AU2001280229A1

AU2001280229A1 - Novel thiourea derivatives and the pharmaceutical compositions containing the same

Info

Publication number: AU2001280229A1
Application number: AU2001280229A
Authority: AU
Inventors: Jin Kyu Choi; Yeon Su Jeong; Yung Hyup Joo; Hee Doo Kim; Jin Kwan Kim; Sun Young Kim; Hyun Ju Koh; Jee Woo Lee; Yong Sil Lee; Kyung Min Lim; Joo Hyun Moh; Uh Taek Oh; Young Im Oh; Hyeung Geun Park; Ok Hui Park; Young Ho Park; Young Ger Suh; Jung Bum Yi
Original assignee: Pacific Corp
Current assignee: Pacific Corp
Priority date: 2000-08-21
Filing date: 2001-08-20
Publication date: 2002-05-30
Anticipated expiration: 2021-08-20

Description

Novel thiourea derivatives and the pharmaceutical compositions containing the

same

Technical Field

The present invention relates to novel thiourea derivatives and the

pharmaceutical compositions containing the same, and particularly, to novel thiourea

compounds as a modulator for vanilloid receptor (VR) and the pharmaceutical

compositions thereof. Here, the modulator means the thing that can be bonded to the

receptor to act as an antagonist or an agonist.

Background Art

As diseases associated with the activity of vanilloid receptor, pain, acute pain,

chronic pain, neuropathic pain, post-operative pain, migraine, arthralgia, neuropathies,

nerve injury, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke,

urinary bladder hypersensitiveness, irritable bowel syndrome, a respiratory disorder

such as asthma or chronic obstructive pulmonary disease, irritation of skin, eye or

mucous membrane, fervescence, stomach-duodenal ulcer, inflammatory bowel disease

and inflammatory diseases can be enumerated. The present invention provides

pharmaceutical compositions for prevention or treatment of these diseases. Yet, the diseases described above are only for enumeration, not to limit the scope of

clinical application of vanilloid receptor modulator.

Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a main pungent component in

hot peppers. Hot peppers have been used, for a long time, not only as a spice but also

as traditional medicine in the treatment of gastric disorders and when applied locally,

for the relief of pain and inflammation (Szallasi and Blumberg, 1999, Pharm, Rev. 51,

ppl59-211). Capsaicm has a wide spectrum of biological actions, and not only

exhibits effects on the cardiovascular and respiratory systems but also induces pain and

irritancy on local application. Capsaicin, however, after such induction of pain,

induces desensitization, both to capsaicin itself and also to other noxious stimuli to

make the pain stopped. Based on this property, capsaicin and its analogues such as

olvanil, nuvanil, DA-5018, SDZ-249482, resiniferatoxin are either used as analgesic

agent, therapeutic agent for incontinentia urinae or skin disorder, or under development

(Wriggleworth and Walpole, 1998, Drugs of the Future 23, pp 531-538).

Transmissions of mechanical, thermal and chemical noxious stimuli are mainly

occurred by primary afferent nerve fibers of fine unmyelinated nerve (C-fiber) and thin

myelinated nerve (A-fiber), and main reaction site of capsaicin and its analog called

vanilloid is present at the nerve fiber transmitting the noxious stimuli. Capsaicin acts at the receptor existing on these neurons to induce potent stimuli by causing potent

inflow of mono-and di-valent cations such as calcium and sodium, then exhibits potent

analgesic effect by blocking the nervous function (Wood et al., 1988, J. Neurosci, 8,

pp3208-3220). Nanilloid receptor (VR-1) has been recently cloned and its existence

becomes clear(Caterina et al., 1997, Nature 389, pp816-824). It was clarified that this

receptor transmits not only stimuli by capsaicin anlogues(vanilloid) but also various

noxious stimuli such as proton and thermal stimuli (Tominaga et al., 1998, Neuron 21,

pp531-543). Based on this, it is considered that vanilloid receptor functions as a

integrative modulator against various noxious stimuli and carries out critical role in

transmissions of pain and noxious stimuli. Recently, knock-out mouse in which gene

encoding for vanilloid receptor was deleted was prepared (Caterina et al., 2000, Science

288, pρ306-313; Davis et al, 2000, Nature 405, ρpl83-187). Compared to normal

mice, the mouse was found out to exhibit much reduced reaction to thermal stimuli and

thermal pain, while exhibiting no difference in general behavior, reconfirming the

importance of the receptor in transmission of noxious signal. However, except proton,

no other endogenous ligand, not exogenous ligand such as capsaicin, actually involved

in transmission of noxious stimuli at vanilloid receptor was known. It is considered

that leucotriene metabolite represented by 12-hydroperoxyeicosatetraenoic acid

(12-HPETE) (Hwang et al, 2000, PNAS 11, ρp6155-6160) and arachidonic aicd derivatives such as anandamide (Zygmunt et al., 2000, Trends Pharmocol. Sci. 21,

pp43-44) act as the most likely endogenous ligand for the receptor and proton acts as a

cofactor with receptor-stimulating activity, rather than as a direct ligand.

As such, a capsaicin-sensitive sensory nerve cell and a vanilloid receptor

existing in the cell are distributed over the entire body and play basic function in

transmission of noxious stimuli and pain, further act as crucial factor in expression of

neuro genie inflammation, thereby to have close relation with the cause of neuropathies,

nerve injury, stroke, asthma, chronic obstructive pulmonary diseases, urinary bladder

hypersensitiveness, irritable bowel syndrome, inflammatory bowel disease, fervescence,

skin disorder and inflammatory disease. Lately, their correlation even with

neuropathic disease is suggested (WO 99/00125). Recently, attention has focused to

the role of afferent sensory nerve responding to capsaicin in gastrointestinal injury, and

it was proposed that the afferent nerve might have a dual character that it exhibits

protective action against gastric damage by improving gastric microcirculation through

releasing peripheral neuropeptide such as CGRP (calcitonin gene-related peptide), while

inducing gastric injury by stimulating sympathetic nervous system (Ren et al., 2000,

Dig. Dis. Sci. 45, pp830-836). It is determined that vanilloid receptor modulator has

very high potential to be used for prevention or treatment of the said various diseases by modulating the activity of the vanilloid receptor conducting such varied functions.

As described above, there has been widely studied for clinical application of

vanilloid receptor agonist, and it is understood that there is a possibility that the agonist

derived from the present studies will be developed for clinical application. Though it

may be, theoretically, anticipated that antagonist for this receptor would exhibit

substantial degree of inhibitory action against pain and neurogenic inflammation, it was

found out that the competitive antagonist for this receptor, capsazepine, almost the only

one known until now, failed to exhibit significant analgesic and anti-inflammatory

effects (Perkins and Campbell, 1992, Br. J. Pharmacol. 107, pp329-333). Therefore,

not much progress was made on this field. However, recently, there has been a report

on significant results for analgesic action of capsazepine in animal studies (Kwak et al,

1998, Neurosci. 86, pp619-626; Santos and calixto, 1997, Neurosci. Lett. 235, ρp73-76),

in particular, the inventors of the present invention clearly demonstrated through animal

studies the analgesic and anti-inflammatory effects of the strong vanilloid receptor

antagonists which were identified through experiments in our laboratory, and based on

this, strongly suggest the development potential of vanilloid receptor antagonist as an

analgesic, anti-inflammatory and anti-ulcerous agent. Yet, though the vanilloid

receptor antagonist or agonist derived from the present studies will mainly act based on the antagonistic or agonistic activity of itself, even a possibility that it could exhibit the

pharmacological activity tlirough transformation into agonist or antagonist via

metabolism after absorption into body is not to be excluded.

The present invention is to provide novel compounds which are acted as a

modulator for vanilloid receptor and exhibit excellent analgesic, anti-inflammatory and

anti-ulcer effects, and pharmaceutical compositions containing the same.

Disclosure of the invention

In order to attain the above objects, the present invention provides a novel

compound of the following formula (I):

(i)

wherein,

X represents S, O or -NCN;

Y represents single bond, NR³, O or S;

R¹ represents

pyridinylmethyl, pyrrolylmethyl, oxazolylmethyl, pyrazolylmethyl, imidazolylmethyl,

anthracenylmethyl, naphthylmethyl, quinolinylmethyl, alkoxycarbonyl or

alkylcarbonyloxy (wherein, m is 0, 1, 2, 3 or 4; R⁴ and R⁵ are independentyl hydrogen,

lower alkyl having 1 to 5 carbon atoms, hydroxy, methanesulfonylamino, lower alkoxy

having 1 to 5 carbon atoms, methoxyalkoxy, methoxyalkoxyalkyl, alkoxycarbonyloxy,

benzyloxy, acetoxymethyl, propinoyloxymethyl, butoxyalkyl, trimethylacetoxy,

trimethylacetoxymethyl or halogen; and R⁶ and R⁷ are independently hydrogen, lower

alkyl having 1 to 5 carbon atoms);

R² represents R⁸-(CH₂)_n-

{wherein, n is 0, 1, 2, 3 or 4; R⁸ is benzoyl, imidazolyl, indolyl, indazolyl,

thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, benzimidazolyl, chromonyl or benzothiazolyl

substituted or unsubstituted with lower alkyl having 1 to 5 carbon atoms, nitro, amino,

cyano, methanesulfonylamino, formyl or halogen, or

(wherein, R is hydrogen, halogen, lower alkyl having 1 to 5 carbon atoms, lower alkoxy having 1 to 5 carbon atoms, hydroxy, nitro, cyano, -NHSO₂R¹², -S(O)_PR¹²,

-NR¹³R¹⁴, carboxyl; R¹⁰ is hydrogen, nitro, NHSO₂R¹², S(O)_PR¹² or NR¹³R¹⁴; R¹¹ is

19 hydrogen or cyano; R is lower alkyl having 1 to 5 carbon atoms, methylphenyl,

NR^R¹ , trifluoromethyl or alkenyl; R¹³ and R¹⁴ are independently hydrogen or lower

alkyl having 1 to 5 carbon atoms; and p is 0 or 2.); or

or

(wherein, Z is O, S, NH or -NCH₃; R¹⁵ is hydrogen, halogen, lower alkyl

1 1 having 1 to 5 carbon atoms, nitro, cyano, -NHSO₂R , -S(O)pR ,

N,N-dimethylaminomethyl or alkoxycarbonylamino; and p and R¹² have the same

meanings as defined in R⁹);

or

r

(wherein, W is O, S, NH, NR¹⁶, -N(SO₂CH₃)- or -CH₂-; and R¹⁶ is pyridinyl

or pyrimidinyl substituted or unsubstituted with lower alkyl having 1 to 5 carbon atoms,

nitro, methanesulfonylamino or halogen; or benzyl or phenethyl substituted or unsubstitued with lower alkyl having 1 to 5 carbon atoms, alkoxy, hydroxy, nitro,

methanesulfonylamino or halogen);

or

(wherein, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are independently hydrogen, halogen, lower

alkyl having 1 to 5 carbon atoms, alkoxy, methylenedioxy,

methanesulfonylaminomethyl, alkoxycarbonyl, hydroxy, sulfamoyl, aminoalkoxy,

alkoxycarbonylamino, -NHCH CO₂H, alkoxyalkylcarbonylamino,

alkoxycarbonylalkylamino, nitro, foπnyl, acetyl, for ylamino, acetoxyamino, cyano,

-OSO₂CH₃, -NHSO₂R¹², -N(SO₂R¹²)CH₃, -N(SO₂R¹²)₂, -S(O)_PR¹², -NR¹³R¹⁴,

thiocarbamoyl, -C(=O)NHNH₂, -C(=O)NHOH, -C =O)NHOCH₃, -PO(=O)(OCH₃)₂,

carboxyl, NHBoc, -NHC(=O)SCH₃ or guanidine; R²² and R²³ are independently

hydrogen, halogen, alkoxy or hydroxy; and p, R¹², R¹³ and R¹⁴ have the same

meanings as defined in R⁹);

or hydroxyphenylalkyl or (methanesulfonylaminophenyl)alkyl} ; and

R³ represents hydrogen, alkyl or cycloalkyl having 1 to 8 carbon atoms, lower

alkylphenyl having 1 to 5 carbon atoms, pyridinylethyl, bisphenyhnethyl; or phenylalkyl substituted with lower alkyl having 1 to 5 carbon atoms, halogen or

methanesulfonylamino .

Preferably, in the above formula (I),

X represents S, O or -NCN;

Y represents NR³ or O;

R¹ represents

(wherein, m is 0, 1 or 2; and R⁴ and R⁵ are independently hydrogen, lower

alkyl having 1 to 4 carbon atoms, hydroxy, methanesulfonylamino, lower alkoxy having

1 to 5 carbon atoms, methoxyalkoxy, methoxyalkoxyalkyl, benzyloxy, acetoxymethyl,

trimethylacetoxymethyl or halogen);

R² represents R⁸-(CH₂)_n-

{wherein, n is 0, 1, 2 or 3; and R⁸ is benzoyl, imidazolyl, indolyl, indazolyl,

thiazolyl, pyrazolyl, oxazolyl, benzimidazolyl or chromonyl substituted or unsubstituted

with lower alkyl having 1 to 5 carbon atoms, nitro, amino, cyano,

methanesulfonylamino, formyl or halogen, or

(wherein, R⁹ is hydrogen, halogen, lower alkyl having 1 to 4 carbon atoms, lower

alkoxy having 1 to 4 carbon atoms, nitro, cyano, -NHSO₂R¹², -NR¹³R¹⁴ or carboxyl;

R¹⁰ is hydrogen, nitro, NHSO₂R¹² or -NR¹³R¹⁴; R¹¹ is hydrogen or cyano; R¹² is lower

alkyl having 1 to 4 carbon atoms, methylphenyl, -NR¹³R¹⁴ or trifluoromethyl; R¹³ and

R¹⁴ are independently hydrogen or lower alkyl having 1 to 4 carbon atoms; and p is 0

or 2);

or

(wherein, Z is O, S, NH or -NCH₃; R¹⁵ is hydrogen, lower alkyl having 1 to 4

carbon atoms, nitro, cyano or NHSO₂R¹²; and R¹² has the same meanings as defined

in R⁹); or or

(wherein, W is O, S, NH, NR¹⁶ or -CH -; and R¹⁶ is pyridinyl or pyrimidinyl

substituted or unsubstituted with lower alkyl having 1 to 4 carbon atoms, nitro or

methanesulfonylamino; or benzyl or phenethyl substituted or unsubstituted with lower

alkyl having 1 to 4 carbon atoms, alkoxy, hydroxy or methanesulfonylamino);

or

alkyl having 1 to 5 carbon atoms, alkoxy, methylenedioxy,

methanesulfonylaminomethyl, alkoxycarbonyl, hydroxy, sulfamoyl,

alkoxycarbonylamino, -NHCH CO₂H, alkoxyalkylcarbonylamino,

alkoxycarbonylalkylamino, nitro, formyl, acetyl, formylamino, acetoxyamino, cyano,

-OSO₂CH₃, -NHSO₂R¹², -N(SO₂R¹²)CH₃, -N(SO₂R¹²)₂, -S(O)_pR¹², NR¹³R¹⁴,

thiocarbamoyl, -C(=O)NHNH₂, -C(=O)NHOH, -C(=O)NHOCH₃, carboxyl, NHBoc,

-NHC(=O)SCH₃, guanidine; R²² and R²³ are independently hydrogen, alkoxy or hydroxy; and p, R¹², R¹³ and R¹⁴ have the same meanings as defined in R⁹);

or hydroxyphenylalkyl or (methanesulfonylaminophenyl)alkyl} ; and

R³ represents hydrogen, alkyl having 1 to 4 carbon atoms, lower alkylphenyl

having 1 to 3 carbon atoms, pyridinylethyl or bisphenyhnethyl; or phenylalkyl

substituted with lower alkyl having 1 to 4 carbon atoms, halogen or

methanesulfonylamino .

More preferably, in the above formula ( ),

X represents S, O or -NCN;

Y represents NR³ or O;

R¹ represents

(wherein, m is 1 or 2; and R and R⁵ are independently hydrogen, t-butyl,

hydroxy, methanesulfonylamino, lower alkoxy having 1 to 5 carbon atoms,

methoxymethoxy, methoxyethoxy, benzyloxy, acetoxymethyl, trimethylacetoxymethyl

or halogen);

R² represents R⁸-(CH₂)_n-

{wherein, n is 1, 2 or 3; R⁸ is benzoyl, imidazolyl, indolyl, indazolyl, thiazolyl, pyrazolyl or benzimidazolyl substituted or unsubstituted with methyl, nitro or halogen;

or

(wherein, R is hydrogen, halogen, methyl, nitro or methanesulfonylamino; R is

hydrogen or nitro; and R 11 is hydrogen or cyano);

or

(wherein, Z is O, S, NH or -NCH₃; and R¹⁵ is hydrogen, methyl, nitro, cyano

or methanesulfonylamino);

or

(wherein, W is O, S, NH, NR , 16 o „_r - rCnHj₂-; . a „n„dJ τ Rj l<> is pyridinyl, pyrimidinyl; or benzyl

or phenethyl substituted or unsubstituted with methyl, methoxy or hydroxy); or

or

alkyl having 1 to 4 carbon atoms, methoxy, methylenedioxy,

methanesulfonylaminomethyl, methoxycarbonyl, hydroxy, sulfamoyl,

alkoxycarbonylamino, -NHCH₂CO H, methoxymethylcarbonylamino,

alkoxycarbonylalkylammo, nitro, acetyl, formylamino, acetoxyamino, cyano,

thiocarbamoyl, -C(=O)NHNH₂, -C(=O)NHOH, -C(=O)NHOCH₃, carboxyl, NHBoc,

-NHC(=O)SCH₃, guanidine; R²² and R²³ are independently hydrogen, methoxy or

hydroxy; and p, R¹², R¹³ and R¹⁴ have the same meanings as defined in R⁹);

or hydroxyphenylalkyl or (methanesulfonylaminophenyl)alkyl} ; and

R represents hydrogen, methyl, isopropyl, isobutyl, cyclohexyl, benzyl,

phenethyl or bisphenylmethyl; or phenylalkyl substituted with t-butyl, halogen or

methanesulfonylamino .

Preferable examples of the compounds of formula (I) according to the present invention are as follows:

l-(4-t-butylbenzyl)-3-[2-(l-methyl-lH-pyrrol-2-yl)ethyl]thiourea;

l-(4-t-butylbenzyl)-3-(4-amino-2,5-difluorobenzyl)thiourea;

1 -(4-t-butylbenzyl)-3 -(4-sulfamoylbenzyl)thiourea;

l-(4-t-butylbenzyl)-3-(3-fluoro-4-methanesulfonylaminobenzyl)thiourea;

l-phenethyl-3-(3-fluoro-4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butylbenzyl)-3-(3-chloro-4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butylbenzyl)-3-(3-methoxycarboxyl-4-methanesulfonylaminobenzyl)thio

urea;

l-(4-t-butylbenzyl)-3-(3-carboxyl-4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butylbenzyl)-3-((3-N-hydroxyaminocarbonyl-4-methanesulfonylamino)b

enzyl)thiourea;

l-(4-t-butylbenzyl)-3-(3-methoxycarboxylbenzyl)thiourea;

l-(4-t-butylbenzyl)-3-(3-carboxylbenzyl)thiourea;

l-(4-t-butylbenzyl)-3-(2,3,5,6-tetrafluoro-4-methanesulfonylaminobenzyl)thiou

rea;

l-(4-t-butylbenzyl)-3-(2,5-difluoro-4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butylbenzyl)-3-[(3-methanesulfonylamino-6-pyridinyl)methyl]thiourea;

l-(4-t-butylbenzyl)-3-(2,6-dichloro-5-methanesulfonylaminobenzyl)thiourea; l-(4-t-butylbenzyl)-3-(4-methanesulfonylaminophenethyl)thiourea;

l-(4-t-butylbenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butylbenzyl)-3-[2,6-difluoro-3-(N-methanesulfonylamino)benzyl]thioure

a;

l-(4-t-butylbenzyl)-3-[3-(N-methanesulfonylamino)benzyl]thiourea;

l-(4-t-butyl-2-methoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butyl-2-ethoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butyl-2-propoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butyl-2-butoxybenzyl)-3-(4-meth-mesulfonylarninobenzyl)thiourea;

l-(4-t-butyl-2-isopropoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butyl-2-isobutoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butyl-2-neopentoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butyl-2-methoxymethoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thio

urea;

1 -(4-t-butyl-2-methoxyethoxybenzyl)-3 -(4-methanesulfonylaminobenzyl)thiour

ea;

l-(4-t-butyl-2-benzyloxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;

l-(2-acetoxymethyl-4-t-butylbenzyl)-3-(4-methanesulfonylaminobenzyl)thioure

a; l-(4-t-butylbenzyl)-3-[2-(4-methylthiazol-5-yl)ethyl]thiourea;

1 -(4-t-butylbenzyl)-3 -((2-chloro-5-pyridinyl)methyl)thiourea;

l-(4-t-butylbenzyl)-3-(2-pyridin-2-ylethyl)thiourea;

l-(4-t-butylbenzyl)-3-(2,5-difluorobenzyl)thiourea;

1 -(4-t-butylbenzyl)-3-(3-fluorophenethyl)thiourea;

1 -(4-t-butylbenzyl)-3 -(4-sulfamoylphenethyl)thiourea;

1 -(4-t-butylbenzyl)-3 -(4-morpholinylethyl)thiourea;

l-(4-t-butylbenzyl)-3-[2-(lH-imidazol-4-yl)ethyl]thiourea;

l-(4-t-butylbenzyl)-3-[2-thiophen-2-ethyl]thiourea;

1 -(4-t-butylbenzyl)-3 -(4-methanesulfonylamino- 1 -methyl- 1 H-pyrrol-2-yl)thiou

rea;

1 -benzyl- 1 -(3 -(4-hydroxy-3 -methoxyphenyl)propyl)-3 -phenethylthiourea;

1 -(3 -(4-hydroxy-3 -methoxyphenyl)propyl)- 1 -phenethyl-3 -phenethylthiourea;

1 -bisphenylmethyl- 1 -(3 -(4-hydroxy-3-methoxyphenyl)propyl)-3 -phenethylthio

urea; or

N"-cyano-N-(4-t-butylbenzyl)-N'-(4-methanesulfonylaminobenzyl)guanidine.

More preferable examples of the compounds of formula (I) according to the

present invention are follows:

l-(4-t-butylbenzyl)-3-(3-fluoro-4-methanesulfonylaminobenzyl)thiourea; l-(4-t-butylbenzyl)-3-(3-chloro-4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butylbenzyl)-3-(3-methoxycarboxyl-4-methanesulfonylaminobenzyl)thio

urea;

1 -(4-t-butylbenzyl)-3 -(4-methanesulfonylaminobenzyl)thiourea; or

l-(4-t-butyl-2-isobutoxybenzyl)-3-(4-methanesulfonylamino)thiourea.

The compounds according to the present invention can chemically be

synthesized by the following reaction schemes. However, these are given only for

illusion of the invention and not intended to limit them.

[SCHEME 1]

LiAIH₄ y X

R¹NCX

^R

R _^Ή X N / ^R ether N

H

1-1 1-2

1-5, R¹=PhCH₂CH₂-, R= 5-indolyl-, X=S

1-6, R¹=PhCH₂CH₂-, R= 5-indolyl-, X=0

1-7, R¹= -t-BuPhCH₂ -, R= 5-indolyl-, X=S

1-8, R¹=4-t-BuPhCH₂ -, R= 4-(methylsulfonyl)phenyl-, X=S

1-9, R¹= -t-BuPhCH₂ -, R=N-methyl-2-pyrrolyl methyl-, X=S

R¹NCS jj

R^ACN H_ZA ^{^}R^A catalyst R¹HN N-^"R^A H

1-3 1-4 1-10, R¹=4-t-BuPhCH₂-, R -4-amino-3,5-dichlorophenyl-

1-11, R¹=4-t-BuPhCH₂-, R^A = pyrazinyl

1-12, R¹=4-t-BuPhCH₂-, R^A = 3-cyano-2-pyrazinyl-

1-13, R¹=4-t-BuPhCH₂-, R^A = 4-amino-2,5-difluorophenyl-,

As depicted in the above Scheme 1, the nitrile compound 1-1 or 1-3 is reduced

with litliium aluminium hydride or hydrogen to afford an amine 1-2 or 1-4, and then suitable isothiocyanate or isocyanate is reacted therewith to prepare thiourea or urea

compound 1-5 ~ 1-13.

[SCHEME 2]

As depicted in the above Scheme 2, pipsyl chloride is treated with ammonia

solution to afford compound 2-2 and the nitrile compound 2-3 is obtained therefrom

using palladium catalyst. The compound 2-3 is subjected to catalytic reduction using

palladium and concentrated hydrochloric acid to prepare amine compound 2-4, and

compounds 2-5, 2-6 and 2-7 are synthesized therefrom according to the procedure as

described in Scheme 1.

[SCHEME 3]

3-7, R¹ = PhCH₂CH₂-, X=S

As depicted in the above Scheme 3, 2-fluoro-4-iodo phenylamine compound

3-1 is mesylated, and cyano group is introduced thereinto in the presence of palladium

catalyst. And the compound 3-3 is reduced to afford primary amine compound 3-4.

The obtained intermediate is reacted with isocyanate or isothiocyanate to synthesize

compounds 3-5 ~ 3-7. And their derivatives such as compound 3-8 ~ 3-10 (Example

16 ~ 18) and 4-6 ~ 4-13 (Example 24 - 31) are synthesized according to the similar

procedure as the synthetic method of the compounds 3-5 ~ 3-7.

[SCHEME 4]

As depicted in the above Scheme 4, the compound 4-1 obtained according to

the procedure as described in Example 19 is reacted with oxalyl chloride to give acid

chloride, and then the acid chloride is subjected to various reaction to yield compounds

4-2 - 4-5.

[SCHEME 5]

N

5-4 R= 4- ethanesulfonylamino-2,3,5,6-tetrafluorophenyl-

5-5 R= 4- ethaπesulfonylamino-2,5-difluorophenyl-

5-6 R= 5-methanesulfoπylaminopyridin-2-yl-

5-7 R= 4-methanesulfonylamino-3,5-dichlorophenyl-

5-8 R= 4-methanesulfonylamiπophenylmethyl-

5-9 R= 2-methanesulfonylaminop-.eny|methyl-

As depicted in the above Scheme 5, amine compound 5-1 is mesylated and the obtained compound 5-2 is hydrogenated to afford amine compound 5-3, and then

4-t-butylbenzylisothiocyanate is reacted therewith to synthesize compound 5-4 - 5-9.

[SCHEME 6]

As depicted in the above Scheme 6, the amine group of

4-nitrobenzylamine hydrochloride compound 6-1 is protected. Nitro group thereof is

reduced to give amino group and then methylchlorothiol formate is reacted therewith to

prepare compound 6-3, followed by reacting 4-t-butylbenzylisothiocyanate therewith to

obtain compound 6-5.

[SCHEME 7]

As depicted in the above Scheme 7, guanidine group and cyano group are

introduced into 4-iodoaniline 7-1 to prepare compound 7-3, and the compound 7-3 is

reduced in the presence of palldium catalyst to give amine compound 7-4. The

compound 7-4 is reacted with 4-t-butylbenzylisothiocyanate, followed by deprotection

to synthesize compound 7-6.

[SCHEME 8]

8-4 As depicted in the above Scheme 8, 4-aminobenzylamine is selectively

protected with t-butoxycarbonyl group (Boc) to prepare compound 8-1 and

methanesulfonyl chloride is reacted with NH₂ group thereof to yield compound 8-2.

Boc group is removed therefrom in acidic condition, and then

2-(l-methyl-lH-pyrrol-2-yl)ethylisocyanate is reacted therewith to yield compound 8-4.

[SCHEME 9]

R^D R^E

9a H H

9b H COCH₃

9c S0₂CH₃ S0₂CH₃ 9d H S0₂CH₃

9e H S0₂CF₃ 9f H CHO

9g H CSNH₂

9h H C0₂CH₂CH₃

Compounds 9a - 9h are synthesized by reacting 4-t-butylbenzylisothiocyanate

with corresponding benzylamine derivatives, respectively.

[SCHEME 10]

1)TFA,CH₂CI₂, 0°C

₁₀.3 2) TEA, THF, 12h, Boc₂ ^Q

3) MsC!,TEA, CH₂CI₂, 0 °C

As depicted in the above Scheme 10, hydroxy group of

2-hydroxy-4-nitrobenzaldehyde is protected with TBDPS, and then oxime 10-1 is

prepared therefrom. The compound 10-1 is reduced with hydrogen in the presence of

palladium catalyst and protected with Boc group to afford compounds 10-2 and 10-3.

The compond 10-2 is reacted with t-butylbenzylisothiocyanate, and then TBDPS is

removed therefrom to synthesize compound 10-4. Two protecting groups of

compound 10-3 are removed using trifluoroacetic acid and the deprotected compound is

protected with Boc group in the presence of triethylamine to synthesize compound 10-5.

TBDPS and Boc group are removed from the compound 10-5 and

t-butylbenzylisothiocyanate is reacted therewith in the presence of triethylamine to give

compound 10-6.

