Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist ; and pharmaceutical compositions containing the same

Technical field

The present invention relates to novel compounds, isomer thereof or

pharmaceutically acceptable salts thereof as TRPV1 antagonist; and a

pharmaceutical composition containing the same

Background Art

The vanilloid receptor-1 (VR1 , or transient receptor potential vanilloid-1 ,

TRPV1 ) is the receptor for capsaicin (8-methyl-N-vanil!yl-6~nonenamide), a

pungent ingredient in hot peppers. The molecular cloning of TRPV1 was

reported in 1997 (Caterina et al., 1997, Nature, 389, pp816-824), which belongs

to the TRP channel family of non-selective cation channel. TRPV1 is activated

or sensitized by stimuli such as capsaicin, resiniferatoxin, heat, acid,

anandamide, lipid metabolites or the like ; thus it plays a crucial role as a

molecular integrator of noxious stimuli in mammals (Tominaga et al., 1998,

Neuron, 21 pp531-543; Hwang et al., 2000, PNAS, 97, pp6155-6160). The

TRPV1 is highly expressed in primary afferent sensory neurons, and also

reportedly expressed in various organs and tissues such as bladder, kidney,

lung, intestine, or skin and in the central nervous system (CNS) including the

brain and non-neuronal tissues (Mezey et al., 2000, PNAS, 97, pp3655-3660;

Stander et al., 2004, Exp. Dermatol. 13, pp129-139; Cortright et al., 2001 ,

BBRC, 281 , pp1183-1189). Activation of the TRPV1 by endogenous/exogenous

stimuli leads to not only transmission of noxious stimuli, but also liberation of

neuropeptides such as substance P, CGRP (Calcitonin Gene-Related Peptide)

in the neurons, thereby causing neurogenic inflammation.

TRPV1 knock-out mice showed normal responses in a wide range of

behavioural tests including noxious mechanical and acute thermal stimuli, but

exhibited little thermal hypersensitivity in inflammation states. (Caterina et al.,

2000, Science, 288, pp306-313; Davis et a!., 2000, Nature, 405, pp183-187;

Karai et al., 2004, J. Clin. Invest, 113, pp1344-1352).

As mentioned above, the TRPV1 knock-out mice exhibited reduced

responses to thermal or noxious stimuli, which is thus raising the possibility that

TRPV1 antagonists may be utilized for the prevention or treatment of various

pain conditions. This possibility is supported by the report that the well-known

TRPV1 antagonist, capsazepine, also decreases hyperalgesia caused by

physical stimuli in several models of inflammatory and neuropathic pain (Walker

et al., 2003, JPET, 304, pp56-62; Garcia-Martinez et al., 2002, PNAS ₁ 99, 2374-

2379). In addition, treatment of the primary culture of afferent sensory neurons

with the TRPV1 agonist, capsaicin etc., results in damage to nerve functions

and furthermore death of nerve cells. The TRPV1 antagonist exerts defense

actions against such damage to nerve functions and nerve cell death (Holzer P,

1991 , Pharmacological Reviews, 43, pp143-201 ; Mezey et al., 2000, PNAS ₁ 97,

3655-3660). The TRPV1 is expressed on sensory neurons distributed in all

regions of the gastrointestinal tract and is highly expressed in inflammatory

disorders such as irritable bowel syndrome and inflammatory bowel disease

(Chan et al., 2003, Lancet, 361 , pp385-391 ; Yiangou et al., 2001 , Lancet, 357,

pp1338-1339). In addition, activation of the TRPV1 stimulates sensory nerves,

which in turn causes release of neuropeptides which are known to play a critical

role in pathogenesis of gastrointestinal disorders such as gastro-esophageal

reflux disease (GERD) and stomach duodenal ulcer (Holzer P, 2004, Eur. J.

Pharmacol. 500, pp231-241 ; Geppetti et al., 2004, Br. J. Pharmacol., 141,

pp1313-1320).

The TRPV1 -expressing afferent nerves are abundantly distributed in

airway mucosa, and bronchial hypersensitivity is very similar mechanism to

hyperalgesia. Protons and lipoxygenase products, known as endogenous

ligands for the TRPV1 , are well known as crucial factors responsible for

development of asthma and chronic obstructive pulmonary diseases (Hwang et

al., 2002, Curr. Opin. Pharmacol. pp235-242; Spina et al., 2002, Curr. Opin.

Pharmacol. pp264-272). Further, it has been reported that air-polluting

substances which are a kind of asthma-causing substances, i.e., particulate

matter specifically acts on the TRPV1 and such action is inhibited by

capsazepine (Veronesi et al., 2001 , NeuroToxicology, 22, pp795-810). Urinary

bladder hypersensitiveness and urinary incontinence are caused by various

central/peripheral nerve disorders or injury, and capsaicin-responsive sensory

nerves play an important role in bladder function control and inflammation. In

addition, immunoreactivity of the TRPV1 was reported in urinary bladder

epithelium (urothelium) in rats, and it was found that bladder overactivity

induced by capsaicin was due to the stimulation of TRPV1 present in nerve

fibers or various transmitters which are released by TRPV1 (Birder et al., 2001,

PNAS, 98, pp13396-13401 ). Further, TRPV1 -/- mice are anatomically normal

but have higher frequency of low-amplitude, non-voiding bladder contractions

and reduced reflex voiding during bladder filling as compared to wild type mice,

which is thus indicating that the TRPV1 affects functions of the bladder (Birder

et al., 2002, Nat. Neuroscience, 5, pp856-860). The TRPV1 is distributed in

human epidermal keratinocytes as well as in primary afferent sensory nerves

(Denda et al., 2001 , Biochem. Biophys. Res. Commun., 285, pp1250-1252;

lnoue et al., 2002, Biochem. Biophys. Res. Commun., 291 , pp124-129), and it is

then involved in transmission of various noxious stimuli and pains such as skin

irritation and pruritus, thereby having close correlation with etiology of

dermatological diseases and disorders, such as skin inflammation, due to

neurogenic/non-neurogenic factors. This is supported by the report that the

TRPV1 antagonist, capsazepine inhibits inflammatory mediators in human skin

cells (Southall et al., 2003, J. Pharmacol. Exp. Then, 304, pp217-222).

Based on the above-mentioned information, development of various

TRPV1 antagonists is under way, and some patents and patent applications

relating to TRPV1 antagonists under development were published. (Rami et al.,

2004, Drug Discovery Today: Therapeutic Strategies, 1 , pp97-104 ; Correll et al.,

2006, Expert. Opin. Ther. Patents, 16, pp783-795 ; Kyle et al., 2006, Expert.

Opin. Ther. Patents, 16, pp977-996)

Compounds of the present invention, are useful for prophylaxis and

treatment of diseases associated with the activity of TRPV1 (Nagy et al., 2004,

Eur. J. Pharmacol. 500, 351-369) including but not limited to, pain such as acute

pain, chronic pain, neuropathic pain, post-operative pain, rheumatic arthritic

pain, osteoarthritic pain, postherpetic neuralgia, neuralgia, headache, dental

pain, pelvic pain and migraine (Petersen et al., 2000, Pain 88, pp125-133;

Walker et al., 2003, J. Pharmacol. Exp. Ther., 304, pp56-62; Morgan et al.,2005,

J. Orofac. Pain, 19, pp248-60 ; Dinis et al., 2005, Eur. Urol., 48, pp162-7;

Akerman et al., 2004, Br. J. Pharmcol., 142, pp1354-1360) ; nerve-related

diseases such as neuropathies, HIV-related neuropathy, nerve injury,

neurodegeneration, and stroke (Park et al., 1999, Arch. Pharm. Res. 22, pp432-

434; Kim et al., 2005, J. Neurosci. 25(3), pp662-671); diabetic neuropathy

(Kamei et al., 2001 , Eur. J. Pharmacol. 422, pp83-86); fecal urgency; irritable

bowel syndrome (Chan et al., 2003, Lancet, 361 , pp385-391 ); inflammatory

bowel disease (Yiangou et al., 2001 , Lancet 357, pp1338-1339); gastrointestinal

disorders such as gastroesophageal reflux disease (GERD), stomach duodenal

ulcer and Crohn's disease (Holzer P, 2004, Eur. J. Pharm., 500, pp231-241 ;

Geppetti et al., 2004, Br. J. Pharmacol., 141 , pp1313-1320); respiratory

diseases such as asthma, chronic obstructive pulmonary disease, cough

(Hwang et al., 2002, Curr. Opin. Pharmacol. pp235-242; Spina et a!.. 2002, Curr.

Opin. Pharmacol. pp264-272; Geppetti et al., 2006, Eur. J. Pharmacol., 533,

pp207-214); urinary incontinence (Birder et al., 2002, Nat. Neuroscience 5,

pp856-860); urinary bladder hypersensitiveness (Birder et al., 2001 , PNAS, 98,

pp13396-13401 ); neurotic/allergic/inflammatory skin diseases such as psoriasis,

pruritus, prurigo and dermatitis (Southall et al., 2003, J. Pharmacol. Exp. Then,

304, pp217-222); irritation of skin, eye or mucous membrane (Tominaga et al.,

1998, Neuron 21 pp531-543); hyperacusis; tinnitus; vestibular

hypersensitiveness (Balaban et al., 2003, Hear Res. 175, pp165-70); cardiac

diseases such as myocardial ischemia (Scotland et al., 2004, Circ. Res. 95,

pp1027-1034; Pan et al., 2004, Circulation 110, pp1826-1831) ; hair growth-

related disorders such as hirsutism, effluvium, alopecia (Bodό et al., 2005, Am.

J. Patho. 166, pp985-998, Birό et al., 2006, J. Invest. Dermatol. pp1-4) ; rhinitis

(Seki et al. 2006, Rhinology, 44, pp128-34) ; pancreatitis (Hutter et al., 2005,

Pancreas 30, pp260-5) ; cystitis (Dinis et al., 2004, J. Neurosci., 24, pp11253-

63; Sculptoreanu et al., 2005, Neurosci. Lett. 381 , pp42-6).

As a result of extensive and intensive studies based on the theoretical background discussed above, the present inventors have synthesized novel

compounds having antagonistic activity by selective action on a vanilloid receptor and thus completed the present invention.

Consequently, present inventors have surprisingly found that the introduction of oxygen atom to the linker between the two phenyl rings provides novel compounds which exhibit potent and highly selective activity at vanilloid receptors.

Therefore, it is an object of the present invention to provide novel compounds useful as a potent antagonist for a TRPV1 , isomer thereof and pharmaceutically acceptable salts thereof; and a pharmaceutical composition comprising the same.

Disclosure of Invention

The present invention provides a novel compound of the following formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof;

(I) wherein,

X is O, S, or N-CN; Y is O or S; R ₁ is hydrogen or C1-C5 alkyl;

R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, halogen, nitro, cyano, carboxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5

alkylthio, C1-C5 alkoxy, or C1-C5 alkoxycarbonyl;

Re, R ₇ , R _θ , and Ri ₀ are independently hydrogen, hydroxy, halogen, nitro, carboxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo (C1-C5) alkyl, halo (C1-C5) alkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkoxy, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5 alkenyloxy, (C1-C5)alkoxy(C1- C5)alkyl, (C1 -C5)alkoxycarbonyl(C1 -C5)alkyl, (C1 -C5)alkyIcarbonyloxy(C1 - C3)alkyl, (C1-C5)alkoxy(C1-C5)alkylamino, (C1-C5)alkoxy(C1-C5)alkoxy, C3- C6 cycloalkyl, C3-C5 cycloalkylmethyl, piperidinyl, or morpholinyl;

R ₈ is halogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo (C1-C5) alkyl, halo (C1-C5) alkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkoxy,

C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5alkenyloxy, (C1-

C5)aIkoxy(C1 -C5)alkyl, (C1 -C5)alkoxycarbonyl(C1 -C5)alkyl, (C1 -C5)alkoxy(C1 -

C5)alkylamino, (C1-C5)alkoxy(C1-C5)alkoxy, C3-C6 cycloalkyl, mono- or di-

(C3-C5)cycloalkyl(C1-C3)alkyl, piperidinyl, morpholinyl, phenyl, pyridyl, or pyrimidinyl, wherein each (C3-C5)cycloalkyl may be unsubstituted or substituted with one or more methyl groups, and phenyl may be unsubstituted or substituted with one or more substituent selected from halogen, nitro, carboxy,

C1-C5 alkyl, C2-C5 alkenyl, halo (C1-C5) alkyl, or C1-C5 alkoxy;

R ₈ and R ₉ may also form together -OCH2O-, C2-C4 alkylene, or - NHN=N-;

R ₁₁ is C1-C5 alkyl or C2-C5 alkenyl; and R ₁₂ and Ri ₃ are hydrogen, halogen, or C1-C5 alkyl.

Another aspect of the present invention is a compound according to the above formula (I), an isomer and/or a pharmaceutically acceptable salt thereof;

wherein,

X is O ₁ S, or N-CN,

Y is O or S;

Ri is hydrogen or C1-C3 alky!; R ₂ , R _3> R ₄ , and R ₅ are independently hydrogen, halogen, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, trifluoromethyl, methoxy, ethoxy, or methoxycarbonyl;

Re, R ₇ , Rg, and R ₁₀ are independently hydrogen, hydroxy, halogen, nitro, carboxy, C1-C5 alky], C2-C5 alkenyl, C2-C5 alkynyl, halo (C1-C5) alkyl, halo (C1-C5) alkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkoxy, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5alkenyloxy, (C1-C5)aikoxy(C1- C5)alkyl, (C1 -C5)alkoxycarbonyl(C1 -C5)alkyl, (C1 -C5)aIkylcarbonyloxy(C1 - C3)alkyl, (C1-C5)alkoxy(C1-C5)alkylamino, (C1-C5)alkoxy(C1-C5)alkoxy, C3- C6 cycloalkyl, piperidinyl, or morpholinyl; R ₈ is halogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo (C1-C5) alkyl, halo (C1-C5) alkoxy, C1-C5 alkoxy, C1-C5 alkylcarbonyl, C1-G5 alkoxycarbonyl, C2-C5alkenyloxy, (C1-C5)alkoxy(C1-C5)alkyl, C3-C6 cycloalkyl, mono- or di- (C3-C5)cycloalkyl(C1-C3)alkyl, piperidinyl, or morpholinyl, wherein each C3-C5 cycloalkyl may be unsubstituted or substituted with one or more methyl groups;

R ₈ and R ₉ may also form together -OCH2O-, C2-C4 alkylene, or - NHN=N-;

R ₁₁ is C1-C3 alkyl or C2-C3 alkenyl; and

R-1 ₂ and R ₁₃ are hydrogen, halogen, or C1-C3 alkyl.

The present invention also provides a novel compound of the formula (II), an isomer and/or a pharmaceutically acceptable salt thereof;

(II) wherein,

X is O ₁ S, or N-CN, Ri is hydrogen or C1-C5 alkyl; R2, R3, R4. and R ₅ are independently hydrogen, halogen, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, trifluoromethyl, methoxy, ethoxy, or methoxycarbonyl;

RQ, R ₇ , Rg, and R-io are independently hydrogen, hydroxy, halogen, nitro, carboxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo (C1-C5) alkyl, halo (C1-C5) alkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkoxy, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5alkenyloxy, (C1-C5)alkoxy(C1-

C5)alkyl, (C1 -C5)alkoxycarbonyl(C1 -C5)alkyl, (C1 -C5)alkyIcarbonyloxy(C1 -

C3)alkyl, (C1-C5)alkoxy(C1-C5)alkylamino, (C1-C5)alkoxy(C1-C5)a!koxy, C3-

C6 cycloalkyl, C3-C5 cycloalkylmethyl, piperidinyl, or morpholinyl; R ₈ is halogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo (C1-C5) alkyl, halo (C1 -C5) alkoxy, C1-C5 alkoxy, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5alkenyloxy, (C1-C5)alkoxy(C1-C5)alkyl, (C1-

C5)alkoxycarbonyl(C1 -C5)alkyl, (C1 -C5)alkoxy(C1 -C5)alkylamino, (C1 -

C5)alkoxy(C1-C5)alkoxy, C3-C6 cycloalkyl, mono- or di- (C3-C5)cycloa!kyl(C1~ C3)alkyl, piperidinyl, morpholinyl, or phenyl, wherein each (C3-C5) cycloalkyl may be unsubstituted or substituted with one or more methyl groups, and phenyl may be unsubstituted or substituted with one or more substituent selected from halogen, nitro, carboxy, C1-C5 alky!, C2-C5 alkenyl, halo (C1-C5) alkyl, or C1-C5 alkoxy;

R ₈ and R ₉ may also form together -OCH2O-, C2-C4 alkylene, or - NHN=N-;

Rt 1 is C1-C5 alkyl or C2-C5 alkenyl; and Ri2 and R^ are hydrogen, halogen, or C1-C5 alkyl.

One preferred aspect of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof; wherein, X is O, S, or N-CN;

Ri is hydrogen, methyl, or ethyl;

R ₂ , R3, R4, and R ₅ are independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, trifiuoro methyl, methoxy, ethoxy, or methoxycarbonyl; R ₆ , R ₇ , R9, and Ri ₀ are independently hydrogen, halogen, nitro, carboxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, ethenyl, propenyl, 2-propynyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, hexafluoropropyl, trifluoromethoxy, methylthio, methoxy, ethoxy, propoxy, allyloxy, acetyl, t-butoxycarbonylmethyl, ethoxycarbonylethyl,

methoxycarbonylmethyl, t-butylcarbonyloxymethyl, ethylcarbonyloxymethyl, isopropylcarbonyloxymethyl, methoxyethylamino, methoxyethoxy, C3-C6 cycloalkyl, piperidinyl, or morpholinyl;

R ₈ is fluoro, chloro, bromo, iodo, C3-C5 alkyl, halo (C1-C5) alkyl, C2-C5 alkynyl, propenyl, butenyl, trifluoromethoxy, pentafluoroethoxy, ethoxy, propoxy, isopropoxy, acetyl, propionyl, allyloxy, methoxyethyl, C3-C6 cycloalkyl, mono- cyclopropylmethyl, di-cyclopropylmethyl, 2,2-dimethylcyclopropyl, 2,3- dimethylcyclopropyl, piperidinyl, or morpholinyl;

R ₈ and R ₉ may also form together -OCH2O-, C2-C4 alkylene, or NHN=N-;

R ₁₁ is C1-C3 alkyl or C2-C3 alkenyl; and

Ri ₂ and Ri ₃ are hydrogen, halogen, or C1-C3 alkyl.

One preferred aspect of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof; wherein,

X is O, S, or N-CN; Ri is hydrogen, methyl, or ethyl; R ₃ and R ₄ are independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, trifluoromethyl, methoxy, ethoxy, or methoxycarbonyl;

R ₂ , R ₅ , and R ₁₀ are hydrogen;

R ₆ , R ₇ , and Rg are independently hydrogen, halogen, nitro, carboxy,

methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, ethenyl, propenyl, 2-propynyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, trifluoromethoxy, methylthio, methoxy, ethoxy, propoxy, allyloxy, acetyl, t- butoxycarbonylmethyl, ethoxycarbonylethyl, t-butylcarbonyloxymethyl, ethylcarbonyloxymethyl, isopropylcarbonyloxymethyl, methoxyethylamino, methoxyethoxy, cyclopropyl, cyclobutyl, piperidinyl, or morpholinyl;

R ₈ is selected from C3-C5 alky], halo (C1-C5) alkyl, or C2-C5 alkynyl;

Rn is methyl; and

Ri ₂ and Ri ₃ are hydrogen, fluoro, chloro, methyl, or ethyl.

Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof; wherein, X is O, or N-CN;

Ri is hydrogen, methyl, or ethyl;

R ₃ and R ₄ are independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, trifluoromethyl, methoxy, ethoxy, or methoxycarbonyl; R ₂ , R ₅ , and Ri _O are hydrogen;

R _δ , R7, and Rg are independently hydrogen, halogen, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, ethenyl, propenyl, 2-propynyl, trifluoromethyl, pentafluoroethyl, trifluoromethoxy, methylthio, methoxy, ethoxy, propoxy, allyloxy, acetyl, t-butoxycarbonylmethyl, ethoxycarbonylethyl, t-

butylcarbonyloxymethyl, ethylcarbonyloxymethyl, isopropylcarbonyloxymethyl, methoxyethylamino, methoxyethoxy, cyclopropyl, or morpholinyl;

Rs is isopropyl, sec-butyl, t-butyl, isobutyl, t-amyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoro-iso-propyl, nonafluorobutyl, nonafluoro-t~butyl, 2-propynyl;

Rn is methyl; and

Ri ₂ and Ri ₃ are hydrogen, methyl, or ethyl.

Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof; wherein,

X is O or N-CN;

Ri is hydrogen or methyl; R ₃ and R ₄ are independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, or trifluoromethyl;

R ₂ , R5, and R-io are hydrogen;

Re, R ₇ , and Rg are independently hydrogen, halogen, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, ethenyl, propenyl, 2-propynyl, trifluoromethyl, pentafluoroethyl, trifluoromethoxy, methylthio, methoxy, ethoxy, propoxy, allyloxy, acetyl, t-butoxycarbonylmethyl, ethoxycarbonylethyl, t- butylcarbonyloxymethyl, ethylcarbonyloxymethyl, methoxyethylamino, methoxyethoxy, cyclopropyl, morpholinyl;

R ₈ is isopropyl, sec-butyl, t-butyl, isobutyl, t-amyl, trifluoromethyl,

pentafluoroethyl, heptafluoropropyl, or 2-propynyl; Rn is methyl; and Ri ₂ and Ri ₃ are hydrogen or methyl.

Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof; wherein,

X is O or N-CN; Ri is hydrogen or methyl;

R ₃ and R ₄ are independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, trifluoromethyl, methoxy, ethoxy, or methoxycarbonyl;

R ₂ , Rs, and Ri _O are hydrogen; Re and Rg are independently hydrogen, halogen, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, ethenyl, propenyl, 2-propynyl, trifluoromethyl, pentafluoroethyl, trifluoromethoxy, methylthio, methoxy, ethoxy, propoxy, allyloxy, acetyl, t-butoxycarbonylmethyl, t-butylcarbonyloxymethyl, ethylcarbonyloxymethyl, methoxyethylamino, methoxyethoxy, cyclopropyl, or morpholinyl;

R ₇ is hydrogen or halogen;

R ₈ is isopropyl, sec-butyl, t-butyl, isobutyl, pentafluoroethyl, or heptafluoropropyl;

Rn is methyl; and

Ri ₂ and Ri ₃ are hydrogen or methyl.

Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof; wherein, X is O;

Ri is hydrogen or methyl;

R ₃ is hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, or methoxy;

R ₄ is hydrogen, fluoro, chloro, methyl or ethyl; R2, R5, R10. and R12 are hydrogen;

R ₆ and R ₉ are independently hydrogen, fluoro, chloro, bromo, iodo, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, ethenyl, propenyl, 2-propynyl, trifluoromethyl, pentafluoroethyl, trifluoromethoxy, methylthio, methoxy, ethoxy, propoxy, t-butylcarbonyloxymethyl, methoxyethylamino, methoxyethoxy, or morpholinyl; R ₇ is hydrogen or fluoro;

R ₈ is isopropyl, sec-butyl, t-butyl, isobutyl, or pentafluoroethyl; R1 ₁ is methyl; and

Ri ₃ is methyl or hydrogen.

Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically

acceptable salt thereof; wherein, X is O;

Ri is hydrogen or methyl; R ₃ is hydrogen, fluoro, chloro, methyl, ethyl, ethenyl, or ethynyl;

R ₄ is hydrogen, fluoro, chloro, methyl or ethyl; R2, R5, R10, R12, and R13 are hydrogen;

R ₆ and R ₉ are independently hydrogen, fluoro, chloro, bromo, nitro, methyl, ethyl, ethenyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, methoxyethylamino, methoxyethoxy, or morpholinyl; R ₇ is hydrogen or fluoro; Rs is t-butyl or isopropyl; and R ₁₁ is methyl.

Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above; wherein Y is O.

Another preferred embodiment of the present invention is a compound

according to the formula (I) and (II), an isomer and/or a pharmaceutically

acceptable salt thereof as described further above; wherein Rn is methyl or

ethyl and particularly preferably methyl.

Another preferred embodiment of the present invention is a compound

according to the formula (I) and (II), an isomer and/or a pharmaceutically

acceptable salt thereof as described further above; wherein X is O or N-CN and

particularly preferably O.

Another preferred embodiment of the present invention is a compound

according to the formula (I) and (II), an isomer and/or a pharmaceutically

acceptable salt thereof as described further above; wherein X is O or N-CN and

particularly preferably O.

Another preferred embodiment of the present invention is a compound

according to the formula (I) and (II), an isomer and/or a pharmaceutically

acceptable salt thereof as described further above; wherein X is O or N-CN and

particularly preferably O.

Another preferred embodiment of the present invention is a compound

according to the formula (I) and (II), an isomer and/or a pharmaceutically

acceptable salt thereof as described further above; wherein R1 is hydrogen or

methyl.

Another preferred embodiment of the present invention is a compound

according to the formula (I) and (II), an isomer and/or a pharmaceutically

acceptable salt thereof as described further above; wherein R12 is hydrogen

and R13 is hydrogen or methyl.

Another preferred embodiment of the present invention is a compound

according to the formula (I) and (II), an isomer and/or a pharmaceutically

acceptable salt thereof as described further above; wherein Y is O.

Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above; wherein, R ₃ is nitro, cyano, C2-C5 alkenyl, C2-C5 alkynyl, or halo (C1-C5) alkyl.

Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above wherein, R ₃ is cyano, ethenyl, ethynyl, or trifluoromethyl,

Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above;

wherein, R ₈ is C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, or mono- or di- (C3-C5)cycloalkyl(C1-C3)alkyl, wherein each (C3-C5) cycloalkyl may be unsubstituted or substituted with one or more methyl groups.

Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above; wherein,

R ₈ is C2-C5 alkynyl, propenyl, butenyl, cyclopropyl, cyclohexyl, mono- cyclopropylmethyl, di-cyclopropylmethyl, 2,2-dimethylcyclopropyl, or 2,3- dimethylcyclopropyl.

Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above; wherein, R ₈ is methylcyclopropyl.

Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above; wherein, Rs is cyclobutyl, methylcyclobutyl, cyclopentyl, or methylcyclopentyl.

Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above; wherein, R ₇ is C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5 alkenyloxy,

C1-C5 alkoxycarbonyl (C1-C5) alkyl, C1-C5 alkylcarbonyloxy (C1-C3) alkyl, C3- C6 cycloalkyl, C3-C5 cycloalkylmethyl, piperidinyl, or morpholinyl.

Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above; wherein,

R ₇ is acetyl, t-butoxycarbonylmethyl, ethoxycarbonylethyl, methoxycarbonyimethyl, t-butylcarbonyloxymethyl, ethylcarbonyloxymethyl, isopropylcarbonyloxymethyl, piperidinyl, or morpholinyl.

