.4, 68.0, 67.9, 55.8, 51.3, 47.1. MS (EI) m/z

(relative intensity): 446 (17) [M⁺], 323 (100). HRMS calcd for

C₂₆H₂₆N₂O₅[M⁺], 446.1842; found 446.1844.

(relative intensity): 518 (14) [M⁺], 323 (33), 183 (100). HRMS calcd

for C₂₅H₂₁³⁵Cl₃N₂O₄, 518.0567; found, 518.0599.

6-[(9H-Carbazol-4-yloxy)methyl]-4-[2-(cyclohexyloxy)ethyl]-

3-morpholinone (20).⁴³Yield: 41%, viscous oil. IR (neat) 3267,

1640 cm⁻¹. ¹H NMR (300 MHz CDCl₃) δ 8.24 (d, J = 7.7 Hz, 1H), 8.14

(s, 1H), 7.49−7.23 (m, 4H), 7.10 (d, J = 7.7 Hz, 1H), 6.68 (d, J = 7.7 Hz,

1H), 4.50−4.24 (m, 5H), 3.78 (d, J = 6.9 Hz, 2H), 3.66 (dd, J = 15.8, 4.6

Hz, 4H), 3.28−3.17 (m, 1H), 1.92−1.78 (m, 2H), 1.76−1.42 (m, 3H),

1.32−1.08 (m, 5H). ¹³C NMR (75 MHz, CDCl₃) δ 166.9, 154.8, 141.2,

139.0, 126.7, 125.3, 123.1, 122.5, 119.8, 112.9, 110.3, 104.5, 101.3, 72.1,

68.3, 67.9, 66.2, 51.1, 47.7, 32.3, 29.9, 25.8, 24.1. MS (EI) m/z (relative

intensity): 422 (24) [M⁺], 296 (16), 183 (100). HRMS (EI) calcd for

C₂₅H₃₀N₂O₄[M⁺], 422.2206; found, 422.2225.

Typical Procedure for the Preparation of Compounds 21−24.

Preparation of 4-{4-[2-(2-Methoxyphenoxy)ethyl]-2-morpholinyl]-

methoxy}-9H-carbazole (21).⁴³A solution of 17 (446 mg, 1.00 mmol)

in THF was added to a suspension of LiAlH₄(38 mg, 1.0 mmol) in THF,

and the mixture was stirred at room temperature for 3 h. The reaction

was quenched with ethyl acetate followed by saturated Na₂SO₄solution.

The crude mixture was ﬁltered through Celite, and the residue was

washed with ethyl acetate. The ﬁltrate was dried over Na₂SO₄,

evaporated under reduced pressure, and puriﬁed by ﬂash chromatog-

raphy over silica gel to aﬀord 259 mg (60%) of 21 as a viscous oil. IR

(neat) 3290 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 8.30 (d, J = 7.7 Hz,

1H), 8.09 (s, 1H), 7.46−7.17 (m, 4H), 7.06 (d, J = 7.7 Hz, 1H), 6.96−

6.84 (m, 4H), 6.66 (d, J = 7.7 Hz, 1H), 4.40−4.05 (m, 5H), 4.04−3.93

(m, 1H), 3.91−3.76 (m, 1H), 3.78 (s, 3H), 3.34−3.22 (m, 1H), 3.04−

2.84 (m, 3H), 2.58−2.31 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 155.3,

149.9, 148.4, 141.1, 138.9, 126.8, 125.1, 123.2, 122.7, 121.8, 121.1, 119.8,

114.2, 112.9, 112.2, 110.1, 104.0, 101.3, 74.2, 69.3, 67.0, 66.9, 57.7, 56.8,

56.0, 53.8. MS (EI) m/z (relative intensity): 432 (17) [M⁺], 295 (100).

HRMS (EI) calcd for C₂₆H₂₈N₂O₄[M⁺], 432.2049; found, 432.2017.

Compounds 22−24 were prepared similarly.

Compounds 18−20 were prepared similarly from the corresponding

amino alcohols.

6-[(9H-Carbazol-4-yloxy)methyl]-4-[2-(4,5-dichloro-2-

methoxyphenoxy)ethyl]-3-morpholinone (18).⁴³Yield: 92%,

1

viscous oil. IR (neat) 3275, 1650 cm⁻¹. H NMR (300 MHz, CDCl₃)

δ 8.20 (d, J = 7.7 Hz, 1H), 8.09 (s, 1H), 7.40−7.34 (m, 2H), 7.31 (t, J =

8.0 Hz, 1H), 7.12 (dd, J = 7.9, 4.5 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.92

(s, 1H), 6.78 (s, 1H), 6.66 (d, J = 7.7 Hz, 1H), 4.48−4.18 (m, 7H),

4.01−3.78 (m, 4H), 3.57 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 167.2,

154.8, 148.9, 147.3, 141.1, 138.8, 128.5, 126.7, 125.4, 123.5, 123.0, 122.4,

119.9, 115.2, 113.3, 112.9, 110.2, 104.4, 101.3, 72.1, 68.3, 68.2, 67.9,

56.1, 51.3, 46.8. MS (EI) m/z (relative intensity): 514 (6) [M⁺] 323

(100), 183 (18), 154 (48). HRMS calcd for C₂₆H₂₄³⁵Cl₂N₂O₅[M⁺],

514.1062; found, 514.1067.

6-[(9H-Carbazol-4-yloxy)methyl]-4-[(2,4,5-trichlorophenoxy)-

ethyl]-3-morpholinone (19).⁴³Yield: 77%, white solid. mp 106−108 °C.

IR (ﬁlm): 3268, 1652 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 8.22 (d, J =

7.7 Hz, 1H), 8.08 (s, 1H), 7.44−7.18 (m, 5H), 7.09 (d, J = 7.7 Hz, 1H),

6.96 (s, 1H), 6.67 (d, J = 7.7 Hz, 1H), 4.44−4.19 (m, 7H), 4.02−3.82

(m, 4H). ¹³C NMR (75 MHz, CDCl₃) δ 167.7, 154.5, 152.9, 141.3,

139.0, 131.3, 130.8, 126.3, 124.9, 124.6, 122.7, 122.1, 121.7, 119.2, 114.6,

112.5, 110.2, 104.4, 100.8, 71.9, 67.9, 67.8, 67.5, 51.0, 46.7. MS (EI) m/z

4-{[4-[2-(4,5-Dichloro-2-methoxyphenoxy)ethyl]-2-morpholinyl]-

methoxy}-9H-carbazole (22).⁴³Yield: 86%, viscous oil. IR (neat):

3280, 1600, 1503 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 8.29 (d, J = 7.7

Hz, 1H), 8.09 (s, 1H), 7.46−7.13 (m, 3H), 7.06 (d, J = 7.7 Hz, 1H),

6.98−6.80 (m, 3H), 6.67 (d, J = 7.7 Hz, 1H), 4.37−3.97 (m, 7H), 3.80

(s, 3H), 3.32−3.22 (m, 1H), 3.02−2.84 (m, 3H), 2.58−2.29 (m, 2H).

¹³C NMR (75 MHz, CDCl₃) δ 155.2, 149.9, 141.1, 138.9, 126.8, 125.1,

123.2, 122.7, 121.9,121.0, 120.5, 119.8, 114.5, 113.0, 112.7, 112.1, 110.1,

104.0, 101.4, 74.2, 69.2, 57.6, 56.1, 56.0, 53.8. MS (EI) m/z (relative

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Table 7. Other Modiﬁed Carvedilol Derivatives as SOICR Inhibitors

intensity): 500 (10) [M⁺], 296 (20), 295 (100). HRMS (EI) calcd for

C₂₆H₂₇³⁵Cl₂N₂O₄[M⁺], 500.1270; found, 500.1263.

4-{[4-[2-(2,4,5-Trichlorophenoxy)ethyl]-2-morpholinyl]-

methoxy}-9H-carbazole (23).⁴³Yield: 66%, viscous oil. IR (neat):

3308 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 8.25 (d, J = 7.7 Hz, 1H), 8.07

(s, 1H), 7.46−7.23, (m, 4H), 7.20−7.12 (m, 1H), 7.07 (d, J = 7.7 Hz,

1H), 7.00 (s, 1H), 6.67 (d, J = 7.7 Hz, 1H), 4.38−4.10 (m, 6H), 4.08−3.86

(m, 2H), 3.46−3.25 (m, 1H), 3.16−2.92 (m, 2H), 2.74−2.48 (m, 2H).

¹³C NMR (75 MHz, CDCl₃) δ 155.2, 153.3, 141.0, 138.8, 131.3, 131.0,

126.8, 125.2, 124.8, 123.1, 122.6, 122.3, 119.8, 115.1, 112.9, 110.1, 104.1,

101.4, 74.0, 69.1, 67.8, 66.8, 57.2, 56.6, 53.8. MS (EI) m/z (relative

intensity): 504 (7) [M⁺], 295 (44), 43 (100). HRMS (EI) calcd for

C₂₅H₂₃³⁵Cl₃N₂O₃[M⁺], 504.0774; found, 504.0757.

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Table 8. SOICR Inhibition by Other Types of Antiarrhythmic Agents

4-{[4-[2-(Cyclohexyloxy)ethyl]-2-morpholinyl]methoxy}-9H-

carbazole (24).⁴³Yield: 60%, viscous oil. IR (neat) 3293, 1606, 1341,

1100 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 8.31 (d, J = 7.7 Hz, 1H), 8.11

(s, 1H),7.46−7.20 (m, 4H), 7.06 (d, J = 7.7 Hz, 1H), 6.66 (d, J = 7.7 Hz,

1H), 4.38−4.28 (m, 1H), 4.23−4.12 (m, 2H), 3.98 (d, J = 9.9 Hz, 1H),

3.84 (ddd, J = 11.3, 11.2, 2.3 Hz, 1H), 3.66 (t, J = 6.1 Hz, 2H), 3.28−3.17

(m, 2H), 2.85 (d, J = 11.6 Hz, 1H), 2.66 (t, J = 6.0 Hz, 2H), 2.37 (ddd,

J = 11.4, 11.3, 3.3 Hz, 1H), 2.32−2.23 (m, 1H), 1.96−1.83 (m, 2H),

1.78−1.62 (m, 2H), 1.55−1.48 (m, 1H), 1.36−1.14 (m, 5H). ¹³C NMR

(75 MHz, CDCl₃) δ 155.3, 141.1, 13.9, 126.8, 125.1, 123.3, 122.7, 119.8,

113.0, 110.1, 103.9, 101.3, 74.2, 69.4, 67.0, 65.5, 58.8, 56.9, 53.9, 32.4, 29.8,

25.9, 24.4. MS (EI) m/z (relative intensity): 408 (6) [M⁺], 295 (100).

HRMS (EI) calcd for C₂₅H₃₂N₂O₃[M⁺], 408.2413; found, 408.2415.

Typical Procedure for the Preparation of Compounds 25−27.

Preparation of 5-[(9H-Carbazol-4-yloxy)methyl]-3-[2-(2-

methoxyphenoxy)ethyl]-2-oxazolidinone (25).^43,46,47A solution

of carvedilol 1 (99 mg, 0.24 mmol), triethylamine (51 μL, 0.37 mmol),

and 1,1′-carbonyldiimidazole (43 mg, 0.27 mmol) in 3 mL of

dichloromethane was stirred at room temperature for 5 h. The mixture

was diluted with dichloromethane and washed with water and saturated

aqueous NH₄Cl solution, dried over Na₂SO₄, and concentrated under

vacuum. The residue was puriﬁed by ﬂash chromatography over silica gel

(methanol/dichloromethane) to aﬀord 96 mg (93%) of 25 as a white

Compounds 26 and 27 were prepared similarly.

5-[(9H-Carbazol-4-yloxy)methyl]-3-[2-(4,5-dichloro-2-

methoxyphenoxy)ethyl]-2-oxazolidinone (26).⁴³Yield: 65%,

white solid. mp 104−106 °C. IR (ﬁlm): 3290, 1749 cm⁻¹. H NMR

1

(300 MHz, CDCl₃) δ 8.12−8.05 (m, 2H), 7.44−7.20 (m, 4H), 7.13 (d,

J = 7.7 Hz, 1H), 6.83 (d, J = 7.7 Hz, 1H), 6.67 (m, 2H), 5.08−5.02 (m,

1H), 4.43−4.39 (m, 2H), 4.14−4.04 (m, 4H), 3.85−3.62 (m, 2H), 3.52

(s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 157.6, 154.4, 148.5, 146.9, 139.7,

137.5, 128.2, 126.8, 124.9, 124.6, 124.4, 123.5, 123.4, 115.5, 114.8, 113.8,

112.9, 107.9, 105.9, 71.3, 68.5, 68.3, 56.0, 48.6, 43.8. MS (EI) m/z

(relative intensity): 500 (6) [M⁺], 222 (10), 68 (100). HRMS (EI) calcd

for C₂₅H₂₂³⁵Cl₂N₂O₅[M⁺], 500.0906; found, 500.0936.

5-[(9H-Carbazol-4-yloxy)methyl]-3-[2-(cyclohexyloxy)ethyl]-

2-oxazolidinone (27).⁴³Yield: 74%, white solid. mp 146−148 °C. IR

(neat) 3290, 1732 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 8.22−8.14 (m,

2H), 7.45−7.19 (m, 4H), 7.10 (d, J = 7.7 Hz, 1H), 6.66 (d, J = 7.7 Hz,

1H), 5.08−4.98 (m, 1H), 4.46−4.36 (m, 2H), 4.08−4.00 (m, 1H) 3.94−

3.83 (m, 2H), 3.68−3.45 (m, 3H), 3.24−3.16 (m, 1H), 1.85−1.39 (m,

6H), 1.28−1.04 (m, 4H). ¹³C NMR (75 MHz, CDCl₃) δ 157.8, 154.7,

141.1, 138.9, 126.7, 125.3, 123.1, 122.5, 120.0, 112.9, 110.2, 104.5, 101.2,

77.9, 71.2, 68.2, 66.5, 48.8, 44.8, 32.2, 25.8, 24.0. MS (EI) m/z (relative

intensity): 408 (100) [M⁺], 183 (87). HRMS (EI) calcd for C₂₄H₂₈N₂O₄

[M⁺], 408.2049; found 408.2027.

Preparation of 5-[(9H-Carbazol-4-yloxy)methyl]-3-[2-(2-

hydroxyphenoxy)ethyl]-2-oxazolidinone (28). A solution of 25

(160 mg, 0.37 mmol) in dry dichloromethane (7 mL) was cooled

in an ice bath and a 1.0 M solution of BBr₃in dichloromethane (1.2 mL)

was added dropwise. After 1 h, the reaction was warmed to room

temperature and stirred an additional 1 h. The reaction was cooled in an

ice bath and slowly quenched with water and diluted further with ethyl

acetate. The organic phase was separated and washed with water and

brine, dried over MgSO₄, and concentrated under vacuum. The residue

was puriﬁed by ﬂash chromatography over silica gel (ethyl acetate/

hexanes) to aﬀord 131 mg (85%) of 28 as a white solid. mp 194−196 °C.

1

solid. mp >350 °C. IR (ﬁlm) 3288, 1730, 1107 cm⁻¹. H NMR (300

MHz, CDCl₃) δ 8.16 (d, J = 7.7 Hz, 1H), 8.08 (s, 1H), 7.46−7.19 (m,

4 H), 7.09 (d, J = 7.7 Hz, 1H), 6.98−6.79 (m, 4H), 6.64 (d, J = 7.7 Hz,

1H), 5.13−4.99 (m, 1H), 4.40 (dd, J = 10.0, 4.5 Hz, 1H), 4.33 (dd, J =

9.9, 5.7 Hz, 1H), 4.28−4.14 (m, 3H), 3.99 (dd, J = 9.0, 6.0 Hz, 1H),

3.88−3.72 (m, 2H), 3.68 (s, 3H). ¹³C NMR (75 MHz, CDCl₃−

CD₃OD) δ 158.4, 154.5, 149.6, 147.7, 141.4, 139.1, 126.3, 125.0, 122.7,

122.1, 122.0, 121.0, 119.2, 114.1, 112.2, 112.0, 110.2, 104.6, 100.5, 71.9,

68.0, 67.9, 55.6, 43.9. MS (EI) m/z (relative intensity): 432 (58) [M⁺],

183 (53), 44 (100). HRMS (EI) calcd for C₂₅H₂₄N₂O₅[M⁺], 432.1685;

found, 432.1672.

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IR (ﬁlm) 3423, 3270, 2919, 2847, 1709, 1505, 1114, 746, 742 cm⁻¹. ¹H

NMR (400 MHz, DMSO-d₆) δ 11.28 (s, 1H), 8.91 (s, 1H), 8.06 (d, J =

7.8 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.30−7.37 (m, 1H), 7.30 (dd, J =

8.0, 8.0 Hz, 1H), 7.15−7.07 (m, 2H), 6.91 (dd, J = 7.9, 1.3 Hz, 1H),

6.84−6.75 (m, 2H), 6.74−6.67 (m, 2H), 5.15−5.02 (m, 1H), 4.43 (dd,

J = 10.8, 3.1 Hz, 1H), 4.34 (dd, J = 10.8, 4.8 Hz, 1H), 4.16 (t, J = 5.4 Hz,

2H), 4.02 (t, J = 9.2 Hz, 1H), 3.80−3.68 (m, 2H), 3.59 (dt, J = 14.5, 5.4

Hz, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ 157.2, 154.2, 147.1, 146.3,

141.0, 138.8, 126.3, 124.6, 122.1, 121.7, 121.4, 119.1, 118.6, 115.8, 114.7,

111.4, 110.3, 104.2, 100.4, 68.1, 68.2, 66.8, 46.6, 43.2. MS (EI) m/z

(relative intensity): 418 (100) [M⁺], 222 (57), 154 (23). HRMS (EI)

calcd for C₂₄H₂₂N₂O₅[M]⁺, 418.1529; found, 418.1524.

Preparation of 1-(9H-Carbazol-4-yloxy)-3-{[2-(2-

hydroxyphenoxy)ethyl]amino}-2-propanol (9).^44,45Compound

28 (77 mg, 0.18 mmol) was dissolved in ethanol (1 mL) and a 2 M

NaOH solution (1.5 mL) and reﬂuxed for 3.5 h. The mixture was cooled

to room temperature, neutralized with a 1 M HCl solution, and extracted

with ethyl acetate. The combined extracts were dried over Na₂SO₄and

concentrated under vacuum. The residue was puriﬁed by ﬂash

chromatography over silica gel (methanol/dichloromethane) to aﬀord

56 mg (78%) of 9 as an oﬀ-white solid. mp 160−162 °C. IR (KBr) 3415,

1605, 1503, 1263, 1100, 755, 722 cm⁻¹. ¹H NMR (400 MHz, DMSO-

d₆) δ 11.24 (s, 1H), 8.21 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H),

7.32 (ddd, J = 7.1, 7.0, 1.2 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.09 (ddd,

J = 8.0, 7.0, 1.0, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.91 (dd, J = 8.1, 1.3 Hz,

1H), 6.82−6.74 (m, 2H), 6.73−6.68 (m, 1H), 6.68 (d, J = 8.1 Hz, 1H),

4.22−4.08 (m, 3H), 4.06−3.97 (m, 2H), 2.96−2.86 (m, 3H), 2.80 (dd,

J = 12.3, 6.9 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ 154.9, 148.0,

146.6, 141.0, 138.8, 126.4, 124.4, 122.4, 122.0, 121.6, 119.0, 118.5, 116.0,

115.8, 111.5, 110.2, 103.7, 100.3, 70.4, 69.2, 68.3, 52.1, 48.2. MS (EI)

m/z (relative intensity): 392 (69) [M⁺], 183 (100), 166 (30). HRMS

(EI) calcd for C₂₃H₂₄N₂O₄[M]⁺, 392.1736; found, 392.1731.