[SCHEME 11] 1) Pd/C. H₂, MeOH, c-HCI 2) TEA, THF; B0C₂O

As depicted in the above Scheme 11, 2,6-difluoro-3-nitrobenzonitrile is reduced

and then proteced with Boc group to prepare compound 11-1. The amino group of the

compound 11-1 is mesylated, and after removing of the Boc group therefrom, the

mesylated compound is reacted with 4-t-butylbenzylisothiocyanate to give compound

11-2.

[SCHEME 12]

R^G=NHMs or NMs₂

As depicted in the above Scheme 12, the carbonyl group of nitrobenzaldehyde

is converted into oxime group, and the oxime group and nitro group are reduced with

hydrogen in the presence of Pd/C catalyst to prepare amine compound 12-1. The amine compound 12-1 is selectively protected and mesylated to afford compound 12-2.

Boc group is removed from compound 12-2, and, in the presence of triethylamine,

t-butylbenzylisothiocyanate compound is reacted therewith to synthesize compound

12-3a ~ 12-3g.

[SCHEME 13]

Tf₂θ

As depicted in the above Scheme 13, 4-t-butyl-2-hydroxybenzonitrile 13-1 as a

starting material is O-alkylated and reduced to prepare amine compound 13-3.

4-Methanesulfonaminobenzylisothiocyanate is reacted therewith to yield thiourea

compound 13-4a ~ 13-4k. And compound 13-1 is reacted with O-triflate, and

subsequently with carbon monoxide in the presence of palladium acetate catalyst to

yield ester 13-6. The ester 13-6 is reduced, and then reacted with 4-methanesulfonaminobenzylisothiocyanate to prepare alcohol compound 13-8. The

prepared compound 13-8 is sbjected to condensation reaction with acid to yield the

corresponding thiourea compound 13-9a and 13-9b.

[SCHEME 14]

RCH₂OH RCH₂NP t or R = 4-methylthiophenyl- RCH₂CI R = 4-methylthiaEol-5-methyl- R = 6-chloro-3-pyridinyl-

As depicted in the above Scheme 14, respective compounds 14-1 and 14-4 are

obtained from 4-(methylthio)benzylalcohol and 4-methylthiazol-5-ethanol, respectively,

under Mitsunobu condition, or obtained by introducing mesyl group into

4-(methylthio)benzylalcohol and 4-methylthiazol-5-ethanol, respectively, followed by

reacting potassium phthalimide therewith. Phthalimide group is removed from

compounds 14-1 and 14-4 with hydrazine to give amine compounds 14-2 and 14-5,

respectively. The obtained amine compounds 14-2 and 14-5 are separately reacted

with one equivalent of 4-t-butylbenzylisothiocyanate to the objective thiourea

compounds 14-3 and 14-6, respectively. 2-Chloro-5-chloromethylpyridine is reacted with potassium phthalimide to yield compound 14-7, and then compound 14-9 is

synthesized according to the same procedure as the synthetic method of the compounds

14-3 and 14-6.

[SCHEME 15]

Thiomo holine is reacted with 2-(bromoethyl)phthalimide in the presence of

base to yield compound 15-1. Phthaloyl group of the compound 15-1 is treated with

hydrazine to prepare amine compound 15-2 and 4-t-butylbenzylisothiocyanate is reacted

therewith to afford the objective compound 15-3.

[SCHEME 16]

R^!NCS

B

R²NH₂ *A A

^H c ^H

R² = furanylmethyl, 2-pyridinyl, 2-thiophenemethyl, 2-thiophenethyl,

2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, 2-pyridinylethyl,

2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl,

3,4-difluorobenzyl, 3,5-difluorobenzyl, 2,5-difluorobenzyl, 2,4-difluorobenzyl,

2,6-difluorobenzyl, 2,3,4-trifluorobenzyl, 2,3,6-trifluorobenzyl,

2-fluorophenethyl, 3-fluorophenethyl, 4-fluorophenethyl, 3,4-difluorophenethyl,

4-methoxyphenethyl, 3-methoxyphenethyl, 2-methoxyphenethyl,

3,4-dimethoxyphenethyl, 3,4,5-trimethoxybenzyl,4-aminosulfonylphenethyl,

3 ,4-dihydroxyphenethyl, 3 ,4-methylenedioxyphenyl,

4-morpholino-,4-morpholinoethyl, 4-morpholinopropyl,

1 -piperidineethyl, lH-imidazolyl-4-ethyl, lH-indolyl-3-ethyl,benzimidazol-2-yl,

5-nitro-pyridin-2-ylaminoethyl, lH-imidazolyl- 1 -propyl,

1 -methylpyrrolidin-2-ylethyl

(2-hydroxy- 1 -methyl-2-phenyl)ethyl

R¹ = 4-t-butylbenzyl, phenethyl,4-methoxybenzyl

As depicted in the above Scheme 16, compound A and isothiocyanate

compound B of the above formula are reacted with each other in the presence of

suitable solvent (dichloromethane, acetonitrile, ethylacetate, dimethylformamide) using

suitable condition (triethylamine) to yield thiourea compound C (Example 16 ~ 122).

[SCHEME 17] i ,CHO NH₂OH.HCI

NaOAc, MeOH ~ \ //

17-1 , R^J=H, R¹= 4-t-BuPhCH₂- 17-2 , R^J=CH₃, R¹=4-t-BuPhCH₂- 17-3 , R^J=CH₃, R¹=P CH₂CH₂-

17- , R¹=4-t-BuPhCH₂-

As depicted in the above Scheme 17, pyrrolecarboxaldehyde and

5-nitro-2-thiophenaldehyde are respectively converted to oximes, and the oximes are

reduced to prepare primary amine hydrochloride. The prepared intermediates are

reacted with isothiocyanates to give compounds 17-1 ~ 17-4, respectively.

[SCHEME 18]

As depicted in the above Scheme 18, ethyl-2-methyl nicotinate 18-1 is reduced

to prepare alcohol, and then amine is introduced thereinto. The prepared intermediate is reacted with 4-t-butylbenzylisothiocyanate to yield compound 18-5.

[SCHEME 19]

As depicted in the above Scheme 19, 5-nitro-lH-indazole is reduced to prepare

amine, and then isothiocyanate is reacted therewith to afford compounds 19-1 and 19-2.

[SCHEME 20]

As depicted in the above Scheme 20, 2-fluoro-4-hydroxybenzonitrile is reduced

with sodium borohydride in the presence of nickel catalyst, and proctected with Boc

group to prepare protected amine compounds 20-la and 20-lb. Phenol group of

compound 20-la is mesylated, and Boc group is removed therefrom, followed by

reacting with t-butylbenzylisothiocyanate to give compound 20-2a. And compound 20-2b is obtained from compound 20-lb, according to the similar procedure as the

synthetic method of compound 20-2a.

[SCHEME 21]

As depicted in the above Scheme 21, 2-aminopicoline is reacted with pivaloyl

chloride to yield compound 21-1. The compound 21-1 is brominated with NBS to

prepare compound 21-2 and potassium phthalimide is reacted therewith to obtain

compound 21-3 protected with phthaloyl group. Pivaloyl group is removed from

compound 21-3 in the presence of concentrated sulfuric acid, and

methanesulfonylchloride is reacted therewith to prepare compound 21-5. The prepared

compound 21-5 is treated with hydrazine and reacted with

4-t-butylbenzylisothiocyanate to yield compound 21-7. [SCHEME 22]

Nitro group is selectively introduced into pyrrolecarboxaldehyde under nitric

acid/acetic anhydride condition and the compound 22-1 was reduced with borane to

prepare alcohol 22-2. The prepared compound 22-2 is reacted with

4-t-butylbenzylisothiocyanate in the presence of sodium hydride to yield compound

22-3. And pyrrolecarboxaldehyde is reacted with hydroxylamine hydrochloride in the

presence of l-methyl-2-pyrrolidinone (NMP) as a solvent to produce nitrile compound

22-4 and nitro goup is introduced thereinto under the similar condition as above. The

nitro goup is reduced and mesylated to give compound 22-7. The nitrile group of the

compound 22-7 is reduced in the presence of palladium/carbon and

4-t-butylbenzylisothiocyanate is reacted therewith to synthesize compound 22-9. [SCHEME 23]

As depicted in the above Scheme 23, 4-nitrobenzylamine hydrochloride is

converted to methanesulfonyl derivatives 23-1. Nitro group of the compound 23-1 is

reduced with tin (II) chloride and 4-t-butylbenzylisothiocyanate is reacted therewith to

give compound 23-2.

[SCHEME 24]

R^KR^LNH = 4-Benzyl-piperazine

4-Pyridin-2-yl-piρerazine 4-Pyrirnidin-2-yl-piperazine 1 ,2,3,4-tetrahydroisoquinoline 4-Pyrazolecarboxylic acid

R¹⁼ 4-t-butylbenzyl, phenethyl As depicted in the above Scheme 24, amine compound D is reacted with

isothiocyanate compound B in suitiable solvent to yield thiourea compound E (Example

136 - 141).

[SCHEME 25]

,

As depicted in the above Scheme 25, benzaldehyde, phenylacetaldehyde and

cinnamaldehyde derivatives are subjected to reductive amination with alkylamine to

prepare the corresponding sencondary amines, respectively, and

phenethylisothiocyanates are reacted therewith to obtain compounds 25-1 ~ 25-26

(Example 142 ~ 167, respectively).

[SCHEME 26]

As depicted in the above Scheme 26, 2-fluoro-4-iodo

methanesulfonylbenzylamine 3-2 is subjected to cross coupling using palladium to

prepare compound 26-1 and the compound 26-1 is hydrogenated in the presence of

palladium/carbon to give compound 26-2. The compound 26-2 is reacted with

4-t-butylbenzylamine to sythesize amide compound 26-3.

[SCHEME 27]

4-t-butylbenzoylchloride is reacted with

3-fluoro-4-methanesulfonylaminobenzylamine hydrochloride (3-4) to yield amide

compound 27. [SCHEME 28]

3-4

As depicted in the above Scheme 28, 3-fluoro-4-methanesulfonylaminobenzyl

amine hydrochloride 3-4 is reacted with 4-t-butylbenzyl bromide and carbon disulfide in

the presence of cesium carbonate to yield compound 28.

[SCHEME 29]

As depicted in the above Scheme 29, 4-t-butylbenzylamine is reacted with

triphosgene to prepare isocyanate, and 3-fluorophenethylamine is reacted therewith to

afford compound 29.

[SCHEME 30]

As depicted in the above Scheme 30, 2-fluorobenzoyl chloride is reacted

successively with KSCN and 4-t-butylbenzylamine to obtain final compound 30.

SCHEM [E 31]

31-1 R² = 2-Pyridinylethyl

31-2 R² = 3-Fluorophenethyl

31-3 R²= 3,4-Difluorophenethyl

31-4 R² = 2-Fluorobenzyl

31-6 R² = 4-Met aπesulfoπylaminobenzyl-

PbNCN

EtOAc

31-7, R = 2,6-difluoro-3-methanesulfonylaminophenyl- 31-8, R = 2-fluoro-S-methanesulfonylaminophenyl- 31-9, R = R = 1-methyl-1H-pyrrol-2-ylmethyl-

As depicted in the above Scheme 31, cyanoguanidine compounds are

synthesized by two methods. As one method, 4-t-butylbenzylamine is reacted with

dimethyl N-cyanodithioiminocarbonate or diphenyl cyanocarbonimidate, and then

amine is reacted therewith to yield final compounds 31-1 ~ 31-6 (Example 173 ~ 178).

And thiourea compound is reacted with lead cyanamide to give compounds 31-7 ~ 31-9 (Example 179 - 181).

[SCHEME 32]

As depicted in the above Scheme 32, tetralone is converted to oxime and the

oxime is reduced with nickel catalyst and sodium borohydride to prepare amine

compounds 32-1, 32-3 and 32-5. These compounds are reacted with various

benzylisothiocyanates to give compounds 32-2, 32-4 and 32-6 ~ 32-10. And methoxy

group of compounds 32-3 and 32-5 are treated with hydrobromic acid to form hydroxy

group and the resulting compound are reacted with various benzylisothiocyanates in the

presence of triethylamine to yield compounds 32-11 and 32-12.

[SCHEME 33]

As depicted in the above Scheme 33, 2-amino-3-formylchromone 33-1 or

3,5-dimethylpyrazole-l-methanol 33-3 is, repectively, reacted with

4-t-butylbenzylisothiocyanate in the presence of base to give compounds 33-2 or 33-4.

[SCHEME 34]

As depicted in the above Scheme 34, 4-t-butylbenzaldehyde is reacted with

phosphonate to prepare compound 34-2, and the compound 34-2 is reduced and hydrolyzed to give 4-t-butylhydrocinnamic aicd 34-4. The obtained compound is

reacted with compound 3-4 which is prepared according to the procedure as described

in Example 13, to synthesize final compound 34-5.

[SCHEME 35]

35-3 35-4 35-5

As depicted in the above Scheme 35,

N-t-butyloxycarbonyl-p-aminobenzylamine 8-1 is reacted with sulfamoyl chloride in

basic condition to prepare compound 35-1. The prepared compound 35-1 is

deprotected with trifluoroacetic acid to afford amine, and 4-t-butylbenzylisothiocyanate

is subjected to condensation reaction therewith to yield thiourea compounds 35-2a,

35-2b and 35-2c. 3-Nitro-4-aminobenzonitrile is mesylated to give compound 35-4,

and then nitrile group of the compound 35-4 is reduced with borane to afford amine.

4-t-Butylbenzylisothiocyanate is subjected to condensation reaction therewith to

synthesize thiourea compound 35-5. [SCHEME 36]

As depicted in the above Scheme 36, oxime 36-2, prepared from

4-aminoacetophenone as a starting material, is reduced to yield compound 36-3.

Isothiocyanates are reacted therewith to give compounds 36-4 and 36-5. And

compound 36-1 is reduced with methylamine to afford benzylamine derivatives, and

4-t-butylbenzylisothiocyanate is reacted therewith to synthesize compound 36-6.

The compound of formula (I) according to the present invention can be

provided as a pharmaceutical composition containing pharmaceutically acceptable

carriers, adjuvants, or diluents. For instance, the compounds of the present invention

can be dissolved in oils, propylene glycol or other solvents which are commonly used to produce an injection. Suitable examples of the carriers include physiological saline,

polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, etc., but are not limited

to them. For topical administration, the compounds of the present invention can be

formulated in the form of ointment or cream.

The pharmaceutical composition containing the compound of the present

invention as an active ingredient can be used for preventing or treating pain, acute pain,

and inflammatory diseases.

Hereinafter, the formulating methods and kinds of excipients will be described,

but the present invention is not limited to them.

The compound according to the present invention may also be used in the forms

of pharmaceutically acceptable salts thereof, for example, alkali metals salts such as

sodium salts, potassium salts and the like; alkali earth metals salts such as calcium salts,

magnesium salts and the like; amines such as triethanolamine or ammonium salts, and may be used either alone or in combination or in admixture with other pharmaceutically

active compounds.

The compounds of the present invention may be formulated into injections by

dissolving, suspending or emulsifying in water-soluble solvent such as saline and 5%

dextrose, or in water-insoluble solvents such as vegetable oils, synthetic fatty acid

glyceride, higher fatty acid esters and propylene glycol. The formulations of the

invention may include any of conventional additives such as dissolving agents, isotonic

agents, suspending agents, emulsifiers, stabilizers and preservatives.

The preferable dose level of the compounds according to the present invention

depends upon a variety of factors including the condition and body weight of the patient,

severity of the particular disease, dosage form, and route and period of administration,

but may appropriately be chosen by those skilled in the art. The compounds of the

present invention are preferably administered in an amount ranging from 0.001 to 100

mg/kg of body weight per day, and more preferably from 0.01 to 30 mg/kg of body

weight per day. Doses may be administered once a day, or several times a day with

each divided portions. The compounds of the present invention are used in a

pharmaceutical composition in an amount of 0.0001 — 10% by weight, and preferably

0.001 — 1% by weight, based on the total amount of the composition.

The pharmaceutical composition of the present invention can be administered to a mammalian subject such as rat, mouse, domestic animals, human being and the like

via various routes. The methods of administration which may easily be expected

include oral and rectal administration; intravenous, intramuscular, subcutaneous,

intrauterine, duramatral and intracerebro ventricular injections.

Best Mode for Carrying Out the Invention

The present invention is more specifically explained by the following examples.

However, it should be understood that the present invention is not limited to these

examples in any manner.

Example 1: Synthesis of l-(lH-indoI-5-yImethyl)-3-phenethylthiourea (1-5)

Step 1: synthesis of (lH-indol-5-yl)methylamine

To an ice cold suspension of aluminium chloride (126mg) in ether (1.5 ml) was

added a suspension of lithium aluminium hydride (55 mg) in ether (1.5 ml), followed by

stirring for 5 min. A solution of 5-cyanoindole (103 mg) in ether (5 ml) was added

dropwise thereto. The mixture was stirred at room temperature for 6 hours, followed by adding aqueous Rochel solution thereto and then stirring for 5 hours. The resulting

mixture was basified with IM aqueous sodium hydroxide solution, extracted twice with

ethyl acetate (50 ml), washed with saturated aqueous sodium chlroride solution, dried

over magnesium sulfate and then filtered to yield (lH-indol-5-yl)methylamine (93 mg,

88 %).

1H NMR(300MHz, CD₃OD) : δ 7.46(d, 1H, J=1.0Hz), 7.29(d, 1H, J=8.3Hz),

7.14(d, 1H, J=3.2Hz), 7.02(dd, 1H, J=1J, 8.3Hz), 6.34(dd, 1H, J=0.7, 3.2Hz), 3.89(s,

2H)

Step 2: synthesis of l-(lH-indol-5-ylmethyl)-3-phenethylthiourea (1-5)

(lH-indol-5-yl)methylamine (8.5 mg) prepared in Step 1 was dissolved in

dimethylformamide (100 f ) and the solution was diluted with dichloromethane (1 ml).

To the diluted solution was added phenethylisothiocyanate (40 μi) and the mixture was

stirred at room temperature for 2 hours. The resulting mixture was concentrated under

reduced pressure and the obtained residue was chromatographed on a silica gel column

eluting with ethyl acetate/hexane (2/3) to yield

l-(lH-indol-5-ylmethyl)-3-phenethylthiourea (15 mg, 83 %).

1H NMR(300MHz, CDC1₃) : δ 8.17(s, 1H), 7.53(s, 1H), 7.28(d, 1H, J=8.3Hz),

7.11-7.19(m, 5H), 6.98-7.04(m, 2H), 6.46(t, 1H, J-2.2Hz), 6.03(s, 1H), 5.59(s, 1H), 4.44(s, 2H), 3.66(m, 2H), 2.77(t, 2H, J=6.8Hz)

Example 2: Synthesis of l-(lH-indol-5-ylmethyI)-3-phenethylurea (1-6)

(lH-indol-5-yl)methylamine (12.5 mg) was reacted with phenethylisocyanate

(30 μJL) according to the similar procedure as described in step 2 of Example 1, to give

l-(lH-indol-5-ylmethyl)-3-phenethylurea (1-6) (19 mg, 76 %).

1H NMR(300MHz, CDC1₃) : δ 8.16(s, IH), 7.44(s, IH), 7.27(d, lH, J=8.3Hz),

7.02-7.21(m, 7H), 6.43-6.45(m, IH), 4.48(t, IH), 4.3 l(d, 2H, J=5.6Hz), 4.22(m, IH),

3.37(q, 2H, J=6.8Hz), 2Jl(t, 2H, J=6.8Hz)

Example 3: Synthesis of l-(4-t-butylbenzyl)-3-(lH-indol-5-ylmethyl)thiourea (1-7)

S

Step 1: synthesis of 4-t-butylbenzylisothiocyanate Di-2-pyridyl thionocarbonate (45 mg) was dissolved in methylenechloride (2

ml) and to the solution were added 4-t-butylbenzylamine (29 mg) and triethylamine (20

βJt), followed by stirring at room temperature for 2 hours. The reaction solution was

concentrated under reduced pressure and the obtained residue was chromatographed on

a silica gel column eluting with ethyl acetate/hexane (1/10) to yield

4-t-butylbenzylisothiocyanate (26 mg, 71 %).

1H NMR(300MHz, CDC1₃) : δ 7.39(d, 2H, J=8.5Hz), 7.23(d, 2H, J=8.3Hz),

4.65(s, 2H), 1.30(s, 9H)

Step 2: Synthesis of l-(4-t-butylbenzyl)-3-(lH-indol-5-ylmethyl)thiourea (1-7)

(lH-indol-5-yl)methylamine (15 mg) was reacted with

4-t-butylbenzylisothiocyanate (20 mg) according to the similar procedure as described

in Step 2 of Example 1, to synthesize

l-(4-t-buylbenzyl)-3-(lH-indol-5-yhnethyl)thiourea (1-7) (21 mg, 70 %).

1H NMR(300MHz, CDC1₃) : δ 8.33(s, IH), 7.48(s, IH), 7.19-7.33(m, 4H),

7.03-7.10(m, 4H), 6.47(t, IH), 6.18(s, IH), 6.06(s, IH), 4.58(d, 2H, J=13Hz), 1.26(s,

9H)

Example 4: Synthesis of l-(4-t-butylbenzyl)-3-(4-methanesulfonylbenzyl)thiourea (1-8)

Lithium aluminum hydride (0.38 g) was dissolved in anhydrous ether (20 ml).

The solution was cooled to 0°C and 4-(methylsulfonyl)benzonitrile (1.81 g) was

slowly added dropwise thereto. The mixture was stirred for 3 hours while allowed

to slowly warm up to room temperature and the reaction was quenched with 20%

aqueous sodium hydroxide solution and water. The water layer was washed with

ether, and then the ether layer was mixed with the organic layer. The combined

organic layer was dried over anhydrous magnesium sulfate and concentrated. The

residue was purified by column-chromatography (acetone) to yield a liquid (0.3 g).

The obtained liquid was dissolved in dichloromethane (10 ml) and

4-t-butylbenzylisothiocyanate (0.33 g) was added thereto, followed by stirring at

room temperature for 19 hours. The reaction mixture was concentrated and then

purified by column-chromatography (hexane/ethyl acetate = 1/1) to yield compound

1-8 (0.02 g) as a white solid.

1H NMR(300MHz, CDC1₃) : δ 7.85-7.81(m, 2H), 7.41-7.30(m, 4H), 7.27-7.23(m, 2H), 6.25(brs, IH), 6.05(brs, IH), 4.88(d, 2H, J= 6Hz), 4.60-4.55(m, .2H),

3.01(s, 3H), 1.31(s, 9H)

Example 5: Synthesis of

l-(4-t-butylbenzyl)-3-[2-(l-methyl-lH-pyrrol-2-yl)ethyl]thiourea (l-9)

Step 1: Synthesis of (l-methyl-lH-pyrrol-2-yl)ethylamine

l-methyl-2-pyrroleacetonitrile (2 g) was slowly added dropwise to a suspension

of lithium aluminium hydride (695 mg) in ether (100 ml) while the temperature was

adjusted to -78°C. The miture was stirred for 1 hour, and then stirred for 3 hours at

room temperature. After confirming the completion of the reaction using TLC, 15 %

aqueous sodium hydroxide solution (10 ml) and water (20 ml) were added dropwise and

the resulting mixture was stirred for 1 hour. The reaction mixture was extracted three

times with ether. The organic layer was washed with saturated aqueous sodium

chloride solution and concentrated under reduced pressure to yield amine compound.

The amine compound, which was not purified, was used in the following reaction. Step 2: Synthesis of

l-(4-t-butylbenzyl)-3-[2-(l-methyl-lH-pyrrol-2-yl)ethyl]thiourea (l-9)

Amine (250 mg) prepared in Step 1 and 4-t-butylbenzylisothiocyanate (420 mg)

were dissolved in ethyl acetate (20 ml) and the solution was stirred at room

temperature for 12 hours. The resulting mixture was concentrated under reduced

pressure to remove the solvent and the residue was purified by

column-chromatography (ethyl acetate/liexane = 1/3) to yield compound 1-9 (498 mg,

75 %) as a liquid.

1H NMR (300MHz, CDC1₃) δ 7.37(d, 2H), 7.19(d, 2H), 6.54(m, IH), 6.01(m,

IH), 5.83(s, IH), 4.46(brs, 2H), 3.72(brs, 2H), 2.841(t, 2H, J=6.9Hz), 1.31(s, 9H)

Example 6: Synthesis of

l-(4-amino-3,5-dichlorobenzyl)-3-(4-t-butylbenzyl)thiourea (l-10)

4-amino-3,5-dichlorobenzonitrile (260 mg) was dissolved in methanol (20 ml)

and a small amount of concentrated hydrochloric acid and 5 % palladium/carbon catalyst was added thereto. After the mixture was stirred for 15 hours, the reaction

mixture was filtered through celite and concentrated. The obtained mixture was

dissolved in dichloromethane (10 ml), and 4-t-butylbenzylisothiocyanate (200 mg)

and triethylamine (2 ml) was added thereto, followed by stirring at room temperature

for 15 hours. The resulting mixture was extracted with water and dichloromethane,

and the residue was purified by column-chromatography (hexane/ethyl acetate = 1/1)

to yield compound 1-10 (72 mg, 13 %). as a liquid.

^!H NMR (300MHz, CDC1₃) δ 7.40-7.00(m, 6H), 5.92(brs, 2H), 4.58(m, 2H),

4.45(m, 2H), 3.71 (bra, 2H), 1.31(s, 9H)

Example 7: Synthesis of l-(4-t-butylbenzyl)-3-(pyrazin-2-yl-methyl)thiourea (1-11)

Pyrazinecarbonitrile (500 mg) and 10 % palladium/carbon (450 mg) were

dissolved in anhydrous methanol (30 ml) and the mixture was stirred under hydrogen

atmosphere for 12 hours.

The resulting mixture was filtered, and then the filtrate was concentrated under reduced pressure. The obained compound (200 mg) and 4-t-butylbenzylisothiocyanate

(330 mg) were dissolved in ethyl acetate (30 ml). The solution was stirred for 12

hours and then concentrated. The resulting residue was purified by

column-chromatography (ethyl acetate/hexne = 3/1) to yield the compound 1-11 (271

mg, 53 %).

¹H NMR (300MHz, CDC1₃) δ 8.51(s, IH), 8.41(s, IH), 8.16(s, IH), 7.38(m,

2H), 7.29(m, 2H), 5.10(s, 2H), 4.86(d, 2H, J=2.25Hz), 1.33(s, 9H)

Example 8: Synthesis of l-(4-t-butylbenzyl)-3-(3-cyanopyrazin-2-ylmethyl)thiourea

(1-12)

2,3-pyrazinedicarbonitrile (200 mg) and 10 % palladium/carbon (200 mg) were

atmosphere for 12 hours. The resulting mixture was filtered, and then the filtrate was

dried under reduced pressure to give an amine. The obtained amine (150 mg) and

4-t-butylbenzylisothiocyanate (180 mg) were dissolved in ethyl acetate (30 ml). The solution was stirred for 12 hours to complete the reaction and purified by

column-chromatography (ethyl acetate/hexane = 3/1) to yield the compond 1-12 (77 mg,

25 %) as a white solid.

1H NMR (300MHz, CDC1₃) δ 8J6(m, IH), 8.67(m, IH), 7.38(m, 4H), 5.38(s,

2H), 4.98(d, 2H, J=2.7Hz), 1.32(s, 9H)

Example 9: Synthesis of

l-(4-amino-2,5-difluorobenzyl)-3-(4-t-butylbenzyl)thiourea (l-13)

Step 1: Synthesis of 4-amino-2,5-difluorobenzylamine

4-amino-2,5-difluorobenzonitrile (400 mg) and Raney nickel Catalyst were

added to methanol (20 ml) and the mixture was stirred under hydrogen atmosphere

at room temperature for 18 hours. After confirming the completion of the reaction,

the resulting mixture was filtered through celite and the filtrate was concentrated

under reduced pressure. The following procedure was carried out, using the

concentrate which was not purified. Step 2: Sythesis of l-(4-amino-2,5-difluorobenzyl)-3-(4-t-butylbenzyl)thiourea

(1-13)

The compound (330 mg) obtained in Step 1 and 4-t-butylbenzylisothiocyanate

(428 mg) were dissolved in ethyl acetate (40 ml) and the solution was stirred at room

temperature for 6 hours. The mixture was concentrated under reduced pressure and the

residue was purified by column-chromatography (ethyl acetate/hexane = 1/3) to yield

the compound 1-13 (190 mg, 25 %).

1H NMR(300MHz, CDC1₃) : δ 7.37(m, 2H), 7.22(m, 2H), 6.95(m, IH),

6.43(m, IH), 6.08(brs, IH), 5.90(brs, IH), 4.59(s, 2H), 4.57(s, 2H), 3.83(s, 2H), 1.31(s,

9H)

Example 10: Synthesis of l-phenethyl-3-(4-sulfamoylbenzyl)thiourea (2-5)

Step 1: Synthesis of 4-iodo-l-sulfamoylbenzene (2-2) Pipsylchloride (100 mg) was dissolved in 28 % ammonia solution (4 ml) and

the solution was stirred at room temperature for 1 hours. The resulting mixture was

extracted with ethyl acetate (20 ml), washed with water and saturated aqueous sodium

chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under

reduced pressure. The residue was chromatographed on column eluting with ethyl

acetate/hexane (1/2) to yield the compound 2-2 (89 mg, 100 %).