Preferred examples of compounds according to the invention are selected from the group consisting of;

2-(4-tert-Buty!phenoxy)-N-(4-methanesulfonylaminobenzyl)a cetamide, : 2-(4-tert-Butylphenoxy)-N-(3-fluoro-4- methanesulfonylaminobenzyl)acetamide, :

2-(4-tert-Butylphenoxy)"N-(4-methanesulfonylamino-3- vinylbenzyl)acetamide,

2-(4-tert-Butylphenoxy)-N-(3-fluoro-4-methanesulfonylamin o-5~

vinylbenzyl)acetamide,

2-(4-tert-Butylphenoxy)-N-(3-ethynyl-5-fluoro-4- methanesulfonylaminobenzy!)acetamide,

2-(4-tert-Butylphenoxy)-N-(3-ethyl-5-fluoro-4- methanesulfonylaminobenzyl)acetamide,

2-(4-tert-ButyIphenoxy)-N-(3-ch!oro-4-methanesulfonylamin o-5- methylbenzyl)acetamide,

2-(4-tert-Butylphenoxy)-N-(5-fluoro-4-methanesulfonylamin o-2- methylbenzyl)acetamide, 2-(4-tert-Butylphenoxy)-N-(3-chloro-4- methanesulfonylaminobenzyl)acetamide,

2-(4-tert-Butylphenoxy)-N-(3-fluoro-4-methanesulfonylamin o-5- methylbenzyl) acetamide,

(R)-2-(4-tert-Butylphenoxy)~N-[1-(4- methanesulfonylaminophenyl)ethyl]acetamide,

(R)-2-(4-tert-Butylphenoxy)-N-[1-(3-fluoro-4- methanesulfonylaminophenyl)ethyl]acetamidθ,

(R)-2-(4-tert-Butylphenoxy)-N-(3-f!uoro-4- methanesulfonylaminobenzyl)propionamide, (R)-2-(4-tert-Butylphenoxy)-N-(4-methanesulfonylaminophenyl) ethyl]-N'- cyanoacetamidine,

2-(4-tert-Butylphenoxy)-N-(3-fluoro-4-methanesulfonylamin obenzyl)-N'- cyanoacetamidine,

2-(4-tert-Butylphenylsulfanyl)-N-(3-ethyny!-5-fluoro-4-

methanesulfonylamino-benzyl)acetamide,

2-[4-(fe/t-butyl)pheπoxy]-N-3-cyano-5-fluoro-4-[(methane sulfonyl) aminojbenzylacetamide,

2-(4-tert-Buty!phenoxy)-2-fluoro-N-(3-fluoro-4- methanesulfonylaminobenzyl)acetamide,

N-(3-Fluoro-4-methanesuIfonylaminobenzyl)-(4- isopropylphenoxy)acetamide, and

N-(3-Fluoro-4-methanesulfonylaminobenzyl)-(4-sec- butylphθnoxy)acθtamide.

Particularly preferred compounds according to the present invention are 2-(4-tert-Butylphenoxy)-N-(4-methanesulfonylamino-3- vinylbenzyl)acetamide,

2-(4-tert-Butylphenoxy)-N-(3-fluoro-4-methanesulfonylamin o-5- vinylbenzyl)acetamide,

2-(4-tert-Butylphenoxy)-N-(3-ethynyl-5-fluoro-4- methanesulfonylaminobenzyl)acetamide,

(R)-2-(4-tert-Butylphenoxy)-N-[1-(4- methanesulfonylaminophenyl)ethyl]acetamide (R)-2-(4-tert-Butylphenoxy)-N-[1 -(3-fluoro-4- methanesulfonylaminopheny!)ethyl]acetamide,

2-[4-(tert-butyl)phenoxy]-N-3-cyano-5-fluoro-4-[(methanes ulfonyl) amino]benzylacetamide,

N-(3-Fluoro-4-methanesulfonylaminobenzyl)-(4-

isopropylphenoxy)acetamide, and

N-(3-Fiuoro-4-methanesulfonylaminobenzyl)-(4-sec- butylphenoxy)acetamide.

Preferred examples of compounds according to the invention are selected from the group consisting of;

2-(4-tert-Butyl-phenoxy)-N-(3-fluoro-4-methanesu!fonylami no-5- trif!uoromethy!-benzyl)-acetamide,

2-(4-tert-ButyI-3-fluoro-phenoxy)-N-(3-ethynyl-5-fluoro-4 - methanesulfonylamino-benzyl)-acetamide,

2-(4-tert-Butyl-2-fluoro-phenoxy)-N-(3-ethynyl-5-fluoro-4 - methanesulfonylamino-benzyl)-acetamide,

2-(4-tert-Butyl-phenoxy)-N-(3-cyano-5-fluoro-4-methanesul fonylamino- benzyl)-thioacetamide, N-(3-Fluoro-4-methanesuIfonylamino-benzyl)-2-[4-(1-methyl- cyclopropyl)-phenoxy]-acetamide,

N-(3-Fluoro-4-methanesulfonylamino-benzyl)-2-(4-isopropen yl- phenoxy)-acetamide,

2-(4-tert-Butyl-2-fluoro-phenoxy)-N-(3-fluoro-4-methanesu lfonylamino- benzyl)-acetamide,

2-(4-tert-Butyl-2,6-difluoro-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide,

2-(2-Bromo-4-tert-butyl-5-fluoro-phenoxy)-N-(3-fluoro-4-

methanesulfonylamino-benzyl)-acetamide,

2-(2-Bromo-4-tert-butyl-phenoxy)-N-(3-fluoro-4-methanesul fonylamino- benzyi)-acetamide,

2-[4-(1 , 1 -Difluoro-2-methyl-propyl)-phenoxy]-N-(3-f!uoro-4- methanesulfonylamino-benzyl)-acetamide,

2-(4-tert~Butyl-3-methyl-phenoxy)-N-(3-fluoro-4-methanesu lfonylamino- benzyl)-acetamide,

2-(2-tert-Butyl-4-methyl-phenoxy)-N-(3-fluoro-4-methanesu lfonylamino-benzyl)- acetamide, and 2-(4-CyclopentyI-phenoxy)-N-(3-fiuoro-4-methanesulfonylamino -benzyl)- acetamide.

The present invention also provides a novel compound of the following formula (III), an isomer, or a pharmaceutically acceptable salt thereof;

(III) wherein,

Ri is hydrogen or C1-C5 alky!;

R2, R3, R4, and R ₅ are independently hydrogen, halogen, nitro, cyano, carboxy, C1-C5 alkyl, halo (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkylthio, C1-C5 alkoxy, or C1-C5 alkoxycarbonyl;

Re, R7, R ₉ , and Ri _O are independently hydrogen, hydroxyl, halogen, C1-

C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkyloxy, halo (C1-C5) alkyl,

halo (C1-C5) alkoxy, C1-C5 alkylcarbonyloxy, C1-C5 alkoxycarbonyl, C2-C5 alkenyloxy, C1-C5 alkoxy (C1-C5) alkyl, phenylcarbonyloxy wherein the phenyl may be substituted with one or more halogens, C1-C5 alkoxycarbonyl (C1-C5) alkyl, C1-C5 alkoxycarbonyl (C1-C5) alkoxy, C1-C5 alkylcarbonyloxy (C1-C3) alkyl, C1-C5 alkoxy (C1-C5) alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkylmethyl, piperidinyl, or morpholinyl;

R ₈ is C1-C3 alkyldithiolanyl or C1-C3 alkyldithianyl;

Rn is C1-C5 alkyl or C2-C5 alkenyl; and

R ₁₂ and Ri ₃ are independently hydrogen, halogen, or C1-C5 alkyl.

One preferred aspect of the present invention is a compound of above formula (III), an isomer, or a pharmaceutically acceptable salt thereof; wherein,

R ₁ is hydrogen or C1-C5 alkyl; R2, R3, R4, and R5 are independently hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, trifluoromethyl, ethenyl, or ethynyl;

Re. R7. R9. and R ₁₀ are independently hydrogen, hydroxy!, halogen, C1- C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkyloxy, halo (C1-C5) alkyl, halo (C1-C5) alkoxy, C1-C5 alkylcarbonyloxy, C1-C5 alkoxycarbonyl, C2-C5 alkenyloxy, C1-C5 alkoxy (C1-C5) alkyl, C1-C5 alkoxycarbonyl (C1-C5) alkyl, C1-C5 alkoxycarbonyl (C1-C5) alkoxy, C1-C5 alkylcarbonyloxy (C1-C3) alkyl, phenylcarbonyloxy, C1-C5 alkoxy (C1-C5) alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkylmethyl, piperidinyl, or morpholinyl;

Rs is C1-C3 alkyldithiolanyl or C1-C3 alkyldithianyl;

R ₁₁ is C1-C5 alkyl or C2-C5 alkenyl; and

Ri ₂ and R ₁₃ are independently hydrogen, fluoro, or methyl.

Another preferred aspect of the present invention is a compound of above formula (III), an isomer, or a pharmaceutically acceptable salt thereof; Ri is hydrogen; R2 and R ₅ are hydrogen;

R3 and R ₄ are independently hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, trifluoromethyl, ethenyl, or ethynyl; RQ and R ₇ are independently hydrogen, hydroxyl, fluoro, chloro, methoxy, piperidinyl, or morpholinyl;

Rs is methyldithiolany! or methyldithianyl;

R ₁ - _I is methyl; and

R-12 and R13 are hydrogen.

Preferred examples of compounds according to the invention are selected from the group consisting of;

N-(3-Ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-2-[3 -fluoro-4-(2- methyl~[1 ,3]dithiolan~2-yl)-phenoxy]-acetamide and N-(3-Fluoro-4-methanesulfonylamino-benzyl)-2-[3-fluoro-4-(2- methyl-

[1 ,3]dithiolan-2-yl)-phenoxy]-acetamide.

The present invention also provides a novel compound of the following formula (IV), an isomer, or a pharmaceutically acceptable salt thereof;

(IV)

wherein, R ₁ is hydrogen or C1-C5 alkyl;

R2, R ₃ . R4, and R ₅ are independently hydrogen, halogen, nitro, cyano, carboxy, C1-C5 alkyl, halo (C1-C5) alkyl, C1-C5 alkylthio, C1-C5 alkoxy, or C1- C5 alkoxycarbonyl;

R ₇ is C1-C5 alkylcarbonyloxy, C1-C5 alkoxycarbonyl (C1-C5) alkoxy, pyridylcarbonyloxy, phenylcarbonyloxy, or phenyl, wherein each phenyl or pyridyl may be unsubstituted or substituted with one or more substituents selected from halogen, C1-C5 alkyl, or halo (C1-5 alkyl);

R ₈ is halogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo (C1-C5) alkyl, halo (C1-C5) alkoxy, C1-C5 alkoxy, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5 alkenyloxy, C1-C5 alkoxy (C1-C5) alkyl, C3-C6 cycloalkyl, mono- or di- (C3-C5) cycloalkyl (C1-C3) alkyl, C1-C3 alkyl dithiolanyl, C1-C3 alkyl dithianyl, piperidinyl, or morpholinyl, wherein each C3-C6 cycloalkyl may be unsubstituted or substituted with one or more methyl groups;

Re, Rg and R ₁₀ are independently hydrogen, hydroxy, halogen, nitro, carboxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo (C1-C5) alkyl, halo

(C1-C5) alkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkoxy, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5 alkenyloxy, C1-C5 alkoxy (C1-

C5)alkyl, C1-C5 alkoxycarbonyl (C1-C5) alkyl, C1-C5 alkoxycarbonyl (C1-C5)

alkoxy, C1-C5 alkylcarbonyioxy (C1-C3) alkyl, arylcarbonyloxy, C1-C5 alkoxy (C1-C5) alkylamino, C1-C5 alkoxy (C1-C5) alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkylmethyl, piperidinyl, or morpholinyl; and

Rn is C1-C5 alkyl.

One preferred aspect of the present invention is a compound of above formula (IV), an isomer, or a pharmaceutically acceptable salt thereof; wherein,

Ri is hydrogen or C1-C5 alkyl; R ₂ , R ₃ , R ₄ , and R ₅ are independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, trifluoromethyl, methoxy, or methoxycarbonyl;

R ₆ is hydrogen, halogen, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, ethenyl, propenyl, 2-propynyl, trifluoromethyl, pentafluoroethyl, trifluoromethoxy, methylthio, methoxy, ethoxy, propoxy, allyloxy, acetyl, t-butoxycarbonylmethyl, ethoxycarbonylethyl, t- butylcarbonyloxymethyl, ethylcarbonyloxymethyl, isopropylcarbonyloxymethyl, methoxycarbonylmethoxy, phenylcarbonyloxy, methoxyethylamino, methoxyethoxy, cyclopropyl, or morpholinyl;

R ₇ is C1-C5 alkylcarbonyioxy, C1-C5 alkoxycarbonyl (C1-C5) alkoxy, pyridylcarbonyloxy, or phenylcarbonyloxy, wherein phenyl or pyridyl may be unsubstituted or substituted with one or more substituents selected from fluoro, chloro, bromo, methyl, ethyl, propyl, and trifluoromethyl;

R ₈ is isopropyl, sec-butyl, t-butyl, isobutyl, t-amyl, isopropenyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoro-iso-propyl,

difluorobutyl, nonafluorobutyl, nonafluoro-t-butyl, 1-methylcyclopropyl, 2- methyl[1 ,3]dithiolan-2-yl, or 2-propynyl;

Rg and Rioare both hydrogen; and

Rn is methyl.

Another preferred aspect of the present invention is a compound of above formula (IV), an isomer, or a pharmaceutically acceptable salt thereof; R ₁ , R ₂ , and R ₅ are hydrogen;

R ₃ and R ₄ are independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, trifluoromethyl, methoxy, or methoxycarbonyl;

R ₆ is hydrogen, fluoro, chloro, bromo, nitro, methyl, ethyl, ethenyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, methoxycarbonylmethoxy, phenylcarbonyloxy, methoxyethylamino, methoxyethoxy, or morpholinyl;

R ₇ is methoxycarbonyimethyloxy, methylcarbonyloxy, phenylcarbonyloxy, or trifluoromethylpyridylcarbonyloxy,

Rs is t-butyl, isopropyl, 1-methylcyclopropyl, or 2-methyI[1 ,3]dithiolan-2-

yi;

Rg and R ₁₀ are both hydrogen; and Rn is methyl.

Preferred examples of compounds according to the invention are selected from the group consisting of;

Benzoic acid 2-tert-butyl-5-[(3-fluoro-4-methanesulfonylamino- benzylcarbamoyl)~methoxy]-phenyl ester,

{2-tert-Butyl-5-[(3-fluoro-4-mθthanesulfonylamino-benzyl carbamoyl)- methoxy]-phenoxy}-acetic acid methyl ester, and β-Trifluoromethyl-pyridine^-carboxylic acid 2-tert-butyl-5-[(3-fluoro-4- methanesulfonylamino-benzylcarbamoyl)-methoxy]-phenyl ester.

The compounds of formula (I), (II), (III), or (IV) according to the present invention can chemically be synthesized by the following reaction schemes. However, these are given only for illustration of the invention and the present invention is not intended to limit to them.

[Scheme 1 ]

The Scheme 1 shows a proposed process for synthesizing the N- benzyl-2-phenoxyacetamide compound (3). The 2-phenoxyacetic acid compound (2) is reacted with the benzylamine compound (1) and diethylphosphoryl cyanide (DEPC) to yield the N-benzyl-2-phenoxyacetamide compound (3).

[Scheme 2]

The Scheme 2 shows another process for synthesizing the N-benzyl-2- phenoxyacetamide compound (5). The benzylamine compound (4) is reacted with the 2-phenoxyacetic acid compound (2) and DMTMM {4-(4,6-dimethoxy~

1 ,3,5-triazin-2-yl)~4-methylmorpholinium chloride} (Tetrahedron Lett., 1999, 40,

5327) instead of DEPC to yield the N-benzyl-2phenoxyacetamide compound (5).

[Scheme 3]

6 7 8 2

The Scheme 3 shows a proposed process for synthesizing 2- phenoxyacetic acid compound (2) with various substituents. Phenol compound (6) is reacted with alkyl 2-bromoacetate compound (7) to yield alkyl 2- phenoxyacetate compound (8). The compound (8) is hydrolyzed with sodium hydroxide in methanol or lithium hydroxide in THF to yield 2-phenoxyacetic acid compound (2) with various substituents.

[Scheme 4]

6 9 8

The Scheme 4 shows another process for synthesizing alkyl 2- phenoxyacetate compound (8). Phenol compound (6) is reacted with alkyl 2- hydroxyacetate compound (9) under Mitsunobu reaction conditions (Synthesis, 1981, 1) to yield alkyl 2-phenoxyacetate compound (8). The compound (8) is hydrolyzed using base in aqueous solvent according to the same procedure as described in scheme 3.

[Scheme 5]

7 11 ^OrUOH ' ^THF 12

13

The Scheme 5 shows a proposed process for synthesizing the N-benzy- 2-phenylthioacetamide compound (13). The thiophenol compound (10) is reacted with the alkyl α-bromoacetate compound (7) to yield the alkyl 2- phenylthioacetate compound (11). The compound (11 ) is hydrolyzed to yield the phenylthioacetic acid compound (12). The acid compound (12) is reacted with benzyl amine compound (1) to yield the N-benzy-2-phenyIthioacetamide compound (13).

[Scheme 6]

14 15 16

The Scheme 6 shows a proposed process for synthesizing the N- benzyl-2-phenoxy-N'-cyanoacetamidine compound (16). The compound (14) is reacted with Lawesson's reagent to yield the thioacetamide compound with phenoxy moiety (15). The thioacetatmide compound (15) is reacted with cyanamide and HgCI ₂ to yield the N-benzyl-2-phenoxy-N'- cyanoacetamidinecompound (16).

[Scheme 7]

The Scheme 7 shows another proposed process for synthesizing the acetamide compound (22). The resorsinol compound (17) is reacted with the fe/f-butyl bromoacetate to give the phenol compound (18), which is reacted with acetic anhydride to yield the compound (19). The ester compound (19) is

hydrolyzed with trifluoroacetic acid to afford the acid compound (20), which is reacted with the benzyl amine salt (21) using the coupling agent DEPC finally to yield the acetamide compound (22).

[Scheme 81

27

The Scheme 8 shows another proposed process for synthesizing the acetamide compound (27). The phenol compound (23) is reacted with 2-methyl-

2-chloropropane to afford 4-t-buylphenol derivative (24) via Friedel-Craft alkylation (J. Org. Chem. 1981 , 46, 3784). The acetamide compound with t- butyl group (27) is synthesized by similar procedure of scheme 2 and 3.

The present invention also provides a novel compound according the above formula (I) or (II) for use as a medicament.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or (II), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.

In said pharmaceutical composition, a compound of formula (I) or (II), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient together with an pharmaceutically acceptable carrier is present in an effective amount for preventing or treating pain, acute pain, neuropathic pain, post-operative pain, migraine, arthralgia, neuropathies, nerve injury, diabetic neuropathy, neurodegeneration, stroke, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, urinary bladder hypersensitiveness, irritable bowel syndrome, fecal urgency, Crohn's disease, 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.

The present invention also provides a pharmaceutical composition for preventing and treating a disease associated with the pathological stimulation and/or aberrant expression of vanilloid receptor, wherein said composition comprises a compound of formula (I) or (II), an isomer thereof or a pharmaceutically acceptable salt thereof; and pharmaceutically acceptable carrier.

The present invention also provides a pharmaceutical composition for preventing and treating a condition related to vanilloid receptor, where said composition comprises a compound of formula (I) or (II), an isomer thereof or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier. In the above, said condition related to vanilloid receptor is pain, migraine, arthralgia, neuralgia, neuropathies, nerve injury, skin disorder, urinary bladder

hypersensitiveness, irritable bowel syndrome, fecal urgency, a respiratory disorder, irritation of skin, eye or mucous membrane, stomach-duodenal ulcer, inflammatory diseases, ear disease, or heart disease.

More specifically, said condition related to vanilloid receptor is acute pain, chronic pain, neuropathic pain, post-operative pain, rheumatic arthrodynia, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, neurodegeneration, stroke, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, asthma, chronic obstructive pulmonary disease, urinary incontinence, inflammatory bowel disease, hyperacusis, tinnitus, vestibular hypersensitiveness, or inotropic ischemia.

In one preferred aspect, the present invention provides a pharmaceutical composition for treating a condition selected from pain, inflammatory disease of the joints including inflammatory autoimmune diseases of the joints, urinary bladder hypersensitivity including urinary incontinence, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), neurotic/allergic/inflammatory skin disease, psoriasis, asthma, chronic obstructive pulmonary disease (COPD), pruritus, or prurigo comprising a compound, an isomer thereof or a pharmaceutically acceptable salt thereof according to anyone of formula (I) or (II), as defined further above.

More specifically, the inventive compounds can be used in a pharmaceutical composition for treating pain, wherein the pain is -or is associated with- a condition selected from osteoarthritis ("OA"), rheumatoid

arthritis ("RA"), Ankylosing Spondylitis ("AS"), diabetic neuropathic pain, postoperative pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headaches.

If the compounds of the present invention are said to be useful to treat pain associated with osteoarthritis, it shall not be excluded that this also comprises the treatment of other signs and symptoms of osteoarthritis. Besides reducing the pain associated with osteoarthritis, the pharmacological intervention of osteoarthritis may be aimed at maintaining the mobility and minimizing the disability of the joints.

The term "inflammatory disease of the joints" includes diseases that involve to a more or less degree inflammatory processes in the joints, e.g. in knees, fingers, hips etc. An example for such a disease is osteoarthritis. The term "inflammatory disease of the joints" does also include diseases or conditions which may involve autoimmune processes, such as e.g. rheumatoid arthrtitis or ankylosing spondylitis. The inventive treatment of "inflammatory diseases of the joints" is primarily aimed at treating pain associated with these conditions but may also aim at improving the function of the affected joints, either directly or indirectly, e.g. by reducing the pain associated with the movement of said joints.

One outcome of the administration of the compounds of the present

invention to patients suffering from an inflammatory disease of the joints may thus be reducing the pain experienced by the subject suffering from said disease relative to the pain experienced by the subject immediately before the administration of the compounds or combinations of the present invention. Another outcome of said treatment may be preventing the re-occurence of pain which has previously been reduced as a result of pharmaco- or other therapy. Another outcome of treatment may be decreasing the occurrence of and/or the severity of manifestations related to an inflammatory disease of the joints, including particularly osteoarthritis, rheumatoid arthritis ankylosing spondylitis. The treatment may suitably result in an improved functionality of the joints, such as decreased stiffness, improved mobility.

The term "osteoarthritis (OA)" as used herein typically includes diseases with a failure of a diarthrodial (movable, synovial-lined) joint. In idiopathic (primary) OA, the most common form of the disease, no predisposing factor is apparent. Secondary OA is attributable to an underlying cause. Pain and joint dysfunction are the cardinal symptoms of OA. The joint pain of OA is often described as a deep ache and is localized to the involved joint. Typically, the pain of OA is aggravated by joint use and relieved by rest, but, as the disease progresses, it may become persistent. Nocturnal pain, interfering with sleep, is seen particularly in advance OA of the hip and may be enervating. Stiffness of the involved joint on arising in the morning or after a period of inactivity may be prominent but usually lasts less than 20 minutes.

The term "RA" refers to Rheumatoid Arthritis. RA is a chronic inflammatory autoimmune disease that causes the immune system to attack the joints, and particularly the synovium in the joint. The synovium becomes inflamed and causes swelling and pain. Cardinal symptoms of RA are joint pain and stiffness but additional symptoms include muscle aches, anemia and fever.

Diagnosis of RA can be confirmed by detecting an antibody in the blood called the "rheumatic (or "rheumatoid") factor" and/or by a blood sedimentation test.

Other useful and common tests are the detection of the "antinuclear antibody" or the "C-reactive protein".

"AS" stands for Ankylosing Spondylitis, which is a chronic, progressive autoimmune disease characterized by arthritis, inflammation and eventual immobility of the joints, particularly the spinal joints. It causes pain and stiffness in the back (often in the morning hours) as a result of ongoing swelling and irritation of the spinal joints (vertebrae). Inflammation of the tendons and ligaments that connect and provide support to the vertebrae can lead to pain and tenderness in the ribs, shoulder blades, hips, thighs, shins, heels and along the bony points of the spines.

If the compounds according to the present invention are said to be of use in treating pain associated with an inflammatory autoimmune disease of the joints, this refers to the administration of the compounds or combinations of the compounds of the present invention to reduce at least one pain symptom experienced by a subject suffering from an inflammatory autoimmune disease

of the joints including back pain, joint pain and muscle pain associated with RA or AS. Besides the pain relief, treatment of an inflammatory autoimmune disease of the joints may also include a decrease of the inflammation and/or swelling of the synovium and may help to improve the functionality (i.e. maintaining mobility, and minimizing disability) of the joints, in particular in patients suffering from RA or AS.

Treatment of "non-inflammatory musculoskeletal pain" refers to the administration of the compounds or combinations of the compounds of the present invention to reduce the pain experienced by a subject suffering from non-inflammatory musculoskeletal pain including back pain, fibromyalgia, and myofascial pain syndrome. One outcome of treatment may be reducing the pain experienced by the subject relative to the pain experienced by the subject immediately before the administration of the compounds or combinations of the present invention. Another outcome of treatment may be preventing reoccurence of pain which has previously been reduced as a result of pharmacotherapy. Another outcome of treatment may be decreasing the occurrence of and/or the severity of manifestations related to non-inflammatory musculoskeletal pain including back pain, fibromyalgia, and myofascial pain syndrome. The treatment may suitably result in a reduction of increased muscle sensitivity characterized by pain evoked by a normally non-nociceptive stimulus (ailodynia) or increased pain intensity evoked by nociceptive stimuli (hyperalgesia). Finally, the treatment of non-inflammatory musculoskeletal pain can also improve the associated symptoms of back pain, fibromyalgia, and

myofascial pain syndrome.

The terms "fibromyalgia" or "FMS" relates to a syndrome that causes widespread pain and stiffness throughout the tissue that supports and moves bones and joints. Fibromyalgia can be diagnosed by the presence of excessive tenderness on applying pressure to at least 11 of 18 specific muscle-tendon sites.

"Myofascial pain syndrome" is a chronic non-degenerative, non- inflammatory musculoskeletal pain condition. Distinct areas within muscles or their delicate connective tissue coverings (fascia) become abnormally thickened or tight. When the myofascial tissues tighten and lose their elasticity, neurotransmitter ability to send and receive messages between the brain and body is damaged. Symptoms include muscle stiffness and aching and sharp shooting pains or tingling and numbness in areas distant from the trigger point.

Most commonly trigger points are in the neck, back, or buttocks.

"Back pain" is a common non-inflammatory musculoskeletal pain condition that may be either acute or chronic. It may be caused by a variety of diseases and disorders that affect the lumbar spine. Low back pain is often accompanied by sciatica, which is pain that involves the sciatic nerve and is felt in the lower back, the buttocks, and the backs of the thighs.

The compounds of the present invention are also useful for treating

signs and symptoms of an overactive bladder such as urinary incontinence, more specific urinary urge incontinence, urinary stress incontinence, urinary urgency, nocturia and/or urinary frequency.

The pharmaceutical compositions according to the present invention are preferably adapted for oral administration. Alternatively, if skin diseases are to be treated the pharmaceutical composition containing the inventive compounds may be also formulated for topical or transcutaneous use.

In another aspect, the present invention relates to a method for inhibiting vanilloid ligand from binding to vanilloid receptor in a patient, comprising contacting cells expressing vanilloid receptor in the patient with a compound of formula (I) or (II), an isomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the present invention relates to a method for preventing or treating a disease selected from pain, migraine, arthralgia, neuropathies, nerve injury, skin disorder, urinary bladder hypersensitiveness, irritable bowel syndrome, fecal urgency, a respiratory disorder, irritation of skin, eye or mucous membrane, stomach-duodenal ulcer, inflammatory diseases, which comprises administering to a mammal including a person in need thereof a therapeutically effective amount of a compound of formula (I) or (II), an isomer thereof, or a pharmaceutically acceptable salt thereof.

In the above method, the disease is also selected from acute pain, chronic pain, neuropathic pain, post-operative pain, diabetic neuropathy,

neurodegeneration, stroke, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, asthma, chronic obstructive pulmonary disease, urinary incontinence or inflammatory bowel disease.

In one preferred aspect of the invention, the above method is treating pain that is or that is associated with a condition selected from osteoarthritis ("OA"), rheumatoid arthritis ("RA"), Ankylosing Spondylitis ("AS"), diabetic neuropathic pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), post-operative pain, migraine and other types of headache.

In another aspect, the present invention relates to the use of a compound of formula (I) or (II), an isomer thereof, or a pharmaceutically acceptable salt thereof as an antagonist of vanilloid receptor.

In another aspect, the present invention relates to the use of a compound of formula (I) or (II), an isomer thereof, or a pharmaceutically acceptable salt thereof for prevention or treatment of a condition related to vanilloid receptor, which is more specifically associated with the aberrant expression and/or aberrant activation of a vanilloid receptor.