1H), 7.06 (d, J = 8.2 Hz, 1H), 6.98−6.88 (m, 4H), 6.70 (d, J = 8.2 Hz,

1H), 4.36−4.22 (m, 3H), 4.17 (t, J = 5.1 Hz, 2H), 3.85 (s, 3H), 3.84 (s,

3H), 3.18−3.06 (m, 3H), 3.00 (dd, J = 12.2, 6.9 Hz, 1H), 2.72 (br s, 1H).

¹³C NMR (75 MHz, CDCl₃) δ 155.3, 149.9, 148.3, 142.7, 140.4, 126.6,

125.0, 123.1, 122.2, 121.8, 121.0, 119.3, 114.4, 112.1, 112.0, 108.1, 101.9,

101.1, 70.5, 69.0, 68.6, 56.0, 52.1, 48.8, 29.4. MS (EI) m/z (relative

intensity): 420 (13) [M⁺], 197 (100). HRMS (EI) calcd for

C₂₅H₂₈N₂O₄[M⁺], 420.2049; found, 420.2085.

Preparation of 2-Methoxy-N-[2-(2-methoxyphenoxy)ethyl]-

N-methyl-3-[(9-methyl-9H-carbazol-4-yl)oxy]-1-propanamine

(31).⁴³A solution of epoxide 103a (307 mg, 1.28 mmol) in DMF

(5 mL) was added dropwise to a mixture of 60% NaH (101 mg, 2.50

mmol) in DMF (5 mL) and was cooled in an ice bath. After 5 min,

iodomethane (87 μL, 1.4 mmol) was added, and the mixture was stirred

at room temperature for 4 h. The reaction was quenched with water and

brine, and diluted with ethyl acetate. The organic phase was separated

and washed with brine, dried over Na₂SO₄, and concentrated under

reduced pressure. The crude material was subjected to ﬂash

chromatography over silica gel (ethyl acetate/hexanes) to aﬀord

300 mg (92%) of the corresponding N-methyl derivative 103b as a

white solid. mp 76−77 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (d,

J = 7.4 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.44 (ddd, J = 8.3, 7.2, 1.2 Hz,

1H), 7.39 (dd, J = 8.1, 8.1 Hz, 1H), 7.27−7.17 (m, 2H), 6.77 (d, J = 7.9

Hz, 1H), 4.58 (dd, J = 11.3, 2.6 Hz, 1H), 4.12 (dd, J = 11.3, 6.3 Hz, 1H),

3.86 (s, 3H), 3.58−3.51 (m, 1H), 2.94 (dd, J = 5.0, 4.3 Hz, 1H), 2.85 (dd,

J = 5.1, 2.7 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ 154.4, 142.0,

139.8, 126.6, 124.8, 122.3, 121.1, 118.9, 110.9, 108.67, 102.4, 101.1, 68.8,

49.9, 43.8, 29.1.

The above product (90 mg, 0.36 mmol) was reﬂuxed with the

N-methyl derivative of amine 104a (72 mg, 0.40 mmol) in isopropanol

for 2 h. The solution was evaporated, and the residue was puriﬁed by

ﬂash chromatography over silica gel (methanol/dichloromethane) to

obtain 117 mg (76%) of the corresponding N,N-methylated product as a

Preparation of 1-(9H-Carbazol-4-yloxy)-3-{[2-(2-

methoxyphenoxy)ethyl]methylamino}-2-propanol (29).⁴⁵

A

colorless oil. IR (ﬁlm) 3496, 3059, 1589, 1503, 1466, 1252 cm⁻¹. H

1

suspension of NaH (60% in oil) (10 mg, 0.25 mmol) in anhydrous

THF was cooled to 0 °C. A solution of carvedilol (1) (100 mg, 0.246

mmol) in THF was added and stirred for 20 min at the same

temperature followed by iodomethane (35 mg, 0.25 mmol). The

reaction mixture was stirred for 4 h at room temperature, quenched with

water, and extracted with ethyl acetate. The combined organic layers

were washed with saturated NH₄Cl solution, dried over Na₂SO₄, and

evaporated under reduced pressure, and the residue was puriﬁed by ﬂash

chromatography over silica gel to obtain 57 mg (54%) of 29 as a viscous

oil. IR (ﬁlm) 3233, 2923, 1600, 1504, 1452, 1252, 732 cm⁻¹. ¹H NMR

(300 MHz, CDCl₃) δ 8.29−8.20 (m, 2H), 7.41−7.31 (m, 3H), 7.28−

7.26 (m, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.93−6.87 (m, 4H), 6.66 (d, J =

8.1 Hz, 1H), 4.36−4.21 (m, 5H), 3.78 (s, 3H), 3.27−3.13 (m, 4H), 2.72

(s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 154.9, 149.7, 147.6, 141.0, 138.8,

126.7, 125.0, 122.9, 122.5, 122.1, 120.9, 119.7, 114.3, 112.7, 111.9, 110.1,

104.0, 101.3, 69.9, 66.1, 66.0, 61.2, 56.4, 55.7, 43.0. MS (EI) m/z

(relative intensity): 420 (5) [M⁺], 283 (41), 194 (100). HRMS (EI)

calcd for C₂₅H₂₈N₂O₄[M⁺], 420.2049; found 420.2038.

NMR (300 MHz, CDCl₃) δ 8.35 (d, J = 7.7 Hz, 1H), 7.49−7.34 (m,

3H), 7.28−7.19 (m, 1H), 7.03 (d, J = 8.1 Hz, 1H), 7.00−6.84 (m, 4H),

6.71 (d, J = 7.9 Hz, 1H), 4.58 (dd, J = 11.3, 2.6 Hz, 1H), 4.41−4.22 (m,

3H), 4.16 (t, J = 5.7 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.18−3.03 (m,

1H), 3.00−2.84 (m, 3H), 2.51 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ

155.4, 149.8, 148.4, 142.6, 140.4, 126.6, 124.8, 123.1, 122.2, 121.5, 120.9,

119.2, 113.7, 112.1, 112.0, 108.0, 101.8, 101.0, 70.4, 67.2, 67.0, 61.1,

56.8, 55.9, 43.5, 29.4. MS (EI) m/z (relative intensity): 434 (4) [M⁺],

297 (10), 194 (100). HRMS (EI) m/z calcd for C₂₆H₃₀N₂O₄[M⁺],

434.2206; found, 434.2206.

The above carvedilol derivative (186 mg, 0.428 mmol) in DMF

(5 mL) was cooled in an ice bath, and 60% NaH (34 mg, 0.85 mmol) was

added. After 20 min, iodomethane (30 μL, 0.47 mmol) was added, and

the mixture stirred at room temperature for 5 h. The reaction was

quenched with water and brine and diluted with ethyl acetate. The

organic phase was separated and washed with brine, dried over Na₂SO₄,

ﬁltered, and concentrated under reduced pressure. The crude material

was subjected to ﬂash chromatography over silica gel (methanol/

dichloromethane) to aﬀord 151 mg (79%) of 31 as a viscous, colorless

oil. IR (ﬁlm) 3062, 1591, 1465, 1249, 1104, 1026 cm⁻¹. ¹H NMR (400

MHz, CDCl₃) δ 8.37 (d, J = 8.0 Hz, 1H), 7.45 (ddd, J = 8.2, 7.1, 1.2, 1H),

7.42−7.32 (m, 2H), 7.23 (ddd, J = 8.0, 7.1, 1.1, 1H), 7.03 (d, J = 8.0 Hz,

1H), 6.95−6.74 (m, 4H), 6.70 (d, J = 7.8 Hz, 1H), 4.44−4.30 (m, 2H),

4.13 (t, J = 6.3 Hz, 2H), 3.97−3.89 (m, 1H), 3.84 (s, 3H), 3.81 (s, 3H),

3.61 (s, 3H), 2.99 (t, J = 6.3 Hz, 2H), 2.96−2.81 (m, 2H), 2.50 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 155.5, 149.6, 148.4, 142.6, 140.3, 126.5,

Preparation of 1-{[2-(2-Methoxyphenoxy)ethyl]amino}-3-[(9-

methyl-9H-carbazol-4-yl)oxy]-2-propanol (30).^43,48A solution of

carvedilol (1) (50 mg, 0.12 mmol) and DABCO (2 mg) in dimethyl

carbonate (4 mL) and DMF (1 mL) was heated at 95 °C for 18 h. The

reaction mixture was partitioned between ether and water. The ether

layer was washed with water and brine, dried over Na₂SO₄, and

evaporated under reduced pressure. The residue was puriﬁed by ﬂash

chromatography on silica gel to give (41 mg, 77%) of the N-methyl

derivative of 25 as an oil. The latter product was dissolved in ethanol,

2 N NaOH (2 mL) was added, and the mixture was reﬂuxed for 6 h. The

ethanol was removed under vacuum, and the residue was taken up in ethyl

acetate and washed with 1 M HCl. The aqueous layer was extracted with

ethyl acetate, and the combined organic layer was washed with water,

brine, dried over Na₂SO₄, and evaporated under reduced pressure. The

residue was puriﬁed by ﬂash chromatography over silica gel to obtain

38 mg (73% overall from 1) of 30 as a white solid. mp 130−132 °C. IR

124.8, 123.2, 122.3, 121.2, 120.9, 119.3, 113.4, 112.1, 111.9, 107.9, 101.6,

100.9, 78.5, 68.5, 67.2, 59.2, 58.1, 57.1, 55.9, 44.3, 29.4. MS (EI) m/z

(relative intensity): 448 (2) [M⁺], 194 (100). HRMS (EI) calcd for

C₂₇H₃₂N₂O₄[M⁺], 448.2362; found, 448.2345.

Preparation of 6-[2-(9H-Carbazol-4-yloxy)ethyl]-4-[2-(2-

methoxyphenoxy)ethyl]-3-morpholinone (32). Compound 32

was obtained from 2 by the same procedure used to obtain 17 from 1.

Yield: 56%, white solid, mp 157−160 °C. IR (KBr) 3256, 1634,

1507, 1452, 1257, 1122, 1098, 722 cm⁻¹. ¹H NMR (300 MHz, CDCl₃)

δ 8.36 (br s, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.39−7.36 (m, 2H), 7.32

1

(ﬁlm) 3300, 1587, 1504, 1252 cm⁻¹. H NMR (300 MHz, CDCl₃) δ

8.30 (d, J = 8.2 Hz, 1H), 7.48−7.36 (m, 3H), 7.24 (dd, J = 12.8, 5.1 Hz,

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(d, J = 8.1 Hz, 1H), 7.19−7.12 (m, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.98−

6.90 (m, 4H), 6.69 (d, J = 8.0 Hz, 1H), 4.44−4.05 (m, 7H), 3.81 (s, 3H),

3.8 −3.74 (m, 2H), 3.70−3.66 (m, 2H), 2.26−2.12 (m, 2H). ¹³C NMR

(75 MHz, CDCl₃) δ 167.1, 155.1, 149.4, 147.9, 141.0, 138.7, 126.6,

124.9, 122.7, 122.5, 121.6, 120.9, 119.5, 113.5, 112.6, 111.8, 110.0, 103.7,

101.0, 70.7, 67.8, 67.6, 63.6, 55.7, 53.6, 46.6, 32.7. MS (EI) m/z (relative

intensity): 460 (14) [M⁺], 338 (20), 337 (100). HRMS (EI) calcd for

C₂₇H₂₈N₂O₅[M⁺], 460.1998; found, 460.2005.

Preparation of 6-(9H-Carbazol-4-yloxy)-1-{[2-(2-

methoxyphenoxy)ethyl]amino}-2-hexanol (33). The product

was obtained from epoxide 106 and amine 104a by the same procedure

as used to obtain 6. Yield: 54%, solid white foam. IR (ﬁlm) 3398, 3227,

3055, 2935, 1608, 1501, 1453, 1250, 1092, 787, 749, 720 cm⁻¹. ¹H NMR

(400 MHz, CDCl₃) δ 8.33 (d, J = 7.7 Hz, 1H), 8.28 (s, 1H), 7.42−7.20

(m, 4H), 7.01 (d, J = 8.0 Hz, 1H), 6.99−6.88 (m, 4H), 6.65 (d, J = 8.0

Hz, 1H), 4.22 (t, J = 6.3 Hz, 2H), 4.09 (t, J = 5.1 Hz, 2H), 3.85 (s, 3H),

3.69−3.58 (m, 1H), 3.06−2.93 (m, 2H), 2.75 (dd, J = 12.0, 2.8 Hz, 1H),

2.47 (dd, J = 12.0, 9.5 Hz, 1H), 2.20−2.80 (br s, 2H), 2.05−1.96 (m,

2H), 1.82−1.48 (m, 4H). ¹³C NMR (101 MHz, CDCl₃) δ 155.8, 149.8,

148.4, 141.2, 138.9, 126.8, 125.0, 123.2, 122.9, 121.8, 121.1, 119.7, 114.3,

112.9, 112.1, 110.1, 103.5, 101.2, 69.4, 68.9, 67.9, 56.0, 55.2, 48.6, 34.8,

29.6, 22.5. MS (CI) m/z (relative intensity): 449 (100) [M + H]⁺.

HRMS (CI) calcd for C₂₇H₃₃N₂O₄[M + H]⁺, 449.2440; found,

449.2460.

140.9, 138.7, 126.6, 125.0, 122.8, 122.4, 121.5, 120.9, 119.6, 113.2, 112.7,

111.7, 110.03, 103.9, 101.2, 78.6, 72.3, 69.8, 67.7, 55.7, 49.0, 47.8, 31.9.

MS (EI) m/z (relative intensity): 460 (16) [M⁺], 337 (100). HRMS

(EI) calcd for C₂₇H₂₈N₂O₅[M⁺], 460.1998; found, 460.1990.

Preparation of 1-(9H-Carbazol-4-yloxy)-3-{[3-(2-

methoxyphenyl)propyl]amino}-2-propanol (36).⁴³Epoxide

103a (100 mg, 0.418 mmol) and amine 110 (151 mg, 0.836 mmol)

were stirred for 24 h at 50 °C in anhydrous DME (6 mL) in the presence

of a catalytic amount of LiBr. The solvent was then removed under

vacuum, and the residue was taken up in ether (10 mL) and washed with

water. The aqueous layer was extracted with ether, and the combined

organic layers were washed with brine, dried over Na₂SO₄, and

evaporated under reduced pressure. The residue was puriﬁed by ﬂash

chromatography over silica gel (ethyl acetate/hexanes) to obtain 86 mg

(49%) of product 36 as a viscous oil. IR (ﬁlm) 3352, 1504, 1452 cm⁻¹.

¹H NMR (300 MHz, CDCl₃) δ 8.29−8.24 (m, 2H), 7.42−7.28 (m, 2H),

7.22−7.18 (m, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.96−6.82 (m, 5H), 6.65

(d, J = 8.2 Hz, 1H), 4.39−4.09 (m, 2H), 4.12 (t, J = 5.1 Hz, 2H), 3.88−

3.79 (m, 1H), 3.85 (s 3H), 3.60−3.20 (m, 2H), 3.20−2.93 (m, 3H),

2.15−2.05 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 155.6, 149.7, 148.3,

141.1, 138.9, 126.9, 125.0, 123.0, 122.8, 121.8, 121.1, 119.7, 114.2, 112.7,

112.0, 110.2, 103.7, 101.3, 70.3, 68.1, 68.0, 56.1, 52.1, 47.7, 28.6. MS

(EI) m/z (relative intensity): 420 (12) [M⁺], 183 (44), 154 (70), 45

(100). HRMS (EI) calcd for C₂₅H₂₈N₂O₄, 420.2049; found 420.2088.

Preparation of 1-(9H-Carbazol-4-yloxy)-3-{[2-(2-

methoxybenzyloxy)ethyl]amino}-2-propanol (37). The product

was obtained from epoxide 103a and amine 111a by the same procedure

used to obtain 6. Yield: 82%, oﬀ-white solid. mp 94−95 °C. IR (ﬁlm)

3402, 3291, 3050, 1606, 1455, 1243, 1100 cm⁻¹. ¹H NMR (400 MHz,

CDCl₃) δ 8.27 (d, J = 7.8 Hz, 1H), 8.15 (s, 1H), 7.42−7.19 (m, 6H),

7.04 (d, J = 8.0 Hz, 1H), 6.93 (td, J = 7.4, 0.9 Hz, 1H), 6.86 (d, J = 8.2 Hz,

1H), 6.66 (d, J = 7.9 Hz, 1H), 4.59 (s, 2H), 4.33−4.15 (m, 3H), 3.82 (s,

3H), 3.67 (t, J = 5.1 Hz, 2H), 3.05 (dd, J = 12.3, 3.5 Hz, 1H), 3.02−2.86

(m, 5H). ¹³C NMR (101 MHz, CDCl₃) δ 157.4, 155.3, 141.1, 138.9,

129.4, 129.0, 126.8, 126.6, 125.1, 123.1, 122.7, 120.6, 119.8, 112.9, 110.5,

110.1, 104.0, 101.4, 70.4, 69.6, 68.5, 68.2, 55.5, 52.1, 49.4. MS (EI) m/z

(relative intensity): 420 (8) [M⁺], 194 (46), 183 (100), 154 (48), 121

(92), 91 (50). HRMS (EI) calcd for C₂₅H₂₈N₂O₄[M]⁺, 420.2049;

found, 420.2056.

Preparation of 1-(9H-Carbazol-4-yloxy)-3-{[2-(benzyloxy)-

ethyl]amino}-2-propanol (38). The product was obtained from

epoxide 103a and amine 111b by the same procedure used to obtain 6.

Yield: 72%, solid white foam. IR (ﬁlm) 3405, 3299, 3056, 2919, 2856,

1603, 1455, 1100, 751, 720 cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 8.27

(d, J = 7.8 Hz, 1H), 8.09 (s, 1H), 7.46−7.18 (m, 9H), 7.06 (d, J = 8.0 Hz,

1H), 6.68 (d, J = 8.0 Hz, 1H), 4.52 (s, 2H), 4.34−4.18 (m, 3H), 3.63 (t,

J = 5.1 Hz, 2H), 3.06 (dd, J = 12.2, 3.4 Hz, 1H), 3.01−2.86 (m, 3H), 2.67

(br s, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 155.2, 141.1, 138.8, 138.2,

128.5, 127.9, 127.8, 126.7, 125.0, 123.0, 122.6, 119.7, 112.7, 110.1, 104.0,

101.3, 73.3, 70.4, 69.5, 68.5, 52.1, 49.4. MS (EI) m/z (relative intensity):

390 (5) [M⁺], 154 (38), 149 (86), 91 (100). HRMS (EI) calcd for

C₂₄H₂₆N₂O₃[M⁺], 390.1943; found, 390.1939.

Preparation of 1-{-2-[(9H-Carbazol-4-yloxy)ethyl]amino}-3-

(2-methoxyphenyloxy)-2-propanol (39). The product was ob-

tained from epoxide 113 and amine 112 by the same procedure used to

obtain 36. Yield: 55%, solid oﬀ-white foam. IR (KBr) 3399, 1606, 1586,

1455, 1254, 1119, 751 cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J =

7.8 Hz, 1H), 8.17 (br s, 1H), 7.40−7.35 (m, 2H), 7.31 (t, J = 8.0 Hz,

1H), 7.20 (ddd, J = 8.1, 6.4, 1.9 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.97−

6.85 (m, 4H), 6.66 (d, J = 8.0 Hz, 1H), 4.35 (t, J = 5.3 Hz, 2H), 4.19−

4.13 (m, 1H), 4.09−4.01 (m, 2H), 3.81 (s, 3H), 3.26 (dd, J = 5.8, 4.4 Hz,

2H), 3.22 (br s, 1H), 3.06 (dd, J = 12.2, 4.1 Hz, 1H), 2.97 (dd, J = 12.2,

7.3 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 155.2, 149.9, 148.2, 140.9,

138.7, 126.6, 125.0, 122.9, 122.5, 122.0, 120.9, 119.7, 115.0, 112.3, 111.9,

110.0, 103.8, 101.2, 72.7, 68.2, 67.2, 55.8, 51.7, 48.9. MS (EI) m/z

(relative intensity): 406 (5) [M⁺], 238 (100). HRMS (EI) calcd for

C₂₄H₂₆N₂O₄[M⁺], 406.1893; found, 406.1904.