1H NMR(300MHz, CD₃OD) : δ 7.91(td, IH, J=9.0Hz), 7.63(td, IH, J=9.0Hz)

Step 2: Synthesis of 4-cyano-l-sulfamoylbenzene (2-3)

The compound 2-2 (58 mg) prepared in Step 1 was dissolved in

dimethylformamide (2 ml) and to the solution were added zinc cyanide [Zn(CN)₂] (58

mg) and tetrakistriphenylphosphine palladium (10 mg), followed by stirring at 80°C for

12 hours. The resulting mixture was basified with aqueous sodium bicarbonate

solution, diluted with ethyl acetate (30 ml), washed with water and saturated aqueous

sodium chloride solution, dried over anhydrous magnesium sulfate, and then

concentrated under reduced pressure. The obtained residue was chromatographed on

silica gel column eluting with ethyl acetate/hexane (1/2) to yield the compound 2-3 (30

mg, 80 %).

1H NMR(300MHz, CDC1₃) : δ 7.92-7.96 (m, 2H), 1.69-1.13 (m, 2H), 6.47 (s, 2H)

Step 3: Sythesis of 4-sulfamoylaminobenzene (2-4)

The compound 2-3 (52 mg) prepared in Step 2 was dissolved in methanol (2

ml) and to the solution were added a catalytic amount of 10% palladium/carbon and

concentrated hydrochloric acid (10 μl), followed by stirring under hydrogen gas

atmosphere at room temperature for 1 hour. The resulting mixture was diluted in ether,

filtered through celite, neutralized with IN aqueous sodium hyroxide solution, and then

washed with water and saturate aqueous sodium chloride solution. The obtained

residue was dried over anhydrous magnesium sulfate and then concentrated under

reduced pressure to yield the compound 2-4 (26 mg, 50 %).

1H-NMR(300MHz, CD₃OD) : δ 7.77 (dd, 2H, J= 1.7, 6.6 Hz), 7.41 (d, 2H, J

= 8.5 Hz), 3.80 (s, 2H)

Step 4: Synthesis of l-phenethyl-3-(4-sulfamoylbenzyl)thiourea (2-5)

The compound 2-4 (10 mg) prepared in Step 3 was dissolved in

dimethylformamide (100 μl). The solution was diluted with dichloromethane (2 ml)

and to the solution was added phenethylisothiocyanate (1.0 ml), followed by stirring at

room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and the obtained residue was chromatographed on a column eluting with ethyl

acetate/hexane (1/1) to yield the compound 2-5 (11 mg, 59 %).

1H NMR(300MHz, CD₃OD) : δ 7.82-7.85 (m, 2H), 7.42 (d, 2H, J = 8.5 Hz),

7.16-7.30 (m, 5H), 4J8 (br s, 2H), 3.72 (br s, 2H), 2.88 (t, 2H, J= 7.1 Hz)

Example 11: Synthesis of l-phenethyl-3-(4-sulfamoylbenzyl)urea (2-6)

Compound 2-6 (13 mg, 79 %) was synthesized according to the same procedure

as described in Step 4 of Example 10 except that compound 2-4 (9 mg) was reacted

with phenethylisocyanate (100 μl).

1H NMR(300MHz, CD₃OD) : δ 7.82-7.84 (m, 2H), 7.39 (d, 2H, J = 8.3 Hz),

7.15-7.32 (m, 5H), 4.35 (s, 2H)

Example 12: Synthesis of l-(4-t-butylbenzyl)-3-(4-sulfamoylbenzyl)thiourea (2-7)

Compound 2-7 (7 mg, 96 %) was synthesized according to the same procedure

as described in Step 4 of Example 10 except that compound 2-4 (7 mg) and

4-t-butylbenzylisothiocyanate (10 mg) were used as reactants.

1H NMR(300MHz, acetone-d₆) : δ 7.81 (d, 2H, J = 8.3 Hz), 7.48 (d, 2H, J =

8.3 Hz), 7.36 (dd, 2H, J= 1.7, 6.3 Hz), 7.26 (d, 2H, J= 8.3 Hz), 4.91 (br s, 2H), 4.75 (br

s, 2H), 1.29 (s, 9H)

Example 13: Synthesis of

l-(4-t-butylbenzyl)-3-(3-fluoro-4-methanesulfonylaminobenzyl)thiourea (3-5)

Step 1: Synthesis of 2-fluoro-4-iodo-l-methanesulfonylaminobenzene (3-2)

2-fluoro-4-iodophenylamine (1.50 g) was dissolved in dichloromethane (40 ml)

and to the solution were added pyridine (1.02 ml) and methanesulfonylchloride (700

μl). The mixture was stirred at room temperature for 1 hour and 1.5 N aqueous

hydrochloric acid was added thereto to quench the reaction. The resulting mixture was

extracted with dichloromethane, dried over anhydrous magnesium sulfate, and then

concentrated under reduced pressure. The obtained residue was column-chromatographed (ethyl acetate/hexane — 1/1) to yield the compound 3-2 (1.89

g, 95%).

1H NMR(300MHz, CDC1₃) : δ 7.47(dd, 2H, J=1.2, 1.7Hz) 7.30(t, IH,

J=8.3Hz) 6.51(s, IH) 3.01(s, 3H)

Step 2: Synthesis of 4-cyano-2-fluoromethanesulfonylaminobenzene (3-3)

The compound 3-2 (1.81 g) prepared in Step 1 was dissolved in

dimethylformamide (10 ml) and to the solution were added zinc (II) cyanide (845 mg)

and tetrakistriphenylphosphine palladium (187 mg), followed by stirring at 80-90°C for

1.5 hours. The resulting mixture was diluted with ethyl acetate (20 ml), washed with

water and saturated aqueous sodium chloride solution, and then dried over anhydrous

magnesium sulfate. The remaining liquid was concentrated under reduced pressure

and the obtained residue was chromatographed on column eluting with ethyl

acetate/hexane (1/2) to yield the compound 3-3 (1.03 g, 80 %).

1H NMR(300MHz, CDC1₃) : δ 7.65(t, IH, J=8.0Hz) 7.41(d, IH, J=9.8Hz)

7.37(dd, 1H, J=9.5, 1.7Hz) 6.83(s, IH) 3.07(s, 3H)

Step 3: Sythesis of 3-fluoro-4-methanesulfonaminobenzylamine hydrochloride

(3-4) The compound 3-3 (1.03 g) prepared in Step 2 was dissolved in methanol (20

concentrated hydrochloric acid (3 ml), followed by stirring at room temperature under

hydrogen gas atmosphere for 1 hour. The resulting mixture was diluted in ether,

filtered through celite, concentrated under reduced pressure, and then washed with ethyl

acetate to yield the compound 3-4 (1.13 g, 92 %).

1H NMR(300MHz, CD₃OD) : δ 7.57(t, IH, J=8.3Hz) 7.33(dd, IH, J=9.8,

1.8Hz) 7.27(d, IH, J=8.5Hz) 4.11(s, 2H) 3.02(s, 3H)

Step 4: Synthesis of

l-(4-t-butylbenzyl)-3-(3-fluoro-4-methanesulfonylaminobenzyl)thiourea (3-5)

Compound 3-4 (1.13 g) prepared in Step 3 was dissolved in dimethylformamide

(6 ml) and the solution were diluted in dichloromethane (35 ml). To the diluted

solution was added 4-t-butylbenzylisothiocyanate (1.09 g) and triethylamine (1.2 ml) in

order, and then the mixture was stirred at room temperature for 2 hours. The resulting

mixture was concentrated under reduced pressure, diluted with ethyl acetate (20 ml),

and then washed with water and saturatated aqueous sodium chloride solution. The

residue was dried over anhydrous magnesium sulfate, and concentrated under reduced

pressure. The obtained residue was purified by cbromatography on column eluting with ethyl acetate/hexane (2/3) to yield the compound 3-5 (1.23 g, 65 %).

1H NMR(300MHz, CDC1₃) : δ 7.41(t, IH, J=8.2Hz) 7.34(d, 2H, J=8.0Hz)

7.20(d, 2H, J=8.0Hz) 7.01(d, IH, J=11.9Hz) 6.97(d, IH, J=9.8Hz) 6.69(brs, IH) 4.68(s,

2H) 4.54(s, 2H) 2.97(s, 3H) 1.28(s, 9H)

Example 14: Synthesis of

l-phenethyl-3-(3-fluoro-4-methanesulfonaminobenzyl)urea (3-6)

3-6

Compound 3-6 (17 mg, 36 %) was synthesized according to the same procedure

as desribed in Step 4 of Example 13 except that compound 3-4 (28 mg) was reacted

with phenethylisocyanate (38 μl).

1H NMR(300MHz, CD₃OD) : δ 7.40(t, IH, J=8.2Hz) 7.28 ~7.06(m, 7H)

4.69(s, 2H, CH2) 3.87 (t, 2H) 2.98(s, 3H) 2.87(t, 2H, J=7.1Hz)

Example 15: Synthesis of

l-phenethyl-3-(3-fluoro-4-methanesulfonylaminobenzyl)thiourea (3-7)

Compound 3-7 (8.3 mg, 24 %) was synthesized according to the same

procedure as desribed in Step 4 of Example 13 except that compound 3-4 (20 mg) and

phenethylisofhiocyanate (27 μl) were used as reactants.

1H NMR(300MHz, CD₃OD) : δ 7.40(t, IH, J=8.2Hz) 7.29~7.14(m, 5H)

7.10~7.03(m, 2H) 4.26(s, 2H) 3.36 (t, 2H) 2.95(s, 3H) 2J6(t, 2H, J=7.1Hz)

Compounds 3-8, 3-9 and 3-10 were synthesized according to the similar

procedure as described in the Example 13, and NMR data thereof are shown below.

Example 19: Synthesis of

l-(4-t-butylbenzyl)-3-(3-carboxyl-4-methanesulfonylaminobenzyl)thiourea (4-l)

Compond 3-10 (1.08 g) prepared according to the procedure as described in

Example 13 was dissolved in acetone (20 ml) and to the solution was added 2.5 M

aqueous lithium hydroxide solution (15 ml). The mixture was stirred at room

temperature for 5 hours and the solvent was removed therefrom. The residue was

dissolved in ethyl acetate and then extracted to yield the compound 4-1 (980 mg, 94 %).

1H NMR(300MHz, CD₃CD) : δ 8.07(d, IH, J=2.2Hz) 7.63(d, IH, J=8.5Hz)

7.51(d, IH) 7.34(d, 2H, J=8.5Hz) 7.20(d, 2H, J=8.0Hz) 4J3(s, 2H) 4.66(s, 2H) 3.03(s,

3H) 1.29(s, 9H)

Example 20: Synthesis of

l-(4-t-butylbenzyl)-3-((3-N-methoxyaminocarbonyl-4-methanesulfonylamino)benz

yl)thiourea (4-2)

Compoxmd 4-1 (50 mg) prepared according to the procedure as described in

Example 19 was dissolved in benzene (2 ml) and to the solution was added dropwise

oxalyl chloride (100 μl), followed by refluxing for 2 hours. The resulting mixture

was concentrated under reduced pressure, and to the concentrate was added

methoxylamine (92 mg). The mixture was dissolved in pyridine (2 ml), and the

solution was stirred at room temperature for 24 hours and then concentrated under

reduced pressure. To the concentrate was added ethyl ether, and the mixture was

filtered and concentrated under reduced pressure. The obtained residue was

chromatogrphed on column eluting ethyl acetate to yield the compound 4-2 (16 mg,

30 %).

1H NMR(300MHz, CDC1₃) : δ 10.14(s, IH) 9.38(s, IH) 7.55(m, 3H) 7.32(m,

4H) 5.04(s, 2H) 5.01(s, 2H) 3.82(s, 3H) 3.00(s, 3H) 1.25(s, 9H)

Compound 4-3 was synthesized according to the similar procedure as described

in the Example 20, and NMR data thereof are shown below.

Example 22: Synthesis of

l-(4-t-butylbenzyl)-3-(3-hydrazido-4-methanesulfonylaminobenzyl)thiourea (4-4)

Compound 4-1 (76 mg) prepared according to the procedure as described in Example 19 was dissolved in benzene (3 ml) and to the solution was added dropwise

oxalyl chloride (200 μl), followed by refluxing for 3 hours. The resulting mixture

was concentrated under reduced pressure and to the concentrate was added hydrazine

(55 mg). The mixture was dissolved in tefrahydrofuran (3 ml), and the solution was

stirred at 0°C for 2 hours and then concentrated under reduced pressure. The obtained

residue was chromatogrphed on silica gel column (ethyl acetate/hexane = 1/1) to yield

the compound 4-4 (5 mg, 6 %).

1H NMR(300MHz, DMSO-d₆) : δ 10.9(s, IH), 10.2(s, IH), 7.75(s, IH),

7.64(d, IH), 7.55(d, IH), 7.41(s, 4H), 5.04(s, 2H), 5.00(s, 2H), 3.14(s, 3H), 1.20(s, 9H)

Example 23: Synthesis of

l-(4-t-butylbenzyl)-3-(3-cyano-4-methanesulfonylaminobenzyl)thiourea (4-5)

Compound 4-1 (50 mg) prepared according to the procedure as described in

Example 19 was dissolved in benzene (3 ml) and to the solution was added dropwise

oxalyl chloride (100 μl), followed by refluxing for 3 hours. The resulting mixture

was concentrated under reduced pressure and to the concentrate was added sulfamide (106 mg). The mixtxire was dissolved in sulfolane (2 ml) and the solution was refluxed

at 120°C for 3 hours. To the reaction mixture was added 1 N-aqueous sodium

hydroxide solution to quench the reaction. The resulting mixture was extracted with

ether, washed several times with water, dried over anhydrous magnesium sulfate, and

then concentrated under reduced pressure. The obtained residue was

column-chromatogrphed (ethyl acetate/hexane = 1/1) to yield the compound 4-5 (8 mg,

16 %).

1H NMR(300MHz, CDC1₃) : δ 10.8(s, IH), 7.65(m, 2H), 7.58(m, IH), 7.33(d,

4H), 5.05(s, 4H), 3.01(s, 3H), 1.24(s, 9H)

Compounds 4-6 ~ 4-13 were synthesized according to the similar procedure as

described in the Example 13, and NMR data thereof are shown below.

Example 32: Synthesis of

l-(4-t-butylbenzyl)-3-(2,3,5,6-tetrafluoro-4-methanesulfonylaminobenzyl)thiourea

(5-4)

Step 1: Synthesis of

4-cyano-2,3,5,6-tetrafluoro-l-methanesulfonylaminobenzene

4-amino-2,3,4,5-tetrafluoronitrile (105 mg) was dissolved in tetrahydrofuran (4

ml) and the solution was cooled to 0°C. To the solution was added dropwise 1.6 M

n-butyl lithium and the mixtrure was stirred for 10 minutes, followed by adding

dropwise methanesulfonyl chloride (100 μl). After 1 hour, the reaction was quenched

with 1.5 N aqueous hydrochloric acid. The resulting mixture was extracted with ethyl

acetate, and then concentrated under reduced pressure. The obtained residue was

chromatographed on column eluting with ethyl acetate/hexane (1/1) to yield

4-cyano-2,3,5,6-tetrafluoro-l-methanesulfonylaminobenzene (20 mg, 10 %).

1H NMR(300MHz, CDC1₃) : δ 6.84(brs, IH) 3.08(s, 3H)

Step 2: Synthesis of 2,3,5, 6-tetrafluoro-4-methanesulfonylaminobenzylamine

hydrochloride

4-cyano-2,3,5,6-tetrafluoro-l-methanesulfonylaminobenzene (11 mg) prepared

in Step 1 was dissolved in methanol (5 ml) and to the solution were added a catalytic

amount of 10 % palladium/carbon and concentrated hydrochloric acid (300 μl),

followed by stirring at room temperature under hydrogen gas atmosphere for 1 hour.

The resulting mixture was diluted in ether, filtered through celite, concentrated under reduced pressure, and then washed with ethyl acetate to yield

2,3,5,6-tetrafluoro-4-methanesulfonylaminobenzylamine hydrochloride (7.0 mg, 59 %).

1H NMR(300MHz, CD₃OD) : δ 4.32(s, 2H) 3.18(s, 3H)

Step 3: Synthesis of

l-(4-t-butylbenzyl)-3-(2,3,5,6-tetrafluoro-4-methanesulfonylaminobenzyl)thiourea (5-4)

2,3,5,6-tetrafluoro-4-methanesulfonylaminobenzylamine hydrochloride (20 mg)

prepared in Step 2 was dissolved in dimethylformamide (800 μl), and the solution was

diluted with dichloromethane (6 ml). To the diluted solution were added

t-butylbenzylisothiocyanate (20 mg) and triethylamine (200 μl), and the mixture was

stirred at room temperature for 2 hours. The mixture was concentrated under reduced

pressure, diluted with ethyl acetate (20 ml), and then washed with water and saturated

aqueous sodium chloride solution. The resulting mixture was dried over anhydrous

magnesium sulfate and concentrated under reduced pressure, and the obtained residue

was chromatographed on column eluting ethyl acetate/hexane (2/3) to yield the

compound 5-4 (28 mg, 91 %).

1H NMR(300MHz, CD₃OD) : δ 7.34(dd, 2H, J=1.8, 6.5Hz) 7.20(d, 2H,

J=8.3Hz) 4.87(s, 2H) 4.63(s, 2H) 3.13(s, 3H) 1.29(s, 9H) Example 33: Synthesis of

l-(4-t-butylbenzyl)-3-(2,5-difluoro-4-methanesulfonylaminobenzyl)thiourea (5-5)

Step 1: Synthesis of 2,5-difluoro-4-cyano-l-methanesulfonylaminobenzene

To an ice-cold solution of 4-amino-2,5-difluorobenzonitrile (1.0 g) in

anhydrous tetrahydrofuran (50 ml) was slowly added n-butyl litliium (2.6 ml) through

an injector with stirring, followed by stirring 30 minutes. To the mixture was slowly

added methanesulfonyl chloride (550 μl), followed by stirring at room temperature for

24 hours. After confirming the completion of the reaction using TLC, the resulting

mixture was concentrated under reduced pressure, diluted with 1 N aqueous

hydrochloric acid (100 ml), extracted with dichloromethane (50 ml ^χ3). The

combined organic layer was dried over magnesium sulfate, filtered, and then

concectrated under reduced pressure. The obtained residue was purified by

column-chromatography (ethyl acetate/hexane = 2/3) to yield

2,5-difluoro-4-cyano-l-methanesulfonylaminobenzene (1.2 g, 79.6 %).

¹H NMR(300MHz, CDC1₃) : δ 7.54(m, IH), 7.40(m, IH), 7.01(brs, IH),

3.18(s, 3H) Step 2: Sythesis of 2,5-difluoro-4-methanesulfonaminobenzyl hydrochloride

2,5-difluoro-4-cyano-l-methanesulfonylaminobenzene (250 mg), a catalytic

amount of 10 % palladium carbon catalyst and methanol (20 ml) were added to a

reactor. The reactor was filled with hydrogen gas while the mixture was stirred.

Concentrated hydrochloric acid (250 μl) was slowly added thereto through an injector ,

followed by stirring for 18 hours. The reaction mixture was filtered through celite and

the filtrate was concentrated under reduced pressure to afford a compound (250 mg,

85 %) as a solid. The obtained compound was washed with ether, and the following

procedure was carried out using the washed compound.

Step 3: Synthesis of

l-(4-t-butylbenzyl)-3-(2,5-difluoro-4-methanesulfonaminebenzyl)thiourea (5-5)

2,5-difluoro-4-methanesulfonaminobenzyl hydrochloride (250 mg) prepared by

Step 2 was dissolved in dimethylformamide (5 ml) and to the solution was added

triethylamine (128 μl) with stirring, followed by stirring for 30 minutes. To the

mixture was added t-butylbenzylisothiocyanate (189 mg), followed by stirring for 6

hours. After the completion of the reaction, the resulting mixture was diluted with

water (30 ml), and extracted with ethyl acetate (30 ml x 3). The organic layer was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure.

The obtained residue was purified by column-chromatography (ethyl acetate/hexane =

1/2) to yield the compound 5-5 (264 mg, 52.4 %).

1H NMR(300MHz, CDC1₃) : δ 7.36(m, 2H), 7.3 l(m, IH), 7.23(m, 2H),

7.17(m, IH), 6.69(brs, IH), 6.31(brs, IH), 6.04(brs, IH), 4J7(d, 2H, J=5JHz), 4.53(d,

2H, J=4.8Hz), 3.04(s, 3H), 1.31(s, 9H)

Example 34: Synthesis of

l-(4-t-butylbenzyl)-3-[(5-methanesulfonylaminopyridin-2-yl)methyl]thiourea (5-6)

Step 1: Synthesis of 3-methanesulfonylamino-6-cyanopyridine

5-Amino-2-cyanopyridine (5 g) was dissolved in pyridine (30 ml). The

solution was cooled to 0°C and to the solution was added dropwise methanesulfonyl

chloride (3.6 ml), followed by stirring at room temperature for 17 hours. The resulting

mixture was concentrated under reduced pressure, extracted with water and

dichloromethane, and then dried. The obtained residue was purified by column-chromatography (hexane/ethyl acetate = 2/1) to yield an orange colored solid

(6.4 g, 77 %).

1H NMR(300MHz, CDC1₃) : δ 8.47-8.46(m, IH), 7.84-7.69(m, 2H), 6.89(brs,

IH), 3.16(s,3H)

Step 2: Synthesis of

The compound (1.97 g) prepared in Step 1 was dissolved in methanol (50 ml)

and to the solution were added concentrated hydrochloric acid (2 ml) and a catalytic

amount of 5 % palladium/carbon, followed by stirring under hydrogen atmosphere for

21 hours. The mixture was filtered through celite and the filtrate was concentrated

under reduced pressure to obtain foamy compound (3 g). Part (135 mg) of the

obtained compound was dissolved in dimethylformamide (5 ml) and to the solution

were added triethylamine (101 mg) and 4-t-butylbenzylisothiocyanate (100 mg),

followed by stirring at room temperature for 20 hours. The mixture was concentrated

under reduced pressure, extracted with water and dichloromethane, and then purified by

column-chromatography (ethyl acetate) to yield the compound 5-6 (98 mg, 48 %) as a

brown liquid.

1H NMR(300MHz, CDC1₃) : δ 8.33-8.31(m, IH), 7.66-7.62(m, IH), 7.40-7.26(m, 5H), 6.99(brs, IH), 6.76(bra, IH), 4J7-4.60(m, 4H), 3.04(s, 3H),

1.32(s,9H)

Example 35: Synthesis of

l-(4-t-butylbenzyl)-3-(3,5-dichloro-4-methanesulfonylaminobenzyl)thiourea (5-7)

4-A-mino-3,5-dichlorobenzonitrile (1 g) was dissolved in acetonitrile (50 ml)

and to the solution were added triethylamine (890 μl) and methanesulfonyl chloride

(670 mg), followed by refluxing for 8 hours. The mixture was extracted with water

and dichloromethane, dried, concentrated, and then purified by column-chromatography

(hexane/ethyl acetate = 4/1) to obtain a compound (80 mg) as a liquid. The obtained

compound was dissolved in methanol (10 ml), and then the solution was stirred for 15

hours in the presence of a small amount of concentrated hydrochloric acid and 5%

palladium/carbon catalyst to hydro genate the compound. The reaction solution was

filtered tlirough celite and concentrated. The concentrate was dissolved in

dichloromethane (5 ml) and to the solution were added 4-t-butylbenzylisothiocyanate (54 mg) and triethylamine (500 μl), followed by stirring at room temperature for 15

hours. The resulting mixture was extracted with water and dichloromethane, and then

purified by column-chromatography (hexane/ethyl acetate = 2/1) to yield the compound

5-7 (38 mg) as a liquid.

1H NMR(300MHz, CDC1₃) : δ 7.42-7.23(m, 6H), 6.23(brs, IH), 5.87(brs, IH),

4.85-4.82(m, 2H), 4.58-4.56(m, 2H), 3.57(s, 3H), 1.31(s,9H)

Example 36: Synthesis of

l-(4-t-butylbenzyl)-3-(4-methanesulfonylaminophenethyl)thiourea (5-8)

Step 1: Synthesis of 4-methanesulfonylaminobenzyl cyanide

To an ice-cold solution of 4-aminobenzyl cyanide (1 g) in dichloromethane (30

ml) were added dropwise triethylamine (1.58 ml) and methanesulfonyl chloride (700

μl), followed by stirring at room temperature for 12 hours. After confirming the completion of the reacion using TLC, to the mixture was added 1 N aqueous

hydrochloric acid (50 ml). The resulting mixture was extracted with dichloromethane

(30 ml x 3), washed with saturated aqueous sodium chloride solution, dried over

magnesium sulfate, and then filtered.

The filtrate was concentrated under reduced pressure and the obtained residue

was purified by column-chromatography (ethyl acetate/hexane = 2/3) to yield

4-methanesulfonylaminobenzyl cyanide (1.35 g, 85 %).

1H NMR(300MHz, CDC1₃) : δ7.34(d, 2H, J=8.4Hz), 7.24(d, 2H, J=8.7Hz),

6.51(bs, IH), 3.74(s, 2H), 3.03(s, 3H)

Step 2: Synthesis of 4-methanesulfonaminophenethylamine

4-Methanesulfonylbenzyl cyanide (200 mg) and Raney nickel (catalytic

amount) were added to methanol (15 ml) and the mixture was stirred for 6 hours with

the reactor filled with hydrogen gas. After confirming the completion of the reaction,

the resulting mixture was filtered through celite and the filtrate was concentrated under

reduced pressure. The following procedure was carried out using the concentrate

which was not purified.

Step 3: Synthesis of l-(4-t-butylbenzyl)-3-(4-methanesulfonylaminophenethyl)thiourea (5-8)

4-Methanesulfonaminophenethylamine (200 mg) prepared in Step 2 and

4-t-butylbenzylisothiocyanate (190 mg) were dissolved in ethyl acetate (30 ml) and the

solution was subjected to reaction for 6 hours. After the completion of the reaction,

the resulting mixture was concentrated under reduced pressure and the obtained residue

was purified by column-chromatography (ethyl acetate/hexane = 1/2) to yield the

compound 5-8 (210 mg, 53 %).

1H NMR(300MHz, CDC1₃) : δ7.38(d, 2H, J=8.4Hz), 7.21(d, 2H, J-8.4Hz),

7.14(s, 4H), 6.56(s, IH), 6.05(brs, IH), 5.69(brs, IH), 4.51(brs, 2H), 3.72(d, 2H,

J=4.8Hz), 2.99(s, 3H), 2.86(t, 2H, J=6.9Hz), 1.32(s, 9H)

Example 37: Synthesis of

l-(4-t-butylbenzyl)-3-(2-methanesulfonylaminophenethyl)thiourea (5-9)

Step 1: Synthesis of (2-methanesulfonylaminophenyl)acetonitrile

To an ice-cold solution of 2-aminophenylacetonitrile (500 mg) in dichloromethane (20 ml) were added triethylamine (330 μl) and methanesulfonyl

chloride (530 μl) and the mixture was stirred for 16 hours, under argon gas atmosphere.

After confirming the completion of the reaction using TLC, the resulting mixture was

diluted with 1 N aqueous hydrochloric acid solution (30 ml), and extracted with

dichloromethane (50 ml x 3). The organic layer was washed with brine, dried over

magnesium sulfate, and then filtered. The filtrate was concentrated under reduced

pressure and the obtained residue was purified by column-chromatography (ethyl

acetate/hexane = 1/2) to yield (2-methanesulfonylaminophenyl)acetonitrile (573 mg,

72 %).

1H NMR(300MHz, CDC1₃) : δ7.56(m, IH), 7.37(m, 3H), 6.55(brs, IH), 3.99(s,

2H), 3.06(s, 3H)

Step 2: Synthesis of 2-methanesulfonylaminophenethylamine

(2-Methanesulfonylaminophenyl)acetonitrile (300 mg) was mixed with 10 %

palladium/carbon (catalytic amount) in methanol (20 ml) and the mixture was stirred

under hydrogen gas atmosphesre for 48 hours. After confirming the completion of the

reaction using TLC, the resulting mixture was filtered through celite and the filtrate was

concentrated under reduced pressure. The following procedure was carried out using

the concectrate which was not purified. Step 3: Sythesis of

l-(4-t-butylbenzyl)-3-(2-methanesulfonylaminophenethyl)thiourea (5-9)

2-Methanesulfonylaminophenethylamine (200 mg) prepared in Step 2 and

t-butylbenzeneisothiocyanate (192 mg) were dissolved in ethyl acetate (20 ml) and the

solution was stirred for 6 hours. After confirming the completion of the reaction, the

resulting mixture was concentrated under reduced pressure and the concefrate was

purified by column-chromatography (ethyl acetate/hexane = 2/3) to yield the compound

5-9 (165 mg, 42 %).

