Scholarly article on 3-bromopropyl 4-(1-(2-methylbenzamido)naphthalene-4-sulfonamido)piperidine-1-carboxylate 1026928-71-1 from Journal of Medicinal Chemistry p. 566

566

J. Med. Chem. 2007, 50, 566-584

Design, Synthesis, and Evaluation of Naphthalene-Sulfonamide Antagonists of Human CCR8

Tracy J. Jenkins,*^,†Bing Guan,^†Mingshi Dai,^†Gang Li,^†Thomas E. Lightburn,^†Shan Huang,^†B. Scott Freeze,^†

Douglas F. Burdi,^†Swanee Jacutin-Porte,^†Robert Bennett,^†Weirong Chen,^†Charles Minor,^†Shomir Ghosh,^†

Christopher Blackburn,^†Kenneth M. Gigstad,^†Matthew Jones,^†Roland Kolbeck,^‡Wei Yin,^§Sean Smith,^‡Daniel Cardillo,^‡

Timothy D. Ocain,^‡and Geraldine C. Harriman^†

Department of Medicinal Chemistry, Department of Pharmacology, and Drug Safety and Disposition, Millennium Pharmaceuticals, 40

Landsdowne Street, Cambridge, Massachusetts 02139

ReceiVed September 26, 2006

The design, synthesis, and structure-activity relationship development of naphthalene-derived human CCR8

antagonists is described. In Vitro binding assay results of these investigations are reported, critical interactions

of the antagonists with CCR8 are defined, and preliminary physicochemical and pharmacokinetic data for

the naphthalene scaffold are presented.

Introduction

To begin, the screening of our compound collection in a

human CCR8 binding assay led to the discovery of several

potential leads possessing high affinity for this receptor.

Naphthalene-sulfonamide 1 (Figure 1, FMAT K_i) 57 nM,

FLIPR IC₅₀) 150 nM)¹⁰was one such antagonist and will be

the focus of the following discussion.

To investigate the SAR, we prepared analogs of 1, incorpo-

rating changes that would aid the elucidation of the structural

features required for binding to human CCR8. Through an

iterative process of synthesis and biological evaluation, we have

gained insight into the pharmacophore for this class of com-

pounds. In addition, we have prepared several derivatives with

extremely high (i.e., picomolar) affinity for CCR8. Selected in

Vitro results of these investigations are reported, and key binding

interactions are described. A follow-up report focusing on in

ViVo profiling and optimization of drug-like properties will be

released in due course.

Chemokines are chemotactic cytokines that regulate develop-

ment, activation, and recruitment of leukocytes through binding

and activation of seven transmembrane G-protein coupled

receptors. Four chemokine subgroups, CXC, CC, C, and CX3C,

have been defined based on the spacing of conserved cysteine

residues at the N-terminus.¹Unlike most chemokine receptors,

which are activated by multiple chemokines, CCR8, which is

the subject of this report, has only one known human endog-

enous ligand, CCL1 (also known as I-309). Additionally, the

pox-viral chemokine MC148 and the human herpes virus 8

(HHV-8) derived chemokine vMIP I have been identified as

being a specific human CCR8 antagonist and agonist, respec-

tively.²

A number of cell types express CCR8, including monocytes

and endothelial cells as well as phagocytic macrophages and

activated microglial cells in the human central nervous system.

CCR8 is also expressed in active demyelinating multiple

sclerosis (MS) lesions, in progressive multifocal leukoencepha-

lopathy (PML), and in cerebral ischemia.³Furthermore, expres-

sion of CCR8 has been noted in endothelial-derived spindle cells

of human Kaposi sarcoma biopsies.⁴The expression of CCR8

is selectively up-regulated upon activation of T-helper-2 (Th2)

cells,⁵which are the primary source of the cytokines IL-4, IL-

5, and IL-13. These cytokines, in turn, are major mediators of

inflammation, airway hyper-reactivity, and mucus hyper-secre-

tion in bronchial asthma.⁶Additionally, the CCR8 ligand, CCL1,

has anti-apoptotic activity in adult T-cell leukemia (ATL),

caused by human T-cell leukemia virus type 1 (HTLV-1).⁷

Based on the expression pattern of CCR8, activation of the

receptor by CCL1 is suspected to play an important role in

various diseases including allergic asthma, multiple sclerosis,

and cancer. Following up on our previously reported work,^8,9

our research efforts aimed to identify small molecule antagonists

to probe the role of CCR8-CCL1 interactions in these diseases

and provide novel therapeutics for their treatment. In this paper,

we describe the design, synthesis, and structure-activity

relationship (SAR) development of a series of naphthalene-

sulfonamide CCR8 antagonists.

Chemistry

Our investigation began with an evaluation of the importance

of each of the two hydrogen-bond donors found in naphthalene-

sulfonamide 1. Thus, 4-amino-1-naphthalenesulfonic acid was

first protected as the phthalimide derivative (Scheme 1), which

was followed by conversion to the corresponding sulfonyl

chloride and treatment with the 4-methoxyaniline to afford

sulfonamide 2. Deprotection, amine methylation, and acylation

then provided tertiary amide 3, in which the amide proton has

been replaced by a methyl substituent.

To probe the role of the sulfonamide proton, tertiary sul-

fonamides were next prepared (Scheme 2). Here, 4-amino-1-

naphthalenesulfonic acid was first acylated with benzoyl

chloride, followed by chlorination using thionyl chloride to

afford sulfonyl chloride 4. Treatment with a series of secondary

amines then provided tertiary sulfonamides 5a-e. This proce-

dure was also employed using primary amines to generate

several secondary sulfonamides 6a-g (see Tables 1 and 3,

respectively, for a list of selected “R” groups).

Having found the two hydrogen bond donors to be essential

for activity, we proceeded with the design and synthesis of

analogs of 1 bearing replacements for the sulfonamide linker,

as in 9 (Scheme 3), which contains a carboxamide, or as in

compound 11, which incorporates an aminomethyl linker. To

this end, treatment of commercially available 4-bromonaphtha-

len-1-amine with the desired acid chloride afforded bromide 7.

* To whom correspondence should be addressed. Phone: (617)-679-

7425. Fax: (617)-444-1483. E-mail: tracy.jenkins@biogenidec.com.

^†Department of Medicinal Chemistry.

^‡Department of Pharmacology.

^§Drug Safety and Disposition.

Published on Web 01/10/2007

Naphthalene-Sulfonamide Antagonists of Human CCR8

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3 567

Scheme 4. General Procedure for Preparation of Left-Hand

Side Amide Variants^a

Figure 1. Naphthalene-sulfonamide 1.

Scheme 1. Preparation of Naphthalene-Sulfonamide 3, Bearing

Only One H-Bond Donor^a

^aReagents and conditions: (a) H₂NNH₂, MeOH, rt.; (b) RCOCl, DMAP,

pyridine, 60 °C.

^aReagents and conditions: (a) phthaloyl chloride, pyridine, reflux; (b)

(i) SOCl₂, DMF, rt; (ii) p-methoxyaniline, Et₃N, CH₂Cl₂; (c) H₂NNH₂,

MeOH, rt; (d) MeI, K₂CO₃, DMF; (e) benzoyl chloride, Et₃N, CH₂Cl₂, rt.

commercially available 4-amino-1-tert-butyloxycarbonyl-pip-

eridine (4-amino-1-Boc-piperidine), followed by deprotection

and acylation, then provided the desired amide 9. Alternatively,

treatment of aldehyde 10 with the 4-amino-1-Boc-piperidine

under reductive amination conditions, again followed by depro-

tection and acylation, provided the desired secondary amine 11.

The above SAR studies led to the identification of piperidyl-

substituted sulfonamides possessing general structure 14 or 15

(Scheme 4) as promising leads for further development. Thus,

based upon this scaffold, a systematic investigation for optimal

left-hand amide substituents was initiated. To this end, piperidyl

sulfonamide 12 (Scheme 4) was prepared following the general

route depicted in Scheme 1. This entailed protection of 4-amino-

1-naphthalenesulfonic as the phthalimide (Phth) derivative,

followed by conversion to the sulfonyl chloride and treatment

with the requisite amine coupling partner. With sulfonamide

12 in hand, hydrazine was employed to effect removal of the

phthalimide protecting group, furnishing amine 13. Introduction

of a series of acid chloride coupling partners then afforded

amides 14a-gg, bearing a diverse range of left-hand amide

substituents. Carbamate 15 was generated independently, ac-

cording to the synthetic route described in Scheme 2.

Scheme 2. Preparation of Tertiary Sulfonamides 5a-e and

Secondary Sulfonamides 6a-g^a

^aReagents and conditions: (a) RCOCl, pyridine, reflux; (b) SOCl₂, DMF,

rt; (c) HNR₁R₂, Et₃N, CH₂Cl₂.

A one-pot sequence entailing halogen metal exchange of

bromide 7 with s-BuLi/NaH, followed by treatment with either

carbon dioxide or dimethylformamide (DMF), provided the key

intermediates, carboxylic acid 8 and aldehyde 10, respectively.

Subsequent EDC-mediated coupling of carboxylic acid 8 with

Ultimately, this method proved successful for the preparation

of many analogs (see Tables 7-9), however, its utility was

limited to amino connectivity on the left-hand side of the

Scheme 3. Preparation of Sulfonamide Replacement Analogs^a

^aReagents and conditions: (a) 2-methylbenzoyl chloride, ET₃N, CH₂Cl₂, rt; (b) NaH, s-BuLi, THF, CO₂, -78 °C-rt; (c) (i) EDCI, pyridine, 4-amino-

1-Boc-piperidine, rt; (ii) 4 N HCL, dioxane; (iii) butyryl chloride, Et₃N, CH₂Cl₂, rt; (d) NaH, s-BuLi, THF, DMF, -78 °C-rt; (e) (i) Na(AcO)₃BH, Boc-

piperidine amine, CH₃OH, rt; (ii) 4 N HCl, dioxane; (iii) butyryl chloride, Et₃N, CH₂Cl₂, rt.

568 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3

Jenkins et al.

Scheme 5. Scheme for the Synthesis of “Reversed” Left-Hand

Amides 20a and 20b^a

catalysis and subsequent reductive amination of the resultant

amine 22 with a series of aldehydes.

Continuing our investigation of the left-hand functionality,

ether and ester derivatives were both accessed from com-

mercially available alcohol 24, as illustrated in Scheme 7. First,

benzyl protection of the naphthol followed by chlorination and

sulfonamide formation furnished benzyl ether 26. For the

production of the ester derivative, the benzyl group of 26 was

removed under hydrogenolytic conditions to afford naphthol 27.

Treatment of the naphthol with benzoyl chloride then provided

the desired ester 28.

After determination of an optimal left-hand amide substituent,

we returned our attention to the right-hand side, focusing on

the incorporation of diverse substituents at the piperidine

nitrogen (Scheme 8). Beginning with sulfonyl chloride 29

(which was prepared as described in Scheme 2), amination with

4-amino-1-Boc-piperidine and deprotection provided key inter-

mediate 30, at which point introduction of a series of coupling

partners then afforded the title sulfonamides. This tactic allowed

the ready incorporation of amide (31a-o), carbamate (32a-

e), or urea (33a-n) functionality as piperidine appendages and

would ultimately lead to the generation of several compounds

exhibiting binding affinities for CCR8 in the low nanomolar to

picomolar range, as discussed in the sections to follow.

^aReagents and conditions: (a) 4-amino-1-Boc-piperidine, NEt₃, CH₂Cl₂;

(b) NaCN, DMF, 60 °C; (c) KOH, MeOH/H₂O, 100 °C; (d) R-NH₂, EDC,

Et₃N, CH₂Cl₂, rt; (e) 4 N HCl, dioxane; (f) EtOCOCl, NEt₃.

Scheme 6. General Scheme for the Synthesis of Aminomethyl

Analogs^a

Results and Discussion

The naphthalene-sulfonamide derivatives prepared in this

study¹¹were evaluated in an in Vitro binding assay (FLIPR and/

or FMAT)¹⁰to determine their affinity for human CCR8.

Although this manuscript deals primarily with SAR with respect

to in Vitro potency, our screening paradigm allowed for parallel

evaluation of various properties in addition to potency, including

ortholog cross reactivity, in Vitro selectivity, eADME properties,

including P450 CYP inhibition, metabolic stability, and perme-

ability.

To establish the SAR of this series of compounds, each

variable of naphthalene-sulfonamide 1 was systematically

modified, including the key H-bond donor/acceptors, right-hand

sulfonamide substituents, the left-hand naphthyl appendages, and

finally the naphthyl substitution patterns. The following structure-

activity tables examine each of these variables in turn and report

the in Vitro activity of the derived compounds against human

CCR8.

^aReagents and conditions: (a) NaBH₄/CoCl₃, EtOH, rt; (b) RCHO,

NaBH₃CN, MeOH/AcOH.

We begin our discussion by examining the effects of

substitution of the key H-bond donor/acceptor amide and

sulfonamide moieties, using the high-throughput screening hit

1 (Figure 1) as a starting point. The importance of the left-

hand side amide proton became immediately apparent, as each

of the tertiary derivatives that were prepared (2 and 3, Table 1)

were completely devoid of binding activity. Likewise, all

compounds bearing a tertiary sulfonamide (i.e., not possessing

a H-bond donor) displayed drastically lowered affinity for CCR8

(5a-5e, Table 1).

Furthermore, as illustrated in Table 2, replacement of the

sulfonamide with a carboxamide (9) or a secondary amine (11)

led to diminished activity against CCR8, indicating that the

acidic sulfonamide was preferred for potent activity.

Having identified that both the amide proton and the

sulfonamide proton are necessary for potent antagonism of

CCR8, we next focused our attention on understanding the effect

of modifying the sulfonamide substituent (right-hand side) of

the molecule. Here, removal of the methoxy substituent from

1, as in 6a (Table 3), reduced potency by over an order of

naphthyl ring system. To investigate the incorporation of

alternate left-hand substituents, routes specific for the function-

ality of interest were required. For example, compounds having

the left-hand amide functionality “reversed” were synthesized

as depicted in Scheme 5. This effort began with commercially

available 4-fluoro-1-naphthalenesulfonyl chloride 16, which

upon treatment with 4-amino-1-Boc-piperidine and then sodium

cyanide afforded cyanonaphthalene 17. Next, cyanonaphthalene

17 was hydrolyzed under basic conditions to afford the requisite

carboxylic acid 18, at which point coupling with either 2-me-

thylaniline or cyclohexylamine and subsequent removal of the

Boc carbamate furnished the reversed amides 19a and 19b,

respectively, in good overall yields. Installation of the ethyl

carbamate moiety then provided the desired reversed amide

congeners 20a and 20b.

Alternatively, benzyl amine derivatives of the left-hand side

(23a-c, Scheme 6) were readily obtained by borohydride-

mediated reduction of the cyanonaphthalene 21 under cobalt

Naphthalene-Sulfonamide Antagonists of Human CCR8

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3 569

Scheme 7. Synthesis of Ether 26 and Ester 28^a

^aReagents and conditions: (a) BnBr, Na₂CO₃, DMF, rt; (b) (i) SOCl₂, DMF, rt; (ii) ethyl-4-aminopiperidine-1-carboxylate, Et₃N, CH₂Cl₂; (c) H₂(1atm),

5% Pd/C, MeOH; (d) PhCOCl, pyridine, CH₂Cl₂, rt.

Table 1. Impact of Amide Hydrogen Bonds on Activity

Scheme 8. General Procedure for the Incorporation of

Piperidine Substituents^a

^aReagents and conditions: (a) (i) 4-amino-1-Boc-piperidine, NEt₃,

CH₂Cl₂; (ii) 4 N HCl in dioxane, THF, rt; (b) for amides, RCOCl, Et₃N,

CH₂Cl₂, rt or RCO₂H, EDCI, Et₃N, CH₂Cl₂; for ureas, RNCO, CH₂Cl₂, rt,

ClCONHR, CH₂Cl₂, NEt₃or carbonyl-1,1-diimidazole, HNR₁R₂; for

carbamates, ROCOCl, NEt₃.

magnitude, while insertion of a methylene spacer between the

naphthalene-sulfonamide core and the phenyl moiety, as in 6b,

resulted in a slight decrease in the binding affinity. The pyridyl

congener 6c and several noncyclic alkyl derivatives (data not

shown) demonstrated very poor binding affinity (>3.3 uM) and,

thus, were not further pursued. On the other hand, the effect of

replacing the right-hand phenyl ring of 6a with a cyclohexyl

group, as in 6d, was particularly striking, resulting in a 400-

fold improvement in activity.

In an effort to increase the solubility of this compound, a

piperidyl moiety was introduced as a surrogate for the cyclo-

hexyl group. Interestingly, while the unsubstituted piperidine

congener 6e showed a significant loss in binding affinity, the

protected tert-butyl carbamate 6f retained potency on par with

cyclohexyl analog 6d, suggesting that the basic amine was

detrimental. Furthermore, not only was modulation of amine

basicity important, but the steric size of the carbamate also had

a dramatic impact on binding, as the ethyl carbamate derivative

6g bound to CCR8 with a K_iof 170 picomolar, a 22-fold

improvement over the branched t-butyl analog 6f.

sensitive to modification than was the right-hand sulfonamide,

with a number of substituent types affording compounds that

retained low nanomolar potency, as summarized in Table 4.

For example, addition of an ortho-methyl subtituent to the

phenyl ring in 6g, as in 15, furnished a compound with a binding

potency of 1.6 nM, while the “reversed-amide” counterpart 20b

proved to be quite potent as well (5.2 nM). Similarly, “reversed”

cyclohexyl amide 20a retained low nanomolar binding to CCR8.

Decreases in the binding affinity were observed when an ether

(26) or ester (28) linkage were substituted for the amide (223-

fold and 96-fold, respectively).

As illustrated with compounds 23a-c, where the terminal

phenyl ring is separated from the napthalene sulfonamide core

by an aminomethyl group bearing various methylene tether

lengths, binding affinity is not drastically altered as the tether

length is increased from one to three methylene units. On the

other hand, replacement of the left-hand amide with a urea

moiety (34) resulted in a 93-fold loss of binding potency. Most

Having identified piperidyl carbamates such as 6g to be

extremely potent CCR8 antagonists, we set out to identify the

appropriate functionality for the left-hand side of the naphtha-

lene. In the event, the left-hand side proved to be far less

570 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3

Table 2. Sulfonamide Replacement Derivatives

Jenkins et al.

Table 4. Derivatives Incorporating Variations of the Left-Hand Amide

Substituent

hFLIPR IC₅₀

X

(nM)

14b

9

11

-SO₂-

-CO-

-CH₂-

0.3 ( 0.01

>3300

Table 3. Modification of the Sulfonamide Substituent

Table 5. Modification of the Piperidine Substituent and Heterocycle

Ring Size

dramatically, truncation to an unsubstituted heteroatom moiety,

as in naphthol 27 or naphthylamine 35, led to compounds that

were devoid of activity (>5 µM), suggesting that a hydrophobic

group is required for potent binding.

Our initial examination of left-hand side functional groups

also provided another important insight. Despite demonstrating

the most potent binding affinities to human CCR8 that we had

yet observed, we found that compound 6g suffered from a

metabolic liability, specifically amidase cleavage in rodent

plasma [T_1/2(mouse plasma) ) 0.5 h]. Pleasingly, we discovered

that introduction of an ortho-methyl substitutent on the phenyl

ring (as in 15) remediated the rodent plasma stability issue [T_1/2

(mouse plasma) ) 8.2 h] while retaining single digit nanomolar

binding affinity. As a consequence, many of the future deriva-

tives utilized this o-methylphenyl amide moiety.

With the metabolic liability of the left-hand amide resolved,

we next sought to probe further the role of the right-hand side

piperidine moiety and its pendent functionality. To this end,

we synthesized and evaluated urea 33c and amide 14b (Table

5), which both exhibited in Vitro binding potency on par with

ethyl carbamate 15. The effects of varying the cycloamine ring

size were also investigated, wherein the five-membered (36)

and four-membered (37) ring sizes led to similarly potent

compounds, though both were some 100-fold less potent at

CCR8 than was piperidyl amide 14b.

Before moving forward, we also sought to examine the

piperidine substituent with respect to eADME properties,

including metabolic stability and permeability. We found that

while carbamates, as represented by compound 15 (Table 5),

ureas (e.g., 33c, Table 5), and amides (e.g., 14b, Table 5), were

all nearly equipotent with respect to binding affinity, they could

be prioritized using Caco-2 and in Vitro clearance data.

Specifically, Caco-2 transport measurements (Table 6) showed

that carbamate 15 and amide 14b displayed acceptable efflux

ratio values of around 1.3, while urea 33c exhibited an efflux

Naphthalene-Sulfonamide Antagonists of Human CCR8

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3 571

Table 8. Heteroaryl Replacements for the Phenyl Ring

Table 6. Permeability and Intrinsic Clearance Data for Selected

Compounds

Caco2 (P_app× 10⁶cm/s)

CL_int

A to B

B to A

ratio

(L/hr/kg)

15

33c

14b

17

1.9

25

24

22

34

1.4

11

1.3

5.7

2.8

3.1

Table 7. Substituted Phenyl Amides

IC₅₀FLIPR

R

(nM)

14a

14b

14c

14d

14e

14f

14g

14h

14i

H

2-Me

3-Me

4-Me

2-F

3-F

4-F

4-ethyl

4-n-butyl

4-t-butyl

4-n-pentyl

4-benzyloxy

12.5 ( 3.7

5.20 ( 0.6

5.10 ( 1.2

9.50 ( 2.5

19.2 ( 5.4

20.0 ( 5.2

59.5 ( 15.0

10.8 ( 3.2

15.3 ( 5.1

6.90 ( 0.7

36.1 ( 10.6

24.6 ( 3.8

14j

14k

14l

ratio of 11, indicating that it may be a P-gp substrate. The human

in Vitro hepatic clearance was also assessed Via microsomal

incubation studies. In this case, both amide 14b and urea 33c

demonstrated hepatic stability superior to carbamate 15. Based

upon these data, we chose the propyl amide as a preferred

piperidine substituent to include during our next investigation,

which entailed a more thorough screening of left-hand amide

substituents.