Preparation of 1-(9H-Carbazol-4-yloxy)-4-[[2-(2-

methoxyphenoxy)ethyl]amino]-2-butanol (34). 4-Hydroxy-

carbazole (56 mg, 0.31 mmol), 107 (160 mg, 0.31 mmol), and

K₂CO₃(85 mg, 0.62 mmol) were heated in DMF (10 mL) at 100 °C for

12 h. The reaction mixture was diluted with water (50 mL) and extracted

with dichloromethane. The combined organic layers were dried over

Na₂SO₄, and the residue was puriﬁed by ﬂash chromatography over silica

gel to aﬀord 120 mg (63%) of 108 as a colorless oil. The latter product

(70 mg, 0.11 mmol) was dissolved in THF, TBAF in THF (0.22 mL,

1 M) was added, and the mixture was stirred at room temperature

overnight. The solvent was removed under vacuum, and the residue was

chromatographed similarly to aﬀord 24 mg (80%) of the corresponding

diol as colorless oil. The diol (735 mg, 2.71 mmol), triethylamine

(1.5 mL, 10.8 mmol), p-toluenesulfonyl chloride (1.03 g, 5.4 mmol), and

DMAP (5 mol %) were stirred in dry chloroform at room temperature

for 2 days. Concentration and ﬂash chromatography aﬀorded 200 mg

(17%) of tosylate 109 along with 500 mg of recovered starting material.

The tosylate (200 mg, 0.471 mmol), amine 104a (400 mg, 2.40 mmol),

and LiBr (104 mg, 1.20 mmol) were heated brieﬂy at 100 °C in DME

(1 mL). The reaction mixture was then stirred for 2 days at room

temperature, diluted with water (20 mL), and extracted with chloro-

form. The combined organic layers were dried over Na₂SO₄,

concentrated, and subjected to ﬂash chromatography over silica gel to

aﬀord 100 mg (51%) of 34 as solid foam. IR (KBr) 3345, 2919, 1605,

1

1502, 1454, 1255, 1123, 1100, 749, 718 cm⁻¹. H NMR (400 MHz,

CDCl₃) δ 8.28 (d, J = 7.7 Hz, 1H), 8.15 (br s, 1H), 7.43−7.38 (m, 2H),

7.33 (t, J = 8.0 Hz, 1H), 7.23 (ddd, J = 8.0, 6.7, 1.5 Hz, 1H), 7.06 (d,

J = 8.0 Hz, 1H), 7.00−6.90 (m, 4H), 6.70 (d, J = 8.0 Hz, 1H), 4.48−4.42

(m, 1H), 4.29 (dd, J = 9.2, 5.2 Hz, 1H), 4.18−4.12 (m, 2H), 3.87 (s, 3H),

3.22−2.98 (m, 5H), 2.10−2.03 (m, 1H), 1.94−1.84 (m, 1H). ¹³C NMR

(101 MHz, CDCl₃) δ 155.3, 149.8, 148.1, 141.0, 138.8, 126.7, 124.9,

123.0, 122.6, 121.9, 121.0, 119.6, 114.5, 112.7, 111.9, 110.0, 103.7, 101.2,

71.6, 71.5, 68.4, 55.8, 48.4, 47.8, 31.8. MS (EI) m/z (relative intensity):

420 (11) [M⁺], 238 (46), 154 (100). HRMS (EI) calcd for C₂₅H₂₈N₂O₄

[M⁺], 420.2049; found, 420.2069.

Preparation of 7-[(9H-Carbazol-4-yloxy)methyl]-4-[2-(2-

methoxyphenoxy)ethyl]-1,4-oxazepan-3-one (35). Compound

35 was obtained from 34 by the same procedure used to obtain 17

from 1. Yield: 23% (overall), viscous oil. IR (KBr): 3285, 2920, 1647,

1

1504, 1455, 1252, 1221, 1123, 1032, 752 cm⁻¹. H NMR (400 MHz,

CDCl₃) δ 8.26 (br s, 1H), 8.24 (d, J = 7.4 Hz, 1H), 7.41−7.39 (m, 2H),

7.32 (t, J = 8.0 Hz, 1H), 7.23 (ddd, J = 8.1, 6.7, 4.0 Hz, 1H), 7.06 (d, J =

8.1 Hz, 1H), 6.97−6.87 (m, 4H), 6.65 (d, J = 8.0 Hz, 1H), 4.57 (d, J =

15.5 Hz, 1H), 4.36−4.31 (m, 2H), 4.27−4.10 (m, 4H), 3.98−3.83 (m,

3H), 3.80 (s, 3H), 3.76−3.70 (m, 1H), 2.39−2.25 (m, 1H), 2.15−2.08

(m, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 172.1, 154.9, 149.4, 148.0,

Preparation of 4-[2-(9H-Carbazol-4-yloxy)ethyl]-6-(2-

methoxyphenoxymethyl)morpholine-3-one (40). Compound

40 was obtained from 39 by the same procedure used to obtain 17

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from 1. Yield: 52% (overall), solid white foam. IR (KBr) 3257, 1646,

1501, 1450, 768, 717 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 8.50 (br s,

1H), 8.27 (d, J = 7.8 Hz, 1H), 7.36−7.33 (m, 2H), 7.29 (d, J = 8.0 Hz,

1H), 7.15 (ddd, J = 8.0, 5.1, 3.1 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.97

(dd, J = 7.0, 1.3 Hz, 1H), 6.89−6.86 (m, 2H), 6.79 (td, J = 7.8, 1.8 Hz,

1H), 6.63 (d, J = 8.0 Hz, 1H), 4.44−4.38 (m, 2H), 4.36 (d, J = 16.7 Hz,

1H), 4.21 (d, J = 16.6 Hz, 1H), 4.10−3.99 (m, 3H), 3.91−3.82 (m, 2H),

3.77 (s, 3H), 3.80−3.72 (m, 1H), 3.62 (dd, J = 11.9, 2.9 Hz, 1H). ¹³C

NMR (75 MHz, CDCl₃) δ 167.0, 154.7, 149.8, 147.6, 141.0, 138.7,

126.6, 125.0, 122.6, 122.3, 120.8, 119.5, 114.8, 112.4, 111.9, 110.1, 104.0,

101.0, 71.8, 69.4, 67.6, 65.9, 55.6, 50.1, 46.6. MS (CI) m/z (relative

intensity): 464 (23) [M + NH₄]⁺, 447 (100) [M + H]⁺. HRMS (CI)

calcd for C₂₆H₂₇N₂O₅[M + H]⁺, 447.1920; found, 447.1942.

Preparation of 5-(9H-Carbazol-3-yloxy)-1-{[2-(2-

methoxyphenoxy)ethyl]amino}-2-pentanol (44). Compound 44

was obtained from epoxide 114c and amine 104a by the same procedure

as used to obtain 6. Yield: 56%, white solid. mp 116−118 °C. IR (ﬁlm)

1

3402, 3236, 2942, 1500, 1449, 1249, 1180, 742 cm⁻¹. H NMR (300

MHz, DMSO-d₆) δ 11.00 (s, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.66 (d, J =

2.3 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.33 (dd,

J = 7.2, 7.0 Hz, 1H), 7.09 (dd, J = 7.6, 7.1 Hz, 1H), 7.00−6.81 (m, 5H),

4.67 (d, J = 4.1 Hz, 1H), 4.08−3.99 (m, 4H), 3.74 (s, 3H), 3.70−3.60

(m, 1H), 2.92 (t, J = 5.5 Hz, 2H), 2.71−2.49 (m, 2H), 1.95−1.45 (m,

4H). ¹³C NMR (101 MHz, DMSO-d₆) δ 152.2, 149.1, 148.0, 140.3,

134.4, 125.2, 122.7, 122.4, 121.0, 120.7, 120.2, 117.8, 115.1, 113.6, 112.2,

111.4, 110.8, 103.9, 68.9, 68.3, 68.2, 55.6, 55.4, 48.2, 31.6, 25.4. MS (EI)

m/z (relative intensity): 434 (50) [M⁺], 252 (77), 180 (100), 154 (14).

HRMS (EI) calcd for C₂₆H₃₀N₂O₄[M⁺], 434.2206; found, 434.2203.

Preparation of 6-(9H-Carbazol-3-yloxy)-1-{[2-(2-

methoxyphenoxy)ethyl]amino}-2-hexanol (45). Compound 45

was obtained from epoxide 114d and amine 104a by the same procedure

as used to obtain 6. Yield: 54%, solid white foam. IR (ﬁlm) 3406, 3234,

3060, 2938, 1502, 1250, 743 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 8.00

(d, J = 8.1 Hz, 1H), 7.98 (br s, 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.40−7.33

(m, 2H), 7.30 (d, J = 8.7 Hz, 1H), 7.20−7.14 (m, 1H), 7.03 (dd, J = 8.7,

2.4 Hz, 1H), 6.96−6.86 (m, 4H), 4.10 (t, J = 5.2 Hz, 2H), 4.05 (t, J = 6.4

Hz, 2H), 3.83 (s, 3H), 3.70−3.60 (m, 1H), 3.08−2.98 (m, 2H), 2.81

(dd, J = 12.1, 2.9 Hz, 1H), 2.77−2.53 (br s, 2H), 2.51 (dd, J = 12.0, 9.5

Hz, 1H), 1.90−1.80 (m, 2H), 1.77−1.42 (m, 4H). ¹³C NMR (101 MHz,

CDCl₃) δ 153.4, 149.8, 148.3, 140.5, 134.6, 125.9, 123.9, 123.5, 121.9,

121.1, 120.4, 119.1, 115.8, 114.4, 112.0, 111.4, 110.9, 104.5, 69.3, 68.0,

68.8, 56.0, 55.1, 48.5, 34.8, 29.7, 22.5. MS (CI) m/z (relative intensity):

449 (100) [M + H]⁺. HRMS (CI) calcd for C₂₇H₃₃N₂O₄[M + H]⁺,

449.2440; found, 449.2437.

Preparation of 1-(9H-Carbazol-3-yloxy)-4-{[2-(2-

methoxyphenoxy)ethyl]amino}-2-butanol (46). A solution of

bromoalcohol 115 (151 mg, 0.452 mmol), amine 104a (149 mg,

0.892 mmol), and Et₃N (0.14 mL, 0.98 mmol) in methanol (2 mL) was

heated at 60 °C for 18 h. The reaction mixture was diluted with water

and extracted with dichloromethane. The combined organic extracts

were washed with brine, dried over Na₂SO₄, and concentrated under

vacuum. The residue was puriﬁed by ﬂash chromatography over silica gel

(methanol/dichloromethane) to aﬀord 94 mg (49%) of 46 as a white

solid. mp 134−136 °C. IR (ﬁlm) 3402, 3351, 2927, 2839, 1500, 1452,

1252, 1180, 1026, 745 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s,

1H), 8.07 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.43 (d, J = 8.0

Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.33 (ddd, J = 8.0, 7.9, 1.2 Hz, 1H),

7.09 (ddd, J = 8.0, 7.9, 1.0 Hz, 1H), 7.02 (dd, J = 8.8, 2.5 Hz, 1H), 6.99−

6.82 (m, 4H), 4.00 (t, J = 5.7 Hz, 2H), 3.98−3.90 (m, 3H), 3.74 (s, 3H),

2.90 (t, J = 5.7 Hz, 2H), 2.79 (t, J = 6.9 Hz, 2H), 1.80−1.75 (m, 1H),

1.65−1.58 (m, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ 152.3, 149.2,

148.0, 140.3, 134.5, 125.2, 122.7, 122.4, 121.1, 120.7, 120.2, 117.9, 115.2,

113.8, 112.2, 111.4, 110.8, 104.0, 73.1, 68.1, 67.7, 55.4, 48.1, 46.1, 33.4.

MS (EI) m/z (relative intensity): 420 (1) [M⁺], 238 (100), 180 (30).

HRMS (EI) calcd for C₂₅H₂₈N₂O₄[M⁺], 420.2049; found, 420.2032.

Preparation of 1-(6-Fluoro-9H-carbazol-3-yloxy)-3-{[2-(2-

methoxyphenoxy)ethyl]amino}-2-propanol (47). Compound 47

was obtained from epoxide 114e and amine 104a by the same procedure

as used to obtain 6. Yield: 53%, white solid. mp 62−64 °C. IR (KBr)

3382, 2927, 2836, 1575, 1497, 1456, 1286, 1249, 11955, 1120, 1023,

794, 756 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 7.91

(dd, J = 9.5, 2.6 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.42 (dd, J = 8.8, 4.4

Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.18 (ddd, J = 9.4, 8.8, 2.6 Hz, 1H),

7.05 (dd, J = 8.8, 2.5 Hz, 1H), 6.99−6.93 (m, 2H), 6.92−6.81 (m, 2H),

5.07 (d, J = 2.6 Hz, 1H), 4.06−3.93 (m, 5H), 3.73 (s, 3H), 2.93 (t, J = 5.5

Hz, 2H), 2.83 (dd, J = 11.4, 3.7 Hz, 1H), 2.71 (dd, J = 11.8, 6.4 Hz, 1H).

¹³C NMR (101 MHz, DMSO-d₆) δ 155.9 (d, ¹J_C−F= 230 Hz), 152.1,

Preparation of 6-[(9H-Carbazol-3-yloxy)methyl]-4-[2-(2-

methoxyphenoxy)ethyl]morpholine-3-one (41). Compound 41

was obtained from 3 by the same procedure used to obtain 17 from 1.

Yield: 49% (overall), white solid. mp 63−65 °C. IR (KBr) 3458, 3378,

1

2922, 2834, 1507, 1452, 1253, 1222, 1186, 1121, 745 cm⁻¹. H NMR

(300 MHz, CDCl₃) δ 7.98 (d, J = 7.8 Hz, 1H), 7.96 (br s, 1H), 7.54 (d,

J = 2.4 Hz, 1H), 7.43−7.36 (m, 2H), 7.32 (d, J = 8.7 Hz, 1H), 7.23−7.15

(m, 1H), 7.05 (dd, J = 8.7, 2.4 Hz, 1H), 6.95−6.82 (m, 4H), 4.40−4.03

(m, 7H), 3.78 (s, 3H), 3.92−3.76 (m, 4H). ¹³C NMR (101 MHz,

CDCl₃) δ 167.1, 152.7, 149.7, 148.1, 140.5, 135.0, 126.2, 123.9, 123.3,

121.9, 120.4, 119.3, 115.6, 113.8, 112.1, 111.5, 111.0, 104.9, 72.2, 69.5,

68.0, 67.9, 56.0, 51.0, 47.0. MS (EI) m/z (relative intensity): 445 (20),

322 (100). HRMS (EI) calcd for C₂₆H₂₆N₂O₅[M⁺], 446.1842; found,

446.1861.

Preparation of 6-[(9H-Carbazol-3-yloxy)methyl]-4-[2-(2-

methoxyphenoxy)ethyl]-1,3λ⁶,4-oxathiazinane-3,3-dione (42).

A suspension of 3 (101 mg, 0.249 mmol) and Et₃N (60 μL, 0.4 mmol) in

dry dichloromethane (3 mL) was cooled in an ice bath. After 5 min, a

solution of bromomethanesulfonyl chloride⁴⁹(84 mg, 0.43 mmol) in

dry dichloromethane (0.5 mL) was added dropwise. The ice bath was

removed, and the reaction was stirred at room temperature for 24 h. The

reaction was concentrated under vacuum, and the residue was puriﬁed

by ﬂash chromatography over silica gel (ethyl acetate/hexanes) to aﬀord

the intermediate sulfonamide as a solid white foam. A solution of the

sulfonamide (48 mg, 0.086 mmol) in dry THF (2 mL) was cooled to

10 °C and treated with NaH (6 mg, 60% dispersion in oil, 0.15 mmol).

The reaction was stirred for 20 h at room temperature, quenched with

water, and extracted with ethyl acetate. The combined organic extracts

were dried over Na₂SO₄and concentrated under vacuum. The residue

was puriﬁed by ﬂash chromatography over silica gel (ethyl acetate/

hexanes) to aﬀord 28 mg (24% overall) of 42 as an oﬀ-white solid. mp

71−73 °C. IR (ﬁlm) 3396, 3007, 2919, 1503, 1452, 1329, 1253, 1160,

1120, 745 cm⁻¹. ¹H NMR (300 MHz, DMSO-d₆) δ 11.05 (s, 1H), 8.06

(d, J = 7.6 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.47−7.29 (m, 3H), 7.15−

6.83 (m, 6H), 5.02 (d, J = 11.7 Hz, 1H), 4.94 (d, J = 11.7 Hz, 1H), 4.44−

4.37 (m, 1H), 4.16−4.10 (m, 4H), 3.72 (s, 3H), 3.92−3.55 (m, 4H). ¹³C

NMR (101 MHz, CDCl₃) δ 152.6, 149.7, 147.8, 140.5, 135.0, 126.2,

124.0, 123.3, 122.2, 121.1, 120.4, 119.4, 115.6, 114.0, 112.1, 111.5, 111.0,

105.0, 81.4, 74.5, 68.9, 68.7, 55.9, 54.2, 47.2. MS (CI) m/z (relative

intensity): 500 [M + NH₄]⁺(100), 418 (30), 354 (20). HRMS (EI)

calcd for C₂₅H₂₆N₂O₆S [M⁺], 482.1512; found, 482.1499.

Preparation of 4-(9H-Carbazol-3-yloxy)-1-{[2-(2-

methoxyphenoxy)ethyl]amino}-2-butanol (43). Compound 43

was obtained from epoxide 114b and amine 104a by the same procedure

as used to obtain 6. Yield: 62%, oﬀ-white solid. mp 126−128 °C. IR

(KBr) 3408, 3299, 3060, 2940, 2877, 2834, 1588, 1495, 1459, 1250,

1183, 1123, 1024, 745 cm⁻¹. ¹H NMR (300 MHz, DMSO-d₆) δ 11.00 (s,

1H), 8.07 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.42 (d, J = 8.0

Hz, 1H), 7.39−7.29 (m, 2H), 7.09 (dd, J = 7.5, 7.4 Hz, 1H), 7.04−6.80

(m, 5H), 4.75 (d, J = 5.0 Hz, 1H), 4.15 (t, J = 6.3 Hz, 2H), 4.02 (t, J = 5.5

Hz, 2H), 3.85−3.77 (m, 1H), 3.74 (s, 3H), 2.92 (t, J = 5.5 Hz, 2H),

2.74−2.53 (m, 2H), 1.96−1.75 (m, 2H). ¹³C NMR (101 MHz, DMSO-

d₆) δ 152.2, 149.1, 148.0, 140.3, 134.4, 125.2, 122.7, 122.4, 121.0, 120.7,

120.2, 117.8, 115.1, 113.6, 112.2, 111.4, 110.9, 103.9, 68.2, 66.3, 65.2,

55.5, 55.4, 48.2, 34.8. MS (EI) m/z (relative intensity): 420 (100) [M⁺],

419 (32), 389 (17), 388 (53). HRMS (EI) calcd for C₂₅H₂₈N₂O₄[M⁺],

420.2049; found, 420.2044.

149.1, 148.0, 136.7, 135.6, 122.7 (d, ³J_C−F= 10 Hz), 122.4 (d, ⁴J_C−F= 4

Hz), 121.0, 120.6, 116.1, 113.6, 113.0 (d, ²J_C−F= 25 Hz), 112.2, 111.8,

111.7 (CH, d, ³J_C−F= 9 Hz), 105.6 (d, ²J_C−F= 23 Hz), 104.1, 71.4, 68.2,

55.4, 52.4, 48.4. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −125.6. MS (EI)

m/z (relative intensity): 424 (18) [M⁺], 201 (97), 180 (100), 172 (28),

8646

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44 (39). HRMS (EI) calcd for C₂₄H₂₅FN₂O₄[M⁺], 424.1798; found,

424.1790.