1H NMR(300MHz, CDC1₃) : δ7.28(m, 8H), 6.38(brs, IH), 4.74(s, IH), 4.72(s,

IH), 3.79(m, 2H), 3.14(m, 4H), 3.01(s, 3H), 1.3 l(s, 9H)

Example 38: Synthesis of

l-(4-t-butylbenzyl)-3-(4-methanesulfanylcarbonylaminobenzyl)thiourea (6-5)

Step 1: Synthesis of (4-nitrobenzyl)carbamic acid t-butyl ester (6-2) 4-Nitrobenzylamine hydrochloride (110 mg) was dissolved in dichloromethane

(2 ml) and to the solution were added dimethylaminopyridine (14 mg) and di-t-butyl

dicarbonate (382 mg), followed by adding triethylamine (200 μl) thereto and stirring at

room temperature for 3 hours. After the completion of the reaction, the resulting

mixture was concenfrated under reduced pressure and the obtained residue was

chromatographed on column eluting with ethyl acetate/hexane (1/3) to yield the

compound 6-2 (88.3 mg, 66 %).

1H NMR(300MHz, CDC1₃) : δ 8.18 (d, 2H, J=8.5Hz), 7.43 (d, 2H, J=8.8Hz)

4.40 (d, 2H, J=6.3Hz), 1.45 (s, 9H)

Step 2: Synthesis of (4-methylsulfanylcarbonylaminobenzyl)carbamic acid

t-butyl ester (6-3)

The compound 6-2 (88.3 mg) prepared in Step 1 was dissolved in methanol (2

ml) and to the solution was added catalytic amount of 10 % palladium/carbon, followed

by stirring at room temperature under hydrogen gas atmosphere for 30 minutes. The

resulting mixture was diluted with ether, and filtered through celite. The filtrate was

concentrated under reduced pressure to yield compound (76 mg). The obtained

compound, which was not purified, was dissolved in dichloromethane (1 ml) and to the

solution were added methylchlorothiolformate (100 μl) and pyridine (49 μl). After stirring the mixture at room temperature for 1 hour, the resulting mixture was extracted

with dichloromethane, dried over anhydrous magnesium sulfate, and then concentrated

under reduced pressure. The obtained residue was column-chromatographed (ethyl

acetate/hexane = 1/1) to yield the compound 6-3 (22 mg, 22 %).

¹H R(300MHz, CDC1₃) : δ 7.36 (d, IH, J=8.5Hz), 7.20-7.25 (m, 2H), 7.03

(d, IH, J-8.3Hz), 4.25 (s, 2H), 2.40 (s, 3H), 1.44 (s, 9H)

Step 3: Synthesis of 4-methylsulfanylcarbonylaminobenzylamine hydrochloride

(6-4)

The compound 6-3 (22 mg) prepared in Step 2 was dissolved in ethyl acetate (1

ml) and to the solution was added 5 N aqueous hydrochloric acid (1 ml). The mixture

was stirred at 60°C for 1 hour and concenfrated under reduced pressure to yield the

compound 6-4 (15 mg, 100 %).

1H NMR(300MHz, CD₃OD) : δ 7.65 (d, IH, J=8.5Hz), 7.57 (d, IH, J=8.3Hz),

7.49 (d, IH, J=8.5Hz), 7.38 (d, IH, J=8.8Hz), 4.05(s, 2H) 2.35(s, 3H)

Step 4: Synthesis of

l-(4-t-butylbenzyl)-3-(4-methylsulfanylcarbonylaminobenzyl)thiourea (6-5)

The compound 6-4 (15 mg) prepared in Step 3 was diluted in dichloromethane (1 ml) and to the solution were added 4-t-butylisothiocyanate (20 mg) and triethylamine

(100 μl), followed by stirring at room temperature for 1 hour. The resulting mixture

was concentrated under reduced pressure and the obtained residue was

chromatographed on column eluting with ethylacetate/hexane (1/3) to yield the

compound 6-5 (20 mg, 83 %).

¹H NMR(300MHz, CDC1₃) : δ 7.16-7.35 (m, 8H), 4.56 (br, 4H), 2.35 (s, 3H),

1.26 (s, 9H)

Example 39: Synthesis of l-(4-t-butylbenzyl)-3-(4-guanidinobenzyl)thiourea (7-6)

Step 1: Synthesis of 4-(l,3-bis(t-butoxycarbonyl)-2-guanidino)phenyliodide

(7-2)

4-Iodoaniline 7-1 (100 mg) was dissolved in dimethylformamide (2 ml) and to

the solution were added l,3-bis(t-butoxycarbonyl)-2-methyl-2-thiopseudourea (200 mg),

mercury (II) chloride (186 mg) and triethylamine (200 μl), followed by stirring for 1

hour. Aftrer the completion of the reaction, the resulting mixture was concentrated under reduced pressure at the temperature not more than 50°C and the obtained residue

was chromatographed eluting with ethyl acetate/hexane (1/3) to yield the compound 7-2

(137 mg, 66 %).

1H NMR(300MHz, CDC1₃) : δ 11.60 (br, IH) 10.33 (br, IH), 7.58-7.63 (d, 2H,

J=8.8Hz), 7.35-7.38 (d, 2H, J=8.8Hz), 1.51 (s, 9H), 1.48 (s, 9H)

Step 2: Synthesis of 4-[l,3-bis(t-butoxycarbonyl)-2-guanidino]benzonitrile

(7-3)

The compound 7-2 (137 mg) prepared in Step 1 was dissolved in

dimethylformamide (2 ml) and to the solution were added zinc (II) cyanide (40 mg) and

tetrakistriphenylphosphine palladium (14 mg), followed by stirring at 80°C for 1 hour.

The reaction was quenched with water. The resulting mixture was exfracted with ethyl

acetate, and the organic phase was dried over anhydrous magnesium sulfate, and then

colunm eluting with ethyl acetate/hexane (1/3) to yield the compound 7-3 (95 mg,

89 %).

1H NMR(300MHz, CDC1₃) : δ 11.58 (br, IH) 10.62 (br, IH), 7.76-7.79 (d, 2H,

J=8.8Hz), 7.58-7.61 (dd, 2H, J=2.0, 6.8Hz), 1.52 (s, 9H), 1.50 (s, 9H) Step 3: Synthesis of

l-(4-t-butylbenzyl)-3-[4-{l,3-bis(t-butoxycarbonyl)-2-guanidino}benzyl]thiourea (7-5)

The compound 7-3 (20 mg) prepared in Step 2 was dissolved in methanol (2

ml) and to the solution was added catalytic amount of palladium/carbon, followed by

stirring at room temperature under hydrogen gas atmosphere for 30 minutes. The

resulting mixture was diluted with ether, filtered through celite, and then concentrated

under reduced pressure to give the compound 7-4. The compound 7-4 was diluted

with dichloromethane (3ml). To the solution was added 4-t-butylbenzylisothiocyanate

(40 mg) and the mixture was stirred at room temperature for 1 hour. The resulting

mixture was concenfrated under reduced pressure and the obtained residue was

chromatographed eluting with ethyl acetate/hexane (1/3) to yield the compound 7-5 (35

mg, 95 %).

1H NMR(300MHz, CD₃OD) : δ 7.18-7.49 (m, 8H), 4.66-4.69 (br, 4H), 1.56 (s,

9H), 1.45 (s, 9H), 1.29 (s, 9H)

Step 4: Synthesis of l-(4-t-butylbenzyl)-3-(4-guanidinobenzyl)tlιiourea (7-6)

The compound 7-5 (35 mg) prepared in Step 3 was dissolved in ethyl acetate

(1.0 ml) and to the solution was added 5 N aqueous hydrochloric acid (1 ml). The

mixture was stirred at 60°C for 1 hour and concentrated under reduced pressure to yield the compoxmd 7-6 (18 mg, 100 %).

¹H NMR(300MHz, acetone-d₆) : δ 7.07-7.37 (m, 8H), 4.73(s, 2H), 4.66 (s,

2H), 1.17 (s, 9H)

Example 40: Synthesis of

l-[2-(l-methyl-lH-pyrrol-2-yl)ethyl]-3-(4-methanesulfonylaminobenzyl)thiourea

(8-4)

Step 1: Syntheis of (4-aminobenzyl)carbamic acid t-butyl ester (8-1)

4-Aminobenzylamine (1.02 g) was dissolved in anhydrous tetrahydrofuran (10

ml) and to the solution was added di-t-butyldicarbonate (2.002 g), followed by stirring

at room temperature for 2 hours. The resulting mixture was concentrated under

reduced pressure to remove the solvent. The obtained residue was purified by

column-chromatography (ethyl acetate/hexane = 2/3) to yield the compound 8-1 (1.78 g,

96 %) as a yellow solid.

1H NMR (300MHz, CDC1₃): δ7.09-7.05 (m, 2H), 6.6-6.62 (m, 2H), 4.70 (bra, IH), 4.18(d, 2H, J = 5.7Hz), 3.64(brs, 2H), 1.45 (s, 9H)

Step 2: Synthesis of (4-methanesulfonylaminobenzyl)carbamic acid t-butyl

ester (8-2)

Compound 8-1 (1 g) was dissolved in anhydrous dichloromethane and the

solution was cooled to 0°C. To the solution was added triethylamine (630 μl) and

methanesulfonyl chloride (350 μl) in order and the mixture was stirred at room

temperature for 24 hours. After confirming the completion of the reaction using TLC,

the resulting mixture was neufralized with hydrochloric acid solution, diluted with water,

and then extracted three times with dichloromethane. The extracted organic layer was

washed with water and saturated aqueous sodium chloride solution, dried over

magnesium sulfate, and then dried under reduced pressure. The obtained residue was

purified by column-chromatography (hexane/ethyl acetate — 2/1) to yield the compound

8-2 (1.28 g, 95 %) as a white solid.

1H NMR (300MHz, CDC1₃): δ 7.1-7.3 (m, 4H), 6.77 (s, IH), 4.88 (bra, IH),

4.28 (d, 2H), 2.99 (s, 3H), 1.46 (s, 9H)

Step 3: Synthesis of 4-methanesulfonylaminobenzylammom^'um trifluoroacetate

(8-3) (4-Methanesulfonylaminobenzyl)carbamic acid t-butyl ester 8-2 (500 mg) was

dissolved in anhydrous dichloromethane (30 ml) and the solution was cooled to 0°C,

followed by slowly adding trifluoroacetic acid (5 ml) thereto. The mixture was stirred

at 0°C for 1 hour and 30 minutes and then, after confirming the completion of the

reaction using TLC, concenfrated under reduced pressure to yield an orange colored

residue. The residue was washed with ether and filtered to yield the compound 8-3

(420 mg, 80 %) as a pink solid.

1H NMR (300MHz, DMSO-d₆): δ 8.14 (brs, 3H), 7.39 (d, 2H), 7.22 (d, 2H),

3.97 (s, 2H), 2.99 (s, 3H)

Step 4: Synthesis of

1 - [2-( 1 -methyl- 1 H-pyrrol-2-yl)ethyl] -3 -(4-methanesulfonylaminobenzyl)thiourea (8-4)

Compound 8-3 (500 mg) was dissolved in dimethylformamide (2 ml) and to the

solution was added triethylamine (230 μl), followed by stirring for 1 hour. To the

mixture was added 2-(2-isothiocyanatoethyl)-l-methyl-lH-pyrrole (280 mg), followed

by adding ethyl acetate (10 ml) thereto. The mixture was stirred for 12 hours, filtered

under reduced pressure, and then purified by column-chromatography (ethyl

acetate hexane =4/1) to yield the compound 8-4 (146 mg, 25 %) as a red solid.

1H NMR (300MHz, CH₃COCH₃-d₆): δ 7.32(m, 4H), 7.16(m, IH), 6.42(d, IH, J=2.1Hz), 6.02(d, IH, J=1.95Hz), 4J6(m, 2H), 3.89(m, 2H), 3.81(m, 2H), 3.01(m, 2H),

2.96(s, 3H)

Example 41: Synthesis of l-(4-aminobenzyl)-3-(4-t-butylbenzyl)thiourea (9a)

4-t-Butylbenzylisothiocyanate (100 mg) was dissolved in dichloromethane (3

ml) and then cooled to 0 °C. To the solution was added 4-nitrobenzylamine (75 mg),

followed by stirring at room temperature for 6 hours. After the completion of the

reaction, dichloromethane was evaporated therefrom under reduced pressure and the

residue was dissolved in methanol (3 ml). To the solution was added catalytic amount

of 5 % platinum/carbon and the mixture was subjected to hydrogenation reacton under

atmospheric pressure. After the completion of the reaction, the methanol was

evaporated under reduced pressure and the obtained residue was

column-chromatographed (hexane/ethyl acetate = 1/1) to yield the compound 9a (137

mg, 85 %) as a white solid.

1H NMR (300MHz,CDCl₃): δ 6J0-7.40(m, 8H), 6.00-6.40(br, 2H), 4.55(br, 2H), 4.45(br, 2H), 1.28(s, 9H)

MS (El) m e 327 [M+]

Example 42: Synthesis of l-(4-acetylaminobenzyl)-3-(4-t-butylbenzyl)thiourea (9b)

Compound 9a (100 mg) and triethylamine (50 mg) were dissolved in

dichloromethane (3 ml) and cooled to 0 °C. To the solution was added anhydrous

acetic acid (35 mg). After the completion of the reaction, dichloromethane was

evaporated under reduced pressure and the obtained residue was

column-chromatographed (hexane/ethyl acetate = 1/1) to yield the compound 9b (107

mg, 95 %) as a white solid.

1H NMR (300MHz, DMSO-d₆): δ 8.3 l(s, IH), 7.87(br, 2H), 7.50(d, 2H,

J=8.40 Hz), 7.32(d, 2H, J=8.25 Hz), 7.16-7.17(m, 4H), 4.59(br, 4H), 2.01(s, 3H), 1.25(s,

9H)

MS (El) m/e 369 [M+] Example 43: Synthesis of

l-(4-(N,N-dimethanesulfonyl)aminobenzyl)-3-(4-t-butylbenzyl)thiourea (9c)

4-t-Butylbenzylisothiocyanate (100 mg) was dissolved in dichloromethane (3

ml) and cooled to 0 °C. To the solution was added

(N,N-dimethylsulfonyl-4-amino)benzylamine (136 mg), followed by stirring at room

temperature for 6 hours. After the completion of the reaction, dichloromethane was

evaporated under reduced pressure and the obtained residue was

column-chromatographed (hexane/ethyl acetate = 1/1) to yield the compound 9c (184

mg, 75 %) as a white solid.

1H NMR (300MHz, CDC1₃): δ 7.00-7.35(m, 8H), 6.30(br, 2H), 4.66(s, 2H),

4.49(s, 2H), 3.26(s, 6H), 1.22(s, 9H); MS (E-Q m/e 469 [M+]

Example 49: Synthesis of

l-(4-t-butylbenzyl)-3-[2-hydroxy-4-(N-t-butoxycarbonyl)aminobenzyl]thiourea

(10-4)

10-4 2-Hydroxy-4-nifrobenzaldehyde (1.67 g), t-butyldiphenylsilylchloride

(TBDPSC1) (2.65 g) and imidazole (681 mg) were dissolved in dichloromethane (100

ml) and the solution was stirred at room temperature for 18 hours. The precipitate was

filtered off and the filtrate was concentrated under reduced pressure. The obtained

residue was purified by column-chromatography (hexane/ethyl acetate = 3/1) to yield

the compound 10-1 (4.00 g, 99 %). The compound 10-1 (3.00 g) was reduced in the

presence of palladium/carbon catalyst to yield an amine. The amine was dissolved in

tetrahydrofxxran (15 ml) and to the solution was added Boc₂O (950 mg), followed by

stirring at room temperature for 18 hours. To the mixture were added water (20 ml)

and ethyl acetate (10 ml). From the mixture, an organic layer was separated and an

aqueous layer was extracted with ethyl acetate (10 ml ^χ2). The combined organic

layer was washed with brine, dried over magnesium sulfate and then concenfrated under

reduced pressure. The obtained residue was purified by column-chromatography

(hexane/ethyl acetate = 3/1) to yield the compound 10-2 (380 mg, 20 %) and 10-3 (764

mg, 41 %). The compound 10-2 was dissolved in ethyl acetate (10 ml) and to the

solution was added t-butylbenzylisothiocyanate (150 mg), followed by stirring at room

temperature for 18 hours. The resulting mixture was concentrated under reduced

pressure and the obtained residue was purified by column-chromatography

(hexane/ethyl acetate = 3/1) to yield thiourea compound (300 mg, 56 %). The compound (300 mg) was dissolved in THF (5.0 ml) and to the solution was added

tefrabutylammonium fluoride (131 mg), followed by stirring at room temperature for 45

minutes. The reaction was quenched with saturated sodium bicarbonate and an

aqueous solution layer was exfracted with ethyl acetate (10 ml x2). The combined

organic layer was washed with saturated aqueous sodium chloride solution, dried over

magnesium sulfate, and then concentrated under reduced pressure. The obtained

residue was purified by column-chromatography (hexane/ethyl acetate = 1/1) to yield

the compound 10-4 (52 mg, 27 %).

¹H NMR (300MHz, CDC1₃): δ 7.35(d, J=8.4Hz, 2H), 7.20(d, J=8.4Hz, 2H),

7.07(dd, J=2.7, 8.4Hz, IH), 6.94(d, J=8.4Hz, IH), 6.89(d, J=2JHz, IH), 6.01(bs, IH),

5.19(bs, IH), 4.83(d, J=5JHz, 2H), 4.15(d, J=6.6Hz, 2H), 1.44(s, 9H), 1.30(s, 9H)

Example 50: Synthesis of

l-(4-t-butylbenzyl)-3-[2-hydroxy-4-methanesulfonylaminobenzyl] thiourea (10-6)

Step 1: Synthesis of 2-(N-t-butyloxycarbonylamino)methyl-4-methanesulfonylamino-l-t-butyldiphenylsilylo

xybenzene (10-5)

The compound 10-3 (700 mg) prepared by Example 49 was dissolved in

dichloromethane (10 ml) and the solution was cooled to 0°C, followed by adding

frifluoroacetic acid (2.0 ml) thereto. The mixture was stirred for 2 hours and

concenfrated under reduced pressure. The obtained residue (186 mg) was dissolved in

THF (2.0 ml) and to the solution was added triethylamine (90 μl), followed by stirring

for 12 hours. To the solution was added Boc₂O (68 mg) and the mixture was stirred at

room temperature for 10 hours. To the resulting mixture were added water (10 ml)

and ethyl acetate (10 ml). The organic layer was separated and the aqueous layer was

exfracted with ethyl acetate (10 ml x2). The combined organic layer was washed with

saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then

concentrated under reduced pressure. The obtained residue was purified by

column-chromatography (hexane/ethyl acetate = 1/2) to yield an alkylamme

intermediate (100 mg, 69 %), protected with Boc group. The intermediate and

triethylamine (40 μl) were dissolved in dichloromethane (2.0 ml) and the solution was

cooled to 0°C. To the solution was added methanesulfonyl chloride (20 μl) and the

mixture was stirred at room temperature for 2 hours. The water was added thereto to

quench the reaction. An organic layer was separated, dried over magnesium sulfate, and then concenfrated under reduced pressure. The obtained residue was purified by

column-chromatography (hexane/ethyl acetate = 3/2) to yield the compound 10-5 (69

mg, 60 %).

¹H NMR (300MHz, CDC1₃): δ 7.68(m, 4H), 7.40(m, 6H), 7.12(d, J=3.0Hz,

IH), 6.73(dd, J=3.0, 8.7Hz, IH), 6.40(d, J=8JHz, IH), 6.04(s, IH), 4.94(bs, IH),

4.46(d, J=5.4Hz, 2H), 2.90(s, 3H), 1.48(s, 9H), 1.1 l(s, 9H).

Step 2: Synthesis of

l-(4-t-butylbenzyl)-3-[2-hydroxy-4-methanesulfonylaminobenzyl]thiourea (10-6)

Compound 10-5 (90 mg) was dissolved in THF (2.0 ml) and to the solution was

added tetrabutylammoniumfluoride (200 μl), followed by stirring at room temperatxxre

for 45 minutes. The reaction was quenched with saturated aqueous sodium

bicarbonate solution and the aqueous layer was exfracted with ethyl acetate (10 ml x2).

The combined organic layer was washed with saturated aqueous sodium chloride

solution, dried over magnesium sulfate, and then concenfrated under reduced pressure.

The obtained residue was purified by column-chromatography (hexane/ethyl acetate ==

1/1) to yield a phenol compound (38 mg, 71 %>). The compound was dissolved in

dichloromethane (3.0 ml) and the solution was cooled to 0°C. To the solution was

added trifluoroacetic acid (500 μl), and the mixture was stirred for 2 hours and concentrated under reduced pressure. The concenfrate was dissolved in ethyl acetate

(2.0 ml) and to the solution was added triethylamine (16 μl), followed by stirring for 1

hour. To the solution was slowly added a solution of t-butylbenzylisothiocyanate (25

mg) in ethyl acetate (1.0 ml), and the mixture was stirred at room temperature for 18

hours and concentrated under reduced pressure. The obtained residue was purified by

column-chromatography (hexane/ethyl acetate = 1/3) to yield the compound 10-6 (37

mg, 73 %).

1H NMR (300MHz, CDC1₃): δ 7.35(d, J=8.1Hz, 2H), 7.19(d, J=8.1Hz, 2H),

7.06(d, J=2.4Hz, IH), 7.00(dd, J=2.4, 8.4Hz, IH), 6.89(d, J=8.4Hz, IH), 6.31(bs, IH),

6.23(bs, IH), 4.80(d, J=6.3Hz, 2H), 4.49(bs, 2H), 2.94(s, 3H), 1.30(s, 9H)

Example 51: Synthesis of

l-(4-t-butylbenzyl)-3-(2,6-difluoro-3-methanesulfonylaminobenzyl)thiourea (ll-2)

Step 1: Synthesis of 2,4-difluoro-3-[N-(t-butoxycarbonylamino)methyl]aniline

(11-1) 2,6-Difluoro-3-nifrobenzonifrile (921 mg) and 10 % palladium/carbon (200 mg)

were mixed in methanol (15 ml) and to the mixture was added c-HCl (900 μl),

followed by stirring under hydrogen atmosphere for 1 day. The mixture was diluted

with ethyl acetate (30 ml) and filtered through celite pad. The filtrate was neutralized

with 1 N aqueous sodium hydroxide solution and the organic layer was separated. The

aqueous layer was extracted with ethyl acetate (10 ml x2). The combined organic

layer was washed with saturated aqueous sodium chloride solution, dried over

magnesium sulfate, and then concentrated under reduced pressure. The residue was

purified by column-chromatography (methanol/ethyl acetate = 2/1) to yield an amine

salt (580 mg, 50 %). The obtained amine salt was dissolved in tefrahydrofiiran (5.0

ml) and to the solution was added triethylamine (700 μl), followed by stirring at room

temperature for 12 hours. To the solution was added Boc₂O (548 mg) and the mixture

was stirred at room temperature for 10 hours. To the resulting mixture were added

water (10 ml) and ethyl acetate (10 ml) and then the organic layer was separated. The

aqueous layer was extrated with ethyl acetate (10 ml x2). The combined organic layer

was washed with saturated aqueous sodium chloride solution, dried over magnesium

sulfate, and then concenfrated under reduced pressure. The obtained residue was

purified by column-chromatography (hexane/ethyl acetate = 1/1) to yield intermediate

material 11-1 (531 mg, 82 %) protected with Boc. 1H NMR (300MHz, CDC1₃) δ 6.67(m, 2H), 4.86(bs, IH), 4.39(d, J=4.8Hz,

2H), 3.59(bs, 2H), 1.44(s, 9H)

Step 2: Synthesis of

1 -(4-t-butylbenzyl)-3-(2,6-difluoro-3-methanesulfonylaminobenzyl)thiourea (11-2)

Compoxmd 11-1 (531 mg) was mesylated and treated with trifluoroacetic acid

to remove Boc group therefrom. 4-t-butylbenzylisothiocyanate was reacted therewith

to yield the compound 11-2 (145 mg, 16 %).

1H NMR (300MHz, CDC1₃): δ 7.50(dt, J=5J, 9.0Hz, IH), 7.38(d, J=8.1Hz,

2H), 7.22(d, J=8.1Hz, 2H), 6.90(dt, J=1.8, 9.0Hz, IH), 6.41(bs, IH), 6.14(bs, IH),

6.02(bs, IH), 4J9(d, J=5JHz, 2H), 4.55(bs, 2H), 3.00(s, 3H), 1.32(s, 9H)

Example 52: Synthesis of

l-(4-t-butylbenzyl)-3-(3-methanesulfonylaminobenzyl)thiourea (12-3b)

12-3b

Step 1: Synthesis of 3-aminomethyl-phenylamine (12-lb) 3-Nifrobenzaldehyde (1.51 g) and hydroxylamine hydrochlride (1.29 g) were

dissolved in methanol (100 ml), and to the solution was slowly added pyridine (2.37 g)

at room temperature, followed by stirring for 18 hours. The resulting mixture was

concenfrated under reduced pressure. The residue was dissolved in ethyl acetate (30

ml), washed with water (10 ml x2) and saturated aqueous copper sulfate solution (10

ml), dried over magnesium sulfate, concenfrated under reduced pressure, and then the

oxime (1.66 g). The obtained oxime was dissolved in methanol (20 ml) and to the

solution was added 10 % palladium/carbon (414 mg), followed by stirring at room

temperature under hydrogen atmosphere for 3 days. The reaction mixture was filtered

to remove the precipitate and the filtrate was concentrated under reduced pressure to

yield the compound 12-lb (643 mg, 53 %).

1H NMRβOOMHz, DMSO-d₆): δ 7.08(t, J=8.1Hz, IH), 6.66(m, 2H), 6.55(d,

J=8.1Hz, IH), 2.40 (bs, 2H)

Step 2: Synthesis of

1 -(4-t-butylbenzyl)-3-(3-methanesulfonylaminobenzyl)thiourea (12-3b)

Compound 12-lb (643 mg) was dissolved in tefrahydrofuran (6.0 ml) and to the

solution was slowly added Boc O (1.26 g) at room temperature, followed by stirring for 18 hours. The resulting mixture was concentrated under reduced pressure and the

obtained residue was purified by column-chromatography (hexane/ethyl acetate = 2/1)

to yield an intermediate compound (622 mg) protected with Boc group. The

intermediate compound and triethylamine (500 μl) were dissolved in dichloromethane

(20 ml) and the solution was cooled to 0°C. To the solution was added

methanesulfonyl chloride (300 μl) and the mixtxire was stirred at room temperature for

50 minutes. The water was added thereto to quench the reaction. The organic layer

was separated, dried over magnesium sulfate, concentrated under reduced pressure, and

then the residue was purified by column-chromatography (hexane/ethylacetate = 1/1) to

yield the compoxmd 12-2b (871 mg, 47 %). The compound 12-2b was dissolved in

dichloromethane (15 ml) and the solution was cooled to 0°C, followed by adding

trifluoroacetic acid (3.0 ml) thereto and stirring for 2 hours. The resulting mixture was

concenfrated under reduced pressure and the residue was dissolved in ethyl acetate (10

ml), followed by adding triethylamine (140 μl) thereto and stirring for 1 hour. To the

solution was slowly added a solution of t-butylbenzylisothiocyanate (421 mg) in ethyl

acetate (2 ml) and the mixture was stirred at room temperature for 18 hours. The

resulting mixture was concenfrated under reduced pressure and the obtained residue was

purified by column-chromatography (hexane/ethyl aceate = 1/1) to yield the compound

12-3b (385 mg, 95 %). 1H NMR (300MHz, CDC1₃): δ7.33(d, J=8.4Hz, 2H), 7.25(t, J=8.1Hz, IH),

7.18(d, J=8.4Hz, 2H), 7.13(m, 2H), 7.03(d, J=7.5Hz, IH), 6.31(bs, 2H), 4.66(d, J=5.1Hz,

2H), 4.58(d, J=4.8Hz, 2H), 2.95(s, 3H), 1.29(s, 9H).

Compounds 12-3a and 12-3c ~ 12-3g of Example 53 ~ Example 59 were

synthesized according to the synthesizing procedure as described above.

12-3 a

12-3C

no

Example 59: Synthesis of

l-(4-t-butyl-2-methoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea (13-4a)

Step 1: Synthesis of 4-t-butyl-2-methoxybenzonitrile (13-2a)

4-t-Butyl-2-hydroxybenzonitrile (1.16 g) and potassium carbonate (376 mg) were dissolved in dimethylformamide (4 ml) and to the solution was added dropwise

iodomethane (226 μl), followed by stirring at 50°C for 2 hours. The resulting mixture

was filtered to remove the remaining potassium carbonate and concentrated under

reduced pressure. The obtained residue was purified by column-chromatography

(hexane/ethyl acetate = 10/1) to yield the compound 13-2a (167 mg, 97 %). .

