DETAILED DESCRIPTION OF INVENTION TECHNICAL FIELD The present invention relates to a phenyltriazole derivative which is useful as an active ingredient of pharmaceutical preparations. The phenyltriazole derivative of the present invention has aminobutyric acid receptor (GABAB receptor) agonistic activity, and can be used for the prophylaxis and treatment of diseases associated with GABAB receptor activity, in particular for the treatment of overactive bladder, urinary incontinence such as urge urinary incontinence, benign prostatic hyperplasia, spasticity and motor control, pain, epilepsy, cognitive defects, psychiatric disorders, alcohol dependence and withdrawal, feeding behaviour, cardiovascular, respiratory disorders and gastrointestinal disorders.

BACKGROUND ART GABAB receptors are the first example of G protein-coupled receptors where heteromerization of two receptor subtypes has been demonstrated to be necessary for normal-function (Jones et a/., Nature, (1998) 396,674-679) ; Kaupmann et al. , Nature, (1998) 396, 683-687 ; Kuner et a/., Science, (1999) 283, 74-77). Currently there are two GABAB receptor subtypes kllown, GABABRI and R2. In the brain there are two predominant N terminal splice variants expressed from the GABAB R1 gene, GABABRIa and Rlb, which heterodimerize with the R2 subunit.

Pharmacologically, the different splice forms of GABABRI could not be distinguished (Kaupmann et al. , Nature, (1997) 386, 239-246.

GABAB receptors are located throughout the central and peripheral nervous systems (see Ong and Kerr, Life Sciences, (1990) 46,1489-1501 ; Bowery et al. , Drug Res. (1992) 42 (1), 2a, 215-223), and are thus involved in the regulation of a wide variety of neurally-controlled physiological responses, from memory and learning to muscle contraction. This makes the GABAB receptor a target for pharmaceutical agents intended to treat central and peripheral neural disorders, and indeed a variety of GABAB agonists and antagonists are known and have been proposed for use in therapy including pain, spasticity and motor control, epilepsy, cognitive defects, psychiatric disorders, alcohol dependence and withdrawal, feeding behaviour, cardiovascular, respiratory disorders and gastrointestinal disorders (Bittiger et al. , in GABA: Receptors, Transporters and Metabolism, Tanaka, C. , and Bowery, N. G. (Eds). Birkhauser Verlag Basel/Switzerland (1996), 297-305 ; Bittiger et al. , Trends Pharmacol. Sci. , 14,391-394, 1993; Froestl et al. , J. Med. Chem., 38, 3297-3312, 1995; Froestl et al. , Ibid. , 3313-3331).

The GABA$ receptor agonist baclofen given intrathecally is used clinically for reducing urethral resistance and detrusor overactivity associated with spasticity (Steers et al. ; J. Urol., 148,1849- 1855, 1992 ; Mertens et al., Acta Neuroc1Zi7, 64,17-25 1995). The main effect of baclofen within the central nervous system is to reduce transmitter release. In the spinal cord it affects the activity of motoneurons and interneurons that are important for micturition and baclofen has previously been reported to have an inhibitory action on rat micturition after intrathecal administration (Igawa etal. J. Urol., 150,537-542, 1993; Pehrsonetal. J. U7-ol., 168, 2700-2705, 2002).

Taken together, it is suggested that GABAB system is involved in the micturition control, both in animals and human. A potent and selective GABAB agonist can provide therapeutic benefit in the treatment of urinary bladder dysfunction as well as other indications described above.

GABAB agonists are also known to have smooth muscle relaxation action, thus a potent and selective GABAB agonist can provide therapeutic benefit in the treatment of BPH.

Urinary incontinence UI is the involuntary loss of urine. UUI is one of the most common types of UI together with stress. urinary incontinence (SUI) which is usually caused by a defect in the urethral closure mechanism.

UUI is often associated with neurological disorders or diseases causing neuronal damages such as dementia, Parkinson's disease, multiple sclerosis, stroke and diabetes, although it also occurs in individuals with no such disorders. One of the usual causes of UUI is overactive bladder (OAB) which is a medical condition referring to the symptoms of frequency and urgency derived from abnormal contractions and instability of the detrusor muscle.

There are several medications for urinary incontinence on the market today mainly to help treating UUI. Therapy for OAB is focused on drugs that affect peripheral neural control mechanisms or those that act directly on bladder detrusor smooth muscle contraction, with a major emphasis on development of anticholinergic agents. These agents can inhibit the parasympathetic nerves which control bladder voiding or can exert a direct spasmolytic effect on the detrusor muscle of the bladder. This results in a decrease in intravesicular pressure, an increase in capacity and a reduction in the frequency of bladder contraction. Orally active anticholinergic drugs are the most commonly prescribed drugs. However, their most serious drawbacks are unacceptable side effects. such as dry mouth, abnormal visions, constipation, and central nervous system disturbances. These side effects lead to poor compliance. Dry mouth symptoms alone are responsible for a 70% non- compliance rate with oxybutynin. The inadequacies of present therapies highlight the need for novel, efficacious, safe, orally available drugs that have fewer side effects.

Benign prostatic hyperplasia (BPH) BPH is the benign nodular hyperplasia of the periurethral prostate gland commonly seen in men over the age of 50. The overgrowth occurs in the central area of the prostate called the transition zone, which wraps around the urethra. BPH causes variable degrees of bladder outlet obstruction resulting in progressive lower urinary tract syndromes (LUTS) characterized by urinary frequency, urgency, and nocturia due to incomplete emptying and rapid refilling of the bladder. The actual cause of BPH is unknown but may involve age-related alterations in balance of steroidal sex hormones.

The selective al-adrenoceptor antagonists, such as prazosin, indoramin and tamsulosin are used as an adjunct in the symptomatic treatment of urinary obstruction caused by BPH, although they do not affect on the underlying cause of BPH. In BPH, increased sympathetic tone exacerbates the degree of obstruction of the urethra through contraction of prostatic and urethral smooth muscle.

These compounds inhibit sympathetic activity, thereby relaxing the smooth muscle of the urinary tract. Uroselective al-antagonists and al-antagonists with high tissue selectivity for lower urinary tract smooth muscle that do not provoke hypotensive side-effects should be developed for the treatment.

Drugs blocking dihydrotestosterone have been used to reduce the size of the. prostate. 5a-reductase inhibitors such as finasteride are prescribed for BPH. These agents selectively inhibit 5a-reductase which mediates conversion of testosterone to dihydrotestosterone, thereby reducing plasma dihydrotestosterone levels and thus prostate growth. The 5a-reductase inhibitors do not bind to, androgen receptors and do not affect testosterone levels nor do they possess feminizing side- effects.

Androgen receptor antagonists are used for the treatment of prostatic hyperplasia due to excessive action or production of testosterone. Various antiandrogens are under investigation for BPH including chlormadione derivatives with no estrogenic activity, orally-active aromatase inhibitors, luteinizing hormone-releasing hormone (LHRH) analogues.

WO01/87855 discloses phenyltriazole derivatives represented by the general formula:

wherein A represents optionally substituted aryl, etc ; B and D independently represent optionally substituted aryl, carbocycles, or 5-or 6-membered heterocycles; Ra represents H, halgen-substituted alkyl, (un) substituted aryl, (un) substituted heterocycles, (un) substituted cycloalkyl, or-[Alkl] m-XP- [Alh2] n-YP-R1 P ; wherein RIP represents H, optionally substituted aryl, etc; XP represents direct bond,-O-,-S-, etc; Y represents direct bond, m and n independently represent an integer of 0 orl ; Alkl and Alk2 independently represent alkyl, etc, as an inhibitor of glycine transporter.

Yamada, N. et al. discloses phenyltriazole derivatives represented by the general formula: wherein Rb 1 represents H, methyl, or ethyl; Rb2 represents H, chloro, fluoro, dichloro, methyl, methoxy, or trifluoromethyl ; Rb3 represents H, chloro, methyl, ethyl, methoxy, ethoxy, fluoro, trifluoromethoxy, or dichloro, as a bleaching herbicide (Bioscience, Biotechnology, and Biochemistry (2002), 66 (8), 1671-1676).

However, none of these references discloses phenyltriazole derivatives having GABAB receptor agonistic activity.

The development of a compound which has effective GABAB agonistic activity and can be used for the prophylaxis and treatment of diseases associated with GAZA$ receptor activity, in particular for the treatment of urinary incontinence, urge urinary incontinence, overactive bladder as well as pain, such as chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia or nerve injury induced pain, spasticity and motor control, epilepsy, cognitive defects, psychiatric disorders, alcohol dependence and withdrawal, feeding behaviour, cardiovascular, respiratory disorders and gastrointestinal disorders has been desired.

SUMMARY OF THE INVENTION This invention is to provide phenyltriazole derivatives of the formula (I), their tautomeric and stereoisomeric form, and salts thereof : wherein R'represents alkyl optionally substituted by one or two substituents selected from the group consisting of alkoxy, amino, alkylamino, di (alkyl) amino, alkanoyloxy, hydroxy, carboxy, alkoxycarbonyl, cycloalkylphenyloxy, halogen, morpholino, carbamoyl, alkylsulfonyl- amino, phenyloxy optionally substituted by cycloalkyl, and 3-8 membered saturated ring optionally having one or two N atom which ring optionally substituted by hydroxy or alkanoyl, or 3-8 membered saturated or unsaturated ring optionally having one or two hetero atoms selected from the group consisting of N and 0, and which ring is optionally substituted by one or two substituents selected from the group consisting of alkyl, halogen, alkoxy, nitro, amino, cyano, alkylamino, di (alkyl) amino, 4-7 membered saturated cyclic amine optionally substituted by hydroxy, and mono-, di-, or tri-halogen substituted alkyl ; represents-COR",- (CH2),,-R' or tert-butyl, wherein 21 iS alkoxy, hydroxy, mono-, di-, or tri-halogen substituted alkyl,

or 3-8 membered saturated or unsaturated ring optionally having one or two heteroatoms selected from the group consisting of N, O, and S and which ring is optionally substituted by one or two substituents independently selected from the group consisting of alkanoyl, halogen, benzyl, alkoxycarbonyl, haloalkyloxy- carbonyl, cyano, hydroxy, amino, alkylamino, di (alkyl) amino, cycloalkylamino, alkoxycarbonyl, sulfamoyl, alkylaminosulfonyl, di (alkyl) aminosulfonyl, alkanoyl, alkanoylamino, carbamoyl, alkylcarbamoyl, di- (alkyl) carbamoyl, alkylsulfonyl, alkyl optionally substituted by alkoxycarbonyl or mono-, di-, or tri-halogen, alkoxy optionally substituted by mono-, di-, or tri-halogen, and alkylthio optionally substituted by mono-, di-, or tri-halogen ; n is 0 or 1 ; R3 and R4 independently represent hydrogen, halogen, cyano, hydroxy, amino, alkylamino, di (alkyl) amino, cycloalkylamino, carboxy, alkoxycarbonyl, sulfamoyl, alkylaminosulfonyl, di (alkyl) aminosulfonyl, alkanoyl, alkanoylamino, carbamoyl, alkylcarbamoyl, di- (alkyl) carbamoyl, alkylsulfonyl, alkyl optionally substituted by hydroxy, alkoxycarbonyl or mono-, di-, or tri-halogen, alkoxy optionally substituted by mono-, di-, or tri-halogen, or alkylthio optionally substituted by mono-, di-, or tri-halogen; Rs represents hydrogen, hydroxy, nitro, cyano, halogen, sulfamoyl, alkylsulfonyl, alkyl- aminosulfonyl, di (alkyl) aminosulfonyl,- (CH2)m-CO-R50, -(CH2)m-R51, -NR52R53, or -OR54, wherein mis0, 1,2, or3 Rso is hydroxy, hydrogen, alkoxy, morpholino, di (phenyl) methyloxy, di (halogen substituted phenyl) methyloxy, -NR501R502 (wherein said R'ol and R'O' independently represent hydrogen, alkoxyalkyl, alkyl, hydroxyalkyl, alkoxycarbonylalkyl, or carboxyallcyl or R'O'and R502 together form with the adjuscent N atom, morpholino, piperazino optionally substituted by oxo, or 4-7 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl) or alkyl optionally substituted by halogen, R 51 is hydrogen, hydroxy,-or-NR'R (wherein said R"'and R"'independently represent hydroge. n, alkoxyalkyl, alkyl, hydroxyalkyl, alkoxycarbonylalkyl, or