Recalling that the o-methylphenyl amide substituent had

imparted both excellent potency and high metabolic stability,

we nonetheless undertook a more systematic search for an even

more potent left-hand amide substituent that retained plasma

stability. In this study, we examined first substituents and

substitution pattern about the phenyl ring moiety, the results of

which are summarized in Table 7. Heteroaryl replacements for

the phenyl ring are then shown in Table 8, while alkyl,

cycloalkyl, and saturated heterocyclic amide derivatives are

reported in Table 9.

Beginning with the substituted phenyl amides (Table 7), no

clear preference was observed for ortho, meta, or para substitu-

tion (e.g., 14b-d and 14e-g). Likewise, neither alkyl groups

of various sizes (e.g., 14a-d and 14h-l) nor fluorine substitu-

tion (14e-g) had a dramatic impact on binding. A number of

other substituents exhibited the same general trends but failed

to improve the potency (data not shown).

Heterocyclic replacements for the phenyl ring were likewise

well-tolerated (Table 8), though none proved superior to the

substituted phenyl analogs. In this series, substituted five-

membered heterocycles (14n-q) were preferred over the lone

unsubstituted congener (14m), while the activity of the six-

membered heterocycles evaluated ranged from moderate (14s,

14t, 14v, and 14w) to reasonably good (14r and 14u). The

influence of heteroatom placement within the heteroaryl ring

was also noteworthy, as the ortho (14u) and para (14w) pyridyl

substituents were preferred over the meta regioisomer 14v.

Consistent binding affinity was also noted when cycloalkyl

groups replaced the phenyl ring, as summarized in Table 9. Here,

in contrast to the heterocyclic replacements, the six-membered

ring size was preferred (cf. 14bb vs 14x, y, z, and aa).

Heteroatom insertion into the cycloalkyl ring resulted in a

decrease in potency, as substituted piperidyl congener 14cc

exhibited greatly diminished activity toward human CCR8, while

the pyran derivative 14dd exhibited 34-fold lower binding than

the cyclohexyl analog 14bb. Finally, compounds bearing acyclic

moieties (as in 14ee and 14ff) were, in general, less potent than

the cycloalkyl derivatives, with the exception of those bearing

a pendent phenyl substituent, as in example 14gg.

By now we had developed a fairly robust picture of the

naphthalene scaffold requirements for potent binding to CCR8.

Most critical was the secondary sulfonamide, as no other

promising surrogates were found. With respect to the left-hand

substituent, while a number of functional groups were well-

tolerated (see Tables 4, 7, 8, and 9), the ortho-methylphenyl

amide ultimately provided the best mix of in Vitro potency and

pharmacokinetic properties. Likewise, the piperidyl sulfonamide

substituent had proven to be optimal, though there was flexibility

in the pendent functionality of the piperidine ring, as carbamates,

ureas, and amides were all exceedingly potent antagonists. As

such, our next investigations were directed toward uncovering

the most favorable substituent to append to the piperidine ring.

As noted previously (Table 6 and accompanying text), amide-

functionalized piperidines exhibited a favorable mix of clearance

and permeability properties, so we began this study by exploring

amide substituents with varying steric and electronic properties

(Table 10). For example, a slight decrease in potency was noted

572 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3

Jenkins et al.

Table 9. Alkyl, Cycloalkyl, and Saturated Heterocyclic Replacements

Table 10. Amide Modification of the Piperidine Nitrogen

for the Phenyl Ring

as the propyl moiety in 14b was truncated to an ethyl group

and then a methyl group (31a and 31b, respectively). Replace-

ment of the alkyl chains with three- (31c) or five-membered

(31d) cycloalkyl rings also had minimal impact on activity.

Likewise, appending 31b with a terminal hydroxyl, as in 31e,

with a methyl ether, as in 31f, or with a primary amine, as in

31g, resulted in a series of compounds that were roughly

equipotent. To investigate the effect of chain length, a series of

compounds were prepared in which the terminal amine was

separated from the amide functionality via methylene spacers

of varying lengths. Binding data showed a slight preference for

shorter chain lengths (cf. 31g-i vs 31j), with the optimal tether

length being three methylene units (31i, K_i) 1.5 nM). With

respect to heterocyclic ring attachments, introduction of a

nitrogen into the ring, as in azetidine 31k and pyrrolidine 31l,

led to a 5-fold improvement in activity when compared to the

carbocyclic counterparts. Similar potency was realized with an

alanine-derived appendage, as in 31m. Finally, the larger phenyl

and substituted-phenyl amides (31n and 31o, respectively) were

by and large 1 to 2 orders of magnitude less potent than the

other analogs prepared in this section.

For completeness, the carbamate and urea functionalized

piperidine subclasses were also explored further, albeit to a lesser

extent (Tables 11 and 12, respectively). Beginning with the

carbamates, our investigation demonstrated that the SAR drawn

from the amide subclass was largely transferable to the

carbamates (data not shown). As such, many of the analogues

prepared featured an alkyl chain spacer appended with an amine

moiety, as in 32a-e (Table 11). Interestingly, while a four-

atom spacer was disfavored in the case of the amides (i.e., 31j),

the four-atom spacer was quite well-tolerated in the context of

the carbamates. Attempts to modulate potency by adding steric

bulk to the terminal amine moiety had minimal impact. While

the data indicate a slight preference for small alkyl groups

(32a,b) and small heterocycles (32c), larger amine groups such

as dimethylmorpholine (32d) and tetrahydroquinoline (32e) were

also tolerated with reasonable potency (<30 nM).

Table 11. Selected Carbamate Piperidine Derivatives

Next, a variety of secondary and tertiary urea-functionalized

piperidine derivatives were prepared; their binding affinities are

summarized in Table 12. For example, while primary urea 33a

showed only moderate potency, the binding affinity of alkyl-

substituted ureas was notable but tended to decrease as steric

bulk was added (33b-f). However, tertiary ureas were well

tolerated and exhibited similar potency to the corresponding

secondary urea (cf. 33b vs 33g). Significant potency was realized

with small cyclic tertiary ureas. However, there was little

difference noted between four-, five-, and six-membered rings

(33h, 33i, and 33j, respectively). Introduction of an additional

heteroatom into the six-membered ring had little effect on

potency (e.g., piperazine 33k and morpholine 33l). Interestingly,

in contrast with the previously discussed amide and carbamate

subclasses, analogs with an n-propyl linker capped by an amine,

as in 33m and 33n, were somewhat less potent.

The final SARs examined in this investigation entailed

modification of the naphthalene core by varying the regiochem-

Naphthalene-Sulfonamide Antagonists of Human CCR8

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3 573

Table 12. Selected Urea Piperidine Derivatives

involving both the right-hand side sulfonamide and left-hand

amide functionality are clearly critical, as alkylation of either

the amide or sulfonamide functionality is quite detrimental to

potency. Furthermore, while our most potent compounds

incorporated an amide moiety on the left-hand side of the

naphthalene core, we noted that a wide variety of substitutents

were tolerated at this position, suggesting the presence of a large

hydrophobic pocket. Likewise, a wide array of secondary

sulfonamide substituents were tolerated, though substituted

piperidyl derivatives were preferred. Further derivatization of

the piperidine nitrogen as an amide, carbamate, amine, or urea

all afforded potent analogs, including a number of compounds

that exhibited subnanomolar binding affinity to human CCR8.

Finally, our studies demonstrated that the substitution pattern

of the naphthalene core was important for binding and that the

1,4- and 1,5-regioisomers were preferred and were roughly

equipotent. A report concerning the impact of naphthalene core

replacements will follow in due course.

Applying our screening paradigm, we also evaluated PK and

selectivity properties for selected compounds. In general, the

compounds tested showed at least 300-fold selectivity versus

GPCRs, including chemokine receptors (e.g., 15, <20% inhibi-

tion at 10 uM against the standard Novascreen panel).¹²They

did not significantly inhibit P450 isozymes, including CYP 3A4

(IC₅₀> 10 uM). Furthermore, these compounds did not display

significant hERG binding in HEK293 cells (e.g., 15, K_i> 10

uM).¹³Unfortunately, however, the oral bioavailability of these

compounds is low to moderate with low clearance rates and

Vss, for example, 15 [rat (10 mpk po, 1 mpk iv, F ) 2%, t_1/2

) 2.6 h, Vss ) 1.6 L/kg, and CL ) 1.4 L/h/kg) and dog (10

mpk po, 1 mpk iv, F ) 10%, t_1/2) 3.7 h, Vss ) 1.5 L/kg, and

CL ) 0.42 L/h/kg)]. We have since explored solubility and

formulation-based approaches to remediate the poor bioavail-

ability. Accordingly, a second follow up report will detail our

efforts to improve the PK profile (i.e., increase oral bioavail-

ability and volume of distribution) of our CCR8 antagonists

and will also address issues such as plasma protein binding and

whole blood potency.

Table 13. Naphthalene Regioisomers

Experimental Section

Materials and MethodssPharmacology. FLIPRsCalcium

Mobilization Assay. CHO/GR16 cells stably expressing human

CCR8 were plated on 384-well plates (Falcon) at a density of 4 ×

10³cells/well and cultured for 2 days at 37 °C and 5% CO₂. On

the third day, the cells were incubated with Fluo-3TM (5 uM) for

1 h (37 °C, 5% CO₂), and excess dye was removed by extensively

washing the cells. To measure the potency of CCR8 antagonists to

inhibit CCL1-induced increases of intracellular Ca²⁺, plates were

loaded onto a Fluorometric Imaging Plate Reader (FLIPR2TM,

Molecular Devices, Inc., Sunnyvale, CA) and either incubated with

different concentrations of antagonists (100% DMSO) or DMSO

alone (negative control), resulting in a final DMSO concentration

of 1%. After 3 min of preincubation with antagonists, Ca²⁺-flux

was induced by adding the CCR8 ligand CCL1 (R&D Systems) at

a final concentration of 2 nM. Antagonist IC₅₀values were

calculated using XLFit 4.0TM (IDBS, Guildford, U.K.).

FMAT Binding Assay. A suspension was prepared of L1.2/

hCCR8 cells at 4.0 × 10⁵cells/mL in a binding buffer (Buffer

consisting of Hanks balanced salt solution (without phenol red),

10 mM HEPES, 0.1% fatty acid free BSA, 0.02% sodium azide).

A solution of 0.375 nM of human CCL1 (biotinylated at the

C-terminus of the ligand after an additional lysine residue using

the Applied Biosystems 433 peptide synthesizer) and 0.375 nM of

mouse Cy-5 Mab-R-Biotin (Jackson ImmunoResearch Laboratories,

Inc., code number 200-172-096) was prepared in binding buffer

immediately prior to the assay.

istry of the functional group connectivity (Table 13). In this

series, the 1,5-regioisomer 38a showed 14-fold lower binding

affinity than the 1,4-regioisomer 6g, while the 1,7-regioisomer

(38b) was several orders of magnitude less potent. Finally, the

2,6-regioisomer (38c) was devoid of any binding affinity.

Although not discussed in this manuscript, several derivatives

based on the 1,5-substituted naphthalene scaffold were prepared,

and the previously discussed SAR for the 1,4-regioisomer

transferred quite well to the 1,5-scaffold with little loss in overall

binding potency.

From the SARs discussed, we have developed a thorough

understanding of the critical interactions between the naphthalene-

sulfonamide scaffold and human CCR8. Hydrogen bonds

574 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3

Jenkins et al.

A dilution series of 10 mM stock concentrations of the test

compounds were prepared in DMSO and further diluted into binding

buffer defined above to three times the final assay concentration.

A ten-point concentration-response curve is constructed for each

compound, starting at 10 µM (final assay concentration in binding

buffer). An amount equal to 25 µL of each concentration of test

was transferred into the appropriate wells of a 384-well plate. Cold

100 nM CCL1 (25 µL; R and D Systems: catalog number 272-I/

CF) was then transferred into empty wells to serve as a control for

nonspecific binding. Biotinylated human CCL1 (25 µL of the 0.375

nM)/0.375 nM Cy5-R-biotin solution were then transferred into each

well of the same 384-well plate, followed by addition of 25 µL of

the resuspended cell solution into each well. The components were

mixed in wells by covering the plate with aluminum foil and rotating

for 0.5 h. The plates were allowed to incubate at room temperature

for approximately 1-2 h and then read on a FMAT 8100 HTS

system (purchased from Applied Biosystems, PMT) 490/518 or

537/568, set threshold ) 1SD MAT). Average fluorescence reported

for each concentration was normalized to percent inhibition based

on negative (no inhibitor) and positive (100 nM excess unlabeled

CCL1 (R and D Systems)) controls.

Materials and MethodssChemistry. All reactions involving

air-sensitive reagents were performed under a nitrogen atmosphere.

Reagents were used as received from commercial suppliers unless

otherwise noted. Anhydrous solvents such as dimethylformamide

(DMF), tetrahydrofuran (THF), and dichloromethane (CH₂Cl₂) were

obtained either from Aldrich Chemical Co. in Sure/Seal bottles or

from Mallinckrodt Baker, Inc., as ultra low water solvent. ¹H NMR

data were recorded using either a Bruker UltraShield 300 MHz/54

mm instrument equipped with Bruker B-ACS60 auto sampler or a

Varian 300 MHz instrument. Chemical shifts are expressed in ppm

from tetramethylsilane resonance in the indicated solvent (TMS:

0.0 ppm), and coupling constants (J-values) are given in hertz (Hz).

¹H NMR data are reported in the following order: ppm, multiplicity

(s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; m, multiplet;

br, broad), and number of protons. Intermediates and final

compounds were purified by chromatography using one of the

following instruments, unless otherwise noted: (1) Biotage 4-chan-

nel Quad UV Flash Collector equipped with a Quad 1 Pump Module

and the Quad 12/25 cartridge module; (2) Isco combi-flash

chromatography instrument; or (3) HPLC/MS system equipped with

Waters 2700 sample manager auto-injector, Waters 600 controller

and pumps, Waters 996 diode array detector, Micro Mass Platform

LCZ mass spectrometer, and Gilson FC-204 fraction collector.

Solvents A (99% water/1% CH₃CN/0.1% formic acid) and B (95%

CH₃CN/5% water/0.1% formic acid) were used for gradient elution

of the compounds using Phenomenex Luna 15 micron, C18(2)

100A, 250 × 21.2 mm column at 20 mL/min flow rate. The reported

yields represent the yields obtained for the final step of the sequence

before optimization. LC/MS spectra were obtained using a Micro-

Mass Platform LC (Phenomenex C18 column, 5 micron, 50 × 4.6

mm) equipped with a Gilson 215 liquid handler. High-resolution

mass spectra (HRMS) were obtained using a QSTAR XL quadruple-

time-of-flight mass spectrometer (Applied Biosystems/MDS Sciex)

coupled with an Agilent 1100 series HPLC system (binary pump,

autosampler, and degasser).

DMF (10 mL) was added thionyl chloride (0.6 mL, 8.8 mmol).

The reaction mixture was stirred at 25 °C for 3 h, at which point

the reaction was quenched by pouring into ice water and then

filtered to afford 4 (1.8 g) as a pale white solid. This material was

used without further purification. ¹H NMR (300 MHz, DMSO-d₆)

δ 8.88 (d, J ) 8.0 Hz, 1H), 8.09 (d, J ) 6.7 Hz, 2H), 7.97 (d, J )

7.7 Hz, 2H), 7.55 (m, 6H).

Step 3. To a solution of 4 (0.32 g, 0.93 mmol) in CH₂Cl₂(20

mL) were added Et₃N (0.26 mL, 1.85 mmol) and p-anisidine (0.14

g, 1.11 mmol). The reaction mixture was stirred at 25 °C for 17 h,

at which point the reaction was quenched with water and extracted

several times with CH₂Cl₂. The combined organic extracts were

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

to provide the crude product as a viscous yellow oil. The oil was

purified via HPLC, affording 1 as a white solid (0.19 g, 47%). ¹H

NMR (300 MHz, CD₃OD) δ 8.78 (d, J ) 6.8 Hz, 1H), 8.11 (m,

2H), 8.04 (d, J ) 7.9 Hz, 2H), 7.70 (m, 7H), 6.85 (d, J ) 8.9 Hz,

2H), 6.60 (d, J ) 8.9 Hz, 2H), 3.62 (s, 3H); LC/MS m/z 433 [M +

H]⁺; HRMS calcd for C₂₄H₂₀N₂O₄S [M + H]⁺, 433.1222; found,

433.1235.

4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-naphthalene-1-sulfon-

ic Acid (4-Methoxy phenyl)-amide (2). The title compound was

prepared following general procedure A using phthaloyl dichloride

instead of benzoyl chloride. Yield: 0.8 g (42%) of a white solid.

¹H NMR (300 MHz, CDCl₃) δ 8.75 (d, J ) 8.5 Hz, 1H), 8.20 (d,

J ) 7.7 Hz, 1H), 8.02 (m, 2H), 7.87 (m, 2H), 7.66 (m, 3H), 7.42

(d, J ) 7.7 Hz, 1H), 6.86 (d, J ) 8.7 Hz, 2H), 6.69 (d, J ) 8.7 Hz,

2H), 3.72 (s, 3H); LC/MS m/z 459 [M + H]⁺; HRMS calcd for

C₂₅H₁₈N₂O₅S [M + H]⁺, 459.1014; found, 459.1023.

N-(4-{[(4-Methoxyphenyl)amino]sulfonyl}-1-naphthyl)-N-me-

thylbenzamide (3). Step 1. To a solution of 2 (2.8 g, 6.3 mmol)

in MeOH (50 mL) was added hydrazine (5 mL, 158 mmol). The

resultant solution was stirred at 55 °C for 2 h, at which point the

precipitate was removed via filtration and washed with a small

amount of MeOH. The filtrate was collected and the solvent was

removed in Vacuo to provide a pale yellow solid (1.2 g, 58%). Step

2. To a DMF (5 mL) solution of the above solid (0.20 g, 0.62 mmol)

were added MeI (43 µL, 0.68 mmol) and K₂CO₃(0.17 g, 1.24

mmol). The reaction mixture was stirred at 25 °C for 17 h. The

reaction mixture was quenched with water and extracted several

times with CH₂Cl₂. The combined organic extracts were washed

with brine, dried over Na₂SO₄, filtered, and concentrated. Column

chromatography of the crude product provided the desired methy-

lated intermediate (0.18 g, 85%). Step 3. To a CH₂Cl₂(5 mL)

solution of the intermediate generated in Step 2 (80 mg, 0.24 mmol)

were added Et₃N (67 µL, 0.48 mmol) and benzoyl chloride (40

µL, 0.35 mmol). The reaction mixture was stirred at 25 °C for

17 h. Concentration and purification by column chromatography

1

provided 3 (45 mg, 42%) as a light yellow solid. H NMR (300

MHz, DMSO-d₆) δ 8.23 (m, 2H), 8.10 (m, 3H), 7.90 (d, J ) 8.2

Hz, 1H), 7.60 (m, 5H), 7.03 (d, J ) 8.6 Hz, 2H), 6.82 (d, J ) 8.6

Hz, 2H), 3.72 [s, 3H], 3.18 (s, 3H); LC/MS m/z 445 (M- H)⁺;

HRMS calcd for C₂₅H₂₀N₂O₄S [M + H]⁺, 447.1378; found,

447.1386.

Sulfonamides 5a-5c and 5e. These compounds were prepared

according to general procedure A from the appropriate starting

materials. Sulfonamide 5d was purchased from a commercial

source.

Experimental Procedures. General Procedure A. N-[4-(4-

Methoxy-phenylsulfamoyl)-naphthalen-1-yl]-benzamide (1). This

compound was prepared in three steps starting from commercially

available 4-amino-1-naphthalenesulfonic acid, as shown below.

Step 1. To a solution of 4-amino-naphthalene-1-sulfonic acid

(2.3 g, 10.0 mmol) in pyridine (15 mL) was added benzoyl chloride

(1.4 mL, 12.0 mmol), and the resultant solution was stirred at

100 °C for 17 h. The solvent was then removed under vacuum,

and the crude material was recrystallized from MeOH (2×) to

afford 4-benzoylamino-naphthalene-1-sulfonic acid pyridinium salt

(2.0 g) as a gray solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.92 (m,

3H), 8.60 (m, 1H), 8.00 (m, 6H), 7.55 (m, 6H); LC/MS m/z 327

[M - H]^-.

N-[4-(Methyl-phenyl-sulfamoyl)-naphthalen-1-yl]-benza-

1

mide (5a). H NMR (300 MHz, CD₃OD) δ 8.29 (d, J ) 6.9 Hz,

1H), 8.12 (m, 2H), 8.05 (d, J ) 8.0 Hz, 2H), 7.85 (d, J ) 8.1 Hz,

1H), 8.55 (m, 4H), 7.37 (m, 1H), 7.26 (m, 3H), 7.12 (m, 2H), 3.25

(s, 3H); LC/MS m/z 417 [M + H]⁺; HRMS calcd for C₂₄H₂₀N₂O₃S

[M + H]⁺, 417.1273; found, 417.1288.

1

N-(4-Diethylsulfamoyl-naphthalen-1-yl)-benzamide (5b). H

NMR (300 MHz, DMSO-d₆) δ 8.60 (d, J ) 8.8 Hz, 1H), 8.05 (m,

5H), 7.60 (m, 5H), 3.35 (q, J ) 7.0 Hz, 4H), 1.07 (t, J ) 7.0 Hz,

6H); LC/MS m/z 383 [M + H]⁺; HRMS calcd for C₂₁H₂₂N₂O₃S

[M + H]⁺, 383.1429; found, 383.1445.

Step 2. 4-Benzoylamino-naphthalene-1-sulfonyl chloride (4).

To a solution of the above pyridinium salt (2.4 g, 5.9 mmol) in

N-(4-(Piperidin-1-ylsulfonyl)naphthalen-1-yl)benzamide (5c).