In another aspect, the present invention relates to the use of a compound of formula (I) or (II), an isomer thereof, or a pharmaceutically acceptable salt thereof, in preparation of a medicament for prevention or treatment of a condition related to vanilloid receptor.

In a preferred aspect, the present invention relates to the use of a compound of formula (I) or (II), an isomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or the treatment of a condition that is selected from pain, inflammatory autoimmune disease of the joints, urinary bladder hypersensitivity including urinary incontinence, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), neurotic/allergic/inflammatory skin disease, psoriasis, asthma, chronic obstructive pulmonary disease (COPD), pruritus, or prurigo.

In a particularly preferred aspect, the present invention relates to the use of a compound for treating pain as described above, wherein the pain is or is associated with a condition that is selected from osteoarthritis ("OA"), rheumatoid arthritis ("RA"), Ankylosing Spondylitis ("AS"), diabetic neuropathic pain, post-operative pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headaches.

The present invention also provides a novel compound according the above formula (III) or (IV) for use as a medicament.

The present invention also provides a compound of formula (111), or (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof for preventing

and treating a condition associated with the pathological stimulation and/or aberrant expression of vanilloid receptors.

In one preferred aspect, the present invention provides a compound of formula (I), (II), (III), or (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof, for treating a condition selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium, alopecia, rhinitis, and pancreatitis.

In a particularly preferred aspect, the present invention relates to a compound of formula (I), (II), (III), or (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof for treating pain as described above, wherein the pain is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headaches.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I), (II), (III), or (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.

The present invention also provides a pharmaceutical composition for preventing and treating a condition associated with the pathological stimulation and/or aberrant expression of vanilloid receptors, wherein said composition comprise a compound of formula (I), (II), (III), or (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof.

In one preferred aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention for treating a condition selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium, alopecia, rhinitis, and pancreatitis.

In a particularly preferred aspect, the present invention relates to the pharmaceutical composition comprising the compound of the present invention for treating pain as described above, wherein the pain is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headaches.

The present invention also provides a pharmaceutical composition which is characterized in that it is adapted for oral administration.

In another aspect, the present invention relates to a method for inhibiting vanilloid ligand from binding to vanilloid receptor in a patient, comprising contacting cells expressing vanilloid receptor in the patient with the compound of formula (I), (II), (III), or (IV) ₁ an isomer thereof, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention also provides a method for preventing or treating a condition selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus,

prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium, alopecia, rhinitis, and pancreatitis, which comprises administering to a mammal including a person in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III), or (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof.

In a particularly preferred aspect, the present invention relates to the method of a compound of the present invention for treating pain as described above, wherein the pain is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine, and other types of headache. In another aspect, the present invention relates to the use of a compound of formula (I), (II), (III), or (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of a condition that is associated with the aberrant expression and/or aberrant activation of a vanilloid receptor. In another aspect, the present invention relates to the use of a compound of formula (I), (II), (III), or (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof, in preparation of a medicament for the prevention or treatment of a condition that is selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related

neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium, alopecia, rhinitis, and pancreatitis. In a particularly preferred aspect, the present invention relates to the use of the compound of formula (I), (II), (III), or (IV) for preventing or treating pain as described above, wherein the condition is pain, which is or which is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post- operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine, and other types of headaches.

Hereinafter, the formulating methods and kinds of excipients will be described, but the present invention is not limited to them.

A compound of formula (I), (II), (III), or (IV), an isomer thereof or a pharmaceutically acceptable salt thereof according to the present invention can be prepared as a pharmaceutical composition containing pharmaceutically acceptable carriers, adjuvants, diluents and the like. 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 compound according to the present invention may also be used in the forms of pharmaceutically acceptable salts thereof, 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 intracerebroventricular injections.

Detailed description of the invention definitions

When describing the compounds, pharmaceutical compositions containing such compounds, methods of using such compounds and compositions, and use of such compounds and compositions, all terms used in the present application shall have the meaning usually employed by a relevant person skilled in the art, e.g. by a medicinal chemists, pharmacist or physician. By the way of example some definitions of specific groups are given below:

"Alkyl" includes monovalent saturated aliphatic hydrocarbyl groups. The hydrocarbon chain may be either straight-chained or branched. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso- butyl, tert-butyl sec-butyl, tert-amyl.

"Alkylcarbonyl" refers to the group -C(=O) alkyl, wherein "alkyl" has the meaning as defined above.

"Alkyldithiolanyl" refers to the group , wherein R is "alkyl" described above.

"Alkyldithianyl" refers to the group S Q — / ' , wherein R is "alkyl" described above.

"Alkoxy" includes the group-OR where R is alkyl. Particular alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, tert-butoxy, iso-butoxy, sec-butoxy, n~peπtoxy, 1 ,2-dimethy!butoxy, and the like.

"Alkoxycarbony!" refers to the group -C(=O) alkyl, wherein "alkoxy" has the meaning as defined above.

"Alkoxyalkoxy" refers to the group -OROR', wherein R and R' are the same or different "alkyl" groups as defined further above.

"Alkoxyalkyl" refers to the group -ROR', wherein R and R' are the same or different "alkyl" groups as defined further above

"Alkoxycarbonylalkyl" refers to the group -RC(=O)OR', wherein R and R' are the same or different "alkyl" groups as defined further above "Alkylcarbonyloxyalkyl" refers to the group -ROC(=O)R', wherein R and

R' are the same or different "alkyl" groups as defined further above

— N-R'-OR"

"Alkoxyalkylamino" refers to the group R , wherein R may be hydrogen or "alkyl", and R' and R" are both "alkyl" as defined further above.'αlkenyl" includes monovalent olefinically unsaturated hydrocarbyl groups being straight-chained or branched and having at least 1 double bond. Particular alkenyl groups include ethenyl (-CH=CH ₂ ), n-propenyl (-CH ₂ CH=CH ₂ ), isopropenyl (C (CH ₃ ) =CH ₂ ), and the like. A preferred "alkenyl" group is ethenyl (vinyl).

"Alkenyloxy" refers to the group -O-alkenyl, wherein "alkenyl" has the meaning as defined above. "Alkynyl" includes acetylenically unsaturated hydrocarbyl groups being straight-chained or branched and having at least 1 triple bond. A preferred alkynyl group is ethynyl (acetylene).

"Alkylamino" includes the group -NR'R", wherein R' is alkyl and R" is selected from hydrogen or alkyl "Alkylsulfonyl" includes a radical-S(O) ₂ R where R is an alkyl group as defined herein. Representative examples include, but are not limited to, methanesulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like.

"Alkylthio" includes a radical-S-R where R is an alkyl group as defined herein that may be optionally substituted as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.

"Carboxy" refers to the radical -C(=O)OH. "Cyano" refers to the radical -C=N

"Cycloalkyl" refers to cyclic saturated aliphatic hydrocarbyl groups. The

numbers of C-atoms referenced in connection with a given cycloalkyl group corresponds to the number of ring forming carbon atoms, e.g. "C3-C5 cycloalkyl" refers to a cycloalkyl with between three and five ring-forming C atoms. Examples of "cycloalkyl" are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc. If indicated, a "cycloalkyl" group may be unsubstituted or substituted with one or more methyl groups. If a "cycloalkyl" carries more than one methyl substituent these substituents may be attached to the same or to different ring-forming carbon atoms.

"Cycloalkyl" refers to the group -CHs-cycloalkyl, wherein "cycloalkyl" is as defined further above

"Ethenyl" refers to -CH=CH ₂ which in the present application is also designated "vinyl".

εthynyl" refers to -C≡CH.

"Halo" or "halogen" refers to fluoro, chloro, bromo and iodo. Preferred halo groups are either fluoro or chloro.

"Haloalkyl" includes an "alky!" group as defined further above which is substituted with one or more halogens which may be the same, e.g. in trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoro-isopropyl, or nonafluorobutyl, or which may be different. "Haloalkoxy" includes an "alkoxy" group as defined further above which is substituted with one or more halogens which may be the same, e.g. in trifluoromethoxy, or which may be different. "Hydroxy" refers to the radical-OH. "Nitro" refers to the radical-NO ₂ .

"(C1-C5)alkoxy(C1-C5)alkyf includes the group-ROR where R is "alkyl" with up to five carbon atoms. Particular alkoxyalkyi groups include, by way of example, methoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxyethyl, n-propoxymethyl, and the like. "(C1-C5)alkoxycarbonyl(C1-C5)alkyl" includes the group RO(C=O)R where R is "alkyl" with up to five carbon atoms. Particular alkoxycarbonylalkyl groups include, by way of example, buthoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylmethyl, and the like.

"(C1-C5)alkoxy(C1-C5)alkylamino" includes the group RORNH- where R is "alkyl" with up to five carbon atoms. Particular alkoxyalkylamino groups include, by way of example, methoxymethylamino, methoxyethylamino, ethoxymethylamino, and the like.

"(C1-C5)alkoxy(C1-C5)alkόxy" includes the group RORO- where R is "alkyl" with up to five carbon atoms. Particular alkoxyalkoxyl groups include, by way of example, methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxyethoxy, and the like.

"(C1-C5)alkylcarbonyloxy(C1-C3)alkyl" includes the group RC=OOR- where R is "alkyl" with up to five carbon atoms. Particular alkylcarbonyloxyalkyl groups include, by way of example, t-butylcarbonyloxymethyl, ethylcarbonyloxymethyl, isopropylcarbonyloxymethyl, and the like.

"Pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more

particularly in humans.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) salts formed when an acid is added to the parent compound, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2- ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, A- chlorobenzenesulfonic acid, 2~naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4methylbicyclo [2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced.

"Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

"Preventing" or "prevention" refers to a reduction in risk of acquiring a disease or disorder (i. e., causing at least one of the clinical symptoms of the

disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).

"Subject" includes humans. The terms "human," "patient" and "subject" are used interchangeably herein. "Therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The"therapeutically effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. "Treating" or "treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i. e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e. g., stabilization of a discernible symptom), physiologically, (e. g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

Best Mode

The present invention is more specifically explained by following examples and experimental examples. However, it should be understood that the extent of the present invention is not limited to the following examples and

experimental examples.

Example 1: 2-(4-tert-ButyIphenoxy)-W-(4-methanesulfonylamino-3- vinylbenzyl)acetamide

DEPC (1.2eq, 0.16mmol, 23.67/^) and TEA (2eq, 0.26mmol, 36.24βi) were added to a solution of (4-tert-buty[-phenoxy)-acetιc acid (1.1 eq, 0.15mmoi, 46.97mg) and N-(4-aminomethyl-2-vinyl-phenyl)-methanesulfonamide (1eq, 0.13mmol, 30mg) in DMF and the resulting mixture was stirred for 12hrs. DMF was concentrated under reduced pressure and the reaction mixture was extracted with Ethyl acetate. The organic phase was washed with H ₂ O, brine, dried over Na ₂ SC> ₄ , filtered and then concentrated under reduced pressure. The remaining residue was subjected to column chromatography (n-Hx: EtOAc= 1 :1) to give a white solid 38.7mg (71.52%).

Mp: 86-88 ⁰ C; IR (NaCI neat, cm ^"1 ): 3286, 2961, 1662, 1512, 1325, 1153; ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.37 (s, 1H), 7.29 (d, 2H, J =8.0Hz), 7.17 (dd, 1H ₁ J =8.4, 1.6Hz), 6.96 (t, 1 H, J =5.6Hz), 6.88 (dd, 1 H ₁ J =17.6, 11.2Hz) ₁ 6.82 (d, 2H ₁ J =8.0Hz), 6.62 (s, 1H), 5.67 (d, 1H, J =17.6Hz), 5.43 (d, 1H ₁ J =11.2Hz) ₁ 4.51 (s, 4H) ₁ 2.94 (s, 3H) ₁ 1.26 (s, 9H)

Example 2: 2-(4-terf-Butylphenoxy)-λ/-(3-fluoro-4-methanesulfony!amϊn o-5- vinylbenzyl)acetamide

A dried 25ml two-neck round bottom flask was filled with argon and (4- tert-butyl-phenoxy)-acetic acid (1.1eq, 0.11 mmol, 34.61mg) and N-(4- aminomethyl-2-fluoro-6-vinylphenyl)methanesulfonamide (1.Oeq, O.IOmmol, 35mg) were dissolved in DMF. To this solution were added DEPC (1.2eq, 0.12ITUTiOl, 18.21 μi) and TEA (2.0eq, 0.20mmol, 27.88≠) and stirred for 12 hours. After confirming the completion of the reaction, the solvent was concentrated under reduced pressure, and the resulting residue was extracted with EtOAc, washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained liquid was column chromatographed (n-Hexane/EtOAc=1/1) to yield a white solid (33.7mg, 77.61%).

Mp: 155~157°C; IR (KBr pellet, cm ^'1 ): 3286, 3232, 3086, 2962, 1658, 1321 , 1155; ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.31 (d, 2H, J =8.4Hz), 7.12 (dd, 1 H, J =17.6, 10.8Hz), 7.01 (t, 1 H, J =6.0Hz), 6.97 (dd, 1 H, J =10.0, 1.2Hz), 6.84 (d, 2H, J =8.4Hz), 6.20 (s, 1 H), 5.73 (d, 1H, J =17.6Hz), 5.41 (d, 1H, J =10.8Hz), 4.53 (s, 2H), 4.50 (d, 2H, J =6.0Hz), 3.03 (s, 3H), 1.27 (s, 9H).

Example 3: 2-(4-ferf-Butylphenoxy)-W-(3-ethynyl-5-fluoro-4- methanesulfonylaminobenzyl)acetamide

To a solution of (4-fe/t-butylphenoxy)acetic acid (1.1eq, 0.12mmol, 39.78mg) and N-(4-aminomethyl-2-ethynyl-6-fluorophenyl)methanesulfonamide (1eq, 0.11mol, 40mg) in DMF under argon were added DEPC (1.2eq, 0.13mmol, 20.03/i£) and TEA (2eq, 0.22mmol, 30.06/rf). The resulting mixture was stirred for 12 hours, concentrated in vacuo, and diluted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was then purified by column chromatography (n-Hx: EtOAc= 1 :1 ) to afford the title compound (39mg, 77.9%) as a white solid.

Mp: 102-104 ⁰ C; IR (KBr pellet, cm ^"1 ): 3235, 3098, 2961 , 1656, 1331, 1148; ¹ H NMR (400MHz, CDCI ₃ ): δ 7.30 (d, 2H, J =8.8Hz), 7.22 (s, 1H), 7.06 (dd, 1 H, J =10.8, 2.0Hz), 7.01 (s, 1 H) ₁ 6.83 (d, 2H, J =8.8Hz), 6.49 (s, 1 H), 4.52 (s, 2H), 4.45 (d, 2H, J =6.4Hz), 3.44 (s, 1H), 3.20 (s, 3H), 1.27 (s, 9H)

Example 4: 2-(4-ferf-Butylphenoxy)-/V-(3-ethyl-5-fluoro-4- methanesu!fonylaminobenzyl)acetamide

Into a dried 25ml two-neck round bottom flask was put 2-(4-tert- butylphenoxy)-λ/-(3-fluoro-4-methanesulfonylamino-5-vinylbe nzyl)acetamide

(27.9mg, 0.06mmol) and was dissolved in methanol. And into this mixture was put 10 wt % palladiumon activated carbon. Then the flask was substituted with

H ₂ gas and stirred for 5 hours. After confirming the completion of this reaction,

the reaction mixture was filtered with celite, concentrated under reduced pressure and column chromatographed (n-Hx: EtOAc= 1 : 1) to yield a white solid (22.3mg, 85.4%).

Mp: 102~104 ^° C ; IR (KBr pellet, crτT ¹ ): 3235, 3079, 2963, 1671 , 1321 , 1154 ; ¹ H NMR(400MHz, CDCI ₃ ): 7.30 (d, 2H, J =8.4Hz), 7.00 (t, 1 H, J =6.0Hz), 6.97 (s, 1H), 6.88 (d, 1 H, J =10.8Hz), 6.83 (d, 2H ₁ J =8.4Hz), 6.17 (s, 1 H), 4.53 (s, 2H), 4.48 (d, 2H, J =6.0Hz), 3.04 (s, 3H), 2.81 (q, 2H, J =8.0Hz), 1.27 (s, 9H), 1.17 (t, 3H, J =7.6Hz),

Example 5: 2-(4-ferf-ButyI-phenoxy)-λ/-(3-chloro-4-methanesulfonyIamin o- 5-methylbenzyI)acetamide

To a solution of (4-ferf-butylphenoxy)acetic acid (1.1eq, 0.11mmol, 34.25mg) and λ/-(4-aminomethyl-2-chloro-6-methyl-phenyl)- methanesulfonamide (1eq, O.IOmmol, 35mg) in DMF under argon were added

DEPC (1.2eq, 0.12mmol, 27.88/zf,) and TEA (2eq, 0.20mmol, 18.22^,)- The resulting mixture was stirred for 12 hours, concentrated in vacuo, and diluted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was then purified by column chromatography (n-Hx: EtOAc= 1:1) to afford the title compound (42.56mg, 88.3%) as a white solid.

Mp: 105-107T:; IR (KBr pellet, cm ^"1 ): 3275, 3039, 2961 , 1664, 1320; ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.31 (d, 2H, J =8.4Hz), 7.18 (s, 1H), 7.07 (s, 1H), 6.95 (t, 1 H, J =5.6Hz), 6.83 (d, 2H, J =8.4Hz), 6.13 (s, 1H), 4.53 (s, 2H), 4.45 (d, 2H, J =6.4Hz), 3.05 (s, 3H), 2.44 (s, 3H), 1.27 (s, 9H)

Example 6: 2-(4-terf-Butylphenoxy)-W-(5-fluoro-4-methanesulfonylamino-2 - methylbenzyl)acetamide

To a solution of (4-ferf-butylphenoxy)acetic acid (1.1eq, 0.13mmol, 41.98mg) and λ/-(4-aminomethyl-2-fluoro-5-methyl-phenyl)- methanesulfonamide (1eq, 0.12mmol, 41 mg) in DMF under argon were added

DEPC (1.2eq, 0.14mmol, 2^ .85μi) and TEA (2eq, 0.24mmol, 33.45(d). The resulting mixture was stirred for 12 hours, concentrated in vacuo, and diluted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was then purified by column chromatography (n-Hx: EtOAc= 1 :1) to afford the title compound (45.61 mg, 83.1%) as a white solid.

Mp: 84~86°C; IR (KBr pellet, cm ^'1 ): 3258, 3022, 2962, 1668, 1511 , 1331 ; ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.30 (d, 2H, J =8.4Hz), 7.29 (s, 1 H), 6.94 (d, 1 H, J =11.2Hz), 6.83 (d, 2H ₁ J =8.4Hz), 6.65 (s, 1H), 4.53 (s, 2H), 2.97 (s, 3H), 2.23 (s, 2H), 1.26 (s, 9H)

Example 7: 2-(4-terf-ButyIphenoxy)-/V-(3-fluoro-4-methanesulfonylamino- 5- methylbenzyl) acetamide

(4-tert-Butyl-phenoxy)-acetic acid (1.1eq, 0.19mmol, 61.07mg) and N-(4- aminomethyl-2-fluoro-6-methylphenyl)methanesulfonamide (1.0eq, 0.17mmol,

40mg) were dissolved in DMF in a dried 25ml two-neck round bottom flask filled with argon,. To this solution were added DEPC (1.2eq, 0.20mmol, 30.95/^) and

TEA (2.0eq, 0.34mmol, 47.39 μi) and the resulting mixture was stirred for 12 hours. After confirming the completion of the reaction, the solvent was concentrated under reduced pressure, extracted with EtOAc, washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The obtained liquid was column chromatographed (n-

Hexane/EtOAc=1/1 ) to yield a white solid (68.50mg, 85.4%).

Mp: 85~87 ^° C; IR (KBr pellet, crrf ¹ ): 3274, 3019, 2963, 1666, 1512, 1326, 1186; ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.29 (d, 2H, J =8.8Hz), 7.16-7.09 (m, 1H), 7.14 (s, 1 H), 7.01 (t, 1 H, J =6.0Hz), 6.88 (bs, 1 H), 6.82 (d, 2H, J =8.8Hz), 4.52 (d, 2H, J =6.0Hz), 4.48 (s, 2H), 2.98 (s, 3H), 2.22 (s, 3H), 1.26 (s, 9H)

Example 8: (R)-2-(4-ferf-Butylphenoxy)-/V-[1-(3-fluoro-4- methanesulfonylaminophenyl)ethyl]acetarnide

To a solution of (4-terf-butylphenoxy)acetic acid (1.1eq, 0.16mmol, 53.44mg) and (R)-N-[4-(1-aminoethyl)-2-fiuoro-phenyl]methanesulfonamide (1eq, 0.15mmol, 35mg) in DMF under argon were added DEPC (1.2eq, 0.18mmol, 27.31/^) and TEA (2eq, 0.30mmol, 41.81 μβ). The resulting mixture was stirred for 12 hours, concentrated in vacuo, and diluted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was then purified by column chromatography (n-Hx: EtOAc= 1 :1) to afford the title compound (52.07mg, 77.1 %) as a white solid.

Mp: 130-132 ⁰ C; [α] _D ²⁰ -14.0 (CHCI ₃ , c 0.52); IR (NaCI neat, cm ^"1 ): 3277, 3034, 2967, 1671 , 1166; ¹ H NMR (400MHz, CDCI ₃ ): δ 7.46 (t, 1H, J =8.0Hz), 7.30 (d, 2H, J =8.8Hz), 7.06-7.01 (m, 2H), 6.83 (d, 2H, J =8.8Hz), 6.78 (s, 1 H), 5.14 (q, 1H, J =7.2Hz), 4.47 (s, 2H), 2.98 (s, 3H), 1.48 (d, 3H, J =6.8Hz), 1.27 (s, 9H)

Example 9: (R)-2-(4-fert-ButyIphenoxy)-W-(3-fluoro-4- methanesulfonylamϊnobenzyl)propionamide

Step 1 : (R)-2-(4-fø/f~Butylphenoxy)propionic acid ethyl ester 4-tert-Butyl-phenol (1.2eq, 1.02mmol, 168.06mg) and (S)-lactic acid ethyl ester (1eq, 0.85mmol, 100mg) were dissolved in toluene and the mixture was cooled to 0 ⁰ C. PPh ₃ (1.2eq, 1.02mmol, 267.53mg) and DEAD (1.2eq, 1.02mmol, 185.82/^,) were added to the reaction mixture and then stirred for

12hrs. The liquid obtained after concentrating toluene under reduced pressure was subjected to column chromatography (n-Hx: EtOAc= 25:1) to yield a colorless syrup 138.43mg (65.1%).

[α] _D ²⁰ +30.89 (CHCl ₃ , c 0.69); IR (NaCI neat, cm ^"1 ): 2963, 1755, 1734, 1608, 1346, 1135; ¹ H NMR (400MHz, CDCI ₃ ): δ 7.26 (d, 2H, J =8.4Hz), 6.79 (d, 2H, J =8.4Hz), 4.69 (q, 1 H, J =6.8Hz), 4.20 (q, 1H, J =6.8Hz), 1.58 (d, 3H, J =7.2Hz), 1.27 (s, 9H), 1.24 (d, 3H, J =7.2Hz)

Step 2: (R)-2-(4-fe/Y-Butylphenoxy)propionic acid

Small amount of water was added to a solution of (R)-2-(4-tert-butyl- phenoxy)-propionic acid ethyl ester (1eq, 0.23mmol, 56.6mg) in MeOH followed by MeOH. After cooling to O ⁰ C, NaOH (5eq, 1.13mmol, 45.25 mg) was slowly added thereto, and the reaction mixture was stirred for 5hrs. After completion of the reaction, the aqueous phase was washed with methylenechloride, acidified, and then extracted with ether. The ethereal phase was concentrated to give a pale yellow syrup 35.8mg (70.26%).

¹ H NMR (400MHz, CD ₃ OD): δ 7.25 (d, 2H, J =8.8Hz), 6.77 (d, 2H, J =8.8Hz), 4.72 (q, 1 H, J =7.2Hz), 1.53 (d, 3H, J =7.2Hz), 1.25 (s, 9H)

Step 3: (R)-2-(4-ferf-Butylphenoxy)-/V-(3-fluoro-4- methanesulfonylaminobenzyl)propionarhide

Tb a solution of (R)-2-(4-tert-butyl-phenoxy)propionic acid (1.1 eq,

O.IOmmol, 22.08mg) and N-(4-aminomethyl-2-fluoro- phenyl)methanesulfonamide (1eq, 0.09mmol, 30mg) in DMF under argon were added DEPC (1.2eq, 0.11 mmol, 16.39/^) and TEA (2eq, O.iδmmol, 25.09 μi). The resulting mixture was stirred for 12 hours, concentrated in vacuo, and diluted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was then purified by column chromatography (n-Hx: EtOAc= 1:1) to afford the title compound (32.2mg, 84.74%) as a white solid.

Mp: 69-71 ⁰ C; [α] _D ²⁰ +15.29 (CHCI ₃ , c 0.51 ); IR (KBr pellet, crrf ¹ ): 3264, 2963, 1664, 1510, 1335, 1159; ¹ H NMR (400 MHz, CDCI ₃ ): δ 7.42 (t, 1 H, J =8.0Hz), 7.29 (d, 2H, J =8.8Hz), 6.93-6.89 (m, 2H), 6.87 (bs, 1H), 6.81 (d, 2H, J =8.8Hz), 6.73 (bs, 1 H), 4.71 (q, 1 H, J =6.8Hz), 4.46-4.35 (m, 2H), 2.96 (s, 3H), 1.57 (d, 3H, J =6.8Hz), 1.26 (s, 9H)

Example 10: fS>2-(4-ferf-Butylphenoxy)-N-(3-fluoro-4- methanesulfonylaminobenzyl)propionamide

Step 1 : (S)-2-(4-te/f-Butylphenoxy)propionic acid ethyl ester 4-tert-Butyl-phenol (1.2eq, 0.71 mmol, 106.82mg) and (R)-2- hydroxypropionic acid ethyl ester (1 eq, 0.59mmol, 70mg) were dissolved in toluene and the mixture was cooled to 0 ^° C . PPh ₃ (1.2eq, 0.71 mmol, 185.70mg) and DEAD (1.2eq, 0.71 mmol, 129.34/i£) were added to the reaction mixture and

then stirred for 12hrs. The liquid obtained after concentrating toluene under reduced pressure was subjected to column chromatography (n-Hx: EtOAc= 25:1) to yield a colorless syrup 89.5mg (60.64%).

[α] _D ²⁰ -30.51(CHCI ₃ , c 0.59); IR (NaCI neat, cm ^"1 ): 2963, 1755, 1734, 1608, 1346, 1135

¹ H NMR (400MHz, CDCI ₃ ): δ 7.25 (d, 2H, J =8.8Hz), 6.79 (d, 2H, J =8.8Hz), 4.69 (q, 1H, J =6.8Hz), 4.19 (q, 1 H, J =7.2Hz), 1.58 (d, 3H ₁ J =6.8Hz), 1.26 (s, 9H), 1.23 (d, 3H, J =7.2Hz)

Step 2: (S)-2-(4-fe/?-Butylphenoxy)propionic acid Small amount of water was added to a solution of (S)-2-(4-tert- butylphenoxy)propionic acid ethyl ester (1eq, 0.36mmol, 89.5mg) in MeOH followed by MeOH. After cooling to 0 ⁰ C, NaOH (5eq, 1.79 mmol, 71.55 mg) was slowly added, and the reaction mixture was stirred for 5hrs. After completion of the reaction, the aqueous phase was washed with methylene chloride, acidified, and then extracted with ether (150 x 3). The ethereal phase was concentrated to give a pale yellow syrup 70.05 mg (87.6%).