carboxyalkyl, or RS"and RS'Z together form with the adjuscent N atom, 4-7 membered'saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl), R52 and R53 independently represent hydrogen, alkyl, hydroxy, cycloalkylcarbonyl, hydroxyalkyl, alkylsulfonyl, hydroxyalkylcarbonyl, carboxyalkylcarbonyl, alkanoyloxyalkylcarbonyl, or alkoxycarbonylalkylcarbonyl, or R52 and R53 together form with adjuscent N atom, morpholino, cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl, R54 represents alkyl optionally substituted by morpholino, amino, di (alkyl) amino, carboxy, alkoxycarbonyl, or mono-, di-, or tri-halogen, or piperazino substituted by carboxy ; R6 and R7 independently represents hydrogen, morpholino, hydroxypyrrolidinylcarbonyl, hydroxyalkylaminocarbonyl, cyano, hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, alkylamino, di (alkyl) amino, cycloalkylamino, alkoxycarbonyl, sulfamoyl, alkylaminosulfonyl, di (alkyl) aminosulfonyl, alkanoyl, alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, alkylcarbamoyl, di- (alkyl) carb- amoyl, alkylsulfonyl, alkyl optionally substituted by alkoxyalkyl (alkyl) amino, di (alkyl) amino, alkoxycarbonyl, carboxy, or mono-, di-, or tri-halogen, alkoxy optionally substituted by morpholino, di (alkyl) amino, or mono-, di-, or tri-halogen, or Cl 6 alkylthio optionally substituted by mono-, di-, or tri-halogen or R6 and R7 together form phenyl fused to adjacent phenyl ; and X represents CRl°Rll, NR", S, O, SO2, or SO wherein Rl°, R", and R''independently representhydrogen or methyl.

The phenyltriazole derivatives of formula (I), their tautomeric and stereoisomeric form, and salts thereof surprisingly show excellent GABAB agonistic activity. They are, therefore, suitable especially for the prophylaxis and treatment of diseases associated with GABAB receptor activity, in particular for the treatment of urinary incontinence, urge urinary incontinence and/or overactive bladder.

The compounds of the present invention are also effective for treating or preventing a disease selected from the group consisting of pain, such as chronic pain, neuropathic pain, postoperative

pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, or nerve injury induced'pain, spasticity and motor control, epilepsy, cognitive defects, psychiatric disorders, alcohol dependence and withdrawal, feeding behaviour, cardiovascular, respiratory disorders and gastrointestinal disorders since the diseases also relate to GABAB receptor activity.

In another embodiment, the phenyltriazole derivatives of formula (I) are those wherein; wherein R'represents alkyl optionally substituted by one or two substituents selected from the group consisting of alkoxy, amino, allcylarnino, di (alkyl) amino, alkanoyloxy, hydroxy, carboxy, alkoxycarbonyl, cycloalkylphenyloxy, halogen, morpholino, carbamoyl, phenyloxy optionally substituted by cycloalkyl, and 3-8 membered saturated ring optionally having one or two N atom which ring optionally substituted by hydroxy or alkanoyl, or 3-8 membered saturated or unsaturated ring optionally having one or two hetero atoms selected from the group consisting of N and 0, and which ring is optionally substituted by one or two substituents selected from the group consisting of alkyl, halogen, alkoxy, nitro, amino, cyano, alkylamino, di (alkyl) amino, 4-7 membered saturated cyclic amine optionally substituted by hydroxy, and mono-, di-, or tri-halogen substituted alkyl ; R2 represents-COR2'or-(CH2), 1-R2', wherein R21 is alkoxy, hydroxy, mono-, di-, or tri-halogen substituted alkyl, or 3-8 membered saturated or unsaturated ring optionally having one or two heteroatoms selected from the group consisting of N, 0, and S and which ring is optionally substituted by one or two substituents independently selected from the group consisting of alkanoyl, halogen, benzyl, alkoxycarbonyl, haloallcyloxy- carbonyl, cyano, hydroxy, amino, alkylamino, di (alkyl) amino, cycloalkylamino, alkoxycarbonyl, sulfamoyl, alkylaminosulfonyl, di (alkyl) aminosulfonyl, alkanoyl, alkanoylamino, carbamoyl, alkylcarbamoyl, di- (alkyl) carbamoyl, alkylsulfonyl, alkyl optionally substituted by alkoxycarbonyl or mono-, di-, or tri-halogen, alkoxy optionally substituted by mono-, di-, or tri-halogen, and alkylthio optionally substituted by mono-, di-, or tri-halogen ; n is 0 or 1 ;

R3 and R4 independently represent hydrogen, halogen, cyano, hydroxy, amino, alkyramino, di (alkyl) amino, cycloalkylamino, alkoxycarbonyl, sulfamoyl, alkylaminosulfonyl, di (alkyl) aminosulfonyl, alkanoyl, alkanoylamino, carbamoyl, alkylcarbamoyl, di- (alkyl) carbamoyl, alkylsulfonyl, alkyl optionally substituted by alkoxycarbonyl or mono-, di-, or tri-halogen, alkoxy optionally substituted by mono-, di-, or tri-halogen, or alkylthio optionally substituted by mono-, di-, or tri-halogen ; R 5 represents hydrogen, hydroxy, nitro, cyano, halogen, sulfamoyl, alkylsulfonyl, alkyl- aminosulfonyl, di (alkyl) aminosulfonyl, -(CH2)m-CO-R50, -(CH2)m-R51, -NR52R53, or -OR54, wherein mis0, 1,2, or3 R50 is hydroxy, hydrogen, alkoxy, morpholino, di (phenyl) methyloxy, di (halogen substituted phenyl) methyloxy, -NR501R502 (wherein said R501 and R502 independently represent hydrogen, alkoxyalkyl, alkyl, hydroxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl or R'O'and R 501 together form with the adjuscent N atom, morpholino, or 4-7 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl) or alkyl optionally substituted by halogen, R5'is hydrogen, hydroxy, or -NR511R512 (wherein said R511 and R512 independently represent hydrogen, alkoxyalkyl, alkyl, hydroxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl, or R5l'and Rsl2 together form with the adjuscent N atom, 4-7 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl), R52 and R53 independently represent hydrogen, alkyl, hydroxy, cycloalkylcarbonyl, or hydroxyalkyl, or R52 and R53 together form with adjuscent N atom, morpholino, cyclic amino optionally substituted by one substituent selected from the group' consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl, R54 represents alkyl optionally substituted by morpholino, amino, di (alkyl) amino, or mono-, di-, or tri-halogen;

R6 and R7 independently represents hydrogen, morpholino, hydroxypyrrolidinylcarbonyl, hydroxyalkylaminocarbonyl, cyano, hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, alkylamino, di (alkyl) amino, cycloalkylamino, alkoxycarbonyl, sulfamoyl, alkylaminosulfonyl, di (alkyl) aminosulfonyl, alkanoyl, alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, alkylcarbamoyl, di- (alkyl) carb- amoyl, alkylsulfonyl, alkyl optionally substituted by alkoxyalkyl (alkyl) amino, di (alkyl) amino, alkoxycarbonyl, carboxy, or mono-, di-, or tri-halogen, alkoxy optionally substituted by morpholino, di (alkyl) amino, or mono-, di-, or tri-halogen, or C1-6 alkylthio optionally substituted by mono-, di-, or tri-halogen or R6 and R7 together form phenyl fused to adjacent phenyl ; and X represents CR'°R", NR", S, O, SO2, or SO wherein R'°, R", and R12 independently representhydrogen or methyl.

Yet another embodiment of formula (I) can be those wherein: X represents CH2, NH, S, O, SOz, or SO; R'represents C3 to C8 cycloalkyl, C1-C6 alkyl optionally substituted by one or two substituents selected from the group consisting of Cl-C6 alkoxy, amino, C1-C6 alkylamino, di (Cl-C6 alkyl) amino, C-C6 alkanoyloxy, hydroxy, C3-C8 cycloalkyl, carboxy, Cl-C6 alkoxycarbonyl, C3-C8 cycloalkylphenyloxy, halogen, morpholino, and pyrrolidinyl, pyridyl, pyrrolidinyl, piperidinyl optionally substituted by methyl, or phenyl optionally substituted by one selected from the group consisting of halogen, C1-C6 alkoxy, nitro, amino, cyano, C1-C6alkylamino, di (Cl-C6alkyl) amino, and mono-, di-or tri- halogen substituted C1-C6alkyl, R2 represents -COR21 or -(CH2)n-R21, wherein R2'represents mono-, di-, tri-halogen sub- stituted Cl-C6 alkyl, morpholino, C1-C6 alkoxy, hydroxy, C3 to C8 cycloalkyl, pyridyl, furanyl, thiophenyl, pyrrolidinyl, piperidinyl optionally substituted by one substituent selected from the group consisting of benzyl, Cl-C6 alkoxycarbonyl, and halo C1-C6 allcyloxycarbonyl, or phenyl optionally substituted by one substituent selected fi-om the group consisting of Cl-C6 alkyl, halogen, C1-C6 alkoxy, and mono-, di-, or tri-halogen substituted Cl-alkyl ;

n is 0 or 1 ; and R'independently represent hydrogen, halogen, cyano, hydroxy, amino, C1-6 alkylamino, di (Cl. 6 alkyl) amino, C3-8 cycloalkylamino, Cl 6 alkoxycarbonyl, sulfamoyl, C1-6 alkyl- aminosulfonyl, di (CI-6 alkyl) aminosulfonyl, Cl 6 alkanoyl, CI-6 alkanoylamino, carbamoyl, Cl. alkylcarbamoyl, di-(Cl 6 alkyl) carbamoyl, Cl 6 alkylsulfonyl, C1-6 alkyl optionally substituted by C1-6 alkoxycarbonyl or mono-, di-, or tri-halogen, C1-6 alkoxy optionally substituted by mono-, di-, or tri-halogen, or C1-6 alkylthio optionally substituted by mono-, di-, or tri-halogen; R'represents hydrogen, nitro, cyano, hydroxy, halogen, sulfamoyl, C,-C6alkylsulfonyl, Cl- C6alkylaminosulfonyl, di (C-C6alkyl) aminosulfonyl,- (CH2)m-CO-R50, -(CH2)m-R51, -NR52R53, or -OR54, wherein m is 0,1, 2, or 3 R50 is hydroxy, hydrogen, C1-C6alkoxy, morpholino, diphenylmethyloxy, -NR501R502 (wherein said R501 and R502 independently represent hydrogen, C1-C6alkoxyalkyl, C,-C6alkyl, hydroxy C1-C6alkyl, C1-C6alkoxycarbonyl C1-C6alkyl, or carboxy Cl- C6alkyl or R501 and R502 together form with the adjacent N atom morpholino, 4-6 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl) or Cl-C6 alkyl optionally substituted by halogen, is hydrogen, hydroxy, or -NR511R512 (wherein said R511 and R512 independently represent hydrogen, Cl-C6 alkoxyalkyl, C1-C6 alkyl, hydroxyalkyl, C1-C6 alkoxy- carbonylalkyl, or carboxyalkyl or R511 and R512 together form with the adjacent N atom, 4-7 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl) R52 and R53 independently represent hydrogen, Cl-C6 alkyl, hydroxy, C3-Cscycloalkyl- carbonyl, or hydroxy Cl-C6 alkyl or R52 and R53 together form with adjacent N atom, morpholino, 4-7 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl R54 represents alkyl optionally substituted by morpholino, amino, or di (alkyl) amino, or mono-, di-, or tri-halogen ; and