¹H NMR (300 MHz, DMSO-d₆) δ 10.68 (s, 1H), 8.70 (d, J ) 8.5

Naphthalene-Sulfonamide Antagonists of Human CCR8

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3 575

Hz, 1H) 8.22 (m, 2H), 8.09 (d, J ) 7.4 Hz, 2H), 7.88 (d, J ) 8.0

Hz, 1H), 7.66 (m, 4H), 3.32 (s, 1H), 3.10 (m, 4H), 1.40 (m, 6H);

LC/MS m/z 395 [M + H]⁺; HRMS calcd for C₂₂H₂₂N₂O₃S [M +

H]⁺, 395.1429; found, 395.1448.

hexane and water to provide 7. The material thus obtained was

used without further purification. LCMS m/z 342 [M + H]⁺.

4-[(2-Methylbenzoyl)amino]-1-naphthoic Acid (8). To a solu-

tion of 7 (1.70 g, 5.00 mmol) in THF (30 mL) was added NaH

(568 mg, 24.0 mmol). The reaction mixture was stirred at 25 °C

for 1 h and then cooled to -78 °C, at which point sec-butyl lithium

was added dropwise as a solution in cyclohexane (1.4 M solution,

7.1 mL, 10.0 mmol). The resulting mixture was stirred at -78 °C

for 1 h and then quenched by addition of dry ice, at which

point the mixture was acidified to pH 3 by addition of 6 N HCl.

The mixture was then extracted with EtOAc (3×), and the

combined organic layers were washed with water, dried over

MgSO₄, filtered, and concentrated. Precipitation of the product from

a water/MeOH mixture then afforded the desired acid 8. LCMS

m/z 306 [M + H]⁺.

N-(1-Butyrylpiperidin-4-yl)-4-[(2-methylbenzoyl)amino]-1-

naphthamide (9). Step 1. To a solution of 8 (305 mg, 1.00 mmol)

in pyridine (5 mL) were added tert-butyl 4-aminopiperidine-1-

carboxylate (214 mg, 1.07 mmol) and EDCI (383 mg, 2.00 mmol).

The reaction mixture was stirred at 25 °C for 17 h, and the solution

was concentrated in Vacuo, affording the requisite N-Boc protected

intermediate (LCMS m/z 488 [M + H]⁺), which was subsequently

stirred in 4 M HCl/dioxane (5.0 mL) at 25 °C for 5 h, to afford

4-[(2-methylbenzoyl)amino]-N-piperidin-4-yl-1-naphthamide as the

corresponding HCl salt. LCMS m/z 388 [M + H]⁺. Step 2. To a

solution of the product from Step 1 in CH₂Cl₂(10.0 mL) was added

Et₃N (0.417 mL, 3.00 mmol) and butanoyl chloride (0.157 mL,

1.50 mmol). The reaction mixture was stirred at 25 °C for 17 h,

followed by aqueous workup and HPLC purification, to afford 9

(142 mg, yield 48%) as a white solid. ¹H NMR (300 MHz, DMSO-

d₆) δ 10.44 (s, 1H), 8.52 (d, J ) 6.6 Hz, 1H), 8.21 (m, 2H), 7.65

(m, 5H), 7.40 (m, 3H), 4.33 (m, 1H), 4.13 (m, 1H), 3.88 (m, 1H),

3.17 (m, 1H), 2.77 (m, 1H), 2.48 (s, 3H), 2.29 (t, J ) 6.9 Hz, 2H),

1.94 (m, 2H), 1.47 (m, 4H), 0.90 (t, J ) 7.1 Hz, 3H); LC/MS m/z

458 [M + H]⁺; HRMS calcd for C₂₈H₃₁N₃O₃[M + H]⁺, 458.2443;

found, 458.2458.

N-[4-(4-Methyl-piperazine-1-sulfonyl)-naphthalen-1-yl]ben-

zamide (5e). ¹H NMR (300 MHz, CD₃OD) δ 8.74 (d, J ) 6.8 Hz,

1H), 8.37 (d, J ) 8.0 Hz, 1H), 8.15 (m, 2H), 8.08 (d, J ) 8.1 Hz,

2H), 7.86 (d, J ) 8.1 Hz, 1H), 7.55 (m, 4H), 3.36 (m, 4H), 2.86

(m, 4H), 2.50 (s, 3H); LC/MS m/z 410 [M + H]⁺; HRMS calcd

for C₂₆H₂₃N₃O₃S [M + H]⁺, 410.1538; found, 410.1534.

Sulfonamides 6a-6d. These compounds were prepared accord-

ing to general procedure A from the appropriate starting materials.

1

N-(4-Phenylsulfamoyl-naphthalen-1-yl)-benzamide (6a). H

NMR (300 MHz, CD₃OD) δ 8.76 (d, J ) 6.8 Hz, 1H), 8.16 (d, J

) 7.9 Hz, 1H), 8.05 (d, J ) 7.8 Hz, 1H), 7.96 (d, J ) 8.0 Hz, 2H),

7.60 (m, 6H), 7.00 (m, 5H); LC/MS m/z 403 [M + H]⁺; HRMS

calcd for C₂₃H₁₈N₂O₃S [M + H]⁺, 403.1116; found, 403.1118.

N-{4-[(Benzylamino)sulfonyl]-1-naphthyl}benzamide (6b). ¹H

NMR (300 MHz, DMSO-d₆) δ 8.71 (d, J ) 6.9 Hz, 1H), 8.18 (m,

2H), 8.11 (d, J ) 8.0 Hz, 2H), 7.90 (d, J ) 8.2 Hz, 1H), 7.60 (m,

5H), 7.40 (m, 5H), 4.05 (s, 2H); LC/MS m/z 417 [M + H]⁺; HRMS

calcd for C₂₂H₂₀N₂O₃S [M + H]⁺, 417.1273; found, 417.1289.

N-{4-[(Pyridin-4-ylmethyl)-sulfamoyl]-naphthalen-1-yl}-ben-

zamide (6c). ¹H NMR (300 MHz, CD₃OD) δ 8.76 (d, J ) 6.8 Hz,

1H), 8.22 (d, J ) 8.0 Hz, 2H), 8.14 (d, J ) 8.5 Hz, 1H), 8.09 (d,

J ) 8.1 Hz, 2H), 7.74 (d, J ) 8.1 Hz, 1H), 7.60 (m, 6H), 7.08 (d,

J ) 6.5 Hz, 2H), 4.10 (s, 2H); LC/MS m/z 418 [M + H]⁺; HRMS

calcd for C₂₃H₁₉N₃O₃S [M + H]⁺, 418.1225; found, 418.1245.

N-(4-Cyclohexylsulfamoyl-naphthalen-1-yl)-benzamide (6d).

¹H NMR (300 MHz, CD₃OD) δ 8.80 (d, J ) 6.8 Hz, 1H), 8.33 (d,

J ) 8.1 Hz, 1H), 8.20 (d, J ) 8.1 Hz, 1H), 8.08 (d, J ) 8.0 Hz,

2H), 7.85 (d, J ) 8.0 Hz, 1H), 7.66 (m, 5H), 3.05 (br, 1H), 1.60

(m, 3H), 1.48 (m, 1H), 1.35 (m, 1H), 1.25 (m, 5H); LC/MS m/z

409 [M + H]⁺; HRMS calcd for C₂₃H₂₄N₂O₃S [M + H]⁺, 409.1586;

found, 409.1596.

N-[4-(Piperidin-4-ylsulfamoyl)-naphthalen-1-yl]-benzamide For-

mic Acid Salt (6e). The title compound was prepared according

to general procedure A, substituting tert-butyl 4-aminopiperidine-

N-(4-Formyl-1-naphthyl)-2-methylbenzamide (10). To a solu-

tion of 7 (1.40 g, 4.10 mmol) in THF at -78 °C was added dropwise

s-butyl lithium as a solution in cyclohexane (1.4 M solution, 11.8

mL, 16.5 mmol). The reaction mixture was stirred at -78 °C for

1 h, at which time the reaction was quenched with DMF (2.0 mL)

followed by the addition of water (2.0 mL). The mixture was then

diluted with EtOAc, the layers were separated, and the aqueous

layer was extracted with EtOAc (2×). The combined organic layers

were washed successively with saturated NaHCO₃solution, 1 N

HCl solution, and brine and then dried over MgSO₄. Filtration and

concentration then provided 10, which was used without further

purification. LCMS m/z 290 [M + H]⁺.

1

1-carboxylate for p-anisidine, followed by Boc deprotection. H

NMR (300 MHz, CD₃OD) δ 8.75 (d, J ) 7.5 Hz, 1H), 8.46 (s,

1H), 8.30 (d, J ) 7.5 Hz, 1H), 8.18 (d, J ) 7.0 Hz, 1H), 8.05 (m,

2H), 7.82 (d, J ) 7.5 Hz, 1H), 7.62 (m, 5H), 3.21 (m, 3H), 2.90

(m, 2H), 1.80 (m, 2H), 1.60 (m, 2H); LC/MS m/z 410 [M + H]⁺;

HRMS calcd for C₂₂H₂₃N₃O₃S [M + H]⁺, 410.1538; found,

410.1543.

Sulfonamides 6f and 6g. These compounds were prepared

according to general procedure A from the appropriate starting

materials.

4-(4-Benzoylamino-naphthalene-1-sulfonylamino)-piperidine-

1-carboxylic Acid tert-Butyl Ester (6f). ¹H NMR (300 MHz, CD₃-

OD) δ 8.75 (d, J ) 7.5 Hz, 1H), 8.30 (d, J ) 7.5 Hz, 1H), 8.18 (d,

J ) 7.0 Hz, 1H), 8.05 (m, 2H), 7.82 (d, J ) 7.5 Hz, 1H), 7.62 (m,

5H), 3.82 (d, J ) 15.0 Hz, 2H), 3.25 (m, 1H), 2.75 (m, 2H), 1.55

(m, 2H), 1.35 (s, 9H), 1.25 (m, 2H); LC/MS m/z 510 [M + H]⁺;

HRMS calcd for C₂₇H₃₁N₃O₅S [M + H]⁺, 510.2062; found,

510.2048.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]methyl}-1-naphthyl)-

2-methylbenzamide (11). Step 1. To a solution of 10 (289 mg,

1.00 mmol) in MeOH (10 mL) were added tert-butyl 4-aminopi-

peridine-1-carboxylate (268 mg, 1.34 mmol) and sodium triac-

etoxyborohydride (318 mg, 1.50 mmol). The reaction mixture was

stirred at 25 °C for 17 h, at which time the solution was concentrated

in Vacuo, and the resulting residue was diluted with EtOAc and

washed with water (1×). The organic layer was dried over MgSO₄,

filtered, and concentrated to provide the desired N-Boc-protected

intermediate, which was used without further purification; LCMS

m/z 474 [M + H]⁺. The above intermediate was next stirred in 4

M HCl/dioxane (5.0 mL) at 25 °C for 5 h, at which point removal

of the solvent in Vacuo provided 2-methyl-N-{4-[(piperidin-4-

ylamino)methyl]-1-naphthyl}benzamide as the corresponding HCl

salt; LCMS m/z 374 [M + H]⁺. Step 2. To a mixture of the above

intermediate in CH₂Cl₂(10 mL) were added Et₃N (0.417 mL, 3.00

mmol) and butanoyl chloride (0.157 mL, 1.50 mmol). The reaction

mixture was stirred at 25 °C for 17 h. Subsequent aqueous workup,

concentration of the resulting organic layer, and purification via

reverse phase HPLC then afforded 11 as a white solid (113 mg,

4-(4-Benzoylamino-naphthalene-1-sulfonylamino)-piperidine-

1

1-carboxylic Acid Ethyl Ester (6g). H NMR (300 MHz, CD₃-

OD) δ 8.75 (d, J ) 7.5 Hz, 1H), 8.30 (d, J ) 7.5 Hz, 1H), 8.18 (d,

J ) 7.0 Hz, 1H), 8.05 (m, 2H), 7.82 (d, J ) 7.5 Hz, 1H), 7.62 (m,

5H), 4.02 (q, J ) 7.1 Hz, 2H), 3.82 (d, J ) 15.0 Hz, 2H), 3.25 (m,

1H), 2.75 (m, 2H), 1.55 (m, 2H), 1.25 (m, 2H), 1.18 (t, J ) 7.1

Hz, 3H); LC/MS m/z 482 [M + H]⁺; HRMS calcd for C₂₅H₂₇N₃O₅S

[M + H]⁺, 482.1749; found, 482.1766.

N-(4-Bromo-1-naphthyl)-2-methylbenzamide (7). To solution

of 4-bromonaphthalen-1-amine (1.01 g, 45.0 mmol) in THF (100

mL) were added pyridine (9.1 mL, 113 mmol) and 2-methyl-

benzoyl chloride (7.0 mL, 54.0 mmol). The reaction mixture was

stirred at 25 °C for 17 h, at which point the solvent was removed

in Vacuo. The crude mixture was then triturated by addition of

toluene and filtration of the resulting solid, which was washed with

1

yield 28%). H NMR (300 MHz, CD₃OD) δ 8.21 (d, J ) 8.1 Hz,

1H), 8.12 (d, J ) 7.5 Hz, 1H), 7.62 (m, 5H), 7.40 (m, 3H), 4.49

(d, J ) 12.9 Hz, 1H), 4.31 (s, 2H), 3.98 (d, J ) 13.5 Hz, 1H), 3.14

576 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3

Jenkins et al.

(m, 1H), 2.93 (m, 1H), 2.74 (t, J ) 12.0 Hz, 1H), 2.57 (s, 3H),

2.38 (m, 2H), 2.07 (m, 2H), 1.63 (m, 2H), 1.36 (m, 2H), 0.98 (m,

3H); LC/MS m/z 444 [M + H]⁺; HRMS calcd for C₂₈H₃₃N₃O₂[M

+ H]⁺, 444.2651; found, 444.2662.

(m, 1H), 3.25 (m, 1H), 2.94 (m, 1H), 2.62 (m, 1H), 2.18 (m, 2H),

1.73 (m, 1H), 1.54 (m, 3H), 1.20 (m, 3H), 0.88 (t, J ) 7.5 Hz,

3H); LC/MS m/z 376 [M + H]⁺.

General Procedure B. N-(4-{[(1-Butyrylpiperidin-4-yl)amino]-

sulfonyl}-1-naphthyl)benzamide (14a). To a vial containing

benzoyl chloride (0.046 mL, 0.40 mmol) were added a solution of

13 (45 mg, 0.12 mmol) in 1,2-dichloroethane (0.6 mL), pyridine

(0.6 mL), and 4-(dimethylamino)pyridine (2.81 mg, 0.023 mmol).

After being shaken at 100 °C for 3 h, the solution was concentrated

in Vacuo to provide a crude residue, which was partitioned between

saturated aqueous sodium bicarbonate (2.0 mL) and CH₂Cl₂(3 mL).

The aqueous layer was further extracted with CH₂Cl₂(1×), and

the combined organic layers were dried over MgSO₄, filtered, and

concentrated. Purification by HPLC provided 14a (0.020 g, 35%)

as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.79 (s, 1H), 8.62

(d, J ) 7.6 Hz, 1H), 8.22 (d, J ) 8.2 Hz, 1H), 8.12 (d, J ) 8.3 Hz,

1H), 8.02 (m, 3H), 7.59 (m, 5H), 5.21 (d, J ) 7.6 Hz, 1H), 4.17

(d, J ) 14.7 Hz, 1H), 3.61 (d, J ) 13.9 Hz, 1H), 3.28 (m, 1H),

2.92 (t, J ) 11.5 Hz, 1H), 2.54 (t, J ) 11.1 Hz, 1H), 2.18 (t, J )

7.9 Hz, 2H), 1.76 (d, J ) 12.1 Hz, 1H), 1.55 (m, 3H), 1.21 (q, J

) 11.0 Hz, 1H), 1.05 (q, J ) 11.1 Hz, 1H), 0.89 (t, J ) 7.3 Hz,

3H); LC/MS m/z 480 [M + H]⁺; HRMS calcd for C₂₆H₂₉N₃O₄S

[M + H]⁺, 480.1957; found, 480.1935.

N-(1-Butyrylpiperidin-4-yl)-4-(1,3-dioxo-1,3-dihydro-2H-isoin-

dol-2-yl)naphthalene-1-sulfonamide (12). This compound was

prepared according to the five-step sequence outlined below.

Step 1. 4-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)naphtha-

lene-1-sulfonic Acid Pyridinium Salt. To a solution of 4-amino-

naphthalene-1-sulfonic acid (4.9 g 10.0 mmol) in pyridine (15 mL)

was added phthaloyl dichloride (3.2 mL, 22 mmol), and the resultant

solution was stirred at 80 °C for 17 h. The solvent was removed in

Vacuo, and the crude material was recrystallized from MeOH (2×)

1

to provide the title compound (2.0 g) as a gray solid. H NMR

(300 MHz, DMSO-d₆) δ 8.90 (m, 2H), 8.57 (m, 1H), 8.00 (m, 7H),

7.77 (d, J ) 8.4 Hz, 1H), 7.58 (m, 2H), 7.49 (m, 2H).

Step 2. 4-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)naphtha-

lene-1-sulfonyl Chloride. To a solution of the sulfonic acid

generated in Step 1 (2.0 g 4.6 mmol) in DMF (10 mL) was added

thionyl chloride (0.5 mL, 6.95 mmol). The resultant solution was

stirred at 25 °C for 3 h. The reaction was then quenched by pouring

into ice water, and this mixture was directly filtered to provide the

title compound (1.4 g) as a pale white solid, which was used without

1

Amides 14b-14v. These compounds were prepared according

to general procedure B from the appropriate starting materials.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

further purification. H NMR (300 MHz, DMSO-d₆) δ 8.95 (d,

J ) 8.4 Hz, 1H), 8.00 (m, 5H), 7.73 (d, J ) 8.3 Hz, 1H), 7.58 (m,

2H), 7.49 (m, 1H).

1

2-methylbenzamide (14b). H NMR (300 MHz, CD₃OD) δ 8.78

Step 3. tert-Butyl 4-(1-(1,3-Dioxoisoindolin-2-yl)naphthalene-

4-sulfonamido)piperidine-1-carboxylate. To a solution of the

sulfonyl chloride generated in Step 2 (1.11 g, 3.0 mmol) in CH₂-

Cl₂(30 mL) were added tert-butyl 4-aminopiperidine-1-carboxylate

(600 mg, 3.00 mmol) and Et₃N (1.25 mL, 9.00 mmol). The resultant

solution was stirred at 25 °C for 3 h, at which point the reaction

mixture was quenched with water and extracted with CH₂Cl₂(3×).

The solvent was removed in Vacuo to provide the title compound

as a pale white solid, which was used without further purification.

LC/MS m/z 536 [M + H]⁺.

Step 4. 4-(1,3-Dioxoisoindolin-2-yl)-N-(piperidin-4-yl)naph-

thalene-1-sulfonamide. To a solution of the product from Step 3

(1.60 g, 3.0 mmol) in MeOH (20 mL) was added HCl as a 1 N

solution in diethyl ether (35 mL, 35.0 mmol). The resultant solution

was stirred at 25 °C for 3 h, at which point the solvent was removed

in Vacuo to provide the title compound (665 mg) as a white solid,

which was used without further purification. LC/MS m/z 436

[M + H]⁺.

Step 5. N-(1-Butyrylpiperidin-4-yl)-4-(1,3-dioxoisoindolin-2-

yl)naphthalene-1-sulfonamide (12). To a solution of the sulfona-

mide from Step 4 (665 mg, 1.53 mmol) in CH₂Cl₂(20 mL) were

added butyl chloride (159 µL, 1.53 mmol) and Et₃N (639 µL, 4.59

mmol). The resultant solution was stirred at 25 °C for 3 h, at which

point the reaction was quenched with water and extracted with CH₂-

Cl₂(3×). The combined organic layers were dried over MgSO₄,

filtered, and concentrated. Purification by column chromatography

(hexane/ethyl acetate, 60/40 as eluent) afforded the desired

compound 12 (410 mg, 53%) as a white solid. ¹H NMR (300 MHz,

CDCl₃) δ 8.72 (d, J ) 9.0 Hz, 1H), 8.38 (d, J ) 7.8 Hz, 1H), 8.03

(m, 2H), 7.87 (m, 2H), 7.67 (m, 3H), 7.53 (d, J ) 7.5 Hz, 1H),

5.43 (d, J ) 7.8 Hz, 1H), 4.30 (m, 1H), 3.67 (m, 1H), 3.41 (m,

1H), 2.99 (m, 1H), 2.70 (m, 1H), 2.22 (m, 2H), 1.79 (m, 1H), 1.58

(m, 2H), 1.34 (m, 2H), 0.90 (t, J ) 7.2 Hz, 3H); LC/MS m/z 506

[M + H]⁺.