1H NMR(300MHz, CDC1₃) : δ7.45(d, IH, J=8.0Hz), 7.01(dd, IH, J=1J,

8.2Hz), 6.94(d, IH, J=1.5 Hz), 3.92(s, 3H), 1.3 l(s, 9H)

Step 2: Synthesis of 4-t-butyl-2-methoxybenzylamine (13-3a)

Lithium aluminium hydride (50 mg) was suspended in ether (2 ml) and the

suspension was cooled to 0°C. To the suspension was added dropwise a solution of the

compound 13-2a (167 mg) prepared by Step 1 in ether (2 ml) and the mixture was

refluxed for 2 hours. After the completion of the reaction, the reaction solution was

basified with 5 N aqueous sodium hydroxide solution. Then, aqueous Rochel solution

was added thereto and stirred for 1 hour, at room temperature. Then, resulting mixture

was extracted with ether (50 ml x 3) and concentrated under reduced pressure to yield

the compound 13-3a (120 mg, 71 %). The following Step 3 was proceeded using the

compound 13-3a which was not purified. Step 3: Synthesis of

l-(4-t-butyl-2-methoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea (13-4a)

The compound 13-3a (132 mg) prepared according to the same procedure as

described in Step 2 was dissolved in dichloromethane (5 ml) and to the solution were

added triethylamine (143 μl) and 4-methanesulfonaminobenzylisothiocyanate (165

mg) in order, followed by stirring at room temperature for 3 hours. The reaction

solution was evaporated under reduced pressure and the obtained residue was purified

by column-chromatography (hexane/ethyl acetate = 2/1) to yield the compound 13-4a

(190 mg, 70 %),

1H NMR(300MHz, CDC1₃) : δ7.11-7.32(m, 5H), 6.96(d, IH, J=7.0Hz), 6.82(s,

IH), 4.67(s, 2H), 4.45(s, 2H), 3.62(s, 3H), 3.00(s, 3H), 1.2(s, 9H) ; MS (FAB) m/e

436[M⁺+1]

Compounds of Example 60 ~ 69 are shown in the Scheme 13. hi Step 1 of the

Examples, compounds 13-2b ~ 13-2k were synthesized according to the similar

procedure as described in Step 1 of Example 59, and properties and spectral data thereof

are shown in below table. And in Step 2 of the respective examples, amines were

synthesized according to the similar procedure as described in Step 2 of Example 59,

and the following Step 3 were proceeded using the obtained amine compounds which was not purified. In the Example 60 ~ 69, the final compounds 13-4b ~ 13-4k were

synthesized according to the similar procedure as described in Step 3 of Example 59

except that amines prepared by Step 2 were used, and properties and spectral data

thereof are shown in below table.

13-2b ~ 13-2k

Example 70: Synthesis of

l-(2-acetoxymethyl-4-t-butylbenzyl)-3-(4-methanesulfonylaminobenzene)thiourea

(13-9a)

Step 1: Synthesis of 4-t-butyl-2-trifluoromethanesulfonyloxybenzonitrile (13.-5)

4-t-butyl-2-hydroxybenzonitrile (800 mg) was dissolved in dichloromethane (16 ml) and cooled to 0 °C. To the solution were added triethylamine (663 μl) and

trifluoromethanesulfonic anhydride (764 μl) in order, followed by stirring for 1 hour.

The reaction solution was evaporated under reduced pressure and the obtained residue

was purified by column-chromatography (hexane/ethyl aceate = 10/1) to yield the

compound 13-5 (1.30 g, 93 %).

1H NMR(300MHz, CDC1₃) : δ7.67(d, IH, J=8.0Hz), 7.49(dd, IH, J=1J,

8.3Hz), 7.43(d, lH, J=1.5Hz), 1.34(s, 9H)

Step 2: Synthesis of methyl 5-t-butyl-2-cyanobenzoate (13-6)

The compound 13-5 (1.30 g) prepared according to the same procedure as

described in Step 1 was mixed with palladium acetate (28 mg) and

l, -bis(diphenylphosphino)ferrocene (141 mg), and the atmosphere of the reactor was

brought into an atmosphere of carbon monoxide. To the mixture was added

dimethylsulfoxide (25 ml) to dissolve the mixture. To the solution was added

triethylamine (1.77 ml) and methanol (3.42 ml) successively with stirring and the

mixture was stirred at 50°C for 4 hours. The resulting mixture was filtered to remove

the catalyst and the filtrate was evaporated under reduced prssure. The obtained

residue was purified by column-chromatography (hexane/ethyl acetate = 20/1) to yield

the compound 13-6 (400 mg, 44 %). 1H NMR(300MHz, CDC1₃) : δ8.13(d, IH, J=2.0Hz), 7.72(d, IH, J=8.1Hz),

7.64(dd, 1H, J=2.2, 8.2Hz), 3.99(s, 3H), 1.34(s, 9H)

Step 3: Synthesis of (2-aminomethyl-5-t-butylphenyl)methanol (13-7)

Lithium aluminium hydride (105 mg) was supended in ether (3 ml) and the

compound 13-6 (140 mg) prepared by Step 2 in ether (4 ml) and the mixture was

refluxed for 2 hours. After the completion of the reaction, the reaction mixture was

basified with 5 N aqueous sodium hydroxide solution, followed by adding aqueous

Rochel solution thereto and then stirring for 1 hour. Then, the resulting mixture was

exfracted with ether (50 ml x 3) and concentrated under reduced pressure to yield the

compound 13-7 (320 mg, 90 %»). The following Step 4 was proceeded using the

compound 13-7 which was not purified

Step 4: Synthesis of

l-(4-t-butyl-2-hydroxymethylbenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea

(13-8)

The compound 13-7a (320 mg) prepared according to the same procedure as

described in Step 3 was dissolved in dichloromethane (7 ml) and to the solution were added triethylamine (231 μl) and 4-methanesulfonaminobenzylisothiocyanate (401

mg) successively, followed by stirring at room temperature for 3 hours. The reaction

by column-chromatography (hexane/ethyl acetate = 1/1) to yield the compound 13-8

(460 mg, 64 %).

1H NMR(300MHz, CDC1₃) : 67.38-7.00 (m, 7H), 4.75-4.60(m, 4H), 4.50(s,

2H), 2.92(s, 3H), 1.25(s, 9H)

Step 5: Synthesis of

l-(2-acetoxymethyl-4-t-butylbenzyl)-3-(4-methanesulfonylammobenzene)thiourea

(13-9a)

1,3-Dicyclohexylcarbodiimide (68 mg) was dissolved in dichloromethane (1

ml), and the solution was stirred and cooled to 0°C. To the solution were added

dropwise a mixed solution of the compound 13-8 (130 mg) prepared according to the

same procedure as described in Step 4 and 4-(dimethylamino)pyridine (4 mg) in

dichloromethane (3 ml), followed by adding acetic acid (34 μl) thereto. The mixture

was stirred at room temperature for 12 hours and concenfrated under reduced pressure.

The obtained residue was purified by column-chromatograpohy (hexane/ethyl acetate =

3/2) to yield the compound 13-9a (52 mg, 37 %). 1H NMR(300MHz, CDC1₃) : δ7.40-7.06(m, 7H), 5.10(s, 2H), 4.68(s, 4H),

2.30(s, 3H), 2.01 (s, 3H), 1.30(s, 9H) ; MS (FAB) m/e 478 [M⁺+l]

Example 71: Synthesis of

l-(2-trimethylacetoxymethyl-4-t-butylbenzyl)-3-(4-methanesulfonylaminobenzene)

thiourea (13-9b)

Compound 13-9b (110 mg, 71 %) was synthesized by reacting compound 13-8

(130 mg) with trimethylacetic acid (45 mg) according to the similar procedure as

described in Step 5 of Example 70.

1H NMR(300MHz, CDC1₃) : δ7.43-7.07(m, 7H), 5.10(s, 2H), 4.72(s, 2H),

4.66(s, 2H), 2.97(s, 3H), 1.29(s, 9H), 1.12(s, 9H) ; MS (FAB) m/e 520 [M⁺+l]

Example 72: Synthesis of l-(4-t-butylbenzyl)-3-(4-methylthiobenzyl)thiourea (14-3)

Step 1: Synthesis of 2-(4-methylthiobenzyl)isoindol-l,3-dione (14-1)

(4-methylthio)benzylalcohol (1.54 g) was dissolved in anhydrous

tetrahydrofuran (10 ml) and to the solution were added phthalimide (1.47 g) and

triphenylphosphine (2.62 g). To the mixture was slowly added dropwise a solution of

diisopropylazodicarboxylate (DIAD) (2.02 g) in anhydrous tetrahydrofuran (4 ml),

while the mixture was stirred at room temperature. After 18 hours, the reaction

mixture was concenfrated and the residue was purified by column-chromatography

(hexane/ethyl acetate = 5/1) to yield a white solid (2.00 g, 71 %).

1H NMR(300MHz, CDC1₃) : δ 7.86-7.68(m, 4H), 7.38-7.35(m, 2H),

7.22-7.18(m, 2H), 4.79(s, 2H), 2.44(s, 3H)

Step 2: Synthesis of l-(4-t-butylbenzyl)-3-(4-methyltlιiobenzyl)thiourea (14-3)

2-(4-methylthiobenzyl)isoindol-l,3-dione (14-1) (1.67 g) was dissolved in

ethanol (10 ml) and to the solution was added hydrazine hydrate (300 mg), followed by

refluxing. After 24 hours, the resulting mixture was diluted with dichloromethane (50

ml) and washed with 2 N hydrochloric acid solution. An organic layer was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate,

concentrated under reduced pressure. The residue was purified by

colmnn-chromatography to obtain a liquid (0.8 g). The obtained liquid mixture (400

mg) was dissolved in dichloromethane (20 ml) and to the solution was added

4-t-butylbenzylisothiocyanate (0.54 g), followed by stirring at room temperature for 24

hours. The reaction mixture was concentrated and the residue was purified by

column-chromatography (dichloromethane) to yield the compound 14-3 (0.52 g, 56 %)

as a white solid.

1H NMR(300MHz, CDC1₃) : δ 7.37-7.15(m, 8H), 6.00(brs, 2H), 4.60-4.50(m,

4H), 2.47(s, 3H), 1.3 l(s, 9H)

Example 73: Synthesis of

l-(4-t-butylbenzyl)-3-[2-(4-methylthiazol-5-yl)ethyl]thiourea (14-6)

Step 1: Synthesis of 5-(2-methylsulfonyloxyethyl)-4-methylthiazole

2-(4-methylthiazol-5-yl)ethanol (5.01 g) was dissolved in dichloromethane (100 ml) and to the solution was added triethylamine (5.06 g), followed by adjusting the

temperature of reactor to 0°C. To the obtained solution was added dropwise

methanesulfonyl chloride (4.58 g), and the mixture was stirred for 21 hours while

allowed to warm up to room temperature. The reaction solution was washed with

water, concentrated under reduced pressure, and then purified by

column-chromatography (hexane/ethyl acetate = 1/3) to yield

5-(2-methylsulfonyloxyethyl)-4-methylthiazole^' (5.18 g, 67 %) as a pale yellow liquid.

¹H NMR(300MHz, CDC1₃) : 6 8.63(s, IH), 4.37(t, 3H, J= 6Hz), 3.23(t, 3H, J=

6Hz), 2.97(s, 3H), 2.43(s, 3H)

Step 2: Synthesis of 2-[2-(4-methylthiazol-5-yl)ethyl]isoindol-l,3-dione (14-4)

5-(2-methylsulfonyloxyethyl)-4-methylthiazole (4.17 g) was dissolved in

dimethylformamide (20 ml) and to the solution was added potassium phthalimide (3.84

g), followed by stirring at 70°C for 5 hours. The mixture was concentrated under

reduced pressure and water was added thereto to form precipitate. The resulting

mixture was filtered to collect the precipitate. The obtained precipitate was dissolved

in dichloromethane. The solution was dried over anhydrous magnesium sulfate,

concenfrated, and then crystallized (dichloromethane/pefroleum ether) to yield the

compoxmd 14-4 (3.77 g, 74 %) as a pale yellow solid. 1H NMR(300MHz, CDC1₃) : δ 8.57(s, IH), 7.86-7J0(m, 4H), 3.91(t, 3H, J=

6Hz), 3.18(t, 3H, J- 6Hz), 2.38(s, 3H)

Step 3: Synthesis of

l-(4-t-butylbenzyl)-3-[2-(4-methylthiazol-5-yl)ethyl]thiourea (14-6)

2-[2-(4-methylthiazol-5-yl)ethyl]isoindol-l,3-dione (3 g) was dissolved in a

mixtxire of methanol (10 ml) and tetrahydrofuran (10 ml) and to the solution was added

dropwise hydrazine hydrate (610 mg), followed by stirring for 20 hours. To the

obtained solution was added 2 N aqueous hydrochloric acid solution (6 ml), and the

mixture was stirred for 3 hours and concentrated under reduced pressure to obtain

reaction mixture (3.5 g) as a yellow solid. The obtained mixtxire (140 mg) was

dissolved in dimethylformamide (5 ml) and to the solution were added

4-t-butylbenzylisothiocyanate (0.2 g) and a small amount of triethylamine, followed by

stirring at room temperature for 21 hours. The resulting mixture was diluted with

dichloromethane, washed with water, dried, concentrated under reduced pressure, and

then purified by column-chromatography (hexane/ethyl acetate = 1/1) to yield the

compound 14-6 (0.07 g) as a liquid.

^!H NMR(300MHz, CDC1₃) : δ 8.53(s,lH), 7.38-7.18(m, 4H), 6.25(brs, IH),

5.77(brs, IH), 4.49(s,2H), 3.78-3.73(m, 2H), 3.08(t, 2H, J=6Hz), 2.36(s, 3H), 1.3 l(s, 9H)

Example 74: Synthesis of

l-(4-t-butylbenzyl)-3-((2-chloro-5-pyridinyl)methyl)thiourea (14-9)

14-9

Step 1: Synthesis of ((2-chloro-5-pyridinyl)methyl)isoindol-l,3-dione (14-7)

2-chloro-5-chloromethylpyridine (5 g) was dissolved in dimethylformamide (60

ml) and to the solution was added phthalimide (6.29 g), followed by stirring at room

temperature for 17 hours. The solvent of the reaction solution was removed under

reduced pressure and the residue was extracted with water and dichloromethane to yield

a white solid (6.2 g, 74 %).

1H NMR(300MHz, CDC1₃) : 6 8.50-8.49(m, IH), 7.88-7J2(m, 5H),

7.30-7.26(m, IH), 4.83(s, 2H), 2.44(s, 3H)

Step 2: Synthesis of

l-(4-t-butylbenzyl)-3-((2-chloro-5-pyridinyl)methyl)thiourea (14-9) ((2-chloro-5-pyridinyl)methyl)isoindol-l,3-dione (4J g) was dissolved in

methanol (100 ml) and to the solution was added hydrazine hydrate (1.1 ml), followed

by stirring at room temperature for 2 hours. The reaction slolution was extracted with

water and dichloromethane and concenfrated under reduced pressure to obtain a liquid

(1.4 g). The obtained liquid mixture (66 mg) was dissolved in dichloromethane (5 ml)

and to the solution was added 4-t-butylbenzylisothiocyanate (95 mg), followed by

stirring at room temperature for 24 hours. The reaction mixture was concenfrated and

14-9 (45 mg, 28 %) as a white solid.

1H NMR(300MHz, CDC1₃) : δ 8.16-8.15(m, IH), 7.61-7.57(m, IH),

7.38-7.18(m, 4H), 6.48(brs, 2H), 6.21(brs, 2H), 4.74(d, 2H, J=5JHz), 4.54(d,2H,

J=4.5Hz), 1.29(s, 9H)

Example 75: Synthesis of

l-(4-t-butylbenzyl)-3-(2-(thiomorpholin-4-yl)ethyl)thiourea (15-3)

15-3 Step 1: Synthesis of 2-(2-thiomorpholin-4-yl)ethyl)isoindol-l,3-dione (15-1)

Thiomorpholine (3.75 g) was dissolved in acetone (100 ml) and to the solution

were added anhydrous potassium carbonate (5.52 g) and 2-(bromoethyl)phthalimide

(9.22 g), followed by refluxing for 26 hours. The obtained mixture was filtered,

concenfrated, and then dissolved in dichloromethane. The solution was washed with

water, dried, concentrated under reduced pressrure, and then purified by

column-chromatography (hexane/ethyl acetate = 1/1) to yield the compound 15-1 (2 g,

20 %) as a yellow solid.

1H NMRQOOMHz, CDC1₃) : δ 7.87-7J0(m, 4H), 3.80(t, 2H, J=6.6Hz),

2.79-2.57(m, 10H)

Step 2: Synthesis of

l-(4-t-butylbenzyl)-3-(2-(thiomorpholin-4-yl)ethyl)thiourea (15-3)

2-(2-thiomorpholin-4-ylethyl)isoindol-l,3-dione 15-1 (2J6 g) was dissolved in

a mixture of methanol (20 ml) and tetrahydrofuran (20 ml) and to the solution was

added dropwise hydrazine hydrate (550 mg), followed by stirring for 21 hours. To

the obtained solution was added 2 N aqueous hydrochloric acid solution (6 ml), and the

mixture was stirred for 3 hours and then concenfrated under reduced pressure. To the

concentrate was added water (15 ml) and the undissolved material was filtered off. The filtrate was concenfrated to obtain reaction mixture (1.62 g) as a solid. The

obtained mixture (150 mg) was dissolved in dimethylformamide (5 ml) and to the

solution was added 4-t-butylbenzylisothiocyanate (210 mg) and a small amount of

triethylamine, followed by stirring at room temperature for 23 hours. The resulting

mixture was diluted with dichloromethane, washed with water, and concentrated under

reduced pressure. The residue was purified by column-chromatography (hexane/ethyl

acetate = 1/3) to the compound 15-3 (0.12 g) as a white solid.

1H NMR(300MHz, CDC1₃) : 6 7.42-7.26(m, 4H), 6.32(brs, IH), 4.60(s,2H),

3.40(s, 2H), 2.62-2.20(m, 10H), 1.32(s, 9H)

Example 76: Synthesis of l-(furan-2-ylmethyl)-3-(4-methoxybenzyl)thiourea (16-1)

16-1

Furan-2-ylmethylamine (190 mg) was dissolved in dimethylformamide (5 ml)

and to the solution were added triethylamine (200 mg) and

4-methoxybenzylisothiocyanate (360 mg), followed by stirring at room temperature for

24 hours. Then, the resulting mixture was diluted with ethyl acetate, washed with

water, dried, and concenfrated under reduced pressure. The residue was purified by column-chromatography (hexane/ethyl acetate = 1/1) to yield the compound 16-1 (0.5 g,

90 %) as a liquid.

1H NMR(300MHz, CDC1₃) : 6 7.33-7.32(m, IH), 7.23-7.19(m, 2H),

6.89-6.85(m, 2H), 6.32-6.23(m, 2H), 6.20(brs,lH), 6.05(brs,lH), 4.67-4.64(m, 2H),

4.55-4.53(m, 2H), 3.80(s, 3H)

Example 77: Synthesis of l-(4-t-butylbenzyl)-3-(furan-2-ylmethyl)thiourea (16-2)

Furan-2-yhnethylamine (0.58 g) was dissolved in dichloromethane (50 ml) and

to the solution was added 4-t-butylbenzylisothiocyanate (1.23 g), followed by stirring at

room temperature for 8 hours. Then, the resulting mixture was diluted with ethyl

acetate, washed with water, dried, and concentrated under reduced pressure. The

residue was purified by column-chromatography (dichloromethane) to yield the

compound 16-2 (1.57 g, 87 %) as a liquid.

1H NMR(300MHz, CDC1₃) : 6 7.37-7.20(m, 5H), 6.31-6.29(m, IH),

6.21-6.19(m, IH), 6.10(brs,lH), 4.65-4.63(m, 2H), 4.58-4.50(m, 2H), 1.30(s, 9H) Example 78 ~ Example 121

Compounds of Example 78 ~ Example 121 are shown in the Scheme 16. The

compounds were synthesized according to the similar procedure as described in

Example 76 or Example 77, and properties and specfral data are shown in below table.

16-18 16-19

16-28

Example 121: Synthesis of l-(4-t-butylbenzyI)-3-(2-pyridinyl)thiourea (16-46)

2-aminopyridine (86 mg) was dissolved in acetonitrile (10 ml) and to the

solution were added 4-t-butylbenzylisothiocyanate (190 mg) and triethylamine (140 μl),

followed by refluxing for 27 hours. The resulting mixture was exfracted with water and dichloromethane, dried, concentrated under reduced pressure, and then crystallized

(dichloromethane/petroleum ether) to yield the compound (90 mg, 33 %) as a white

solid.

1H NMR(300MHz, CDCl₃) : δ 11.99(brs, IH), 8.13-8.11(m, IH), 7.67-7.61(m,

IH), 7.41-7.27(m, 4H), 6.96-6.92(m, IH), 6.68-6.64(m, IH), 4.99-4.96 (m, 2H), 1.32(s,

9H)

Example 122: Synthesis of

l-(4-t-butyIbenzyl)-3-((2-hydroxy-l-methyl-2-phenyl)ethyI)thiourea (16-47)

Phenylpropanolamine hydrochloride (100 mg) was dissolved in

dimethylformamide (5 ml) and to the solution was added triethylamine (80 μl),

followed by stirring for 30 minutes. To the obtained reaction mixture was added

t-butylbenzeneisothiocyanate (135 mg), and the mixture was stirred for 4 hours, diluted

with water (20 ml), extracted with dichloromethane (30 ml x3), dried over magnesium

sulfate, and then flitered. The filtrate was concenfrated under reduced pressure and the obtained residue was purified by column-chromatography (ethyl acetate/hexane = 1/3)

to yield the compound 16-47 (159 mg, 83.7 %).

1H NMR(300MHz, CDC1₃) : δ7.32(m, 9H), 6.65(brs, IH), 5.69(d, IH,

J=7.8Hz), 4.92(s, IH), 4.57(s, 2H), 2.66(s, IH), 1.58(s, IH), 1.31(s, 9H), 0.98(d, 3H,

J=6.9Hz)

Example 123: Synthesis of l-(4-t-butylbenzyl)-3-(lH-pyrrol-2-ylmethyl)thiourea

(17-1)

Step 1: Synthesis of lH-pyrrol-2-carboxaldehyde oxime

Pyrrole-3-carboxaldehyde (120.4 mg) was dissolved in methanol (4 ml) and to

the solution were added hydroxylamine hydrochloride (106 mg) and sodium acetate

(127 mg), followed by stirring for 1 hour. The resulting mixture was extracted with

ethyl acetate, and then dried over anhydrous magnesium sulfate. The filtrate was

concenfrated under reduced pressure, and then column-chromatographed (ethyl

acetate/hexane = 1/3) to yield the compound (122 mg, 100 %). 1H MR(300MHz, CD₃OD) : δ 7.19(s, IH), 6.92 (t, IH, J= 2.1 Hz), 6.52 (q,

IH, J= 3.1 Hz), 6.15 (q, IH, J= 3.7 Hz)

Step 2: Synthesis of (lH-pyrrol-2-yl)methylamine hydrochloride

lH-pyrrol-2-carboxaldehyde oxime (60 mg) prepared according to the same

procedure as described in Step 1 was dissolved in methanol (2 ml) and to the solution

were added a catalytic amount of 10 % palladium/carbon and concentrated hydrochloric

acid (100 μl), followed by stirring at room temperature under hydrogen gas atmosphere

for 1 hour. The resulting mixture was diluted with ether, and then filtered through

celite. The filtrate was concenfrated under reduced pressure to yield

(lH-pyrrol-2-yl)methylamine hydrochloride (60 mg, 100 %).

1H NMR(300MHz, CD₃OD) : δ 6J8 (q, IH, J= 4.2 Hz), 6.23 (s, IH), 6.10 (q,

lH, J= 5.9 Hz), 4.08 (s, 2H)

Step 3: Sythesis of l-(4-t-butylbenzyl)-3-(lH-pyrrol-2-ylmethyl)thiourea (17-1)

(lH-pyrrol-2-yl)methylamine hydrochloride (60 mg) prepared according to the

same procedure as described in Step 2 was dissolved in dichloromethane (2 ml) and to

the solution was added 4-t-butylbenzylisothiocyanate (155 mg), followed by stirring at

room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure and the obtained residue was column-chromatographed (ethyl acetate/hexane =

1/3) to yield the compound 17-1 (120 mg, 65 %).

1H-NMR(300MHz, CD₃OD) : δ 7.23-7.35 (t, 2H, J = 7.4 Hz), 7.18-7.21 (d,

2H, J= 8.5 Hz), 6.65 (d, IH, J= 2.2 Hz), 5.97-5.98 (d, 2H, J= 2.0 Hz), 4.61 (br, 4H),

1.29 (s, 9H)

Example 124: Synthesis of

l-(4-t-butylbenzyl)-3-(l-methyl-lH-pyrrol-2-yl)methylthiourea (17-2)

17-2

Step 1: Synthesis of methyl- lH-pyrrol-2-carboxaldehyde oxime

Methyl-2-pyrrolecarboxaldehyde (5 g), hydroxylamine hydrochloride (9.55 g)

and sodium acetate (11.28 g) were dissolved in methanol (100 ml) and the solution was

refluxed for 12 hours. Aftre confirming the completion of the reaction using TLC, the

resulting mixture was purified by column-chromatography (ethyl acetate/hexane = 3/1)

to yield the compound (5.01 g, 88 %) as a brown solid.

1H NMR (300MHz, CDC1₃): δ 7.40(s, IH), 7.31(m, IH), 6J0(m, IH), 6.23(m, IH), 3J4(s, 3H)

Step 2: Synthesis of (1 -methyl- lH-pyrrol-2-yl)methylamine

Sodium borohydride (310 mg) was dried under vacuum and anhydrous

tetrahydrofuran (30 ml) was added thereto tlirough an injector, followed by adjusting

the temperature down to -15°C. To the mixture at -15°C was added a solution of

methyl- lH-pyrrol-2-carboxaldehyde oxime (500 mg) and nickel (II) chloride

hexahydrate (catalytic amount) in anhydrous methanol (30 ml) and the mixture was

stirred, followed by stirring at room temperature for 12 hours. After confirming the

completion of the reaction, the resulting mixture was filtered and the obtained brown oil

was purified by column-chromatography (ethyl acetate) to yield

(l-mehtyl-lH-pyrrol-2-yl)methylamine (275 mg, 62 %) as solid.

1H NMR (300MHz, CDC1₃): δ 6.63(m, IH), 6.1 l(m, 2H), 3.94(m, 2H),

3.72(brs, 2H), 3.64(s, 3H)

Step 3: Synthesis of

l-(4-t-butylbenzyl)-3-(l-methyl-lH-pyrrol-2-yl)methylthiourea (17-2)

(1 -methyl- lH-pyrrol-2-yl)methylamine (65 mg) and

4-t-butylbenzylisothiocyanate (120 mg) were dissolved in ethyl acetate (30 ml) and the solution was stirred for 12 hours. After the completion of the reaction, the resulting

mixture was purified by column-chromatography (ethyl acetate/hexane = 1/3) to yield

the compound 17-2 (140 mg, 75 %)

1H NMR (300MHz, CDC1₃): δ 7.36(m, 2H), 7.19(m, 2H), 6.58(m, IH),

6.18(brs, IH), 6.01(m, 2H), 5.69(brs, IH), 4.63(d, 2H, J=2.1Hz), 4.52(d, 2H, J=2.4Hz),

3.52(s, 3H), 1.31(s, 9H)

Example 125: Synthesis of l-(l-methyl-lH-pyrroI-2-ylmethyl)-3-phenethylthiourea

(17-3)

17-3

(1 -methyl- lH-pyrrol-2-yl)methylamine (65 mg) and

(2-isothiocyanatoethyl)benzene (100 mg) were dissolved in ethyl acetate (20 ml) and

the solution was stirred for 12 hours. After the completion of the reaction, the

resulting mixture was purified by column-chromatography (ethyl acetate/hexane = 1/3)

to yield the compound 17-3 (97 mg, 60 %) as a brown liquid.

1H NMR (300MHz, CDC1₃): δ 7.25(m, 5H), 6.60(m, IH), 6.02(m, IH), 5.97(s,

IH), 4.51(brs, 2H), 3.69(brs, 2H), 2.87(t, 2H, J=6.9Hz) Example 126: Synthesis of

l-(4-t-butylbenzyl)-3-(5-nitrothiophen-2-ylmethyl)thiourea (17-4)

Step 1: Synthesis of 5-nifrothiophen-2-carboxaldehyde oxime

5-Nifrothiophen-2-carboxaldehyde oxime (yield: 85 %, pale yellow solid) was

synthesized according to the similar procedure as described in Step 1 of Example 124

except that 5-nitrothiophen-2-carboxaldehyde was usded as a starting material.

1H NMR (300MHz, CDC1₃): δ 8.21(s, IH), 7.91(d, IH, J=2.1Hz), 7.85(d, IH,

J=2.25Hz), 7.76(s, IH), 7.26(s, IH), 7.1 l(d, IH, J=2.1Hz)

Step 2: Synthesis of (5-nifrothiophen-2-yl)methylamine

Sodium borohydride (132 mg) was dried under vacuum and then anhydrous

tetrahydrofuran (30 ml) was added thereto through an injector, followed by adjusting

5-nitrothiophen-2-carboxaldehyde oxime (200 mg; synthesized in Step 1) and nickel

chloride (II) hexahydrate (catalytic amount) in anhydrous methanol (20 ml), and the mixture was stirred for 12 hours. After confirming the completion of the reaction, the

resulting mixture was filtered to obtain the compound as a brown liquid.

Step 3: Synthesis of l-(4-t-butylbenzyl)-3-(5-nifrothiophen-2-ylmethyl)thiourea

(17-4)

The compound 17-4 (yield: 40 %, yellow solid) was synthesized by reacting the

compound prepared in Step 2 with 4-t-butylbenzylisothiocyanate according to the

similar procedure as described in Step 3 of Example 124.