R6 and R7 independently represent hydrogen, morpholino,. hydroxypyrrolidinylcarbonyl, hydroxyC-C6alkylaminocarbonyl, cyano, hydroxy, hydroxyC,-C6alkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, C1-6 alkylamino, di (C1-6 alkyl) amino, C35 cycloalkylamino, C1 6 alkoxycarbonyl, sulfamoyl, Cl-6 alkylaminosulfonyl, di (C1-6 alkyl) aminosulfonyl, C ;-6 alkanoyl, C1-6 alkanoylamino, carbamoyl, diphenylmeth- yloxycarbonyl, C1-6 alkylcarbamoyl, di-(C1-6 alkyl) carbamoyl, Cl. alkylsulfonyl, C, _6 alkyl optionally substituted by alkoxyalkyl (alkyl) amino, di (alkyl) amino, C1-6 alkoxycarbonyl, carboxy, or mono-, di-, or tri-halogen, Cl 6 alkoxy optionally substituted by morpholino, di (alkyl) amino, or mono-, di-, or tri-halogen, or C1-6 alkylthio optionally substituted by mono-, di-, or tri-halogen or R6 and R7 together form phenyl fused to adjacent phenyl.

Yet another embodiment of formula (1) can be those wherein: X represents CH2, NH, S, or SO ; R'represents cyclopropyl, pyridyl, phenyl optionally substituted by halogen, Cl-C6alkoxy, nitro, amino, cyano, Cl- C6alkylamino, di (CI-C6alkyl) amino, or halogen substituted Cl-Coalkyl, C1-C6 alkyl optionally substituted by one or two substituents selected from the group con- sisting of Cl-C6alkoxy, amino, C1-C6 alkylamino, di (Cl-C6 alkyl) amino, Cl-C6 alkanoyloxy, hydroxy, C3-C8 cycloalkyl, carboxy, C1-C6 alkoxycarbonyl, C3-C8 cycloalkylphenyloxy, halogen, morpholino, and pyrrolidinyl, pyrrolidinyl, or piperidinyl optionally substituted by methyl; R represents -COR21 or -(CH2)n-R21, wherein R21 represents mono-, di-or tri-halogen substi- tuted alkyl, morpholino, C1-C6alkoxy, hydroxy, C3 to Cs cycloalkyl, pyridyl, furanyl, thiophenyl, pyrrolidinyl, piperidinyl optionally substituted by one selected from the group consisting from benzyl, Cl-C6alkoxycarbonyl, and haloC,-C6alkyloxycarbonyl, or phenyl optionally substituted by one selected from the group consisting of C1-C6 alkyl, halogen, Cl-Cd alkoxy, and mono-, di-or tri-halogen substituted Cl-C6alkyl ; n is 0 or 1 ; R3 and R4 independently represent hydrogen, halogen, methyl, or amino;

R'represents hydrogen, morpholino, hydroxypyrrolidinylcarbonyl, hydroxyalkylaminocatbonyl, cyano, hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, Ci. g alkylamino, di (C1-6 alkyl) amino, C38 cycloalkylamino, CI-6 alkoxycarbonyl, sulfamoyl, C1-6 alkylaminosulfonyl, di (C1-6 alkyl) aminosulfonyl, C1_6 alkanoyl, C-6 alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, C1-6 alkylcarbamoyl, di-(C1-6 alkyl) carbamoyl, C1-6 alkylsulfonyl, Cl 6 alkyl optionally substituted by alkoxy- alkyl (alkyl)amino, di (alkyl) amino, C1-6 alkoxycarbonyl, carboxy, or mono-, di-, or tri- halogen, C1-6 alkoxy optionally substituted by morpholino, di (alkyl) amino, or substituted by mono-, di-, or tri-halogen, or C1-6 alkylthio optionally substituted by mono-, di-, or tri- halogen; and R6 and R7 represènt hydrogen, or R6 and R7 together form phenyl fused to adjacent phenyl.

Yet another embodiment of formula (I) can be those wherein: X represents CH2, NH, or S ; R'represents cyclopropyl, pyridyl, phenyl optionally substituted by halogen, alkoxy, nitro, amino, cyano, alkylamino, di (alkyl) amino, or halogen substituted alkyl, C-C6 alkyl optionally substituted by one or two substituents selected from the group consisting of alkoxy, amino, C1-C6 alkylamino, di (C1-C6 alkyl) amino, Cl-C6 alkanoyloxy, hydroxy, C3-C8 cycloalkyl, carboxy, Cl-C6 alkoxycarbonyl, C3-Cg cycloalkylphenyloxy, halogen, morpholino, and pyrrolidinyl, pyrrolidiny, or piperidinyl optionally substituted by methyl.

Further, another embodiment of formula (I) can be those wherein : X represents CH2, NH, or S; R2 represents -COR21, -(CH2)nR21, wherein R21 is phenyl optionally substituted by C1-C6 alkyl, halogen, halogen substituted alkyl or alkoxy and n is 0 or 1.

Additional embodiment of formula (I) can be those wherein: X represents CH2, NH, or S; R3 and R4 independently represent hydrogen, halogen, methyl, amino; and

R 5 represents hydrogen, morpholino, hydroxypyrrolidinylcarbonyl, hydroxyalkyramino- carbonyl, cyano, hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, C1-6 alkylamino, di (C1-6 alkyl) amino, C3-8 cycloalkylamino, C1-6 alkoxy- carbonyl, sulfamoyl, Ci. 6 alkylaminosulfonyl, di (C1-6 alkyl) aminosulfonyl, Ci. e alkanoyl, . C,-6 alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, C1-6 alkylcarbamoyl, di-(C1-6 alkyl) carbamoyl, C, -6 alkylsulfonyl, C1-6 alkyl optionally substituted by alkoxy- alkyl (alkyl) amino, di (alkyl) amino, C1-6 alkoxycarbonyl, carboxy, or mono-, di-, or tri- halogen, C). 6 alkoxy optionally substituted by morpholino, di (alkyl) amino, or substituted by mono-, di-, or tri-halogen, or Cl 6 alkylthio optionally substituted by mono-, di-, or tri- halogen; and R6 and R7 represents hydrogen.

More preferably, said phenyltriazole derivative of the formula (I) is selected from the group consisting of: (4-{3-cyclopropyl-5-[(diphenylmethyl)thio]-4H-1, 2, 4-triazol-4-yl}phenyl) dimethylamine; (4- {3- [ (diphenylmethyl) thio]-5-ethyl-4H-l, 2, 4-triazol-4-yl} phenyl ! dimethylamine ; (4- {3- [ (diphenylmethyl) thio]-5-propyl-4H-l, 2, 4-triazol-4-yl} phenyl) dimethylamine ; [4-(3-cyclopropyl-5-{[(2-methylphenyl) (phenyl) methyl] thio}-4H-1, 2, 4-triazol-4-yl) phenyl] dimeth- ylamine; [4- (3- { [bis (4-chlorophenyl) methyl] thio}-5-cyclopropyl-4H-1, 2,4-triazol-4-yl)phenyl]dimethyl- amine; [4- (3-cyclopropyl-5- { [ (4-methylphenyl) (phenyl) methyl] thio}-4H-1, 2,4-triazol-4-yl) phenyl] dimeth- ylamine ; [4-(3-{[bis(4-fluorophenyl) methyl] thio}-5-cyclopropyl-4H-1, 2, 4-triazol-4-yl) phenyl] dimethyl- amine; [4- (3- { [(4-chlorophenyl) (phenyl) methyl] thio}-5-cyclopropyl-4H-1, 2, 4-triazol-4-yl) phenyl]dimeth- ylamine; (4- {3-cyclobutyl-5-[(diphenylmethyl)thio]-4H-1,2,4-triazol-4-yl }phenyl)dimethylamine ; (4- {3-butyl-5-[(diphenylmethyl) thio]-4H-1, 2, 4-triazol-4-yl} phenyl) dimetlylamine ;

[4- (3- { [bis (4-methylphenyl) methyl] thio}-5-cyclopropyl-4H-1, 2,4-triazol-4-yl) phenyl] dimetH-' ylamine ; {4-[3-cyclopropyl-5-( {phenyl [4- (trifluoromethyl) phenyl] methyl} thio)-4H-1, 2, 4-triazol-4-yl] phen- yl} dimethylamino; [4-(3-{[4-chlorophenyl)(cyclohexyl) methyl] thio}-5-cyclopropyl-4H-1, 2, 4-triazol-4-yl) phenyl] di- methylamine ; 3-[(diphenylmethyl) thio]-5-ethyl-4-(4-isopropylphenyl)-4H-1, 2, 4-triazole ; {4-[2-{[bis(4-chlorophenyl)methyl]thio}-5-(3-fluorophenyl)-4 H-1, 2, 4-triazol-4-yl] phenyl} dimeth- ylamine; [4- (3- { [bis (4-chlorophenyl) methyl] thio}-5-propyl-4H-1, 2, 4-triazol-4-yl) phenyl] dimethylamine ; 3- (3- { [bis (4-chlorophenyl) methyl] thio}-5-propyl-4H-1, 2, 4-triazol-4-yl) benzoic acid; 3- {5- { [bis (4-chlorophenyl) methyl] thio}-4- [4- (dimethylamino) phenyl]-4H-1, 2, 4-triazol-3- yl} propan-1-ol ; 3-[3-{ [bis (4-chlorophenyl) methyl] thio}-5- (3-fluorophenyl)- 4H-1, 2, 4-triazol-4-yl] benzoic acid ; 3-[3-{[bis(4-chlorophenyl) methyl] thio}-5- (3-fluorophenyl)- 4H-1, 2, 4-triazol-4-yl] phenol ; 3- (3- { [bis (4-chlorophenyl) methyl] thio)-5-propyl-4H-1, 2, 3-triazol-4-yl) benzoic acid; 3- (3- { [bis (4-chlorophenyl) methyl] thio}-5-cyclopropyl-4H-1, 2, 4-triazol-4-yl) benzoic acid; 5- [3- { [bis (4-chlorophenyl) methyl] thio}-5- (3-fluorophenyl)-4H-1, 2, 4-triazol-4-yl]-2- (dimethyl- amino) benzoic acid; 1- [4- (3- { [bis (4-chlorophenyl) methyl] thio}-5-propyl-4H-1, 2, 4-triazol-4-yl) phenyl]-piperidine-3- carboxylic acid; and 1- {4- [3- { [bis (4-chlorophenyl)methyl]thio}-5-(3-fluorophenyl)-4H-1,2,4-tri azol-4-yl]-phenyl}- piperidine-3-carboxylic acid or the salt thereof.