6-[2-(9H-Carbazol-2-yloxy)ethyl]-4-[2-(2-methoxyphenoxy)-

ethyl]-3-morpholinone (51). Yield: 61% overall from 50, white solid.

mp 160−161 °C. IR (ﬁlm) 3396, 3002, 2932, 2876, 1641, 1503,

1460, 1255, 1219, 768 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s,

1H), 7.97 (d, J = 7.8 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.41 (d, J = 8.0

Hz, 1H), 7.27 (dd, J = 8.0, 7.1 Hz, 1H), 7.09 (dd, J = 7.5, 7.4 Hz, 1H),

7.01−6.94 (m, 5H), 6.76 (dd, J = 8.5, 1.9 Hz, 1H), 4.20−4.05 (m, 6H),

4.03−3.95 (m, 1H), 3.77−3.68 (m, 1H), 3.73 (s, 3H), 3.66−3.49 (m,

3H), 2.08−1.94 (m, 2H). ¹³C NMR (101 MHz, DMSO-d₆) δ 166.0,

157.5, 149.1, 147.7, 140.9, 139.7, 124.1, 122.5, 121.3, 120.8, 120.7, 119.2,

118.4, 116.2, 113.6, 112.3, 110.5, 107.9, 95.2, 70.1, 67.0, 66.3, 63.7, 55.5,

52.1, 45.4, 32.0. MS (EI) m/z (relative intensity): 460 (24) [M⁺], 337

(100). HRMS (EI) calcd for C₂₇H₂₈N₂O₅[M⁺], 460.1998; found,

460.1988.

5-[2-(9H-Carbazol-2-yloxy)ethyl]-3-[2-(2-methoxyphenoxy)-

ethyl]-2-oxazolidinone (52). Yield: 87% overall from 50, white solid.

mp 61−63 °C. IR (ﬁlm) 3399, 3320, 3002, 2926, 1739, 1500, 1460,

1249, 749 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.98

(d, J = 7.8 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H),

7.28 (dd, J = 7.8, 7.3 Hz, 1H), 7.10 (dd, J = 7.6, 7.3 Hz, 1H), 7.01−6.83

(5H, m), 6.76 (dd, J = 8.5, 1.9 Hz, 1H), 4.80−4.70 (m, 1H), 4.21−4.11

(m, 2H), 4.09 (t, J = 5.3 Hz, 2H), 3.88 (t, J = 8.6 Hz, 1H), 3.73 (s, 3H),

3.58−3.50 (m, 3H), 2.19−2.11 (2H, m). ¹³C NMR (101 MHz, DMSO-

d₆) δ 157.4, 157.1, 149.3, 147.6, 140.9, 139.7, 124.1, 122.5, 121.5, 120.8,

120.7, 119.2, 118.4, 116.3, 114.1, 112.4, 110.5, 107.9, 95.2, 70.9, 66.6,

63.7, 55.5, 50.1, 43.1, 33.9. MS (EI) m/z (relative intensity): 446 (100)

[M⁺], 236 (48). HRMS (EI) calcd for C₂₆H₂₆N₂O₅[M⁺], 446.1842;

found, 446.1835.

Preparation of 1-[(9H-Carbazol-3-yl)amino]-3-{[2-(2-

methoxyphenoxy)ethyl]amino}-2-propanol (48). A mixture of

9-t-butyloxycarbonyl-3-aminocarbazole (576 mg, 2.04 mmol) and

epichlorohydrin (0.11 mL, 1.4 mmol) in absolute ethanol (3.5 mL)

was reﬂuxed for 6 h. The reaction mixture was cooled to room

temperature and concentrated under vacuum, and the residue was

puriﬁed by ﬂash chromatography over silica gel (methanol/dichloro-

methane) to aﬀord 369 mg (70%) of 116 as a yellow foam. A mixture of

116 (201 mg, 0.536 mmol), 104a (177 mg, 1.06 mmol), K₂CO₃(91 mg,

0.66 mmol), and catalytic KI in absolute ethanol (3.5 mL) was reﬂuxed

for 3 h. The reaction mixture was cooled to room temperature, ﬁltered,

and washed with dichloromethane. The ﬁltrate was concentrated under

vacuum, and the residue was puriﬁed by ﬂash chromatography over silica

gel (methanol/dichloromethane) to aﬀord 177 mg (66%) of t-Boc-

protected 48 as a yellow solid foam. A solution of the latter product

(100 mg, 0.198 mmol) in dichloromethane (2.5 mL) was stirred in TFA

(0.38 mL, 4.9 mmol) at room temperature for 3.5 h. The reaction mix-

ture was treated with 1 M NaOH and extracted with dichloromethane.

The combined organic extracts were dried over Na₂SO₄and concentrated

under vacuum. The residue was puriﬁed by ﬂash chromatography over

silica gel (methanol/dichloromethane) to aﬀord 52 mg (65%) of 48 as a

white solid. mp 135−137 °C. IR (KBr) 3408, 3299, 3060, 2940, 2877,

2834, 1588, 1495, 1459, 1250, 1183, 1123, 1024, 745 cm⁻¹. ¹H NMR (400

MHz, DMSO-d₆) δ 10.75 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.0

Hz, 1H), 7.32−7.20 (m, 3H), 7.12−6.80 (m, 6H), 4.92 (br s, 1H), 4.03 (t,

J = 4.8 Hz, 2H), 3.89−3.80 (m, 1H), 3.74 (s, 3H), 3.20 (dd, J = 12.2, 5.1

Hz, 1H), 3.05 (dd, J = 12.2, 6.4 Hz, 1H), 2.93 (t, J = 5.0 Hz, 2H), 2.79 (dd,

J = 11.6, 3.9 Hz, 1H), 2.68 (dd, J = 11.6, 7.3 Hz, 1H). ¹³C NMR (101

MHz, DMSO-d₆) δ 149.1, 148.0, 142.4, 140.0, 132.6, 124.7, 123.0, 122.3,

121.0, 120.6, 119.8, 117.4, 114.5, 113.7, 112.2, 111.3, 110.6, 101.0, 68.2,

68.1, 55.4, 53.6, 49.1, 48.3. MS (EI) m/z (relative intensity): 405 (100)

[M⁺], 220 (50), 195 (80), 182 (40), 167 (33). HRMS (EI) calcd for

C₂₄H₂₇N₃O₃[M⁺], 405.2052; found, 405.2038.

Compounds 49−58 were prepared in the usual manner by conver-

sion of the corresponding hydroxycarbazoles to the epoxides 117a−e

followed by epoxide-opening with amines 104a or 104m−o, as shown in

Scheme 5. The lactams 49 and 51 and the oxazolidinone 52 were

obtained by cyclization of the corresponding amino alcohols with

chloroacetyl chloride and 1,1-carbonyldiimidazole, respectively.

6-[(9H-Carbazol-2-yloxy)methyl]-4-[2-(2-methoxyphenoxy)-

ethyl]morpholine-3-one 49. Yield: 57% (overall from 4), white solid.

mp 69−71 °C. IR (KBr) 3407, 3063, 2929, 2873, 1647, 1607, 1500,

1460, 1250, 1175, 1022, 747 cm⁻¹. ¹H NMR (300 MHz, DMSO-d₆) δ

11.12 (s, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.42 (d,

J = 8.0 Hz, 1H), 7.28 (dd, J = 7.9, 7.2 Hz, 1H), 7.10 (dd, J = 7.5, 7.2 Hz,

1H), 7.04−6.83 (m, 5H), 6.80 (dd, J = 8.5, 2.1 Hz, 1H), 4.28−4.10 (m,

7H), 3.77 (s, 3H), 3.86−3.58 (m, 4H). ¹³C NMR (101 MHz, DMSO-

d₆) δ 165.9, 157.3, 149.2, 147.7, 140.9, 139.7, 124.2, 122.5, 121.4, 120.9,

120.7, 119.2, 118.5, 116.5, 113.7, 112.4, 110.6, 107.8, 95.4, 71.5, 68.1,

66.8, 66.4, 55.6, 49.1, 45.6. MS (EI) m/z (relative intensity): 445 (15),

322 (75), 181 (49), 153 (100), 77 (21). HRMS (EI) m/z calcd for

C₂₆H₂₆N₂O₅[M⁺], 446.1842; found, 446.1824.

1-(6-Fluoro-9H-carbazol-2-yloxy)-3-{[2-(2-methoxyphenoxy)-

ethyl]amino}-2-propanol (53). Yield: 54% from epoxide 117c and

amine 104a; 38% overall from 6-ﬂuoro-2-hydroxycarbazole, white solid.

mp 157−159 °C. IR (KBr) 3388, 3059, 2924, 2855, 1631, 1503, 1487,

1

1456, 1249, 1164, 1104, 1035, 819, 747 cm⁻¹. H NMR (400 MHz,

DMSO-d₆) δ 11.10 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.81 (dd, J = 9.5, 2.6

Hz, 1H), 7.40 (dd, J = 8.8, 4.4 Hz, 1H), 7.11 (ddd, J = 9.5, 8.8, 2.6 Hz,

1H), 6.99−6.81 (m, 5H), 6.77 (dd, J = 8.6, 2.2 Hz, 1H), 5.08 (br s, 1H),

4.07−3.94 (m, 5H), 3.74 (s, 3H), 2.93 (t, J = 5.5 Hz, 2H), 2.82 (dd, J =

12.0, 4.2 Hz, 1H), 2.71 (dd, J = 11.7, 6.2 Hz, 1H). ¹³C NMR (101 MHz,

1

DMSO-d₆) δ 158.2, 156.4 (d, J_C−F= 230 Hz), 149.1, 148.0, 142.1,

136.1, 123.2 (d, ³J_C−F= 10 Hz), 121.3, 121.0, 120.6, 115.9 (d, ⁴J_C−F= 4.0

2

Hz), 113.7, 112.2, 111.3 (d, J_C−F= 33 Hz), 111.2, 108.3, 104.9 (d,

²J_C−F= 24 Hz), 95.2, 70.9, 68.2, 68.1, 55.4, 52.3, 48.3. ¹⁹F NMR (376

MHz, DMSO-d₆) δ −125.2. MS (EI) m/z (relative intensity): 424

(5) [M⁺], 368 (10), 201 (34), 180 (100), 56 (34). HRMS (EI) calcd for

C₂₄H₂₅N₂O₄F [M⁺], 424.1798; found, 424.1807.

1-(6,8-Diﬂuoro-9H-carbazol-2-yloxy)-3-{[2-(2-methoxyphenoxy)-

ethyl]amino}-2-propanol (54). Yield: 55% from epoxide 117d and

amine 104a; 33% overall from 6,8-diﬂuoro-2-hydroxycarbazole, white

solid. mp 136−138 °C. IR (KBr) 3309, 3176, 2927, 2860, 1652, 1632,

1592, 1505, 1256, 1117, 984, 838, 815, 735 cm⁻¹. ¹H NMR (400 MHz,

DMSO-d₆) δ 11.55 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 7.7 Hz,

1H), 7.17 (t, J = 9.5 Hz, 1H), 7.05−6.80 (m, 6H), 5.10 (br s, 1H), 4.09−

3.92 (m, 5H), 3.73 (s, 3H), 2.92 (t, J = 5.1 Hz, 2H), 2.87−2.66 (m, 2H).

¹³C NMR (101 MHz, DMSO-d₆) δ 158.9, 155.5 (dd, J_C−F= 233, 9.9

Hz), 149.2, 148.0, 147.3 (dd, J_C−F= 242, 13.9 Hz), 142.3, 125.7 (dd,

J_C−F= 11.3, 7.2 Hz), 123.8 (d, J_C−F= 12.6 Hz), 121.8, 121.1, 120.7, 116.0

(dd, J_C−F= 4.2, 4.1 Hz), 113.7, 112.2, 109.2, 101.2 (dd, J_C−F= 23, 3.7

Hz), 98.9 (dd, J_C−F= 29, 21 Hz), 95.4, 71.0, 68.3, 68.2, 55.5, 52.3, 48.4.

¹⁹F NMR (376 MHz, DMSO-d₆) δ −122.5, −130.4. MS (EI) m/z

4-(9H-Carbazol-2-yloxy)-1-{[2-(2-methoxyphenoxy)ethyl]-

amino}-2-butanol (50). Yield: 65% from epoxide 117b and amine

104a; 39% overall from 2-hydroxycarbazole. mp 93−95 °C. IR (KBr)

1

3415, 3052, 2928, 2871, 1605, 1503, 1263, 1100, 755, 722 cm⁻¹. H

NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H),

7.94 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.27 (ddd, J = 8.2, 7.1,

1.2 Hz, 1H), 7.09 (ddd, J = 7.9, 7.8, 1.0 Hz, 1H), 6.99−6.93 (m, 3H),

6.92−6.82 (m, 2H), 6.76 (dd, J = 8.5, 2.2 Hz, 1H), 4.75 (d, J = 4.1 Hz,

1H), 4.14 (t, J = 6.6 Hz, 2H), 4.01 (t, J = 5.6 Hz, 2H), 3.85−3.75 (m,

1H), 3.74 (s, 3H), 2.90 (t, J = 5.6 Hz, 2H), 2.64 (dd, J = 11.8, 4.2 Hz,

1H), 2.63 (dd, J = 11.8, 7.4 Hz, 1H), 1.99− 1.88 (m, 1H), 1.84−1.78 (m,

1H). ¹³C NMR (101 MHz, DMSO-d₆) δ 157.8, 149.1, 148.0, 141.0,

139.6, 124.0, 122.6, 121.0, 120.8, 120.7, 119.1, 118.4, 116.0, 113.6, 112.2,

110.5, 108.0, 95.0, 68.3, 66.3, 64.7, 55.6, 55.4, 48.3, 34.7. MS (EI) m/z

(relative intensity): 238 (100), 180 (45), 100 (16). HRMS (EI) calcd for

C₂₅H₂₈N₂O₄[M⁺], 420.2049; found, 420.2029.

(relative intensity): 442 (9) [M⁺], 219 (13), 180 (100). HRMS (EI⁺)

calcd for C₂₄H₂₄F₂N₂O₄[M⁺], 442.1704; found, 442.1715.

1-(9H-Carbazol-2-yloxy)-3-{[2-(4-ﬂuoro-2-methoxyphenoxy)-

ethyl]amino}-2-propanol (55). Yield: 60% from epoxide 117a and

amine 104m; 37% overall from 2-hydroxycarbazole, white solid. mp

141−143 °C. IR (KBr) 3400, 3303, 3247, 3081, 2927, 2839, 1609, 1503,

1462, 1173, 1032, 948, 750, 728 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆)

11.07 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.41 (d,

J = 8.0 Hz, 1H), 7.27 (td, J = 8.2, 1.2 Hz, 1H), 7.09 (td, J = 7.9, 1.0 Hz,

1H), 6.99−6.92 (m, 2H), 6.88 (dd, J = 10.7, 3.0 Hz, 1H), 6.77 (dd, J =

8.6, 2.2 Hz, 1H), 6.65 (td, J = 8.6, 3.0 Hz, 1H), 5.08 (d, J = 4.0 Hz, 1H),

8647

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Article

4.06−3.92 (m, 5H), 3.75 (s, 3H), 2.90 (t, J = 5.5 Hz, 2H), 2.80 (dd, J =

11.8, 4.0 Hz, 1H), 2.69 (dd, J = 11.8, 6.4 Hz, 1H). ¹³C NMR (101 MHz,

DMSO-d₆) δ 157.8, 156.8 (d, ¹J_C−F= 235 Hz), 150.2 (d, ³J_C−F= 10 Hz),

144.4 (d, ⁴J_C−F= 2.0 Hz), 141.0, 139.6, 124.0, 122.6, 120.8, 119.1, 118.4,

116.1, 114.4 (d, ³J_C−F= 10 Hz), 110.5, 108.0, 105.5 (d, ²J_C−F= 22 Hz),

100.6 (d, ²J_C−F= 27 Hz), 95.2, 70.9, 69.1, 68.2, 55.8, 52.3, 48.4. ¹⁹F NMR

(376 MHz, DMSO-d₆) δ −120.4. MS (EI) m/z (relative intensity): 424

(28) [M⁺], 198 (39), 183 (100), 154 (65), 56 (37). HRMS (EI) calcd

for C₂₄H₂₅N₂O₄F [M⁺], 424.1798, found: 424.1792.

1-(9H-Carbazol-2-yloxy)-3-{[2-(2-triﬂuoromethylphenoxy)-

ethyl]amino}-2-propanol (56). Yield: 52% from epoxide 117a and

amine 104n; 32% overall from 2-hydroxycarbazole, white solid. mp

138−140 °C. IR (ﬁlm) 3400, 3292, 1607, 1455, 1319, 1131, 1034, 766,

749 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 7.97 (d, J =

7.7 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.57−7.65 (m, 2H), 7.40 (d, J = 8.0

Hz, 1H), 7.32−7.23 (m, 2H), 7.14−7.03 (m, 2H), 6.95 (d, J = 2.2 Hz,

1H), 6.76 (dd, J = 8.5, 2.2 Hz, 1H), 5.03 (d, J = 4.6 Hz, 1H), 4.17 (t, J =

5.2 Hz, 2H), 4.07−3.90 (m, 3H), 2.96 (t, J = 5.5 Hz, 2H), 2.86−2.65 (m,

2H). ¹³C NMR (101 MHz, DMSO-d₆) δ 157.8, 156.3, 140.9, 139.6,

134.1, 126.6 (q, ³J_C−F= 5 Hz), 124.0 (CH), 123.7 (q, ¹J_C−F= 270 Hz),

122.5, 120.7, 120.1, 119.1, 118.4, 117.1 (q, ²J_C−F= 30 Hz), 116.1, 113.6,

110.5, 108.0, 95.2, 70.8, 68.5, 68.2, 52.2, 48.0. ¹⁹F NMR (376 MHz,

DMSO-d₆) δ −60.7. MS (EI) m/z (relative intensity): 444 (10) [M⁺],

198 (25), 183 (100). HRMS (EI) calcd for C₂₄H₂₃N₂O₃F₃[M⁺],

444.1661; found, 444.1663.

chromatography over silica gel (dichloromethane/hexanes) to aﬀord

1.26 g (85%) of epoxide 103c.

Epoxide 103c (200 mg, 0.396 mmol) and amine 104a (132 mg, 0.792

mmol) were reacted in the usual manner to aﬀord 88 mg (33%) of 59 as

a white solid. mp 94−95 °C. IR (KBr) 3451, 2922, 2836, 1705, 1594,

1507, 1441, 1237, 739, 717 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 8.31

(d, J = 7.4 Hz, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H),

7.45−7.31 (m, 3H), 6.95−6.81 (m, 5H), 4.28−4.13 (m, 5H), 3.82 (s,

3H), 3.14−2.95 (m, 6H), 1.97−1.87 (m, 2H), 1.28 (br s, 28H), 0.90 (t,

J = 6.6 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 173.5, 154.6, 149.6,

148.0, 139.7, 137.8, 127.7, 126.2, 125.5, 123.6, 123.1, 121.6, 120.8, 115.7,

115.3, 114.0, 111.7, 109.1, 105.6, 70.5, 68.6, 68.2, 55.7, 51.9, 48.6, 39.2,

31.9, 29.6, 29.6, 29.5, 29.3, 29.2, 24.7, 22.6, 14.1. MS (EI) m/z (relative

intensity): 672 (2) [M]⁺, 549 (10), 183 (60), 180 (100). HRMS (EI)

calcd for C₄₂H₆₀N₂O₅[M⁺], 672.4502; found, 672.4504.