¹ H NMR (400MHz, CD ₃ OD): δ 7.25 (d, 2H, J =8.8Hz), 6.77 (d, 2H, J =8.8Hz), 4.71 (q, 1 H, J =6.8Hz), 1.53 (d, 3H, J =6.8Hz), 1.24 (s, 9H)

Step 3: (SJ-2-(4-ferf-butylphenoxy)-/V-(3-fluoro-4- methanesulfonylaminobenzyl)propionamide

To a solution of (S)-2-(4-tert-butyl-phenoxy)propionic acid (1.1 eq, 0.12mmol, 25.75mg) and N-(4-aminomethyI-2-fluoro- phenyl)methanesulfonamide (1eq, 0.11 mmol, 35mg) in DMF under argon were added DEPC (1.2eq, 0.13mmol, 20.03ø ^β ) and TEA (2eq, 0.22mmol, 30.66M). The resulting mixture was stirred for 12 hours, concentrated in vacuo, and diluted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was then purified by column chromatography (n-Hx: EtOAc= 1 :1) to afford the title compound (41.98mg, 90.4%) as a white solid.

Mp: 55-57 ⁰ C; [α] _D ²⁰ -10.93 (CHCI ₃ , c 0.28); IR (NaCI neat, crrf ¹ ): 3263, 3025, 2963, 1663, 1510, 1335, 1159; ¹ H NMR (400MHz, CDCI ₃ ): δ 7.43 (t, 1H, J =8.0Hz), 7.29 (d, 2H, J =8.4Hz), 6.94-6.90 (m, 2H) ₁ 6.86-6.79 (m, 1 H), 6.81 (d, 2H, J =8.4Hz), 6.60 (bs, 1 H), 4.71 (q, 1 H, J =6.8Hz), 4.47-4.35 (m, 2H), 2.97 (s, 3H), 1.57 (d, 3H, J =6.8Hz), 1.27 (s, 9H)

Example 11 : (R)-2-(4-ferf-Butylphenoxy)-/V-[1-(4- methanesu!fonylaminophenyl)ethyl]thioacetamide

(R)-2-(4-tert-butyl-phenoxy)-N-[1 -(4- methanesulfonylaminophenyl)ethyl]acetamide (1 eq, O.IOmmol, 41.4mg) was dissolved in toluene under argon, and Lawesson's reagent (2eq, 0.20mmol, 82.86mg) was added into the mixture. The reaction mixture was stirred for 12

hrs in reflux. The reaction solvent was removed in vacuo. The residue was purified with column chromatography (n-Hx: EtOAc= 3:1) to yield the title compound (37.1 mg, 88.30%) as a yellow solid.

Mp: 63-65 ⁰ C ; [crfo ²⁰ +90.43(CHCI ₃ , c 0.28); IR (KBr pellet, cm ^"1 ): 3281 , 2963, 1610, 1512, 1325, 1155; ¹ H NMR (400MHz, CDCI ₃ ): δ 8.40 (d, 1 H, J =8.0Hz), 7.29 (d, 2H, J =8.4Hz), 7.23 (d, 2H, J =8.4Hz), 7.19 (d, 2H, J =8.4Hz), 7.04 (bs, 1 H), 6.81 (d, 2H, J =8.8Hz), 5.77 (q, 1H, J =7.2Hz), 4.83 (s, 2H), 2.97 (s, 3H), 1.56 (d, 3H, J =7.2Hz), 1.26 (s, 9H)

Example 12: (R)-2-(4-tert-ButyIphenoxy)-N-[1 -(4-methanesulfonylamino- phenyI)ethyl]-N'-cyanoacetamidine

(R)-2-(4-tert-Butyl-phenoxy)-N-[1-(4-methanesulfonylamino-ph enyl)- ethyljthioacetamide (0.08 mmol, 35.0 mg) was dissolved in DMF under argon, and cyanamide (0.08 mmol, 3.5 mg), HgCI ₂ (0.08 mmol, 21.72 mg), and TEA (0.08 mmol, 11.15 μi) were added into the mixture. The reaction mixture was stirred for 12hrs. The reaction mixture was extracted with ethyl acetate. A combined organic layer was washed with H ₂ O and brine, dried with Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified with column chromatography (n-Hx: EtOAc= 1 :1) to yield the title compound (33.7 mg, 98.37%) as a white solid.

Mp: > 200°C; [cr] _D ²⁰ +27.2(CHCI _3l c 0.1 ); IR (KBr pellet, cnT ¹ ): 3325, 3183, 2952, 2177, 1605, 1334, 1154; ¹ H NMR (400MHz, CDCI ₃ ): δ 8.40 (d, 1H, J =8.0Hz), 7.29 (d, 2H, J =8.4Hz), 7.23 (d, 2H ₁ J =8.4Hz), 7.19 (d, 2H, J =8.4Hz), 7.04 (bs, 1H), 6.81 (d, 2H, J =8.8Hz), 5.77 (q, 1 H, J =7.2Hz), 4.83 (s, 2H), 2.97 (s, 3H) ₁ 1.56 (d, 3H, J =7.2Hz), 1.26 (s, 9H)

Example 13: 2-(4-ferf-Butylphenoxy)-/V-(3-fluoro-4- methanesulfonylaminobenzyI)-λT-cyanoacetamidine

2-(4-ferf-Butyl-phenoxy)-λ/-(3~fluoro-4-methanesulfonylamin obenzyl)- thioacetamide (0.08 mmol, 34.9 mg) was dissolved in DMF ₁ and cyanamide (0.08 mmol, 3.5mg), HgCI ₂ (0.08 mmol, 21.72 mg), and TEA (0.08 mmol, 11.15 μJL) were added into the mixture. The reaction mixture was stirred for 12 hrs in reflux. The reaction mixture was extracted with ethyl acetate. A combined organic layer was washed with H ₂ O and brine, dried with Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified with column chromatography (n-Hx: EtOAc= 1:1 ) to yield the title compound (33.12 mg, 95.8%) as a white solid.

TLC : R _f = 0.33 (n-Hx: EtOAc= 1 :1/ KMnO ₄ ); Mp: 96-98 ⁰ C; IR (KBr pellet, cm ^"1 ): 3259, 3142, 2965, 2927, 2179, 1610, 1330, 1164; ¹ H NMR (400MHz, CDCI ₃ ): δ 7.52 (t, 1 H ₁ J =8.0Hz), 7.32 (d, 2H ₁ J =8.8Hz), 7.08-7.05 (m, 3H), 6.82 (d, 2H,

J =8.8Hz), 6.56 (bs, 1 H), 4.97 (s, 2H), 4.55 (d, 2H, J =6.0Hz), 3.01 (s, 3H) ₁ 1.27

(S, 9H)

Example 14: 2-(4-tert-Butyl-phenylsuIfanyI)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide

Step 1 : (4-tert-Butyl-phenylsulfanyl)-acetic acid

4-tert-Butylthiophenol (1.0eq, 1.Og, 6.01 mmol) was put into the 100 ml one-neck round bottom flask , which was then filled with 30ml of EtOH. To the solution was poured K ₂ CO ₃ (1.5eq, 1.25g) slowly and stirred for 10 minutes at room temperature. After then, 4-tert-butylbromoacetate (1.0eq, 1.07ml) was added in this mixture. The reaction mixture was stirred for 6 hours. After confirming the completion of the reaction with TLC, the reaction solution was concentrated in vacuo, extracted with EtOAc, washed with water and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The obtained liquid was column chromatographed (n-hexane/EtOAc=8/1 ). The obtained liquid was dissolved in methylene chloride, added 3ml trifluoroacetic acid and stirred for 24 hours. After confirming the completion of the reaction with TLC, the reaction solution was extracted with methylene chloride, washed with 1N HCI and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure to yield a liquid (1.3g, 73.0%).

¹ H NMR (300MHZ, DMSO-d ₆ ): δ 1.30 (s, 9H), 3.83 (s, 2H), 7.45 (m, 4H)

Step 2: 2-(4-tert-Butyl-phenylsulfanyl)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide

(4-tert-Butyl-phenyIsulfanyl)-acetic acid (0.28g, 0.95mmol) and DMTMM

(1.1eq, 288mg) were put into the 50 ml round bottom flask , whcih was then filled with 20ml THF, and the resulting mixture was stirred for 10 minutes. To this reaction mixture were added N-(4-aminomethyl-2-fluoro- phenyl)methanesulfonamide hydrochloride (1.0eq, 0.24g) and TEA (excess,

0.5ml) and then stirred for 18 hours. After confirming the completion of the reaction with TLC, the reaction mixture was extracted with ethyl acetate, washed with 1 N HCI solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was column chromatographed (n-hexane/EtOAc=3/2) to yield a solid (195mg, 48.3%).

Mp: 133-134 ⁰ C; ¹ H NMR (300MHZ, CDCI ₃ ): δ 1.31 (s, 9H), 3.00 (s, 3H), 3.69 (s, 2H), 4.42 (d, 2H, J=6.3Hz), 6.41 (bs, 1H), 6.89 (m, 2H), 7.21 (m, 2H), 7.34 (m, 2H), 7.45 (t, 1 H, J=8.7Hz)

Example 15: 2-(4-tert-Butyl-phenyIsulfanyl)-N-(3-ethynyI-5-f luoro-4- methanesu!fonylamino-benzyl)-acetamide

(4-tert-Butyl-phenylsulfanyl)-acetic acid (0.28g, 0.95mmol) and DMTMM

(1.2eq, 129mg) were put into the 25 ml round bottom flask and was filled with

20ml of THF, and the resulting mixture was stirred for 10 minutes. To this

reaction mixture were added N-(4-aminomethyl-2-ethynyl-6-fluoro- phenyl)methanesulfonamide hydrochloride (1.0eq, 0.108g) and TEA (excess, 0.3ml) and then stirred for 18 hours. After confirming the completion of the reaction with TLC, the reaction mixture was extracted with ethyl acetate, washed with 1N HCI solution and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The obtained liquid was column chromatographed (n-hexane/EtOAc=1/1) to yield a solid (136mg, 77.7%)

Mp: 139-140 ⁰ C; ¹ H NMR (300MHZ, CDCI ₃ ): δ 1.30 (s, 9H), 3.25 (s, 3H), 3.47 (s, 1 H), 3.68 (s, 2H), 4.40 (d, 2H, J=6Hz), 6.36 (bs, 1 H), 6.92 (m, 1 H), 7.21 (m, 2H), 7.25 (m, 1 H), 7.34 (m, 2H)

Example 16: N-(3-Fluoro-4-methanesulfonyIamino-benzyl)-2-(4- trifluoromethyl-phenoxy)-acetamide

Step 1 : (4-Trifluoromethyl-phenoxy)-acetic acid

To a suspension of α,α,α-trifluoro-p-cresol (500 mg, 3.08 mmol) and ethyl bromoacetate (0.373 ml, 3.38 mmol) in CH ₃ CN (10 ml) was added Cs ₂ CO ₃

(1.5 g, 4.62 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (20 ml) and then washed three times with H ₂ O (20 ml) and brine, dried over MgSO ₄ , filtered, and concentrated under

reduced pressure. To a suspension of the crude residue in THF (10 ml) was added a solution of 0.5 N LiOH (12.32 ml), and the mixture was stirred for 1.5 hrs at room temperature. The resulting residue was dissolved in H ₂ O (10 ml) and then washed three times with EtOAc (10 ml), acidified with 1 N HCI to pH 1~2. The solution was extracted three times with methylene chloride and then dried over anhyd. Na ₂ SO ₄ and concentrated in vacuo to give (4-trifluoromethyl- phenoxy)-acetic acid (475 mg, 70%).

¹ H NMR (300 MHz, CDCI ₃ ): δ 9.45 (s, 1H, br), 7.58 (d, 2H, J = 9.0 Hz), 6.99 (d, 2H ₁ J = 9.0 Hz), 4.75 (s, 2H)

Step 2: N-(3-Fluoro-4~methanesulfonylamino-benzyl)-2-(4- trifluoromethyl-phenoxy)-acetamide

To a suspension of 3-fluoro-3-methanesulfonylamino-benzylamine HCI salt (233 mg, 0.914 mmol) in THF (4 ml) at 5 ⁰ C was added TEA (0.153 ml, 1.101 mmol). The mixture was stirred for 5 minutes at the same temperature, to which were added (4-trifluoromethyl-phenoxy)-acetic acid ethyl ester (200 mg, 0.918 mmol) and DMTMM (279 mg, 1.01 mmol). The mixture was stirred overnight at room temperature and concentrated in vacuo. The residue was diluted with EtOAc (20 ml) and water (20 ml). The organic layer was washed with saturated sodium bicarbonate, 1N HCI, and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a solid. The solid was purified by recystallization from EtOAc/hexane to afford the title compound (200 mg, 60 %).

Mp: 126 ~ 132 ⁰ C; ¹ H NMR (300 MHz, CDCI ₃ ): δ 7.55 (d, 2H, J = 9.0 Hz), 7.45 (t, 1 H, J = 8.1 Hz), 7.04 (d, 2H, J = 9.0 Hz), 6.96 (d, 2H, J = 8.7 Hz), 6.88 (s, 1 H, br), 6.58 (s, 1 H), 4.56 (s, 2H), 4.48 (d, 2H, J = 6.3 Hz), 2.97 (s, 3H)

Example 17: 2-(3,4-Dichloro-phenoxy)-N-(3-fIuoro-4- methanesulfonylamino-benzyl)-acetamϊde

Step 1 : 2-Bromo-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acetannid e

3-FIuoro-4-methanesulfonylamino-benzylamine HCI salt (278 mg, 1.17 mmol), pyridine (0.2 ml) and 2-bromoacetyIbromide (0.15 ml) were added in

THF (50 ml). The reaction mixture was stirred overnight. A reaction solvent was removed in vacuo. The residue was extracted with methylene chloride (30 ml x 3) and H ₂ O (50 ml). A combined organic layer was washed with brine, dried with MgSO ₄ , and then concentrated in vacuo. The residue was column chromatographed to yield the title compound (317 mg)

¹ H NMR (300 MHz, CDCI ₃ ): δ 7.55 (t, 1H, J = 8.7 Hz), 7.08 (m, 2H), 6.53 (br, 1 H), 4.47 (m, 2H), 3.95 (s, 1 H), 3.08 (s, 3H).

Step 2: 2-(3,4-Dichloro-phenoxy)-N-(3-fluoro-4-methanesulfonylamino- benzyl)-acetamide

2-Bromo-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acetamicl e (165 mg, 0.486 mmol), 3,4-dichlorophenol (96 mg, 0.59 mmol) and sodium hydride (60 wt% 57 mg, 1.4 mmol) were added in THF (20 ml). The reaction mixture was stirred overnight. The reaction solvent was removed in vacuo. The residue was extracted with methylene chloride (30 ml x 3) and H ₂ O (30 ml). The combined organic layer was dried with MgSO ₄ and concentrated in vacuo. The residue was purified with column chromatography to yield the title compound (14 mg).

¹ H NMR (300 MHz, CDCI ₃ ): δ 7.53 (m, 1 H), 7.41 (m, 1 H), 7.08 (m, 4H), 6.97 (br, 1 H), 6.83 (m, 1 H) ₁ 4.56 (s, 2H), 4.50 (m, 2H), 3.05 (s, 3H)

Example 18: N-(3-FIuoro-4-methanesulfonylamino-benzyl)-2-(4-iodo- phenoxy)-acetamide

Step 1 : Synthesis of ethyl-(4-iodo-phenoxy)-acetate 4-lodophenol (327.7 mg, 1.48 mmol) and sodium hydride (60 wt%, 85 mg, 2.1 mmol ) were added in THF (20 ml). After the mixture was stirred for 20 min, ethyl 2-bromoacetate (0.2 ml, 1.8 mmol) was added into the mixture. The reaction mixture was stirred overnight. A reaction solvent was removed in vacuo. The residue was extracted with methylene chloride (30 ml x 2) and H ₂ O (30 ml). The combined organic layer was washed with 1 M KOH (30 ml x 3), dried with MgSO ₄ , and concentrated in vacuo to yield the title compound.

¹ H NMR (300 MHz, CDCI ₃ ): δ 7.53 (d, 2H), 6.64 (d, 2H), 4.53 (s, 2H), 4.22 (q, 2H, J = 7.2 Hz), 1.26 (t, 3H)

Step 2: Synthesis of (4-iodo-phenoxy)-acetic acid

Ethyl-(4-iodo-phenoxy)-acetate was dissolved in methanol (30 ml_) and then 1 M KOH aqueous solution (3 ml) was added to the solution. The reaction mixture was stirred for 4 hrs. The reaction solvent was removed in vacuo. The residue was acidified with 5 % HCI solution and then extracted with methylene chloride. The combined organic layer was dried with MgSO ₄ and then concentrated to give the title compound.

¹ H NMR (300 MHz, CDCI ₃ ): δ 7.60 (d, 2H), 6.71 (d, 2H), 4.66 (s, 2H)

Step 3: N-(3-Fluoro-4-methanesulfonylamino-benzyl)-2-(4-iodo- phenoxy)-acetamide

3-Fluoro-4-methanesulfonylamino-benzylamine HCI salt (120 mg, 0.471 mmol), NMP (0.25 ml), and (4-iodo-phenoxy)-acetic acid (121 mg, 0.435 mmol) were added in THF (50 ml). After the mixture was stirred for 10 min, DMTMM (138 mg, 0.500 mmol) was added into the mixture. The reaction mixture was stirred overnight. The reaction solvent was removed in vacuo. The resulting residue was extracted with ethyl acetate (60 ml) and H ₂ O (30 ml). The organic layer was washed with saturated K ₂ CO ₃ (30 ml), 5% HCI solution (30 ml) and brine (30 ml). The organic layer was dried with MgSO ₄ and concentrated in

vacuo. The residue was purified with column chromatography to yield the title compound (172 mg, 83%) as a white solid.

Mp: 172 - 153 ⁰ C; ¹ H NMR (300 MHz, CDCI ₃ ): δ 7.60 (d, 2H), 7.53 (m, 1H), 7.08 (d, 2H), 6.89 (br, 1H), 6.69 (m, 1 H), 6.45 (br, 1 H), 4.52 (m, 2H), 4.50 (s, 2H), 3.02 (s, 3H)

IR (neat, cm ^'1 ): 1674, 1650, 1523, 1482, 1330, 1152. MS : 478 (M)

Example 19: 2-(2,6-Diiodo-4-trifluoromethyI-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide

Step 1 : 2,6-Diiodo-4-trifluoromethyI-phenol

To a solution of iodine (411 mg, 3.24 mmol) in EtOH was added a solution of α,α,α-trifluoro-p-cresol (263 mg, 1.62 mmol) and Ag ₂ SO ₄ (607 mg, 1.94 mmol) in EtOH, and the mixture was stirred for 3hrs at ambient temperature under dark. The reaction mixture was filtered through celite pad and then concentrated. The resulting residue was dissolved in EtOAc and then washed three times with 10% IS^SaO ₃ solution, washed with brine, dried over anhyd. MgSO ₄ , filtered, and concentrated under reduced pressure. The obtained residue was column chromatographed to yield 2,6-diiodo-4-trifluoromethyl- phenol (100 mg, 21 %).

¹ H NMR (300MHz, CDCI ₃ ): δ 7.92 (s, 2H) ₁ 6.06 (s, 1 H)

Step 2: (2,6-Diiodo-4-trifluoromethyl-phenoxy)-acetic acid

To a suspension of 2,6-diiodo-4-trifluoromethyl-phenol (40 mg, 0.096 mmol) and ethyl bromoacetate (0.013 ml, 0.116 mmol) in CH ₃ CN (1 ml) was added CS ₂ CO ₃ (47.23 mg, 0.145 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (5 ml) and then washed three times with H ₂ O (5 ml) and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. To a suspension of the crude residue in THF (5 ml) was added a solution of 0.5 N-LiOH (0.4 ml), and the mixture was stirred for 1 .5 hrs at room temperature. The resulting residue was dissolved in

H ₂ O (5 ml) and then washed three times with EtOAc (2 ml), acidified with 1 N

HCI to pH 1 -2. The solution was extracted three times with methylene chloride

(2 ml) and then dried over anhyd. Na ₂ SO ₄ and concentrated in vacuo to give (2,6-diiodo-4-trifluoromethyl-phenoxy)-acetic acid (41 mg, 90%).

¹ H NMR (300MHz, CDCI ₃ ): δ 8.04 (s, 2H), 4.71 (s, 2H)

Step 3: 2-(2,6-Diiodo-4-trifluoromethyl-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide

3-Fluoro-4-methanesulfonylamino-benzylamine HCI salt (22.1 mg, 0.087mmol) was suspended in THF (2mL) and treated with TEA (0.012mL). The resulting mixture was stirred for 10min. To the reaction mixture was added (2,6- diiodo-4-trifluoromethyl-phenoxy)-acetic acid (41 mg, 0.087 mmol) followed by

DMTMM (24 mg, 0.095 mmol) after 10 min. The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, sat'd NaHCO ₃ (x3), 1 N HCI, and brine, and then dried over anhyd. MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was recrystallized from EtOAC/n-hexane to yield the title compound (35 mg, 60%).

Mp: 190 - 192 ^° C ;

¹ HNMR (300MHz, CDCI ₃ ): δ 8.03 (s. 2H), 7.57 (t, 1 H, J = 8.4Hz), 7.22 ~ 7.17 (m, 2H), 6.55 (s, 1 H), 4.61 (d, 2H ₁ J = 7.2 Hz), 4.59 (s, 2H), 3.03 (s, 3H)

Example 20: 2-[4-(fe/t-butyl)-phenoxy]-/V-(3-cyano-5-fluoro-4- methanesulfonylamino)benzylacetamide

Step 1 : 4-Amino~3-fluorobenzenecarbonitrile

2-Fluoro-2-iodoaniiine (2.Og, 8.4mmol) and coppercyanide (982mg, 11.0mmol, 1.5eq) were added into DMF (30ml). And the reaction mixture was heated to 130°C, stirred for 8hrs. The reaction mixture was diluted with ethyl acetate. A diluted solution was washed with H ₂ O (2 times) and brine, and then dried with MgSO ₄ . The resulting residue was purified with column chromatography (n-Hexane: EtOAc =3 : 1) to yield solid (914mg, 84%).

¹ H NMR (300 MHz, CDCI ₃ ): 7.21-7.26 (m, 2H), 6.74 (t, 1H, J = 8.3 Hz), 4.20 (bs, 2H)

Step 2: 4-Amino-3-fluoro-5-iodobenzenecarbonitrile

4~Amino~3-fluorobenzenecarbonitrile (4.06g, 29.9mmol) and ICI(LOM in methylene chloride, 40.0 ml, 40.0mmol) were added into methylene chloride (100ml). And the reaction mixture was stirred for 20 hrs. The reaction was quenched by adding sodium thiosulfate solution, and the aqueous solution was extracted with MC. The combined organic solution was washed with H ₂ O and brine, dried with Na ₂ SO ₄ , and then concentrated in vacuo. A residue was purified with column chromatography (n-Hexane: EtOAc = 5: 1) to yield solid (4.8Og, 91 %). ¹ H-NMR (300MHz, CDCI ₃ ): δ 7.69 (t, 1 H, J = 1.5 Hz), 7.23 (del, 1 H, J = 10.0, 1.7 Hz), 4.68 (bs, 2H)

Step 3: 4-Aminomethyl-2-fluoro-6-iodophenylamine

A 50 ml two-neck round bottom flask was filled with argon gas and a solution of 4-amino-3-fluoro-5-iodo-benzonitriIe 84.4mg (0.322mmol, leg.) in tetrahydrofuran was put into the flask and then cooled to 0 ⁰ C . To the solution was added Borane-THF complex solution (1.0M solution in THF, 0.64ml,

0.644mmol, 2eq.). The temperature of reaction mixture was raised to room temperature, heated, and refluxed. After confirming the completion of the reaction with TLC, to the solution was added 5% HCI and the resulting mixture

was stirred for 20 minutes. The resulting solution was basified using 1 N KOH ₁ extracted with ether, washed with brine and dried over Na ₂ SO ₄ . The obtained liquid was concentrated under reduced pressure to yield a pale yellow solid (78.4mg, 80.5%).

¹ H NMR (400MHz, CD ₃ OD) : 7.33 (s, 1 H), 6.93 (dd, 1 H, J=11.6, 2.0Hz), 3.58 (s, 2H) ₁

Step 4 : (4-Amino-3-fluoro-5-iodobenzyl)carbamic acid t-butyl ester A 25 ml two-neck round bottom flask was filled with argon gas and the solution of 4-aminomethyl-2-fluoro-6-iodophenylamine (31.9mg, 0.120mmol, 1 eg.) and triethylamine (18.4/^, 0.132mmol, 1.1eg.) in methylene chloride was put into the flask and then cooled to 0 ^° C . To the solution were added A- dimethylaminopyridine (1.47mg, 0.012mmol, 0.1 eg.) and di-t-butyl dicarbonate (27.6μi, 0.120mmol, leg.) and the resulting mixture was stirred for 5 hours.

After confirming the completion of the reaction with TLC, the resulting solution was extracted with methylene chloride, washed with water and brine, dried over

Na ₂ SO ₄ and concentrated under reduced pressure. The obtained liquid was column-chromatographed (n-hexane /ethyl acetate = 5/1 ) to yield a yellow liquid (9.8mg, 22.3%).

¹ H NMR (400 MHz, CDCI ₃ ): 7.87 (s, 0.2H), 7.44 (d, 0.2H, J=11.2Hz), 7.26 (s, 1 H), 6.87 (d, 1 H, J=11.2Hz), 4.72 (bs, 2H), 4.08 (d, 2H, J=4.4Hz), 1.39 (s, 9H)

Step 5 : (3-Fluoro-5-iodo-4-methanesulfonylamino)carbamic acid t-butyl ester

A 25 ml two-neck round bottom flask was filled with argon gas and the solution of (4-amino-3-fluoro-5-iodobenzyl)carbamic acid t-butyl ester (5.8g, 17.2mmol, leg.) and pyridine (1.65ml, 20.6mmol, 1.2eg.) in methylene chloride

(70ml)was put into the flask and then cooled to 0 ⁰ C . To the solution was added methanesulfonyl chloride (1.73ml, 22.4mmol, 1.3eq.) and heated to reflux for one night. After confirming the completion of the reaction with TLC, the reaction solution was acidified by 10% HCI, extracted with ethylacetate, washed with water and brine, dried over MgSO ₄ and evaporated. The obtained solid was column-chromatographed (n-hexane /ethyl acetate = 2/1) to yield a yellow liquid.

(5.55g, 73%)

¹ H-NMR (300MHz ₁ CDCI ₃ ): δ 7.56 (s, 1 H), 7.08 (d, 1 H, J = 10.0 Hz), 6.12 (s, 1 H) ₁ 4.92 (bs, 1 H), 4.24 (d, 2H ₁ J = 5.9 Hz) ₁ 3.23 (s, 3H), 1.44 (s, 9H)

Step 6: (3-Cyano-5-fluoro-4-methanesulfonylamino)carbamic acid t-butyl ester

(3-Fluoro-5-iodo-4-methanesulfonylamino)carbamic acid t-butyl ester (156 mg,

0.35mmol) and copper cyanide (36mg, 0.42mmol, 1.2eq) was added into DMF(3ml). The reaction mixture was heated to 130°C and stirred for 3hrs. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with H ₂ O (2 times) arid brine, and then dried with MgSO ₄ . The resulting residue

was purified with column chromatography (n-Hexane: EtOAc =3 : 1) to yield solid (42mg, 35%).

¹ H-NMR (300MHz, CDCI ₃ ): δ 7.34-7.40 (m, 2H), 6.48 (s, 1 H), 5.01 (bs, 1H), 4.31 (d, 2H, J = 6.4 Hz ), 3.28 (s, 3H), 1.44 (s, 9H)

Step 7: N-(4-Aminomethyl-2-cyano-6-fluorophenyl)methanesulfonamide (3-Cyano-5-fluoro-4-methanesulfonylamino)carbamic acid t-butyl ester (30mg, 0.12mmol) was put into 25ml round-bottom flask and then dissolved in methylene chloride(3ml). To the solution was added trifluoroacetic acid (0.5ml) and the reaction mixture was stirred for one night. After confirming the completion of the reaction with TLC, the reaction solution was concentrated under reduced pressure to yield a brown crude liquid (crude 100%).