1H NMR (300MHz, CDC1₃): δ 7Jl(d, IH, J=1.95Hz), 7.37(m, 2H), 7.23(m,

2H), 6.85(d, IH, J=1.95Hz), 6.59(brs, IH), 6.30(brs, IH), 4.96(d, 2H, J=3Hz), 4.55(brs,

2H), 1.29(s, 9H)

Example 127: Synthesis of

l-(4-t-butylbenzyl)-3-(2-methyl-pyridin-3-ylmethyl)thiourea (18-5)

18-5

Step 1: Synthesis of (2-methylpyridin-3-yl)methanol (18-2)

Ethyl 2-methylnicotinate 18-1 (257 mg) was mixed with dichloromethane (4 ml) and to the mixture at -78°C was added dropwise 1 M diisobutyl aluminium hydride

(4 ml), followed by stirring for 1 hour. The reaction was quenched with methanol and

to the mixture was added aqueous Rochel solution (20 ml), followed by stirring for 2

hours. The resulting mixture was extracted with dichloromethane, dried over

anliydrous magnesium sulfate, and concenfrated under reduced pressure. The residue

was column-chromatographed (ethyl acetate/hexane = 1/1) to yield the compound 18-2

(166 mg, 87 %).

1H NMR(300MHz, CDC1₃) : δ 8.34 (d, IH, J = 3.4 Hz), 7.74 (d, IH, J= 7.6

Hz), 7.15 (dd, IH, J= 5.1 Hz, J= 7.8 Hz), 4J0 (s, 2H), 3.21 (br, IH), 2.51 (s, 3H)

Step 2: Synthesis of (2-methylpyridin-3-yl)methylaminophthalimide (18-3)

Compound 18-2 (166 mg) prepared in Step 1 was dissolved in tefrahydrofiiran

(4 ml) and to the solution were added phthalimide (401 mg) and triphenylphosphine

(716 mg), followed by adding diethylazodicarbonate (0.24 ml) thereto and stirring for

30 minutes. After the completion of the reaction, the resulting mixture was

concentrated under reduced pressure and the obtained residue was

column-chromatographed (ethyl acetate/hexane = 1/1) to yield the compound 18-3 (300

mg, 88 %).

1H NMR(300MHz, CDC1₃) : δ 8.40 (dd, IH, J = 1.7 Hz, J = 3.2 Hz), 7.87-7.83 (m, 2H), 1.16-1.12 (m, 2H), 7.61 (d, IH, J= 6.6 Hz), 7.10 (dd, IH, J= 4.9 Hz,

J= 7.8 Hz) 4.80 (s, 2H), 2.72 (s, 3H)

Step 3: Synthesis of

l-(4-t-butylbenzyl)-3-(2-methylpyridin-3-ylmethyl)thiourea (18-5)

The compound 18-3 (19 mg) prepared in Step 2 was dissolved in ethanol and to

the solution was added a drop of methylamine. After stirring the mixture at 55°C for

30 hours, t-butylbenzylisothiocyanate (62 mg) was added thereto, and the mixture was

stirred at room temperature for 1 hour. The resulting mixture was concentrated under

reduced pressure and the obtained residue was column-chromatographed

(methanol/dichloromethane = 1/10) to yield the compound 18-5 (26.2 mg, 100 %).

1H NMR(300MHz, CDC1₃) : δ 8.56-8.55 (m, IH), 8.37-8.30 (m, IH),

7J5-7.67(m, IH), 7.40-7.10 (m, 4H), 4.74 (s, 2H), 4.44 (s, 2H), 3.05 (s, 3H), 1.30 (s,

9H)

Example 128: Synthesis of l-(lH-indazol-5-yl)-3-phenethylthiourea (19-1)

Step 1: Synthesis of 5-amino-lH-indazole

5-Nitro-lH-indazole (20 mg) was dissolved in methanol (1 ml) and to the

solution was added a catalytic amount of palladium/carbon, followed by stirring at room

temperature under hydrogen gas atmosphere for 30 minutes. The resulting mixture

was diluted with ether, filtered through celite, and then concentrated under reduced

pressure to yield 5-amino-lH-indazole (16 mg, 100 %).

1H NMR(300MHz, CD₃OD) : δ 7.78 (s, IH), 7.32 (d, IH, J= 8.7 Hz),

7.01-6.95 (m, 2H)

Step 2: Synthesis of l-(lH-indazol-5-yl)-3-phenethylthiourea (19-1)

5-Amino-lH-indazole (9 mg) prepared according to the same procedure as

described in Step 1 was dissolved in dichloromethane (1 ml) and the solution was

stirred at room temperature for 3 hours. The resulting mixture was concenfrated under

reduced pressure and the obtained residue was column-chromatographed eluting with

ethyl acetate/hexane (1/2) to yield the compound 19-1 (10 mg, 60 %).

1H NMR(300MHz, CD₃OD) : δ 7.99 (d, IH, J= 1.0 Hz), 7.51-7.47 (m, 2H),

7.27-7.13 (m, 6H), 3.78 (t, 2H, J= 6.8 Hz), 2.90 (t, 2H, J= 7.3 Hz)

Example 129: Synthesis of l-(4-t-butylbenzyl)-3-(lH-indazolyl)thiourea (19-2)

Compound 19-2 (25 mg, 65 %) was synthesized using 5-amino-lH-indazole

(15 mg) and t-butylbenzylisothiocyanate (30 mg) according to the similar procedure as

described in Step 2 of Exmaple 128.

1H NMR(300MHz, CD₃OD) : δ 7.99(s, IH), 7.65 (s, IH), 7.50 (d, IH, J- 8.8

Hz), 7.33-7.21 (m, 5H), 4.73 (brs, 2H), 1.27 (s, 9H)

Example 130: Synthesis of

l-(4-t-butylbenzyl)-3-(2-fluoro-4-methanesulfonyloxybenzyl)thiourea (20-2a)

Step 1 : Synthesis of 3-fluoro-4-(N-t-butyloxycarbonylaminomethyl)phenol

(20-la) and 3-fluoro-4-(N-t-butyloxycarbonylaminomethyl)phenol t-butyloxycarbonyl

ether (20-lb) 2-Fluoro-4-hydroxybenzonitrile (686 mg), nickel chloride (II) (1.18 g) and

Boc₂O (2.18 mg) were dissolved in methanol (40 ml) and the solution was cooled to 0°C.

To the solution was slowly added sodium borohydride (1.32 g), and the mixture was

stirred at 0°C for 10 minutes and then at room temperature for 24 hours. The resulting

mixture was concentrated under reduced pressure and to the concentrate were added

ethyl acetate (60 ml) and sodium borohydride (300 mg), followed by filtering. The

filtrate was extracted twice with ethyl acetate. The total filtrate was concentrated

under reduced pressure, and then purified by column-chromatography (hexane/ethyl

acetate = 3/1) to yield the compound 20-la (134 mg, 11 %) and 20-lb (710 mg, 42 %).

20-la: 1H NMR (300MHz, CDC1₃) δ 7.11(t, J=8.2Hz, IH), 6.62(bs, IH),

6.61(d, J=9.6Hz, 2H), 4.91(bs, IH), 4.24(d, J=4.8Hz, 2H), 1.46(s, 9H)

20-lb: 1H NMR (300MHz, CDC1₃) δ 7.37(t, J=8.3Hz, IH), 6.93(m, 2H),

4.88(bs, IH), 4.32(d, J=5.7Hz, 2H), 1.55(s, 9H), 1.44(s, 9H)

Step 2: Synthesis of

l-(4-t-butylbenzyl)-3-(2-fluoro-4-methanesulfonyloxybenzyl)thiourea (20-2a)

Compound 20-la (134 mg) prepared in Step 1 was dissolved in

dichloromethane (2 ml) and to the solution at 0°C were added dropwise

methanesulfonyl chloride (44 μl) and pyridine (45 μl), followed by stirring at room temperature for 24 hours. The resulting mixture was concentrated under reduced

pressure and the obtained residue was purified by column-chromatography

(hexane/ethyl acetate = 3/1) to obtain methanesulfonyl compound (55 mg, 31 %). The

obtained compound was dissolved in dichlorormethane (2.0 ml) and the solution was

cooled to 0°C, followed by adding trifluoroacetic acid (100 μl) thereto and stirring for

2 hours. The resulting mixture was concentrated under reduced pressure and dissolved

in dimethylformamide (5.0 ml). To the solution was added triethylamine (30 μl) and

the mixure was stirred for 1 hour. To the obtained solution was added

4-t-butylbenzylisothiocyanate (40 mg) and the mixture was stirred at room temperature

for 18 hours. The resulting mixture was concenfrated under reduced pressure and the

to yield the compound 20-2a (61 mg, 85 %).

1H NMR (300MHz, CDC1₃) δ 7.43(t, J=8JHz, IH), 7.37(d, J=8.1Hz, 2H),

7.22(d, J=8.1Hz, 2H), 7.02(m, 2H), 6.20(bs, IH), 6.00(bs, IH), 4J9(d, J=5.4Hz, 2H),

4.53(d, J=4.2Hz, 2H), 3.16(s, 3H), 1.3 l(s, 9H).

Example 131: Synthesis of l-(4-t-butylbenzyl)-3-(2-fluoro-4-hydroxy)thiourea

(20-2b)

The compound 20-lb (710 mg) prepared in Step 1 of Example 130 was

dissolved in dichloromethane (10 ml) and the solution was cooled to 0°C, followed by

adding trifluoroacetic acid (1.0 ml) thereto and stirring for 2 hours. The resulting

mixture was concentrated under reduced pressure and part (211 mg) of the obtained

residue was dissolved in dimethylformamide (5.0 ml). To the solution was added

triethylamine (120 μl) and the mixture was stirred for 1 hour. To the obtained

solution was slowly added 4-t-butylbenzylisothiocyanate (170 mg) and the mixture was

stirred at room temperature for 18 hours. The resulting mixture was concenfrated

under reduced pressure and purified by column-chromatography (hexane/ethyl acetate =

1/1) to yield the compound 20-2b (196 mg, 68 %).

¹H NMR (300MHz, CDC1₃): δ 7.35(d, J=8.4Hz, 2H), 7.20(d, J=8.4Hz, 2H),

7.13(t, J=8.4Hz, IH), 6.54(m, 2H), 6.08(bs, IH), 6.02(bs, IH), 5J5(bs, IH), 4.59(m,

4H), 1.31(s, 9H)

Example 132: Synthesis of

l-(4-t-butylbenzyl)-3-[(6-methanesulfonylaminopyridin-2-yl)methyl]thiourea (21-7)

Step 1: Synthesis of 2,2-dimethyl-N-(6-methyl-2-pyridinyl)propaneamide

(21-1)

2-amino-6-picoline (26 g) was dissolved in dichloromethane (280 ml) and the

reactor was cooled to 0°C, followed by adding triethylamine (30 g) thereto. To the

obtained solution was slowly added dropwise a solution of trimethylacetylchloride (31.8

g) in dichloromethane (20 ml) and the mixture was stirred at room temperature for 3

hours. The resulting mixture was filtered, washed with water, dried over anhydrous

magnesium sulfate, concentrated under reduced pressure and then crystallized

(dichloromethane/pefroleum ether) to yield a pale yellow solid (38 g, 82 %).

Step 2: Synthesis of

N-[6-(bromomethyl)-2-pyridinyl]-2,2-dimethylpropaneamide (21-2)

2,2-dimethyl-N-(6-methyl-2-pyridinyl)propaneamide (21-1) (32 g) and

N-bromosuccinimide (29.6 g) were added to carbon tefrachloride (300 ml) and to the

mixture was added AIBN (15 mg), followed by reluxing for 20 hours under light emitted by 500W lamp. The resulting mixture was cooled to room temperature,

filtered, and concentrated under reduced pressure. The residue was purified by

column-chromatography (hexane/ethyl acetate = 10/1) to yield the compound 21-2 (1.94

g, 5 %) as a pure white solid.

1H NMR(300MHz, CDC1₃) : δ 8.20-8.17(m, IH), 8.00(brs, IH), 7.72-7.66(m,

IH), 7.16-7.13(m, IH), 4.42(s, 2H), 1.34(s, 9H)

Step 3: Synthesis of

N-[6- {(1 ,3-dihydro-l ,3-dioxo-2H-isoindol-2-yl)methyl}-2-pyridinyl]-2,2-dimethylprop

aneamide (21-3)

N-[6-(bromomethyl)-2-pyridinyl]-2,2-dimethylpropaneamide (21-2) (1.9 g) was

dissolved in dimethylformamide (20 ml) and to the solution was added potassium

phthalimide (1.43 g), followed by stirring at room temperature for 24 hours. The

resulting mixture was concentrated under reduced pressure and extrated with water and

dichloromethane. An organic layer was concenfrated under reduced pressure to yield

the compound 21-3 (2.27 g, 96 %) as a bright yellow solid.

1H NMR(300MHz, CDC1₃) : δ 8.15-8.12(m, IH), 7.92-7J4(m, 4H),

7.66-7.60(m, IH), 7.00-6.97(m, IH), 4.90(s, 2H), 1.29(s, 9H) Step 4: Synthesis of

2-[(2-amino-6-pyridinyl)methyl]-lH-isoindol-l,3(2H)-dione (21-4)

N-[6- {(1 ,3-dihydro- 1 ,3-dioxo-2H-isoindol-2-yl)methyl} -2-pyridinyl]-2,2-dimet

hylpropaneamide 21-3 was dissolved in ethanol (20 ml) and to the solution was added

concentrated sulfuric acid (2 ml), followed by refluxing for 6 hours. The obtained

solution was basified with ammonia solution, exfracted with dichloromethane, and then

dried over anhydrous magnesium sulfate. The residue was concenfrated under reduced

pressure and purified by column-chromatography (hexane/ethyl acetate = 1/1) to yield

the compound 21-4 (400 mg, 23 %) as a pale yellow solid.

^!H NMR(300MHz, CDC1₃) : δ 7.90-7Jl(m, 4H), 7.38-7.32(m, IH),

6.59-6.56(m, IH), 6.37-6.33(m, IH), 4.83(s, 2H), 4.36(brs, 2H)

Step 5: Synthesis of

2-[(2-methanesulfonylamino-6-pyridinyl)methyl]-lH-isoindol-l,3(2H)-dione (21-5)

The compound 21-4 (200 mg) prepared in Step 4 was dissolved in

dichloromethane (10 ml) and to the solution were added triethylamine (130 μl) and

methanesulfonyl chloride (67 μl), followed by stirring at room temperature for 24

hours. The resulting mixture was exfracted with water and dichloromethane, dried,

concenfrated under reduced pressure, and then crystallized (dichloromethane/pefroleum ether) to yield the compound 21-5 (260 mg, 99 %) as a white solid.

Step 6: Synthesis of

l-(4-t-butylbenzyl)-3-[(2-methanesulfonylamino-6-pyridinyl)methyl]thiourea (21-7)

The compound 21-5 (220 mg) prepared in Step 5 was dissolved in methanol (5

ml) and to the solution was added hydrazine hydrate (270 μl), followed by stirring at

room temperature for 2 hours. The obtained reaction solution was concentrated under

reduced pressure to obtain the compound 21-6. The compound 21-6 (690 mg) was

dissolved in dimethylformamide (20 ml) and to the solution was added

4-t-butylbenzylisothiocyanate (370 mg), followed by stirring at 100°C for 7 hours.

The reaction mixture was concenfrated and purified by column-chromatography

(hexane/ethyl acetate = 1/2) to yield the compound 21-7 (58 mg, 23 %) as a green

foamy solid.

1H NMR(300MHz, CDC1₃) : 6 7.69-7.63(m, IH), 7.42-7.38(m, 2H),

7.31-7.25(m, 3H), 7.04-6.65(m, 3H), 4J6-4.60(m, 4H), 3.07(s, 3H), 1.31(s,9H)

Example 133: Synthesis of (4-t-butylbenzyl)thiocarbamic acid

(l-methyl-4-nitro-lH-pyrrol-2-yl)methyl ester (22-3)

Step 1: Synthesis of N-methyl-4-nitro-pyrrol-2-carboxaldehyde (22-1)

N-methylpyrrol-2-carboxaldehyde (5 g) was dissolved in anhydrous acetic acid

(50 ml), and to an ice-cold of the solution was slowly added dropwise nitric acid (1.84

ml) with stirring. The mixture was stirred at this temperature for 1 hour, and then at

room temperature for 18 hours. After confirming the completion of the reaction, to the

mixture was added an ice-water (200 ml), followed by slowly adding solid sodium

hydroxide (20 g) thereto and stirring for 1 hour. The obtained mixture was exfracted

with ether (150 ml 3). The obtained organic layer was washed with aqueous sodium

bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium

sulfate, and then filtered. The filtrate was concenfrated under reduced pressure and

purified by column-chromatography (ethyl acetate/hexane = 1/4) to yield the compound

22-1 (3.5 g, 49.6 %).

1H NMR(300MHz, CDC1₃) : δ9.63(s, IH), 7.68(s, IH), 7.43(s, IH), 4.03(s,

3H)

Step 2: Synthesis of 2-hydroxymethyl-N-methyl-4-nitro-pyrrole (22-2) Compound 22-1 (550 mg) was dissolved in anhydrous tetrahydrofuran (30 ml)

and cooled to 0 °C. To the solution was slowly added dropwise IM

borane-tetrahydrofuran (3.25 ml), followed by refluxing at 80°C for 3 hours. After the

completion of the reaction, the solvent was evaporated under reduced pressure to be

removed, and then the residue was purified by column-chromatography (ethyl

acetate/hexane = 2/1) to yield the compound 22-2 (500 mg, 90 %).

1H NMR(300MHz, CDC1₃) : δ 7.51(s, IH), 6.65(s, IH), 4.59(s, 2H), 3J5(s,

3H)

Step 3: Synthesis of (4-t-butylbenzyl)thiocarbamic acid

(l-methyl-4-mfro-lH-pyrrol-2-yl)methyl ester (22-3)

Compond 22-2 (100 mg) was dissolved in anhydrous tetrahydrofuran (15 ml)

and cooled to 0 °C. To the solution was slowly added sodium hydride (190 mg) with

stirring, followed by stirring for 30 minutes. To the mixture was added

t-butylbenzylisothiocyanate (130 mg), followed by stirring for 6 hours. The solvent

was evaporated under reduced pressure to be removed, and then the residue was diluted

with water (20 ml). The obtained mixture was extracted with ethyl acetate (20 ml ><3),

dried over magnesium sulfate, and then filtered. The filtrate was evaporated under

reduced pressure and the obtained residue was purified by column-chromatography (ethyl acetate/hexane = 1/3) to yield the compound 22-3 (130 mg, 56.2 %).

1H NMR(300MHz, CDC1₃) : 57.5 l(m, IH), 7.31(m, 3H), 7.10(m, IH), 6.83(m,

IH), 6.47(brs, IH), 5.44(s, 2H), 4.71(d, 2H, J=5JHz), 3.68(s, 3H), 1.31(s, 9H)

Example 134: Synthesis of

l-(4-t-butylbenzyl)-3-(4-methanesulfonylamino-l-methyl-lH-pyrrol-2-yl)thiourea

(22-9)

22-9

Step 1: Synthesis of 2-cyano-N-methylpyrrole (22-4)

N-methyl-2-pyrrolcarboxaldehyde (5 g) and hydroxylamine hydrochloride

(3.82 g) were mixed in l-methyl-2-pyrrolidinone (50 ml) and the mixture was refluxed

at 110°C for 2 hours. After confirming the completion of the reaction, to the reaction

mixture was slowly added an ice-water (200 ml) and the resulting mixure was exfracted

with ethyl acetate (150 ml x 3), washed with brine, dried over sodium sulfate, and then

filtered. The filtrate was concenfrated under reduced pressure and the obtained residue

was purified by column-chromatography (ethyl acetate/hexane = 1/4) to yield the

compound 22-4 (3.5 g, 72 %). 1H NMR(300MHz, CDCl₃) : δ 6J9(m, 2H), 6.16(m, IH), 3.78(s, 3H)

Step 2: Synthesis of 4-nifro-2-cyano-N-methylpyrrole (22-5)

Compound 22-4 (1 g) was dissolved in anhydrous acetic acid (100 ml), and

cooled to 0 °C. To the solution was slowly added dropwise nitric acid (380 μl) with

stirring, followed by stirring at the same temperature for 1 hour and subsequently at

mixture was added an ice-water (200 ml), followed by slowly adding solid sodium

with ether (50 ml x3). The obtained organic layer was washed with aqueous sodium

purified by column-chromatography (ethyl acetate hexane = 1/3) to yield the compound

22-5 (1.05 g, 73.7 %).

1H MR(300MHz, CDC1₃) : δ 7.65(s, IH), 7.32(s, IH), 3.88(s, 3H)

Step 3: Synthesis of 2-cyano-4-amino-N-methylpyrrole (22-6)

Compoxmd 22-5 (500 mg) and 10 % palladium/carbon (50 mg) were poured

into the reactor and dissolved in methanol (10 ml), and then reacted under hydrogen gas atmosphere for 2 hours. After confirming the completion of the reaction, the resulting

mixture was filtered through celite, and the filtrate was concentrated under reduced

pressure and purified by column-chromatography (ethyl acetate/hexane = 3/1) to yield

the compound 22-6 (310 mg, 77.4 %).

1H NMR(300MHz, CDC1₃) : δ6.36(d, IH, J=2.1Hz), 6.30(d, IH, J=4.2Hz),

3.66(s, 3H)

Step 4: Synthesis of 4-methanesulfonylamino-2-cyano-N-methylpyrrole (22-7)

Compound 22-6 (310 mg) was dissolved in dichloromethane (30 ml) and

cooled to 0 °C. To the solution were added triethylamine (430 μl) and

methanesulfonyl chloride (210 μl) successively through an injector, followed by

stirring at room temperature for 24 hours. The resulting mixture was diluted with 1 N

aqueous hydrochloric acid, and an organic layer was dried over magnesium sulfate and

filtered. The filtrate was concentrated under reduced pressure and the obtained residue

was purified by column-chromatography (ethyl aceate/hexane = 1/1) to yield the

compound 22-7 (400 mg, 78.5 %)

1H NMR(300MHz, CDC1₃) : δ 6J8(d, IH, J=1.8Hz), 6.53(d, IH, J=1.8Hz),

5.95(brs, IH), 3.92(s, 3H), 2.97(s, 3H) Step 5: Synthesis of

(4-methanesulfonylamino-l-methyl-lH-pyrrol-2-yl)methylamine (22-8)

Compound 22-7 (150 mg) and 10 % palladium/carbon (catalytic amount),

together with methanol (10 ml), were poured into reactor and the reactor was filled with

hydrogen gas, followed by stirring at room temperature for 24 hours. After the

completion of the reaction, the resulting mixture was filtered through celite and

the obtained residue which was not purified.

Step 6: Synthesis of

l-(4-t-butylbenzyl)-3-(4-methanesulfonylamino-l-methyl-lH-pyrrol-2-yl)thiourea

(22-9)

The compound 22-8 (95 mg) prepared in Step 5 and

4-t-butylbenzylisothiocyanate (96 mg) were added to ethyl acetate (20 ml) and the

mixture was stirred for 16 hours. The resulting mixture was concentrated under

reduced pressure and the obtained residue was purified by column-chromatography

(ethyl acetate/hexane = 3/2) to yield the compound 22-9 (105 mg, 55 %).

1H NMR(300MHz, CDC1₃) : δ7.37(d, 2H, J=8.1Hz), 7.22(d, 2H, J=8.1Hz),

6.61(d, IH, J=1.8Hz), 5.95(d, IH, J=2.1Hz), 6.26(brs, IH), 5.87(brs, IH), 5J7(brs, IH), 4.64(d, 2H, J=4.8Hz), 4.54(d, 2H, J=3.9Hz), 3.48(s, 3H), 2.91(s, 3H), 1.31(s, 9H)

Example 135: Synthesis of

l-(4-t-butylbenzyl)-3-[(4-methanesulfonylaminomethyl)phenyl]thiourea (23-2)

Step 1: Synthesis of (4-methanesulfonylaminomethyl)-l -nitrobenzene (23-1)

4-nitrobenzylamine hydrochloride (3.77 g) was dissolved in dichloromethane

(20 ml) and to the solution at 0°C was added triethylamine (6.14 ml), followed by

adding dropwise methanesulfonyl chloride (1.7 ml) thereto and stirring at room

temperature for 23 hours. After the completion of the reaction, the resulting mixture

was exfracted with water and dichloromethane, concenfrated under reduced pressure,

and then crystallized (dichloromethane/petroleum ether) to yield an ocherous solid (1.2

g, 26 %).

Step 2: Synthesis of

l-(4-t-butylbenzyl)-3-[(4-methanesulfonylaminomethyl)phenyl]thiourea (23-2)

The compound 23-1 prepared in Step 1 was dissolved in ethyl acetate (30 ml) and to the solution was added tin (II) chloride dihydrate (6.1 g), followed by refluxing at

50 °C for 2 hours. After allowed to cool down to room temperature, the resulting

mixture was basified with saturated aqueous sodium bicarbonate solution, washed with

water and brine, dried, and then concenfrated under reduced pressure to obtain a yellow

solid (610 mg, 59 %). The obtained compound (107 mg), which was not purified, was

dissolved in acetonitrile (10 ml) and to the solution were added triethylamine (100 μl)

and 4-t-butylbenzylisothiocyanate (110 mg), followed by refluxing for 24 hours. The

resultant mixture was concenfrated under reduced pressure and purified by

column-chromatography (hexane/ethyl acetate = 1/2) to yield the compound 23-2 (73

mg, 34 %) as a solid.

1H NMR(300MHz, CDC1₃) : δ 7.84(brs, IH), 7.46-7.18(m, 8H), 6.26(brs, IH),

5.00-4.81(m, 3H), 4.31-4.28(m, 2H), 2.92(s, 3H), 1.29(s,9H)

Example 136 ~ Example 141

Compounds of Example 136 ~ Example 141, which are shown in the Scheme

24, were synthesized according to the similar procedure as described in Example 76 or

Example 77, and properties and spectral data thereof are shown in below table.

24-

24-3

Example 142: Synthesis of 1-benzyl-

l_(4_hydroxy-3-methoxybenzyl)-3-phenethylthiourea (25-l)

Naniline (200 mg) and benzylamine (129 mg) were dissolved in methanol (3

ml) and the solution was stirred for 30 minutes. To the solution was added a catalytic

amount of 10 % platmum/carbon to be subjected to the hydrogenation reaction (1 atm) .

After the completion of the reaction, the resulting mixture was filtered and evaporated

under reduced pressure to remove methanol. The obtained residue was dissolved in

dichloromethane (3 ml) and to the solution was added phenethylisothiocyanate (196 mg,

1.2 mmol), followed by stirring at room temperature for 5 hours. Then,

dichloromethane was evaporated under reduced pressure and the obtained residue was

column-chromatographed (hexane/ethyl acetate = 1/1) to yield the compound 25-1 (400

mg, 82 %) as a white solid.

^lH ΝMR (300MHz, CDC1₃): δ 7.25 (m, 10H), 6.94 (m, 3H), 6.69(m, 2H),

5.69(s, IH), 5.51(t, IH, J=4.68 Hz), 4.88(s, 2H), 4.75(s, 2H), 3.89(m, 2H), 3.75(s, 3H),

2.78(t, 2H, J=6.57 Hz): MS (El) m/e 406 [M⁺] Example 143 ~ Example 167

Compounds 25-2 ~ 25-26 of Example 143 ~ Example 167, which are shown in

the Scheme 25, were synthesized according to the similar procedure as described in

Example 142, and properties and specfral data thereof are shown in below table.

25-6

25-9

25-10

25-14

25-15

Example 168: Synthesis of

N-(4-t-butylbenzyl)-3-(3-fluoro-4-methanesulfonylaminophenyl)propionamide

(26-3)

Step 1 : Synthesis of (3-fluoro-4-methanesulfonylamino)cinnamic acid methyl

ester (26-1)

2-fluoro-4-iodomethanesulfonylaminobenzene 3-2 (200 mg) was dissolved in

dimethylformamide (16 ml) and to the solution were added palladium acetate (7.2 mg), l,l'-bis(diphenylphosphino)ferrocene (20 mg), triethylamine (200 μl) and

methylacrylate (550 mg), followed by stirring at 60 °C for a day. The reaction mixture

was cooled to room temperature, diluted with dichloromethane (40 ml) and then washed

with water and aqueous hydrochloric acid solution. The obtained mixture was dried

over anhydrous magnesium sulfate, concenfrated under reduced pressure, and then

column-chromatographed (ethyl acetate/hexane = 1/1) to yield the compound 26-1 (214

mg, 70 %).