Further, the present invention provides a medicament, which includes one of the compounds, described above and optionally pharmaceutically acceptable excipients.

Alkyl per se and"alk"and"alkyl"in alkenyl, alkynyl, alkoxy, alkanoyl, alkylamino, alkylamino- carbonyl, alkylaminosulphonyl, alkylsulphonylamino, alkoxycarbonyl and alkoxycarbonylamino represent a linear, branched alkyl radical having generally 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms, representing illustratively and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

"Alk"in alkanoylamino represent a linear, branched and cyclo alkyl radical having generally 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms, representing illustratively and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, n-hexyl, and cyclopropyl.

Alkoxy illustratively and preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, tert- butoxy, n-pentoxy and n-hexoxy.

Alkylamino illustratively and preferably represents an alkylamino radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexyl-amino, N, N- <BR> <BR> <BR> <BR> dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N- isopropyl-N-n-propylamino, N-t-buyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl- N-methylamino.

4-7 membered. saturated Cyclic amine illustratively and preferably represent pyrrolidine, piperidine, azepane, and azetidine.

Heterocycle and/or heterocyclic as used herein, designate a closed ring structure, in which one or more of the atoms in the ring is a heteroatom such as sulfur, nitrogen, oxygen, and the like.

Suitable examples include, without limitation, pyrrolidinyl, piperidino, piperazinyl, homo- piperidino, morpholinyl, thiomorpholinyl, tetrahydrofuryl, furyl, thienyl, pylTolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl and the like.

EMBODIMENT OF THE INVENTION The compound of the formula (I) of the present invention can be, but not limited to be, prepared by combining various known methods. In some embodiments, one or more of the substituents, such as amino group, carboxyl group, and hydroxyl group of the compounds used as starting materials or intermediates are advantageously protected by a protecting group known to those skilled in the art. Examples of the protecting groups are described in"Protective Groups in Organic Synthesis (3rd Edition) "by Greene and Wuts, John Wiley and Sons, New York 1999. The compound of the formula (I-a) of the present invention can be, but not limited to be, prepared by the Method [A] below.

[Method A]

The compound of the formula (I-a) (wherein R', R', R', R, R', R° and R' are the same as defined above and X'represents O, S or NR12) can be prepared by reacting the compound of the formula (In (wherein R', R5, R6 and R7 are the same as defined above) with the compound of the formula (E) (wherein R2, R3 and R4 are the same as defined above and L, represents a leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom; Cg. io arylsulfonyloxy group such as benzenesulfonyloxy, or p-toluenesulfonyloxy ; and Cl-4 alkylsulfonyloxy group such as methanesulfonyloxy, and the like.) The reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1, 2-dichloroethane ; ethers such as diethyl ether, iso- propyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane ; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethyl- formamide (DMF), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP) ; urea such as 1, 3-dimethyl-2-imidazolidinone (DMI) ; sulfoxides such as dimethylsulfoxide (DMSO) ; and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about 20°C to 50 °C. The reaction may be conducted for, usually, 30 minutes to 10 hours and preferably 1 to 24 hours.

The reaction can be advantageously carried out in the presence of a base including, for instance, organic amines such as pyridine, triethylamine and N, N-diisopropylethylamine, dimethylaniline, diethylaniline, or 4-dimethylaminopyridine, and inorganic base such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, or potassium bicarbonate, and others.

R5, R6, and/or R7 of compound of the formula (I) can be further modified using conventional methods.

X'is further modified to be converted to SO or SO2.

Preparation of intermediate (II-a) [Method (i)] s cs H N-N N-NHa NCS N-HNH R/' - , N S H --\0 tep i-2 O R6 Step i-1 R Step i-2 R5 R a-6 R5 R () . R' (viz (Il-a) The compound of the formula (II-a) (wherein R', Rs) R6 and R7 are the same as defined above) can be prepared by the following procedures in two steps.

In Step i-1, the compound of the formula (VI) (wherein R', R5, R6 and R7 are the same as defined above) can be prepared by reacting the compound of the formula (IV) (wherein R'is the same as defined above) with the compound of the formula (V) (vherein R5, R5 and R7 are the same as defined above).

The reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1, 2-dichloroethane; ethers such as diethyl ether, iso- propyl ether, dioxane and tetrahydrofuran (THF) and 1, 2-dimethoxyethane ; aromatic hydrocarbons such as benzene, toluene and xylene ; nitriles such as acetonitrile; amides such as N, N- dimethylformamide (DMF), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP) ; urea such as 1, 3-dimethyl-2-imidazolidinone (DMI) ; sulfoxides such as dimethylsulfoxide (DMSO) ; and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about room temperature to 100°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 24 hours.

In Step i-2, the compound of the formula (lI-a) (wherein Rl, R5, R6 and R are the same as defined above) can be prepared by cyclization reaction of the compound of the formula (VI) (wherein R', R5, R'and R'are the same as defined above).

The reaction can be advantageously carried out in the presence of a base including, for instance, organic amines such as pyridine, triethylamine and N, N-diisopropylethylamine, dimethylaniline, diethylaniline, or 4-dimethylaminopyridine, and inorganic base such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, or potassium bicarbonate, and others.

The reaction can be carried out in a solvent including, for instance, alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol, water and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about 0°C to 200°C and preferably about 20°C to 100°C. The reaction may be conducted for, usually, 30 minutes to 4S hours and preferably 2 hours to 24 hours.

The compound of the formula (V) is commercially available or can be prepared by the use of known techniques.

Preparation of intermediate [Method (ii)] 0 C) H 2N-NH, Rv/'. L H R L2 Step ii-1a (IV) (Vll) \ p ii-1b | Step ii-2b O H2N L3 R N,, N, L, H a (VIII) (IX) In step ii-la, the compound of the formula (IV) (wherein R'is the same as defined above) can be prepared by reacting the compound of the formula (VII) (wherein R'is the same as defined above and L2 represents a leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom, hydroxy and C). 6 alkoxy) with hydrazine (free base, its salt or its hydrate).

The reaction can be carried out in a solvent including, for instance, alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butahol, water and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about 0°C to 200°C and preferably about 0°C to 100°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 24 hours.

Alternatively, the compound of the formula (fiv) can be prepared by the following procedures.

In Step ii-lb, the compound of the formula (IX) (wherein wherein R'is the same as defined above and L3 represents a protecting group including, for instance, tert-butoxycarbonyl) can be prepared by reacting the compound of the formula (VIt) (wherein R'and L2 are the same as defined above) with the compound of the formula (VE¢) (wherein L3 is the same as defined above).

When L, is hydroxy, the reaction can be done using a coupling agent including, for instance, carbodiimides such as N, N-dicyclohexylcarbodiimide and 1- (3-dimethylaminopropyl)-3-ethyl- carbodiimide, benzophenyltriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide. N-hydroxysuccinimide, 1-hydroxybenzotiazole monohydrate (HOBt), and the like can be used as an accelerator of the reaction.

The reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1, 2-dichloroethane ; ethers such as diethyl ether, iso- propyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane ; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N- dimethylformamide (DMF), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea such as 1, 3-dimethyl-2-imidazolidinone (DMI) ; sulfoxides such as dimethylsulfoxide (DMSO); and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about 0°C to 180°C and preferably about 20°C to 100°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 12 hours.

In Step ii-2b, the compound of the formula (IV) (wherein R'is the same as defined above) can be prepared by removing the protecting group L3 of the compound of the formula (IX) (wherein R' and L3 are the same as defined above).

The removal of protective group L3 can be done by using a reagent including, for instance, an acid such as trifluoroacetic acid and hydrochloric acid.

The reaction may be carried out without solvent or in a, solvent including, for instance, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1, 2-dimethoxyethane ; aromatic hydrocarbons such as benzene, toluene and xylene ; nithles such as acetonitrile, amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC) and N- methylpyrrolidone (NMP); urea such as 1, 3-dimethyl-2-imidazolidinone (DMI) ; and others.

Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on compoundss to be reacted. The reaction temperature is usually, but not limited to, about 20°C to 120°C. The reaction may be conducted for, usually, 30 minutes to 60 hours and preferably 1 to 48 hours.

Hydrazine (free base, its salt or its hydrate), the compound of the formula (VE) and (VE) are commercially available or can be prepared by the use of Icnown techniques.

Alternative procedures for the preparation of intermediate (VI) [Method (iii)] NUS Lav Lav H-NH R H-H NH HN-'HNH + 6-t N s S (X) (Xi) (xi) S - Nlk NH L'J 0 R O/R7 Step iii-3 R (vy The compound of the formula (VI) (wherein R', R5, R6 and R'are the same as defined above) can be alternatively prepared by the following procedures in three steps.

In Step iii-1, the compound of the formula (X) (wherein wherein L3, R5, R6 and R7 are the same as defined above) can be prepared by reacting the compound of the formula (VD) (wherein L3 is the

same as defined above) with the compound of the formula (V) (wherein R5, R6 and R7 are the same as defined above) in a similar manner described in Step i-1 for the preparation of compounds of the formula (VI).

In Step iii-2, the compound of the formula (XI) (wherein R5, R6 and R7 are the same as defined above) can be prepared by removing the protecting group L3 of the compound of the formula (X) (wherein L3, R5, R6 and R'are are the same as defined above) in a similar manner described in Step ii-2b for the preparation of compounds of the formula (IV).

In Step iii-3, the compound of the formula (VI) (wherein R', R5, R6 and R7 are the same as defined above) can be prepared by reacting the compound of the formula (XI) (wherein R5, R6 and R7 are the same as defined above) with the compound of the formula (VII) (wherein R'and L2 are the same as defined above) in a similar manner described in Step ii-la for the preparation of compounds of the formula (IV).

Preparation of intermediate (II-b) [Method (iv)] L2 H R N 1 V 1 Rs Stepiv-1 R R' Step iv-2 R5 R6 Step iv-1 R5 Rs R (hll I) (XIV), (XIV) (Xll) (Xlil) N-N 1 H2N-NH2 R N Br N R N-7 3-6-- Step iv-4 Srep iv-3 HZN 5 s' R R Rs Rs (XV) (I l-b) The compound of the formula (II-b) (wherein R', R5, R6 and R7 are the same as defined above) can be prepared by the following procedures.

In Step iv-1, the compound of the formula (XIII) (wherein R', R5, R° and R7 are the same as defined above) can be prepared by reacting the compound of the formula (XII) (wherein R5, R6 and R7 are the same as defined above) with the compound of the formula (VII) (wherein R'and L2 are the same as defined above).

When L2 is hydroxy, the reaction can be done using a coupling agent including, for instance, carbodiimides such as N, N-dicyclohexylcarbodiimide and 1- (3-dimethylaminopropyl)-3-ethyl- carbodiimide, benzophenyltriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide. N-hydroxysuccinimide, 1-hydroxybenzotiazole monohydrate (HOBt), and the like can be used as an accelerator of the reaction.

The reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane ; ethers such as diethyl ether, iso- propyl ether, dioxane and tetrahydrofuran (THF) and 1, 2-dimethoxyethane ; aromatic hydrocarbons such as benzene, toluene and xylene ; nitriles such as acetonitrile; amides such as N, N-dimethyl- formamide (DMF), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP) ; urea such as 1, 3-dimethyl-2-imidazolidinone (DMn ; sulfoxides such as dimethylsulfoxide (DMSO); and others Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about 0°C to 180°C and preferably about 20°C to 100°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 12 hours.

In Step iv-2, the compound of the formula (XIV) (wherein Rl, R5, VEt6 and R7 are the same as defined above) can be prepared by reacting the compound of the formula (XE) (wherein Rl, R5, R6 and R7 are the same as defined above) with an appropriate halogenating reagent including, for instance, SOC12, POCl3, and the like.

The reaction may be carried out without solvent or in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane ; ethers such as dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane ; aromatic hydrocarbons such as benzene, toluene and xylene, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about 0°C to 200°C and preferably about 20°C to 100°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 24 hours.

In Step iv-3, the compound of the formula (XV) (wherein R, R5, R and R'are the same as defined above) can be prepared by reacting the compound of the formula (XIRI) (wherein R', R5, R6 and R' are the same as defined above) with hydrazine (free base, its salt or its hydrate).

The reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1, 2-dichloroethane ; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1, 2-dimethoxyethane ; aromatic hydro- carbons such as benzene, toluene and xylene ; nitriles such as acetonitrile ; amides such as N, N-di- methylformamide (DMF), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP) ; urea such as 1, 3-dimethyl-2-imidazolidinone (DMt) ; sulfoxides such as dimethylsulfoxide (DMSO); and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about 0°C to 180°C and preferably about 20°C to 100°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 12 hours.

In Step iv-4, the compound of the formula (II-b) (wherein R', R5, 6 and R7 are the same as defined above) can be prepared by reacting the compound of the formula (XV) (wherein R', R5, R6 and R' are the same as defined above) with cyanogen halides such as cyanogen bromide.

The reaction may be carried out in a solvent including, for instance, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1, 2-dimethoxyethane ; aromatic hydro- carbons such as benzene, toluene and xylene; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone ; alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol; and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about-10°C to 200°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 hour to 24 hours.

The compound of the formula (XII) is commercially available or can be prepared by the use of known techniques. Preparation of intermediate (ni) [Method (v)]- 0 H R 3 R'L4 (XVII) ; I R R (XVI) Step v-1 3 Step v-2 3 HO-Q Ll-'-a R4 R 4 o uR3 Step v'-1 / 4 zizi (XIX)

The compound of the formula (III) (wherein R2, R'and R4 are the same as defined above) can be prepared by the following procedures.

In Step v-1, the compound of the formula (XVE) (wherein wherein R2, R3 and R4 are the same as defined above) can be prepared by reacting the compound of the formula (XVI) (wherein R3 and R4 are the same as defined above) with the compound of the formula (XVH) (wherein R is the same as defined above and L4 represents metal or metal complex including, for instance, lithium, magnesium chloride and magnesium bromide).

The reaction may be carried out in a solvent including, for instance, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1, 2-dimethoxyethane ; aliphatic hydrocarbons such as n-hexane, cyclohexane ; aromatic hydrocarbons such as benzene, toluene and xylene; and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about-20°C to 50°C.

The reaction may be conducted for, usually, 30 minutes to 10 hours and preferably 1 to 24 hours.

The compound of the formula (XVIII) (wherein wherein R, R3 and R4 are the same as defined above) can be alternatively prepared by reacting the compound of the formula (XIX) (wherein R2, R3 and R4 are the same as defined above) with a reducing agent including, for instance, sodium borohydride or lithium aluminum hydride as shown in Step v'-1.

The reaction may be carried out in a solvent including, for instance, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1, 2-dimethoxyethane ; aliphatic hydro-

carbons such as n-hexane, cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about 20°C to 50°C.

The reaction may be conducted for, usually, 30 minutes to 24 hours and preferably 1 to 10 hours.

In Step v-2, the compound of the formula (E) (wherein Ll, R2, R3 and R4 are the same as defined above) can be prepared by reacting the compound of the formula (XVIS) (wherein wherein R2, R3 and R4 are the same as defined above) with an appropriate halogenating reagent including, for instance, POC13, PCIs, SOCS, and the like; or with the corresponding sulfonyl chloride for instance methanesulfonyl chloride.

The reaction may be carried out without solvent or in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane ; ethers such as dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane ; aromatic hydrocarbons such as benzene, toluene and xylene, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction can be advantageously conducted in the presence of a base, including, for instance, pyridine, triethylamine and N, N-diisopropylethylamine, dimethylaniline, diethylaniline, and others.

The reaction temperature is usually, but not limited to, about 0°C to 200°C and preferably about 20°C to 100°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 24 hours.

The compound of the formula (XVI), (XVII) and (XIX) are commercially available or can be prepared by the use of known techniques.

Preparation of compound of (I-b) The compound of the formula (I-b) of the present invention can be, but not limited to be, prepared by the Method [B] below.

[Method B]

The compound of the formula (I-b) (wherein R', R2, R3, R4, R5, R6, R', Rl° and R"are the same as defined above) can be prepared by reacting the compound of the formula (JXV) (wherein Rl, R5, R6 and R7 are the same as defined above) with the compound of the formula (XS) (wherein R2, R3, R4, R° and R"are the same as defined above and L4 represents a leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom).

The reaction can be carried out in a solvent including, for instance, alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol, water and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used. he reaction temperature can be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about 20°C to 50 °C. The reaction may be conducted for, usually, 30 minutes to 24 hours and preferably 1 to 10 hours.

The compound of the formula (XX) is commercially, available or can be prepared by the use of known techniques.

When the compound shown by the formula (I) or a salt thereof has an asymmetric carbon in the structure, their optically active compounds and racemic mixtures are also included in the scope of the present invention.

Typical salts of the compound shown by the formula (I) include salts prepared by reaction of the compounds of the present invention with a mineral or organic acid, or an organic or inorganic base. Such salts are lcmorvn as acid addition and base addition salts, respectively.

Acids to form acid addition salts include inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid and the like, and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.

Base addition salts include those derived from inorganic bases, such as, without limitation, ammonium hydroxide, alkaline metal hydroxide, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, tris (hydroxymethyl) aminomethane, and the like. Examples of inorganic bases include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.

The compound of the present invention or a salt thereof, depending on its substituents, may be modified to form lower alkylesters or known other esters; and/or hydrates or other solvates. Those esters, hydrates, and solvates are included in the scope of the present invention.

The compound of the present invention may be administered in oral forms, such as, without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions. They may also be administered in parenteral forms, such as, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like forms, tell-brown to those of ordinary skill in the pharmaceutical arts. The compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal delivery systems well-knonvn to those of ordinary skilled in the art.

The dosage regimen with the use of the compounds of the present invention is selected by one of ordinary skill in the arts, in view of a variety of factors, including, without limitation, age, weight, sex, and medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed, the particular compound and salt thereof employed.

The compounds of the present invention are preferably formulated prior to administration together with one or more pharmaceutically-acceptable excipients. Excipients are inert substances such as, without limitation carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material.

Yet another embodiment of the present invention is pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically-acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Pharmaceutical formulations of the invention are prepared by combining a therapeutically effective amount of the compounds of the invention together with one or more pharmaceutically- acceptable excipients therefore. In making the compositions of the present invention, the active ingredient may be mixed with a diluent, or enclosed within a carrier, which may be in the form of a

capsule, sachet, paper, or other container. The carrier may serve as a diluent, which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

For oral administration, the-active ingredient may be combined with an oral, and non-toxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose, and the like; together with, optionally, disintegrating agents, such as, without limitation, maize, starch, methyl cellulose, agar bentonite, xanthan gum, alginic acid, and the like; and optionally, binding agents, for example, without limitation, gelatin, natural sugars, beta- lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, tale, and the like.

In powder forms, the carrier may be a finely divided solid which is in admixture with the finely divided active ingredient. The active ingredient may be mixed with a carrier having binding properties in suitable proportions and compacted in the shape and size desired to produce tablets.

The powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel composition of the present invention. Suitable solid carriers are magnesium carboxymethyl cellulose, low melting waxes, and cocoa butter.

Sterile liquid formulations include suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carriers, such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.

The active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol. Other compositions can be made by dispersing the finely divided active ingre- dient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.

The formulation may be in unit dosage fonn, which is a physically discrete unit containing a unit dose, suitable for administration in human or other mammals. A unit dosage form can be a capsule or tablets, or a number of capsules or tablets. A"unit dose"is a predetermined quantity of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more excipients. The quantity of active ingredient in a unit dose may be

varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved.

Typical oral dosages of the present invention, when used for the indicated effects, will range from about 0.01 mg/kg/day to about 100 mg/lcg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day. In the case of parenteral administration, it has generally proven advantageous to administer quantities of about 0.001 to 100mg/kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or more times per day. Where delivery is via transdermal forms, of course, administration is continuous.

EXAMPLES The present invention will be described as a form of examples, but they should by no means be construed as defining the metes and bounds of the present invention.

In the examples below, all quantitative data, if not stated otherwise, relate to percentages by weight.

Mass spectra were obtained using electrospray (ES) ionization techniques (micromass Platform LC). Melting points are uncorrected. TLC was performed on a precoated silica gel plate (Merck silica gel 60 F-254). Silica gel (WAKO-gel C-200 (75-150 um)) was used for all column chromatography separations. All chemicals were reagent grade and were purchased from Sigma- Aldrich, Wako pure chemical industries, Ltd. , Great Britain, Tokyo kasei kogyo Co. , Ltd. , Nacalai tesque, Inc., Watanabe Chemical Ind. Ltd. , Maybridge plc, Lancaster Synthesis Ltd., Merck KgaA, Germany, Kanto Chemical Co. , Ltd.

Analytical HPLC Retention times of intermediates and examples are measured as follows: Method A Equipment: Waters 2690 separation module Column temperature: 40 °C.

Mobile phase: water/acetonitrile (each of them containing lOmM ammonium acetate) Column: Chromolith Rash RP-18e, 25 * 4. 6mm Flow rate: 1.3 mL/min.

Injection volume : 5 gL Gradient (Time) : (water/acetonitrile) 0 Minutes : 9/1 0.2 Minutes: 9/1 2.0 Minutes: 1/9 3.5 Minutes: 1/9 4.0 Minutes: 9/1

Method B Equipment: Hewlett Packard series 1100 Column temperature: 40 °C.

Mobile phase : water/acetonitrile (each of them containing l OmM ammonium acetate) Column: YMC PackPro C-18, 35 * 4. 6mm Flow rate: 1.0 mL/min.

Injection volume: 5 microL Gradient (Time) : (water/acetonitrile) 1 Minutes: 9/1 0.1 Minutes: 9/1 1.5 Minutes: 1/9 3.5 Minutes: 1/9 4.5 Minutes: 9/1 Method C Equipment: Hewlett Packard series 1100 Column temperature: 40 °C.