4-Amino-N-(1-butyrylpiperidin-4-yl)naphthalene-1-sulfona-

mide (13). To a solution of 12 (380 mg, 0.752 mmol) in MeOH

(5.00 mL) was added hydrazine (119 µL, 3.76 mmol), at which

point precipitation was observed, signaling completion of the

reaction. The solvent was removed in Vacuo, and the crude product

was dissolved in CH₂Cl₂and washed with water (3×). The organic

layer was dried over MgSO₄, filtered, and concentrated to provide

the title compound (275 mg, 97%) as a white solid. ¹H NMR (300

MHz, CDCl₃) δ 8.55 (d, J ) 8.7 Hz, 1H), 8.09 (d, J ) 8.1 Hz,

1H), 7.85 (d, J ) 7.5 Hz, 1H), 7.62 (m, 1H), 7.52 (m, 1H), 6.69

(d, J ) 8.1 Hz, 1H), 4.88 (d, J ) 7.2 Hz, 1H), 4.16 (m, 1H), 3.61

(m, 1H), 8.33 (m, 1H), 8.23 (m, 1H), 7.94 (m, 1H), 7.71 (m, 3H),

7.39 (m, 3H), 4.19 (m, 1H), 3.74 (m, 1H), 3.33 (m, 1H), 3.01 (m,

1H), 2.64 (m, 1H), 2.54 (s, 3H), 2.27 (t, J ) 7.5 Hz, 2H), 1.62 (m,

2H), 1.55 (m, 2H), 1.29 (m, 2H), 0.90 (t, J ) 7.5 Hz, 3H); LC/MS

[M + 1]⁺m/z 494; HRMS calcd for C₂₇H₃₁N₃O₄S [M + H]⁺,

494.2113; found, 494.2121.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

1

3-methylbenzamide (14c). H NMR (300 MHz, CDCl₃) δ 8.66

(d, J ) 7.8 Hz, 1H), 8.53 (s, 1H), 8.32 (s, 2H), 8.02 (d, J ) 7.6

Hz, 1H), 7.81 (m, 2H), 7.70 (m, 2H), 7.46 (d, J ) 4.1 Hz, 2H),

4.77 (d, J ) 7.62 Hz, 1H), 4.25 (d, J ) 13.5 Hz, 1H), 3.65 (d, J )

13.9 Hz, 1H), 3.33 (m, 1H), 2.96 (t, J ) 13.3 Hz, 1H), 2.57 (t, J

) 12.6 Hz, 1H), 2.49 (s, 3H), 2.20 (t, J ) 7.1 Hz, 2H), 1.80 (d, J

) 12.7 Hz, 1H), 1.57 (m, 3H), 1.20 (m, 2H), 0.90 (t, J ) 7.2 Hz,

3H); LC/MS m/z 494 [M + H]⁺; HRMS calcd for C₂₇H₃₁N₃O₄S

[M + H]⁺, 494.2113; found, 494.2137.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

1

4-methylbenzamide (14d). H NMR (300 MHz, CDCl₃) δ 8.91

(s, 1H), 8.59 (d, J ) 7.7 Hz, 1H), 8.14 (d, J ) 8.3 Hz, 1H), 7.96

(t, J ) 8.8 Hz, 4H), 7.56 (quin, J ) 6.6 Hz, 2H), 7.32 (d, J ) 8.4

Hz, 1H), 5.58 (d, J ) 7.6 Hz, 1H), 4.11 (d, J ) 13.5 Hz, 1H), 3.56

(d, J ) 14 Hz, 1H), 3.24 (m, 1H), 2.87 (t, J ) 11.6 Hz, 1H), 2.50

(t, J ) 11.8 Hz, 1H), 2.45 (s, 3H), 2.14 (t, J ) 7.7 Hz, 2H), 1.69

(d, J ) 10.5 Hz, 1H), 1.52 (m, 2H), 1.17 (q, J ) 10.6 Hz, 1H),

0.99 (q, J ) 10.5 Hz, 1H), 0.87 (t, J ) 7.4 Hz, 3H); LC/MS m/z

494 [M + H]⁺; HRMS calcd for C₂₇H₃₁N₃O₄S [M + H]⁺, 494.2113;

found, 494.2105.

N-[4-(1-Butyryl-piperidin-4-ylsulfamoyl)-naphthalen-1-yl]-2-

fluoro-benzamide (14e). ¹H NMR (300 MHz, DMSO-d₆) δ 10.73

(s, 1H), 8.69 (dd, J ) 8.4, 1.8 Hz, 1H), 8.28 (dd, J ) 7.2, 2.7 Hz,

1H), 8.21 (d, J ) 7.1 Hz, 1H), 8.11 (d, J ) 8.4 Hz, 1H), 7.99 (d,

J ) 8.1 Hz, 1H), 7.83 (m, 1H), 7.76 (m, 2H), 7.64 (m, 1H), 7.40

(m, 2H), 4.00 (m, 1H), 3.59 (m, 1H), 3.26 (m, 1H), 2.93 (m, 1H),

2.59 (m, 2H), 2.17 (t, J ) 7.5 Hz, 2H), 1.46 (m, 2H), 1.43 (m,

2H), 1.17 (m, 1H), 0.82 (t, J ) 7.5 Hz, 3H), LC/MS m/z 496 [M

- H]^-, 498 [M + H]⁺; HRMS calcd for C₂₆H₂₈FN₃O₄S [M + H]⁺,

498.1862; found, 498.1874.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

3-fluorobenzamide (14f). ¹H NMR (300 MHz, CDCl₃) δ 8.66 (d,

J ) 7.6 Hz, 1H), 8.50 (s, 1H), 8.31 (q, J ) 8.2 Hz, 2H), 8.01 (d,

J ) 7.6 Hz, 1H), 7.79 (d, J ) 8.9 Hz, 1H), 7.71 (m, 3H), 7.57 (q,

J ) 8.2 Hz, 1H), 7.35 (t, J ) 8.2 Hz, 1H), 4.67 (d, J ) 7.6 Hz,

1H), 4.26 (d, J ) 13.4 Hz, 1H), 3.74 (t, J ) 6.9 Hz, 1H), 3.66 (d,

J ) 15.4 Hz, 1H), 3.33 (m, 1H), 2.97 (t, J ) 12.9 Hz, 1H), 2.59 (t,

Naphthalene-Sulfonamide Antagonists of Human CCR8

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3 577

J ) 12.8 Hz, 1H), 2.20 (t, J ) 7.7 Hz, 2H), 1.85 (t, J ) 6.7 Hz,

1H), 1.79 (s, 1H), 1.90 (m, 1H), 1.27 (m, 1H), 1.13 (m, J ) Hz,

1H), 0.91 (t, J ) 7.3 Hz, 3H); LC/MS m/z 498 [M + H]⁺; HRMS

calcd for C₂₆H₂₈FN₃O₄S [M + H]⁺, 498.1862; found, 498.1886.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

4-fluorobenzamide (14g). ¹H NMR (300 MHz, CDCl₃/CD₃OD (1:

1)) δ 8.65 (d, J ) 7.6 Hz, 1H), 8.56 (s, 1H), 8.29 (d, J ) 8.2 Hz,

1H), 8.19 (d, J ) 8.2 Hz, 1H), 8.03 (m, 3H), 7.68 (m, 2H), 7.25 (t,

J ) 8.5 Hz, 1H), 4.82 (d, J ) 7.6 Hz, 1H), 4.23 (d, J ) 13.5 Hz,

1H), 3.64 (d, J ) 15.3 Hz, 1H), 3.32 (m, 1H), 2.95 (t, J ) 11.6

Hz, 1H), 2.57 (t, J ) 11.7 Hz, 1H), 2.20 (t, J ) 7.6 Hz, 2H), 1.85

(m, 5H), 1.24 (m, 1H), 1.11 (m, 1H), 0.90 (t, J ) 7.3 Hz, 3H);

LC/MS m/z 498 [M + H]⁺; HRMS calcd for C₂₆H₂₈FN₃O₄S [M +

H]⁺, 498.1862; found, 498.1853.

7.9 Hz, 1H), 8.31 (m, 2H), 8.17 (d, J ) 7.7 Hz, 1H), 7.75 (m, 4H),

7.03 (s, 1H), 4.18 (d, J ) 13.2 Hz, 1H), 3.74 (d, J ) 13.2 Hz, 1H),

3.35 (m, 1H), 3.03 (m, 1H), 2.67 (m, 1H), 2.27 (m, 2H), 1.55 (m,

4H), 1.32 (m, 2H), 0.90 (m, 3H); LC/MS m/z 470 [M + H]⁺; calcd

for C₂₄H₂₇N₃O₅S [M + H]⁺, 470.1749; found, 470.1765.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

1-benzothiophene-2-carboxamide (14n). ¹H NMR (300 MHz,

CDCl₃) δ 8.79 (s, 1H), 8.62 (m, 1H), 8.23 (d, J ) 8.1 Hz, 1H),

8.15 (d, J ) 9.9 Hz, 2H), 8.04 (m, 1H), 7.92 (m, 2H), 7.66 (m,

2H), 7.49 (m, 2H), 4.98 (d, J ) 7.7 Hz, 1H), 4.20 (d, J ) 13.6 Hz,

1H), 3.63 (d, J ) 14.3 Hz, 1H), 3.29 (m, 1H), 2.92 (m, 1H), 2.54

(m, 1H), 2.19 (t, J ) 7.6 Hz, 2H), 1.76 (m, 1H), 1.59 (m, 3H),

1.22 (m, 1H), 1.05 (m, 1H), 0.90 (t, J ) 7.4 Hz, 3H); LC/MS m/z

536 [M + H]⁺; HRMS calcd for C₂₈H₂₉N₃O₄S₂[M + H]⁺,

536.1677; found, 536.1666.

3-tert-Butyl-N-(4-{[(1-butyrylpiperidin-4-yl)amino]sulfonyl}-

1-naphthyl)-1-methyl-1H-pyrazole-5-carboxamide (14o). ¹H NMR

(400 MHz, DMSO-d₆) δ 8.66 (m, 1H), 8.40 (s, 1H), 8.29 (d, J )

8.3 Hz, 1H), 8.15 (d, J ) 8.2 Hz, 1H), 7.99 (m, 1H), 7.70 (m, 2H),

6.72 (s, 1H), 4.79 (d, J ) 7.6 Hz, 1H), 4.20 (s, 3H), 3.64 (d, J )

13.4 Hz, 1H), 3.31 (m, 1H), 2.95 (m, 1H), 2.54 (m, 1H), 2.20 (t, J

) 7.6 Hz, 2H), 1.80 (m, 1H), 1.59 (m, 3H), 1.38 (s, 9H), 1.29 (s,

1H), 1.25 (s, 1H), 1.08 (m, 1H), 0.91 (t, J ) 7.4 Hz, 3H); LC/MS

m/z 540 [M + H]⁺; HRMS calcd for C₂₈H₃₇N₅O₄S [M + H]⁺,

540.2644; found, 540.2647.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

1

4-ethylbenzamide (14h). H NMR (300 MHz, CDCl₃) δ 8.66 (d,

J ) 7.6 Hz, 1H), 8.54 (s, 1H), 8.32 (s, 2H), 8.01 (d, J ) 7.7 Hz,

1H), 7.94 (d, J ) 8.2 Hz, 2H), 7.69 (m, 2H), 7.40 (d, J ) 8.2 Hz,

2H), 4.75 (d, J ) 7.7 Hz, 1H), 4.25 (d, J ) 13.5 Hz, 1H), 3.65 (d,

J ) 15.2 Hz, 1H), 3.34 (m, 1H), 2.96 (t, J ) 12.9 Hz, 1H), 2.77

(q, J ) 7.6 Hz, 2H), 2.59 (t, J ) 12.7 Hz, 1H), 2.20 (t, J ) 7.6 Hz,

2H), 1.83 (m, 2H), 1.58 (m, 2H), 1.31 (t, J ) 7.6 Hz, 3H), 1.17

(m, 2H), 0.90 (t, J ) 7.3 Hz, 3H); LC/MS m/z 508 [M + H]⁺;

HRMS calcd for C₂₈H₃₃N₃O₄S [M + H]⁺, 508.2270; found,

508.2283.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

5-methyl-2-(trifluoromethyl)-3-furamide (14p). H NMR (300

4-Butyl-N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-

naphthyl)benzamide (14i). H NMR (300 MHz, CDCl₃) δ 8.89

1

MHz, CD₃OD) δ 8.75 (d, J ) 8.4 Hz, 1H), 8.32 (m, J ) 6.9 Hz,

1H), 8.17 (d, J ) 7.3 Hz, 1H), 7.86 (d, J ) 7.3 Hz, 1H), 7.73 (m,

2H), 6.74 (s, 1H), 4.16 (m, 1H), 3.71 (m, 1H), 3.35 (m, 1H), 3.03

(m, 1H), 2.66 (m, 1H), 2.45 (s, 3H), 2.27 (m, 2H), 1.54 (m, 4H),

1.30 (m, 2H), 0.91 (m, 3H); LC/MS m/z 552 [M + H]⁺; calcd for

C₂₆H₂₈F₃N₃O₅S [M + H]⁺, 552.1780; found, 552.1758.

(s, 1H), 8.60 (d, J ) 8.3 Hz, 1H), 8.15 (d, J ) 8.3 Hz, 1H), 7.98

(m, 4H), 7.56 (m, 2H), 7.34 (d, J ) 8.3 Hz, 2H), 5.54 (d, J ) 8.2

Hz, 1H), 4.12 (d, J ) 13.6 Hz, 1H), 3.57 (d, J ) 13.5 Hz, 1H),

3.25 (m, 1H), 2.88 (t, J ) 11.4 Hz, 1H), 2.71 (t, J ) 7.6 Hz, 2H),

2.50 (t, J ) 10.9 Hz, 1H), 2.14 (t, J ) 8.4 Hz, 2H), 1.64 (m, 3H),

1.53 (m, 3H), 1.88 (m, 2H), 1.17 (m, 1H), 1.01 (m, 1H), 0.95 (t, J

) 7.4 Hz, 3H), 0.87 (t, J ) 7.2 Hz, 3H); LC/MS m/z 536 [M +

H]⁺; HRMS calcd for C₃₀H₃₇N₃O₄S [M + H]⁺, 536.2583; found,

536.2588.

4-tert-Butyl-N-(4-{[(1-butyrylpiperidin-4-yl)amino]sulfonyl}-

1-naphthyl)benzamide (14j). ¹H NMR (300 MHz, CDCl₃) δ 8.85

(d, J ) 2.7 Hz, 1H), 8.61 (d, J ) 9.3 Hz, 1H), 8.17 (d, J ) 8.2 Hz,

1H), 8.02 (m, 4H), 7.59 (m, 4H), 5.44 (t, J ) 7.3 Hz, 1H), 4.14 (d,

J ) 13.5 Hz, 1H), 3.58 (d, J ) 13.9 Hz, 1H), 3.26 (m, 1H), 2.89

(t, J ) 11.3 Hz, 1H), 2.52 (t, J ) 11.3 Hz, 1H), 2.15 (t, J ) 7.6

Hz, 2H), 1.73 (m, 2H), 1.53 (m, 2H), 1.38 (s, 9H), 1.22 (m, 1H),

1.03 (m, 1H), 0.88 (t, J ) 7.3 Hz, 3H); LC/MS m/z 536 [M +

H]⁺; HRMS calcd for C₃₀H₃₇N₃O₄S [M + H]⁺, 536.2583; found,

536.2557.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

1-methyl-1H-imidazole-2-carboxamide (14q). ¹H NMR (300

MHz, DMSO-d₆) δ 10.66 (s, 1H), 8.69 (m, 1H), 8.11 (m, 4H),

7.74 (m, 2H), 7.51 (m, 1H), 7.17 (m, 1H), 4.02 (m, 4H), 3.62 (m,

1H), 3.23 (m, 1H), 2.92 (m, 1H), 2.59 (m, 1H), 2.16 (m, 2H), 1.55

(m, 4H), 1.22 (m, 2H), 0.80 (m, 3H); LC/MS m/z 484 [M + H]⁺;

calcd for C₂₄H₂₉N₅O₄S [M + H]⁺, 484.2018; found, 484.2023.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

2-chloro-6-methylisonicotinamide (14r). LC/MS m/z 530.059 [M

+ H]⁺; C₂₆H₂₉ClN₄O₄S, found 529.13; HRMS calcd for C₂₆H₂₉-

ClN₄O₄S [M + H]⁺, 529.1676; found, 529.1701.

N-[4-(1-Butyryl-piperidin-4-ylsulfamoyl)-naphthalen-1-yl]-2-

1

methyl-nicotinamide (14s). H NMR (300 MHz, DMSO-d₆) δ

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

4-pentylbenzamide (14k). ¹H NMR (300 MHz, CDCl₃) δ 8.89 (s,

1H), 8.59 (d, J ) 8.2 Hz, 1H), 8.15 (d, J ) 8.2 Hz, 1H), 7.99 (t,

J ) 8 Hz, 3H), 7.56 (m, 2H), 7.33 (d, J ) 7.7 Hz, 2H), 5.54 (d,

J ) 7.6 Hz, 1H), 4.11 (d, J ) 13.4 Hz, 1H), 3.56 (d, J ) 13.4 Hz,

1H), 3.24 (m, 1H), 2.87 (t, J ) 11.8 Hz, 1H), 2.69 (t, J ) 7.6 Hz,

2H), 2.50 (t, J ) 11.4 Hz, 1H), 2.14 (t, J ) 7.6 Hz, 2H), 1.66 (m,

3H), 1.52 (m, 3H), 1.34 (m, 4H), 1.17 (q, J ) 10.6, 1H), 1.01 (q,

J ) 10.4, Hz, 1H), 0.88 (m, 7H); LC/MS m/z 550 [M + H]⁺;

HRMS calcd for C₂₇H₃₁N₃O₄S [M + H]⁺, 550.2739; found,

550.2758.

4-(Benzyloxy)-N-(4-{[(1-butyrylpiperidin-4-yl)amino]sulfonyl}-

1-naphthyl)benzamide (14l). ¹H NMR (300 MHz, CDCl₃) δ 8.93

(s, 1H), 8.57 (d, J ) 8 Hz, 1H), 8.10 (d, J ) 8.3 Hz, 1H), 8.02 (d,

J ) 9.4 Hz, 2H), 7.96 (d, J ) 8.7 Hz, 1H), 7.90 (d, J ) 8.3 Hz,

1H), 7.53 (m, 2H), 7.40 (m, 5H), 7.07 (d, J ) 8.9 Hz, 2H), 5.65

(d, J ) 7.6 Hz, 1H), 5.14 (s, 2H), 4.09 (d, J ) 13.5 Hz, 1H), 3.54

(d, J ) 13.7 Hz, 1H), 3.25 (m, 1H), 2.85 (t, J ) 11.5 Hz, 1H),

2.47 (t, J ) 11.2 Hz, 1H), 2.13 (t, J ) 7.4 Hz, 2H), 1.67 (d, J )

10.5 Hz, 1H), 1.53 (m, 2H), 1.44 (d, J ) 13.5 Hz, 1H), 1.14 (m,

1H), 0.93 (m, 1H), 0.87 (t, J ) 7.3 Hz, 3H); LC/MS m/z 586 [M

+ H]⁺; HRMS calcd for C₃₃H₃₅N₃O₅S [M + H]⁺, 586.2375; found,

586.2363.

10.76 (s, 1H), 8.68 (d, J ) 8.7 Hz, 1H), 8.59 (d, J ) 4.2 Hz, 1H),

8.31 (d, J ) 7.8 Hz, 1H), 8.24 (d, J ) 7.8 Hz, 1H), 8.10 (d, J )

7.5 Hz, 1H), 8.04 (d, J ) 7.2 Hz, 1H), 7.98 (d, J ) 8.1 Hz, 1H),

7.73 (m, 2H), 7.41 (m, 1H), 4.00 (d, J ) 13.5 Hz, 1H), 3.61 (d, J

) 13.5 Hz, 1H), 3.23 (m, 1H), 2.93 (t, J ) 11.7 Hz, 1H), 2.66 (s,

3H), 2.59 (m, 1H), 2.17 (t, J ) 10.2 Hz, 2H), 1.48 (m, 2H), 1.43

(m, 2H), 1.19 (m, 2H), 0.82 (t, J ) 7.2 Hz, 3H); LC/MS m/z 493

[M - H]^-, 495 [M + H]⁺; HRMS calcd for C₂₆H₃₀N₄O₄S [M +

H]⁺, 495.2066; found, 495.2075.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

pyrazine-2-carboxamide (14t). LC/MS m/z 482 [M + H]⁺; HRMS

calcd for C₂₄H₂₇N₅O₄S [M + H]⁺, 482.1862; found, 482.1857.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

pyridine-2-carboxamide (14u). LC/MS m/z 481 [M + H]⁺;

C₂₅H₂₈N₄O₄S, found 481.18; HRMS calcd for C₂₅H₂₈N₄O₄S [M +

H]⁺, 481.1909; found, 481.1933.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

1

nicotinamide (14v). H NMR (300 MHz, CDCl₃) δ 9.44 (d, J )

11.8 Hz, 2H), 8.81 (d, J ) 4.6 Hz, 1H), 8.58 (d, J ) 8.5 Hz, 1H),

8.42 (d, J ) 8.4 Hz, 1H), 8.03 (d, J ) 8.4 Hz, 1H), 7.93 (d, J )

8.1 Hz, 1H), 7.66 (d, J ) 8.4 Hz, 1H), 7.58 (t, J ) 7.7 Hz, 1H),

7.50 (t, J ) 6.8 Hz, 2H), 6.27 (d, J ) 7.7 Hz, 1H), 4.12 (d, J )

13.4 Hz, 1H), 3.56 (d, J ) 13.5 Hz, 1H), 3.14 (m, 1H), 2.84 (t, J

) 11.4 Hz, 1H), 2.42 (t, J ) 11.4 Hz, 1H), 2.16 (m, 2H), 1.69 (m,

1H), 1.55 (m, 2H), 1.39 (m, 1H), 1.24 (s, 1H), 1.09 (m, 1H), 0.88

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

1

3-furamide (14m). H NMR (300 MHz, CD₃OD) δ 8.75 (d, J )

578 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3

Jenkins et al.

(m, 3H); LC/MS m/z 481 [M + H]⁺; HRMS calcd for C₂₅H₂₈N₄O₄S

[M + H]⁺, 481.1909; found, 481.1907.

8.29 (dd, J ) 8.1, 2.1 Hz, 1H), 8.14 (d, J ) 8.1 Hz, 1H), 8.05 (d,

J ) 7.8 Hz, 1H), 7.89 (d, J ) 8.1 Hz, 1H), 7.72 (m, 2H), 3.62 (m,

2H), 3.40 (m, 2H), 3.15 (m, 1H), 2.95 (m, 2H), 2.78-2.67 (m,

6H), 2.17 (m, 2H), 2.09 (m, 2H), 2.0 (m, 2H), 1.84 (m, 1H), 1.43

(m, 2H), 1.39 (m, 1H), 1.18 (m, 2H), 0.82 (t, J ) 7.2 Hz, 3H);

LC/MS m/z 501 [M + H]⁺; HRMS calcd for C₂₆H₃₆N₄O₄S [M +

H]⁺, 501.2535; found, 501.2533.