1H NMR(300MHz, CDC1₃ + CD₃OD) : δ 7.62(d, IH, J=16.3Hz), 7.55(t, IH,

J=8.3Hz), 7.46(dd, IH, J=2.0, HJHz), 7.41(dd, IH, J=2.0, 8.3Hz), 6.50(d, IH,

J=15.8Hz), 3J7(s, 3H), 3.03(s, 3H)

Step 2: Synthesis of methyl

3-(3-fluoro-4-methanesulfonylaminophenyl)propionate (26-2)

The compound 26-1 (78 mg) prepared according to the same procedure as

described in Step 1 was dissolved in methanol (10 ml) and to the solution was added a

catalytic amount of 10 % palladium/carbon, followed by stirring at room temperature

under hydrogen atmosphere for 2 hours. The resulting mixture was diluted with ether,

filtered through celite, and then concenfrated under reduced pressure to yield the

compound 26-2 (68 mg, 86 %). 1H MR(300MHz, CDC1₃) : δ 7.45(t, IH, J=8.2Hz), 6.98(d, 2H), 6.46(s, IH),

3.66(s, 3H), 3.00(s, 3H), 2.9 l(t, 2H, J=7.6Hz), 2.60(t, 2H, J=7.6Hz)

Step 3: Synthesis of N-(4-t-butylbenzyl)

3-(3-fluoro-4-methanesulfonylaminophenyl)propionamide (26-3)

The compound 26-2 (30 mg) prepared in Step 2 was dissolved in toluene (4 ml)

and to the solution was added 4-t-butylbenzylamine (150 μl), followed by refluxing for

3 hours. The resulting mixture was concentrated under reduced pressure and the

obtained residue was chromatographed on silica gel column (ethyl acetate/hexane = 1/1)

to yield the compound 26-3 (28 mg, 58 %).

1H NMR(300MHz, CDCI₃) : δ 7.39(t, IH, J=8.3Hz) 7.29(d, 2H), 7.07(d, 2H),

6.95(m, 2H), 6.33(s, IH), 5.54(s, IH), 4.3 l(d, 2H, J=5.6Hz), 2.93(s, 3H), 2.92(t, 2H,

7=7.4Hz), 2.41(t, 2H, 7=7.6Hz), 1.24(s, 9H)

Example 169: Synthesis of N-(3-fluoro-4-methanesulfonylaminobenzyl)

4-t-butylbenzamide (27)

27

Hydrochloride salt 3-4 (100 mg) prepared according to the same procedure as

described in Example 13 was dissolved in dichloromethane (6 ml) and to the solution

were added 4-t-butylbenzoylchloride (85 mg) and triethylamine (60 μl), followed by

stirring at room temperature for 2 hours. The resulting mixture was concentrated

under reduced pressure and the obtained residue was column-chromatographed (ethyl

acetate/hexane = 1/1) to yield the compound 27 (110 mg, 72 %).

1H NMR(300MHz, CDC1₃) : δ 7J2(d, 2H), 7.49(t, IH, J=8.0Hz) 7.43(d, 2H),

7.13(m, 2H), 6.54(s, IH), 4.59(d, 2H, J=5.9Hz), 2.93(s, 3H), 2.99(s, 3H), 1.31(s, 9H)

Example 170: Synthesis of

(3-fluoro-4-methanesulfonylaminobenzyl)dithiocarbamic acid 4-t-butylbenzyl ester

(28)

28 The compound 3-4 (15.4 mg) prepared by Example 13 was dissolved in

dimethylformamide (1 ml) and to the solution were added tefrabutylammonium iodide

(67 mg), cesium (I) carbonate (59 mg) and carbon bisulfide (7 μl), followed by stirring

at 0 °C for 1 hour. To the mixture was added 4-t-butylbenzylbromide (34 μl) and

stirred at room temperature for 1 hour. After the completion of the reaction, the

resulting mixture was concentrated under reduced pressure and the obtained residue was

chromatographed on silica gel column eluting with ethyl acetate/hexane (1/3) to yield

the compound 28 (12 mg, 52 %).

1H NMR(300MHz, CD₃OD) : δ 7.43 (t, IH, J=8.3Hz), 7.25-7.34 (m, 4H),

7.10-7.16 (t, 2H, 7=8.3Hz), 4.88 (s, 2H), 4.55 (s, 2H), 2.97 (s, 3H), 1.30 (s, 9H)

Example 171: Synthesis of l-(4-t-butylbenzyl)-3-(3-fluorophenethyl)urea (29)

4-t-butylbenzylamine (3.2 g) was dissolved in dichloromethane (10 ml) and to

the solution was added triethylamine (2.79 ml), followed by cooling to 0°C and slowly

adding dropwise a solution of triphosgene (1.98 g) in dichloromethane (5 ml). The

mixture was stirred at room temperature for 5 hours and water (10 ml) was added thereto. The resulting mixture was exfracted with dichloromethane, dried over

anhydrous sodium sulfate, and then concentrated under reduced pressure. The

obtained residue was purified by column-chromatography (hexane/ethyl acetate = 20/1)

to yield 4-t-butylbenzylisocyanate (880 mg) as a solid. The obtained compound (400

mg) and 3-fluorophenethylamine (290 mg) were dissolved in dichloromethane (20 ml)

and the solution was stirred at room temperature for 22 hours. The solvent was

removed therefrom and the residue was purified by column-chromatography

(hexane/ethyl acetate = 4/1) to yield the compound 29 (400 mg, 58 %) as a solid.

1H NMRβOOMHz, CDC1₃) : δ 7.35-6.82(m, 8H), 4.91(s, IH), 4.39(d, 2H,

J=5.4Hz), 3.60-3.48(m, 2H), 2J9(t, 2H, J = 6.9Hz), 1.31(s,9H)

Example 172: Synthesis of l-(4-t-butylbenzyl)-3-(2-fluorobenzoyl)thiourea (30)

Potassium thiocyanate (KSCN) (240 mg) was dissolved in acetone (5 ml) and

the solution was allowed to warm up to 50°C. To the solution was added

2-fluorobenzoylchloride (330 mg) and the mixture was stirred at 50°C for 4 hours.

The produced potassium chloride was filtered off and to the obtained solution was 4-t-butylbenzylamine (330 mg), followed by stirring at room temperature for 24 hours.

The resulting mixture was concentrated and the residue was purified by

column-chromatography (hexane/ethyl acetate = 5/1) to yield the compound 30 (156 mg,

23 %) as a liquid.

1H NMR(300MHz, CDC1₃) : δ 8.18-8.11(m, IH), 7.50-7.07(m, 8H), 7.02(brs,

IH), 4J0-4.65(m, 2H), 1.31(s,9H)

Example 173: Synthesis of

N"-cyano-N-(4-t-butylbenzyl)-N'-(2-pyridinylethyl)guanidine (31-l)

N-(4-t-butylbenzyl) N'-cyano-S-methylisothiourea (180 mg) was dissolved in

xylene (10 ml) and to the solution was added 2-(2-aminoethyl)pyridine (86 mg),

followed by refluxing for 7 hours. The resulting mixture was concentrated under

reduced pressure and the obtained residue was purified by column-chromatography

(acetone/ethyl acetate = 1/1) to yield the compound 31-1 (70 mg, 30 %) as a liquid.

1H NMR(300MHz, CDC1₃) : δ 8.01 (brs, IH), 7.62-7.56(m, IH), 7.39-7.35(m,

2H), 7.26-7.20(m, 3H), 7.14-7.03(m, 2H), 6.42(brs, IH), 4.34(d,2H, J=5.1Hz), 3Jl-3.65(m, 2H), 3.03-2.98(m, 2H), 1.32(s, 9H)

Example 174 ~ Example 178

Compounds of Example 174 ~ Example 178, which are shown in the Scheme

31, were synthesized according to the similar procedure as described in Example 173,

and properties and spectral data thereof are shown in below table

Example 179: Synthesis of

N"-cyano-N-(4-t-butylbenzyl)-N'-(2,6-difluoro-3-methanesulfonylaminobenzyl)gua

nidine (31-7)

l-(4-t-butylbenzyl)-3-(2,6-difluoro-3-methanesulfonylaminobenzyl)thiourea

(44 mg) and lead cyanamide (30 mg) were added to ethyl acetate (10 ml) and the mixture was refluxed for 18 hours. The resulting mixture was purified by

column-cliromatogrphy (hexane/ethyl acetate = 1/1) to yield the compound 31-7 (35 mg,

78 %).

1H NMR (CDC1₃): δ 7.47(dt, J=5J, 8JHz, IH), 7.37(d, J=8.4Hz, 2H), 7.21(d,

J=8.4Hz, 2H), 6.90(t, J=8JHz, IH), 6.67(bs, IH), 6.28(bs, IH), 6.16(bs, IH), 4.78(d,

7=5.4Hz, 2H), 4.55(d, J=4.2Hz, 2H), 3.00(s, 3H), 1.31(s, 9H)

Example 180: Synthesis of

N"-cyano-N-(4-t-butylbenzyl)-N'-(2-fluoro-5-methanesulfonylaminobenzyl)guanidi

ne (31-8)

Compound 31-8 was synthesized according to the similar procedure as

described in Example 179.

¹H NMR(CDC1₃): δ 7.34(d, 7=8.1Hz, 2H), 7.28(dd, J=2.4, 6.0Hz, IH), 7.20(d,

J=8.1Hz, 2H), 7.18(m, IH), 6.98(t, J=9.0Hz, IH), 6.48(bs, IH), 6.34(bs, IH), 4.74(d,

7=5 JHz, 2H), 4.56(d, J=4.2Hz, 2H), 2.95(s, 3H), 1.29(s, 9H) Example 181: Synthesis of

N"-cyano-N-[2-(l-methyl-lH-pyrrol-2-yl)ethyl]-N'-[l-(4-t-butylbenzyl)]guanidine

(31-9)

l-(4-t-butylbenzyl)-3-[2-(l -methyl- lH-pyrrol-2-yl)ethyl]thiourea (0.2 g) and

lead cyanamide (170 mg) were dissolved in ethyl acetate (20 ml) and the solution was

refluxed for 12 hours. After confirming the completion of the reaction, the resulting

mixture was filtered to remove the yellow solid, and the obtained residue was

concentrated under reduced pressure and purified by column-chromatography (ethyl

acetate/hexane = 2/3) to yield the compound 31-9 (174 mg, 85 %) as a yellow solid.

1H NMR (300MHz, CDC1₃): δ 7.38(d, 2H), 7.21(d, 2H), 7.15(m, 2H), 6.05(d,

IH, J=2.1Hz), 4.48(m, 2H), 3.86(m, 2H), 2.99(t, 2H, J=6.9Hz), 1.31(s, 9H)

Example 182: Synthesis of

l-(4-chlorobenzyl)-3-(6-methoxy-l,2,3,4-tetrahydronaphthalen-l-yl)thiourea (32-2)

Step 1: Synthesis of 6-methoxy- 1,2,3, 4-tefrahydro-naphthalen-l-ylamine (32-1)

6-methoxy-l-tefralone (881 mg) and hydroxylamine hydrochloride (1.19 g)

were dissolved in methanol (50 ml) and to the solution was slowly added pyridine (645

mg) at room temperature, followed by stirring for 18 hours. The resulting mixture was

concentrated under reduced pressure. The concenfrate was dissolved in ethyl acetate

(30 ml), washed with water (10 ml x 2) and aqueous saturated copper sulfate solution

(10 ml), dried over magnesium sulfate, and then concentrated under reduced pressure.

The residue was purified by column-chromatography (hexane/ethyl acetate = 3/1) to

yield an intermediate material, oxime (886 mg, 93 %).

The obtained oxime (586 mg) was dissolved in methanol (50 ml) and the

solution was cooled to -30°C, followed by adding nickel(II) chloride hexahydrate (1.46

g) thereto. After the solid was completely dissolved, to the solution was slowly added

sodium borohydride (1.16 g) and the mixture was stirred at -30°C for 30 minutes.

Then, the mixture was stirred at room temperature for 90 minutes and concenfrated

under reduced pressure. The obtained residue was dissolved in 10 % hydrochloric acid

(30 ml) and the solution was slowly basified with 1 N aqueous sodium hydroxide solution. The obtained solution was extracted with ethyl acetate (50 ml x3) and the

organic layers were collected. The total organic layer was washed with brine, dried

over magnesium sulfate, concenfrated under reduced pressure, and then purified by

column-chromatography (dichloromethane/methanol = 10/1) to yield the compound

32-1 (385 mg, 71 %).

¹H NMR(CDC1₃): δ 7.31(d, 7=8JHz, IH), 6J5(dd, 7=8.5, 2.4Hz, IH), 6.61(d,

J=2.4Hz, IH), 3.94(t, J=5.4Hz, IH), 3J8(s, 3H), 2J5(m, 2H), 1.96(m, 2H), 1.73(bs,

2H), 1.70(m, 2H)

The similar compounds 32-3 and 32-5 were synthesized according to the same

procedure as described above.

Step 2: Synthesis of

1 -(4-chlorobenzyl)-3 -(6-methoxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)thiourea (32-2)

The compound 32-1 (100 mg) prepared according to the same procedure as

described in Step 1 was dissolved in ethyl acetate (4 ml) and to the solution were added

a solution of 4-chlorobenzylisothiocyanate (123 mg) in ethyl acetate (2 ml), followed by

stirring at room temperarure for 18 hours. The obtained reaction mixture was

concentrated under reduced pressure and purified by column-chromatography

(hexane/ethyl acetate = 2/1) to yield the compound 32-2 (201 mg, 99 %).

1H NMR(DMSO-d₆): δ 7.62(d, J=7.5Hz, IH), 7.52(bs, IH), 7.23(d, 7=8.4 Hz,

2H), 7.14(d, J=8.4Hz, 2H), 6.92(bs, IH), 6.55(d, J=8JHz, IH), 6.47(s, IH), 5.30(bs,

IH), 4.50(bs, 2H), 3.53(s, 3H), 2.52(m, 2H), 1.71(m, IH), 1.55(m, 3H)

The similar compounds 32-4 and 32-6 ~ 32-10 were synthesized according to

the same procedure as described above.

Example 189: Synthesis of

l-(4-t-butylbenzyl)-3-(5-hydroxy-l,2,3,4-tetrahyronaphthalen-l-yl)thiourea (32-11)

The compound 32-3 (570 mg) prepared by Step 1 of Example 183 was

dissolved in 48 % hydrobromic acid (10 ml) and the mixture was refluxed for 24 hours.

The mixture was cooled to room temperature, and then concenfrated under reduced

pressure to remove the hydrobromic acid (residue : 766 mg, 97 %). Part (500 mg) of

the residue was dissolved in dimethylformamide (5 ml) and the solution was cooled to

0°C. To the obtained mixture was added 5 M sodium hydroxide (800 μl), followed by

stirring for 15 minutes to obtain a solution. To the solution was slowly added a

solution of 4-t-butylbenzylisothiocyanate (421 mg) in dimethylformamide (5 ml) and

the mixture was stirred at room temperature for 48 hours. Then, to the obtained

solution was added water and the resulting mixture was extracted with ether (50 ml x3).

The exfracted organic layer was collected, washed with 1 N hydrochloric acid, water

and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then

concenfrated under reduced pressure. The residue was purified by

column-cliromatography (hexane/ethyl acetate = 2/1) to yield the compound 32-11 (550

mg, 73 %). 1H NMR(acetone-d₆): δ 7.38(d, 7=8.4Hz, 2H), 7.29(d, 7=8.4Hz, 2H), 7.15(bs,

IH), 7.03(bs, IH), 6.95(t, 7=7.8Hz, IH), 6.8 l(d, 7=7.8 Hz, IH), 6.69(d, J=7.8Hz, IH),

5.70(bs, IH), 4J7(d, J=5.1Hz, 2H), 2.63(t, 7=6.0Hz, 2H), 2.00(m, IH), 1.81(m, 3H),

1.30(s, 9H)

The similar compound 32-12 was synthesized according to the same procedure

as described above.

32-12 Example 191: Synthesis of l-(4-t-butylbenzyl)-3-(3-formylchromone)thiourea

(33-2)

2-amino-3-formylchromone 33-1 (100 mg) was dissolved in anhydrous

tetrahydrofuran (15 ml) and the solution was stirred. To the solution was added sdium

hydride (15 mg) at 0°C and the mixture was stirred for 30 minutes. To the mixture was

added 4-t-butylbenzylisothiocyanate (130 mg), followed by stirring for 6 hours. The

resulting mixture was neufralized with an iced water and concenfrated under reduced

pressure. The residue was extracted with ethyl acetate (30 ml x3), dried over

magnesium sulfate, and then filtered. The filtrate was purified by

column-chromatography (ethyl acetate/hexane = 3/2) to yield the compound 33-2 (25

mg, 10 %).

1H NMR(300MHz, CDC1₃) : δ8J5(s, IH), 8.14(m, IH), 7J7(m, IH), 7.42(m,

6H), 5J3(s, 2H), 1.33(s, 9H) Example 192: Synthesis of (4-t-butylbenzyl)thiocarbamic acid

-O-(3,5-dimethylpyrazol-l-ylmethyl)ester (33-4)

3, 5 -dimethylpyrazol-l -methanol 33-3 (200 mg) and sodium hydride (42 mg)

were dissolved in anhydrous tetrahydrofuran (20 ml) and the solution was stirred for 1

hour. To the solution was added 4-t-butylbenzylisothiocyanate (330 mg) and the

mixture was stirred at room temperature for 12 hours. The resulting mixture was

filtered under reduced pressure and the solvent was removed therefrom. The residue

was purified by column-chromatography (ethyl acetate/hexane = 1/2) to yield the

compound 33-4 (253 mg, 48 %) as a solid.

1H NMR (300MHz, acetone-d₆) δ 7.29(m, 4H), 7.09(m, IH), 6.30(s, 2H),

4.68(d, 2H, J=2.85Hz), 2.33(s, 3H), 2.22(s, 3H), 1.30(s, 9H)

Example 193: Synthesis of N-(3-fluoro-4-methanesulfonylaminobenzyl)

3-(4-t-butylphenyl)propionamide (34-5)

Step 1: Synthesis of 4-t-butylcinnamic acid ethyl ester (34-2)

4-t-butylbenzaldehyde (34-1) (69 mg) was dissolved in acetonitrile (16 ml) and

to the solution were added diisopropylethylamine (84 mg) and triethyl

phosphonoacetate (117 mg), followed by stirring at room temperature for 1 hours. The

resulting mixture was diluted with dichloromethane (20 ml), washed with water and

aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate, and then

concentrated under reduced pressure. The residue was column-chromatographed

(ethyl acetate/hexane = 1/5) to yield the compound 34-2 (64 mg, 65 %)

1H NMR(300MHz, CDC1₃) : δ 7.65(d, IH, J=16.1Hz), 7.46-7.34 (m, 4H),

6.38(d, lH, 7=16.1Hz), 4.24(q, 2H, J=7.2Hz), 1.31(m, 12H)

Step 2: Synthesis of ethyl 3-(4-t-butylphenyl)propionate (34-3)

The compound 34-2 (64 mg) according to the same procedure as described in

Step 1 was dissolved in methanol (10 ml) and to the solution was added a catalytic

amount of 10 % palladium/carbon, followed by stirring at room temperature under

hydrogen gas atmosphere for 2 hours. The resulting mixture was diluted with ether, filtered through celite, and then concentrated under reduced pressure to yield the

compound 34-3 (60 mg, 93 %)

1H NMR(300MHz, CDC1₃) : δ 7.28(d, 2H, 7=8.0Hz), 7.1 l(d, 2H, J=8.0Hz),

4.1 l(q, 2H, J=7.1Hz), 2.90(t, 2H, J=7.6Hz), 2.59(t, 2H, J=7.6Hz), 1.29(s, 9H), 1.21(t,

3H, J=6.8Hz)

Step 3: Synthesis of N-(3-fluoro-4-methanesulfonylaminobenzyl)

3 -(4-t-butylphenyl)propionamide (34-5)

The compound 34-3 (60 mg) prepared according to the same procedure as

described in Step 2 was dissolved in 50 % aqueous tetrahydrofuran solution (10 ml) and

to the solution was added lithium hydroxide (24 mg). The mixture was stirred at room

temperature for 5 hours to hydrolyze the compound 34-3 and the solvent was removed

therefrom. The residue was dissolved in ethyl acetate and extracted to the obtain the

compound 34-4 (43 mg, 81 %). The compound 34-4 was dissolved in benzene (2 ml)

and to the solution was added dropwise oxalyl chloride (100 μl), followed by refluxing

for 2 hours. The reaction mixture obtained by concentrating the resultant under

reduced pressure and hydrochloride compound 3-4 (67 mg) prepared in Example 13

were added to dichloromethane (6 ml), and to the mixture was added triethylamine (60

μl), followed by stirring at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure and the obtained residue was purified by

column-chromatography (ethyl acetate/hexane = 1/1) to yield the compound 34-5 (34

mg, 38 %).

1H NMR(300MHz, CDC1₃) : δ 7.40(t, IH, 7=8.2Hz) 7.23(d, 2H, 7=8.3Hz),

7.06(d, 2H, J=8.3Hz), 6.90(m, 2H), 6.49(s, IH), 5.68(s, IH), 4.30(d, 2H, J=5.6Hz),

2.93(s, 3H), 2.89(t, 2H, 7=7.6Hz), 2.47(t, 2H, 7=7.4Hz ), 1.19(s, 9H)

Example 194: Synthesis of

l-(4-t-butylbenzyl)-3-(4-methylaminosulfonylaminobenzyl)thiourea (35-2a)

Step 1: Synthesis of

N-t-butyloxycarbonyl-4-methylaminosulfonylaminobenzylamine (35-la)

Sodium hydride (18 mg) was suspended in dimethylformamide, and to the

suspension was added a solution of N-t-butyloxycarbonyl-p-aminobenzylamine (150

mg) and methylaminosulfamoylcliloride (97 mg) in dimethylformamide while the

temperature was controlled to 0°C, followed by stirring at room temperature for 3 hours.

The reaction solution was evaporated under reduced pressure, and the residue was diluted with ethyl acetate (70 ml), washed with saturated aqueous sodium bicarbonate

solution, water and saturated saline, and then evaporated under reduced pressrure. The

obtained residue was purified by column-chromatography (hexane/ethyl acetate = 5/1)

to yield the compound 35-la (170 mg, 79 %).

1HNMR(300MHz, DMSO) : δ7.27(d, 2H, 7=8.5 Hz), 7.10(m, 2H), 4.18(s, 2H),

3.29(s, 3H), 1.43(s, 9H)

Step 2: Synthesis of

l-(4-t-butylbenzyl)-3-(4-methylaminosulfonylaminobenzyl)thiourea (35-2a)

The compound 35-la (170 mg) prepared in Step 1 was dissolved in anliydrous

dichloromethane (4 ml), and to the solution was added excess trifluoroacetic acid while

the temperature was contolled to 0°C, followed by stirring for 30 minutes. The

resulting mixture was evaporated under reduced pressure to remove excess

trifluoroacetic acid and the residue was dissolved in anhydrous dichloromethane (4 ml).

To the solution were added triethylamine (98 μl) and 4-t-butylbenzylisothiocyanate

(144 mg) and the mixture was stirred at room temperature for 3 hours. The reaction

solution was evaporated under reduced pressure, and the remained was diluted with

ethyl acetate (70 ml), washed with water and saturated saline, and then concenfrated

under reduced pressure. The obtained residue was purified by column-chromatography (hexane/ethyl acetate = 10/1) to yield the compound 35-2a

(157 mg, 69 %).

1H NMR(300MHz, MeOH-d₅) : δ7.33(d, 2H, 7=8.5 Hz), 7.17(m, 2H), 4.65(s,

4H), 2.55(s, 3H), 1.25(s, 9H)

MS (FAB) m/e 421[M⁺+l]

Example 195: Synthesis of

l-(4-t-butylbenzyl)-3-(4-N,N-dimethylaminosulfonylaminobenzyl)thiourea (35-2b)

Step 1: Synthesis of

N-t-butyloxycarbonyl-4-N,N-dimethylaminosulfonylaminobenzylamine (35-lb)

Compound 35-lb (393 mg, 53 %) was synthesized by adding

dimethylsulfamoylchloride (266 μl) and then by being allowed to warm up to 60 °C

according the procedure as described in Example 194.

1H NMR(300MHz, CDC1₃) : δ7.18(m, 8H), 4.16(s, 4H), 2J7(s, 3H), 1.45(s,

9H) Step 2: Synthesis of

l-(4-t-butylbenzyl)-3-(4-N,N-dimethylaminosulfonylaminobenzyl)thiourea (35-2b)

Compound 35-2b (337 mg, 65 %) was synthesized according to the similar

procedure as described in Example 194.

1H NMR(300MHz, CDC1₃) : δ7.18(m, 8H), 4.56(s, 4H), 3.92(s, 3H), 1.27(s,

9H)

MS (FAB) m/e 435[M⁺+1]

Example 196: Synthesis of

l-(4-t-butylbenzyl)-3-(4-aminosulfonylaminobenzyl)thiourea (35-2c)

Step 1: Synthesis of

N-t-butyloxycarbonyl-4-N-(t-butyloxycarbonylaminosulfonyl)aminobenzylamine

(35-lc)

Compound 35-lc (333 mg, 54 %) was synthesized by adding

N-(t-butyloxycarbonyl)-N-[4-(dimethylazaniumylidene)- 1 ,4-dihydropyridin- 1 -ylsulfony

l]azanide (464 mg) and then by being allowed to warm up to 60 °C according the procedure as described in Example 194.

1H NMR(300MHz, DMSO) : δ7.12(m, 4H), 4.06(d, 2H, 7=5.9 Hz), 1.37(s, 9H),

1.33(s, 9H)

Step 2: Synthesis of

l-(4-t-butylbenzyl)-3-(4-aminosulfonylaminobenzyl)thiourea (35-2c)

Compound 35-2c (257 mg, 69 %) was synthesized according to the similar

procedure as described in Example 194.

1H NMR(300MHz, DMSO) : δ7.18(m, 8H), 4.58(s, 4H), 1.25(s, 9H)

MS (FAB) m/e 407[M⁺+1]

Example 197: Synthesis of

l-(4-t-butylbenzyl)-3-(4-methanesulfonylamino-3-nitrobenzyl)thiourea (35-5)

Step 1: Synthesis of 4-methanesulfonylamino-3-nifrobenzonitrile (35-4)

3-nifro-4-aminobenzonitrile (150 mg) and sodium bistrimethylsilylamide (2 ml)

were dissolved in anhydrous tetrahydrofuran (6 ml), and to the solution was added methanesulfonic anhydride (191 mg) at 0°C, followed by stirring for 3 hours. The

reaction solution was evaporated under reduced pressure and the residue was diluted

with ethyl acetate (70 ml), washed with diluted aqueous hydrochloric acid solution,

saturated aqueous sodium bicarbonate solution, water and brine, and then evapoarated

under reduced pressure. The obtained residue was purified by column-cliromatogaphy

(hexane/ethyl acetate = 5/1) to yield the compound 35-4 (120 mg, 54 %)

1H NMR(300MHz, Pyridine-d₅) : δ8.60(s, IH), 8.17(d, IH, J=8J6 Hz),

7.88(dd, IH, J=1.95, 8.79 Hz), 3.48(s, 3H)

Step 2: Synthesis of

l-(4-t-butylbenzyl)-3-(4-methanesulfonylamino-3-nifrobenzyl)thiourea (35-5)

The compound 35-4 (90 mg) prepared according to the same procedure as

described in Step 1 was dissolved in ahydrous tetrahydrofuran and to the solution was

added borane (1 M, 1.1 ml), followed by stirring for 6 hours. The resulting mixture

was evaporated under reduced pressure, and the residue was diluted with ethyl acetate

(50 ml), washed with water and brine, and then evaporated under reduced pressure to

obtain amine. The obtained amine, which was not purified, was dissolved in

dichloromethane (2 ml) and to the solution were added triethylamine (57 μl) and

4-t-butylbenzylisothiocyanate (8.4 mg) at 0°C, followed by stirring at room temperature for 3 hours. The reaction solution was evaporated under reduced pressure. The

residue was diluted with ethyl acetate (70 ml), and washed with water and brine. The

solvent was evaporated under reduced pressure, and then the obtained residue was

purified by column-chromatography (hexane/ethyl acetate = 30/1) to yield the

compound 35-5 (56 mg, 33 %).