Step 8: 2-[4-(tert-Butyl)phenoxy]-/V-(3-cyano-5-fluoro-4-methanesulf onyl amino)benzylacetamide

A 25 ml two-neck round bottom flask was filled with argon gas and a solution of 2-[4-(ferf-butyl)phenoxy]acetic acid (33mg, 0.16mmol, 1.2 eg.) in THF was put into the flask. To the solution were added DMTMM (86mg, 0.31 mmol, 2.4 eg) and NMM (20.0μβ, 0.18mmol, 1.4 eq.) and stirred at room temperature for 12 hours. The resulting solution was cooled to 0 ^° C and the solution of S-cyano-δ-fluoro^-methanesulfonylamino-ammonium and trifluoroacetate (32mg, 0.13mmol, leg.) in THF was added. The mixture was stirred at room temperature for one night. After confirming the completion of the

reaction with TLC, methylene chloride was removed under reduced pressure. The residue was column-chromatographed (n-hexane /ethyl acetate = 1/1 (only ethylacetate)) to yield a white solid (37mg, 66%).

Mass (FAB) 434 [M+H]+

IR (KBr pellet, cm ^"1 ) : 3433, 2960, 1655, 1548, 1513, 1434, 1333, 1246 ; ¹ H NMR (300 MHz, CDCI ₃ ) : 7.40( s, 1 H) ₁ 7.32~7.36( m, 3H), 7.089( bs, 1 H), 6.85(d, 2H, J=9.0Hz), 6.41 ( s, 1 H), 4.56( s, 2H), 4.53( d, 2H, J=6.2Hz), 3.29( s, 3H), 1.28( s, 9H)

Example 21 : 2-(4-tert-ButyIphenoxy)-2-fluoro-N-(3-f!uoro-4- methanesulfonylaminobenzyl)acetamide

N-(4-Aminomethyl-2-fluorophenyl)methanesulfonamide HCI salt (65.64mg, 0.32mmol) and (4-tert-butylphenoxy)fluoroacetic acid (1.1 eq, 0.35mmol, 80.00mg) were added in anhydrous DMF under argon atmosphere. TEA (5eq, 1.60mmol, 222.00 μi) and diethylcyanophosphonate (1.2eq, 0.38mmol, 58.OQpJL) were added into the mixture. The reaction mixture was stirred for 12 hrs at room temperature. The reaction mixture was extracted with ethylacetate (2 times), washed with brine, dried with Na2SO ₄ , and then concentrated in vacuo. The residue was purified with column chromatography (n-Hx: EA= 2: 1) to yield the title compound (35 mg, 46%) as a yellow solid.

IR (NaCI neat, cπT ¹ ): 3267, 2962, 1684, 1333, 1219, 1158, 1108, 1028; ¹ H NMR (400MHz, CDCI ₃ ): ): 1.23 (s, 9H), 2.94 (s, 3H), 4.44 (dd, 2H J=4.8, 60.8Hz), 6.76 (s, 1 H), 6.98 (d, 2H ₁ J=8.8Hz), 4.03 (d, 2H, J=8.0Hz), 7.28 (d, 1H, J=8.4Hz), 7.46 (dd, 1H, J=8.4Hz)

Example 22: N-(3-Fluoro-4-methanesuIfonylaminobenzyl)-2-(4- isopropylphenoxy)acetamide

Step 1 : Synthesis of 4-isopropylphenoxyacetic acid To a solution of 4-isopropylphenol (0.38 g, 2.79 mmol) in acetonitrile (10 mL) were added cesium carbonate (1.37 g, 4.2 mmol) and ethyl bromoacetate (0.34 mL, 3.01 mmol). The resulting mixture was stirred for 1.5 hours at room temperature, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was washed with brine and concentrated under reduced pressure. The crude residue was diluted with THF (7 mL) and 1 N LiOH (5 mL), and then stirred for 1 hour at room temperature. The mixture was acidified with 6 N HCI, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was then purified by recrystallization from EtOAc/hexane to afford 0.35 g (64.6%) as a white solid. ¹ H NMR (300 MHz, CDCI ₃ ): δ 7.17 (d, 2 H, J = 8.7 Hz), 6.86 (d, 2 H, J = 8.7 Hz),

4.66 (s, 2 H), 2.87 (sept, 1 H ₁ J = 7.2 Hz), 1.22 (d, Q H ₁ J = 7.2 Hz)

Step 2: Synthesis of N-(3-fluoro-4-methanesulfonylaminobenzyl)-2-(4- isopropylphenoxy)acetamide To a suspension of 3-fluoro-4-methanesulfonylaminobenzylamine hydrochloride (100 mg, 0.39 mmol) in THF (5 mi_) was added triethyiamine (82 μl_, 0.59 mmol). The mixture was stirred for 5 min, to which were added 4- isopropylphenoxyacetic acid (81 mg, 0.42 mmol) and 4-(4,6- dimethoxy[1 ,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM ₁ 120 mg, 0.43 mmol). The mixture was stirred overnight at room temperature and was concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was washed with 3N HCI, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by recrystallization from EtOAc/hexane to afford 110 mg (71.0%) as a white solid.

Melting point: 118 - 119.5 ⁰ C;

¹ H NMR (300 MHz, CDCI ₃ ): δ 7.52 (t, 1 H, J = 8.1 Hz), 7.18 (d, 2 H, J = 8.4 Hz), 7.10 ~ 7.05 (m, 2 H), 6.97 (br, 1 H), 6.85 (d, 2 H, J = 8.7 Hz), 6.48 (br s, 1 H), 4.55 (s, 2 H), 4.52 (d, 2 H, J = 6 Hz), 3.02 (s, 3 H), 2.88 (sept, 1 H ₁ J = 7.2 Hz), 1.23 (d, 6 H, J = 7.2 Hz)

Example 23: N-(3-Fluoro-4-methanesuIfonylaminobenzyl)-2-(4-sec- butylphenoxy)acetamide

Step 1 : Synthesis of 4-sec-butylphenoxyacetic acid

To a solution of 4-sec-butylphenol (0.42 g, 2.80 mmol) in acetonitrile (10 ml_) were added cesium carbonate (1.37 g, 4.2 mmol) and ethyl bromoacetate (0.34 mL, 3.01 mmol). The resulting mixture was stirred for 1.5 hours at room temperature, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was washed with brine and concentrated under reduced pressure. The crude residue was diluted with THF (7 mL) and 1 N LiOH (5 mL), and then stirred for 1 hour at room temperature. The mixture was acidified with 6 N HCI, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was then purified by recrystallization from EtOAc/hexane to afford 0.18 g (30.9%) as a white solid.

¹ H NMR (300 MHz, CDCI ₃ ): δ 7.12 (d, 2 H ₁ J = 8.7 Hz), 6.86 (d, 2 H, J = 8.7 Hz), 4.66 (s, 2 H), 2.56 (sext, 1 H, J = 6.9 Hz), 1.56 (dq, 2 H, J = 7.5 Hz), 1.21 (d, 3 H ₁ J = 6.9 Hz), 0.81 (t, 3 H, J = 7.5 Hz)

Step 2: Synthesis of N~(3-fluoro-4-methanesulfonylaminobenzyl)-2-(4-sec-

butylphenoxy) acetamide

To a suspension of 3-fluoro-4-methanesulfonylaminobenzylamine hydrochloride

(100 mg, 0.39 mmol) in THF (5 ml_) was added triethylamine (82 μl_, 0.59 mmol).

The mixture was stirred for 5 min, to which were added 4-sec- butylphenoxyacetic acid (87 mg, 0.42 mmol) and 4-(4,6-dimethoxy[1 ,3,5]triazin-

2-yl)-4~methylmorpholinium chloride hydrate (DMTMM, 120 mg, 0.43 mmol).

The mixture was stirred overnight at room temperature and was concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was washed with 3N HCI, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by recrystallization from

EtOAc/hexane to afford 120 mg (74.8%) as a white solid.

Melting point: 100 ~ 101 ⁰ C ₁ - ¹ H NMR (300 MHz, CDCI ₃ ): δ 7.52 (t, 1 H, J = 7.8

Hz), 7.13 (d, 2 H ₁ J = 8.7 Hz), 7.10 ~ 7.05 (m, 2 H), 6.99 (br, 1 H), 6.85 (d, 2 H, J = 8.7 Hz), 6.51 (br s, 1 H), 4.55 (s, 2 H), 4.52 (d, 2 H ₁ J = 6.3 Hz), 3.02 (s, 3 H) ₁

2.56 (sext, 1 H, J = 6.9 Hz), 1.56 (ddq, 2 H ₁ J = 7.5, 1.5 Hz), 1.20 (d, 3 H, J =

6.6 Hz), 0.80 (t, 3 H ₁ J = 7.5 Hz)

Example 24: N ^« (3-Fluoro-4-methanesulfonylaminobenzyl)-2-(indan-5- yloxy)acetamide

Step 1 : Synthesis of indan-5-yloxyacetic acid

To a solution of 5-indanol (0.38 g, 2.83 mmol) in acetonitrile (10 mL) were added cesium carbonate (1.37 g, 4.2 mmol) and ethyl bromoacetate (0.34 mL, 3.01 mmol). The resulting mixture was stirred for 1.5 hours at room temperature, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was washed with brine and concentrated under reduced pressure. The crude residue was diluted with THF (7 mL) and 1 N LiOH (5 mL), and then stirred for 1 hour at room temperature. The mixture was acidified with 6 N HCI, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was then purified by recrystallization from EtOAc/hexane to afford 433 mg (79.6%) as a white solid.

¹ H NMR (300 MHz, CDCI ₃ ): δ 7.13 (d, 1 H, J = 8.1 Hz), 6.80 (d, 1 H, J = 2.1 Hz), 6.71 (dd, 1 H, J = 8.4, 2.7 Hz), 4.66 (s, 2 H), 2.88 (t, 2 H, J = 7.8 Hz) ₁ 2.84 (t, 2 H, J = 7.2 Hz), 2.08 (quint, 2 H ₁ J = 7.2 Hz)

Step 2: Synthesis of N-(3-fluoro-4-methanesulfonylaminobenzyl)-2-(indan-5- yloxy)acetamide

To a suspension of 3-fluoro-4-methanesulfonylaminobenzylamine hydrochloride (100 mg, 0.39 mmol) in THF (5 mL) was added triethylamine (82 μL, 0.59 mmol). The mixture was stirred for 5 min, to which were added indan-5-yloxyacetic acid (80 mg, 0.42 mmol) and 4-(4,6-dimethoxy[1 ,3,5]triazin-2-yl)-4- methylmorpholinium chloride hydrate (DMTMM, 120 mg, 0.43 mmol). The mixture was stirred overnight at room temperature and was concentrated under

reduced pressure. The residue was diluted with EtOAc and water. The organic layer was washed with 3N HCI ₁ saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by recrystallization from EtOAc/hexane to afford 127 mg (82.4%) as a white solid.

Melting point: 118 ~ 120 ^° C; ¹ H NMR (300 MHz, CDCI ₃ ): δ 7.52 (t, 1 H, J = 7.8 Hz), 7.14 (d, 1 H, J = 8.4 Hz), 7.07 (d, 2 H, J = 8.7 Hz), 6.97 (br, 1 H), 6.80 (d, 1 H, J = 2.1 Hz), 6.70 (dd, 1 H ₁ J = 8.1 , 2.4 Hz) ₁ 6.47 (br s, 1 H), 4.54 (s, 2 H), 4.51 (d, 2 H ₁ J = 6.3 Hz) ₁ 3.02 (s, 3 H) ₁ 2.86 (q, 4 H ₁ J = 7.8 Hz) ₁ 2.09 (quint, 2 H, J = 7.8 Hz)

Example 25: 2-(2-Butoxymethyl-4-trifluoromethy!-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide

Step 1 : 2-(2-ButoxymethyI-4-trifluoromethy!-phenoxy)-tetrahydropyran

To a suspension of [2-(tetrahydro-pyran~2-yloxy)-5-trifluoromethyl-phenyl]- methanol (100 mg, 0.362 mmol) in n-butyl bromide (2 ml) was added Cs2CO3 (235.8 mg, 0.724 mmol). The mixture was stirred for overnight at 90 oC. The reaction mixture was diluted with EtOAc (5 ml) and then washed three times with H2O (5 ml) and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was column-chromatographed to yield 2-(2- butoxymethyl-4-trifluoromethyl-phenoxy)-tetrahydro-pyran (46 mg, 38 %).

¹ H NMR (300 MHz, CDCI ₃ ): δ 7.67 (s, 1H), 7.46 - 7.45 (m, 1H), 7.16 (d, 1H, J = 8.7 Hz), 5.52 - 5.51 (m, 1 H), 4.58 (s, 2H), 3.82 - 3.77 (m, 1 H), 3.63 ~ 3.53 (m, 3H), 1.91 - 1.86 (m, 3H), 1.74 - 1.59 (m, 5H), 1.46 - 1.41 (m, 2H), 0.94 (t, 3H, J = 7.5 Hz).

Step 2 : 2-Butoxymethyl-4-trifluoromethyl-phenol

2-(2-Butoxymethyl-4-trifluoromethyl-phenoxy)-tetrahydro-pyra n (46 mg, 0.138 mmol) was suspended in 4M-HCI/dioxane (2 ml) and then the resulting mixture was stirred for 12hrs to room temperature. The resulting mixture was diluted with EtOAc. The resulting solution was washed with water and then dried over anhyd. Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was column-chromatographed to yield 2-butoxy methyI-4-trifluoromethyl-phenoI (23 mg, 67 %). ¹ H NMR (300 MHz, CDCI3): δ 8.23 (s, 1 H), 7.46 - 7.44 (m, 1 H), 7.26 - 7.25 (m, 1 H), 6.94 (d, 1 H, J = 8.7 Hz), 4.73 (s, 2H), 3.57 (t, 2H, J = 6.0 Hz), 1.68 - 1.59 (m, 2H), 1.46 - 1.25 (m, 2H), 0.93 (t, 3H, J = 7.2 Hz).

Step 3 : (2-ButoxymethyI-4-trifluoromethyI-phenoxy)-acetic acid

To a suspension of 2-butoxy methyl-4-trifluoromethyl-phenol (23 mg, 0.092mmol) and bromoethyl acetate (18.6 mg, 0.11 mmol) in CH3CN (4 ml) was added Cs2CO3 (45.2 mg, 0.139 mmol). The mixture was stirred for overnight at room temperature. The reaction mixture was diluted with EtOAc (20 ml) and then washed three times with H2O (20 ml), brine, dried. MgSO4, filtered and concentrated under reduced pressure. To a suspension of the crude residue in

THF (2 ml) was added a solution of 0.5 N-LiOH (2 ml) and the mixture was stirred for 1.5 hrs at room temperature. The resulting residue was dissolved in H2O (10 ml) and then washed three times with EtOAc (2 ml), acidified with 1 N HCI to pH 1~2. The solution was extracted three times with methylene chloride and then dried over anhyd. Na2SO4 and concentrated in vacuo to give (2- Butoxymethyl-4-trifluoromethyl-phenoxy)-acetic acid (20 mg, 70 %).

¹ H NMR (300 MHz, CDCI3): δ 8.23 (s, 1H, br), 7.63 (d, 1 H, J = 1.8 Hz), 7.56 (d, 1 H ₁ J = 8.7 Hz), 6.89 (d, 1H ₁ J = 8.4 Hz), 4.77 (s, 2H), 4.63 (s, 2H) ₁ 3.57 (t, 2H ₁ J - 6.6 Hz) ₁ 1.68 - 1.58 (m, 2H), 1.44 ~ 1.34 (m, 2H) ₁ 0.92 (t, 3H ₁ J = 7.2 Hz).

Step 4 : 2-(2-ButoxymethyI-4-trifluoromethyl-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide

3-fluoro-4-methanesulfonylaminobenzylamine hydrochloride (16.6 mg, 0.065 mmol) was suspended in THF (0.5 mL) and treated with triethylamine (7.26 mg,

0.072 mmol) and then the resulting mixture was stirred for 10min. (2- butoxymethyl-4-trifluoromethyl-phenoxy)-acetic acid (20 mg, 0.065 mmol) was added to the reaction mixture followed by DMTMM (19.8 mg, 0.072 mmol) after

10 min. The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, sat'd NaHCO3 (x3), 1 N HCI, brine, and then dried over anhyd. MgSO4, filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to yield title compound (25 mg, 76 %).

¹ H NMR (300 MHz ₁ CDCI3): δ 7.82 (t, 1H ₁ J = 6.0 Hz), 7.60 - 7.56 (m, 2H) ₁ 7.44 (t, 1 H ₁ J = 7.6 Hz) ₁ 6.99 - 6.85 (m, 4H), 4.73 (s, 2H) ₁ 4.55 (s, 2H) ₁ 4.44 (d,

2H, J = 6.3 Hz), 3.43 (t, 2H, J = 6.9 Hz), 2.99 (s, 3H), 1.51 - 1.41 (m, 2H), 1.33 - 1.21 (m, 2H), 0.84 (t, 3H, J = 7.2 Hz) ₁

Example 26: N-(3-Fluoro-4-methanesulfonyIaminobenzyI)-(4- cyclopentylphenoxy)acetamide

Step 1 : Synthesis of 4-cyclopentylphenoxyacetic acid To a solution of 4-cyclopentylphenol (0.45 g, 2.77 mmol) in acetonitrile (10 ml_) were added cesium carbonate (1.37 g, 4.2 mmol) and ethyl bromoacetate (0.34 mL, 3.01 mmol). The resulting mixture was stirred overnight at room temperature, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was washed with brine and concentrated under reduced pressure. The crude residue was diluted with THF (7 mL) and 1 N LiOH (5 mL), and then stirred for 1 hour at room temperature. The mixture was acidified with 6 N HCI, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was then purified by recrystallization from EtOAc/hexane to afford 475 mg (77.7%) as a white solid. ¹ H NMR(300MHz, CDCI ₃ ): δ 7.20 ~ 7.15 (m, 1 H), 6.88 ~ 6.83 (m, 1 H) ₁ 4.66 (s, 2 H), 3.00 ~ 2,89 (m, 1 H), 2.09 ~ 1.99 (m, 2 H), 1.85 ~ 1.73 (m, 2 H), 1.73 ~ 1.62 (m, 2 H), 1.61 ~ 1.47 (m, 2 H)

Step 2: Synthesis of N-(3-fluoro-4-methanesuIfonylaminobenzyl)-(4- cyclopentylphenoxy) acetamide

To a suspension of 3-fluoro-4-methanesulfonylaminobenzylamine hydrochloride (100 mg, 0.39 mmol) in THF (5 ml_) was added triethylamine (82 μL, 0.59 mmol). The mixture was stirred for 5 minutes, to which were added 4- cyclopentylphenoxyacetic acid (88 mg, 0.40 mmol) and 4-(4,6- dimethoxy[1 ,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM, 120 mg, 0.43 mmol). The mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was washed with 3N HCI, saturated sodium bicarbonate, and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by recrystallization from EtOAc/hexane to afford 143 mg (85.1 %) as a white solid. ¹ H NMR(300MHz, CDCI ₃ ): δ 7.52 (t, 1 H, J = 8.1 Hz), 7.21 ~ 7.17 (m, 2 H), 7.09 (br, 1 H), 7.06 (br s, 1 H), 6.87 ~ 6.82 (m, 2 H), 6.48 (br, 1 H), 4.55 (s, 2 H), 4.52 (d, 2 H, J = 6.3 Hz), 3.02 (s, 3 H), 3.00 ~ 2.89 (m, 1 H), 2.09 ~ 1.99 (m, 2 H), 1.85 - 1.73 (m, 2 H), 1.73 ~ 1.64 (m, 2 H), 1.62 - 1.47 (m, 2 H) ESI [M+H] ⁺ ; 421.0.

Example 27: 2-(2-ChIoro-4-trifIuoromethyI-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide

Step 1 : 2-(2-ChIoro-4-trifluoromethyl-phenoxy)-tetrahydro-pyran

To a stirred solution of BuLi in hexane (1.2 eq) in a 25 ml_ round-bottomed flask at

-70 ⁰ C was added dropwise a solution of 2-(4-trifluoromethyl-phenoxy)- tetrahydro-pyran (400 mg, 1.62 mmol) in THF (4 ml_). After 30 min, a solution of hexachloroethane (805 mg, 3.40 mmol) in THF (4 ml_) was added thereto at -

70 ⁰ C. After 4 hrs, the mixture was allowed to warm up to 20 ⁰ C and it was evaporated the next day. The residue was taken up in petroleum ether and the insoluble salts were separated by filtration. After evaporation of the solvent from the filtrate, the crude residue was column-chromatographed to yield title compound (100 mg, 22 %).

¹ H NMR (300 MHz, CDCI3): δ 7.63 (d, 1 H, J = 2.1 Hz), 7.47 - 7.43 (m, 1 H), 7.27 - 7.24 (m, 1 H), 5.56 - 5.48 (m, 1 H), 3.87 - 3.78 (m, 1 H), 3.71 - 3.61 (m, 1 H), 2.19 - 1.84 (m, 3H), 1.81 - 1.66 (m, 3H).

Step 2: 2-Chloro-4-trifluoromethyl-phenol

2-(2-Chloro-4-trifluoromethyl-phenoxy)-tetrahydro-pyran was suspended in HCI/dioxane (2 ml, 8 mmol, 4M) and then the resulting mixture was stirred for 12hrs at 0 ⁰ C to room temperature . The resulting mixture was diluted with EtOAc. The resulting solution was washed with water and then dried over anhyd. Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to yield title compound (200 mg, 99 %).

¹ H NMR (300 MHz, CDCI3): δ 7.62 (d, 1 H, J = 2.1 Hz), 7.46 - 7.44 (m, 1 H) ₁ 7.10 (d, 1 H, J = 8.7 Hz), 5.95 (s, 1 H).

Step 3: (2-Chloro-4-trifluoromethyl-phenoxy)-acetic acid ethyl ester

To a suspension 2-Chloro-4-trifluoromethyl-phenol (1eq)) and ethyl bromoacetate (1.2eq) in CH ₃ CN (1 ml) was added Cs ₂ CO ₃ (1.2 eq). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and then washed three times with H ₂ O and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to yield title compound (188 mg, 72 %)

¹ H NMR (300 MHz, CDCI3): δ 7.67 (d, 1 H ₁ J = 2.1 Hz), 7.49 - 7.45 (m, 1 H), 6.88 (d, 1 H, J = 8.4 Hz), 4.76 (s, 2H), 4.28 (q, 2H, J = 7.2 Hz), 1.30 (t, 3H, J = 7.2 Hz)

Step 4 : 2-(2-Chloro-4-trifluoromethyl-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide 3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (50 mg, 0.196 mmol) was suspended in THF and treated with triethylamine (21.8 mg, 0.216 mmol) and then the resulting mixture was stirred for lOmins. (2-Chloro-4- trifluoromethyl-phenoxy)-acetic acid (50 mg, 0.196 mmol) was added to the reaction mixture followed by DMTMM (59.7 mg, 0.216 mmol) after 10 mins. The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, sat'd NaHCO ₃ (x3), 1 N HCI, and brine, and then dried over anhyd. MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was column- chromatographed to yield title compound (72 mg, 91 %).

¹ H NMR (300 MHz, CDCI3): δ 7.68 (t, 1 H ₁ J = 2.1 Hz), 7.57 - 7.52 (m, 2H), 7.13 - 7.10 (m, 3H), 7.01 (t, 1 H, J = 8.4 Hz), 6.21 (s, 1 H), 4.66 (s, 2H), 4.55 (d, J = 3.0 Hz), 3.27 (s, 3H).

Example 28: N-(3-Fluoro-4-methanesuIfonylamino-benzyl)-2-(4- isopropenyl-phenoxy)-acetamide

Step 1 : [4-(1-Hydroxy-1-methyl-ethyl)-phenoxy]-acetic acid ethyl ester

To a solution of 4-hydroxyacetophenone (2.72g, 20mmol) in THF was slowly added MeLi (1.6M 3OmL), and the resulting mixture filled with white solid was stirred overnight. The reaction was quenched by adding EtOAc and water. The pH of the reaction mixture was adjusted to pH 4-5 by adding 2N HCI. The aqueous phase was extracted with EtOAc, and the combined organic phase was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The resulting solid and ethyl bromoacetate (2.22ml) were dissolved in acetonitrile and Cs ₂ CO ₃ (6.46g, 20mmol) was added to the reaction mixture. The resulting mixture was stirred for 12hrs at ambient temperature and then diluted with EtOAc and water. The aqueous phase was extracted with EtOAc, and the combined organic phase was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex/EtOAc = 3/1) to give title compound (4.36g, 91 %). ¹ H NMR(300MHz, CDCI ₃ ): δ 7.40(d, 2H, J =9.0Hz), 6.87(d, 2H, J =9.0Hz), 4.60(s, 2H), 4.26(q, 2H, J =6.9Hz), 1.55(s, 6H), 1.29(t, 3H, J =6.9Hz)

Step 2: (4-lsopropenyl-phenoxy)-acetic acid

KF (1.16g, 20mmol) was added to a mixture of [4-(1-hydroxy-1-methyl-ethyl)- phenoxy]-acetic acid ethyl ester (2.38g lOmmol) and triphenylphosphine (6.56g, 20mmol) dissolved in 15mL CCI4-DMF (1 :4). The mixture was stirred at room temperature. After the completion of the reaction by TLC, the mixture was extracted with 2 x 15mL pentane. The combined organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex/EtOAc = 4/1) to give ethyl (4-isopropenyl-phenoxy)-acetate (200mg, 10%). To a solution of ethyl (4- isopropenyl-phenoxy)-acetate in THF was added 1 N LiOH (1.5 mL) with vigorous stirring. The reaction was completed in 1 hr, and the pH of the reaction mixture was adjusted to pH 2~3 by adding 2N HCI. The aqueous phase was extracted with EtOAc, and the combined organic phase was dried over anhydrous MgSO ₄ and concentrated under reduced pressure to give (4- isopropenyl-phenoxy)-acetic acid (200mg).

¹ H NMR(300MHz, CDCI ₃ ): δ 7.42(d, 2H, J =8.7Hz), β.89(d, 2H, J =8.7Hz), 5.30(m, 1H), 5.02(m, 1 H), 4.70(s, 2H) ₁ 2.13(m, 3H)

Step 3: N-(3-Fluoro-4-methanesulfonylamino-benzyl)-2-(4-isopropenyl- phenoxy)-acetamide

A/-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide (270mg, 1.Ommol) was reacted with (4-isopropenyl-phenoxy)-acetic acid (200mg) to give title compound (215mg, 55%) after purification by column chromatography

(Hex/EtOAc = 1/1 ).

¹ H NMR(300MHz, DMSO-d ₆ ): δ 9.53(s, 1 H), 8.70(t, 1 H), 7.45(d, 2H, J =8.7Hz), 7.31 (t, 1 H), 7.08(m, 2H), 6.96(d, 2H, J =8.7Hz), 5.34(s, 1 H) ₁ 5.00(s, 1 H) ₁ 4.58(s, 2H), 4.32(d, 2H, J =6.3Hz), 2.99(s, 3H), 2.08(s, 3H) ESI [M+H] ⁺ ; 393.0.

Example 29: 2-(4-tert-Butyl-2-fIuoro-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide

N-(4-Aminomethyl-3-fluoro-phenyl)-methanesulfonamide HCI salt (131 mg, 0.515 mmol) and NMP (0.15 ml) were added in 10 ml THF. The mixture was stirred for 10 mins. DMTMM (135 mg, 0.487 mmol) and (4-tert-butyl-2-fluoro- phenoxy)-acetic acid (109 mg, 0.481 mmol) were added into the mixture. The reaction mixture was stirred overnight. The reaction solvent was removed in vacuo. The residue was extracted with methylene choride (30 ml x 3) and H ₂ O (30 ml). The combined organic layer was washed with sat'd NaHCO3 (30ml) and washed with brine (30 ml), dried with MgSO4, and concentrated in vacuo. The residue was purified with column chromatography to yield white solid (116 mg).