Tetrahydro-pyran-4-carboxylic Acid [4-(1-Butyryl-piperidin-

4-ylsulfamoyl)-naphthalen-1-yl]-amide (14dd). ¹H NMR (300

MHz, DMSO-d₆) δ 10.12 (s, 1H), 8.65 (d, J ) 7.5 Hz, 1H), 8.27

(d, J ) 7.5 Hz, 1H), 8.15 (d, J ) 8.1 Hz, 1H), 8.04 (d, J ) 7.8 Hz,

1H), 7.93 (d, J ) 8.1 Hz, 1H), 7.71 (m, 2H), 3.97 (m, 3H), 3.61

(m, 1H), 3.40 (m, 2H), 3.19 (m, 1H), 2.90 (m, 2H), 2.56 (m, 1H),

2.15 (t, J ) 7.5 Hz, 2H), 1.82 (m, 2H), 1.74 (m, 2H), 1.42 (m,

4H), 1.13 (m, 2H), 0.81 (t, J ) 7.5 Hz, 3H); LC/MS m/z 488 [M

+ H]⁺; HRMS calcd for C₂₅H₃₃N₃O₅S [M + H]⁺, 488.2219; found,

488.2209.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

2-ethylbutanamide (14ee). LC/MS m/z 474 [M + H]⁺; C₂₅H₃₅N₃O₄S

found, 474.18; HRMS calcd for C₂₅H₃₅N₃O₄S [M + H]⁺, 474.2426;

found, 474.2422.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

3,3-dimethylbutanamide (14ff). ¹H NMR (300 MHz, DMSO-d₆)

δ 10.05 (s, 1H), 8.64 (m, 1H), 8.26 (m, 1H), 8.14 (d, J ) 7.6 Hz,

1H), 8.05 (d, J ) 7.8 Hz, 1H), 7.94 (m, 1H), 7.70 (m, 2H), 3.98

(m, 1H), 3.60 (m, 1H), 3.20 (m, 1H), 2.90 (m, 1H), 2.56 (m, 1H),

2.41 (s, 2H), 2.15 (t, J ) 7.3 Hz, 2H), 1.41 (m, 4H), 1.20 (m, 2H),

1.08 (s, 9H), 0.80 (t, J ) 7.3 Hz, 3H); LC/MS m/z 474 [M + H]⁺;

HRMS calcd for C₂₅H₃₅N₃O₄S [M + H]⁺, 474.2426; found,

474.2420.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

2-phenylbutanamide (14gg). ¹H NMR (300 MHz, CDCl₃) δ 8.53

(d, J ) 8.0 Hz, 1H), 8.21 (m, 2H), 7.80 (s, 1H), 7.59 (t, J ) 7.6

Hz, 1H), 7.46 (m, 5H), 7.41 (m, 1H), 7.31 (m, 1H), 4.68 (d, J )

7.7 Hz, 1H), 4.21 (m, 1H), 3.64 (m, 2H), 3.25 (m, 1H), 2.93 (m,

1H), 2.55 (m, 1H), 2.40 (m, 1H), 2.18 (t, J ) 7.6 Hz, 2H), 1.98

(m, 1H), 1.74 (m, 1H), 1.56 (m, 3H), 1.37 (s, 1H), 1.21 (m, 1H),

0.99 (t, J ) 7.6 Hz, 3H), 0.89 (t, J ) 7.3 Hz, 3H); LC/MS m/z 522

[M + H]⁺; HRMS calcd for C₂₉H₃₅N₃O₄S [M + H]⁺, 522.2426;

found, 522.2427.

4-[4-(2-Methyl-benzoylamino)-naphthalene-1-sulfonylamino]-

piperidine-1-carboxylic Acid Ethyl Ester (15). The title compound

was prepared following general procedure A, using 2-methyl

benzoyl chloride instead of benzoyl chloride in Step 1 and using

4-amino-piperidine-1-carboxylic acid ethyl ester instead of p-

anisidine in Step 3. Yield: 2.32 g (84%) of a white solid. ¹H NMR

(300 MHz, CD₃OD) δ 8.74 (d, J ) 8.54, 1H), 8.31 (d, J ) 8.1 Hz,

1H), 8.23 (d, J ) 8.1 Hz, 1H), 7.92 (d, J ) 7.7 Hz, 1H), 7.72 (m,

3H), 7.39 (m, 3H), 4.04 (q, J ) 7.3 Hz, 2H), 3.83 (m, 2H), 3.25

(m, 1H), 2.78 (m, 2H), 2.55 (s, 3H), 1.56 (m, 2H), 1.28 (m, 2H),

1.18 (t, J ) 7.3 Hz, 3H); LC/MS [M + H]⁺m/z 496; HRMS calcd

for C₂₆H₂₉N₃O₅S [M+H]⁺, 496.1906; found, 496.1914.

Ethyl 4-({[4-(Isonicotinoylamino)-1-naphthyl]sulfonyl}amino)-

piperidine-1-carboxylate (14w). Pyridine (0.5 mL) was added to

a sealed vial containing 13 (37.7 mg, 0.1 mmol) and isonicotinic

acid (12.3 mg, 0.1 mmol), and the resulting solution was cooled to

-78 °C. A solution of POCl₃(10.3 µL, 0.11 mmol) in CH₂Cl₂(90

µL) was then added to the sealed tube, and the resulting solution

was allowed to warm to 25 °C over 2 h. The resultant solution was

concentrated in Vacuo, at which point purification by HPLC

1

afforded the desired product (0.002 g, 4%) as a white solid. H

NMR (300 MHz, CDCl₃) δ 8.90 (d, J ) 6.1 Hz, 2H), 8.66 (d, J )

9.9 Hz, 1H), 8.55 (s, 1H), 8.32 (d, J ) 8.2 Hz, 1H), 8.24 (d, J )

8.2 Hz, 1H), 8.00 (m, 1H), 7.87 (d, J ) 6.5 Hz, 2H), 7.71 (m, 2H),

4.60 (d, J ) 7.5 Hz, 1H), 4.06 (q, J ) 7.2 Hz, 2H), 3.88 (m, 2H),

3.30 (m, 1H), 2.76 (m, 2H), 1.64 (m, 1H), 1.25 (m, 1H), 1.20 (m,

4H); LC/MS m/z 483 [M + H]⁺; HRMS calcd for C₂₄H₂₆N₄O₅S

[M + H]⁺, 483.1702; found, 483.1678.

Amides 14x-14gg. These compounds were prepared according

to general procedure B from the appropriate starting materials.

Cyclopropanecarboxylic Acid [4-(1-Butyryl-piperidin-4-yl-

1

sulfamoyl)-naphthalen-1-yl]-amide (14x). H NMR (300 MHz,

DMSO-d₆) δ 10.43 (s, 1H), 8.64 (m, 1H), 8.33 (m, 1H), 8.13 (d,

J ) 8.1 Hz, 1H), 8.02 (d, J ) 7.8 Hz, 1H), 7.98 (d, J ) 8.1 Hz,

1H), 7.73 (m, 2H), 3.98 (m, 1H), 3.59 (m, 1H), 3.19 (m, 1H), 2.90

(m, 1H), 2.61 (m, 1H), 2.13 (m, 3H), 1.40 (m, 4H), 1.16 (m, 2H),

0.88 (d, J ) 6.0 Hz, 4H), 0.80 (t, J ) 7.2 Hz, 3H); LC/MS m/z

442 [M - H]^-, 444 [M + H]⁺; HRMS calcd for C₂₃H₂₉N₃O₄S [M

+ H]⁺, 444.1957; found, 444.1977.

Cyclobutanecarboxylic Acid [4-(1-Butyryl-piperidin-4-ylsul-

famoyl)-naphthalen-1-yl]-amide (14y). ¹H NMR (300 MHz,

DMSO-d₆) δ 9.98 (s, 1H), 8.62 (d, J ) 8.4 Hz, 1H), 8.21 (d, J )

8.2 Hz, 1H), 8.12 (d, J ) 8.4 Hz, 1H), 7.99 (d, J ) 8.1 Hz, 1H),

7.95 (d, J ) 8.1 Hz, 1H), 7.70 (m, 2H), 3.59 (m, 2H), 3.51 (m,

1H), 3.13 (m, 1H), 2.67 (m, 2H), 2.24 (m, 4H), 2.16 (m, 2H), 1.99

(m, 1H), 1.84 (m, 1H), 1.42 (m, 2H), 1.37 (m, 2H), 1.10 (m, 2H),

0.81 (t, J ) 7.2 Hz, 3H); LC/MS m/z 457 [M- H]^-, 459 [M +

H]⁺; HRMS calcd for C₂₄H₃₁N₃O₄S [M + H]⁺, 458.2113; found,

458.2103.

Cyclopentanecarboxylic Acid [4-(1-Butyryl-piperidin-4-yl-

1

sulfamoyl)-naphthalen-1-yl]-amide (14z). H NMR (300 MHz,

DMSO-d₆) δ 10.12 (s, 1H), 8.66 (m, 1H), 8.34 (m, 1H), 8.13 (d, J

) 8.4 Hz, 1H), 7.95 (d, J ) 8.4 Hz, 1H), 7.71 (m, 2H), 3.98 (m,

1H), 3.59 (m, 1H), 3.19 (m, 1H), 3.09 (m, 1H), 2.90 (m, 1H), 2.57

(m, 1H), 2.16 (m, 2H), 1.94 (m, 2H), 1.81 (m, 2H), 1.71 (m, 2H),

1.62 (m, 2H), 1.40 (m, 4H), 1.16 (m, 2H), 0.81 (t, J ) 7.2 Hz,

3H); LC/MS m/z 471 [M - H]^-, 473 [M + H]⁺; HRMS calcd for

C₂₅H₃₃N₃O₄S [M + H]⁺, 472.2270; found, 472.2269.

N-(4-{[(1-Butyrylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

1

2-cyclopentylacetamide (14aa). H NMR (300 MHz, CDCl₃) δ

8.61 (d, J ) 8.9 Hz, 1H), 8.23 (d, J ) 8.2 Hz, 1H), 8.12 (d, J )

7.8 Hz, 1H), 7.92 (d, J ) 8.0 Hz, 2H), 7.63 (m, 2H), 4.87 (d, J )

7.7 Hz, 1H), 4.21 (d, J ) 13.4 Hz, 1H), 3.63 (d, J ) 13.9 Hz, 1H),

3.28 (m, 1H), 2.94 (m, 1H), 2.57 (m, 3H), 2.41 (m, 1H), 2.19 (t,

J ) 7.6 Hz, 2H), 1.96 (m, 2H), 1.69 (m, 4H), 1.57 (m, 4H), 1.29

(m, 3H), 1.09 (m, 1H), 0.89 (t, J ) 7.3 Hz, 3H); LC/MS m/z 486

[M + H]⁺; HRMS calcd for C₂₆H₃₅N₃O₄S [M + H]⁺, 486.2426;

found, 486.2424.

4-(4-Cyano-naphthalene-1-sulfonylamino)-piperidine-1-car-

boxylic Acid tert-Butyl Ester (17). This compound was prepared

in the following three steps. Step 1. 1-Fluoronaphthalene (20.0 g,

0.14 mol) was added in small portions to a stirred solution of

chlorosulfonic acid (79 g, 45 mL, 0.68 mol) at 25 °C. The reaction

mixture was stirred for 30 min until gas evolution ceased, at which

point it was poured carefully over a mixture of ice (300 g) and

CH₂Cl₂(300 mL). The organic layer was separated, washed with

water (2×) and brine (2×), and then dried over MgSO₄. Filtration

and concentration in Vacuo afforded 4-fluoro-naphthalene-1-sulfonyl

Cyclohexanecarboxylic Acid [4-(1-Butyryl-piperidin-4-ylsul-

famoyl)-naphthalen-1-yl]-amide (14bb). ¹H NMR (300 MHz,

DMSO-d₆) δ 10.05 (s, 1H), 8.64 (dd, J ) 7.2, 2.1 Hz, 1H), 8.25

(dd, J ) 7.2, 2.1 Hz, 1H), 8.13 (d, J ) 7.8 Hz, 1H), 8.03 (d, J )

8.1 Hz, 1H), 7.91 (d, J ) 8.1 Hz, 1H), 7.71 (m, 2H), 3.98 (m, 1H),

3.59 (m, 1H), 3.18 (m, 1H), 2.91 (m, 1H), 2.61 (m, 2H), 2.16 (m,

2H), 1.90 (m, 2H), 1.77 (m, 2H), 1.67 (m, 2H), 1.35 (m, 10H),

0.81 (t, J ) 7.2 Hz, 3H); LC/MS m/z 484 [M - H]^-, 486 [M +

H]⁺; HRMS calcd for C₂₆H₃₅N₃O₄S [M + H]⁺, 486.2426; found,

486.2437.

1

chloride 16 (27.6 g, 82%) as a tan solid. H NMR (300 MHz,

CDCl₃) δ 8.79 (m, 1H), 8.38 (m, 1H), 8.28 (m, 1H), 7.88 (m, 1H),

7.77 (m, 1H), 7.26 (m, 1H).

Step 2. To a solution of 16 (10.0 g, 40.9 mmol) in THF (100

mL) were added 4-amino-piperidine-1-carboxylic acid tert-butyl

ester (8.19 g, 40.9 mmol) and Et₃N (4.14 g, 5.75 mL, 40.9 mmol).

The reaction mixture was stirred at 25 °C for 17 h, at which point

the solvent was removed in Vacuo. CH₂Cl₂(250 mL) was added,

and the organic layer was washed with water (2×) and brine (2×)

1-Methyl-piperidine-4-carboxylic Acid [4-(1-Butyryl-piperi-

din-4-ylsulfamoyl)-naphthalen-1-yl]-amide (14cc). ¹H NMR (300

MHz, DMSO-d₆) δ 10.39 (s, 1H), 8.64 (dd, J ) 8.4, 1.8 Hz, 1H),

Naphthalene-Sulfonamide Antagonists of Human CCR8

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3 579

and then dried over MgSO₄. Filtration and concentration in Vacuo

afforded 4-(4-fluoro-naphthalene-1-sulfonylamino)-piperidine-1-

carboxylic acid tert-butyl ester as a yellow foam (15.1 g, 90%). ¹H

NMR (300 MHz, CDCl₃) δ 8.62 (d, J ) 8.4 Hz, 1H), 8.26 (m,

2H), 7.69 (m, 2H), 7.20 (m, 1H), 4.92 (d, J ) 7.8 Hz, 1H), 3.82

(m, 2H), 3.26 (m, 1H), 2.70 (m, 2H), 1.61 (m, 2H), 1.40 (s, 9H),

1.24 (m, 2H); LC/MS m/z 409 [M + H]⁺.

99:1 CH₂Cl₂/MeOH) to afford 20a as a white solid (60 mg, 65%).

¹H NMR (300 MHz, CDCl₃) δ 8.60 (dd, J ) 7.5, 2.1 Hz, 1H),

8.30 (dd, J ) 7.5, 2.1 Hz, 1H), 8.25 (d, J ) 7.5 Hz, 1H), 7.64 (m,

2H), 7.54 (d, J ) 7.5 Hz, 1H), 5.96 (m, 1H), 4.74 (m, 1H), 4.10

(m, 1H), 4.03 (q, J ) 14.1 Hz, 2H), 3.86 (m, 2H), 3.22 (m, 1H),

2.68 (m, 2H), 2.12 (m, 2H), 1.79 (m, 2H), 1.68 (m, 1H), 1.58 (m,

2H), 1.47 (m, 2H), 1.24 (m, 6H), 1.18 (t, J ) 7.5 Hz, 3H); LC/MS

m/z 488 [M + H]⁺; HRMS calcd for C₂₅H₃₃N₃O₅S [M + H]⁺,

488.2219; found, 488.2213.

Step 3. To a solution of the product from Step 2 (2.00 g, 4.9

mmol) in DMF (20 mL) were added sodium cyanide (1.2 g, 24.5

mmol) and tetra-n-butylammonium bromide (7.9 g, 24.5 mmol).

The reaction mixture was stirred at 100 °C for 17 h and then diluted

with CH₂Cl₂(100 mL). The organic layer was washed with water

(2×) and brine (2×) and then dried over MgSO₄, followed by

filtration and concentration in Vacuo, affording a dark oil. Flash

column chromatography (98:2 CH₂Cl₂/MeOH) afforded a dark oil

that was rechromatographed (99:1 CH₂Cl₂/MeOH) to afford 17 as

N-(2-Methylphenyl)-4-[(piperidin-4-ylamino)sulfonyl]-1-naph-

thamide HCl Salt (19b) and 4-(4-o-Tolylcarbamoyl-naphthalene-

1-sulfonylamino)-piperidine-1-carboxylic Acid Ethyl Ester (20b).

The title compounds were prepared from 18 according to the

1

procedure described for 19a and 20a. Yield: 60 mg (64%). H

NMR (300 MHz, CDCl₃) δ 8.67 (d, J ) 8.1 Hz, 1H), 8.46 (d, J )

8.4 Hz, 1H), 8.33 (d, J ) 7.5 Hz, 1H), 8.03 (d, J ) 7.8 Hz, 1H),

7.79 (d, J ) 7.2 Hz, 1H), 7.71 (m, 2H), 7.55 (s, 1H), 7.30 (m, 1H),

7.21 (m, 1H), 4.71 (d, J ) 7.5 Hz, 1H), 4.05 (q, J ) 14.1 Hz, 2H),

3.89 (m, 2H), 3.27 (m, 1H), 2.72 (m, 2H), 2.31 (s, 3H), 1.65 (m,

2H), 1.26 (m, 2H), 1.20 (t, J ) 7.5 Hz, 3H); LC/MS m/z 494 [M

- H]^-; HRMS calcd for C₂₆H₂₉N₃O₅S [M + H]⁺, 496.1906; found,

496.1918.

1

an orange solid (640 mg, 31%). H NMR (300 MHz, CDCl₃) δ

8.71 (m, 1H), 8.40 (m, 1H), 8.34 (m, 1H), 8.00 (d, J ) 7.5 Hz,

1H), 7.83 (m, 2H), 4.80 (d, J ) 7.8 Hz, 1H), 3.87 (m, 2H), 3.32

(m, 1H), 2.61 (m, 2H), 1.63 (m, 2H), 1.38 (s, 9H), 1.27 (m, 2H);

LC/MS m/z 414 [M - H]^-.

4-(4-Carboxy-naphthalene-1-sulfonylamino)-piperidine-1-car-

boxylic Acid tert-Butyl Ester (18). A mixture of 17 (0.48 g, 1.15

mmol) in aqueous potassium hydroxide (20 mL, 1.8 N, 36 mmol)

and isopropanol (25 mL) was stirred at 75 °C for 48 h. After

removing isopropanol in Vacuo, the aqueous layer was washed with

EtOAc. The aqueous layer was then acidified to pH 3 and extracted

with EtOAc (3×). The combined organic layers were washed with

water and brine and then dried over MgSO₄. Filtration and

concentration in Vacuo afforded 18 as a tan foam (360 mg, 72%).

¹H NMR (300 MHz, CDCl₃) δ 9.03 (m, 1H), 8.70 (m, 1H), 8.33

(dd, J ) 15.9, 7.5 Hz, 2H), 7.74 (m, 2H), 4.78 (d, J ) 7.8 Hz,

1H), 3.85 (m, 2H), 3.31 (m, 1H), 2.71 (m, 2H), 1.62 (m, 2H), 1.40

(s, 9H), 1.27 (m, 2H); LC/MS m/z 433 [M - H]^-; HRMS calcd

for C₂₁H₂₆N₂O₆S [M + Na]⁺, 457.1409; found, 457.1392.

4-(Piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic Acid

Cyclohexylamide HCl Salt (19a). Step 1. To a solution of 18 (400

mg, 0.92 mmol) in CH₂Cl₂(5 mL) were added 1-[3-(dimethylami-

no)propyl]-3-ethylcarbodiimide hydrochloride (350 mg, 1.84 mmol),

1-hydroxybenzotriazole (186 mg, 1.38 mmol), Et₃N (0.38 mL, 2.76

mmol), and cyclohexylamine (0.16 mL, 1.38 mmol). The reaction

mixture was stirred at 25 °C for 17 h and then diluted with CH₂Cl₂

(30 mL). The organic layer was washed with water (2×) and brine

(2×) and then dried over Na₂SO₄. Filtration and concentration in

Vacuo afforded a foam that was purified via flash column

chromatography (98:2 CH₂Cl₂/MeOH) to afford 4-(4-cyclohexyl-

carbamoyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid

tert-butyl ester (320 mg, 68%). ¹H NMR (300 MHz, CDCl₃) δ 8.61

(dd, J ) 7.2, 1.8 Hz, 1H), 8.31 (dd, J ) 7.2, 1.8 Hz, 1H), 8.26 (d,

J ) 7.5 Hz, 1H), 7.68 (m, 2H), 7.59 (d, J ) 7.5 Hz, 1H), 5.91 (m,

1H), 4.64 (d, J ) 7.8 Hz, 1H), 4.12 (m, 1H), 3.82 (m, 2H), 3.22

(m, 1H), 2.68 (m, 2H), 2.13 (m, 2H), 1.79 (m, 2H), 1.57 (m, 6H),

1.38 (s, 9H), 1.27 (m, 4H); LC/MS m/z 516 [M + H]⁺; HRMS

calcd for C₂₇H₃₇N₃O₅S [M + H]⁺, 516.2532; found, 516.2534. Step

2. A solution of the product from Step 1 (320 mg, 0.62 mmol) in

4 N HCl/dioxane (10 mL) was stirred at 25 °C for 2 h and then

concentrated in Vacuo to afford 19a (271 mg, 97%). ¹H NMR (300

MHz, DMSO-d₆) δ 8.68 (d, J ) 8.4 Hz, 1H), 8.59 (d, J ) 7.8 Hz,

1H), 8.40 (d, J ) 7.2 Hz, 1H), 8.15 (m, 2H), 7.72 (m, 2H), 7.60

(d, J ) 7.5 Hz, 1H), 3.75 (m, 1H), 3.67 (m, 1H), 3.08 (m, 2H),

2.80 (m, 2H), 2.54 (m, 1H), 1.92 (m, 2H), 1.74 (m, 2H), 1.62 (m,

4H), 1.48 (m, 1H), 1.32 (m, 4H), 1.25 (m, 1H); LC/MS m/z 416

[M + H]⁺; HRMS calcd for C₂₂H₂₉N₃O₃S [M + H]⁺, 416.2008;

found, 416.2012.