4-[2-(2-Methoxyphenoxy)ethyl]-6-{[(9-octadecanoyl-9H-car-

bazol-4-yl)oxy]methyl}morpholin-3-one (60). The product was

prepared by the acylation of 17 with octadecanoyl chloride, as in the

preceding procedure. Yield: 80%, white solid. mp 98−99 °C. IR (KBr)

1704, 1639, 1500, 1257, 1160, 752, 739, 721 cm⁻¹. ¹H NMR (300 MHz,

CDCl₃) δ 8.29 (d, J = 7.7 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.90 (d,

J = 8.4 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.28−

7.24 (m, 1H), 6.98−6.91 (m, 3H), 6.84 (t, J = 7.3 Hz, 2H), 4.45−4.23

(m, 7H), 3.99−3.80 (m, 4H), 3.68 (s, 3H), 3.14 (t, J = 7.4 Hz, 2H),

1.98−1.88 (d, J = 7.2 Hz, 2H), 1.27 (br s 28H), 0.89 (t, J = 6.6 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 173.6, 166.8, 154.3, 149.5, 147.9, 140.00,

1-(9H-Carbazol-2-yloxy)-3-{[2-(2-ﬂuorophenoxy)ethyl]-

amino}-2-propanol (57). Yield: 58% from epoxide 117a and amine

104o; 36% overall from 2-hydroxycarbazole, white solid. mp 160−

162 °C. IR (KBr) 3397, 3303, 3068, 2924, 2848, 1609, 1509, 1456, 1311,

1286, 1199, 1173, 1108, 738, 722 cm⁻¹. ¹H NMR (400 MHz, DMSO-

d₆) δ 11.05 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H),

7.41 (d, J = 8.0 Hz, 1H), 7.27 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 7.23−7.06

(m, 4H), 6.96 (d, J = 2.1 Hz, 1H), 6.95−6.90 (m, 1H), 6.77 (dd, J = 8.5,

2.2 Hz, 1H), 5.05 (d, J = 4.5 Hz, 1H), 4.11 (t, J = 5.6 Hz, 2H), 4.07−3.90

(m, 3H), 2.95 (t, J = 5.5 Hz, 2H), 2.81 (dd, J = 11.8, 3.9 Hz, 1H), 2.71

(dd, J = 11.8, 6.5 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ 157.8,

151.7 (d, ¹J_C−F= 241 Hz), 146.5 (d, ³J_C−F= 10 Hz), 141.0, 139.6, 124.7

(d, ⁴J_C−F= 3.0 Hz), 124.0, 122.6, 121.0 (d, ³J_C−F= 7.0 Hz), 120.7, 119.1,

118.4, 116.1, 115.9 (d, ²J_C−F= 18 Hz), 115.0, 110.5, 108.0, 95.2, 70.9,

68.6, 68.2, 52.3, 48.2. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −134.9. MS

(EI) m/z (relative intensity): 394 (20) [M⁺], 183 (100), 168 (46), 154

(40), 56 (27). HRMS (EI) calcd for C₂₃H₂₃FN₂O₃[M⁺], 394.1693;

found, 394.1679.

1-(9H-Carbazol-1-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]-

amino}-2-propanol (58).⁵⁰Yield: 66% from epoxide 117e and amine

104a; 44% overall from 1-hydroxycarbazole, white solid. mp 58−60 °C.

IR (ﬁlm) 3215, 3057, 2927, 2833, 1576, 1502, 1452, 1250, 738 cm⁻¹. ¹H

NMR (300 MHz, DMSO-d₆) δ 11.17 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H),

7.68 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.36 (dd, J = 7.2, 7.2

Hz, 1H), 7.13 (dd, J = 7.4, 7.3 Hz, 1H), 7.05 (dd, J = 7.8, 7.8 Hz, 1H),

6.99−6.80 (5H, m), 5.07 (d, J = 4.0 Hz, 1H), 4.20−4.00 (m, 5H), 3.73

(s, 3H), 2.95 (t, J = 5.4 Hz, 2H), 2.99−2.73 (m, 2H). ¹³C NMR (101

MHz, CDCl₃) δ 149.1, 148.0, 144.8, 139.4, 129.8, 125.2, 123.5, 122.6,

121.0, 120.7, 120.1, 119.0, 118.4, 113.7, 112.6, 112.2, 111.3, 107.1, 70.7

(2 signals), 68.2, 55.4, 52.1, 48.3. MS (EI) m/z (relative intensity): 405

(45), 223 (18), 182 (55), 181 (63), 179 (98), 153 (100), 123 (34), 77

(30), 56 (63). HRMS (EI) calcd for C₂₄H₂₆N₂O₄[M⁺], 406.1893;

found, 406.1880.

137.9, 127.8, 126.5, 125.3, 123.7, 123.2, 121.8, 120.9, 115.7, 115.6, 113.8,

111.8, 109.7, 105.6, 72.0, 68.4, 68.0, 67.8, 55.6, 51.0, 46.9, 39.3, 31.9, 29.7

(2 signals), 29.6, 29.5, 29.4, 29.3, 24.7, 22.7, 14.1. MS (CI) m/z 713 (71)

[M + H]⁺, 447 (100). HRMS (EI) calcd for C₄₄H₆₀N₂O₆, 712.4451;

found, 712.4418 [M⁺].

Compounds 61, 63, 64, and 66−80 were prepared by alkylation of

the corresponding phenols or alcohols with 3-chloro-1,2-epoxypropane

or 4-bromo-1,2-epoxybutane followed by epoxide opening with amine

104a, as in the preparation of 6.

1-{[2-(2-Methoxyphenoxy)ethyl]amino}-3-(2,3,4,9-tetrahydro-

1H-carbazol-6-yloxy)- 2-propanol (61). Yield: 75% from epoxide

103d; 53% overall from the corresponding phenol, white solid. mp 114−

116 °C. IR (ﬁlm) 3388, 3309, 3060, 2930, 2837, 1592, 1505, 1456, 1253,

1123, 1024, 908, 738 cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (br s,

1H), 7.12 (d, J = 8.4 Hz, 1H), 6.96−6.84 (m,5H), 6.75 (dd, J = 8.7, 2.5

Hz, 1H), 4.13 (t, J = 5.3 Hz, 2H), 4.13−4.07 (m, 1H), 4.02 (d, J = 5.2 Hz,

2H), 3.82 (s, 3H), 3.08 (t, J = 5.3 Hz, 2H), 2.98 (dd, J = 12.2, 3.9 Hz,

1H), 2.88 (dd, J = 12.2, 7.8 Hz, 1H), 2.69 (t, J = 5.9 Hz, 2H), 2.63 (t, J =

5.8 Hz, 2H), 1.93−1.80 (m, 4H). ¹³C NMR (101 MHz, CDCl₃) δ 153.1,

150.1, 148.4, 135.4, 131.2, 128.5, 122.0, 121.1, 114.7, 112.2, 111.1, 110.3,

102.0, 71.7, 69.0, 68.7, 56.1, 52.0, 48.9, 23.6, 23.5, 23.4, 21.1. MS (EI)

m/z (relative intensity): 410 (30) [M⁺], 187 (100), 180 (25), 158 (24).

HRMS (EI) calcd for C₂₄H₃₀N₂O₄[M]⁺, 410.2266; found, 410.2208.

4-(2-Hydroxy-3-{[2-(2-methoxyphenoxy)ethyl]amino}-

propoxy)-9H-ﬂuoren-9-one (63). Yield: 40% from epoxide 103e;

53% overall from the corresponding phenol, yellow solid. mp 97−99 °C.

IR (KBr) 3326, 1710, 1598, 1505, 1251, 726 cm⁻¹. ¹H NMR (400 MHz,

CDCl₃) δ 7.81 (d, J = 7.4 Hz, 1H), 7.63 (d, J = 7.3 Hz, 1H), 7.42 (t, J =

7.5 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.21 (d,

J = 7.3 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.95−6.87 (m, 4H), 4.21−4.15

(m, 6H), 3.83 (s, superimposed on m, 4H), 3.14−3.11 (m, 2H), 3.07

(dd, J = 12.2, 3.2 Hz, 1H), 2.96−2.89 (m, 1H). ¹³C NMR (101 MHz,

CDCl₃) δ 194.1, 154.5, 149.6, 148.0, 143.7, 135.8, 134.9, 133.5, 131.4,

130.4, 128.1, 124.2, 124.0, 121.7, 120.9, 118.8, 116.9, 114.0, 111.8, 70.7,

68.7, 68.1, 55.7, 51.7, 48.6. MS (CI) m/z (relative intensity): 420 (100)

[M + H]⁺. HRMS (CI) calcd for C₂₅H₂₆NO₅[M + H]⁺, 420.1811;

found, 420.1815.

Preparation of 1-[4-(2-Hydroxy-3-{[2-(2-methoxyphenoxy)-

ethyl]amino}propoxy-9H-carbazol-9-yl]octadecan-1-one (59).

Epoxide 103a (700 mg, 2.93 mmol) was dissolved in dry THF and

cooled to 0 °C. Sodium hydride (220 mg, 60% dispersion in oil,

5.5 mmol) was added, and the mixture was stirred for 45 min and then

warmed to room temperature. Octadecanoyl chloride (1.26 g, 4.16

mmol) in THF was added, and the reaction mixture was stirred for 1 h at

room temperature and quenched with water, and the aqueous phase was

extracted with chloroform and ethyl acetate. The combined organic

layers were washed with brine and dried over Na₂SO₄. After removal of

the solvent under reduced pressure, the residue was puriﬁed by ﬂash

1-{[2-(2-Methoxyphenoxy)ethyl]amino}-1-{8-oxatricyclo-

[7.4.0.0^2,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yloxy}-2-propanol

(64). Yield: 56% from epoxide 103f; 42% overall from the corresponding

phenol, white solid. mp 110−112 °C. IR (nujol) 3257, 1461, 1371, 1247,

1171, 738 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (dd, J = 7.8, 1.9

Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H), 7.65 (dd, J = 8.2, 0.8 Hz, 1H), 7.58 (d,

J = 8.9 Hz, 1H), 7.49 (ddd, J = 8.6, 8.4, 1.4 Hz, 1H), 7.36 (ddd, J = 7.7,

8648

dx.doi.org/10.1021/jm401090a | J. Med. Chem. 2013, 56, 8626−8655

Journal of Medicinal Chemistry

Article

7.5, 1.0 Hz, 1H), 7.10 (dd, J = 8.9, 2.7 Hz, 1H), 6.99−6.93 (m, 2H),

6.92−6.82 (m, 2H), 5.09 (d, J = 4.4 Hz, 1H), 4.09−3.93 (m, 5H), 3.73

(s, 3H), 2.93 (t, J = 5.5 Hz, 2H), 2.82 (dd, J = 11.9, 4.3 Hz, 1H), 2.72 (dd,

J = 11.9, 6.7 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ 156.1, 155.1,

150.0, 149.2, 148.1, 127.4, 124.1, 123.9, 122.7, 121.2, 121.0, 120.7, 115.9,

113.7, 112.2, 112.1, 111.6, 105.1, 71.5, 68.4, 68.3, 55.4, 52.4, 48.5. MS

(EI) m/z (relative intensity): 284 (6), 270 (7), 210 (8), 180 (100).

HRMS (EI) calcd for C₂₄H₂₅NO₅[M⁺], 407.1733; found, 407.1733.

1-{[2-(2-Methoxyphenoxy)ethyl]amino}-1-(10H-phenothia-

zin-2-yloxy)-2-propanol (66). Yield: 63% from epoxide 103g; 33%

overall from the corresponding phenol, oﬀ-white solid. mp 48−50 °C.

IR (KBr) 3388, 3059, 2924, 2855, 1631, 1503, 1487, 1456, 1249, 1164,

1104, 1035, 819, 747 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (s,

1H), 7.02−6.82 (m, 5H), 6.79 (d, J = 8.4 Hz, 1H), 6.74 (ddd, J = 7.5, 7.5,

1.0 Hz, 1H), 6.67 (dd, J = 7.9, 0.8 Hz, 1H), 6.38 (dd, J = 8.4, 2.5 Hz, 1H),

6.34 (d, J = 2.5 Hz, 1H), 5.03 (br s, 1H), 4.00 (t, J = 5.5 Hz, 2H), 3.93−

3.75 (m,3H), 3.73 (s, 3H), 2.89 (t, J = 5.5 Hz, 2H), 2.73 (dd, J = 11.8, 4.1

Hz, 1H), 2.64 (dd, J = 11.8, 6.2 Hz, 1H). ¹³C NMR (101 MHz, DMSO-

d₆) δ 158.6, 149.1, 148.0, 143.2, 141.7, 127.2, 126.7, 126.1, 121.6, 121.0,

120.6, 116.9, 114.3, 113.6, 112.2, 107.8, 107.0, 101.2, 70.6, 68.3, 68.0,

55.4, 52.2, 48.4. MS (EI) m/z (relative intensity): 438 (100) [M⁺], 224

(22), 215 (82). HRMS (EI) calcd for C₂₄H₂₆N₂O₄S [M⁺], 438.1613;

found, 438.1600.

2H), 3.05 (t, J = 5.3 Hz, 2H), 2.82 (dd, J = 12.0, 4.0 Hz, 1H), 2.72 (dd, J =

12.1, 7.6 Hz, 1H), 2.60 (br s, 1H), 2.09−2.17 (m, 3H), 1.69−1.78 (m,

6H), 1.54−1.68 (m, 6H). ¹³C NMR (75 MHz, CDCl₃) δ 149.6, 148.2,

121.4, 120.8, 114.0, 111.8, 72.2, 69.3, 68.7, 62.5, 55.8, 52.1, 48.7, 41.4,

36.3, 30.4. MS (CI) m/z (relative intensity): 376 (100) [M + H]⁺.

HRMS (CI) calcd for C₂₂H₃₄NO₄[M + H]⁺, 376.2488; found,

376.2475.

1-(Adamantan-2-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]-

amino}-2-propanol (71). Yield: 50% from epoxide 103k; 32% overall

from 2-adamantanol, white solid. mp 53−57 °C. IR (KBr) 3334, 2896,

1509, 1256, 740 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 6.97−6.86 (m,

4H), 4.13 (t, J = 5.4 Hz, 2H), 3.86 (s, 3H), 3.92−3.84 (m, 1H), 3.52−

3.42 (m, 3H), 3.07 (t, J = 5.4 Hz, 2H), 2.85 (dd, J = 12.1, 4.2 Hz, 1H),

2.77 (dd, J = 12.1, 7.5 Hz, 1H), 1.96−2.07 (m, 4H), 1.73−1.88 (m, 4H),

1.70−1.62 (m, 4H), 1.43−1.52 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ

149.7, 148.2, 121.5, 120.8, 114.1, 111.8, 82.0, 70.00, 69.1, 68.8, 55.8,

52.2, 48.7, 37.5, 36.4, 31.63, 31.59, 31.5, 27.3. MS (CI) m/z (relative

intensity): 376 (100) [M + H]⁺. HRMS (CI) calcd for C₂₂H₃₄NO₄[M +

H]⁺, 376.2488; found, 376.2501.

1-(Adamantan-1-ylmethoxy)-3-{[2-(2-methoxyphenoxy)-

ethyl]amino}-2-propanol (72). Yield: 87% overall from (1-

adamantyl)methanol via epoxide 103l, viscous oil. IR (KBr) 3211,

1

1596, 1509, 1452, 1254, 1125, 1029, 744 cm⁻¹. H NMR (300 MHz,

2-(2-Hydroxy-3-{[2-(2-methoxyphenoxy)ethyl]amino}-

propoxy)-10H-5λ6,10-phenothiazine-5,5-dione (67). Yield: 54%

from epoxide 103h; 28% overall from the corresponding phenol, white

solid. mp 67−69 °C. IR (ﬁlm) 3518, 3309, 3183, 3076, 2930, 2834,

2249, 1622, 1260, 1024, 911, 725 cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ

8.70 (s, 1H), 7.94 (dd, J = 8.0, 1.1 Hz, 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.31

(t, J = 8.4 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H),

6.94−6.81 (m, 4H), 6.57 (dd, J = 8.9, 2.1 Hz, 1H), 6.34 (d, J = 2.0 Hz,

1H), 4.09 (t, J = 4.9 Hz, 2H), 4.07−3.98 (m, 1H), 3.90−3.78 (m, 2H),

3.76 (s, 3H), 3.27 (br s, 2H), 3.03 (t, J = 4.9 Hz, 2H), 2.87 (dd, J = 12.3,

4.0 Hz, 1H), 2.76 (dd, J = 12.3, 7.8 Hz, 1H). ¹³C NMR (101 MHz,

CDCl₃) δ 162.2, 149.6, 148.1, 139.9, 138.1, 133.0, 124.9, 123.0, 122.0,

121.8, 121.6, 121.3, 116.8, 114.3, 114.2, 112.2, 110.6, 100.3, 70.8, 68.5,

68.1, 56.0, 51.5, 48.8. MS (EI) m/z (relative intensity): 470 (3) [M⁺],

347 (10), 333 (13), 247 (13), 180 (100), 178 (25), 148 (12), 56 (20).

HRMS (EI) calcd for C₂₄H₂₆N₂O₆S [M+], 470.1512; found, 470.1490.

1-{[2-(2-Methoxyphenoxy)ethyl]amino}-3-(naphthalen-1-

yloxy)-2-propanol (68). Yield: 38% from epoxide 103i; 32% overall

from the corresponding phenol, white solid. mp 110−112 °C. IR (KBr)

3435, 1504, 1256, 782, 773, 743 cm⁻¹. ¹H NMR (300 MHz, DMSO-d₆)

δ 8.24 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.35−7.55 (m, 4H),

6.80−7.04 (m, 5H), 5.16 (d, J = 3.9 Hz, 1H), 3.97−4.19 (m, 5H), 3.72

(s, 3H), 2.92 (t, J = 5.5 Hz, 2H), 2.87 (dd, J = 11.7, 3.7 Hz, 1H), 2.77 (dd,

J = 12.0, 6.3 Hz, 1H), 1.98 (br s, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ

154.2, 149.2, 148.1, 134.0, 127.4, 126.4, 126.2, 125.1, 125.0, 121.8, 121.0,

120.7, 119.8, 113.6, 112.2, 105.1, 70.9, 68.4, 68.4, 55.4, 52.5, 48.5. MS

(CI) m/z (relative intensity): 368 (100) [M + H]⁺. HRMS (EI) calcd

for C₂₂H₂₅NO₄[M⁺], 367.1784; found, 367.1797.

CDCl₃) δ 6.96−6.88 (m, 4H), 4.12 (t, J = 5.3 Hz, 2H), 3.86 (s, 3H),

3.90−3.83 (m, 1H), 3.37−3.47 (m, 2H), 3.05 (t, J = 5.4 Hz, 2H), 2.97−

3.07 (m, 2H), 2.82 (dd, J = 12.1, 4.1 Hz, 1H), 2.73 (dd, J = 12.1, 7.7 Hz,

1H), 1.91−2.02 (m, 3H), 1.58−1.78 (m, 6H), 1.49−1.56 (m, 6H). ¹³C

NMR (75 MHz, CDCl₃) δ 149.7, 148.1, 121.6, 120.9, 114.3, 111.8, 82.5,

74.0, 68.6, 68.5, 55.8, 52.0, 48.6, 39.6, 37.1, 34.1, 28.2. MS (CI) m/z

(relative intensity): 390 (100) [M + H]⁺. HRMS (CI) calcd for

C₂₃H₃₆NO₄[M + H]⁺, 390.2644; found, 390.2631.