Mobile phase: water/acetonitrile (each of them containing lOmM ammonium acetate) Column: Phenomenex Luna 3u C18 (2) 30 * 4. 6mm Flow rate: 1.0 mL/min.

Injection volume: 10 microL Gradient (Time) : (water/acetonitrile) 2 Minutes : 9/1 0.5 Minutes: 9/1

4.5 Minutes: 1/9 6.5 Minutes: 1 / 9 8.5 Minutes: 9/1 HPLC-Methods: Analytical HPLC as follows were determined on a HP 1100 with DAD-detection (Hewlett Packard) under the following conditions: Method 2A Column: Kromasil CIS 60*2 at 30 °C ; injection volume: 1.00 ul ; flowrate : 0.75 ml/min ; eluent: A= 0.01 M H3PO4 in H2O, B= CH3CN ; gradient [t (min) : A/B]: 0.0 : 90/10; 0.5 : 90/10; 4.5 : 10/90 ; 8.0 : 10/90; 8.5 : 90/10 10.0 : 90/10.

Method 2B Column: Kromasil C18 60*2 at 30 °C ; injection volume: 0.20-0. 30 Ill ; flowrate: 0.75 ml/min; eluent: A= 0.01 M H3PO4 in H2O, B= CH3CN ; gradient [t (min) : A/B] : 0.0 : 90/10 ; 0.5 : 90/10; 4.5 : 10/90; 6.5 : 10/90; 7.5 : 90/10.

Method 2C Column : Kromasil C18 60*2 at 30 °C ; injection volume: 1. 0 µl ; flowrate : 0. 75 ml/min ; eluent: A= 5ml 70% HC104/IL H2O, B= CH3CN ; gradient [t (min): A/B] : 0.0 : 98/2; 0.5 : 98/2; 4.5 : 10/90; 6.5 : 10/90 ; 6.7 : 98/2; 7.5 : 98/2.

LC/MS-Methods : Retention times for peaks with the correct product mass were recorded as follows: Method 2D Instrument MS: Micromass TOF (LCT); instrument HPLC: Waters2690; column: YMC-ODS-AQ, 50 mm x 2.0 mm, 3.0 urn ; eluent A: water + 0.1% formic acid, eluent B: CH3CN + 0.1% formic acid; gradient: 0.0 min 100% A # 0. 2 min 100% A-> 2.9 min 30% A # 3.1 min 10% A # 4.5 min 10% A @ 4.51 min 100% Axe 6.5 min 100% A; oven: 40°C ; flow rate: 0. 8 ml/min ; UV-detection : 210 nm.

Method 2E Instrument MS: Micromass ZQ; instrument HPLC : Waters Alliance 2790; column : Uptisphere C 18,50 mm x 2.0 mm, 3.0 urn ; eluent A : water + 0.05% formic acid, eluent B: CH3CN + 0.05% formic acid; gradient: 0.0 min 5% B # 2. 0 min 40% B # 4.5 min 90% BE 5.5 min 90% B ; oven : 45°C ; flow rate: 0.0 min 0.75 ml/min # 4.5 min 0.75 ml/minE 5.5 min 1.25 ml/min; W- detection: 210 nm.

'H NMR spectra were recorded using either Bruker DRX-300 (300 MHz for'H) spectrometer or Brucker 500 UltraShieledTM (500 MHz for 1H). Chemical shifts are reported in parts per million (ppm) with tetramethylsilane (TMS) as an internal standard at zero ppm. Coupling constant (J) are given in hertz and the abbreviations s, d, t, q, m, and br refer to singlet, doublet, triplet, quartet, multiplet ; and broad, respectively. The mass detenninations were carried out by MAT95 (Finnigan MAT).

All starting materials are commercially available or can be prepared using methods cited in the literature.

The effect of the present compounds was examined by the following assays and pharmacological tests.

[Measurement of change of intracellular cAMP accumulation by luciferase detection in the human GABAB receptor-transfected HEK293 cell line] (Assay 1) (1) Cloning of GABAB receptors and generation of stable cell lines The human GABAB (ia), GABAB (ib) and GABAB (2) receptor subunits were cloned into pcDNA3 (Invitrogen) as previously described (White J. H. et al. , Nature 1998, 396 (6712) : 679-82). The cell culture and transfection of Human Embryonic Kidney (HEK293) cells was done as follows. HEK293-Luc cells were grown in Dulbecco's modified Eagle's medium (DMEM, Gibco BRL) supplemented with 5% modified bovine serum (MBS, Gibco BRL) in fibronectin coated 96-well microtiter plates. For transfection (mammalian transfection kit; Stratagene) cells were grown at 20000 cells per well at 35 °C with 3% C02 for 24 h with 0.1 ml per well. DNA suspension: 10 llg expression plasmid DNA of each human GABAB (aa) and human GABAB (2) in pcDNA3 was dissolved in 450 u. I of water with 50 ml CaCI2 (2.5 M) + 500 ul 2x phosphate buffered saline (PBS, pH 6.95) and incubated for 10 to 20 min at room temperature. In the meantime cell medium was aspirated and cells were washed twice with 200 IAI PBS per well and then 200 u. I medium plus 5% MBS was added. For transfection 20 u. I of

suspended DNA was added and incubated for 3 h at 35 °C with 3% COz, celts were washed with PBS and 200 ul of growth medium was added and cells were grown for 2 days. Cells were then trypsinized and diluted 1: 10 in fibronectin coated wells and incubated with growth medium supplemented with 1 mg/ml G418 (Gibco BRL) and grown under selection pressure for 10 days with 2-3 medium changes. After G418 selection cells were grown until colonies had formed.

(2) Folskolin-stimulated luciferase-reporter gene assay GABAB (tb/2)-HEK293/CRE-Iuc cells were seeded into poly-D-lysine-coated 384-well white/opaque plates (BD BIOCOAT) at 4000 cells/well in 40 pI DMEM/F12 medium supplemented with 2.5% FBS, and grown for 48 hours at 370 in a humidified atmosphere with 5% CO2. Test compounds dissolved in DMSO were diluted into DMEM/F12 medium containing 0.1% BSA and transferred to the test cultures at 5 p1/well. 10 minutes after the test compound addition, forskolin prepared in a manner similar to the test compounds was added at 5 well (1.6 uM of final concentration), and cells were then incubated for 3 hours at 370 in 5% CO2. After the incubation, the medium was discarded, followed by addition of 20 Ill/well of 1: 1 mixture of Steady-GloTT'reagent (Promega) and Phenol-red free DMEM/F12 medium. The plates were incubated at least 5 minutes to ensure complete cell lysis and then luciferase activity was measured with ViewLux microplate imager (Perkin Elmer).

[Measurement of rhythmic bladder contraction in anesthetized rats] (Assay 2) (1) Animals Female Sprague-Dawley rats (200-250 g/Charles River Japan) were used.

(2) Rhythmic bladder contraction in anesthetized rats Rats were anesthetized by intraperitoneal administration of urethane (Sigma) at 1.25 g/kg.

The trachea was cannulated with a polyethylene tube (HIBIKI, No. 8) to facilitate respiration; and a cannula (BECTON DICKINSON, PE-50) was placed in the left femoral vein for intravenous administration of testing compounds. The abdomen was opened through a midline incision, and after both ureters were cut, a water-filled baloon (about 1 ml capacity) was inserted through the apex of the bladder dome. The baloon was connected to a pressure transducer onto a polygraph. Rhythmic bladder contraction was elicited by raising up intravesical pressure to approximately 15 cm H2O. After the rhythmic bladder contraction was stable, a testing compound was administered

intravenously. Activity was estimated by measuring disappearance time and amplitude of the rhythmic bladder contraction. The effect on amplitute of bladder contractions was expressed as a percent suppression of the amplitude of those after the disappearance was recovered. Experimental values were expressed as the meanS. E. M. The testing compounds-mediated inhibition of the rhythmic bladder contraction was evaluated using Student's t-test. A probability level less than 5% was accepted as significant difference.

Results in folskolin-stimulated luciferase-reporter gene assay (Assay 1) are shown in Examples and tables of the Examples below. For practical reasons, the compounds are grouped in four classes based on activity as follows: ICso= A (< or =) 0. 1 pLM < B (< or =) 0.5 uM < C (< or ==) 1 uM < D [Cystometry in anesthetized rats] (Assay 3) Effect of a compound on cystometric parameters in rats were studied as described previously [Takeda H et al: J. Pharmacol. Exp. Ther. 126: 939-945,2000].

Female rats, weighing from 200 to 230 g, were anesthetized with urethane (1.2 g/kg i. p. ). Through a midline abdominal incision, the ureter on each side was ligated and cut proximal to the ligature.

A polyethylene catheter (PE-50) was inserted into the urinary bladder and connected through a three-way connector to: 1) a pressure transducer (Viggo-Spectramed Pte Ltd, DT-XXAD) for measurement of bladder pressure, and 2) a syringe infusion pump (TERUMO) for continuous infusion of saline into the bladder. During cystometry, saline was infused at a rate of 2.4 ml/h.

Bladder pressure was recorded continuously on a PowerLab systems (BioResearch Center). The following cystometric parameters were obtained: micturition interval and micturition pressure (maximum bladder pressure during micturition). Two reproducible micturition cycles were recorded before drug administration and used to provide a baseline value to be compared with the first two micturition cycles just after drug administration. Relative values for the. various cystometric parameters were calculated as follows: (mean value from two micturition cycles just after drug administration)/ (mean value from two micturition cycles just before drug administration). A venous catheter was inserted into the left femoral vein for drug injection.

Z used in Melting point in the following section indicates decomposition.

(Example 1-1 Method A 3- (3-benzhydrylsulfanyl-5-cyclopropyl- [1, 2,4] triazol-4-yl)-benzoic acid

A solution of 3- (3-cyclopropyl-5-thioxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzoic acid (152 mg, 0.58 mmol) iri N, N-dimethylformamide (1 mL) was added potassium carbonate (403 mg, 2.91 mmol) and bromodiphenylmethane (187 mg, 0.76 mmol), and the mixture was stirred at 60 °C for 16 hours. The inorganic salts were filtered, and the filtrate was diluted with aqueous sodium bicarbonate solution. The mixture was washed with ethylacetate, and the aqueous layer was acidified to pH 2 with 1N aqueous HCI solution. The mixture was extracted with ethylacetate, and the organic layer was concentrated under reduced pressure. The obtained residue was recrystallized from the mixture of dichloromethane, diethylether, and hexane to provide 3- {3- cyclopropyl-5-[(diphenylmethyl)thio]-4H-1, 2, 4-triazol-4-yl}benzoic acid (65.9 mg).

'H NMR (DMSO-d6) : 8 0.82-0. 89 (m, 4H), 1.48-1. 53 (m, 1H), 5.88 (s, 1H), 7.21-7. 30 (m, 10H), 7.55 (d, J= 7. 9 Hz, 1H), 7. 70-7. 74 (m, 2H), 8.12 (d, J= 7.9 Hz, 1H), 13.40 (s (br), 1H). mp 193 °C ; Molecular weight: 427. 53 MS (M+H): 428 Activity Class: B Preparation of intermediates Method (i)

A mixture of cyclopropanecarbohydrazide (255 mg, 2.55 mmol) and methyl 3-isothiocyanato- benzoate (492 mg, 2.55 mmol) in ethanol (3 mL) was stirred at refluxing temperature for 16 hours.