¹ H NMR (CDCI ₃ , 300 MHz) δ 7.52 (t, J = 8.4 Hz, 1 H), 7.20 (t, 1 H), 7.16 (dd, 1 H), 7.11 - 7.07 (m, 2H), 6.89 (t, J = 8.7, 1 H), 6.73 (br, 1 H), 4.58 (s, 2H), 4.52 (d, J = 6.3 Hz, 2H), 3.01 (s, 3H), 1.28 (s, 9H).

ESI [M+H] ⁺ : 427.0.

Example 30: 2-(4-tert-Butyl-2-chIoro-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide

N-(4-Aminomethyl-3-fluoro-phenyl)-methanesulfonamide HCI salt (127mg, 0.499) and NMP (0.15 ml) were added in 10 ml THF. The mixture was stirred for 10 mins. DMTMM (135 mg, 0.487 mmol) and (4-tert-butyl-2-chloro-phenoxy)- acetic acid (112 mg, 0.463 mmol) were added into the mixture. The reaction mixture was stirred overnight. The reaction solvent was removed in vacuo. The residue was extracted with methylene chloride (30 ml x 3) and H ₂ O (30 ml). The combined organic layer was washed with sat. NaHCOs (30ml) and washed with brine (30 ml), dried with MgSO ₄ , and concentrated in vacuo. The residue was purified with column chromatography to yield white solid (117 mg). ¹ H NMR (CDCI ₃ , 300 MHz) δ 7.51 (t, J = 8.4 Hz, 1 H), 7.39 (dd, 1 H), 7.29 (t, 1 H), 7.23 (dd, 1 H), 7.10 (d, J = 2.4 Hz, 2H), 7.07 (s, 1 H), 6.96 (br, 1 H), 6.85 (d, J = 7.2 Hz, 11-1)4.59 (s, 2H), 4.53 (d, J = 6.3 Hz, 2H), 3.01 (s, 3H), 1.28 (s, 9H). ESI [M+Hf: 442.9.

Example 31: 2-(2-Bromo-4-tert-butyI-phenoxy)-N-(3-fluoro-4- methanesulfonySamϊno-benzyl)-acetamide

Step 1 : 2-Bromo-4-tert-butyl-phenol

To a suspension of t-buthylphenol (7 g, 46.6 mmol) in CHCI ₃ (H ml) / CCI ₄ (11 ml) was slowly added bromine (8.2 g, 51.3 mmol) at 0 ⁰ C. The mixture was stirred for 6 hrs at room temperature. The reaction mixture was diluted with ether, then washed three times with 10% Na ₂ S ₂ Oa and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was distilled (10 torr, 120 - 130 ⁰ C) to yield 2-bromo-4-tert-butyl-phenol (8.5 g, 79.6%).

¹ H-NMR (300MHz, CDCI ₃ ): δ 7.44 (d, 1 H, J = 2.4 Hz), 7.23 (dd, 1 H, J = 8.4, 2.4 Hz), 6.95 (d, 1 H, J = 8.4 Hz), 5.36 (s, 1 H), 1.28 (s, 9H).

Step 2 : (2-Bromo-4-tert-butyl-phenoxy)-acetic acid ethyl ester To a suspension 2-bromo-4-tert-butyl-phenol (1900 mg, 8.29 mmol) and bromoethyl acetate (1662 mg, 9.95 mmol) in CH ₃ CN (20 ml) was added Cs ₂ CO ₃ (4.53 mg, 12.44 mmol). The mixture was stirred for overnight at room temperature. The reaction mixture was diluted with EtOAc and then washed three times with H ₂ Oand brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The obtained residue was column chromatographed to yield the (2~bromo-4-tert-butyl-phenoxy)-acetic acid ethyl ester (2.5 g, 96 %).

¹ H-NMR (300MHz, CDCI ₃ ): δ 7.55 (d, 1 H, J = 2.4 Hz), 7.23 (dd, 1 H, J = 8.4, 2.4 Hz), 4.67 (s, 2H), 4.26 (q, 2H ₁ J = 7.2 Hz), 1.27 (s, 9H).

Step 3: (2-Bromo-4-tert-butyl-phenoxy)-acetic acid

(2-Bromo-4-tert-butyl-phenoxy)-acetic acid ethyl ester (500 mg, 1.59 mmol) in THF was added a solution of 0.5 N-LiOH (3 ml) and the mixture was stirred for 1.5 hrs at room temperature. The resulting residue was dissolved in H ₂ O and then washed three times with Et ₂ O, acidified with 1 N HCI to pH 1-2. The solution was extracted three times with methylene chloride and then dried over anhyd. Na ₂ SO ₄ and concentrated in vacuo to give (2-bromo-4-tert-butyl- phenoxy)-acetic acid (417 mg, 91.5 %). ¹ H NMR (300 MHz ₁ CDCI ₃ ): δ 7.56 (d, 1H ₁ J = 2.1 Hz), 7.26 (dd, 1 H, J = 8.4, 2.4 Hz), 6.78 (d, 1 H ₁ J = 8.4 Hz) ₁ 4.72 (s, 2H), 1.28 (s, 9H).

Step 4: 2-(2-Bromo-4-tert-butyl-phenoxy)~N-(3-fluoro-4-methanesulfon ylamino- benzyl)-acetamide 3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (369mg, 1.44 mmol) was suspended in THF and treated with triethylamine (161.2 mg, 0.093 mmol), and then the resulting mixture was stirred for 10mins. (2-Bromo-4-tert- butyl-phenoxy)-acetic acid (417 mg, 1.44 mmol) was added to the reaction mixture followed by DMTMM (440.9 mg, 1.59 mmol) after 10 mins. The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, sat'd NaHCO ₃ (x3), 1 N HCI and brine, and then dried over anhyd. MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was column- chromatographed to yield title compound (487.3 mg, 59 %).

¹ H NMR (300 MHz, CDCI3): δ 7.56 (t, 1 H ₁ J = 3.0 Hz), 7.33 - 7.09 (m, 2H), 7.12 -7.10 (m, 2H), 6.83 (d, 1H ₁ J = 8.7 Hz), 6.53 (s, 1 H), 4.58 (s, 2H), 4.55 (s, 2H), 4.49 (d, 2H, J = 6.3 Hz ), 3.02 (s, 3H), 1.27 (s, 9H).

ESI [M+H] ⁺ : 486.9

Example 32: 2-(2-tert-Butyl-4-methyl-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide

N-(4-Aminomethyl-3-fluoro-phenyl)-methanesulfonamide HCI salt (133mg, 0.522) and NMP (0.2 ml) were added in 10 ml THF. The mixture was stirred for 10 mins. DMTMM (153 mg, 0.550 mmol) and (2-tert-butyl-4-methyl-phenoxy)- acetic acid (116 mg, 0.521 mmol) were added into the mixture. The reaction mixture was stirred overnight. The reaction solvent was removed in vacuo. The residue was extracted with methylene chloride (30 ml x 3) and H ₂ O (30 ml). A combined organic layer was washed with sat. NaHCOs (30ml) and washed with brine (30 ml), dried with MgSO ₄ , and concentrated in vacuo. The residue was purified with column chromatography to yield white solid (132 mg).

¹ H NMR (CDCI ₃ , 300 MHz) δ 7.51 (t, J = 8.1 Hz, 1 H), 7.39 (dd, 1 H), 7.29 (t, 1 H), 7.10 (d, J = 2.4 Hz, 1 H), 7.07 (d, J = 2.7 Hz, 2H), 7.04 (s, 1 H), 6.98 (m, 1 H), 6.93 (br, 1 H), 6.72 (d, J = 8.4 Hz, 1 H), 4.59 (s, 2H), 4.52 (d, J = 6.3 Hz ₁ 2H),

3.01 (s, 3H), 2.29 (s, 3H), 1.36 (s, 9H). ESI [M+H] ⁺ : 422.9.

Example 33: 2-(4-tert-Butyl-2-trifluoromethyl-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide

Step 1 : 4-tert-Butyl-2-trifluoromethyl-phenol

To a suspension of 2-trifluoromethyl-phenol in t-butylalcohol (480 mg, 6.47 mmol) and CF ₃ COOH (4 ml) was added H ₂ SO ₄ (80 ml). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with benzene and then washed three times with H ₂ O, sat'd NaHCO ₃ and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was column-chromatographed to yield 4-tert-butyl-2-trifluoromethyl-phenol (200 mg, 19 %). ¹ H NMR (300 MHz, CDCI3): δ 7.49 - 7.41 (m, 2H), 6.89 (d, 1 H ₁ J = 8.7 Hz), 5.51 (s, 1 H). 1.28 (s, 9H).

Step 2 : (4-tert-Butyl-2-trifluoromethyl-phenoxy)-acetic acid ethyl ester

To a suspension of 4-tert-Butyl-2-trifluoromethyl-phenol (1eq) and ethyl bromoacetate (1.2eq) in CH ₃ CN (1 ml) was added Cs ₂ CO ₃ (1.2 eq). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and then washed three times with H ₂ O and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to yield title compound (88 mg, 78 %)

¹ H NMR (300 MHz, CDCI3): δ 7.59 (d, 1 H ₁ J = 2.4 Hz), 7.46 (dd, 1 H, J = 8.7, 2.4 Hz) ₁ 6.80 (d, 1 H ₁ J = 8.7 Hz) ₁ 4.69 (s, 2H) ₁ 4.26 (q, 2H, J = 7.2 Hz), 1.35 - 1.22 (m, 12H). Step 3: 2-(4-tert-Butyl-2-trifluoromethyl-phenoxy)-N-(3-fluoro-4- methanesulfony!amino-benzyl)-acetamϊde

3-Fluoro-4-methanesulfonylaminobenzyIamine hydrochloride (33 mg, 0.126 mmol) was suspended in THF and treated with triethylamine (14 rng, 0.139 mmol) and then the resulting mixture was stirred for 10mins. (4-tert-Butyl-2- trifluoromethyl-phenoxy)-acetic acid (35 mg, 0.126 mmol) was added to the reaction mixture followed by DMTMM (38 mg, 0.139 mmol) after 10 mins. The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, sat'd NaHCO ₃ (x3), 1 N HCI and brine, and then dried over anhyd. MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was column- chromatographed to yield title compound (42 mg, 70 %).

¹ H NMR (300 MHz, CDCI3): δ 7.60 - 7.52 (m, 3H), 7.10 -7.07 (m, 3H), 6.91 (d, 1 H ₁ J = 9.0 Hz), 6.53 (s, 1 H), 4.61 (s, 2H), 4.53 (d, 2H, J = 6.3 Hz), 3.01 (s, 3H), 1.31 (s, 9H).

Example 34: 2-[4-(1,1-Difluoro-2-methyl-propyI)-phenoxy]-N-(3- fIuoro-4-methanesulfonylamino-benzyl)-acetamide

N-(3-Fluoro-4-methanesulfonylamino-benzyl)-2-[3-fluoro-4-(2- isopropyl- [1 ,3]dithiolan-2-yl)-phenoxy]-acetamide (81.5 mg, 0.163 mmol), NIS (84 mg, 0.373 mmol) and TBAH2 (176 mg, 0.583 mmol) were added in 10 ml CH ₂ CI ₂ at -78 ⁰ C. The mixture was stirred for 2 hrs. The reaction solvent was removed in vacuo. The residue was extracted with methylene chloride (30 ml x 3) and H ₂ O (30 ml). A combined organic layer was washed with sat. NaHCO ₃ (30ml) and washed with brine (30 ml), dried with MgSO ₄ , and concentrated in vacuo. The residue was purified with column chromatography to yield white solid (21 mg). ¹ H NMR (CDCI ₃ , 300 MHz) δ 7.46 (t, J = 8.4 Hz, 1 H), 7.34 (d, J = 8.7 Hz, 1 H), 7.04 (m, 1 H), 7.01 (s, 1 H), 6.92 - 6.87 (m, 2H), 6.60 (br, 1 H), 4.53 (s, 2H) ₁ 4.47 (d, J = 6.3 Hz, 2H), 2.96 (s, 3H), 2.45 (n, J = 6.7 Hz, 3H), 0.95 (s, 3H), 0.93 (s, 3H) ESI [M+H] ⁺ : 445.1.

Example 35: 2-(4-tert-Butyl-3-methyl-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide

Step 1 : (4-tert-Butyl-3-methyl-phenoxy)-acetic acid ethyl ester

To a suspension of 4-tert-butyl-3-methyl-phenol (1500 mg, 9.13 mmol) and bromoethyl acetate (2287 mg, 13.7 mmol) in CH ₃ CN was added Cs ₂ CO ₃ (4463 mg, 13.7 mmol). The mixture was stirred for overnight at room temperature. The

reaction mixture was diluted with EtOAc and then washed three times with H ₂ Oand brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The obtained residue was column-chromatographed to yield the (4- tert-butyl-3-methyl-phenoxy)-acetic acid ethyl ester (1.39 g, 60.7 %).

¹ H-NMR (300MHz, CDCI ₃ ): 5 7.18 (d, 1 H ₁ J = 8.1 Hz) ₁ 6.73 (d, 1 H, J = 8.4 Hz), 4.62 (s, 2H), 4.27 (q, 2H ₁ J = 7.2 Hz), 2.29 (s, 3H), 1.44 (s, 9H), 1.31 (t, 3H, J = 7.2 Hz).

Step 2 : (4-tert-Butyl-3-methyl-phenoxy)-acetic acid

(4-tert-Butyl-3-methyl-phenoxy)-acetic acid ethyl ester (200 mg, 0.79 mmol) in THF was added a solution of 0.5 N-LiOH (2eq) and the mixture was stirred for 1.5 hrs at room temperature. The resulting residue was dissolved in H ₂ O and then washed three times with Et ₂ O, acidified with 1 N HCI to pH 1-2. The solution was extracted three times with methylene chloride and then dried over anhyd. Na ₂ SO ₄ and concentrated in vacuo to give (4-tert-butyl-3-methyl- phenoxy)-acetic acid (150 mg, 84 %).

¹ H-NMR (300MHz, CDCI ₃ ): δ 7.19 (d, 1 H ₁ J = 8.1 Hz), 6.78 (d, 1 H ₁ J = 7.8 Hz), 6.57 (s, 2H), 2.60 (s, 3H), 1.40 (s, 9H).

Step 3 : 2-(4-tert-Butyl-3-methyl-phenoxy)-N-(3-fluoro-4-methanesulfo nylamino- benzyl)-acetamide 3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (68.7mg, 0.27

mmol) was suspended in THF and treated with triethylamine (27.3 mg, 0.27 mmol) and then the resulting mixture was stirred for 10mins. (4-tert-Butyl-3- methyl-phenoxy)-acetic acid (50 mg, 0.22 mmol) was added to the reaction mixture followed by DMTMM (74.7 mg, 0.27 mmol) after 10 mins. The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, sat'd NaHCOs (x3), 1 N HCI and brine, and then dried over anhyd. MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was column- chromatographed to yield title compound (74 mg, 78 %). ¹ H NMR (300 MHz, CDCI3): δ 7.57 (t, 1 H ₁ J = 8.7 Hz), 7.20 (d, 1 H ₁ J = 7.8 Hz), 7.07 (d, 1 H ₁ J = 3.0 Hz), 7.06 (s, 1 H), 6.87 (s, 1 H, br), 6.80 (d, 1 H, J = 7.2 Hz), 6.64 (s, 1 H), 6.48 (s, 1 H), 4.62 (s, 2H), 4.53 (d, 2H, J = 6.0 Hz), 3.02 (s, 3H), 2.30 (s, 3H), 1.36 (s, 9H). ESI [M+Hf: 422.9

Example 36: 2-(2-Bromo-4-tert-butyl-5-fluoro-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide

Step 1 : (2-Bromo-4-tert-butyl-5-fluoro-phenoxy)-acetic acid ethyl ester To a suspension of 2-bromo-4-tert-butyl~5-fluoro-phenol (424 mg, 1.716 mmol) and bromoethyl acetate (429 mg, 2.57 mmol) in CH ₃ CN was added C-S ₂ CO ₃ (838 mg, 2.57 mmol). The mixture was stirred for overnight at room temperature. The reaction mixture was diluted with EtOAc and then washed

three times with H ₂ O and brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The obtained residue was column-chromatographed to yield the (2-bromo-4-tert-butyl-5-fluoro-phenoxy)-acetic acid ethyl ester (527 mg, 92 %).

¹ H-NMR (300MHz, CDCI ₃ ): δ 7.44 (d, 1H, J = 8.4 Hz), 6.51 (d, 1 H, J = 13.2 Hz), 4.65 (s, 2H), 4.27 (q, 2H, J = 7.2 Hz), 1.39 - 1.28 (m, 12H).

Step 2: (2-Bromo-4-tert-butyl-5-fluoro-phenoxy)-acetic acid (2-Bromo-4-tert-butyl-5-fluoro-phenoxy)-acetic acid ethyl ester (120 mg, 0.36 mmol) in THF was added a solution of 0.5 N-LiOH (2 eq) and the mixture was stirred for 1.5 hrs at room temperature. The resulting residue was dissolved in H ₂ O and then washed three times with Et ₂ O, acidified with 1 N HCI to pH 1-2. . The solution was extracted three times with methylene chloride and then dried over anhyd. Na ₂ SO ₄ and concentrated in vacuo to give (2-bromo-4-tert-butyl-5- fluoro-phenoxy)-acetic acid (61 mg, 55 %).

¹ H-NMR (300MHz, CDCI ₃ ): δ 7.45 (d, 1H ₁ J = 8.4 Hz), 6.56 (d, 1 H, J = 13.2 Hz), 4.71 (s, 2H), 1.33 (S ₁ 9H).

Step 3: 2-(2-Bromo-4-tert~butyl-5-fluoro-phenoxy)-N-(3-fluoro-4- methanesulfonylarnino-benzyl)-acetamide

3-Fuoro-4-methanesulfonylaminobenzylamine hydrochloride (50.5mg, 1.44 mmol) was suspended in THF and treated with triethylamine (20 mg, 0.198

mmol) and then the resulting mixture was stirred for lOmins. (2-Bromo-4-tert- buty!-5-fluoro-phenoxy)-acetic acid (55 mg, 0.18 mmol) was added to the reaction mixture followed by DMTMM (54.8 mg, 0.198 mmol) after 10 mins. The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, sat'd NaHCO ₃ (x3), 1 N HCI and brine, and then dried over anhyd. MgSO ₄ , filtered, and concentrated under reduced pressure. The crude residue was column- chromatographed to yield title compound (60 mg, 66 %).

¹ H NMR (300 MHz, CDCI3): δ 7.54 (t, 1H, J = 8.4 Hz), 7.45 (d, 1 H, J = 8.7 Hz), 7.26 - 7.25 (m, 1 H), 7.13 (t, 1 H, J = 2.1 Hz), 7.10 (s, 1 H), 6.63 - 6.59 (m, 2H), 4.56 - 4.54 (m, 4H), 3.03 (s, 3H), 1.34 (s, 9H). ESI [M+H] ⁺ : 504.9

Example 37: 2-(4-tert-ButyI-2,6-difluoro-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide

Step 1 : (4-tert-Butyl-2,6-difluoro-phenoxy)-acetic acid ethyl ester

To a suspension of 4-tert-butyl-2,6-dif!uoro-phenol (300 mg, 1.61 mmol) and bromoethyl acetate (403 mg, 2.41 mmol) in CH ₃ CN was added Cs ₂ CO ₃ (787.4 mg, 2.41 mmol). The mixture was stirred for overnight at room temperature. The reaction mixture was diluted with EtOAc and then washed three times with H ₂ O and brine, dried over MgSO. ₄ , filtered, and concentrated under reduced pressure.

The obtained residue was column-chromatographed to yield the (4-tert-butyl- 2,6-difluoro-phenoxy)-acetic acid ethyl ester (301 mg, 68 %).

¹ H-NMR (300MHz, CDCI ₃ ): δ 6.90 (dd, 1H ₁ J = 9.6, 0.9 Hz), 4.71 (s, 2H), 4.25 (q, 2H, J = 7.2 Hz), 1.26 - 1.24 (m, 12H).

Step 2 : (4-tert-Butyl-2,6-difluoro-phenoxy)-acetic acid

(4-tert-Butyl-2,6-difluoro-phenoxy)-acetic acid ethyl ester (100 mg, 0.37 mmol) in THF was added a solution of 0.5 N-LiOH (2 eq) and the mixture was stirred for 1.5 hrs at room temperature. The resulting residue was dissolved in

H ₂ O and then washed three times with Et ₂ O ₁ acidified with 1 N HCI to pH 1~2.

The solution was extracted three times with methylene chloride and then dried over anhyd. Na ₂ SO ₄ and concentrated in vacuo to give (4-tert-butyl-2,6-difluoro- phenoxy)-acetic acid (82 mg, 91 %).

¹ H-NMR (300MHz, CDCI ₃ ): δ 6.92 (dd, 1 H, J = 8.7, 0.9 Hz), 4.77 (s, 2H), 1.27 (s,

9H).

Step 3 : 2-(4-tert-Butyl-2,6-difluoro-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide

3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (94 mg, 0.37 mmol) was suspended in THF and treated with triethylamine (37 mg, 0.369 mmol) and then the resulting mixture was stirred for 10mins. (4-tert-Butyl-2,6- difluoro-phenoxy)-acetic acid (82 mg, 0.335 mmol) was added to the reaction

mixture followed by DMTMM (102 mg, 0.396 mmol) after 10 mins. The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, sat'd NaHCO ₃ (x3), 1 N HCI and brine, and then dried over anhyd. MgSO ₄ , filtered, and concentrated under reduced pressure. The crude residue was column- chromatographed to yield title compound (111 mg, 75 %).

¹ H NMR (300 MHz, CDCI3): δ 7.53 (t, 1H, J = 8.7 Hz) ₁ 7.34 (s, 1H, br), 7.15 - 7.10 (m, 2H), 6.97 - 6.88 (m, 3H), 4.63 (s, 2H), 4.53 (d, 2H, J = 6.3 Hz), 3.02 (s, 3H), 1.24 (s, 9H).

ESI [M+H] ⁺ : 445.0

Example 38: 2-(4-tert-Butyl-3-fluoro-phenoxy)-N-(3-ethynyl-5-fluoro-4- methanesulfonylamino-benzyQ-acetamide

Step 1 : 4-t-Butyl-3-fIuorophenoI

3-Fluorophenol (1 g, 8.92 mmol) was added in the rounded flask (no solvent), to which was added aluminium chloride (0.4 eq) . 2-Ch!oro-2-methyl propane (1 eq) was added slowly by syringe pump. The reaction mixture was stirred for 1 hr. The reaction mixture was poured into ice and water mixture. An aqueous mixture was extracted with CH2CI2 (30 ml x 3). A combined organic layer was dried with MgSO4 and then concentrated in vacuo. The resulting residue was purified with column chromatography to yield white solid (87.4%)

¹ H NMR (CDCI ₃ , 300 MHz) δ 7.129 (t, 1H), 6.540 (dd, 1H), 4,786 (br, 1H), 1.227

((J ₁ 9H)

Step 2: (4-tert-Butyl-3-fluoro-phenoxy)-acetic acid

3-Fluoro-4-t-butyl-phenol (425 mg, 2.54 mmol) and sodium hydride (1.4 eq) were added in CH ₃ CN. After being stirred for 10 mins, 2-bromo ethylacetate was added. The reaction mixture was stirred for 2 hrs. The reaction mixture was quenched by adding 5 ml H2O. Solvent was removed in vacuo. The resulting residue was extracted with methylene chloride (40 ml x 2) and H2O (30 ml). A combined organic layer was washed with sat. NaHCO3 (30 ml x 2), brine (30ml), dried with MgSO4 and concentrated in vacuo to yield ethyl (4-tert-butyl-3-fluoro- phenoxy)-acetate.

¹ H NMR (CDCI ₃ , 300 MHz) δ 7.18 ( t, 1 H), 6.62 (m, 1 H), 6.58 (m, 1 H) ₁ 4.58 (s, 2H), 4.27 (q, J = 7.2 Hz, 2H), 1.34 (d, 9H), 1.28 (t, 3H)

Ethyl (4-tert-butyl-3-fluoro-phenoxy)-acetate was dissolved in 50 ml of MeOH, and6.5 ml of 1 M KOH solution was added thereto. The reaction mixture was stirred for 1.5 hrs. The solvent was removed in vacuo. The residue was neutralized with aqueous HCI solution. The aqueous solution was extracted with EA (30 ml x 3). A combined organic layer was dried with MgSO ₄ and then concentrated in vacuo to yield title compound quantitatively. ¹ H NMR (CDCI ₃ , 300 MHz) δ 9.95 (br, 1H), 7.21 ( dt, 1H), 6.63 (m, 1 H), 6.58 (m, 1 H) ₁ 4.65 (s, 2H), 1.34 (d, 9H)

Step 3: 2-(4-tert-Butyl-3-fluoro-phenoxy)-N-(3-ethynyl-5-fluoro-4- methanesulfony!amino-benzyl)-acetamide

N-(4-Aminomethyl-2-ethynyI-6-fluoro-phenyl)-methanesulfon amide HCI salt

(131 mg, 0.515 mmol) and NMP (0.15 ml) were added in 10 ml THF. The mixture was stirred for 10 mins. DMTMM (135 mg, 0.487 mmol) and (4-tert- butyl-3-fluoro-phenoxy)-acetic acid (0.481 mmol) were added into the mixture. The reaction mixture was stirred overnight. The reaction solvent was removed in vacuo. The residue was extracted with methylene chloride (30 ml x 3) and

H ₂ O (30 ml). A combined organic layer was washed with sat'd NaHCO3 (30ml) and washed with brine (30 ml), dried with MgSO4, and concentrated in vacuo.

The residue was purified with column chromatography to yield white solid (116.2 mg).

¹ H NMR (CDCI ₃ , 300 MHz) δ 7.20 (d, J = 8.7 Hz, 1 H), 7.10 (d, J = 10.8 Hz, 1 H), 6.95 (br, 1 H), 6.65 - 6.60 (m, 3H), 6.46 (m, 1 H), 4.53 (s, 2H), 4.49 (d, J = 9.0 Hz, 2H), 3.48 (s, 1H) ₁ 3.25 (s, 3H), 1.35 (d, 9H).

ESI [M+H] ⁺ ; 450.9.

Example 39: 2-(4-tert-Butyl-2-fluoro-phenoxy)-N-(3-ethynyl-5-fluoro- 4-methanesulfonylamino-benzyl)-acetamide

N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfon amide HCI salt (113 mg, 0.407 mmol) and NMP (0.1 ml) were added in 10 ml THF. The mixture was stirred for 10 mins. DMTMM (123 mg, 0.444 mmol) and (4-tert-butyl-2- f!uoro-phenoxy)-acetic acid (90.7 mg, 0.481 mmol) were added into the mixture.

The reaction mixture was stirred overnight. The reaction solvent was removed

in vacuo. The residue was extracted with methylene chloride (30 ml x 3) and H ₂ O (30 ml). A combined organic layer was washed with sat. NaHCO3 (30ml) and washed with brine (30 ml), dried with MgSO4, and concentrated in vacuo. The residue was purified with column chromatography to yield white solid (85 mg).

¹ H NMR (CDCI ₃ , 300 MHz) δ 7.20 (t, 1H), 7.15 (dd, 1H), 7.10 - 7.07 (m, 2H) ₁ 6.89 (t, J = 8.7, 1 H), 6.55 (br, 1 H), 4.58 (s, 2H), 4.49 (d, J = 6.3 Hz, 2H), 3.47 (s, 1H), 3.23 (s, 3H), 1.28 (s, 9H).

ESI [M+H] ⁺ : 451.0.