6-(2-Hydroxy-3-{[2-(2-methoxyphenoxy)ethyl]amino}-

propoxy)-1,2-dihydroquinolin-2-one (73). Yield: 40% from

epoxide 103m; 9% overall from the corresponding phenol, white

solid. mp 154−155 °C. IR (ﬁlm) 3283, 2909, 1654, 1502, 1249, 1119

cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆) δ 11.60 (br s, 1H), 7.82 (d, J =

9.6 Hz, 1H), 7.10−7.25 (m, 3H), 6.80−6.99 (m, 4H), 6.47 (d, J = 9.5 Hz,

1H), 5.05 (br s, 1H), 3.87−4.05 (m, 5H), 3.73 (s, 3H), 2.91 (t, J = 5.4

Hz, 2H), 2.78 (dd, J = 11.8, 3.6 Hz, 1H), 2.68 (dd, J = 11.7, 6.0 Hz, 1H).

¹³C NMR (101 MHz, DMSO-d₆) δ 161.4, 153.5, 149.2, 148.1, 139.7,

133.3, 122.2, 121.0, 120.7, 119.9, 119.6, 116.3, 113.7, 112.3, 110.2, 71.1,

68.3, 68.1, 55.5, 52.3, 48.4. MS (ESI) m/z (relative intensity): 385 (100)

[M + H]⁺. HRMS (ESI) calcd for C₂₁H₂₅N₂O₅[M + H]⁺, 385.1758;

found, 385.1754.

6-(2-Hydroxy-3-{[2-(2-methoxyphenoxy)ethyl]amino}-

propoxy)-1,2,3,4-tetrahydroquinolin-2-one (74). Yield: 29% from

epoxide 103n; 10% overall from the corresponding phenol, white solid.

mp 126−128 °C. IR (ﬁlm) 3302, 3167, 2920, 2830, 1625, 1593, 1503,

1450, 1252, 1121, 1022, 743 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆) δ

9.87 (br s, 1H), 6.96 (d, J = 7.6, 2.1 Hz, 2H), 6.93−6.83 (m, 2H), 6.81−

6.68 (m, 3H), 4.98 (br s, 1H), 4.00 (t, J = 5.6 Hz, 2H), 3.92−3.80 (m,

3H), 3.74 (s, 3H), 2.90 (t, J = 5.5 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.75

(dd, J = 12.0, 3.7 Hz, 1H), 2.65 (dd, J = 11.8, 6.1 Hz, 1H), 2.39 (dd, J =

8.3, 6.8 Hz, 2H). ¹³C NMR (101 MHz, DMSO-d₆) δ 169.7, 153.8, 149.2,

148.1, 131.7, 124.8, 121.0, 120.7, 115.7, 114.0, 113.7, 113.0, 112.3, 71.0,

68.3, 68.1, 55.5, 52.3, 48.4, 30.3, 25.1. MS (ESI) m/z (relative intensity):

387 (100) [M + H]⁺. HRMS (ESI) m/z (relative intensity): calcd for

C₂₁H₂₇N₂O₅[M + H]⁺, 387.1914; found, 387.1910.

1-{[2-(2-Methoxyphenoxy)ethyl]amino}-4-(naphthalen-1-

yloxy)-2-butanol (69). Yield: 51% from 103u; 12% overall from the

corresponding phenol, white solid. mp 65−67 °C. IR (KBr) 3310, 2917,

1

1591, 1578, 1504, 1454, 1391, 1252, 1127, 1098, 770 cm⁻¹. H NMR

(400 MHz, CDCl₃) δ 8.27 (ddd, J = 6.7, 1.7, 0.7 Hz, 1H), 7.82−7.80 (m,

1H), 7.50−7.46 (m, 2H), 7.44 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.3 Hz,

1H), 6.97−6.84 (m, 5H), 4.38−4.29 (m, 2H), 4.12 (t, J = 5.2 Hz, 2H),

4.07−4.01 (m, 1H), 3.85 (s, 3H), 3.12−3.02 (m, 2H), 2.94 (dd, J = 12.1,

3.2 Hz, 1H), 2.68 (dd, J = 12.1, 9.2 Hz, 1H), 2.14−1.99 (m, 2H). ¹³C

NMR (101 MHz, CDCl₃) δ 154.5, 149.7, 148.2, 134.4, 127.4, 126.3,

125.9, 125.6, 125.1, 121.9, 121.6, 120.9, 120.1, 114.1, 111.8, 104.70, 68.7,

66.9, 65.00, 55.7, 55.1, 48.4, 34.5. MS (EI) m/z (relative intensity): 381

(<1) [M⁺] 238 (100), 180 (74). HRMS (EI) calcd for C₂₃H₂₇NO₄[M⁺],

381.1940; found, 381.1941.

7-(2-Hydroxy-3-{[2-(2-methoxyphenoxy)ethyl]amino}-

propoxy)-1,2,3,4-tetrahydroquinolin-2-one (75). Yield: 65% from

epoxide 103o; 13% overall from the corresponding phenol, white solid.

mp 161−163 °C. IR (ﬁlm) 3584, 3183, 2914, 2831, 1678, 1588, 1223,

1

1123, 1027, 738 cm⁻¹. H NMR (400 MHz, DMSO-d₆) δ 9.96 (br s,

1H), 7.14−6.78 (m, 5H), 6.62−6.37 (m, 2H), 5.03 (br s, 1H), 4.01 (t,

J = 5.3 Hz, 2H), 3.95−3.76 (m, 3H), 3.74 (s, 3H), 2.91 (t, J = 5.3 Hz, 2H),

2.78 (t, J = 7.3 Hz, 2H), 2.79−2.71 (m, 1H), 2.66 (dd, J = 11.7, 6.2 Hz,

1H), 2.41 (t, J = 7.4 Hz, 2H). ¹³C NMR (101 MHz, DMSO-d₆) δ 170.2,

157.9, 149.2, 148.0, 139.1, 128.3, 121.1, 120.7, 115.5, 113.8, 112.3,

107.5, 101.7, 70.6, 68.3, 68.0, 55.5, 52.2, 48.4, 30.7, 24.0. MS (ESI) m/z

1-(Adamantan-1-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]-

amino}-2-propanol (70). Yield: 50% from epoxide 103j; 13% overall

from 1-adamantanol, viscous oil. IR (KBr) 3428, 2904, 1498, 1252,

1

1119, 742 cm⁻¹. H NMR (300 MHz, CDCl₃) δ 6.93−6.87 (m, 4H),

4.12 (t, J = 5.3 Hz, 2H), 3.85 (s, 3H), 3.85−3.77 (m, 1H), 3.47−3.38 (m,

8649

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(relative intensity): 387 (100) [M + H]⁺. HRMS (ESI) calcd for

C₂₁H₂₇N₂O₅[M + H]⁺, 387.1914; found, 387.1909.

Preparation of 3-(9H-Fluoren-4-yloxy)-1-{[2-(2-methoxyphenoxy)-

ethyl]amino}-2-propanol (62). The product was prepared by the

Wolﬀ−Kishner reduction of 63 in 54% yield, white solid. mp 104.5−

106.0 °C. IR (KBr) 3290, 2922, 1582, 1503, 1457, 1274, 1253, 1221, 738

cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 8.14 (d, J = 7.5 Hz, 1H), 7.53 (d,

J = 7.3 Hz, 1H), 7.36 (t, J = 7.1 Hz, 1H), 7.30−7.28 (m, 1H), 7.24 (d, J =

7.8 Hz, 1H), 7.18 (d, J = 7.3 Hz, 1H), 6.98−6.88 (m, 5H), 4.30−4.14 (m,

5H), 3.92 (s, 2H), 3.84 (s, 3H), 3.14−3.07 (m, 3H), 2.97 (dd, J = 7.7,

12.3 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 154.9, 149.7, 148.2, 145.3,

142.5, 140.8, 129.9, 127.6, 126.7, 125.8, 124.3, 123.6, 121.6, 120.9, 117.6,

114.1, 111.8, 109.6, 70.4, 68.8, 68.4, 55.7, 51.9, 48.6, 37.2. MS (EI) m/z

(relative intensity): 405 (3) [M⁺], 268 (25), 180 (100). HRMS (EI)

calcd for C₂₅H₂₇NO₄[M⁺], 405.1940; found, 405.1945.

1-(1H-Indol-4-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]-

amino}-2-propanol (76).⁵¹Yield: 63% from epoxide 103p; 43%

overall from 4-hydroxyindole, white solid. mp 98−100 °C. IR (ﬁlm)

3378, 3066, 2924, 2868, 2834, 1586, 1506, 1453, 1249, 1122, 1091,

1051, 1027, 909, 742 cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 8.20 (br s,

1H), 7.11−7.00 (m, 3H), 6.97−6.83 (m, 4H), 6.65−6.59 (m, 1H), 6.51

(dd, J = 7.6, 0.7 Hz, 1H), 4.24−4.08 (m, 5H), 3.81 (s, 3H), 3.20−3.10

(br s, 1H), 3.10 (t, J = 5.2 Hz, 2H), 3.02 (dd, J = 12.4, 3.5 Hz, 1H), 2.93

(dd, J = 12.4, 7.5 Hz, 1H), 2.96−2.92 (m, 1H). ¹³C NMR (101 MHz,

CDCl₃) δ 152.6, 150.1, 148.4, 137.6, 123.0, 122.9, 122.0, 121.2, 119.0,

114.7, 112.2, 105.0, 101.1, 100.1, 70.6, 69.0, 68.5, 56.1, 52.0, 48.9. MS

(EI) m/z (relative intensity): 356 (25) [M⁺], 180 (100), 133 (35).

HRMS (EI) calcd for C₂₀H₂₄N₂O₄[M⁺], 356.1736; found, 356.1727.

1-(1H-Indol-5-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]-

amino}-2-propanol (77). Yield: 58% from epoxide 103q; 44% overall

from 5-hydroxyindole, white solid. mp 109−110 °C. IR (ﬁlm) 3375,

2930, 2867, 1592, 1505, 1456, 1253, 1220, 1157, 1123, 1027, 748, 727

cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆) δ 10.89 (s, 1H), 7.28−7.24 (m,

2H), 7.03 (d, J = 2.4 Hz, 1H), 6.98−6.93 (m, 2H), 6.92−6.82 (m, 2H),

6.73 (dd, J = 8.7, 2.4 Hz, 1H), 6.32−6.30 (m, 1H), 5.00 (br s, 1H), 4.01

(t, J = 5.6 Hz, 2H), 3.95−3.85 (m, 3H), 3.73 (s, 3H), 3.32 (br s, 1H),

2.92 (t, J = 5.6 Hz, 2H), 2.80 (dd, J = 11.9, 3.9 Hz, 1H), 2.68 (dd, J = 11.9,

6.4 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ 152.5, 149.2, 148.0,

131.0, 127.9, 125.7, 121.0, 120.7, 113.7, 112.2, 111.8, 111.6, 102.8, 100.8,

71.3, 68.3, 68.2, 55.4, 52.5, 48.4. MS (ESI) m/z (relative intensity): 357

(100%) [M + H]⁺. HRMS (ESI) calcd for C₂₀H₂₄N₂O₄[M + H]⁺,

357.1809; found, 357.1819.

Preparation of 3-(2-Hydroxy-3-{[2-(2-methoxyphenoxy)-

ethyl]amino}propoxy-N-phenylaniline (65). A mixture of 66 (88

mg, 0.20 mmol) and NiCl₂·6H₂O (337 mg, 1.41 mmol) in methanol/

THF/H₂O (8 mL; 1:2:1) at room temperature was treated with small

portions of NaBH₄(162 mg, 4.28 mmol) over 1 h.³⁴Stirring was

continued for an additional 2 h, the mixture was ﬁltered through a pad of

Celite, and the ﬁltrate was concentrated under vacuum. The residue was

puriﬁed by ﬂash chromatography over silica gel (methanol/dichloro-

methane) to aﬀord 29 mg (36%) of 65 as a yellow oil. IR (ﬁlm) 3355,

1

3279, 3061, 2928, 2835, 1588, 1495, 1251, 745 cm⁻¹. H NMR (400

MHz, CDCl₃) δ 7.28−7.21 (m, 3H), 7.11 (t, J = 8.0 Hz, 1H), 7.08−7.02

(m, 2H), 6.97−6.83 (m, 5H), 6.66−6.58 (m, 2H), 6.44 (dd, J = 8.2, 2.0

Hz, 1H), 4.14 (t, J = 5.1 Hz, 2H), 4.15−4.07 (m, 1H), 4.00−3.92 (m,

2H), 3.81 (s, 3H), 3.10 (t, J = 5.1 Hz, 2H), 3.00 (dd, J = 12.3, 3.7 Hz,

1H), 2.88 (dd, J = 12.3, 8.0 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ

159.9, 150.0, 148.2, 144.9, 142.9, 130.3, 129.5, 122.2, 121.5, 121.2, 118.6,

115.0, 112.2, 110.6, 106.9, 104.1, 70.4, 68.7, 68.0, 56.0, 51.7, 48.7. MS

(EI) m/z (relative intensity): 408 (40) [M⁺], 368 (19), 285 (19), 186

(19), 185 (100), 180 (73). HRMS (EI) calcd for C₂₄H₂₈N₂O₄[M⁺],

408.2049; found, 408.2030.

Preparation of 1-[(Benzofuran-2-ylmethyl)amino]-3-(9H-car-

bazol-2-yloxy)-2-propanol (81). A mixture of 117a (304 mg, 1.27

mmol) and benzylamine (0.42 mL, 3.84 mmol) were reﬂuxed for 2 h in

isopropanol (3 mL). The solvent was removed under vacuum, and the

residue was puriﬁed by ﬂash chromatography over silica gel (methanol/

dichloromethane) to aﬀord 211 mg (48%) of amino alcohol 119 as an

oﬀ-white solid. mp 160−161 °C. IR (ﬁlm) 3392, 3043, 2919, 2847, 1607,

1455, 749, 724 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H),

7.97 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.41 (d, J = 8.0 Hz,

1H), 7.38−7.20 (m, 6H), 7.09 (dd, J = 7.7, 7.2 Hz, 1H), 6.96 (s, 1H),

6.76 (d, J = 8.6 Hz, 1H), 4.09−3.93 (m, 3H), 3.77 (s, 2H), 2.73 (dd, J =

11.7, 3.5 Hz, 1H), 2.65 (dd, J = 11.6, 5.9 Hz, 1H). ¹³C NMR (101 MHz,

DMSO-d₆) δ 157.8, 141.0, 140.3, 139.7, 128.1, 128.0, 126.6, 124.1,

122.6, 120.8, 119.2, 118.5, 116.2, 110.5, 108.1, 95.3, 70.9, 68.1, 52.9,

51.6. MS (EI) m/z (relative intensity): 346 (32) [M⁺], 183 (100), 154

(20), 120 (18), 91 (48). HRMS (EI) calcd for C₂₂H₂₂N₂O₂[M⁺],

346.1681; found, 346.1686.

A mixture of 119 (188 mg, 0.542 mmol), aldehyde 121 (85 mg,

0.58 mmol), and NaBH(OAc)₃(168 mg, 0.792 mmol) in 1,2-dichloroethane

(5 mL) was stirred at room temperature for 4 h. The mixture was

partitioned between water and dichlormethane, and the aqueous phase

was extracted with dichloromethane. The combined organic extracts

were washed with brine, dried over MgSO₄, and concentrated under

vacuum. The residue was puriﬁed by ﬂash chromatography over silica gel

(methanol/dichloromethane) to furnish 196 mg (76%) of the N-benzyl

derivative of 81 as a white solid foam. ¹H NMR (400 MHz, CDCl₃) δ

7.94 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.87 (br s, 1H), 7.54−

7.50 (m, 1H), 7.48−7.44 (m, 1H), 7.40−7.31 (m, 6H), 7.29−7.16 (m,

4H), 6.84−6.76 (m, 2H), 6.58 (s, 1H), 4.14−4.23 (m, 1H), 4.03 (d, J =

5.1 Hz, 2H), 3.90 (d, J = 15.1 Hz, 1H), 3.89 (d, J = 13.5 Hz, 1H), 3.84 (d,

J = 15.1 Hz, 1H), 3.70 (d, J = 13.5 Hz, 1H), 3.31 (s, 1H), 2.77−2.92 (m,

2H). ¹³C NMR (101 MHz, CDCl₃) δ 158.3, 155.3, 155.1, 140.9, 139.7,

138.4, 129.3, 128.7, 128.4, 127.6, 124.8, 124.2, 123.6, 122.9, 121.1, 121.0,

119.8, 119.7, 117.6, 111.4, 110.5, 108.8, 106.0, 95.8, 70.9, 67.0, 58.7,

56.5, 50.7.

Preparation of 1-(1H-Indazol-5-yloxy)-3-{[2-(2-methoxyphenoxy)-

ethyl]amino}-2-propanol (78). The reaction of the N-t-Boc-protected

epoxide derivative 103r with amine 104a was carried out as in the

preparation of 6 followed by deprotection with TFA in dichloromethane

at room temperature to aﬀord 78 in 43% overall yield, white solid. mp

114−116 °C. IR (ﬁlm) 3000−3600 (br), 3062, 2924, 2848, 1591, 1500,

1

1450, 1249, 1221, 1123, 1026, 948, 744 cm⁻¹. H NMR (400 MHz,

CDCl₃) δ 7.96 (br s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.15−7.04 (m, 2H),

6.84−7.02 (m, 4H), 4.17 (t, J = 5.1 Hz, 2H), 4.20−4.11 (m, 1H), 4.04

(d, J = 5.1 Hz, 2H), 3.84 (s, 3H), 3.13 (t, J = 5.0 Hz, 2H), 3.03 (dd, J =

12.3, 3.7 Hz, 1H), 2.91 (dd, J = 12.2, 8.0 Hz, 2H). ¹³C NMR (101 MHz,

CDCl₃) δ 153.9, 150.0, 148.3, 135.9, 134.6, 123.5, 122.1, 121.1, 119.5,

114.8, 112.2, 110.8, 101.6, 71.2, 68.9, 68.2, 56.0, 51.8, 48.8. MS (ESI)

m/z (relative intensity): 358 (100%) [M + H]⁺. HRMS (ESI) calcd for

C₁₉H₂₄N₃O₄[M + H]⁺, 358.1761; found, 358.1756.

Products 79 and 80 were prepared similarly.

1-(1H-Indazol-6-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]-

amino}-2-propanol (79). Overall yield from 103s: 47%, white solid.

mp 131−133 °C. IR (ﬁlm) 3300, 3018, 2933, 2870, 1628, 1503,

1456, 1252, 1123, 1026, 941, 741 cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ

7.94 (br s, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.02−6.77 (m, 6H), 4.30−4.22

(m, 1H), 4.20 (t, J = 5.1 Hz, 2H), 4.10−4.01 (m, 2H), 3.83 (s, 3H), 3.20

(dd, J = 8.1, 4.8 Hz, 2H), 3.14 (dd, J = 12.3, 3.9 Hz, 1H), 3.01 (dd, J =

12.3, 8.2 Hz, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 158.6, 149.6, 147.9,

141.3, 134.2, 122.1, 121.6, 121.2, 118.1, 114.5, 113.4, 112.2, 91.9, 70.6,

68.0, 67.7, 55.9, 51.7, 48.4. MS (ESI) m/z (relative intensity): 358 (100)

[M⁺]. HRMS (ESI) calcd for C₁₉H₂₄N₃O₄[M + H]⁺, 358.1761; found,

358.1752.

1-(1H-Benzodiazol-5-yloxy)-3-{[2-(2-methoxyphenoxy)-

ethyl]amino}-2-propanol (80). Overall yield from 103t: 20%, white

solid. mp 125−127 °C. IR (ﬁlm) 3302, 3167, 2920, 2830, 1625, 1593,

1503, 1450, 1252, 1121, 1022, 743 cm⁻¹. ¹H NMR (400 MHz, CD₃OD)

δ 8.05 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.13 (s, 1H), 7.03−6.84 (m, 5H),

6.51 (dd, J = 7.6, 0.7 Hz, 1H), 4.18−4.01 (m, 5H), 3.80 (s, 3H), 3.03 (t,

J = 5.0 Hz, 2H), 2.96 (dd, J = 12.2, 4.0 Hz, 1H), 2.85 (dd, J = 12.2, 8.0 Hz,

1H), 2.96−2.92 (m, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 154.3, 148.3,

146.7, 139.2, 120.1, 119.2, 119.0, 112.9, 111.2, 110.5, 100.0, 69.6, 67.0,

66.8, 53.5, 50.3, 46.7. MS (EI) m/z (relative intensity): 179 (100), 133

(35). HRMS (ESI) calcd for C₁₉H₂₄N₃O₄[M + H]⁺, 358.1761; found,

358.1760.