The mixture was concentrated under reduced pressure, and to the obtained residue was added a solution mixture of diethylether and hexane. The precipitates were collected and dried to afford methyl 3-({[2-(cyclopropylcarbonyl) hydrazino] carbonothioyl} amino) benzoate (399 mg). 1H NMR (DMSO-dó) 8 0.77-0. 79 (m, 4H), 1.60-1064 (m, 1H), 3. 32 (s, 3H), 7.47 (t, J= 7.9 Hz, 1H), 7.73 (d, J= 7.3 Hz, 1H), 7. 80 (d, J= 7.3 Hz, 1H), 8.08 (s (br), 1H), 9.86 (s (br), 1H), 10.10 (s (br), 1H) ;; MS m/z 294 (M++1).

Next, a solution of methyl 3-({[2-(cyclopropylcarbonyl)hydrazino]carbonothioyl}amino) benzoate (399 mg, 1.36 mmol) in 4N aqueous solution of sodium hydroxide (7 mL) was stirred at refluxing temperature for 16 hours. After having cooled to ambient temperature, the mixture was acidified to pH 2 with IN aqueous solution of HC1. The mixture was extracted with ethylacetate, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 3- (3-cyclopropyl-5- thioxo-1, 5-dihydro-4H-1, 2, 4-triazol-4-yl) benzoic acid (355 mg). lH NMR (DMSO-d6) õ 0.77-0. 92 (m, 4H), 1.47-1. 52 (m, 1H), 7.70-7. 77 (m, 2H), 8. 01 (s, 1H), S. 09 (d, J= 6.3 Hz, 1H), 13.00 (s (br), 1H), 13.64 (s, 1H) ; MS m/z 262 (M++1).

Preparation of intermediates Method (ii) <BR> <BR> cyclopropanecarbohydrazide

To a solution of tert-butyl hydrazinecarboxylate (6.38 g, 48.3 mmol) and triethylamine (7. 26 g, 71. 8 mmol) in dichloromethane (10 mL) was added cyclopropanecarbonyl chloride (5.00 g, 47.8 mmol) at 0 °C. The mixture was stirred for 16 hours at ambient temperature, and the resulting suspension was filtered and washed with dichloromethane. The filtrate was concentrated under reduced pressure to provide tert-butyl 2-(cyclopropylcarbonyl) hydrazinecarboxylate (13. 0 g).'H NMR (DMSO-d6) 8 0.67-0. 72 (m, 4H), 1.39 (s, 1H), 1.52-1. 54 (m, 1H), 8.64 (s, 1H), 9.70 (s, 1H).

Next, to a stirred solution of tert-butyl 2-(cyclopropylcarbonyl) hydrazinecarboxylate (3.00 g, 15.0 mmol) in 1,4-dioxane (50 mL) was added 4N HCI in 1,4-dioxane (20 mL). The mixture was stirred at 80 °C for 1 hour, and after cooled to ambient temperature, it was concentrated under reduced pressure. To the obtained residue was added ethylacetate and triethylamine (8. 04 g, 79.4 mmol), and the organic layer was washed with saturated sodium bicarbonate aqueous solution and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain cyclo- propanecarbohydrazide (0.89 g).

Preparation of intermediates Method (iv) 5- (3-fluorophenyl)-4-phenyl-4H-1, 2, 4-triazol-3-amine

To a solution of aniline (1. 00 g, 10.7 mmol) and pyridine (0.849 g, 10.7 mmol) in dichloromethane (20 mL) was added 3-fluorobenzoyl chloride, (1.70 g, 10.7 mmol) at 0 °C and stirred for 1 hour.

After water was added, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 3-fluoro-N-phenylbenzamide (2.45 g).'H NMR (DMSO-d6) 5 : 7.09-7. 15 (m, 1H), 7.33-7. 40 (m, 2H), 7.41-7. 49 (m, 1H), 7.55-7. 64 (m, 1H), 7.73-7. 84 (m, 4H); m/z 216.15 (M+l !.

Next, a mixture of 3-fluoro-N-phenylbenzamide (1.00 g, 4.65 mmol) and thionyl chloride (3.4 mL) was heated at 80 °C for 16 hours. After cooled to ambient temperature, excess of thionyl chloride was removed under reduced pressure to obtain 3-fluoro-N-phenylbenzenecarboximidoyl chloride (1.00 g).

Next, to a solution of anhydrous hydrazine (2.72 g, 84. 9 mmol) in benzene (15 mL) was added 3- fluoro-N-phenylbenzenecarboxilllidoyl chloride (0.800 g, 3.39 mmol) at 0 °C. After having stirred at room temperature for 16 hours, water was added and the mixture was extracted with diethylether. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over MgS04, filtered, and concentrated under reduced pressure to provide 3- fluoro-N-phenylbenzenecarbohydrazonamide (0.822 g).

Next, a mixture of 3-fluoro-N-phenylbenzenecarbohydrazonamide (200 mg, 0.65 mmdl) and cyanogen bromide (69.3 mh, 0. 65 mmol) in methanol (3 mL) was heated at 90 °C for 48 hours.

After having cooled to ambient remperature, the mixture was concentrated under reduced pressure, and the obtained residue was purified by preparative TLC (eluent: dichloromethane 7 methanol = 95/5) to provide 5-(3-fluorophenyl)-4-phenyl-4H-1, 2, 4-triazol-3-amine (108 mg). 'H NMR (DMSO-d6) b : 5. 82 (s, 2H), 6.90 (t, J=7. 3Hz, 1H), 6. 98-7. 27 (m, 3H), 7.28-7. 42 (m, 3H), 7.52-7. 54 (m, 2H) ; m/z 255.25 (M++1).

Preparation of intermediates Method (v)-l Phenyl (pyridin-3-yl) methanol To a solution of 3-pyridinecarboxaldehyde (1.00 g, 9.34 mmol) in tetrahydrofuran (50 mL) was added 1.09 M phenyl magnesium bromide in tetrahydrofuran solution (10.3 mL, 11.20 mmol).

After the mixture was stirred at room temperature for 2 hours, water was added and extracted with ethylacetate. The organic layer was washed with brine, dried over MgSO4 filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/diethylether 4/1) to provide phenyl (pyridin-3- yl) methanol (1.07 g).'H NMR (CDC13-d) : 5 3. 85 (1H, s), 5. 83 (1H, sz), 7.20-7. 37 (6H, m), 7.69 (1H, ddd, J = 2.5, 2.5, 7.9 Hz), 8. 38 (1H, dd, J= 2.5, 4. 8 Hz), S. 51 (1H, d, J= 2.5 Hz); MS m/z 186 (M+1).

Method (v')-l cyclobutyl (phenyl) methanol To a solution of cyclobutyl (phenyl) methanone (1.00 g, 6. 24 mmol) in methanol was added sodium borohydride (0.315 g, 7.49 mmol) at 0 °C. After the mixture was stirred for 1 hour at 0 °C, water was added and extracted with ethylacetate. The organic layer was dried over MgS04, filtered, and

concentrated under reduced pressure to obtain cyclobutyl (phenyl) methanol (1.03 g). IH'w (CDCl3-d): # 1. 74-1. 88 (4H, t, m), 1.91-2. 15 (2H, m), 2. 63 (1H, m), 4.57 (1H, d, J= 7.9 Hz), 7.23- 7.35 (5H, m).

Method (v)-2 1, 1'-(chloromethylene) bis (4-chlorobenzene)

To a solution of 4, 4'-dichlorobenzhydrol (4. 78 g, 18. 9 mmol) in dichloromethane (400 mL) was added thionyl chloride (2.81 g, 23.6 mmol) and 1H-benzotriazole (2.81 g, 23.6 mmol) at room temperature. After the mixture was stirred for 10 minutes, it was filtered, and to the filtrate was added water and extracted with dichloromethane. The organic layer was washed with 3% aqueous sodium hydroxide solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 1, 1'- (chloromethylene) bis (4-chlorobenzene) (5.14 g).'H NMR (CDC13-(6. 05 (1H, s), 7. 26-7. 32 (8H, m).

In the similar manner as described in Example 1-1 and with the use of intermediates described above, compounds in Example 1-2 to 1-167 as shown in Table 1 were synthesized.

Table 1 Melting Point Example No. Structure MW MS (M+1 ° LC Activity retention time class (roi NU N-'S s N Example 1-2 463, 603 464 189, 1 D N H3 : uCH3 Example 1-3 N-S 531, 721 (method2C) D -son\ N (method 2B) N N r Jt -S-- Non \ S w N Rt=4. 41 Example 1-5 /420, 538 B \ (method 2B) l . S Example 1-6 F 481, 549 B (method 2A) po 0 Table 1 Melting Point Example No. Structure MU MS (M+1 r LC Activity retention time class fRf \ I/ Example 1-7 426, 5S5 427 (method A) A W N-N N-N \ NN j jL-S Rt=4. 52 Example 1-S </W) 481, 549 (method 2A) 1 0 OH OH Example 1-9-N N s 443, 6185 444 Rt = 2. 75 B ' (method A) N-_ zon l _"S. 7 Example 1-10-S 480, 6118 481 (method A) 'r (methodA) , N.