Example 40: 2-(4-fert-Butylphenoxy)-W-(3-fluoro-4-methanesulfonylamino-

5-trifluoromethyI benzyl) acetamide

Step 1 : 2-Fluoro-4-iodo-6-trifluoromethylphenylamine 2-Fluoro-6-trifluoromethylphenylamine (600.1 mg, 3.35mmol, 1.0eq) was dissolved in methylene chloride in a dried 25ml one-neck round bottom flask filled with argon.. To this solution was slowly added Iodine monochloride (1.1 eq, 3.68mmol, 598.2mg) and the resulting mixture was refluxed for 8 hours. After confirming the completion of the reaction, the reaction mixture was extracted with methylene chloride, washed with H2O and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained liquid was column chromatographed (n-Hexane/EtOAc=20/1) to yield a brown solid (821.2mg, 80.4%)

IR (NaCI neat, cm ^"1 ): 3343, 3256, 1748, 1616, 1500, 120; ¹ H NMR (400MHz, CDCI ₃ ) : δ 7.44(s, 1H), 7.35(d, J=10.0, 1H)

Step 2: 4-Amino-3-fluoro-5-trifluoromethylbenzonitrile

2-Fluoro-4-iodo-6-trifluoromethylphenylamine(821.2mg, 2.69mmol, 1.0eq) was dissolved in DMF in a dried 50ml two-neck round bottom flask filled with argon and. To this solution was added copper(I) cyanide (1.5eq, 4.04mmol, 365.7mg) and the resulting mixture was refluxed at 100 ⁰ C for overnight. After confirming the completion of the reaction with TLC, the reaction mixture was extracted with EtOAc, washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained liquid was column chromatographed (n-Hexane/EtOAc=5/1 ) to yield a pale brown solid(301.0mg, 54.8%)

Melting point: 101.3-102.1 ⁰ C; IR(NaCI Neat, cm ^"1 ) : 3380, 2229, 1574 ; ¹ H NMR (400MHz, CDCI ₃ ) : δ 7.52(s, 1H), 7.36(dd, J=10.4, 1.6Hz ₁ 1 H)

Step 3: (4-Amino-3-fluoro-5 -trifluoromethylbenzyl)-carbamic acid terf-butylester Lithum aluminumhydride (465.72mg, 12.27mmol, 3eq) was suspended in THF at a two-neck round bottom flask. To this suspension was added slowly 4- amino-3-fluoro-5-trifluorobenzonitrile (204.12mg, 2.45mmol, 1 eq) and refluxed at 7O ⁰ C for one hour. After confirming the completion of the reaction with TLC, to this reaction mixture were added 0.8ml H2O and 0.4ml 5N NaOH, and the

resulting mixture was stirred for 30 minutes. And to this solution was added K ₂ CO ₃ , and the reaction mixture was extracted with THF, filtered through celite, concentrated under reduced pressure to give a yellow 4-aminomethyl-2-fluoro- 6-trifluorophenyIamine (208.2mg). 4-AminomethyI-2-fluoro-6-trifluorophenylamine (208.2mg, 1.37mmol, 1.0eq) was dissolved in THF in a dried 50ml two-neck round bottom flask filled with argon . To this solution was slowly added di-terf-butyldicarbonate (346.12μ£, 1.51 mmol, 1.1eq) and stirred at room temperature for 3 hours. After confirming the completion of the reaction with TLC, the reaction mixture was extracted with EtOAc, washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained liquid was column chromatographed (n-Hexane/EtOAc=3/1 ) to yield a yellow syrup (293.2mg, 81.8%).

IR (NaCI Neat, cm ^" ) :3362, 2977, 1698 ; ¹ H NMR (400MHz, CDCI ₃ ) : δ 7.28(d, JM 1.2Hz, 1 H), 6.68(s, 1 H), 4.70(s, 1 H), 4.07(s, 3H), 1.38(s,9H)

Step 4: (3-Fluoro-4-methanesulfonylamino-5-trifluoromethylbenzyl) carbamic acid tert-butyl ester. (4-Amino-3-fluoro-5-trifluoromethylbenzyl)carbamic acid ferf-butyl ester (293.2mg, LUmmol, 1.0eq)was dissolved in pyridine in a dried 50ml two-neck round bottom flask filled with argon. And the mixture was cooled with ice and were added methanesulfonyl chloride (429.4//1, 5.55mmol, 5.0eq) and triethlyamine(270.1/^, 3.33mmol, 3.0eq) stepwise and stirred overnight at

ambient temperature. After confirming the completion of the reaction with TLC, to the reaction mixture was added NaHCO ₃ solution and stirred for 1 hour. The mixture was extracted with methylene chloride and washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained substance was dissolved in THF/H ₂ O = 2/1 solution, and 5% NaOH solution was added, and then the resulting mixture was stirred at room temperature for 8 hours. After confirming the completion of the reaction with TLC, the mixture was concentrated in vacuo, acidified with 5% HCI solution to pH 7.0 and extracted with methylene chloride. The organic layer was washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained substance was column chromatographed (n- Hexane/EtOAc=3/1 ) to yield a yellow syrup (141.9mg, 41.4%). Melting point: 67.1~67.3°C; IR (NaCI Neat, cm ^"1 ) : 3389, 3021 , 1695 ; ¹ H NMR (400MHz, CDCI ₃ ) : δ 6.92(m, 1H), 6.87(d, J=10.0Hz 1 H), 4.83(m, 1H), 4.21 (s, 2H), 2.38(S ₁ 3H), 1.39(s, 9H)

Step 5: λ/-(4-Ethyl-2-fluoro-6-trifluoromethylphenyl)methansylfonam ide To a solution of (3-fluoro-4-methanesulfonylamino-5- trifluoromethy!benzy])carbamic acid fe/f-butylester (143.6mg, 0.47mmol, 1eq) in methylene chloride was added 1.0ml trifluoroacetic acid. The resulting solution was stirred for 8 hours. After confirming the completion of the reaction, to the reaction was added toluene. The resulting mixture was stirred for 10 minutes, and concentrated under reduced pressure to give a brown syrup (222.2mg, 100.9%).

IR (NaCI Neat, cm ^"1 ): 3189, 3001 , 1575 ; ¹ H NMR (400MHz, CDCI ₃ ) : δ 7.12(s, 2H) ₁ 7.07(s, 2H) ₁ 4.00(s, 2H), 2.97(s, 3H)

Step 6: 2-(4~fe/t-Butylphenoxy)-/V-(3-fluoro-4-methanesuifonylamino- 5- trifluoromethyl benzyl) acetamide

To a solution of λ/-(4-ethyl-2-fluoro-6-trifluoromethylphenyl) (50mg, 0.12mmol, 1eq). dissolved in DMF were added (4-tert-butylphenoxy)acetate (28.62mg, 0.14mmol, 1.1eq), triethylamine(83.5/^, O.θOmmol, 5eq), and diethylcyanophosphonate (21.8μl, 0.14mmol, 1.2eq) stepwise and the resulting mixture was stirred at room temperature for 12 hours. After confirming the completion of the reaction, the mixture was extracted with EtOAc and washed with H2O and brine, dried over Na2SO ₄ , filtered and concentrated under reduced pressure. The obtained substance was column chromatographed (n- Hexane/EtOAc=3/1) to yield a white solid (10.1 mg, 17.8%). IR(NaCI Neat, cm-):3350~3029,2368, 1667 ; ¹ H NMR (400MHz, CDCI ₃ ) : δ 7.26(s, J=7.6Hz, 2H), 6.90(d, J=8.4Hz, 1 H), 6.83(d, J=10.4Hz 1H), 6.79(d, J=8.0Hz, 2H), 4.483(s, 2H), 4.42(d, , J=6.4Hz 2H), 2.99(s, 3H), 1.22(s, 9H)

Example 41 : 2-(4-tert-Butyl-phenylsulfanyl)-2,2-difIuoro-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide

step 1 : ethyl 2-[4-(fert-butyl)phenoxy]-2,2-difIuoroacetate

A 25 ml two-neck round bottom flask was filled with argon gas and the

solution of NaH (60% in mineral oil, 106.5 mg, 2.66 mmol, 2.0eq.) in

tetrahydrofuran (10 ml) was put into the flask and then cooled to 0 "C. To the

solution were added 4-f-buthylphenol (200 mg, 1.33 mmol, 1.0eg.),

tetrabuthylammonium iodide (98. 4 mg, 0.27 mmol, 0.2 eg) and ethyl

bromodifluoroacetate (223 μl, 1.73 mmol, 1.3 eq). The reaction mixture was

heated to 40 ^° C for 12 hrs. After confirming the completion of the reaction with

TLC, the reaction solution was quenched by aq. NH ₄ CI, extracted with

ethylether, washed with water and brine, dried over anhydrous magnesium

sulfate and evaporated. The obtained solid was column-chromatographed (n-

hexane /ethyl acetate = 5/1) to yield a yellow liquid. (127 mg, 35%)

¹ H NMR (300 MHz, CDCI ₃ ): δ 7.35 (d, 2H, J = 9.0 Hz), 7.12 (d, 2H, J = 9.0 Hz),

4.36 (q, 2H, J = 7.1 Hz), 1.34 (t , 3H, J = 7.1 Hz), 1.29 (s, 9H)

step 2 : . 2-[4-(terf-butyI)phenoxy]-2,2-difluoroacetic acid

Ethyl 2-[4-(fe/f-butyl)phenoxy]-2,2-difluoroacetate (127 mg, 0.47 mmol,

1.0eg.) and LiOH (23.4 mg, 0.56 mmol, 1.2 eq) were diluted with THF/H ₂ O (1 : 1 ,

5 mL), and then stirred for 4 hrs at 35 ^° C. The mixture was acidified with 1λ/ HCI,

concentrated under reduced pressure, and diluted with and water. The

organic layer was washed with brine, dried over anhydrous magnesium sulfate,

filtered, and concentrated under reduced pressure to yield the crude title

compound as a white solid (98 mg, 85%).

step 3 : 2-[4-(fe/t-butyl)phenoxy3-2,2-difIuoro-λ/-3-fluoro-4-

[(methylsulfonyl)amino]benzylacetamide

To solution of 2-[4-(te/t-butyl)phenoxy]-2,2-difluoroacetic acid (98 mg,

0.40 mmol, 1.0 eg.) in THF were added DMTMM (221 mg, 0.80 mmol, 2.0 eq)

and NMM (44 μl, 0.40 mmol, 1.0 eq.). The reaction mixture was stirred at room

temperature for 12 hrs. The resulting solution was cooled to 0 ^° C and the

solution of λ/-[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide (122mg,

0.48 mmol, 1.2 eg.) in THF was added. The mixture solution was stirred at room

temperature overnight. After confirming the completion of the reaction with TLC,

the reaction solvent was removed under reduced pressure. The liquid was

column-chromatographed (n-hexane /ethyl acetate = 1/1 (methylene chloride/

methyl alcohol = 20/1 )) to yield a white solid (102 mg, 58%).

Mass (FAB) 445 [M+H]+

¹ H NMR (300 MHz, CDCI ₃ ): δ 7.53 (t, 1 H ₁ J = 8.4 Hz), 7.35 (d, 2H, J = 8.8 Hz),

7.06 ~ 7.12 (m, 4H), 6.87 (bs, 1 H), 6.55 (bs, 1 H), 4.50 (d, 2H, J = 6.1 Hz), 3.01

(s, 3H), 1.29 (s, 9H)

Example 42: λ/-(3-fluoro-4-methylsulfonylamϊno-benzyI)-2-[4-(1- methylcyclopropyl)phenoxy]acetamide

step 1 : 1-[4-(methoxymethoxy)phenyl]-1-ethanone

1-(4-hydroxyphenyl)-1-ethanone (500 mg, 3.67mmol), MOMCI (444 mg, 5.51 mmol, 1.5eq) and /-Pr ₂ NEt (712 mg, 5.51 mmol, 1.5 eq) were added CH ₂ CI ₂ (10 ml) at 0 ^° C . A reaction mixture was heated to r.t, and stirred for 1hr. A diluted solution was washed with H ₂ O (2 times) and brine, and then dried with MgSO ₄ . A residue was purified with column chromatography (n-Hexane: EtOAc =5 : 1 ) to yield solid (615 mg, 93%).

¹ H NMR (300MHz, CDCI ₃ ): δ 7.90(d, 2H, J = 9.0 Hz), 7.04(d, 2H, J = 9.0 Hz), 5.20 ( s, 2H), 3.45 ( s, 3H) ₁ 2.53 (s,3H)

step 2: 1~isopropenyl-4-(methoxymethoxy)benzene

A 50 ml round bottom flask was filled with argon gas and the solution of

CH ₃ PPh ₃ Br (892 mg, 2.51 mmol, 1.5 eg.) in tetrahydrofuran was put into the flask and then cooled to O ⁰ C. To the solution was added n-BuLi (1.6 M solution in THF, 1.35 ml, 2.17 mmol, 1.3eq.). After the reaction mixture was stirred for 2hrs at same temperature, a solution of 1-[4-(methoxymethoxy)phenyl]-1- ethanone (300 mg, 1.67 mmol) in tetrahydrofuran was added. The temperature of the reaction mixture was raised to room temperature. After confirming the completion of the reaction with TLC, the solution was quenched by aq. NH ₄ CI and stirred for 20 minutes. The resulting solution was concentrated, extracted with ethyl acetate, washed with brine and dried over MgSO ₄ . A residue was purified with column chromatography (n-Hexane: EtOAc =5 : 1 ) to yield colorless oil (222 mg, 75%).

¹ H-NMR (300MHz, CDCI ₃ ): δ 7.39 (d, 2H ₁ J = 8.8 Hz), 6.98 (d, 2H, J = 8.8 Hz) ₁ 5.28 ( s, 1H), 5.17 ( s, 2H), 4.99 ( t, 1 H, J = 1.5 Hz), 3.47 (s, 3H), 2.11 (s, 3H)

step 3: 1-(methoxymethoxy)-4-(1-methylcyclopropyl)benzene

To solution of 1-isopropenyl-4-(methoxymethoxy)benzene (100 mg, 0.561 mmol, leg.) in toluene were added CH ₂ I2 ( -45 ml, 5.61 mmol, 10eq) and Et ₂ Zn (1.0M solution in THF, 5.61 ml, 5.61 mmol, 10eg.) at 0 ⁰ C. The temperature of the reaction mixture was raised to room temperature. After confirming the completion of the reaction with TLC, the reaction mixture was quenched by aq. NH ₄ CI and stirred for 20 minutes. The resulting solution was concentrated, extracted with ethyl acetate, washed with brine and dried over MgSO ₄ . The obtained liquid was concentrated under reduced pressure to yield a pale yellow oil (101 mg, 94%).

¹ H NMR(300MHz, CDCI ₃ ) : <5 7.25 ( d, 2H ₁ J=8.8 Hz), 7.02 ( d, 2H, J=8.8 Hz ), 5.22 ( s, 3H ), 3.54 ( s, 3H ), 1.44( s, 3H ), 0.85~0.89( m, 2H) ₁ 0.73-0.76 ( m, 2H)

step 4 : ethyl 2-[4-(1-methylcyclopropyl)phenoxy]acetate

A 25 ml round bottom flask was filled with argon gas and the solution of 1-(methoxymethoxy)-4-(1-methylcyclopropyl)benzene (100 mg, 0.52 mmol, 1 eg.) and cone. HCI (33.6 μl, 1.56 mmol, 3eq.) in methylalcohol were put into the flask and then cooled to 0 ^° C . The mixture was stirred for 5 hours. After confirming the completion of the reaction with TLC, the mixture was concentrated under reduced pressure to yield a white solid (76 mg, 99%). ¹ H NMR (300 MHz, CDCI ₃ ): δ 7.12 ( d, 2H, J= 8.4Hz), 6.72 ( d, 2H, J=8.6 Hz), 4.52 ( s, 1 H), 1.34 ( s, 3H), 0.75-0.78 ( m, 2H), 0.63-0.66 ( m, 2H)

A 25 ml two-neck round bottom flask was filled with argon gas and the solution of NaH (60% in mineral oil, 31 mg, 0.77 mmol, 1.5eg.) in tetrahydrofuran (4ml) was put into the flask and then cooled to 0 ⁰ C. To the solution was added 1-hydroxy-4-(1-rnethylcyclopropyl)benzene (75.6 mg, 0.51 mmol, 1.0eg.) in tetrahydrofuran and heated to reflux for 1 hr. After confirming the completion of the reaction with TLC, the reaction solution was quenched by aq. NH ₄ CI, extracted with ethylacetate, washed with water and brine, dried over MgSO ₄ and evaporated. The obtained solid was column-chromatographed (n- hexane /ethyl acetate = 3/1) to yield a yellow liquid. (66 mg, 59%) ¹ H NMR (300 MHz, CDCI ₃ ): δ 7.25 (d, 2H, J= 8.8Hz), 6.89 ( d, 2H, J= 8.8Hz), 4.68 ( s, 2H), 1.44 ( s, 3H), 0.85-0.88 ( m, 2H), 0.73-0.76 ( m, 2H)

step 5 : 2-[4-(1-methylcyclopropyl)phenoxyJacetic acid A ethyl 2-[4-(1-methylcyclopropyl)phenoxy]acetate (60 mg, 0.27 mmol, LOeqr.) and LiOH (14 mg, 0.32 mmol, 1.2 eq) were diluted with THF/H2O (1 : 1 , 2 mL), and then stirred for 3 hours at room temperature. The mixture was acidified with 1 N HCI, concentrated under reduced pressure, and diluted with CH ₂ CI ₂ and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to yield the crude title compound as a white solid. ( 51.4 mg, 92%)

step 6 : /V-(3-fluoro-4-methylsulfonylaminobenzyl)-2-[4-(1- methylcyclopropyl)phenoxy]acetamide

To solution of 2-[4-(1-methylcyclopropyl)phenoxy]acetic acid (51.4 mg,

0.25mmol, 1.0 eq.) in THF were added DMTMM (138 mg, 0.50mmol, 2.0 eq) and NMM (27. O≠, 0.25 mmol, 1.0 eq.). The reaction mixture was stirred at room temperature for 12 hours. The resulting solution was cooled to 0 ^° C and the solution of λ/-[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide (76.2mg, 0.30 mmol, 12eq.) in THF was added into the mixture. The mixture solution was stirred at room temperature for one night. After confirming the completion of the reaction with TLC, the reaction mixture was removed under reduced pressure. The liquid was column-chromatographed (n-hexane /ethyl acetate = 1/1 (only ethylacetate)) to yield a white solid (53mg, 52%).

Mass (FAB) 407 [M+H]+

IR(KBr pellet, cnT ¹ ) : 2954, 1667, 1586, 1514, 1469, 1365, 1310, 1155, 971 , 817, 756

¹ H NMR(300MHz, CDCI ₃ ) : δ 7.55( t, 1 H, J= 8.2 Hz), 7.25 ( d, 2H, J=8.8 Hz), 7.07-7.13 (m ,3H), 6.88 ( d, 2H, J= 8.8Hz), 6.82 (bs, 1 H), 4.59( s, 2H), 4.55 ( d, 2H, J= 6.2Hz), 3.06 ( s, 3H), 1.44( s, 3H), 0.81~0.86( m, 2H), 0.73-0.78 ( m, 2H)

Example 43: 2-[4-(fert-butyl)phenoxy]-/V-(3-cyano-5-fluoro-4- methylsulfonylaminobenzyl)-thioacetamide

step 1 : 4-amino-3-fluorobenzenecarbonitrile

2-Fluoro-2-iodoaniline (2.Og, 8.4mmol) and coppercyanide(982mg, H .Ommol, 1.5eq) were added to DMF(30ml). A reaction mixture was heated to 13O ⁰ C, stirred for 8hrs. The reaction mixture was diluted with ethyl acetate. A diluted solution was washed with H ₂ O (2 times) and brine, and then dried with MgSO ₄ . A residue was purified with column chromatography (n-Hexane: EtOAc =3 : 1) to yield solid (914mg, 84%). ¹ H NMR(300MHz, CDCI ₃ ): 7.21-7.26 (m, 2H), 6.74 (t, 1 H, J = 8.3 Hz), 4.20 (bs, 2H)

step 2: 4-amino-3-fluoro-5-iodobenzenecarbonitrile

4-amino-3-fluorobenzenecarbonitrile (4.06g, 29.9mmol) and ICI (1.0M in methylene chloride, 40.0 ml, 40.0mmol) were added to methylene chloride (100ml). A reaction mixture was stirred for 20hrs. A reaction was quenched by adding sodium thiosulfate solution. An aqueous solution was extracted with MC. A combined organic solution was washed with H ₂ O and brine, dried with Na ₂ SOz _J , concentrated in vacuo. The residue was purified with column chromatography (n-Hexane: EtOAc = 5: 1) to yield solid (4.8Og, 91%). ¹ H-NMR (300MHz, CDCI ₃ ): 57.69 (t, 1 H ₁ J = 1.5 Hz), 7.23 (dd, 1 H, J = 10.0, 1.7 Hz), 4.68 (bs, 2H)

step 3 : 4-aminomethyl-2-fluoro-6-iodophenylamine To solution of 4-amino-3-fluoro-5-iodo-benzonitrile (84.4 mg, 0.322mmol, l eg.) in tetrahydrofuran was added Borane-THF complex solution (1.0M solution in THF, 0.64ml, 0.644mmol, 2eg.) at 0 ⁰ C. The temperature of reaction mixture was raised to room temperature, heated, and refluxed. After confirming the completion of the reaction with TLC, 5% HCI solution was added into the reaction mixture. The mixture was stirred for 20 minutes. The resulting solution was basified using 1 N KOH, extracted with ether, washed with brine and dried over Na ₂ SO ₄ . The obtained liquid was concentrated under reduced pressure to yield a pale yellow solid (78.4mg, 80.5%).

¹ H NMR(400MHz, CD ₃ OD) : 7.33( s, 1H), 6.93( dd, 1 H, J=11.6, 2.0Hz) ₁ 3.58( s, 2H),

step 4 : (4-amino-3-fluoro-5-iodobenzyl)carbamic acid t-butyl ester

A 25 ml two-neck round bottom flask was filled with argon gas and the solution of 4-aminomethyl-2-fluoro-6-iodophenylamine (31.9mg, 0.120mmol, 1 eg.) and triethylamine (18.4/^, 0.132mmol, 1.1 eg.) in methylenechloride were put into the flask and then cooled to 0 ^° C. To the solution were added 4- dimethylaminopyridine (1.47mg, 0.012mmol, 0.1 eg.) and di-t-butyl dicarbonate (27.6μi, 0.120mmol, leg.). The reaction mixture was stirred for 5 hours. After confirming the completion of the reaction with TLC, the reaction mixture was extracted with methylenechloride, washed with water and brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The obtained liquid was column-chromatographed (n-hexane /ethyl acetate = 5/1) to yield a yellow liquid (9.8mg, 22.3%).

¹ H NMR (400 MHz, CDCI ₃ ): 7.87( s, 0.2H), 7.44( d, 0.2H, J=11.2Hz), 7.26( s, 1 H), 6.87( d, 1 H, J=11.2Hz) ₁ 4.72( bs, 2H), 4.08( d, 2H, J=4.4Hz), 1.39( s, 9H)

step 5 : (3-fluoro-5-iodo-4-methanesulfonylamino)carbamic acid t-butyl ester

(4-Amino-3-fluoro-5-iodobenzyl)carbamic acid t-butyl ester (5.8g, 17.2mmol, leg.) and pyridine (1.65ml, 20.6mmol, 1.2eg.) were added into methylene chloride (70ml). The reaction mixture was cooled down 0 ⁰ C . To the solution was added methanesulfonyl chloride (1.73ml, 22.4mmol, 1.3eg.) and heated to reflux for one night. After confirming the completion of the reaction with TLC, the reaction solution was acidified by 10% HCI, extracted with ethylacetate, washed with water and brine, dried over MgSO ₄ and evaporated. The obtained solid was column-chromatographed (n-hexane /ethyl acetate =

2/1) to yield a yellow liquid. (5.55g, 73%)

¹ H-NMR (300MHz, CDCI ₃ ) : δ 7.56 (s, 1 H), 7.08(d, 1 H, J = 10.0 Hz), 6.12 (s,

1 H), 4.92 (bs, 1 H), 4.24 (d, 2H, J = 5.9 Hz), 3.23 (s, 3H), 1.44 (s, 9H)

step 6 : (3-cyano-5-fluoro-4-methanesulfonylamino)carbamic acid t-butyl ester

(3-fluoro-5-iodo-4-methanesulfonylamino)carbamic acid t-butyl ester

( 156mg,

0.35mmol) and copper cyanide(36mg, 0.42mmol, 1.2eq) were added to DMF(3ml). A reaction mixture was heated to 130 ^° C and stirred for 3hrs. The reaction mixture was diluted with ethyl acetate. A diluted solution was washed with H ₂ O (2 times) and brine, and then dried with MgSO ₄ . A residue was purified with column chromatography (n-Hexane: EtOAc =3 : 1) to yield solid (42mg,

35%). ¹ H-NMR(300MHz, CDCI ₃ ) : 5 7.34-7.40 ( m, 2H), 6.48( s, 1 H), 5.01 (bs, 1 H),

4.31 (d, 2H, J = 6.4 Hz ), 3.28 (s, 3H), 1.44 (s, 9H)

step 7 : N-(4-aminomethyl-2-cyano-6-fluorophenyl)methanesulfonamide (3-cyano-5-fluoro-4-methanesulfonylamino)carbamic acid t-butyl ester (30mg, 0.12mmol) was put into 25ml round-bottom flask and dissolved in methylenechloride(3ml). To the solution was added trifluoroacetic acid (0.5ml) and stirred for one night. After confirming the completion of the reaction with TLC, the reaction solution was concentrated under reduced pressure to yield a brown crude liquid (crude 100%).

step 8 : 2-[4-(te/f-butyl)phenoxy]-λ/-(3-cyano-5-fluoro-4-methylsulf onyl aminobenzyl)acetamide

To solution of 2-[4-(fe/f-butyl)phenoxy]acetic acid (33mg, 0.16mmol, 1.2 eg.) in

THF were added DMTMM (86mg, 0.31 mmol, 2.4 eg) and NMM (20.0/λ,, 0.18mmol, 1.4 eq.). The reaction mixture was stirred at room temperature for 12 hours. The resulting solution was cooled to 0 ⁰ C . The solution of 3-cyano-5- fluoro-4-methanesulfonylamino-ammonium,and trifluoroacetate (32mg,

0.13mmol, l eg.) in THF were added. The mixture solution was stirred at room temperature for one night. After confirming the completion of the reaction with TLC, methylenechloride was removed under reduced pressure. The residue was column-chromatographed (n-hexane /ethyl acetate = 1/1 (only ethylacetate)) to yield a white solid (37mg, 66%).

Mass (FAB): 434 [M+H]+

IR (KBr pellet, cm ^"1 ) : 3433, 2960, 1655, 1548, 1513, 1434, 1333, 1246 ; ¹ H NMR (300MHz, CDCI ₃ ) : 7.40( s, 1 H), 7.32~7.36( m, 3H), 7.089( bs, 1 H),

6.85(d, 2H, J=9.0Hz), 6.41 ( s, 1 H) ₁ 4.56( s, 2H), 4.53( d, 2H, J=6.2Hz), 3.29( s,

3H), 1.28( s, 9H)

step 9 : 2-[4-(te/f-butyl)phenoxy]-λ/-(3-cyano-5-fluoro-4- methylsulfonylaminobenzyl)-thioacetamide

2-[4-(fe/f-butyl)phenoxy]-/V-(3-cyano-5-fluoro-4- methylsulfonylaminobenzyl)acetamide (25mg, 0.058mmol) and Lawesson's reagent (47mg, 0.12mmol) were put into toluene (2ml). The reaction mixture was refluxed, stirred for 5 hrs, and then cooled to room temperature. The

reaction mixture was diluted with ethyl acetate. A diluted solution was washed with H ₂ O (2 times) and brine, and then dried with MgSO ₄ . A residue was purified with column chromatography (n-Hexane: EtOAc =2 : 1) to yield solid (16mg, 61 %). Mass (FAB) 450 [M+H]+

IR (KBr pellet, crrf ¹ ) : 3305, 2960, 1740, 1514, 1450, 1335, 1236, 1157, 1034, 972, 831 , 762; ¹ H NMR(300MHz, CDCI ₃ ) : 8.73(bs, 1 H), 7.31~7.40(m, 4H), 6.84(d, 2H, J=8.4Hz) 6.75( bs, 1 H), 4.98( d, 2H, J=6.6Hz), 4.93( s, 2H) 3.28( s, 3H) ₁ 1.28( S ₁ 9H)

Example 44: N-(3-Ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-2-[3- fIuoro-4-(2-methyl-[1,3]dithiolan-2-yl)-phenoxy]-acetamide

Step 1 : Ethyl 4-acetyl-3-fluoro-phenoxy acetate 3-F!uoro-4-acetyl-phenol (797.7 mg, 5.17 mmol), ethyl bromoacetate (0.61 ml, 5.5 mmol) and cesium carbonate (1.667 g, 5.12 mmol) were added in 70 ml of acetonitrile. The reaction mixture was stirred overnight. The reaction solvent was removed in vacuo. The residue was washed saturated with NaHCO ₃ and brine. The residue was dried and then concentrated in vacuo. ¹ H NMR (CDCI ₃ , 300 MHz) δ 7.85 (t, J = 8.4 Hz, 1 H), 6.68 (d, 1 H), 6.56 (d, 1 H), 4.62 (s, 2H), 4.23 (q, 2H), 2.55 (d, 3H), 1.23 (t, 3H).