4-(4-Cyano-naphthalene-1-sulfonylamino)-piperidine-1-car-

boxylic Acid Ethyl Ester (21). Step 1. To a THF (15 mL) solution

of 16 (730 mg, 2.99 mmol) were added 4-amino-piperidine-1-

carboxylic acid ethyl ester (1.03 g, 3.58 mmol) and Et₃N (3.5 mL,

15.0 mmol). The reaction mixture was stirred at 25 °C for 17 h, at

which point the solvent was removed in Vacuo. CH₂Cl₂(50 mL)

was added, and the organic layer was washed with water (2×) and

brine (2×) and then dried over MgSO₄. Filtration and concentration

in Vacuo afforded the crude product that was chromatographed (50:

50 hexanes/EtOAc) to afford 4-(4-fluoro-naphthalene-1-sulfony-

lamino)-piperidine-1-carboxylic acid ethyl ester 924 mg (81%

yield). LC/MS m/z 381 [M + H]⁺. Step 2. To a DMF (5.0 mL)

solution of the product from Step 1 (924 mg, 2.43 mmol) were

added NaCN (429 mg, 8.76 mmol) and tetra-n-butylammonium

bromide (2.82 g, 8.76 mmol). The reaction mixture was stirred at

100 °C for 17 h and then diluted with CH₂Cl₂(50 mL). The organic

layer was washed water (3×) and brine (3×) and then dried over

MgSO₄. Filtration and concentration in Vacuo afforded a dark oil,

which was purified by column chromatography (98:2 CH₂Cl₂/

MeOH) to afford a dark oil that was rechromatographed (99:1 CH₂-

1

Cl₂/MeOH) to furnish 21 (770 mg, 82%). H NMR (300 MHz,

CDCl₃) δ 8.71 (m, 1H), 8.40 (m, 1H), 8.34 (m, 1H), 7.97 (m, 1H),

7.83 (m, 2H), 5.70 (d, J ) 7.6 Hz, 1H), 4.03 (q, J ) 7.1 Hz, 2H),

3.88 (m, 2H), 3.32 (m, 1H), 2.75 (m, 2H), 1.64 (m, 2H), 1.28 (m,

2H), 1.17 (t, J ) 7.1 Hz, 3H); LC/MS m/z 386 [M - H]^-.

4-(4-Aminomethyl-naphthalene-1-sulfonylamino)-piperidine-

1-carboxylic Acid Ethyl Ester (22). To an EtOH (10 mL) solution

of 21 (615 mg, 1.59 mmol) at 0 °C was added cobalt chloride (207

mg, 1.59 mmol). The reaction mixture was stirred at 0 °C for 5

min under argon, at which point NaBH₄(181 mg, 4.77 mmol) was

added. The resultant solution was stirred at 0 °C for 30 min further

and then allowed to warm to 25 °C. After stirring for another 30

min, the resultant mixture was quenched with water and the aqueous

layer was extracted with CH₂Cl₂(3×). The organic extracts were

combined, washed with brine (1×), and dried over MgSO₄. The

solution was filtered and concentrated in Vacuo to give the crude

product, which was purified by column chromatography (CH₂Cl₂/

MeOH) to afford 22 (268 mg, 43.0%). LC/MS m/z 392 [M + H]⁺.

4-[4-(Benzylamino-methyl)-naphthalene-1-sulfonylamino]pi-

peridine-1-carboxylic Acid Ethyl Ester Formic Acid Salt (23a).

The title compound was made following the procedure described

1

for 23b. Yield: 0.015 g (14%) of a yellow solid. H NMR (300

4-(4-Cyclohexylcarbamoyl-naphthalene-1-sulfonylamino)-pi-

peridine-1-carboxylic Acid Ethyl Ester (20a). To a solution of

19a (87 mg, 0.19 mmol) in CH₂Cl₂(2 mL) were added Et₃N (58

mg, 0.08 mL, 0.57 mmol) and ethyl chloroformate (41 mg, 0.037

mL, 0.39 mmol). The reaction mixture was stirred at 25 °C for 17

h, at which point the solvent was removed in Vacuo. The crude

residue was directly purified Via column chromatography (eluent:

MHz, CD₃OD) δ 8.73 (d, J ) 8.0 Hz, 1H), 8.29 (s, 1H), 8.22 (d,

J ) 7.5 Hz, 1H), 8.04 (m, 1H), 7.68 (m, 3H), 7.40 (m, 3H), 7.20

(m, 2H), 4.59 (s, 2H), 4.23 (s, 2H), 3.97 (q, J ) 7.0 Hz, 2H), 3.67

(m, 2H), 3.16 (m, 1H), 2.70 (m, 2H), 1.44 (m, 2H), 1.22 (m, 2H),

1.13 (t, J ) 7.0 Hz, 3H); LC/MS m/z 482 [M + H]⁺; HRMS calcd

for C₂₆H₃₁N₃O₄S [M + H]⁺, 482.2113; found, 482.2120.

580 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3

Jenkins et al.

4-[4-(Phenethylamino-methyl)-naphthalene-1-sulfonylamino]-

piperidine-1-carboxylic Acid Ethyl Ester (23b). To a solution

of 22 (277 mg, 0.708 mmol) in MeOH (10 mL) were added phenyl-

acetaldehyde (0.147 mL, 1.42 mmol) and NaBH₃CN (223 mg, 3.55

mmol). The reaction mixture was stirred at 25 °C for 2 h, at which

point the solution was concentrated in Vacuo to give a solid, which

was purified by reverse phase HPLC, affording 23b (5 mg, 6.4%)

further, and the solvent was removed in Vacuo. The crude residue

was directly purified via HPLC to afford 28 (0.03 g, 5%) as a yellow

solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.72 (d, J ) 8.6 Hz, 1H),

8.24 (m, 3H), 8.05 (d, J ) 8.3 Hz, 1H), 7.70 (m, 6H), 3.95 (q, J )

7.0 Hz, 2H), 3.69 (m, 2H), 3.31 (s, 1H), 3.26 (m, 2H), 2.78 (m,

2H), 1.51 (m, 2H), 1.20 (m, 2H), 1.11 (t, J ) 7.1 Hz, 3H); LC/MS

m/z 483 [M + H]⁺; HRMS calcd for C₂₅H₂₆N₂O₆S [M + H]⁺,

483.1589; found, 483.1610.

1

as a white solid. H NMR (300 MHz, CD₃OD) δ 8.74 (m, 1H),

8.19 (m, 2H), 7.67 (m, 2H), 7.59 (m, 1H), 7.22 (m, 5H), 4.35 (s,

2H), 4.05 (q, J ) 7.1 Hz, 2H), 3.78 (m, 2H), 3.18 (m, 1H), 2.92

(m, 4H), 2.62 (m, 2H), 1.48 (m, 2H), 1.25 (m, 2H), 1.17 (t, J )

7.1 Hz, 3H); LC/MS m/z 496 [M + H]⁺; HRMS calcd for

C₂₇H₃₃N₃O₄S [M + H]⁺, 496.2270; found, 496.2275.

4-{4-[(3-Phenyl-propylamino)-methyl]-naphthalene-1-sulfo-

nylamino}-piperidine-1-carboxylic Acid Ethyl Ester (23c). The

title compound was made following the procedure described for

23b. Yield: 0.003 g (3.5%) of a white solid. ¹H NMR (300 MHz,

CD₃OD) δ 8.74 (m, 1H), 8.25 (m, 1H), 8.20 (d, J ) 7.5 Hz, 1H),

7.70 (m, 2H), 7.59 (m, 1H), 7.19 (m, 5H), 4.33 (s, 2H), 4.05 (q, J

) 7.1 Hz, 2H), 3.78 (d, J ) 13.6 Hz, 2H), 3.18 (m, 1H), 2.73 (m,

6H), 1.90 (m, 2H), 1.48 (m, 2H), 1.23 (m, 2H), 1.17 (t, J ) 7.1

Hz, 3H); LC/MS m/z 510 [M + H]⁺; HRMS calcd for C₂₈H₃₅N₃O₄S

[M + H]⁺, 510.2426; found, 510.2425.

4-(Benzyloxy)naphthalene-1-sulfonic Acid Potassium Salt

(25). To a solution of 24 (3.5 g, 10 mmol) in MeOH (50 mL) were

added benzylbromide (2.8 mL, 20 mmol) and KOH (2.24 g, 40

mmol) as a solution in water (4 mL). The reaction mixture was

stirred at 25 °C for 20 h. The mixture was then filtered, and the

solid was washed with a small amount of MeOH (5 mL) to afford

25 (3.1 g), which was used without further purification.

General Procedure C: Preparation of Right-Hand Side

Amides. The title compounds were prepared following the three-

step sequence outlined below.

Step 1. 4-(2-Methylbenzamido)naphthalene-1-sulfonyl Chlo-

ride (29). The title compound was prepared according to the

1

procedure described for the production of 4. H NMR (300 MHz,

CDCl₃) δ 8.48 (d, J ) 8.1 Hz, 1H), 8.46 (m, 1H), 8.39 (m, 1H),

8.01 (d, J ) 8.1 Hz, 1H), 7.81 (m, 1H), 7.69 (m, 1H), 7.59 (m,

1H), 7.42 (m, 1H), 7.31 (m, 2H), 2.53 (s, 3H).

Step 2. 2-Methyl-N-{4-[(piperidin-4-ylamino)sulfonyl]-1-

naphthyl}benzamide HCl Salt (30). To a solution of 29 (4.0 g,

11 mmol) in THF (150 mL) were added tert-butyl 4-aminopiperi-

dine-1-carboxylate (2.2 g, 0.011 mmol) and Et₃N (2.2 mL, 17

mmol). The reaction mixture was stirred at 25 °C for 3 h and then

filtered. The filtrate was collected, and the solvent was removed in

Vacuo to provide a yellow solid (5.5 g). This solid was dissolved

in 4 N HCl/dioxane solution (20 mL) and stirred at 25 °C for 2 h.

Removal of the solvent in Vacuo then afforded 30 (5.0 g, 98%) as

a white solid. ¹H NMR (300 MHz, MeOH) δ 8.75 (d, J ) 7.7 Hz,

1H), 8.33 (d, J ) 7.9 Hz, 1H), 8.23 (m, 1H), 7.94 (d, J ) 8.7 Hz,

1H), 7.71 (m, 3H), 7.39 (m, 3H), 3.49 (m, 1H), 3.15 (m, 2H), 2.90

(m, 2H), 2.50 (s, 3H), 2.21 (m, 1H), 1.82 (m, 2H), 1.59 (m, 1H);

LC/MS [M + 1]⁺m/z 424.

Ethyl 4-(1-(Benzyloxy)naphthalene-4-sulfonamido)piperidine-

1-carboxylate (26). To a solution of 25 (0.3 g, 0.89 mmol) in DMF

(5 mL) was added thionyl chloride (0.074 mL, 1.07 mmol). The

reaction mixture was stirred at 25 °C for 18 h, at which time Et₃N

(0.75 mL, 5.4 mmol) and 4-amino-piperidine-1-carboxylic acid ethyl

ester (0.31 mL, 1.79 mmol) were added. The reaction mixture was

stirred for 19 h further, and the solvent was then removed in Vacuo.

The crude residue was directly purified by HPLC to afford 26 (0.29

Step 3. Method 1: Preparation of Amides Using Acid

Chloride Reagents. 2-Methyl-N-[4-(1-propionyl-piperidin-4-yl-

sulfamoyl)-naphthalen-1-yl]-benzamide (31a). To a mixture of

30 (391 mg, 0.85 mmol) in THF (15 mL) were added propionyl

chloride (0.103 mL, 1.19 mmol) and Et₃N (0.726 mL, 8.33 mmol).

The reaction was stirred at 25 °C for 20 h and then filtered. The

filtrate was concentrated in Vacuo, followed by purification via

column chromatography, to provide 31a (210 mg, 52%) as a white

1

g, 63%, 2 steps). H NMR (300 MHz, DMSO-d₆) δ 8.58 (d, J )

1

8.4 Hz, 1H), 8.32 (d, J ) 8.1 Hz, 1H), 8.12 (d, J ) 8.3 Hz, 1H),

7.93 (d, J ) 7.8 Hz, 1H), 7.70 (m, 4H), 7.38 (m, 2H), 7.20 (d, J )

8.4 Hz, 1H), 5.39 (s, 2H), 3.92 (q, J ) 7.1 Hz, 2H), 3.65 (m, 2H),

3.11 (m, 1H), 2.73 (m, 2H), 1.40 (m, 2H), 1.15 (m, 2H), 1.10 (t, J

) 7.1 Hz, 3H); LC/MS m/z 469 [M + H]⁺; HRMS calcd for

C₂₅H₂₈N₂O₅S [M + H]⁺, 469.1797; found, 469.1820.

solid. H NMR (300 MHz, CD₃OD) δ 8.78 (m, 1H), 8.33 (d, J )

7.9 Hz, 1H), 8.23 (m, 1H), 7.94 (m, 1H), 7.71 (m, 3H), 7.43 (m,

1H), 7.38 (m, 2H), 4.19 (m, 1H), 3.72 (m, 1H), 3.25 (m, 1H), 3.01

(m, 1H), 2.69 (m, 1H), 2.55 (s, 3H), 2.41 (q, J ) 7.5 Hz, 2H), 1.61

(m, 2H), 1.31 (m, 2H), 1.02 (t, J ) 7.5 Hz, 3H); LC/MS [M + 1]⁺

m/z 480; HRMS calcd for C₂₆H₂₉N₃O₄S [M + H]⁺, 480.1957;

found, 480.1968.

Ethyl 4-(1-Hydroxynaphthalene-4-sulfonamido)piperidine-1-

carboxylate (27). To a solution of 26 (0.10 g, 0.21 mmol) in MeOH

(10 mL) was added Pd/C (10%, 30 mg, 0.028 mmol). The reaction

vessel was charged with H₂(50 psi) and shaken for 17 h. After

removing the solid via filtration, the MeOH solution was concen-

trated under vacuum to afford 27 (0.03 g, 38%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 11.2 (s, 1H), 8.53 (d, J ) 8.5

Hz, 1H), 8.25 (d, J ) 8.1 Hz, 1H), 8.00 (d, J ) 8.2 Hz, 1H), 7.78

(d, J ) 8.0 Hz, 1H), 7.66 (m, 1H), 6.91 (d, J ) 8.2 Hz, 1H), 3.94

(q, J ) 7.0 Hz, 2H), 3.65 (m, 2H), 3.31 (s, 1H), 3.06 (m, 1H), 2.72

(m, 2H), 1.49 (m, 2H), 1.16 (m, 2H), 1.10 (t, J ) 7.2 Hz, 3H);

LC/MS m/z 379 [M + H]⁺; HRMS calcd for C₁₈H₂₂N₂O₅S [M +

H]⁺, 379.1327; found, 379.1343.

Method 2: Preparation of Amides from Carboxylic Acid

Reagents. N-{4-[({1-[(2S)-2-Aminopropanoyl]piperidin-4-yl}-

amino)sulfonyl]-1-naphthyl}-2-methylbenzamide HCl Salt (31m).

To a mixture of 30 (690 mg, 1.50 mmol) in CH₂Cl₂(12 mL) were

added HOBT (223 mg, 1.65 mmol), EDCI (345 mg, 1.80 mmol),

N-methylmorpholine (455 mg, 4.50 mmol), and (s)-2-tert-butoxy-

carbonylamino-propionic acid (181 mg, 0.80 mmol). The reaction

mixture was stirred at 25 °C for 20 h and then filtered, and the

filtrate was concentrated in Vacuo. The crude mixture was

suspended in 4 N HCl/dioxane (20 mL) and stirred for 2 h. The

reaction mixture was filtered, and the collected solid was washed

1

with dioxane to afford 31m (560 mg, 70%) as a white solid. H

NMR (300 MHz, CD₃OD) δ 8.75 (m, 1H), 8.33 (d, J ) 8.1 Hz,

1H), 8.23 (m, 1H), 7.96 (d, J ) 8.1 Hz, 1H), 7.71 (m, 3H), 7.43

(m, 1H), 7.38 (m, 2H), 4.30 (m, 1H), 4.14 (m, 1H), 3.65 (m, 1H),

3.34 (m, 1H), 3.08 (m, 1H), 2.80 (m, 1H), 2.55 (s, 3H), 1.66 (m,

2H), 1.33 (m, 5H); LC/MS [M + 1]⁺m/z 495; HRMS calcd for

C₂₆H₃₀N₄O₄S [M + H]⁺, 495.2066; found, 495.2080.

Amides 31b-31d. The title compounds were prepared according

to general procedure C from the appropriate starting materials,

employing Method 1 for Step 3.

Ethyl

4-({[4-(Benzoyloxy)-1-naphthyl]sulfonyl}amino)-

piperidine-1-carboxylate (28). To a solution of 24 (3.5 g, 10 mmol)

in pyridine (20 mL) was added benzoyl chloride (1.4 mL, 12 mmol)

at 25 °C. The reaction mixture was stirred at reflux for 20 h, at

which point the solvent was removed in Vacuo to provide crude

4-(benzoyloxy)naphthalene-1-sulfonic acid pyridinium salt (4.2 g,

orange solid), which was used without further purification. To a

DMF (10 mL) solution of the above pyridinium salt (1.2 g, 3.0

mmol) was added thionyl chloride (0.25 mL, 3.6 mmol) at 0 °C.

The reaction mixture was stirred for 17 h while allowing to warm

slowly to 25 °C, followed by the addition of Et₃N (1.25 mL, 9.0

mmol) and 4-amino-piperidine-1-carboxylic acid ethyl ester (0.51

mL, 3.0 mmol). The reaction mixture was stirred at 25 °C for 4 h

N-(4-{[(1-Acetylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

1

2-methylbenzamide (31b). H NMR (300 MHz, CD₃OD) δ 8.77

(m, 1H), 8.33 (d, J ) 7.9 Hz, 1H), 8.25 (m, 1H), 7.94 (m, 1H),

7.72 (m, 3H), 7.40 (m, 3H), 4.16 (m, 1H), 3.67 (m, 1H), 3.25 (m,

Naphthalene-Sulfonamide Antagonists of Human CCR8

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3 581

1H), 3.03 (m, 1H), 2.65 (m, 1H), 2.56 (s, 3H), 1.20 (s, 3H), 1.60

(m, 2H), 1.30 (m, 2H); LC/MS [M + 1]⁺m/z 466.

3H), 7.39 (m, 3H), 4.13 (m, 5H), 3.90 (m. 1H), 3.37 (m, 2H), 2.96

(m, 1H), 2.76 (m, 1H), 2.55 (s, 3H), 1.62 (m, 2H), 1.30 (m, 2H);

LC/MS [M + 1]⁺m/z 507; HRMS calcd for C₂₇H₃₀N₄O₄S [M +

H]⁺, 507.2066; found, 507.2059.

N-[4-(1-Cyclopropanecarbonyl-piperidin-4-ylsulfamoyl)-naph-

thalen-1-yl]-2-methyl-benzamide (31c). ¹H NMR (300 MHz, CD₃-

OD) δ 8.78 (m, 1H), 8.33 (m, 1H), 8.25 (m, 1H), 7.94 (m, 1H),

7.71 (m, 3H), 7.41 (m, 3H), 4.17 (m, 2H), 3.13 (m, 1H), 2.71 (m,

2H), 2.54 (s, 3H), 1.84 (m, 1H), 1.71 (m, 1H), 1.59 (m, 1H), 1.29

(m, 2H), 0.79 (m, 4H); LC/MS [M + 1]⁺m/z 492; HRMS calcd

for C₂₇H₂₉N₃O₄S [M + H]⁺, 492.1957; found, 492.1963.

2-Methyl-N-{4-[({1-[(2S)-pyrrolidin-2-ylcarbonyl]piperidin-

4-yl}amino)sulfonyl]-1-naphthyl}benzamide) Formic Acid Salt

1

(31l). H NMR (300 MHz, DMSO-d₆) δ 10.66 (br, 1H), 8.70 (m,

1H), 8.26 (s, 1H), 8.23 (m, 2H), 7.96 (d, J ) 8.3 Hz, 1H), 7.71 (m,

3H), 7.43 (m, 1H), 7.38 (m, 2H), 4.03 (m, 2H), 3.40 (m, 2H), 3.02

(m, 2H), 2.78 (m, 2H), 2.49 (s, 3H), 2.06 (m, 1H), 1.62 (m, 5H),

1.25 (m, 2H); LC/MS [M + 1]⁺m/z 521; HRMS calcd for

C₂₈H₃₂N₄O₄S [M + H]⁺, 521.2222; found, 521.2244.

N-[4-(1-Cyclopentanecarbonyl-piperidin-4-ylsulfamoyl)-naph-

thalen-1-yl]-2-methyl-benzamide (31d). The title compound was

1

made following general procedure C. H NMR (300 MHz, CD₃-

OD) δ 8.78 (m, 1H), 8.33 (m, 1H), 8.25 (m, 1H), 7.94 (m, 1H),

7.71 (m, 3H), 7.41 (m, 3H), 4.19 (m, 1H), 3.88 (m, 1H), 3.00 (m,

2H), 2.68 (m, 2H), 2.54 (s, 3H), 1.65 (m, 9H), 1.29 (m, 3H); LC/

MS [M + 1]⁺m/z 520; HRMS calcd for C₂₉H₃₃N₃O₄S [M + H]⁺,

520.2270; found, 520.2279.

Amides 31e-31l. The title compounds were prepared according

to general procedure C from the appropriate starting materials,

employing Method 2 for Step 3.

Amides 31n and 31o. The title compounds were prepared

according to general procedure C from the appropriate starting

materials, employing Method 1 for Step 3.