A solution of the above N-benzyl derivative (50 mg, 0.10 mmol) in a

2:1 mixture of methanol/dichloromethane (1.5 mL) was added to 10%

8650

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palladium on charcoal (27 mg). The mixture was heated at 45 °C for 4 h

under positive pressure of hydrogen (balloon). The reaction was cooled

to room temperature and ﬁltered through Celite. The ﬁltrate was con-

centrated under vacuum, and the residue was puriﬁed by ﬂash

chromatography over silica gel (methanol/dichloromethane) to provide

27 mg (68%) of 81 as a white solid. mp 159−160 °C. IR (ﬁlm) 3355,

(t, J = 4.4 Hz, 2H), 3.69 (dd, J = 14.8, 5.4 Hz, 1H), 3.57 (dd, J = 14.8,

7.1 Hz, 1H), 3.53−3.34 (m, 2H), 2.61 (s, 1H). ¹³C NMR (101 MHz,

CDCl₃) δ 154.9, 144.4, 141.1, 138.9, 135.4, 126.9, 125.3, 122.9, 122.5,

121.9, 119.9, 118.5, 116.8, 113.0, 112.8, 110.3, 104.3, 101.4, 69.8, 68.4, 64.4,

55.2, 49.0. MS (ESI) m/z (relative intensity): 375 (100) [M + H]⁺. HRMS

(ESI) calcd for C₂₃H₂₃N₂O₃[M + H]⁺, 375.1709; found, 375.1708.

Preparation of 4-[3-(9H-Carbazol-4-yloxy)-2-hydroxypropyl]-

3,4-dihydro-2H-1,4-benzoxazin-3-one (84). A mixture of epoxide

103a (179 mg, 0.748 mmol), 118b (101 mg, 0.677 mmol), and

Cs₂CO₃(309 mg, 0.948 mmol) in DMF (2 mL) was heated at 80 °C

for 20 h. The reaction was then partitioned between ethyl acetate and

water. The organic phase was separated, washed with brine, dried over

Na₂SO₄, and concentrated under vacuum. The residue was puriﬁed by

ﬂash chromatography over silica gel (ethyl acetate/hexanes) to aﬀord 94

mg (36%) of 84, oﬀ-white solid. mp 133−135 °C. IR (ﬁlm) 3402, 3342,

1

3279, 3061, 2928, 2835, 1588, 1495, 1251, 745 cm⁻¹. H NMR (400

MHz, DMSO-d₆) δ 11.04 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.94 (d, J =

8.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.41 (d,

J = 8.0 Hz, 1H), 7.31−7.17 (m, 3H), 7.09 (dd, J = 7.7, 7.2 Hz, 1H), 6.96

(d, J = 2.2 Hz, 1H), 6.76 (dd, J = 8.5, 2.2 Hz, 1H), 6.73 (s, 1H), 5.03 (d,

J = 4.5 Hz, 1H), 3.92−4.09 (m, 2H), 3.91 (s, 3H), 2.79 (dd, J = 11.8, 4.3

Hz, 1H), 2.70 (dd, J = 11.8, 6.0 Hz, 1H). ¹³C NMR (101 MHz, DMSO-

d₆) δ 157.8, 157.7, 154.1, 140.9, 139.6, 128.1, 124.0, 123.5, 122.6, 122.5,

120.7, 120.6, 119.1, 118.4, 116.1, 110.7, 110.4, 108.0, 103.1, 95.2, 70.8,

68.2, 51.7, 46.0. MS (EI) m/z (relative intensity): 386 (74) [M⁺], 183

(100), 131 (82), 43 (54). HRMS (EI) calcd for C₂₄H₂₂N₂O₃[M⁺],

386.1630; found, 386.1626.

Preparation of 1-[(Benzoxazol-2-ylmethyl)amino]-3-(9H-car-

bazol-2-yloxy)-2-propanol (82). A mixture of amino alcohol 119

(88 mg, 0.25 mmol), chloride 122 (47 mg, 0.28 mmol), N,N-

diisopropylethylamine (71 μL, 0.41 mmol), and a catalytic amount of KI

in acetonitrile (2 mL) was stirred at 60 °C for 16 h. The reaction was

cooled to room temperature and partitioned between water and ethyl

acetate. The aqueous phase was separated and extracted with ethyl

acetate. The combined extracts were washed with brine, dried over

Na₂SO₄, and concentrated under vacuum. The residue was puriﬁed by

ﬂash chromatography over silica gel (methanol/dichloromethane) to

provide 101 mg (85%) of the N-benzyl derivative of 82 as an oﬀ-white

solid. mp 77−79 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H),

7.98 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.79−7.73 (m, 1H),

7.72−7.66 (m, 1H), 7.46−7.21 (m, 9H), 7.15−7.06 (m, 1H), 6.91 (d, J =

2.1 Hz, 1H), 6.67 (dd, J = 8.5, 2.2 Hz, 1H), 5.01 (d, J = 4.8 Hz, 1H),

4.13−4.01 (m, 4H), 3.94−3.89 (m, 1H), 3.90 (d, J = 16.0 Hz, 1H), 3.83

(d, J = 16.0 Hz, 1H), 2.85 (dd, J = 13.3, 5.9 Hz, 1H), 2.77 (dd, J = 13.3,

5.8 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ 164.0, 157.8, 150.2,

141.0, 140.6, 139.7, 138.7, 128.8, 128.2, 127.0, 125.0, 124.3, 124.0, 122.6,

120.7, 119.6, 119.2, 118.5, 116.1, 110.7, 110.5, 108.0, 95.2, 70.9, 67.5,

58.4, 56.3, 50.5. MS (EI) m/z (relative intensity): 477 (7) [M⁺], 345

(21), 252 (20), 251 (100), 91 (79). HRMS (EI) calcd for C₃₀H₂₇N₃O₃

[M⁺], 477.2052; found, 477.2068.

1

3050, 2925, 2870, 1663, 1497, 1094, 748, 720 cm⁻¹. H NMR (400

MHz, DMSO-d₆) δ 11.25 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 7.44 (d, J =

8.1 Hz, 1H), 7.41−7.47 (m, 1H), 7.33 (ddd, J = 8.8, 7.5, 1.5 Hz, 1H),

7.28 (dd, J = 8.0, 7.9 Hz, 1H), 7.10 (ddd, J = 8.0, 7.2, 1.0 Hz, 1H), 7.08

(dd, J = 8.0, 0.5 Hz, 1H), 6.97−7.03 (m, 3H), 6.66 (d, J = 7.6 Hz, 1H),

5.49 (d, J = 5.3 Hz, 1H), 4.67 (d, J = 14.8 Hz, 1H), 4.61 (d, J = 14.8 Hz,

1H), 4.32−4.40 (m, 1H), 4.09−4.31 (m, 4H). ¹³C NMR (101 MHz,

DMSO-d₆) δ 164.3, 154.7, 145.0, 141.1, 138.9, 129.3, 126.4, 124.5,

123.4, 122.6, 122.4, 121.6, 118.5, 116.5, 116.1, 111.5, 110.3, 104.0, 100.4,

70.2, 67.1, 66.4, 44.5. MS (EI) m/z (relative intensity): 388 (25) [M⁺],

206 (100). HRMS (EI) calcd for C₂₃H₂₀N₂O₄[M⁺], 388.1423; found,

388.1417.

4-(9H-Carbazol-4-yloxy)-1-(3,4-dihydro-2H-1,4-benzoxazin-

4-yl)-2-butanol (85). From 105 and 118a.Yield: 20% (35% based on

recovered starting material), oﬀ-white solid. mp 172−174 °C. IR (ﬁlm)

1

3516, 3319, 2945, 2879, 1600, 1500, 1091, 734, 720 cm⁻¹. H NMR

(400 MHz, DMSO-d₆) δ 11.21 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.42 (d,

J = 8.1 Hz, 1H), 7.25−7.35 (m, 2H), 6.97−7.10 (m, 2H), 6.76 (dd, J =

8.1, 1.5 Hz, 1H), 6.62−6.73 (m, 3H), 6.48 (ddd, J = 7.9, 7.2, 1.5 Hz, 1H),

4.99 (d, J = 5.6 Hz, 1H), 4.06−4.40 (m, 5H), 3.52−3.58 (m, 1H), 3.37−

3.43 (m, 2H), 3.22 (dd, J = 14.6, 7.5 Hz, 1H), 2.13−2.23 (m, 1H), 1.82−

1.94 (m, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 155.0, 143.3, 141.0,

138.8, 135.4, 126.5, 124.4, 122.2, 121.7, 121.3, 118.5, 116.1, 115.7, 111.7,

111.4, 110.3, 103.7, 100.3, 64.6, 64.1, 63.9, 57.5, 48.3, 34.7. MS (EI) m/z

(relative intensity): 388 (26) [M⁺], 148 (100). HRMS (EI) calcd for

C₂₄H₂₄N₂O₃[M⁺], 388.1787; found, 388.1786.

A solution of the N-benzyl derivative of 82 (79 mg, 0.17 mmol) in

methanol (1.5 mL) was added to 10% palladium on charcoal (21 mg).

The mixture was hydrogenated as in the preceding procedure for 48 h.

The reaction was cooled to room temperature and ﬁltered through

Celite. The ﬁltrate was concentrated under vacuum, and the residue was

puriﬁed by ﬂash chromatography over silica gel (methanol/dichloro-

methane) to obtain 22 mg (34%) of 82 as a beige solid. mp 136−138 °C.

IR (ﬁlm) 3355, 3279, 3061, 2928, 2835, 1588, 1495, 1251, 745 cm⁻¹. ¹H

NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H),

7.93 (d, J = 8.5 Hz, 1H), 7.75−7.65 (m, 2H), 7.43−7.32 (m, 3H), 7.27

(t, J = 7.2 Hz, 1H), 7.10 (t, J = 7.3 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 6.75

(dd, J = 8.5, 2.1 Hz, 1H), 5.07 (d, J = 4.2 Hz, 1H), 4.09−3.93 (m, 3H),

4.07 (s, 2H), 2.83 (dd, J = 12.0, 3.7 Hz, 1H), 2.75 (dd, J = 11.5, 5.6 Hz,

1H). ¹³C NMR (101 MHz, DMSO-d₆) δ 165.8, 157.8, 150.2, 141.0,

140.7, 139.7, 124.9, 124.3, 124.1, 122.6, 120.8, 119.5, 119.2, 118.5, 116.2,

110.7, 110.5, 108.1, 70.9, 68.4, 51.9, 46.2. MS (EI) m/z (relative

intensity): 387 (82) [M⁺], 183 (100), 161 (25), 133 (32), 132 (39).

HRMS (EI) calcd for C₂₃H₂₁N₃O₃[M⁺], 387.1583; found, 387.1587.

Compounds 83−90 and 92 were prepared by the treatment of

the corresponding epoxides 103a, 105, 114a, 117a, or 117c with the

appropriate amines by means of the same procedure as for the

preparation of 6 except for the variation described below for 84.

1-(9H-Carbazol-4-yloxy)-3-(3,4-dihydro-2H-1,4-benzoxazin-

4-yl)-2-propanol (83). From 103a and 118a.Yield: 67%, oﬀ-white

solid. mp 68−70 °C. IR (ﬁlm) 3398, 3056, 2930, 2870, 1605, 1502,

1452, 1343, 1097, 722 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 8.30 (d, J =

7.8 Hz, 1H), 8.08 (s, 1H), 7.47−7.37 (m, 2H), 7.33 (dd, J = 8.0, 7.9 Hz,

1H), 7.30−7.21 (m, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.90−6.79 (m, 3H),

6.75−6.61 (m, 2H), 4.57−4.45 (m, 1H), 4.40−4.24 (m, 2H), 4.21

1-(9H-Carbazol-3-yloxy)-3-(3,4-dihydro-2H-1,4-benzoxazin-

4-yl)-2-propanol (86). From 114a and 118a. Yield: 76%, white solid.

mp 61−62 °C. IR (ﬁlm) 3402, 3056, 2925, 2862, 1500, 1183, 745 cm⁻¹.

¹H NMR (300 MHz, CDCl₃) δ 8.01 (d, J = 7.8 Hz, 1H), 7.95 (s, 1H),

7.59 (d, J = 2.4 Hz, 1H), 7.38−7.44 (m, 2H), 7.35 (d, J = 8.7 Hz, 1H),

7.17−7.25 (m, 1H), 7.10 (dd, J = 8.7, 2.5 Hz, 1H), 6.76−6.87 (m, 3H),

6.66 (ddd, J = 8.1, 6.2, 2.4 Hz, 1H), 4.31−4.50 (m, 1H), 4.24 (t, J = 4.4

Hz, 2H), 4.07−4.22 (m, 2H), 3.59 (dd, J = 14.8, 5.6 Hz, 1H), 3.40−3.57

(m, 3H), 2.53 (d, J = 4.8 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 152.8,

144.4, 140.5, 135.5, 134.9, 126.1, 124.0, 123.3, 121.8, 120.4, 119.3, 118.3,

116.8, 115.5, 112.9, 111.5, 110.9, 104.9, 71.0, 68.5, 64.5, 54.8, 49.0. MS

(EI) m/z (relative intensity): 374 (42) [M⁺], 148 (100). HRMS (EI+)

m/z calcd for C₂₃H₂₂N₂O₃[M⁺], 374.1630; found, 374.1621.

1-(9H-Carbazol-2-yloxy)-3-(3,4-dihydro-2H-1,4-benzoxazin-

4-yl)-2-propanol (87). From 117a and 118a. Yield: 61%, beige solid.

mp 172−174 °C. IR (ﬁlm) 3402, 3053, 2930, 2870, 1602, 1502, 1097,

908, 725 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.98

(d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H),

7.28 (ddd, J = 8.2, 7.2, 1.2 Hz, 1H), 7.18−7.05 (ddd, J = 8.0, 7.0, 1.0 Hz,

1H), 6.99 (d, J = 2.1 Hz, 1H), 6.81 (dd, J = 8.5, 2.2 Hz, 1H), 6.76 (dd, J =

8.1, 1.5 Hz, 1H), 6.71 (ddd, J = 8.1, 7.1, 1.5 Hz, 1H), 6.65 (dd, J = 7.9, 1.5

Hz, 1H), 6.47 (ddd, J = 7.8, 7.2, 1.5 Hz, 1H), 5.26 (s, 1H), 4.23−4.08 (m,

3H), 4.04 (d, J = 5.1 Hz, 2H), 3.56 (dd, J = 14.7, 4.9 Hz, 1H), 3.53−3.40

(m, 2H), 3.28 (dd, J = 14.7, 6.8 Hz, 1H). ¹³C NMR (101 MHz, DMSO-

d₆) δ 157.7, 143.4, 141.0, 139.7, 135.4, 124.1, 122.6, 121.3, 120.9, 119.2,

118.5, 116.4, 116.3, 115.8, 111.9, 110.6, 108.1, 95.3, 70.4, 66.8, 63.9,

54.0, 48.2. MS (EI) m/z (relative intensity): 374 (40) [M⁺], 148 (100).

HRMS (EI) calcd for C₂₃H₂₂N₂O₃[M⁺], 374.1630; found, 374.1613.

8651

dx.doi.org/10.1021/jm401090a | J. Med. Chem. 2013, 56, 8626−8655

Journal of Medicinal Chemistry

Article

1-(3,4-Dihydro-2H-1,4-benzoxazin-4-yl)-3-(6-ﬂuoro-9H-carbazol-

2-yloxy)-2-propanol (88). From 117c and 118a. Yield: 86%, white

solid. mp 180−181 °C. IR (ﬁlm) 3392, 2917, 2850, 1605, 1502, 1163,

911, 738 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 7.98

(d, J = 8.6 Hz, 1H), 7.82 (dd, J = 9.5, 2.6 Hz, 1H), 7.40 (dd, J = 8.8, 4.5

Hz, 1H), 7.11 (ddd, J = 9.5, 9.4, 2.6 Hz, 1H), 6.98 (d, J = 2.1 Hz, 1H),

6.82 (dd, J = 8.6, 2.2 Hz, 1H), 6.76 (dd, J = 8.1, 1.4 Hz, 1H), 6.70 (ddd,

J = 8.1, 7.6, 1.5 Hz, 1H), 6.65 (dd, J = 7.8, 1.5 Hz, 1H), 6.47 (ddd, J = 7.9,

7.8, 1.5 Hz, 1H), 5.24 (d, J = 4.8 Hz, 1H), 4.23−4.07 (m, 3H), 4.04 (d,

J = 4.9 Hz, 2H), 3.55 (dd, J = 14.7, 4.8 Hz, 1H), 3.54−3.46 (m, 1H),

3.44−3.35 (m, 1H), 3.35−3.23 (m, 1H). ¹³C NMR (101 MHz, DMSO-

d₆) δ 158.1, 156.5 (d, ¹J_C−F= 231 Hz), 143.4, 142.1, 136.1, 135.4, 123.2

(d, ³J_C−F= 10 Hz), 121.4, 121.3, 116.4, 116.1 (d, ⁴J_C−F= 4.0 Hz), 115.8,

111.9, 111.5 (d, ²J_C−F= 27 Hz), 111.3 (d, ³J_C−F= 12 Hz), 108.3, 104.9

(d, ²J_C−F= 24 Hz), 95.3, 70.4, 66.8, 63.8, 54.0, 48.2. ¹⁹F NMR (376 MHz,

DMSO-d₆) δ −127.1. MS (EI) m/z (relative intensity): 392 (24%)

[M⁺], 148 (100%). HRMS (EI) calcd for C₂₃H₂₁N₂O₃F [M⁺], 392.1536;

found, 392.1523.

1-(9H-Carbazol-4-yloxy)-3-[4-(2-methoxyphenyl)piperazin-

1-yl]-2-propanol (89). From 103a and 118c. Yield: 87%, white solid.

mp 88−89 °C. IR (ﬁlm) 3406, 3273, 3060, 2943, 2828, 1502, 1240,

1098, 909, 751, 724 cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J = 7.9

Hz, 1H), 8.12 (s, 1H), 7.42−7.37 (m, 2H), 7.33 (t, J = 8.0 Hz, 1H),

7.29−7.21 (m, 1H), 7.08−6.92 (m, 4H), 6.88 (dd, J = 8.0, 1.1 Hz, 1H),

6.70 (d, J = 7.8 Hz, 1H), 4.43−4.31 (m, 2H), 4.29−4.22 (m, 1H), 3.88

(s, 3H), 3.16 (br s, 4 H), 3.02−2.91 (m, 2H), 2.86−2.79 (m, 2H), 2.79−

2.68 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 155.4, 152.4, 141.3,

141.1, 138.9, 126.8, 125.1, 123.2, 123.1, 122.7, 121.2, 119.8, 118.4, 112.9,

111.4, 110.1, 103.9, 101.4, 70.5, 65.9, 61.3, 55.5, 53.8, 50.9. MS (EI) m/z

(relative intensity): 431 (25) [M⁺], 205 (100). HRMS (EI) calcd for

C₂₆H₂₉N₃O₃[M]⁺, 431.2209; found, 431.2220.