Step 2: [3-Fluoro-4-(2-methyl-[1 ,3]dithiolan-2-yI)-phenoxy]-acetic acid ethyl ester

Ethyl 4-acetyl-3-fluoro-phenoxy acetate (917.6 mg, 3.82 mmol), ethyldithiol

(0.37 ml, 4.3 mmol) and boron trifluoride dietherate (0.65 ml, 5.1 mmol) were added to 40 ml of CH ₂ Cb- The reaction mixture was stirred overnight at room temperature. The reaction solvent was removed in vacuo. The residue was purified with column chromatography to yield title compound (797.3 mg)

¹ H NMR (CDCI ₃ , 300 MHz) δ 7.69 (t, J = 6.6 Hz, 1 H), 6.62- 6.53 (m, 2H), 4.54 (s, 2H), 4.24 (q, 2H), 3.36 (m, 2H), 3.20 (m, 2H), 2.09 (d, 3H), 1.24 (t, 3H).

Step 3: [3-Fluoro-4-(2-methyl-[1 ,3]dithiolan-2-yI)-phenoxy]-acetic acid [3-Fluoro-4-(2-methyl-[1 ,3]dithiolan-2-yl)-phenoxy]-acetic acid ethyl ester (790 mg) and aqueous 1 M KOH solution (5 ml, 5 mmOI) were added in 50 ml of methanol. The reaction mixtue was stirred for 1.5 hrs. The reaction solvent was removed in vacuo. The residue was neutralized with 1 N HCI solution. An aqueous solution was extracted with EtOAc (30 ml x 3). The combined organic layer was dried with MgSO ₄ .

¹ H NMR (CDCI ₃ , 300 MHz) δ 7.68 (t, J = 6.6 Hz, 1 H), 6.69- 6.58 (m, 2H) ₁ 4.68 (s, 2H), 3.41 (m, 2H), 3.26 (m, 2H), 2.14 (s, 3H)

Step 4: N-(3-Ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-2-[3-fl uoro-4-(2- methyl-[1 ,3]dithiolan-2-yl)-phenoxy]-acetamide

N-(4-Aminomethyl-2-ethynyI-6-fluoro-phenyl)-methanesulfon amide HCI salt (205 mg, 0.407 mmol) and NMP (0.3 ml) were added in 10 ml THF. The mixture was stirred for 10 mins. DMTMM (213 mg) and [3-fluoro-4-(2-methyl- [1 ,3]dithiolan-2-yl)-phenoxy]-acetic acid (202 mg, 0.700 mmol) were added into

the mixture. The reaction mixture was stirred overnight. The reaction solvent was removed in vacuo. The residue was extracted with MC (30 ml x 3) and H ₂ O (30 ml). A combined organic layer was washed with sat. NaHCθ ₃ (30ml) and washed with brine (30 ml), dried with MgSO ₄ , and concentrated in vacuo. The residue was purified with column chromatography to yield white solid (154.5 mg).

¹ H NMR (CDCI ₃ , 300 MHz) δ 7.79 (t, J = 9.0 Hz, 1H), 7.25 (s, 1 H), 7.11 (dd, 1 H), 7.00 (t, 1 H), 6.70 (d, 1 H), 6.65-6.58 (m, 2H), 4.53 (s, 2H), 4.48 (d, J = 6.3 Hz, 2H), 3.48, (s, 1 H), 3.43 (m, 2H), 3.28 (m, 2H), 3.23 (s, 3H), 2.14 (s, 3H) ESI [M+H] ⁺ : 513.0.

Example 45: N-(3-Fluoro-4-methanesulfonyIamino-benzyl)-2-[3- fluoro-4-(2-methyl-[1 ₎ 3]dithioIan-2-yl)-phenoxy]-acetamide

N-(4-Aminomethyl-3-fluoro-phenyl)-methanesulfonamide HCI salt (153 mg, 0.600 mmol) and NMP (0.2 ml) were added in 10 ml THF. The mixture was stirred for 10 mins. DMTMM (153 mg) and [3-Fluoro-4-(2-methyl-[1,3]dithiolan- 2-yl)-phenoxy]-acetic acid (153 mg, 0.530 mmol) were added into the mixture. The reaction mixture was stirred overnight. The reaction solvent was removed in vacuo. The residue was extracted with MC (30 ml x 3) and H ₂ O (30 ml). A combined organic layer was washed with sat. NaHCO ₃ (30ml) and washed with

brine (30 ml), dried with MgSO ₄ , and concentrated in vacuo. The residue was purified with column chromatography to yield white solid (210 mg).

¹ H NMR (CDCI ₃ , 300 MHz) δ 7.78 (t, J = 9.0 Hz, 1 H), 7.50 (t, J = 8.4 Hz, 1 H) ₁ 7.07 (m, 2H), 6.95 (t, 1 H), 6.79 (br, 1 H), 6.68 (dd, 1 H), 6.63-6.58 (m, 2H), 4.54 (s, 2H), 4.51 (d, J = 6.0 Hz, 2H), 3.43 (m, 2H), 3.27 (m, 2H), 3.01 (s, 3H), 2.14 (d, J = 0.9 Hz, 3H)

ESI [M+H] ⁺ : 489.0.

Example 46: N-(3-Fluoro-4-methanesulfonyIamϊno-benzyl)-2-[3-fluoro-4-(2 - isopropyl-[1 ,3]dϊthiolan-2-yI)-phenoxy]-acetamide

N-(4-Aminomethyl-3-fluoro-phenyl)-methanesulfonamide HCI salt (190 mg, 0.746 mmol) and NMP (0.2 ml) were added in 10 ml THF. The mixture was stirred for 10 mins. DMTMM (181 mg, 0.654 mmol) and [3-fluoro-4-(2-isopropyl- [1 ,3]dithiolan-2-yl)-phenoxy]-acetic acid (193 mg, 0.645 mmol) were added into the mixture. The reaction mixture was stirred overnight. The reaction solvent was removed in vacuo. The residue was extracted with MC (30 ml x 3) and H ₂ O (30 ml). A combined organic layer was washed with sat. NaHCO ₃ (30ml) and washed with brine (30 ml), dried with MgSO^ and concentrated in vacuo. The residue was purified with column chromatography to yield white solid (136 mg, 42%). ¹ H NMR (CDCI ₃ , 300 MHz) δ 7.64 (dt, 2H), 7.43 (t, J = 8.7 Hz ₁ 1 H), 7.01 (m,

2H), 6.82 (br, 1H), 6.76 (m, 2H), 4.50 (s, 2H) ₁ 4.44 (dd 2H), 3.26 (m, 2H), 3.07 (m, 2H) ₁ 2.95 (s, 3H), 2.47 (m, 1 H), 2.11 (d, J = 0.9 Hz, 3H), 0.92 (s, 6H) ESI [M+H] ⁺ : 499.0.

Example 47: {2-tert-Butyl-5-[(3-fluoro~4- methanesulfonylaminobenzylcarbamoyl)methoxy] phenoxy} acetic acid methyl ester

Step 1: (4-tert-Butyl-3-methoxycarbonylmethoxyphenoxy)acetic acid tert-butyl ester

A dried 100ml two neck round bottom flask was filled with Ar gas and to this flask were added bromoacetic acid methyl ester(1.2eq, O.δδmmol, 81.09/rf), (4- tert-Butyl-3-hydroxy-phenoxy)acetic acid tert-butyl ester (200mg, 0.71 mmol), and.K2CO3 (3.0eq, 2.13mmol, 277.45mg) , dissolved in acetone, and stirred at room temperature for 84 hours. After confirming the completion of the reaction, the reaction mixture was quenched with sat.NH ₄ CI solution, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained substance was column chromatographed (n-Hexane/EtOAc=10/1 ) to yield a transparent liquid (251.5mg, 100%). IR(NaCI neat, cm ^"1 ): 2977, 1746, 1611 , 1218, 1152 ; ¹ H NMR(400MHz, CDCI ₃ ): δ 1.27(s, 9H) ₁ 1.38(s, 9H), 4.34(s, 2H), 4.49(s, 2H), 6.24(dd, 1H, J=8.4Hz, 2.4Hz), 6.28(d, 1H ₁ J=2.4Hz), 7.05(d, 1 H ₁ J=8.4Hz)

Step 2: ^-tert-Butyl-S-methoxycarbonylmethoxyphenoxyJacetic acid A dried 100ml two neck round bottom flask was filled with Ar gas and to this flask were added (4-tert-Butyl-3-methoxycarbonylmethoxyphenoxy) acetic acid tert-butyl ester(0.79mmol, 280mg), and . CF ₃ COOH 1.0ml, and dissolved in methylene chloride, stirred at room temperature for 5 hours. After confirming the completion of the reaction, the reaction mixture was concentrated under reduced pressure at low temperature. To the resulting liquid was added anh. benzene and reconcentrated under reduced pressure to yield a gray syrup (251.5mg,100%) IR (NaCI neat, crrf ¹ ):1176, 1217, 1609, 1741 , 2953 ; ¹ H NMR(400MHz, CDCI ₃ ): δ 1.32(S ₁ 9H), 3.75(S ₁ 3H), 4.57(s, 4H), 6.33~6.35(m, 2H), 7.14(d, 1 H, J=8.8Hz)

Step 3: {2-tert-Butyl-5-[(3-fluoro-4- methanesulfonylaminobenzylcarbamoyl)methoxy] phenoxy} acetic acid methyl ester

4-Aminomethyl-2-fluorophenylamine (128.16mg, 0.63mmol) and (4-tert-Butyl-3- methoxycarbonylmethoxyphenoxy)acetic acid(1.1eq, 0.69mmol, 204.6mg), were added in DMF. To this mixture were added triethylamine(5eq, 3.15mmol, 438.70/if,), diethylcyanophosphonate(1.2eq, 0.76mmol, 115.31 μλ) stepwise. The reaction mixture was stirred at room temperature for 12 hours. After confirming the completion of the reaction, the reaction mixture was extracted with EtOAc twice, washed with brine, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The resulting liquid was was column chromatographed (n- Hexane/EtOAc=1/1) to yield a white solid (96.3mg, 28.09%)

Melting point : 85.5 ⁰ C ; IR(NaCI neat, cm ^"1 ): 3376, 3268, 1756, 1666, 1158, 1105 ; ¹ H NMR(400MHz, CDCI ₃ ): δ 1.34(s, 9H), 2.97(s, 3H), 3.77(s, 3H), 4.47(d, 2H, J=6.4Hz), 4.59(s, 2H), 6.33(s, 1H, J=2.4Hz), 6.41 (dd, 1 H ₁ J=2.4Hz, 8.8Hz), 7.03~7.04(m, 4H) ₁ 7.19(d, 1 H, J=8.8Hz), 7.44(d, 1 H, J=8.8Hz)

Example 48: Benzoic acid 2-tert-butyI-5-[(3-fluoro-4- methanesulfonylaminobenzylcarbamoyl)methoxy]phenyl ester

Step 1 : Benzoic acid δ-tert-butoxycarbonylmethoxy^-tert-butylphenyl ester

A dried 100ml two neck round bottom flask was filled with Ar gas and to this flask were added benzoyl chloride(5eq, 6.23mmol, 72.26/z£), (4-tert-Butyl-3- hydroxyphenoxy)acetic acid tert-butyl ester (79.6mg, 0.48mmol), and anh.triethylamine(3eq, 1.44mmol, 200.53/^,)- And the mixture was dissolved in anh. Methylene chloride, and stirred at room temperature for overnight. After confirming the completion of the reaction, to the mixture was washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained substance was column chromatographed (n-Hexane/EtOAc=5/1 ) to yield a white solid (58.0mg, 100%) IR(NaCI, neat, cm ^'1 ): 2966, 2908, 1736, 1615, 1258, 1141 ; ¹ H NMR(400MHz, CDCI ₃ ): δ 1.26(s, 9H), 1.41(s, 9H), 4.41 (s, 2H), 6.58(d, 1 H, J=2.8Hz), 6.69(dd, 1H, J=8.8Hz, 2.8Hz), 7.26(d, 1 H, J=8.8Hz), 7.44~7.48(m, 2H), 7.56~7.59(m,

1 H), 8.13~8.15(m, 2H)

Step 2: Benzoic acid 2-tert~butyl-5-carboxymethoxyphenyI ester To a dried 100ml two neck round bottom flask were added benzoic acid 5-tert- butoxycarbonylmethoxy-2-tert-butylphenyl ester (0.17mmol, 65mg) and CF ₃ COOH 0.8ml and the mixture was dissolved in methylene chloride, stirred at room temperature for 4 hours. After confirming the completion of the reaction, the reaction mixture was concentrated under reduced pressure at low temperature, added anh. benzene, and reconcentrated under reduced pressure to yield a white solid (55.4mg. 100%) IR(NaCI neat, crrf ¹ ):1143, 1165, 1259, 1615, 1734 ; ¹ H NMR(400MHz, CDCI ₃ ): δ 1.32(s, 9H), 4.63(s, 2H), 6.68(d, 1 H, J=2.8Hz), 6.78(dd, 1 H, J=2.8Hz, 8.8Hz), 7.35(d, 2H, J=1.6Hz), 7.50~7.53(m, 2H), 7.64(dd, 1 H, J=7.6Hz), 8.19(d, 1 H, J=8.8Hz)

Step 3: Benzoic acid 2-tert-butyl-5-[(3-fluoro-4- methanesulfonylaminobenzylcarbamoyl)methoxy]phenyl ester A dried 100ml two neck round bottom flask was filled with Ar gas and to this flask were added 4-aminomethyl-2-fluorophenylamine (36.18mg, 0.18mmol) and benzoic acid 2-tert-butyl-5-carboxymethoxyphenyl ester (1.1 eq, 0.19mmol, 64mg), and dissolved in DMF. To this mixture were added triethylamine(5eq, 0.90mmol, 125.33/^) and diethy!cyanophosphonate(1.2eq, 0.22mmol, 32.77 ≠) stepwise. And the reaction mixture was stirred for 12 hours. After confirming the completion of the reaction, the reaction mixture was extracted with EtOAc twice and washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under

reduced pressure. The obtained substance was column chromatographed (n- Hexane/EtOAc=1/2) to yield a white solid (51.5mg,49.99%) Melting point : 132.2-132.5 ⁰ C ; IR(NaCI neat, cm ^"1 ): 1159, 1261 , 1330, 1669, 1733 ; ¹ H NMR(400MHz, CDCI ₃ ): δ 1.33(s, 9H), 2.99(s, 3H), 4.49(d, 2H, J=6.0Hz), 4.54(s, 2H), 6.41 (s, 1 H), 6.70(d, 1H, J=2.4Hz), 6.75(dd, 1 H, J=9.2Hz, 3.2Hz), 7.06~7.07(m, 2H), 7.36(d, 1 H, J=8.4Hz), 7.50~7.55(m, 3H), 7.64~7.67(m, 1 H), 8.20(d, 2H, J=7.6Hz)

Example 49: 6-TrifIuoromethylnicotlnic acid 2-tert-butyl-5-[(3-fluoro4- methanesulfonylamino benzylcarbamoyl)methoxy]phenyl ester

Step 1 : 6-Trifluoromethylnicotinic acid 5-tert-butoxycarbonylmethoxy-2-tert- butylphenyl ester

6-(Trifluoromethyl)nicotinoyl chloride(1.3eq, 2.30mmol, 355.2/^), (4-tert-Butyl-3- hydroxyphenoxy)acetic acid tert-butyl ester(500mg, 1.80mmol), and anh.triethylamine(3eq, 5.40mmol, 752.0/^) were added in methylene chloride.

The reaction mixture was stirred at room temperature for overnight. After confirming the completion of the reaction, the reaction mixture was quenched with 5% HCI solution, washed with H ₂ O and brine, dried over Na ₂ SO _4, concentrated under reduced pressure. The residue was column chromatographed (n-Hexane/EtOAc=15/1 ) to yield a pale yellow liquid (591.3mg,

73.07%).

IR (NaCI neat, crrf ¹ ): 1144, 1226, 1263, 1616, 1748, 2972, 3478 ; ¹ H NMR(400MHz, CDCI ₃ ): δ 1.26(s, 9H) ₁ 1.42(s, 9H), 4.43(s, 2H), 6.61 (d, 1H, J=2.8Hz), 6.72(dd, 1H ₁ J=2.8Hz, 8.8Hz), 7.82(d, 1 H ₁ J=8.0Hz), 8.58(d, 1 H, J=8.0Hz), 9.04(s, 1 H)

Step 2: 6-Trifluoromethyl-nicotinic acid 2-tert-butyl-5-carboxymethoxyphenyl ester

6-trifluoromethylnicotinic acid 5-tert-butoxycarbonylmethoxy-2-tert-butylphenyl ester (1.30mmol, 591.3mg) and CF ₃ COOH 1.5ml were added in methylene chloride. The reaction mixture was stirred at room temperature for 5 hours. After confirming the completion of the reaction, the reaction mixture was concentrated under reduced pressure at low temperature. To the resulting liquid was added anh.toluene, reconcentrated under reduced pressure to yield a gray syrup (518.1 mg, 100%). Melting Point :107.4υ ; IR(NaCI neat, crrr ¹ ):2965, 1743, 1616, 1264, 1219, 1097 ; ¹ H NMR(400MHz, CDCI ₃ ): δ 1.32(s, 9H), 4.66(s, 2H), 6.69(d, 1H ₁ J=2.8Hz), 6.81 (dd, 1 H, J=8.8Hz, 2.8Hz), 7.38(d, 1H, J=8.8Hz), 7.88(d, 1 H, J=8.0Hz), 8.64(d, 1H, J=8.0Hz), 9.50(s, 1H)

Step 3: 6-TrifluoromethyInicotinic acid 2-tert-butyl-5-[(3-fluoro-4- methanesulfonylamino benzylcarbamoyl)methoxy]phenyl ester 4-Aminomethyl-2-fluoropheny!amine (54.11mg, 0.27mmol) and 6- trifluoromethylnicotinic acid 2-tert-butyl-5-carboxymethoxy-phenyl ester (1.1 eq, 0.29mmol, 115mg) were added in DMF. Triethylamine(5eq, 1.32mmol,

168.12/^,) and diethylcyanophosphonate(1.2eq, 0.76mmol, 115.31 /^) were added into the mixture. And the mixture was stirred at room temperature for 12 hours. After confirming the completion of the reaction, the reaction mixture was diluted with EtOAc, washed with H ₂ O ten times, washed with brine, dried over Na ₂ SO _4, and concentrated under reduced pressure. The resulting liquid was column chromatographed (n-Hexane/EtOAc=1/1) to yield a white solid (82..9mg, 47.39%)

Melting point : 66.0~68.6°C ; IR(NaCI neat, cm ^'1 ): 3369, 3270, 1660, 1610, 1330, 1157, 1109, 1057 ; ¹ H NMR(400MHz, CDCI ₃ ): δ 1.35(s, 9H) ₁ 2.98(s, 3H), 4.47(d, 2H, J=6.0Hz), 4.49(S ₁ 2H), 5.69(s, 1H), 6.30(d, 1 H, J=2.4Hz), 6.39(dd, 1H, J=2.4Hz, 8.8Hz), 6.53(s, 1 H), 6.93(s, 1 H), 7.01~7.03(m, 2H) ₁ 7.15(d, 1 H, J=8.8Hz), 7.47(dd, 1 H, J=8.0Hz)

Example 50: Acetic acid 2-tert-butyl~5-[(3-fluoro-4- methanesulfonylaminobenzylcarbamoyl) methoxy]phenyl ester

Step 1 : (4-tert-Butyl-3-hydroxyphenoxy)acetic acid tert-butyl ester A dried 100ml two neck round bottom flask was filled with Ar gas and to this flask anh.K ₂ CO ₃ (3.0βq, 1.80mmol, 234.38mmol), 4-tert~Butylbenzene-1 ,3- diol(100mg, 0.60mmol), and bromoacetic acid tert-butyl ester (1.2eq, 0.72mmol, 106.32≠) were added in acetonitrile. The mixture was stirred at -10 ^° C for overnight. After confirming the completion of the reaction, the mixture was

quenched with ammoniun chloride sol'n and was concentrated in vacuo. The filtrate was extracted with EtOAc and washed with H2O and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained substance was column chromatographed (n-Hexane/EtOAc=10/1 ) to yield a yellow solid (1024mg, 55.23%).

IR(NaCI neat, cm ^"1 ): 3447, 1735, 1251 , 1217; ¹ H NMR(400MHz, CDCI ₃ ): δ 1.29(s, 9H), 1.43(s, 9H), 4.39(s, 2H), 5.57(s, 1 H), 6.25(dd, 1 H ₁ J=8.4Hz, 2.4Hz), 6.32(d, 1 H, J=2.4Hz), 7.05(d, 1 H, J=8.4Hz)

Step 2: (3-Acetoxy-4-tert-butylphenoxy)acetic acid tert-butyl ester Acetic anhydride(5.0eq, 1.67mmol, 150.96/^), (4-tert-Butyl-3-hydroxyphenoxy)- acetic acid tert-butyl ester (90mg, 0.32mmol) and anh. triethylamine(3eq, 0.96mmol, 134.20/^) were added in anh. methylene chloride. The reaction mixture was stirred at room temperature for overnight. After confirming the completion of the reaction, the mixture was quenched with 5% HCI sol'n and washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained substance was column chromatographed (n- Hexane/EtOAc=50/1 ) to yield a transparent liquid (29.3mg, 28.31 %) ¹ H NMR(400MHz, CDCI ₃ ): δ 1.24(s, 9H), 1.41 (s, 9H), 2.25(s, 3H), 4.39(s, 2H), 6.50(d, 1H, J=2.8Hz), 6.63(dd, 1H, J=2.8Hz, 8.8Hz)

Step 3: (3-Acetoxy-4-tert-butylphenoxy)acetic acid

A dried 100ml two neck round bottom flask were added (3-Acetoxy-4-tert~

butylphenoxy)acetic acid tert-butyl ester (0.01 mmol, 5.8mg), and CF ₃ COOH acetic anhydride(5.0eq, 1.67mmol, 150.96/iβ) and the mixture was dissolved in methylene chloride, stirred at room temperature for 4 hours. After confirming the completion of the reaction, the mixture was concentrated at low temperature and to this mixture was added benzene, concentrated under reduced pressure to yield a brown liquid (21.8mg, 93.86%).

¹ H NMR(400MHz, CDCI ₃ ): δ 1.24(s, 9H) ₁ 2.226(s, 3H), 4.56(s, 2H), 6.53(d, 1 H, J=2.4Hz), 6.66(dd, 1 H, J=8.8Hz, 2.4Hz) ₁ 7.23(d, 1 H, 8.8Hz), 8.01 (s, 1 H)

Step 4: Acetic acid 2-tert-butyl~5-[(3-fluoro-4- methanesulfonylaminobenzylcarbamoyl) methoxy]phenyl ester 4-Aminomethyl-2-fluorophenylamine (14.94mg, 0.07mmol) and (3-acetoxy-4- tert-butylphenoxy)acetic acid(1.1eq, O.Oδmmol, 20mg) were added in DMF, Triethylamine(5eq, 0.35mmol, 48.73μi) and diethylcyanophosphonate(1.2eq, 0.82mmol, 12.43μ£) were added into the mixture. The reaction mixture was stirred for 12 hours at room temperature. After confirming the completion of the reaction, to the mixture was extracted with EtOAc twice and washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained substance was column chromatographed (n-Hexane/EtOAc=1/5) to yield a white solid (9.1mg, 24.26%).

IR(NaCI neat, cm ^"1 ): 3352, 3268, 1756, 1668, 1208, 1159, 1088 ; ¹ H NMR(400MHz, CDCI ₃ ): δ 1.25,(s, 9H) ₁ 2.67(s, 3H), 2.95(s, 3H) ₁ 4.43(d, 2H,

J=6.4Hz), 4.46(s, 2H), 6.46(s, 1 H), 6.55(d, 1H, J=2.8Hz), 6.65(dd, 1 H ₁ J=2.8Hz, 8.4Hz), 6.68(s, 1 H), 7.00(s, 1 H), 7.02(d, J=2.8Hz), 7.25(d, J=8.4Hz), 7.46(dd, J=8.4Hz)

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 (2-3 day old or younger than 2-3 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 1.2g/l sodium bicarbonate, 50mg/l gentamycin were added. The DRG were incubated sequentially at 37 ⁰ C for 30 mins in 200 U/ml collagenase and 2.5mg/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 80 membrane to obtain single cell suspension and the suspension was washed once more. This was subjected to centrifugation, then resuspended in cell culture medium at certain level of cell density. As the cell culture medium, DME/F12 medium supplemented with 10% horse serum was diluted with identical medium conditioned by C6 glioma cells 2 days on a confluent monolayer (1 :1), and NGF (Nerve Growth Factor) was added to adjust 200ng/ml

as final concentration. 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 1500-2000 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 days were equilibrated by washing 4 times with HEPES (1OmM, pH 7.4)-buffered Ca ²⁺ , Mg ²⁺ -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 ⁴⁵ Ca (final concentration 10 μCi/ml) in H-HBSS was added to each well and incubated at room temperature for 10 mins. Terasaki plates were washed five times with H-HBSS and dried at room temperature. To each well, 0.3% SDS (10 μl) was added to elute ⁴⁵ Ca. After the addition of scintillation cocktail of into each well, the amount of ⁴⁵ Ca 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 the results are given as IC ₅₀ .

[Table 1 ] Results of Calcium Influx Test

Antagonist Exampies

Calcium Uptake Test (IC ₅₀ , μM )

2. Analgesic activity test: Mouse writhing test by inducing with phenyl-p-quinone Male ICR mice (mean body weight 25g) 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 mins later, the number of abdominal constrictions was counted in the subsequent 6 mins period. Animals (10 animals/group) received 0.2ml of test compounds solution in vehicle of ethanol/Tween 80/saIine (10/10/80) intraperitoneally 30 mins before the injection of phenyl-p-quinone. In the case of oral administration, 0.2ml of test compounds solution in vehicle of ethanol/Tween 80/saline (5/5/90) were administered 54 mins prior to the 0.2ml of 0.02% phenyl-p-quinone injection. A reduction in the number of writhes responding to the test drug compound relative to the number responding in saline control 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.

Most examples of the present invention having good in vitro activities, were tested at various doses (ranging from 0.1 to 3 mg/kg) and resulted in good analgesic effect from 27 to 59% inhibition.

Industrial Applicability

As explained above, the compound according to the present invention is useful to prevent or to treat pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium, alopecia, rhinitis, and pancreatitis.

More specifically, the compound according to the present invention is useful to preventing and treating of pain, which is or which is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine, and other types of headaches.