N-(4-{[(1-Benzoylpiperidin-4-yl)amino]sulfonyl}-1-naphthyl)-

2-methylbenzamide (31n). ¹H NMR (300 MHz, CD₃OD) δ 8.75-

(m, 1H), 8.31 (d, J ) 7.7 Hz, 1H), 8.22 (m, 1H), 7.92 (d, J ) 8.1

Hz, 1H), 7.71 (m, 3H), 7.36 (m, 8H), 4.29 (m, 1H), 3.51 (m. 1H),

3.35 (m, 1H), 2.96 (m, 2H), 2.54 (s, 3H), 1.62 (m, 2H), 1.35 (m,

2H); LC/MS [M + 1]⁺m/z 528; HRMS calcd for C₃₀H₂₉N₃O₄S

[M + H]⁺, 528.1957; found, 528.1974

N-{4-[1-(2-Hydroxy-acetyl)-piperidin-4-ylsulfamoyl]-naphtha-

1

len-1-yl}-2-methyl-benzamide (31e). H NMR (300 MHz, CD₃-

OD) δ 8.78 (m, 1H), 8.33 (d, J ) 8.1 Hz, 1H), 8.23 (m, 1H), 7.94

(m, 1H), 7.71 (m, 3H), 7.43 (m, 1H), 7.38 (m, 2H), 4.16 (m, 1H),

4.13 (s, 2H), 3.55 (m, 1H), 3.34 (m, 1H), 2.95 (m, 1H), 2.74 (m,

1H), 2.55 (s, 3H), 1.63 (m, 2H), 1.41 (m, 2H); LC/MS [M + 1]⁺

m/z 482; HRMS calcd for C₂₅H₂₇N₃O₅S [M + H]⁺, 482.1749;

found, 482.1756.

N-{4-[({1-[4-(Dimethylamino)benzoyl]piperidin-4-yl}amino)-

sulfonyl]-1-naphthyl}-2-methylbenzamide (31o). ¹H NMR (300

MHz, CD₃OD) δ 8.76(m, 1H), 8.32 (d, J ) 8.1 Hz, 1H), 8.23 (m,

1H), 7.93 (m,1H), 7.71 (m, 3H), 7.36 (m, 3H), 7.22 (d, J ) 8.6

Hz, 2H), 6.69 (d, J ) 8.6 Hz, 2H), 4.00 (br, 2H), 3.38 (m, 1H),

3.00 (m, 2H), 2.96 (s, 6H), 2.54 (s, 3H), 1.60 (m, 2H), 1.32 (m,

2H); LC/MS [M + 1]⁺m/z 571; HRMS calcd for C₃₂H₃₄N₄O₄S

[M + H]⁺, 571.2379; found, 571.2378.

N-{4-[1-(2-Methoxy-acetyl)-piperidin-4-ylsulfamoyl]-naphtha-

1

len-1-yl}-2-methyl-benzamide (31f). H NMR (300 MHz, CD₃-

OD) δ 8.76 (m, 1H), 8.33 (d, J ) 8.3 Hz, 1H), 8.23 (m, 1H), 7.94

(m, 1H), 7.71 (m, 3H), 7.43 (m, 1H), 7.38 (m, 2H), 4.08 (m, 4H),

3.63 (m, 1H), 3.34 (s, 3H), 2.98 (m, 1H), 2.71 (m, 1H), 2.55 (s,

3H), 1.61 (m, 2H), 1.30 (m, 2H); LC/MS [M + 1]⁺m/z 496; HRMS

calcd for C₂₆H₂₉N₃O₅S [M + H]⁺, 496.1906; found, 496.1912.

N-{4-[1-(2-Amino-acetyl)-piperidin-4-ylsulfamoyl]-naphtha-

len-1-yl}-2-methyl-benzamide Formic Acid Salt (31g). ¹H NMR

(300 MHz, DMSO-d₆) δ 10.66 (br, 1H), 8.70 (m, 1H), 8.30 (s,

1H), 8.20 (m, 2H), 7.94 (d, J ) 8.7 Hz, 1H), 7.71 (m, 3H), 7.43

(m, 1H), 7.38 (m, 2H), 4.05 (m, 1H), 3.60 (m, 4H), 2.95 (m, 1H),

2.74 (m, 1H), 2.49 (s, 3H), 1.55 (m, 2H), 1.31 (m, 2H); LC/MS

[M + 1]⁺m/z 481; HRMS calcd for C₂₅H₂₈N₄O₄S [M + H]⁺,

481.1909; found, 481.1917.

3-(Dimethylamino)propyl 4-[({4-[(2-Methylbenzoyl)amino]-

1-naphthyl}sulfonyl)amino]piperidine-1-carboxylate Formic Acid

Salt (32a). The title compound was made following the procedure

1

described for 32d. H NMR (300 MHz, CD₃OD) δ 8.75 (d, J )

7.5 Hz, 1H), 8.38 (s, 1H), 8.31 (d, J ) 7.8 Hz, 1H), 8.23 (d, J )

8.8 Hz, 1H), 7.92 (m, 1H), 7.70 (m, 3H), 7.37 (m, 3H), 4.08 (m,

2H), 3.82 (d, J ) 13.5 Hz, 2H), 3.22 (m, 2H), 3.09 (m, 2H), 2.85

(m, 1H), 2.84 (s, 6H), 2.55 (s, 3H), 2.00 (m, 2H), 1.57 (m, 2H),

1.30 (m, 2H); LC/MS m/z 553 [M + H]⁺; HRMS calcd for

C₂₉H₃₆N₄O₅S [M + H]⁺, 553.2484; found, 553.2469.

3-(Diethylamino)propyl 4-[({4-[(2-Methylbenzoyl)amino]-1-

naphthyl}sulfonyl)amino]piperidine-1-carboxylate Formic Acid

Salt (32b). The title compound was made following the procedure

1

N-{4-[1-(3-Amino-propionyl)-piperidin-4-ylsulfamoyl]-naph-

described for 32d. H NMR (300 MHz, CD₃OD) δ 8.75 (d, J )

1

thalen-1-yl}-2-methyl-benzamide Formic Acid Salt (31h). H

7.5 Hz, 1H), 8.38 (s, 1H), 8.31 (d, J ) 8.1 Hz, 1H), 8.24 (d, J )

7.8 Hz, 1H), 7.94 (m, 1H), 7.71 (m, 3H), 7.37 (m, 3H), 4.09 (m,

2H), 3.83 (d, J ) 13.5 Hz, 2H), 3.16 (m, 7H), 2.55 (s, 3H), 1.99

(m, 3H), 1.57 (m, 2H), 1.26 (m, 9H); LC/MS m/z 581 [M + H]⁺;

HRMS calcd for C₃₁H₄₀N₄O₅S [M + H]⁺, 581.2797; found,

581.2822.

NMR (300 MHz, CD₃OD) δ 8.75 (m, 1H), 8.53 (s, 1H), 8.31 (d,

J ) 8.1 Hz, 1H), 8.24 (m, 1H), 7.92 (d, J ) 8.1 Hz, 1H), 7.70 (m,

3H), 7.38 (m, 3H), 4.19 (m, 1H), 3.65 (m. 1H), 3.05 (m, 3H), 2.71

(m, 1H), 2.62 (m, 3H), 2.55 (s, 3H), 1.62 (m, 2H), 1.29 (m, 2H);

LC/MS [M + 1]⁺m/z 495; HRMS calcd for C₂₆H₃₀N₄O₄S [M +

H]⁺, 495.2066; found, 495.2085.

N-{4-[1-(4-Amino-butyryl)-piperidin-4-ylsulfamoyl]-naphtha-

len-1-yl}-2-methyl-benzamide Formic Acid Salt (31i). ¹H NMR

(300 MHz, CD₃OD) δ 8.75 (m, 1H), 8.51 (s, 1H), 8.31 (m, 1H),

8.24 (m, 1H), 7.89 (m, 1H), 7.68 (m, 3H), 7.38 (m, 3H), 4.16 (m,

1H), 3.69 (m. 1H), 3.00 (m, 1H), 2.85 (m, 2H), 2.69 (m, 1H), 2.55

(s, 3H), 2.42 (m, 2H), 1.82 (m, 2H), 1.60 (m, 3H), 1.28 (m, 2H);

LC/MS [M + 1]⁺m/z 509; HRMS calcd for C₂₇H₃₂N₄O₄S [M +

H]⁺, 509.2222; found, 509.2229.

N-[4-({[1-(5-Aminopentanoyl)piperidin-4-yl]amino}sulfonyl)-

1-naphthyl]-2-methyl-benzamide Formic Acid Salt (31j). ¹H

NMR (300 MHz, CD₃OD) δ 8.76 (m, 1H), 8.53 (s, 1H), 8.32 (d,

J ) 8.1 Hz, 1H), 8.24 (m,1H), 7.93 (d, J ) 8.1 Hz, ,1H), 7.70 (m,

3H), 7.39 (m, 3H), 4.18 (m, 1H), 3.72 (m. 1H), 3.01 (m, 1H), 2.86

(m, 2H), 2.70 (m, 1H), 2.55 (s, 3H), 2.36 (m, 2H), 1.60 (m, 6H),

1.30 (m, 3H); LC/MS [M + 1]⁺m/z 523; HRMS calcd for

C₂₈H₃₄N₄O₄S [M + H]⁺, 523.2379; found, 523.2383.

N-[4-({[1-(Azetidin-3-ylcarbonyl)piperidin-4-yl]amino}sulfonyl)-

1-naphthyl]-2-methyl-benzamide Formic Acid Salt (31k). ¹H

NMR (300 MHz, CD₃OD) δ 8.75 (m, 1H), 8.52 (s, 1H), 8.31 (d,

J ) 8.1 Hz, 1H), 8.23 (m, 1H), 7.93 (d, J ) 8.1 Hz, 1H), 7.71 (m,

3-Pyrrolidin-1-ylpropyl 4-[({4-[(2-Methylbenzoyl)amino]-1-

naphthyl}sulfonyl)amino]piperidine-1-carboxylate Formic Acid Salt

(32c). The title compound was made following the procedure

1

described for 32d. H NMR (300 MHz, CD₃OD) δ 8.75 (d, J )

8.4 Hz, 1H), 8.38 (s, 1H), 8.30 (d, J ) 8.1 Hz, 1H), 8.23 (d, J )

8.1 Hz, 1H), 7.93 (m, 1H), 7.71 (m, 3H), 7.38 (m, 3H), 4.08 (s,

3H), 3.82 (d, J ) 13.8 Hz, 3H), 3.17 (m, 2H), 2.85 (m, 3H), 2.55

(s, 3H), 2.02 (m, 7H), 1.58 (m, 2H), 1.29 (m, 3H); LC/MS m/z

579 [M + H]⁺; HRMS calcd for C₃₁H₃₈N₄O₅S [M + H]⁺, 579.2461;

found, 579.2610.

3-(2,6-Dimethylmorpholin-4-yl)propyl-4-[({4-[(2-methylben-

zoyl)amino]-1-naphthyl}sulfonyl)amino]piperidine-1-carboxy-

late Formic Acid Salt (32d). Step 1. To a solution of 30 (468 mg,

1.0 mmol) in DMF (10 mL) at 0 °C were added Et₃N (0.663 mL,

5.0 mmol) and 3-bromopropyl chloroformate (0.13 mL, 1.2 mmol).

The reaction mixture was stirred at 0 °C for 4 h. Aqueous workup

then afforded 3-bromopropyl 4-(1-(2-methylbenzamido)naphtha-

lene-4-sulfonamido)piperidine-1-carboxylate as an off-white solid

(411 mg), which was used without further purification. Step 2. To

a DMF (10 mL) solution of the product from Step 1 (411 mg, 0.70

mmol) were added Cs₂CO₃(1.10 g, 3.5 mmol) and 2,6-dimethyl-

582 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3

Jenkins et al.

morpholine (0.172 mL, 1.4 mmol). The resultant solution was stirred

at 100 °C for 12 h, then quenched with water and filtered. The

solid was purified via HPLC to provide 32d (113 mg, 26%) as a

1.30 (m, 2H), 1.05 (d, J ) 8.3 Hz, 6H); LC/MS [M + 1]⁺m/z

509; HRMS calcd for C₂₇H₃₂N₄O₄S [M + H]⁺, 509.2222; found,

509.2240.

1

white solid. H NMR (300 MHz, CD₃OD) δ 8.72 (d, J ) 8.1 Hz,

4-[4-(2-Methyl-benzoylamino)-naphthalene-1-sulfonylamino]-

piperidine-1-carboxylic Acid Phenylamide (33f). ¹H NMR (300

MHz, DMSO-d₆) δ 10.64 (s, 1H), 8.69 (d, J ) 8.2 Hz, 1H), 8.38

(s, 1H), 8.25 (m, 2H), 8.11 (d, J ) 7.3 Hz, 1H), 7.95 (d, J ) 7.9

Hz, 1H), 7.74 (m, 3H), 7.39 (m, 5H), 7.17 (t, J ) 7.6 Hz, 2H),

6.88 (t, J ) 7.3 Hz, 1H), 3.83 (d, J ) 13.4 Hz, 2H), 3.32 (s, 3H),

3.25 (m, 1H), 2.77 (t, J ) 11.3 Hz, 2H), 1.48 (m, 2H), 1.25 (m,

2H); LC/MS m/z 543 [M + H]⁺; HRMS calcd for C₃₀H₃₀N₄O₄S

[M + H]⁺, 543.2066; found, 543.2078.

1H), 8.38 (s, 1H), 8.23 (m, 2H), 7.89 (d, J ) 7.8 Hz, 1H), 7.67 (m,

3H), 7.37 (m, 3H), 4.03 (m, 2H), 3.76 (m, 3H), 3.24 (m, 5H), 2.83

(m, 4H), 2.51 (s, 3H), 2.30 (t, J ) 11.4 Hz, 2H), 1.93 (m, 2H),

1.53 (d, J ) 11.1 Hz, 2H), 1.18 (m, 7H); LC/MS m/z 623 [M +

H]⁺; HRMS calcd for C₃₃H₄₂N₄O₄S [M + H]⁺, 623.2903; found,

623.2905.

3-(3,4-Dihydroisoquinolin-2(1H)-yl)propyl 4-[({4-[(2-Meth-

ylbenzoyl)amino]-1-naphthyl}sulfonyl)amino]piperidine-1-car-

boxylate Formic Acid Salt (32e). The title compound was made

4-({[4-(Benzoylamino)-1-naphthyl]sulfonyl}amino)-N,N-dim-

ethylpiperidine-1-carboxamide (33g). To a suspension of 30 (322

mg, 0.70 mmol) in THF (10 mL) were added dimethylcarbamoyl

chloride (90 µL, 0.98 mmol) and Et₃N (682 µL, 4.9 mmol). The

reaction mixture was stirred at 25 °C for 2 h and then filtered. The

filtrate was concentrated in Vacuo, and the crude residue was

1

following the procedure described for 32d. H NMR (300 MHz,

CD₃OD) δ 8.76 (d, J ) 8.4 Hz, 1H), 8.38 (s, 1H), 8.28 (m, 2H),

7.93 (d, J ) 7.8 Hz, 1H), 7.75 (m, 3H), 7.39 (m, 3H), 7.22 (m,

4H), 4.30 (s, 2H), 4.14 (t, J ) 4.5 Hz, 2H), 3.83 (d, J ) 13.2 Hz,

2H), 3.44 (t, J ) 5.7 Hz, 2H), 3.17 (m, 5H), 2.83 (m, 2H), 2.56 (s,

3H), 2.11 (m, 2H), 1.57 (d, J ) 10.8 Hz, 2H), 1.30 (m, 2H); LC/

MS m/z 641 [M + H]⁺; HRMS calcd for C₃₆H₄₀N₄O₅S [M + H]⁺,

641.2797; found, 641.2796.

4-(1-(2-Methylbenzamido)naphthalene-4-sulfonamido)piperi-

dine-1-carboxamide (33a). To a suspension of 30 (500 mg, 1.08

mmol) in 10 mL THF were added Et₃N (150 µL, 1.49 mmol) and

isocyanato(trimethyl)silane (578 µL, 4.3 mmol), and the reaction

mixture was stirred at 25 °C for 17 h. The mixture was then cooled

in an ice bath and aqueous ammonium chloride (10 mL) was added.

The reaction mixture was directly extracted with EtOAc (3×), and

the combined organic layers were dried over Na₂SO₄and concen-

trated in Vacuo to afford a white solid. Purification via HPLC then

provided 33a (0.13 g, 26%) as a white solid. ¹H NMR (300 MHz,

CD₃OD) δ 8.78 (m, 1H), 8.30 (m, 2H), 7.96 (m, 1H), 7.73 (m,

3H), 7.43 (m, 3H), 3.77 (m, 2H), 2.77 (m, 2H), 2.59 (m, 1H), 2.56

(s, 3H), 1.57 (m, 2H), 1.33 (m, 2H); LC/MS m/z 467 [M + H]⁺;

HRMS calcd for C₂₄H₂₆N₄O₄S [M + H]⁺, 467.1753; found,

467.1753.

Ureas 33b-33g. These compounds were prepared following the

procedure described for 33a from the appropriate starting materials.

The reported yields represent the yields obtained for the final step

of the sequence.

4-[4-(2-Methyl-benzoylamino)-naphthalene-1-sulfonylamino]-

piperidine-1-carboxylic Acid Methylamide (33b). ¹H NMR (300

MHz, CD₃OD) δ 8.76 (m, 1H), 8.33 (d, J ) 8.3 Hz, 1H), 8.23 (m,

1H), 7.94 (d, J ) 8.3 Hz, 1H), 7.71 (m, 3H), 7.39 (m, 3H), 3.73

(m, 2H), 3.25 (m, 1H), 2.72 (m, 2H), 2.65 (s, 3H), 2.56 (s, 3H),

1.53 (m, 2H), 1.28 (m, 2H); LC/MS [M + 1]⁺m/z 481; HRMS

calcd for C₂₅H₂₈N₄O₄S [M + H]⁺, 481.1909; found, 481.1909.

1

purified via HPLC to afford 33g (0.137 g, yield 40%). H NMR

(300 MHz, DMSO-d₆) δ 10.6 (s, 1H), 8.68 (d, J ) 7.3, 1H), 8.24

(m, 2H), 8.08 (m, 1H), 7.94 (m, 1H), 7.71 (m, 3H), 7.36 (m, 3H),

3.58 (m, 1H), 2.63 (s, 6H), 2.59 (m, 4H), 1.74 (s, 1H), 1.45 (m,

2H), 1.26 (m, 2H); LC/MS m/z 495 [M + H]⁺; HRMS calcd for

C₂₆H₃₀N₄O₄S [M + H]⁺, 495.2066; found, 495.2049.

N-{4-[1-(Azetidine-1-carbonyl)-piperidin-4-ylsulfamoyl]-naph-

thalen-1-yl}-2-methyl-benzamide (33h). The title compound was

prepared according to the procedure described for 33n, using

azetidine instead of N,N-dietheyl-1,3-propanediamine. ¹H NMR

(300 MHz, CD₃OD) δ 8.76 (d, J ) 8.1 Hz, 1H), 8.32 (m, 1H),

8.23 (d, J ) 7.7 Hz, 1H), 7.93 (d, J ) 7.3 Hz, 1H), 7.73 (m, 3H),

7.39 (m, 3H), 3.93 (m, 4H), 3.60 (d, J ) 13.6 Hz, 2H), 3.25 (m,

1H), 2.72 (t, J ) 11.6 Hz, 2H), 2.56 (s, 3H), 2.18 (m, 2H), 1.54

(m, 2H), 1.30 (m, 2H); LC/MS m/z 507 [M + H]⁺; HRMS calcd

for C₂₇H₃₀N₄O₄S [M + H]⁺, 507.2066; found, 507.2084.

2-Methyl-N-[4-({[1-(pyrrolidin-1-ylcarbonyl)piperidin-4-yl]-

amino}sulfonyl)-1-naphthyl]benzamide (33i). The title compound

was prepared according to the procedure described for 33g, using

pyrrolidine-1-carbonyl chloride instead of dimethylcarbamoyl chlo-

1

ride. H NMR (300 MHz, CD₃OD) δ 8.76 (d, J ) 8.3 Hz, 1H),

8.32 (d, J ) 8.1 Hz, 1H), 8.24 (m, 1H), 7.92 (d, J ) 7.7 Hz, 1H),

7.71 (m, 3H), 7.39 (m, 3H), 3.50 (d, J ) 11.4 Hz, 2H), 3.20 (m,

5H), 2.77 (t, J ) 11.4 Hz, 2H), 2.56 (s, 3H), 1.81 (m, 2H), 1.58

(m, 2H), 1.33 (m, 2H), 0.92 (m, 2H); LC/MS m/z 521 [M + H] ⁺

;

HRMS calcd for C₂₈H₃₂N₄O₄S [M + H]⁺, 521.2222; found,

521.2238.

2-Methyl-N-{4-[1-(piperidine-1-carbonyl)-piperidin-4-ylsul-

famoyl]-naphthalen-1-yl}-benzamide (33j). The title compound

was prepared according to the procedure described for 33g, using

piperidine-1-carbonyl chloride instead of dimethylcarbamoyl chlo-

4-[4-(2-Methyl-benzoylamino)-naphthalene-1-sulfonylamino]-

1

ride. H NMR (300 MHz, CD₃OD) δ 8.78 (d, 1H), 8.32 (d, J )

piperidine-1-carboxylic Acid Ethylamide (33c). Yield: 0.477 g

8.3 Hz, 1H), 8.25 (m, 1H), 7.94 (d, J ) 8.3 Hz, 1H), 7.71 (m, 3H),

7.39 (m, 3H), 3.41 (m, 4H), 3.15 (m, 5H), 2.72 (m, 2H), 2.56 (s,

3H), 1.58 (m, 8H); LC/MS [M + 1]⁺m/z 535; HRMS calcd for

C₂₉H₃₄N₄O₄S [M + H]⁺, 535.2379; found, 535.2393.

1

(69%) as a white solid. H NMR (300 MHz, CD₃OD) δ 8.78 (d,

J ) 7.9 Hz, 1H), 8.33 (d, J ) 8.5 Hz, 1H), 8.23 (d, J ) 7.3 Hz,

1H), 7.94 (d, J ) 7.3 Hz, 1H), 7.71 (m, 3H), 7.39 (m, 3H), 3.73

(m, 2H), 3.23 (m, 1H), 3.11 (q, J ) 6.1 Hz, 2H), 2.69 (m, 2H),

2.54 (s, 3H), 1.53 (m, 2H), 1.29 (m, 2H), 1.04 (t, J ) 6.1 Hz, 3H);

LC/MS [M + H]⁺m/z 495; HRMS calcd for C₂₆H₃₀N₄O₄S [M +

H]⁺, 495.2066; found, 495.2083.