1-(9H-Carbazol-4-yloxy)-3-(4-phenylpiperazin-1-yl]-2-propanol

(90). From 103a and 118d. Yield: 97%, oﬀ-white solid. mp 75−77 °C. IR

(ﬁlm) 3405, 3295, 3056, 2940, 2824, 1598, 1505, 1449, 1094, 908, 752,

725 cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J = 7.9 Hz, 1H), 8.08

(s, 1H), 7.44−7.37 (m, 2H), 7.37−7.22 (m, 4H), 7.05 (d, J = 7.9 Hz,

1H), 7.01−6.92 (m, 2H), 6.89 (dd, J = 7.3, 7.2 Hz, 1H), 6.70 (d, J = 7.9

Hz, 1H), 4.43−4.30 (m, 2H), 4.31−4.21 (m, 1H), 3.57 (br s, 1H), 3.34−

3.18 (m, 4H), 2.97−2.86 (m, 2H), 2.86−2.74 (m, 2H), 2.75−2.64 (m,

2H). ¹³C NMR (101 MHz, CDCl₃) δ 155.3, 151.3, 141.1, 138.9, 129.3,

126.8, 125.2, 123.1, 122.7, 120.0, 119.8, 116.3, 112.9, 110.2, 104.0, 101.4,

70.4, 66.0, 61.2, 53.6, 49.4. MS (EI) m/z (relative intensity): 401 (30)

[M⁺], 175 (100). HRMS (EI) calcd for C₂₅H₂₇N₃O₂[M]⁺, 401.2103;

found, 401.2114.

N-[3-(9H-Carbazol-4-yloxy)-2-hydroxypropyl]-2-(2-

methoxyphenoxy)aniline (92). From 103a and 118e. Yield: 88%,

white solid. mp 62−64 °C. IR (ﬁlm) 3407, 3059, 2930, 1603, 1497,

1261, 1208, 725 cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J = 7.6

Hz, 1H), 8.08 (s, 1H), 7.46−7.36 (m, 2H), 7.32 (t, J = 8.0 Hz, 1H), 7.24

(ddd, J = 8.0, 6.5, 1.8 Hz, 1H), 7.12−7.05 (m, 2H), 7.04−6.98 (m, 1H),

6.99−6.91 (m, 3H), 6.88 (ddd, J = 8.0, 7.3, 1.5 Hz, 1H), 6.78 (dd, J = 8.0,

1.4 Hz, 1H), 6.72−6.66 (m, 1H), 6.64 (d, J = 8.0 Hz, 1H), 5.31 (br s,

1H), 4.53−4.43 (m, 1H), 4.31 (d, J = 5.2 Hz, 2H), 3.82 (s, 3H), 3.68 (dd,

J = 13.4, 4.5 Hz, 1H), 3.53 (dd, J = 13.3, 7.3 Hz, 1H), 2.70 (s, 1H). ¹³C

NMR (101 MHz, CDCl₃) δ 155.1, 150.9, 145.7, 144.9, 141.1, 139.4,

138.9, 126.8, 125.2, 124.4, 124.3, 123.0, 122.6, 121.2, 119.9, 119.7, 117.8,

117.7, 112.8, 112.2, 110.2, 104.2, 101.5, 70.1, 69.1, 56.1, 47.2. MS (EI)

m/z (relative intensity): 454 (78) [M⁺], 228 (100), 183 (40), 120 (25).

HRMS (EI) calcd for C₂₈H₂₆N₂O₄[M⁺], 454.1893; found, 454.1885.

Preparation of 2-(9H-Carbazol-4-yloxy)-N-[2-(2-

methoxyphenoxy)ethyl]acetamide (93). A mixture of amine

104a (208 mg, 1.24 mmol) in dry THF (12 mL) was cooled in an ice

bath and treated with Et₃N (0.34 mL, 2.4 mmol). After 15 min, acid

120⁵²(292 mg, 1.21 mmol), N-(3-diethylaminopropyl)-N′-ethyl-

carbodiimide hydrochloride (EDC hydrochloride) (356 mg, 1.86

mmol), and 1-hydroxybenzotriazole hydrate (HOBT·H₂O) (280 mg,

1.8 mmol) were added sequentially, and the reaction mixture was stirred

at room temperature for 3 h. It was partitioned between ethyl acetate

and water, and the organic phase was separated and washed with

saturated aqueous NH₄Cl and NaHCO₃, H₂O, and brine, dried over

Na₂SO₄, and concentrated under vacuum. The residue was puriﬁed by

ﬂash chromatography over silica gel (ethyl acetate/hexanes) to aﬀord

318 mg (67%) of 93 as a white solid. mp 155−156 °C. IR (ﬁlm) 3425,

1

3292, 3053, 2937, 2827, 1671, 1502, 1256, 752, 722 cm⁻¹. H NMR

(400 MHz, DMSO-d₆) δ 11.29 (s, 1H), 8.28 (t, J = 5.5 Hz, 1H), 8.22 (d,

J = 7.8 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.26 (t,

J = 8.0 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 7.06 (t, J = 8.0 Hz, 1H), 6.82−

7.02 (m, 4H), 6.61 (d, J = 7.9 Hz, 1H), 4.76 (s, 2H), 4.05 (t, J = 5.8 Hz,

2H), 3.70 (s, 3H), 3.57 (q, J = 5.7 Hz, 2H). ¹³C NMR (101 MHz,

DMSO-d₆) δ 168.0, 154.0, 149.3, 147.8, 141.1, 138.9, 126.3, 124.6,

122.6, 121.4 (2C), 120.7, 118.5, 114.2, 112.4, 111.7, 110.3, 104.5, 100.8,

67.3, 67.2, 55.4, 38.2. MS (EI) m/z (relative intensity): 390 (64) [M⁺],

267 (100), 196 (42), 154 (57). HRMS (EI) calcd for C₂₃H₂₂N₂O₄[M⁺],

390.1580; found, 390.1577.

Preparation of 2-(9H-Carbazol-4-yloxy)-N-[1-hydroxy-3-(2-

methoxyphenoxy)propan-2-yl]acetamide (94). A solution of

118f·HCl (354 mg, 1.51 mmol) in dry THF (20 mL) was cooled in

an ice bath and treated with Et₃N (0.65 mL, 4.5 mmol). After 15 min,

acid 120⁵²(365 mg, 1.51 mmol), EDC hydrochloride (435 mg, 2.26

mmol), and HOBT·H₂O (348 mg, 2.3 mmol) were added sequentially,

and the reaction mixture was stirred at room temperature for 4 h. It was

worked up and puriﬁed as in the preceding procedure to aﬀord 481 mg

(76%) of 94 as a white solid. mp 169−170 °C. IR (ﬁlm) 3412, 3285,

1

3056, 2933, 1661, 1502, 1253, 1216, 1107, 722 cm⁻¹. H NMR (400

MHz, DMSO-d₆) δ 11.27 (s, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.97 (d, J =

8.1 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.27 (t, J =

8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.08−7.00 (m, 2H), 6.83−7.00 (m,

3H), 6.64 (d, J = 7.9 Hz, 1H), 4.99 (t, J = 5.4 Hz, 1H), 4.77 (s, 2H),

4.28−4.16 (m, 1H), 4.15−4.00 (m, 2H), 3.70 (s, 3H), 3.69−3.63 (m,

1H), 3.63−3.55 (m, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ 167.6,

153.9, 149.3, 148.0, 141.1, 138.9, 126.3, 124.6, 122.5, 121.4, 121.3, 120.7,

118.6, 114.1, 112.6, 111.5, 110.4, 104.5, 100.9, 67.3, 67.2, 59.8, 55.6,

50.1. MS (EI) m/z (relative intensity): 420 (40) [M⁺], 297 (100), 196

(42), 154 (44). HRMS (EI) calcd for C₂₄H₂₄N₂O₅[M⁺], 420.1685;

found, 420.1667.

Preparation of 4-{[4-(2-Methoxyphenoxymethyl)-4,5-dihy-

dro-1,3-oxazol-2-yl]methoxy}-9H-carbazole (91). A solution of

94 (75 mg, 0.18 mmol) in a 2:1 mixture of dichloromethane/THF (4

mL) was cooled to −78 °C and treated with diethylaminosulfur

triﬂuoride⁴¹(DAST) (32 μL, 0.24 mmol). After 1 h, K₂CO₃(38 mg,

0.26 mmol) was added, and the cold bath was removed. The reaction

mixture was stirred at room temperature for 2 h, diluted with saturated

aqueous NaHCO₃solution, and extracted with dichloromethane. The

combined organic extracts were dried over Na₂SO₄and concentrated

under vacuum. The residue was puriﬁed by ﬂash chromatography over

silica gel (ethyl acetate/hexanes) to aﬀord 44 mg (62%) of 91 as a white

solid. mp 152−154 °C. IR (ﬁlm) 3402, 3062, 2936, 1669, 1606, 1583,

1500, 1452, 1252, 1117, 751, 722 cm⁻¹. ¹H NMR (400 MHz, DMSO-

d₆) δ 11.28 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H),

7.34 (ddd, J = 8.2, 7.2, 1.2 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.10−7.15

(m, 1H), 7.11 (d, J = 7.7 Hz, 1H), 6.82−7.05 (m, 4H), 6.75 (d, J = 7.7

Hz, 1H), 5.02 (s, 2H), 4.43−4.62 (m, 2H), 4.27−4.35 (m, 1H), 4.09

(dd, J = 9.7, 4.4 Hz, 1H), 3.98 (dd, J = 9.7, 5.4 Hz, 1H), 3.75 (s, 3H). ¹³C

NMR (101 MHz, DMSO-d₆) δ 163.8, 153.9, 149.3, 148.0, 141.1, 138.9,

126.3, 124.7, 122.5, 121.5, 121.4, 120.8, 118.6, 114.5, 112.7, 111, 110.4,

104.5, 100.8, 70.6, 69.9, 65.2, 62.3, 55.7. MS (EI) m/z (relative

intensity): 402 (100) [M⁺], 182 (38), 154 (72). HRMS (EI) calcd for

C₂₄H₂₂N₂O₄[M⁺], 402.1580; found, 402.1560.

Preparation of 1-(4,6-Dibromo-9H-carbazol-3-yloxy)-3-{[2-

(2-methoxyphenoxy)ethyl]amino}-2-propanol (97). Compound

97 was obtained from 4,6-dibromo-3-hydroxycarbazole (96) by treat-

ment with epichlorohydrin followed by amine 104a by the same

procedure as employed for the preparation of 3.³²Yield: 42%, oﬀ-white

solid. mp 141−143 °C. IR (KBr) 3458, 3378, 2922, 2834, 1507, 1452,

1253, 1222, 1186, 1121, 745 cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 8.90

(d, J = 1.8 Hz, 1H), 8.22 (br s, 1H), 7.55 (dd, J = 8.6, 2.0 Hz, 1H), 7.31

(d, J = 8.7, 2.6 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 6.98−6.90 (m, 4H),

4.20−4.10 (m, 5H), 3.86 (s, 3H), 3.13 (dd, J = 5.8, 5.7 Hz, 2H), 2.99 (dd,

J = 6.4, 4.7 Hz, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 149.9, 149.5, 148.4,

139.2, 136.3, 129.5, 125.5, 125.1, 121.8, 121.1, 115.2, 114.4, 112.1,

8652

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Journal of Medicinal Chemistry

Article

112.07, 112.02, 110.1, 110.0, 107.4, 74.1, 69.0, 68.6, 56.0, 51.7, 49.0. MS

(CI) m/z (relative intensity): 566 (52) [M⁺(⁸¹Br₂)], 564 (100)

[M⁺(⁸¹Br⁷⁹Br)], 562 (47) [M⁺(⁷⁹Br₂)], 487 (40), 485 (41), 407 (18),

224 (36). HRMS (EI) m/z calcd for C₂₄H₂₄⁸¹Br⁷⁹BrN₂O₄[M⁺],

564.0082; found, 564.0099.

and other compounds on SOICR. SOICR was measured using single-

cell Ca²⁺imaging and the ﬂuorescent Ca²⁺indicator dye fura-2/AM

(Invitrogen) as described previously^55,56Brieﬂy, cells grown on glass

coverslips for 18−22 h after induction by 1 μg/mL of tetracycline were

loaded with 5 μM fura 2/AM in KRH (Krebs−Ringer−Hepes) buﬀer

(125 mM NaCl, 5 mM KCl, 1.2 mM KH₂PO₄, 6 mM glucose, 1.2 mM

MgCl₂, and 25 mM Hepes, pH 7.4) plus 0.02% pluronic F-127 and 0.1

mg/mL BSA for 20 min at room temperature (23 °C). The coverslips

were then mounted in a perfusion chamber (Warner Instruments) on an

inverted microscope (Nikon TE2000-S). The Ca²⁺concentration was

then stepped to 0.5 mM for 5 min before increasing to 1 mM. The cells

were continuously perfused with KRH buﬀer containing 1 mM CaCl₂

and diﬀerent drugs for 8−10 min. Caﬀeine (10 mM) was applied at the

end of each experiment to conﬁrm the expression of active RyR2

channels. Time-lapse images (0.25 frame/s) were captured and analyzed

with the Compix Simple PCI 6 software (Compix Inc.). Fluorescence

intensities were measured from regions of interest centered on indi-

vidual cells. Only cells that responded to caﬀeine were used in analyses.

All chemicals were obtained from Sigma unless otherwise speciﬁed.

Preparation of 6-[(-(4,6-Dibromo-9H-carbazol-3-yloxy)-

methyl]-4-[2-(2-methoxyphenoxy)ethyl]morpholin-3-one (98).

Compound 98 was prepared from 97 by the same procedure as

employed for the preparation of 17. Yield: 34%, white solid. mp 208−

209 °C. IR (KBr) 3430, 3277, 2926, 2875, 1634, 1504, 1290, 1255, 751

cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆) δ 11.63 (s, 1H), 8.72 (d, J = 2.0

Hz, 1H), 7.59 (dd, J = 8.6, 2.0 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.50 (d,

J = 8.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.02−6.83 (m, 4H), 4.28−4.10

(m, 7H), 3.72 (s, 3H), 3.85−3.61 (m, 4H). ¹³C NMR (101 MHz,

DMSO-d₆) δ 165.9, 149.2, 148.3, 147.7, 139.3, 136.5, 128.6, 123.6,

121.4, 120.7, 120.4, 115.6, 113.8, 113.2, 112.3, 111.0, 110.0, 105.5, 104.4,

71.6, 71.0, 66.9, 66.4, 55.5, 49.0, 45.6. MS (EI) m/z (relative intensity):

482 (39), 480 (100), 478 (44). HRMS (EI) calcd for C₂₆H₂₄⁸¹Br⁷⁹BrN₂O₅

[M⁺], 604.0031; found, 604.0007.

Preparation of 7-Methoxy-5-methyl-2,3,4,5-tetrahydro-1,5-

benzothiazepine (101). Thiapyrone 123⁴⁰(1.00 g, 5.15 mmol) was

dissolved in TFA (5 mL). Trimethylsilyl azide (0.68 mL, 5.2 mmol) was

added at room temperature, the mixture was stirred for 2 days, and the

reaction was quenched with water and basiﬁed with NaOH. The mixture

was extracted with dichloromethane, the combined organic phase was

dried over Na₂SO₄, the solvent was evaporated under reduced pressure,

and the residue was puriﬁed by ﬂash chromatography over silica gel

(ethyl acetate/hexanes) to aﬀord lactams 124⁵³(260 mg, 24%) and

ASSOCIATED CONTENT

* Supporting Information

Elemental analyses of new compounds. This material is available

free of charge via the Internet at http://pubs.acs.org.

■

S

AUTHOR INFORMATION

Corresponding Author

*Tel.: 1-403-220-6256. E-mail: tgback@ucalgary.ca.

Notes

■

125⁵⁴(500 mg, 47%). Product 125 had the following properties: H

1

NMR (300 MHz, CDCl₃) δ 8.25 (br s, 1H), 7.50 (d, J = 8.5 Hz, 1H),

6.73 (dd, J = 8.5, 2.6 Hz, 1H), 6.67 (d, J = 2.6 Hz, 1H), 3.82 (s, 3H), 3.39

(t, J = 7.0 Hz, 2H), 2.62 (t, J = 6.9 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃)

δ 173.9, 161.0, 142.7, 136.4, 117.6, 112.1, 109.2, 55.6, 34.4, 33.6. MS

(EI) m/z (relative intensity): 209 (100) [M⁺], 154 (75). HRMS (EI)

calcd for C₁₀H₁₁NO₂S [M⁺], 209.0511; found, 209.0507.

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

This work was supported by a grant (R01HL75210) from the

U.S. National Institutes of Health to S.R.W.C. and T.G.B. and by

the Heart and Stroke Foundation/Libin Cardiovascular Institute

Professorship in Cardiovascular Research to S.R.W.C. We thank

the King family and the Libin Cardiovascular Institute of Alberta

for their generous donations.

To lactam 125 (500 mg, 2.39 mmol) in dry THF/ether (15 mL, 1:1),

LiAlH₄(181 mg, 4.77 mmol) was added at 0 °C, and the mixture was

then heated at 40 °C overnight. The reaction was carefully quenched

with 0.5 mL of water and ﬁltered through Celite. The solid was washed

repeatedly with ether, the ﬁltrate was evaporated, and the crude product

was puriﬁed by ﬂash chromatography over silica gel to give the cor-

responding amine (260 mg, 56%) as an oil that solidiﬁed upon standing.

mp 71.5−72.5 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.33 (d, J = 8.5 Hz,

1H), 6.41 (dd, J = 8.5, 2.6 Hz, 1H), 6.34 (d, J = 2.6 Hz, 1H), 3.76 (s, 3H),

3.24−3.22 (m, 2H), 2.76−2.73 (m, 2H), 2.12−2.06 (m, 2H). ¹³C NMR

(101 MHz, CDCl₃) δ 159.8, 153.3, 134.1, 117.0, 106.6, 105.9, 55.3, 47.7,

33.5, 32.1. MS (EI) m/z (relative intensity): 195 (97) [M⁺], 166 (100).

HRMS (EI) calcd for C₁₀H₁₃NOS [M⁺], 195.0718; found, 195.0710.

The above amine (250 mg, 1.28 mmol) was dissolved in 10 mL of

methanol and 1.1 mL of 37% formaldehyde. Sodium cyanoborohydride

(476 mg, 7.57 mmol) was added at room temperature, and the mixture

was stirred for 30 min, during which the pH was maintained between

4 and 5 by the addition of a few drops of 1 N HCl. The solvent was

removed under reduced pressure, and the residue was dissolved in

dichloromethane, washed with water, and dried over Na₂SO₄. The

solvent was evaporated, and the residue was puriﬁed by ﬂash

chromatography over silica gel (ether/pentane) to aﬀord 245 mg

(91%) of 101, colorless oil. IR 2933, 2822, 1593, 1555, 1478, 1107,

1074, 1032 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 7.33 (d, J = 8.4 Hz,

1H), 6.50 (d, J = 2.6 Hz, 1H), 6.40 (dd, J = 8.4, 2.6 Hz, 1H), 3.78 (s, 3H),

3.17−3.13 (m, 2H), 2.91 (s, 3H), 2.78−2.74 (m, 2H), 2.07−2.00 (m,

2H). ¹³C NMR (75 MHz, CDCl₃) δ 159.9, 155.1, 133.7, 117.9, 105.3,

104.4, 55.6, 55.2, 42.6, 30.5, 30.3. MS (EI) m/z (relative intensity): 209

(77) [M⁺], 180 (100). HRMS (EI) calcd for C₁₁H₁₅NOS [M⁺],

209.0874; found, 209.0875.

ABBREVIATIONS USED

■

SOICR, store-overload-induced calcium release; RyR, ryanodine

receptor; DAD, delayed after-polarization; CPVT, catecholami-

nergic polymorphic ventricular tachycardia; EDC, N-(3-

diethylaminopropyl)-N′-ethylcarbodiimide; HOBT·H₂O, 1-hy-

droxybenzotriazole hydrate; DAST, diethylaminosulfur triﬂuor-

ide; TBDPS, t-butyldiphenylsilyl

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Novel carvedilol analogues that suppress store-overload-induced Ca 2+ release

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