1H NMR(300MHz, CDC1₃) : δ8.60(s, IH), 8.17(d, IH, J=8J6 Hz), 7.88(dd,

IH, 7=1.95, 8.79 Hz), 7.40(m, 4H), 4.80(d, 2H, 7=5.13 Hz), 4.55(s, 2H), 3.10(s, 3H),

1.27(s, 9H)

MS (FAB) m/e 451[M⁺+1]

Example 198: Synthesis of

l-(4-t-butylbenzyl)-3-(l-(4-methanesulfonylphenyl)ethyl)thiourea (36-4)

36-4

Step 1: Synthesis of 4-methanesulfonylaminoacetophenone (36-1)

4-aminoacetophenone (300 mg) was dissolved in dichloromethane, and to the

solution were added methanesulfonic anhydride (2.44 mmol) and pyridine (53.85 μl) at

0°C, followed by stirring at room temperature for 3 hours. After confirming the completion of the reaction using TLC, the reaction was quenched with saturated sodium

bicarbonate solution. The reaction mixture was diluted with dichloromethane, washed

with water and saturated aqueous sodium chloride solution, dried over anhydrous

sodium sulfate, and then concenfrated under reduced pressure to obtain a solid. The

solid was recrystalhzed with ethyl acetate and hexane, to yield a pale yellow crystal

(293.2 mg, 61.95 %).

mp: 155.1-161.2 ^°C;

1H NMR(400MHz, CDC1₃) : δ 7.98(d, 2H, J=8.8Hz), 7.27(d, 2H, J=8.8 Hz),

3.11(d, 3H, J=1.6 Hz),2.59(d, 3H, J=1.6 Hz)

IR(KBr pellet, cm^"1) : 3290.93, 3003.59, 2928.38, 1667.16, 1600.63, 1469.49,

1330.64, 1279.54, 1146.47

Step 2: Synthesis of 4-methanesulfonylaminoacetophenonoxime (36-2)

4-methanesulfonylaminoacetophenone (36-1) (360.2 mg) was dissolved in

ethanol and to the solution was added a solution of hydroxylamine hydrochloride

(129.11 mg) and sodium acetate (249.40 mg) in minimal amount of water. To the

mixture was added ethanol until the solution became clear and then the solution was

refluxed for 20 hours, thereby to be changed from transparent yellow to transparent

colorlessness. After confirming the completion of the reaction using TLC, the ethanol was removed therefrom, and the residue was exfracted with ethyl acetate, washed with

water and saturated aqueous sodium chloride solution, dried over anliydrous sodium

sulfate, and then concenfratd under reduced pressure to obain a solid. The solid was

recrystalhzed with ethyl acetate and hexane to yield a pale yellow crystal (289.6 mg,

75.11 %).

mp: 181.5 - 182.1 TJ;

1H NMR(400MHz, CDC1₃): δ 7.60(d, 2H, J=7.2 Hz), 7.26(d, 2H, J=7.4 Hz),

2.96(s, 3H), 2.21(s, 3H). .

IR(KBr pellet, cm^"1) : 3495.35, 3255.25, 3023.84, 2926.38, 1605.45, 1323.89,

1155.15;

Step 3: Synthesis of l-(4-methanesulfonylaminophenyl)ethylamine (36-3)

4-methanesulfonylamino acetophenonoxime (36-2) (279 mg) was dissolved in

methanol and to the solution was added palladium/carbon (55.8 mg), followed by

stirring under hydrogen atmosphere. After confirming the completion of the reaction

using TLC, palladium/carbon was filtered off and the filtrate was concentrated under

reduced pressure to remove the methanol, thereby to yield a fransparent yellow liquid

(251.1 mg, 95.89 %).

1H NMR(400MHz, CDC1₃) : δ 7.28(d, 2H, J=8.8 Hz), 7.15(d, 2H, J=8.8 Hz), 4.09(q, IH, J=6.6 Hz), 2.95 (s, 3H), 1.35(d, 3H, J=6.4 Hz)

IR(NaCl neat, cm^"1) : 3350.71, 3270.69, 3136.65, 3023.84, 2965.98, 1610.27,

1512.88, 1325.82, 1153.22;

Step 4: Synthesis of

1 -(4-t-butylbenzyl)-3-(l -(4-methanesulfonylphenyl)ethyl)thiourea (36-4)

The compound 36-3 (56.3 mg) prepared in Step 3 was dissolved in

dichloromethane and to the solution was added 4-t-butylbenzylisothiocyanate (64.7 mg),

followed by stirring at room temperature for 12 hours. After confiming the completion

of the reaction using TLC, dichloromethane was evaporated under reduced pressure and

the residue was purified by column-chromatography (hexane/ethyl acetate = 4/1) to

yield a white solid (41.9 mg, 38.01 %).

mp: 177.8-178.5 ^"C

1H NMR(400MHz, CDC1₃) : δ 9.33(s, IH), 7.28(m, 8H), 5.51(s, IH), 4.68(s,

2H), 4.08(q, IH, J=4.8Hz), 2.93(s, 3H), 1.48(d, 3H, J=4.8Hz),1.31(s, 9H).

IR(KBr pellet, cm^"1) : 3356.50, 3262.97, 3057.58, 3025.76, 2964.05, 2868.59,

1544.70, 1512.88, 1325.82

Example 199: Synthesis of l-(l-(4-methanesulfonylphenyl)ethyl)-3-phenethylthiourea (36-5)

36-5

Solution of compound 36-3 (50 mg) in dichloromethane was mixed with

phenethylisothiocyanate (65 J mg) and the mixture was stirred at room temperature for

12 hours, followed by confirming the completion of the reaction using TLC.

Dichloromethane was evaporated and the residue was column-chromatographed

(hexane/ethyl acetate = 2/1) to yield a white solid (12.8 mg, 14.53 %).

mp : 190.8-192.l t:

1H NMR(400MHz, DMSO-d₆) : δ 9.63(s, IH), 7.78(s, IH), 7.19(m, 9H), 5.34(s, IH),

3.56(s, IH), 2.92(s, 2H), 2J4(t, 2H, J=6.6Hz), 2.47(s, 3H), 1.33(d, 3H,

J=6.6Hz).IR(NaCl neat, cm^"1) : 3365.17, 3229.22, 3020.94, 1731.76, 1523.49,

1374.03;

Example 200: Synthesis of

l-(4-t-butylbenzyl)-3-(l-(4-methanesulfonylphenyl)ethyl)-3-methylthiourea (36-6)

36-6

Compound 36-1 (200 mg) was dissolved in methanol and to the solution was

added palladium/carbon (30.0 mg), followed by bringing the atmosphere of the reactor

into an atmsphere of hydrogen gas. To the solution was added methylamine solution

(2 M) and the mixture was allowed to be reacted for 5 days. After confirming the

completion of the reaction using TLC, palladium/carbon was filtered off and the filtrate

was purified by column-chromatography eluting with hexane/ethyl acetate (3/1) to

remove neural material and subsequently eluting with dichloromethane/methanol (10/1)

to obtain a yellow liquid (70 mg, 32.70 %). The obtained compound (70 mg) was

dissolved in dichloromethane and to the solution was added phenethyhsothiocyanate

(75.5 mg), followed by stirring at room temperature for 4 hours. After confirming the

completion of the reaction using TLC, the resulting mixture was diluted with

dichloromethane, washed with water and saturated aqueous sodium chloride solution,

dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to

obain a solid. The solid was purified by column-chromatography (hexane/ethyl

acetate = 3/1) to yield a colorless liquid (42.6 mg, 32 %). 1H NMR(400MHz, CDC1₃) : δ 7.27(m, 8H), 6.90(q, IH, J=7.2Hz), 5.53(s, IH),

4.84(d, 2H, J=4.4Hz), 2.98(s, 3H), 2.66(s, 3H), 1.58(s, IH), 1.52(d, 3H, J=7.2Hz),

1.29(s, 3H).

IR(NaCl neat, cm^"1) : 3386.39, 3267.79, 2963.09, 1512.88, 1326.79;

Experimental Example. Biological potency test

(1) ⁴⁵ Ca influx test

1) Separation of spinal dorsal root ganglia (DRG) in newborn rats and primary

culture thereof

Neonatal(2-day old or younger than 2-day old) SD rats were put in ice for 5

minutes to anesthetize and disinfected with 70% ethanol. DRG of all part of spinal

cord were dissected (Wood et al., 1988, J. Neurosci. 8, pp3208-3220) and collected in

DME/F12 medium to which 1.2 g/1 sodium bicarbonate, 50 mg/1 gentamycin were

added. The DRG were incubated sequentially at 37°C for 30 min in 200 U/ml

collagenase and 2.5 mg/ml trypsin, separately. The ganglia were washed twice with

DME/F12 medium supplemented with 10% horse serum, triturated through a

fire-polished Pasteur pipette, filtered through Nitex 40 membrane to obtain single cell

suspension. This was subjected to centrifugation, then re-suspended in cell culture

medium at certain level of cell density. As the cell culture medium, DME/F12 medium supplemented with 10% horse serum, diluted 1:1 with identical medium

conditioned by C6 glioma cells (2 days on a confluent monolayer) was used, and

NGF(Nerve Growth Factor) was added to final concentration of 200 ng/ml. After the

cells were grown 2 days in medium where cytosine arabinoside (Ara-C, 100 μM) was

added to kill dividing nonneuronal cells, medium was changed to one without Ara-C.

The resuspended cells were plated at a density of 1500-1700 neurons/well onto Terasaki

plates previously coated with 10 μg/ml poly-D-ornithine.

2) ⁴⁵ Ca influx experiments

DRG nerve cells from the primary culture of 2-3 days were equilibrated by

washing 4 times with HEPES (lOmM, pH 7.4)-buffered Ca ²⁺, Mg²⁺-free HBSS

(H-HBSS). The solution in each well was removed from the individual well. Medium

containing the test compound plus capsaicin (final concentration 0.5 μM) and ⁴⁵Ca

(final concentration 10 μCi/ml) in H-HBSS was added to each well and incubated at

room temperature for 10 min. Terasaki plates were washed six times with H-HBSS

and dried in an oven. To each well, 0.3% SDS (10 μl) was added to elute ⁴⁵Ca. After

the addition of 2ml of scintillation cocktail into each well, the amount of ⁴⁵Ca influx

into neuron was measured by counting radioactivity. Antagonistic activities of test

compounds against vanilloid receptor were calculated as percent of the inhibition of

maximal response of capsaicin at a concentration of 0.5 μM and results are given as ICso (Table la, lb and lc).

Agonistic activities of the test compounds for vanilloid receptor were

determined as a concentration of the test compound showing 50% of the 45, Ca influx,

compared to the maximal amount of ^■ 45 Ca influx in case of using 3 μM capsaicin and

results are given as EC₅₀ (Table Id).

(2) Chamiel activity assay

Antagonistic activities of test compounds were assayed based on electrical

change of cation channel coimected to vanilloid receptor and experiments were

conducted according to reference method (Oh et al., 1996, J. Neuroscience 16,

ppl659-1667) (Table la, lb and lc).

Table la. Results of Calcium Influx and Patchclamp Tests

NR: no response

+: antagonistic potency equal to capsazepine

-: antagonistic potency 10 times higher than capsazepine

Table lb. Results of Calcium Influx and Patchclamp Tests

+: antagonistic potency equal to capsazepine

Table lc. Results of Calcium Influx and Patchclamp Tests

+: antagonistic potency equal to capsazepine

Table Id. Results of Calcium Influx Tests

(3) Analgesic activity test: Mouse writhing test by inducing with phenyl-p-quinone

Male ICR mice (mean body weight 25 g) were maintained in a controlled

lighting environment (12 h on 12 h off) for experiment. Animals received an

intraperitoneal injection of 0.3ml of the chemical irritant phenyl-p-quinone (dissolved in saline containing 5% ethanol to be a dose of 4.5mg/kg) and 6 min later, the number of

abdominal constrictions was counted in the subsequent 6 min period. Animals (10

animals/group) received 0.2ml of test compounds solution in vehicle of ethanol/Tween

80/saline (10/10/80) intraperitoneally 30 min before the injection of phenyl-p-quinone.

A reduction in the number of writhes responding to the test drug compound relative to

the number responding in saline confrol group was considered to be indicative of an

analgesic effect. Analgesic effect was calculated by % inhibition equation (%

inhibition=(C-T)/C x 100), wherein C and T represent the number of writhes in control

and compound-treated group, respectively (Table 2).

The test results demonstrated that analgesic effect of the compounds used in

this experiment is as potent as indomethacin which is a very potent antiinflmmatory and

analgesic agent. In particular, it is significant to clarify that vanilloid receptor

antagonist can exhibit such potent analgesic effect, and the results suggests that

vanilloid receptor antagonist has potential as an analgesic agent.

Table 2. Test result of analgesic activity for writhing by phenyl-p-quinone

(4) Antiinflammatory activity test: TPA(12-O-tetradecanoylphorbol 13-acetate)-induced

mouse ear edema test

Male ICR mice(body weight 25-30g), 10 animals/group, were treated topically

on the right ear with 30 μl of TPA (2.5 μg) solution in acetone and after 15 min, 30 μl

of acetone or test compound solution in acetone was applied topically. After six hours,

an identical treatment was applied again. After twenty four hours following the

treatment of TPA, the animals were sacrificed and ear tissue was dissected using 6

mm-diameter punch. Ear tissue dissected were weighed to the nearest 0.1 mg on an

electrobalance. The increased weight of the tissue compared to confrol group was

considered as an index of inflammation. The percent inhibition is defined by the

following equation: % inhibition =(C-T)/C x 100, wherein C and T represent an increase of ear

weight in TPA-freated and TPA+drug-freated group, respectively (Table 3).

The above experiment shows that vanilloid receptor antagonist exhibits

anti-inflammatory effects of the same level with indomethacin which is very potent

anti-inflammatory and analgesic agent. This phenomenon can be understood by

connecting with the action of vanilloid receptor in neurogenic inflammation, and

suggests potential applicability of vanilloid receptor antagonist in various inflammatory

diseases, in particular, neurogenic inflammatory diseases.

Table 3. TPA-induced mice ear edema test

(5) Ulcer test: ethanol-induced anti-ulcer test

Male SD rats (body weight 180-200 g), 5 animals/group, were fasted for 24 hours, and their stomaches were damaged. The rats were administered with 10 ml/kg

of test drug suspended in 1 % methylcellulose orally and, after 1 hour, 1 ml of 99%

ethanol orally. After 1 hour without food and water, the rats were sacrificed by

cervical dislocation and stomaches thereof were removed. The removed stomaches

were incised along the greater curvature and opened. Then, the degree of gastric

damage was scored based on the following ulcer index which is a criterion for

evaluation and the percent inhibition of test drug against ulcer was calculated compared

to control group (1% methylcellulose) (table 4). % inhibition =[(ulcer index of confrol

group - ulcer index of drug-treated group)/( ulcer index of control group)] x 100

According to the present study using ethanol-induced ulcer model, the vanilloid

receptor antagonist was found out to exhibit significant anti-ulcerous activities, confrary

to ranitidine, which is a representative antiulcerant but did not show anti-ulcer activity

in the present study. This study is the first to demonstrate the anti-ulcerous potential

of vanilloid receptor antagonist. Based on the result, possibility that vanilloid receptor

antagonist will be developed as an anti-ulcerant is suggested.

Table 4. Ethanol-induced anti-ulcer test

Industrial Applicability

The compounds according to the present invention are useful in the prevention

or freatment of pain, acute pain, chronic pain, neuropathic pain, post-operative pain,

migraine, arthralgia, neuropathies, nerve injury, diabetic neuropathy, neurodegeneration,

neurotic skin disorder, sfroke, urinary bladder hypersensitiveness, irritable bowel syndrome, a respiratory disorder such as asthma and chronic obstructive pulmonary

diseases, irritation in skin, eye or mucous membrane, stomach-duodenal ulcer,

inflammatory bowel disease, inflammatory disease, etc.

Claims

1. A compound of the following formula (I):

(i)

or a pharmaceutically acceptable salt thereof,

wherein:

X represents S, O or -NCN;

Y represents single bond, NR , O or S;

R¹ represents

pyridinyhnethyl, pyrrolylmethyl, oxazolylmetliyl, pyrazolylmethyl, imidazolyhnethyl,

anthracenylmethyl, naphthylmethyl, quinolinylmethyl, alkoxycarbonyl or

lower alkyl having 1 to 5 carbon atoms, hydroxy, methanesulfonylamino, lower alkoxy having 1 to 5 carbon atoms, methoxyalkoxy, methoxyalkoxyalkyl, alkoxycarbonyloxy,

benzyloxy, acetoxymethyl, propinoyloxymethyl, butoxyalkyl, trimethylacetoxy,

alkyl having 1 to 5 carbon atoms);

R² represents R⁸-(CH₂)_n-

cyano, methanesulfonylamino, formyl or halogen, or

(wherein, R is hydrogen, halogen, lower alkyl having 1 to 5 carbon atoms,

10 λ lower alkoxy having 1 to 5 carbon atoms, hydroxy, nitro, cyano, -NHSO₂R , -S(O)pR ,

hydrogen or cyano; R¹² is lower alkyl having 1 to 5 carbon atoms, methylphenyl,

NR¹³R¹⁴, trifluoromethyl or alkenyl; R¹³ and R¹⁴ are independently hydrogen or lower

alkyl having 1 to 5 carbon atoms; and p is 0 or 2.); or or

(wherein, Z is O, S, NH or -NCH₃; R¹⁵ is hydrogen, halogen, lower alkyl

having 1 to 5 carbon atoms, nitro, cyano, -NHSO₂R¹², -S(O)pR¹²,

19

N,N-dimethylaminomethyl or alkoxycarbonylamino; and p and R have the same

meanings as defined in R⁹);

or

nifro, methanesulfonylamino or halogen; or benzyl or phenethyl substituted or

unsubstitued with lower alkyl having 1 to 5 carbon atoms, alkoxy, hydroxy, nifro,

methanesulfonylamino or halogen);

or or

alkyl having 1 to 5 carbon atoms, alkoxy, methylenedioxy,

methanesulfonylaminomethyl, alkoxycarbonyl, hydroxy, sulfamoyl, aminoalkoxy,

alkoxycarbonylamino, -NHCH₂CO₂H, alkoxyalkylcarbonylamino,

alkoxycarbonylalkylammo, nifro, formyl, acetyl, formylamino, acetoxyamino, cyano,

-OSO₂CH₃, -NHSO₂R¹², -N(SO₂R¹²)CH₃, -N(SO₂R¹²)₂, -S(O)_PR¹², -NΕ.¹³R¹⁴,

thiocarbamoyl, -C(=O)NHNH₂, -C(=O)NHOH, -C(=O)NHOCH₃, -PO(=O)(OCH₃)₂,

carboxyl, NHBoc, -NHC(=O)SCH₃ or guanidine; R²² and R²³ are independently

hydrogen, halogen, alkoxy or hydroxy; and p, R¹², R ³ and R¹⁴ have the same

meanings as defined in R⁹);

or hydroxyphenylalkyl or (methanesulfonylaminophenyl)alkyl}; and

R³ represents hydrogen, alkyl or cycloalkyl having 1 to 8 carbon atoms, lower

alkylphenyl having 1 to 5 carbon atoms, pyridinylethyl, bisphenylmethyl; or

phenylalkyl substituted with lower alkyl having 1 to 5 carbon atoms, halogen or

methanesulfonylamino .

2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein,

X represents S, O or -NCN;

Y represents NR³ or O;

R¹ represents

(wherein, m is 0, 1 or 2; and R and R are independently hydrogen, lower

trimethylacetoxymethyl or halogen);

R² represents R⁸-(CH₂)_n-

{wherein, n is 0, 1, 2 or 3; R⁸ is benzoyl, imidazolyl, indolyl, indazolyl,

with lower alkyl having 1 to 5 carbon atoms, nifro, amino, cyano,

methanesulfonylamino, formyl or halogen, or

R¹⁰ is hydrogen, nifro, NHSO₂R¹² or -NR¹³R¹⁴; R¹¹ is hydrogen or cyano; R¹² is

lower alkyl having 1 to 4 carbon atoms, methylphenyl, -NR¹³R¹⁴ or trifluoromethyl;

R¹³ and R¹ are independently hydrogen or lower alkyl having 1 to 4 carbon atoms;

and p is 0 or 2);

or

carbon atoms, nifro, cyano or NHSO R¹²; and R¹² has the same meanings as defined

in R⁹); or

or

(wherein, W is O, S, NH, NR¹⁶ or -CH₂-; and R¹⁶ is pyridinyl or pyrimidinyl

substituted or unsubstituted with lower alkyl having 1 to 4 carbon atoms, nifro or methanesulfonylamino; or benzyl or phenethyl substituted or unsubstituted with lower

alkyl having 1 to 4 carbon atoms, alkoxy, hydroxy or methanesulfonylamino);

or

alkyl having 1 to 5 carbon atoms, alkoxy, methylenedioxy,

methanesulfonylaminomethyl, alkoxycarbonyl, hydroxy, sulfamoyl,

alkoxycarbonylamino, -NHCH₂CO₂H, alkoxyalkylcarbonylamino,

alkoxycarbonylalkylammo, nitro, formyl, acetyl, formylamino, acetoxyamino, cyano,

thiocarbamoyl, -C(=O)NHNH₂, -C(=O)NHOH, -C(=O)NHOCH₃, carboxyl, NΗBoc,

-NHC(=O)SCH₃, guanidine; R²² and R²³ are independently hydrogen, alkoxy or

or hydroxyphenylalkyl or (methanesulfonylaminophenyl)alkyl}; and

R³ represents hydrogen, alkyl having 1 to 4 carbon atoms, lower alkylphenyl

having 1 to 3 carbon atoms, pyridinylethyl or bisphenyhnethyl; or phenylalkyl

substituted with lower alkyl having 1 to 4 carbon atoms, halogen or methanesulfonylamino .

3. A compound or a pharmaceutically acceptable salt thereof according to claim

2, wherein,

X represents S, O or -NCN;

Y represents NR³ or O;

R¹ represents

(wherein, m is 1 or 2; and R and R are independently hydrogen, t-butyl,

hydroxy, methanesulfonylamino, lower alkoxy having 1 to 5 carbon atoms,

methoxymethoxy, methoxyethoxy, benzyloxy, acetoxymethyl, trimethylacetoxymethyl

or halogen);

R² represents R^s-(CH₂)_n-

{wherein, n is 1, 2 or 3; R⁸ is benzoyl, imidazolyl, indolyl, indazolyl, thiazolyl,

pyrazolyl or benzimidazolyl substituted or unsubstituted with methyl, nifro or halogen;

or

(wherein, R is hydrogen, halogen, methyl, nitro or methanesulfonylamino; R 10 is

hydrogen or nitro; and R π is hydrogen or cyano);

or

(wherein, Z is O, S, NH or -NCH₃; and R 15 is hydrogen, methyl, nifro, cyano

or methanesulfonylamino);

or

(wherein, W is O, S, NH, NR¹⁶ or -CH₂-; and R¹⁶ is pyridinyl, pyrimidinyl; or benzyl

or phenethyl substituted or unsubstituted with methyl, methoxy or hydroxy);

or or

alkyl having 1 to 4 carbon atoms, methoxy, methylenedioxy,

methanesulfonylaminomethyl, methoxycarbonyl, hydroxy, sulfamoyl,

alkoxycarbonylamino, -NHCH₂CO₂H, methoxymethylcarbonylamino,

alkoxycarbonylalkylammo, nitro, acetyl, formylamino, acetoxyamino, cyano,

thiocarbamoyl, -C(=O)NHNH₂, -C(=O)NHOH, -C(=O)NHOCH₃, carboxyl, NHBoc,

hydroxy; and p, R¹², R¹³ and R¹⁴ are the same meanings as defined in R⁹);

or hydroxyphenylalkyl or (methanesulfonylaminophenyl)alkyl}; and

R represents hydrogen, methyl, isopropyl, isobutyl, cyclohexyl, benzyl,

methanesulfonylamino .

4. A compound or a pharmaceutically acceptable salt thereof according to claim

1, wherein the fomula (I) represents

l-(4-t-butylbenzyl)-3-[2-(l-methyl-lH-pyrrol-2-yl)ethyl]thiourea; l-(4-t-butylbenzyl)-3-(4-amino-2,5-difluorobenzyl)thiourea;

1 -(4-t-butylbenzyl)-3 -(4-sulfamoylbenzyl)thiourea;

l-(4-t-butylbenzyl)-3-(3-fluoro-4-methanesulfonylaminobenzyl)thiourea;

l-phenethyl-3-(3-fluoro-4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butylbenzyl)-3-(3-chloro-4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butylbenzyl)-3-(3-methoxycarboxyl-4-methanesulfonylaminobenzyl)thio

urea;

l-(4-t-butylbenzyl)-3-(3-carboxyl-4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butylbenzyl)-3-((3-N-hydroxyaminocarbonyl-4-methanesulfonylamino)b

enzyl)thiourea;

l-(4-t-butylbenzyl)-3-(3-methoxycarboxylbenzyl)thiourea;

l-(4-t-butylbenzyl)-3-(3-carboxylbenzyl)thiourea;

l-(4-t-butylbenzyl)-3-(2,3,5,6-tetrafluoro-4-methanesulfonylaminobenzyl)thiou

rea;

1 -(4-t-butylbenzyl)-3-(2,5-difluoro-4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butylbenzyl)-3-[(3-methanesulfonylamino-6-pyridinyl)methyl]thiourea;

l-(4-t-butylbenzyl)-3-(2,6-dichloro-5-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butylbenzyl)-3-(4-ιnethanesulfonylaminophenethyl)thiourea;

l-(4-t-butylbenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea; l-(4-t-butylbenzyl)-3-[2,6-difluoro-3-(TSr-methanesulfonylamino)benzyl]thioure

l-(4-t-butylbenzyl)-3-[3-(N-methanesulfonylamino)benzyl]thiourea;

l-(4-t-butyl-2-methoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butyl-2-ethoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butyl-2-propoxybenzyl)-3-(4-methanesulfonylaminobenzyl)tlιiourea;

l-(4-t-butyl-2-butoxybenzyl)-3-(4-methanesulfonylaminobenzyl)tl iourea;

l-(4-t-butyl-2-isopropoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butyl-2-isobutoxybe-nzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;

1 -(4-t-butyl-2-neopentoxybenzyl)-3 -(4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butyl-2-methoxymethoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thio

urea;

l-(4-t-butyl-2-methoxyethoxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiour

ea;

1 -(4-t-butyl-2-benzyloxybenzyl)-3-(4-methanesulfonylaminobenzyl)thiourea;

l-(2-acetoxymethyl-4-t-butylbenzyl)-3-(4-methanesulfonylaminobenzyl)thioure

1 -(4-t-butylbenzyl)-3- [2-(4-methylthiazol-5-yl)ethyl]thiourea;

l-(4-t-butylbenzyl)-3-((2-chloro-5-pyridinyl)methyl)thiourea; l-(4-t-butylbenzyl)-3-(2-pyridin-2-ylethyl)thiourea;

l-(4-t-butylbenzyl)-3-(2,5-difluorobenzyl)thiourea;

l-(4-t-butylbenzyl)-3-(3-fluorophenethyl)thiourea;

l-(4-t-butylbenzyl)-3-(4-sulfamoylphenethyl)thiourea;

l-(4-t-butylbenzyl)-3-(4-morpholinylethyl)thiourea;

l-(4-t-butylbenzyl)-3-[2-(lH-imidazol-4-yl)ethyl]thiourea;

1 -(4-t-butylbenzyl)-3 - [2-thiophen-2-ethyl] thiourea;

1 -(4-t-butylbenzyl)-3 -(4-methanesulfonylamino- 1 -methyl- lH-pyrrol-2-yl)thiou

rea;

1 -benzyl- 1 -(3 -(4-hydroxy-3 -methoxyphenyl)propyl)-3 -phenethylthiourea;

l-(3-(4-hydroxy-3-methoxyphenyl)propyl)-l-phenethyl-3-phenethylthiourea;

1 -bisphenylmethyl- 1 -(3 -(4-hydroxy-3 -methoxyphenyl)propyl)-3 -phenethylthio

urea; or

N"-cyano-N-(4-t-butylbenzyl)-N'-(4-methanesulfonylaminobenzyl)guanidine.

5. A compound or a pharmaceutically acceptable salt thereof according to claim

1, wherein the fomula (I) represents

l-(4-t-butylbenzyl)-3-(3-fluoro-4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butylbenzyl)-3-(3-chloro-4-methanesulfonylaminobenzyl)thiourea;

l-(4-t-butylbenzyl)-3-(3-methoxycarboxyl-4-methanesulfonylaminobenzyl)thio urea;

1 -(4-t-butylbenzyl)-3 -(4-methanesulfonylaminobenzyl)thiourea; or

l-(4-t-butyl-2-isobutoxybenzyl)-3-(4-methanesulfonylamino)thiourea.

6. A pharmaceutical composition comprising the compound according to claim

1 or a pharmaceutically acceptable salt thereof as an active ingredient together with a

pharmaceutically acceptable carrier.

7. A pharmaceutical composition according to claim 6, wherein the compound

according to claim 1 or a pharmaceutically acceptable salts thereof as an active

ingredient together with an pharmaceutically acceptable carrier is present in an

effective amount for preventing or treating pain, acute pain, chronic pain, neuropathic

pain, post-operative pain, migraine, arthralgia, neuropathies, nerve injury, diabetic

neuropathy, neurodegeneration, neurotic skin disorder, stroke, urinary bladder

hypersensitiveness, irritable bowel syndrome, a respiratory disorder such as asthma

or chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane,

stomach-duodenal ulcer, inflammatory bowel disease or inflammatory diseases.

8. A method for preventing or treating pain, acute pain, chronic pain,

neuropathic pain, post-operative pain, migraine, arthralgia, neuropathies, nerve injury,

diabetic neuropathy, neurodegeneration, neurotic skin disorder, sfroke, urinary

bladder hypersensitiveness, irritable bowel syndrome, a respiratory disorder such as asthma or chronic obstructive pulmonary disease, irritation of skin, eye or mucous

membrane, stomach-duodenal ulcer, inflammatory bowel disease or inflammatory

diseases, wherein the method comprises administering a therapeutically effective

amoxmt of the compound selected from the group consisting of compounds of

formula I or a pharmaceutically acceptable salt thereof.

9. Use of a compound selected from the group consisting of compound of

formula I or a pharmaceutically acceptable salt thereof as an antagonist of vanilloid

receptor.

10. Use of a compound selected from the group consisting of compound of

formula I or a pharmaceutically acceptable salt thereof as an agonist of vanilloid

receptor.