2-Methyl-N-{4-[1-(4-methyl-piperazine-1-carbonyl)-piperidin-

4-ylsulfamoyl]-aphthalen-1-yl}-benzamide Formic Acid Salt

(33k). The title compound was prepared according to the procedure

described for 33n, using 1-methylpiperazine instead of N,N-diethyl-

1,3-propanediamine. ¹H NMR (300 MHz, CD₃OD) δ 8.76 (d, J )

8.3 Hz, 1H), 8.40 (s, 1H), 8.32 (d, J ) 8.1 Hz, 1H), 8.24 (m, 1H),

7.92 (d, J ) 7.7 Hz, 1H), 7.71 (m, 3H), 7.39 (m, 3H), 3.50 (d, J )

11.4 Hz, 2H), 3.20 (m, 5H), 2.77 (t, J ) 11.4 Hz, 2H), 2.66 (m,

4H), 2.56 (s, 3H), 2.46 (s, 3H), 1.57 (m, 2H), 1.33 (m, 2H); LC/

MS m/z 550 [M + H]⁺; HRMS calcd. for C₂₉H₃₅N₅O₄S [M + H]⁺

550.2488, found 550.2469.

2-Methyl-N-[4-({[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]-

amino}sulfonyl)-1-naphthyl]benzamide (33l). The title compound

was prepared according to the procedure described for 33g, using

morpholine-4-carbonyl chloride instead of dimethylcarbamoyl

chloride. ¹H NMR (300 MHz, CD₃OD) δ 8.76 (m, 1H), 8.31 (d, J

) 7.7 Hz, 1H), 8.24 (m, 1H), 7.94 (m, 1H), 7.70 (m, 3H), 7.37 (m,

4-[({4-[(2-Methylbenzoyl)amino]-1-naphthyl}sulfonyl)amino]-

1

N-propylpiperidine-1-carboxamide (33d). H NMR (300 MHz,

CD₃OD) δ 8.75 (m, 1H), 8.33 (d, J ) 7.9 Hz, 1H), 8.23 (m, 1H),

7.94 (m, 1H), 7.71 (m, 3H), 7.43 (m, 1H), 7.38 (m, 2H), 3.75 (m,

2H), 3.25 (m, 1H), 3.06 (t, J ) 7.2 Hz, 2H), 2.74 (m, 2H), 2.59 (s,

3H), 1.59 (m, 2H), 1.49 (m, 2H), 1.30 (m, 2H), 0.89 (t, J ) 7.3

Hz, 3H); LC/MS [M + 1]⁺m/z 509; HRMS calcd for C₂₇H₃₂N₄O₄S

[M + H]⁺, 509.2222; found, 509.2239.

N-Isopropyl-4-[({4-[(2-methylbenzoyl)amino]-1-naphthyl}-

1

sulfonyl)amino]piperidine-1-carboxamide (33e). H NMR (300

MHz, CD₃OD) δ 8.78 (d, 1H), 8.33 (d, J ) 8.3 Hz, 1H), 8.23 (m,

1H), 7.94 (m, 1H), 7.71 (m, 3H), 7.43 (m, 1H), 7.38 (m, 2H), 3.76

(m, 2H), 3.25 (m, 2H), 2.71 (m, 2H), 2.57 (s, 3H), 1.59 (m, 2H),

Naphthalene-Sulfonamide Antagonists of Human CCR8

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3 583

3H), 3.58 (m, 4H), 3.51 (m, 2H), 3.15 (m, 4H), 2.74 (m, 2H), 2.55

recrystallized from MeOH (2×) to provide the title compound (2.0

g) as a gray solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.90 (m, 2H),

8.57 (m, 1H), 8.00 (m, 7H), 7.77 (d, J ) 8.4 Hz, 1H), 7.58 (m,

2H), 7.49 (m, 2H).

+

(s, 3H), 1.54 (m, 2H), 1.31 (m, 3H); LC/MS m/z 537 [M + H]

;

HRMS calcd for C₂₈H₃₂N₄O₅S [M + H]⁺, 537.2171; found,

537.2183.

4-[4-(2-Methyl-benzoylamino)-naphthalene-1-sulfonylamino]-

piperidine-1-carboxylic Acid (3-Morpholin-4-yl-propyl)-amide

Formic Acid Salt (33m). The title compound was prepared

according to the procedure described for 33n (below), using

3-morpholin-4-yl-propylamine instead of N,N-diethyl-1,3-propanedi-

Step 2. 4-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)naphtha-

lene-1-sulfonyl Chloride. To a solution of the sulfonic acid

generated in Step 1 (2.0 g 4.6 mmol) in DMF (10 mL) was added

thionyl chloride (0.5 mL, 6.95 mmol). The resultant solution was

stirred at 25 °C for 3 h. The reaction was then quenched by pouring

into ice water, and this mixture was directly filtered to provide the

title compound (1.4 g) as a pale white solid, which was used without

1

amine. H NMR (300 MHz, CD₃OD) δ 8.76 (d, J ) 8.5 Hz, 1H),

8.39 (s, 1H), 8.32 (d, J ) 7.9 Hz, 1H), 8.24 (d, J ) 8.3 Hz, 1H),

7.92 (d, J ) 7.9 Hz, 1H), 7.74 (m, 3H), 7.38 (m, 3H), 3.79 (m,

6H), 3.18 (m, 2H), 2.92 (m, 4H), 2.76 (m, 4H), 2.56 (s, 3H), 2.04

(s, 1H), 1.79 (m, 2H), 1.57 (m, 2H), 1.28 (m, 2H); LC/MS m/z

594 [M + H]⁺; HRMS calcd for C₃₁H₃₉N₅O₅S [M + H]⁺, 594.2750;

found, 594.2740.

1

further purification. H NMR (300 MHz, DMSO-d₆) δ 8.95 (d,

J ) 8.4 Hz, 1H), 8.00 (m, 5H), 7.73 (d, J ) 8.3 Hz, 1H), 7.58 (m,

2H), 7.49 (m, 1H).

Step 3. To a solution of the above sulfonyl chloride (3.3 g 10.1

mmol) in CH₂Cl₂(80 mL) were added Et₃N (2.8 mL, 20.2 mmol)

and 4-amino-piperidine-1-carboxylic acid ethyl ester (2.1 mg, 12.1

mmol). The resultant solution was stirred at 25 °C for 17 h, at which

point it was quenched with water and extracted with CH₂Cl₂(3×).

The combined organic extracts were washed with brine, dried over

Na₂SO₄, filtered, and concentrated to provide a yellow oil, which

was purified via chromatography to afford ethyl 4-({[4-(1,3-dioxo-

1,3-dihydro-2H-isoindol-2-yl)-1-naphthyl]sulfonyl}amino)piperidine-

4-[4-(2-Methyl-benzoylamino)-naphthalene-1-sulfonylamino]-

piperidine-1-carboxylic Acid (3-Diethylamino-propyl)-amide

Formic Acid Salt (33n). This compound was prepared according

to the three-step sequence that follows. Step 1. To a solution of 30

(6.90 g, 15.0 mmol) in THF (100 mL) at 25 °C were added carbonyl

diimidazole (3.97 g, 1.59 mmol) and Et₃N (4.2 mL, 30.0 mmol).

The reaction mixture was stirred at 25 °C for 24 h, at which point

the reaction was quenched with water and the aqueous layer was

extracted with CH₂Cl₂(3×). The organic extracts were combined,

washed with brine, and dried over MgSO₄. The solution was filtered,

concentrated in Vacuo, and purified by column chromatography

(98:2 CH₂Cl₂/MeOH) to afford N-{4-[1-(imidazole-1-carbonyl)-

piperidin-4-ylsulfamoyl]-naphthalen-1-yl}-2-methyl-benzamide (6.8

1

1-carboxylate as a pale white solid (3.0 g, yield 58%). H NMR

(300 MHz, CDCl₃) δ 8.70 (d, J ) 8.5 Hz, 1H), 8.40 (d, J ) 8.0

Hz, 1H), 8.03 (m, 2H), 7.88 (m, 2H), 7.63 (m, 2H), 7.58 (m, 2H),

4.90 (m, 1H), 4.25 (q, J ) 6.9 Hz, 2H), 3.95 (m, 2H), 3.40 (m,

1H), 2.80 (m, 2H), 1.75 (m, 2H), 1.20 (m, 5H); LC/MS m/z 508

[M + H]⁺.

1

g, 87.7%). H NMR (300 MHz, DMSO-d₆) δ 10.6 (s, 1H), 8.70

Step 4. To a solution of the product from Step 1 (2.3 g, 4.5

mmol) in MeOH (50 mL) was added hydrazine (1.4 mL, 45.4

mmol) at 25 °C. The clear colorless solution became cloudy and

precipitation was observed. The solid was filtered and the filtrate

was concentrated in Vacuo to afford the desired product (1.7 g,

100%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (d,

J ) 8.6 Hz, 1H), 8.20 (d, J ) 8.3 Hz, 1H) 7.86 (d, J ) 8.3 Hz,

1H), 7.55 (m, 2H), 6.63 (m, 2H), 3.93 (q, J ) 7.2 Hz, 2H), 3.63

(m, 3H), 3.00 (m, 1H), 2.72 (m, 2H), 1.40 (m, 2H), 1.08 (m, 2H),

1.07 (t, J ) 7.2 Hz, 3H); LC/MS m/z 378 [M + H]⁺; HRMS calcd

for C₁₈H₂₃N₃O₄S [M + H]⁺, 378.1487; found, 378.1506.

(()-N-(4-{[(1-Butyrylpyrrolidin-3-yl)amino]sulfonyl}-1-naph-

thyl)-2-methylbenzamide (36). The title compound was prepared

according to general procedure C (Method 1), using tert-butyl

3-aminopyrrolidine-1-carboxylate instead of tert-butyl 4-aminopi-

peridine-1-carboxylate for Step 2. ¹H NMR (300 MHz, CD₃OD) δ

8.74 (m, 1H), 8.31 (dd, J ) 7.9, 4.5 Hz, 1H), 8.24 (m, 1H), 7.95

(m, 1H), 7.70 (m, 3H), 7.42 (m, 1H), 7.34 (m, 2H), 3.95 (m, 1H),

3.50 (m, 3H), 3.25 (m, 1H), 2.54(s, 3H), 2.16 (m, 1H), 2.00 (1.85,

3H), 1.60 (m, 2H), 0.98 (m, 3H); LC/MS m/z 480 [M + H]⁺;

HRMS calcd for C₂₆H₂₉N₃O₄S [M + H]⁺, 480.1957; found,

480.1980.

(d, J ) 8.2 Hz, 1H), 8.20 (m, 3H), 7.95 (m, 2H), 7.65 (m, 3H),

7.38 (m, 4H), 6.98 (s, 1H), 3.70 (d, J ) 13.4 Hz, 2H), 3.33 (m,

1H), 3.07 (m, 2H), 2.47 (s, 3H), 1.62 (m, 2H), 1.40 (m, 2H); LC/

MS m/z 518 [M + H]⁺.

Step 2. To a solution of the product from Step 1 (2.8 g, 5.41

mmol) in acetonitrile (25 mL) was added methyl iodide (3.07 g,

21.6 mmol). The reaction mixture was stirred at 50 °C for 17 h

and then concentrated in Vacuo to afford 1-methyl-3-{4-[4-(2-

methyl-benzoylamino)-naphthalene-1-sulfonylamino]-piperidine-1-

carbonyl}-3H-imidazol-1-ium iodide, which was used without

further purification. LC/MS m/z 532 [M + H]⁺.

Step 3. To a solution of the product from Step 2 (150 mg, 0.228

mmol) in CH₂Cl₂(5 mL) and DMF (5 mL) were added N,N-diethyl-

1,3-propanediamine (0.033 mL, 0.228 mmol) and Et₃N (0.053 µL,

0.228 mmol). The reaction mixture was stirred at 25 °C for 2 h, at

which point the solution was concentrated in Vacuo and directly

purified by reverse phase HPLC to afford 33n (0.141 g, 74%) as a

1

white solid. H NMR (300 MHz, CD₃OD) δ 8.76 (d, J ) 8.0 Hz,

1H), 8.52 (s, 1H), 8.32 (d, J ) 8.1 Hz, 1H), 8.24 (m, 1H), 7.93 (d,

J ) 7.9 Hz, 1H), 7.72 (m, 3H), 7.39 (m, 3H), 3.75 (d, J ) 13.6

Hz, 2H), 3.30 (m, 3H), 3.18 (m, 4H), 3.05 (t, J ) 7.5 Hz, 2H),

2.77 (t, J ) 11.4 Hz, 2H), 2.56 (s, 3H), 1.83 (m, 2H), 1.57 (m,

2H), 1.33 (m, 8H); LC/MS m/z 580 [M + H]⁺; HRMS calcd for

C₃₁H₄₁N₅O₄S [M + H]⁺, 580.2957; found, 580.2978.

N-(4-{[(1-Butyrylazetidin-3-yl)amino]sulfonyl}-1-naphthyl)-

2-methylbenzamide (37). The title compound was prepared

according to general procedure C (Method 1), using tert-butyl

3-aminoazetidine-1-carboxylate instead of tert-butyl 4-aminopip-

Ethyl 4-[({4-[(Piperidin-1-ylcarbonyl)amino]-1-naphthyl}-

sulfonyl)amino]piperidine-1-carboxylate (34). The title compound

was prepared according to general procedure A, using piperidine-

1-carbonyl chloride instead of benzoyl chloride in Step 1, and using

4-amino-piperidine-1-carboxylic acid ethyl ester instead of p-

1

eridine-1-carboxylate in Step 2. H NMR (300 MHz, CD₃OD) δ

8.78 (m, 1H), 8.28 (m, 2H), 7.99 (m, 1H), 7.74 (m, 3H), 7.38 (m,

3H), 4.18 (m, 2H), 3.92 (m, 1H), 3.77 (m, 1H), 3.52 (m, 1H), 2.56

(s, 3H), 1.96 (t, J ) 7.5 Hz, 2H), 1.51 (m, 2H), 0.86 (t, J ) 7.3

Hz, 3H). LC/MS m/z 466 [M + H]⁺; HRMS calcd for C₂₅H₂₇N₃O₄S

[M + H]⁺, 466.1800; found, 466.1793.

1

anisidine in Step 3. Yield: 0.007 g (4.5%) of a white solid. H

NMR (300 MHz, CD₃OD) δ 8.80 (m, 1H), 8.25 (m, 1H), 8.10 (m,

1H), 7.65 (m, 2H), 7.50 (m, 1H), 4.05 (m, 2H), 3.80 (m, 2H), 3.55

(m, 4H), 3.20 (m, 1H), 2.75 (m, 2H), 1.65 (m, 5H), 1.25 (m, 5H),

1.18 (m, 3H); LC/MS m/z 489 [M + H]⁺.

Ethyl 4-(1-Aminonaphthalene-4-sulfonamido)piperidine-1-

carboxylate (35). Step 1. 4-(1,3-Dioxo-1,3-dihydro-2H-isoindol-

2-yl)naphthalene-1-sulfonic Acid Pyridinium Salt. To a solution

of 4-amino-naphthalene-1-sulfonic acid (4.9 g 10.0 mmol) in

pyridine (15 mL) was added phthaloyl dichloride (3.2 mL, 22

mmol), and the resultant solution was stirred at 80 °C for 17 h.

The solvent was removed in Vacuo, and the crude material was

Ethyl 4-({[5-(Benzoylamino)-1-naphthyl]sulfonyl}amino)-

piperidine-1-carboxylate (38a). The title compound was prepared

according to general procedure A, using 5-amino-naphthalene-1-

sulfonic acid instead of 4-amino-naphthalene-1-sulfonic acid in Step

1 and using 4-amino-piperidine-1-carboxylic acid ethyl ester instead

1

of p-anisidine in Step 3. H NMR (300 MHz, CDCl₃) δ 9.40 (s,

1H), 8.56 (d, J ) 8.7 Hz, 1H), 8.22 (m, 2H), 8.02 (m, 2H), 7.78

(d, J ) 7.2 Hz, 1H), 7.61 (m, 1H), 7.47 (m, 4H), 6.72 (br, 1H),

3.97 (q, J ) 7.2 Hz, 2H), 3.80 (m, 2H), 3.15 (m, 1H), 2.67 (m,

2H), 1.55 (m, 2H), 1.34 (m, 2H), 1.12 (t, J ) 7.2 Hz, 3H). LC/MS

584 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 3

Jenkins et al.

[M + 1]⁺m/z 482; HRMS calcd for C₂₅H₂₇N₃O₅S [M + H]⁺,

482.1749; found, 482.1758.

(5) Zingoni, A.; Soto, H.; Hedrick, J. A.; Stoppacciaro, A.; Storlazzi, C.

T.; Sinigaglia, F.; D’Ambrosio, D.; O’Garra, A.; Robinson, D.;

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receptor CCR8 is preferentially expressed in Th2 but not Th1 cells.

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perresponsiveness. Annu. ReV. Immunol. 1999, 17, 255-281.

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Autocrine antiapoptotic stimulation of cultured adult T-cell leukemia

cells by overexpression of the chemokine I-309. Blood 2001, 98 (4),

1150-1159.

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Preparation of oxazolidin-2-ones as antiasthmatics. WO2004032856,

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of the cytokine receptor Ccr8 for the treatment of Th2- and

eosinophil-mediated diseases. WO2004058709, 2004. Dai, M.;

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Q.; Bennett, R.; Chi, S.; Jenkins, T.; Guan, B.; Kolbeck, R.; Smith,

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(10) In the early stages of the program, compound potency was determined

using FLIPR, which was also useful in identifying any undesired

agonist activity. Later, a higher throughput FMAT binding assay was

developed and implemented as the primary screening paradigm.

While not shown, there was excellent correlation between FMAT

(K_i) and FLIPR (IC₅₀) values. For clarity, SAR tables are organized

using data from one or the other of these assays but not both.

(11) Naphthalene core replacement results will be disclosed in a subsequent

manuscript.

(12) A table containing selected data from the Novascreen panel is

presented in the Supporting Information section. Note that, although

only select entries are reproduced here, compound 15 displayed

<20% inhibition at 10 µM across all 40 receptors evaluated.

(13) HEK-293 cells that were stably transfected with hERG cDNA were

obtained according to Zhou, Z.; Gong, Q.; Ye, B.; Fan, Z.; Makielski,

J. C.; Robertson, G. A. Biophys. J. 1998, 74, 230. Membrane

homogenates were prepared from cell pellets, suspended in 50 mM

Tris-HCl buffer (pH 7.4), containing 10 mM KCl and 1 mM MgCl₂,

and centrifuged at 4 °C. The hERG binding assay was conducted as

described in the following references: (a) Finlayson, K.; Sharkey, J.

In Optimization in Drug DiscoVery; Yan, Z., Caldwell, G. W., Eds.;

Humana Press: Totowa, NJ, 2004; pp 353-368. (b) Diaz, G. J.;

Daniell, K.; Leitza, S. T.; Martin, R. L.; Su, Z.; McDermott, J. S.;

Cox, B. F.; Gintant, G. A. J. Pharmacol. Toxicol. Methods 2004,

50, 187.

4-(8-Benzoylamino-naphthalene-2-sulfonylamino)-piperidine-

1-carboxylic Acid Ethyl Ester (38b). The title compound was

prepared according to general procedure A, using 8-aminonaph-

thalene-2-sulfonic acid instead of 4-amino-naphthalene-1-sulfonic

acid in Step 1 and using 4-amino-piperidine-1-carboxylic acid ethyl

1

ester instead of p-anisidine in Step 3. H NMR (300 MHz, CD₃-

OD) δ 8.62 (s, 1H), 8.05 (m, 3H), 7.90 (m, 2H), 7.60 (m, 5H),

4.00 (q, J ) 7.1 Hz, 2H), 3.80 (d, J ) 15.0 Hz, 2H), 3.20 (m, 1H),

2.80 (m, 2H), 1.65 (m, 2H), 1.20 (m, 2H), 1.15 (t, J ) 7.1 Hz,

3H); LC/MS m/z 482 [M + H]⁺; HRMS calcd for C₂₅H₂₇N₃O₅S

[M + H]⁺, 482.1749; found, 482.1759.

4-[6-(2-Methyl-benzoylamino)-naphthalene-2-sulfonylamino]-

piperidine-1-carboxylic Acid Ethyl Ester (38c). The title com-

pound was prepared according to general procedure A, using

6-amino-naphthalene-2-sulfonic acid for 4-amino-naphthalene-1-

sulfonic acid 2-methyl-benzoyl chloride for benzoyl chloride in Step

1 and using 4-amino-piperidine-1-carboxylic acid ethyl ester instead

1

of p-anisidine in Step 3. H NMR (300 MHz, DMSO-d₆) δ 10.65

(s, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 8.05 (m, 2H), 7.75 (m, 3H),

7.45 (m, 1H), 7.35(m, 1H), 7.30 (m, 2H), 3.90 (q, J ) 7.1 Hz,

2H), 3.65 (d, J ) 15.0 Hz, 2H), 3.15 (m, 1H), 2.72 (m, 2H), 2.35

(s, 3H), 1.50 (m, 2H), 1.20 (m, 2H), 1.05 (t, J ) 7.1 Hz, 3H);

LC/MS m/z 496 [M + H]⁺; HRMS calcd for C₂₆H₂₉N₃O₅S [M +

H]⁺, 480.1957; found, 480.1980.

Acknowledgment. The authors thank Nanda Gulavita,

Marjorie Solomon, and May Zhu for analytical support.

Supporting Information Available: Tabulated data from the

Novascreen panel for compound 15. This material is available free

of charge via the Internet at http://pubs.acs.org.

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JM061118E

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Design, synthesis, and evaluation of naphthalene-sulfonamide antagonists of human CCR8

DOI: 10.1021/jm061118e

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