Table 1 Melting Point Example No. Structure MW MS (M+1) r Aetivity retention time class lut CI_ cow Example 1-11 t 516, 5405 444 207, 8 B zu OH h)-N) , S Example 1-12 458, 58 459, 2 (method B) A (method B) N . N w N-N Example 1-13 N S 414, 57 415, 2 82. 1-86. 5 A ZU /nez xi H0//\ Example 1-14 t¢3 416, 55 417, 2 214. 4-215. 2 B zu w / _ zu Example 1-15 428, 6 429, 3 81. 2-84. 6 A w Table 1 Melting Point or HPLC Activity Example No. Structure MW MS (M+l) retention time class (Rfi /\ Example 1 16 ¢ 5< 437, 54 438, 25 156-157 A w N-N GHa '% C H3 w S Example 1-17"N'- 440, 612 441 48, 7 A t HsC C 3 a ci N-N jy \ Example 1-18 N ci 495, 476 496 57, 4 A HaC HIC N-N 440, 612 441 60, 8 A r w HCNCH3 Table 1 Melting Point or HPLC Activit Example No. Structure 1Ç'MS +1 or HPLC Activity relent xatinxe elass (Rt) 6 N-N N-N Example 1-20 N S, < 462, 566 463 41, 3 A I w H3. N. CH3 i f N-N /\\ S w Example 1-21 ? ß 485, 6998 484 (method A) B . (method A) Y zNs H0, Example 1-22 Ñ S) C 446, 6192 445 Rt-2. 54 A (method A) -S N-N w Example 1-23 558, 6217 484 203, 8 B CIL N H3c GIH , Nez Table 1 Memng fomt Melting Point Example No. Structure 1 7 MS w +1) or BLC Activity retention time class (roi N-N /\\ w Example 1-24 ci 461, 031 462 56, 2 A Zu HgC CHg N-N . . w 1 N-N Example 1-25 N 428, 6 429, 3 135. 8-138. 6 A N N-N Example 1-26 7 440, 61 441, 3 150. 8-151. 7 A N i F N-N \ S Example 1-27 N 467, 57 468 2 169-170 (method B) o CH3 F N-N w i _,--_ s Example 1-28 N 467, 57 468, 2 Rt =3. 21 A Ct % (method B) OH OH Table 1 Mettmg Fomt Example No. Structure MW MS (M+1 ° LC Activity retention time class (RI) p N-N r F N-N Example 1-29 N's 453, 54 454, 06 69-70 A OU w / Example 1-30 519, 65 2. 2 (-38 [K >300 A 0 0 KA GOOEY 'Ph N Example 1-31 463, 53 464 Rt = 5. 14 D (method C) OMe COOED N-N N S N Example 1-32 447, 54 448 141-142 D Me Table1 Melting Point or HI'LC Activity Example No. Structure MW MS (M+1) AcUvtty N-N OH N-COOH N F N k X Example 1-33 435, 48 436 110-111 D OMe N-COOH N S Example 1-34 419, 48 420 S8-89 D Me Ph N Example 1-35 397, 55 398 Rt = 5. 08 A (Method C) Me N-N N s Example 1-36 482, 693 483 146, 8 A f zNX- Table 1 Melting Point or HPLC Activity Example No. Structure MW MS (M+1) retention time class lut fR N-N Y H0-\ (sY . retention time class . fRfi, Example 1-37 'i 444, 557 5 (method A) I- o N lKamPIel-3S, NS 472, 61 473 (met Od A) lu F Nw p N-N Y=" Example 1-39 N 4S2, 54 483, 07 79-80 B Nez F/\ IJN - Example 1-40 N 480, 57 481, 12 81-82 A by 0 w o NH2 N-mut Example 1-41 N r 1 442, 63 443, 3 59. 5-62. 4 A N Table1 Melting Point or HPLC Activaty Example No. Structure MW MS (M+1 retention time class retention time class fez N-N \//\\ / Example 1-42 N 442, 63 443, 3 194-198. 8 B zoo Example 1-43 N 456, 66 457, 3 108. 2-109. 1 D /NX O 11" N p Example 1-44 o N 1 486, 64 487, 3 149. 8-155. 2 A /nez w Example 1-45 N » t3 456, 66 457, 3 126. 4-127. 2 B N-N w N-N S Example 1-46 432, 633 433 47, 1 A If H3CNCH3 Table 1 Melting Point or HPLC Activity Example No. Structure MW MS (M+1 retention time class (RX _ N-N IN-X L S Example 1-47"N 390, 552 391 Rt = 3. 39 c (method B) H C CH 3 3 N-N . w Example 1-48 0 416, 547 417 (th dB) A (method B) N W \ N S3 ) Example 1-49 N 427, 574 428 46, 9 D I HC CHg Q _ C' N, CH, CL, Example 1-50 0 422, 55 423 50, 9 D f , Ns H H3C c 3 Table 1 Melting Point or retention time class run N-N'OH Is Example o 394, 497 395 114, 6 D Example 1-51 N Q N . : Rt = 3. 48 Example 1-51) 404, 579 405 (method B) N (method B) zu N-N % N"s \/Rt=357 Example 1-53 1 418, 606 419,,.-, A N-N , nu H9C CHg H. C Example 1-54 454, 639 455 46, 6 A N. HIC CHU Table 1 Melting Point Example No. Structure MW MS (M+I) r or H-PLC ActiNity etention time class fry) N-NEZ 1 N-N I -S s Example 1-55 ß 432, 614 433 45 A t N-N / r\ --c-ri t=01 Example 1-56 N 566, 7 567, 17 (methodA) B (method A) 0'N\_2 F N-N /"rK. -s'\ Rt=274 Example 1-57 N 452, 56 453, 08 (Rethod7A) D NH2 nu2 F \ % _ i-- S, 7 Example 1-58 495358 496, 08 (method A) B nos OH N-N \ N-N , . S w F Example 1-59 F 494, 583 495 54, 2 A I HC CH H, C' N, CH, Table 1 Melting Point Example No. Structure 1VIVV MS (M+1 r LC Actiity retention time class n1. ;. 1 R-s zu Example 1-60 440, 612 441 54, 8 B , nu W Q N-N \ N-N Example 1-61 N 427, 574 428 79, 9 A HC'NCH, 0 N-N li Example 1-62 f A 493589 494 201, 5 B o OH o_ 1 1 + N-N 0-N Example 1-63 N 508, 56 509 211, 1 B zu OH OU Table 1 Melting Point Example No. Structure 1\TW hIS (M+1 or EPLC Activity retention time class (rif) (Rfi w -,. Example 1-64 01 N-S o o ou OH 0 Cbr 0 OH Example 1-65 N 506, 6313 507, 15 229. 8-232. 0 B oc ou 0 0 N-N bzw Example 1-66 H, cNsr 1, 1 401, 4908 402, 09 158. 0-160. 2 D on o N X ruz 427, 574 428 45, 8 A Example 1-67 I -N HCNCH3 . 1 i N F 418, 485 419 (Rethod B) 6c c, N HC CH Table 1 Melting Point Example No. Structure MW MS (1+1) r LC Activity retention time class (rif) ci 6 N-N Example 1-69 467, 078 46S 52, 7 A I w H3C CH. N-N Ph Et'"S-Ph Example 1-70 413, 59 414 Rt = 5. 64A (method C) H, C CH, F N-N S N 468, 56 469, 09 Rt = 2. 64 w (method A) NH OH OU / S F I \ NfJ N 462, 55 463, 09 62-63 A N w fol F N-N i Example 1-73 538, 69 539, 27 (method B) B N o, CH3 I .

Table 1 Melting Point Example No. Structure MW MS (11Z+1 r LC Actiity retention time class (roi c N-N \, N S T/ '\L Rt=285 Example 1-74 N 494, 64 495, 11 method A) (method A) , N- CL C ! sua N-N hls Example 1-75 H3c s 546, 519 547 126-127 B N ci OBEN C) bon Example 1-76 N 434, 99 435, 2 126. 8-127. 3 B _ zNs 0 N 's 09 X Example 1-77 485, 65 486, 3 54. 0-57. 9 B .

Table 1 Melting Point Example No. Structure MW MS (M+1 or RPLC Activity retention time class 1 N-N Rt = 3. 17 Example 1-7$ (469, 65 470, 3 (meth d B) (method B) I 0 , % N- i w Example 1-79 N 464, 547 465, 07 196-198 D OH ou N , ; l O N N w Example 1-80 's 492, 65 493 Rt = 2. 96 A (method A) zu /nez r Example 1-81 N N 507, 62 508 179, 1 A ) " Table 1 Melting Point Example No. Structure MW MS (M+1 r On Actiity retention time class (ru 9 (I i N , : "Ty'L Example 1-S2 U 506, 63 507 177, 3 C zozo o 0 N-N \/, f Example 1-83 (/"'477, 59 478"'. A (method A) 0 0 Ci HO N-N Example 1-84 N ci 514, 431 515 114, 4 D t> OH 0 c F N Example 1-85 549, 499 550 69, 5 A ci H, C- N, CH, Table 1. Melting Point Example No. Structure l\r MS (M+1 or HPLC Activity retention time class (rif) N-N Example 1-86 ci 497, 491 498 53, 7 A H, C, NsCc ci -N Example 1-S7 N S t CI 498, 432 499 201, 6 A N 1 i ci i OH OH ci N-N Example 1-8S N 's cl 496, 416 497 139, 4 A 6--r OH oh N-N F \ N-J-w S Example 1-S9 tNH 520, 63 521, 2 95-96 A 'NU F N-N / " Example 1-90 N 516, 44 518, 05 61-62 A 4 vBr Table1 Melting Point Example No. Structure MW MS (M+1) F Actmty retention time class HO N-N a Example 1-91 N-S C, 513, 49 514 59, 4 A H C'NCI-L c CL i i Example 1-92 N'S ci 529, 92 530 58, 1 A ci N. CL 'L 6 N-N \ Example 1-93 cl 529, 92 530 67, 2 A Cil N CL F-N Example 1-94 550, 439 551 235, 4 A OH 0 Table 1 Melting Point Example No. Structure AIW MS (M+1 r LC Activity retention time class cl N-N p N-N Example 1-95 g XCz 522, 429 523 212 A 1',/i''ci OU su , f HO % _ Example 1-96 0 N 458, 58 4 5 9,'-) 98. 7-103. 7 B I w ci CI Hic ; S Example 1-97 N 1''S36, 522 499 95, 7 A 0 0 K C ! N-N . ,, S Example 1-98 N S ci 534, 506 467 127, 2 A i 0 K K Table 1 Melting Point Example No. Structure MW MS (lZ+1 °r LC Actiity retention time class cl ci F N'N, Example 1-99 T/NSL 635, 588 636 51, 2 A ci N ci N-N N-N Example 1-100 N ci 593, 551 594 48, 5 A ce Cl, N ci CI Example 1-101 ci 564, 466 567 90, 4 A Example 1-101 ci cl, HO, Example 1-102 N 485, 093 486 53, 4 A 43 H3C CH3 Table 1 Melting Point Example No. Structure MW MS (M+1 or EEPLC Activity retention time class (Rf) ci 0 N-N Hic Example 1-103 N 4 470, 034 471 89, 3 A 6-1 (OH oh cri CI HO N-N WO \ Example 1-104 0 N ci 527, 474 528 109, 5 D I w N HC CH3 Ci 6 1 EXamPIel-l0S N+1) 482548 482 (thSdC) A (method C) "r Ci F N-N F 'TL= Example 1-1 N-s ci 588, 529 551 164, 5 A 06 O K Table 1 Melting Point Example No. Structure Nrw MS (Mf1) or IIPLC Activity retention time class (Rfi ci N-N ! _ Example 1-107 N>-, 470, 42 470, 06 Rt = 2. 73 A ci (method A) COH ci N-N f"3C", Jc^ N Example 1-108 ci 539, 53 539, 11 60-61 B W C, ci F o Example 1-109 ci 591, 54 591, 11 84-85 B N Ca C ! F F XN N 1 A Example 1-110 C N t>CI 549, 455 550 204 A NH 2 0 Table 1 Melting Point Example No. Structure MW MS (M+1) orHPLC Actiiity retention time class cor cl N-N Example 1-111 N S N 558, 19 559 57, 6 A zu cri 3 1- N-N N s Example l-112 aNsC H 468, 066 469 146, 8 D I N H3C \CH3 /. 6 N-N't r< -s o E sample 1-113 H H, 8 526, 102 527 59, 4 A OH rj CL Cf Caf N-N Example 1-114 'N"s 567, 538 568 60, 5 A i t--OH o 0 Table 1 Melting Point ,... . , ., orHPLC Activity Example No. Structure MW MS (M+11 r LC Activity retention time class ci ci N-N Example I-115 ci 541, 5 5 4'-) 70, 3 A o H OH cri CL i HC' Example 1-116 N ci 497, 448 49S 90, 3 A 6-- (NH, 0 ci CL N H3C r T/r Example 1-117 539, 53 539, 09 S4-85 A N OH p N-N N Example 1-118' I cI 591, 54 591, 06 108-109 A cl N Table 1 Melting Point Example No. Structure MW MS (M+1) r LC Activity retention time class ci cri 6 ci N-N Example 1 19 526 (Nl), Example 1-119 0 528 (M+2)' zu ci CL / Example 1-120 Ns' 510, 103 511 74, 6 B /I CHa zu CRI Ci 0 {F N N { cri F E ample 1-121 t>'Cl 563, 482 564 75, 5 A I 0 N H,, N-N 1 N-N t Example 1-122 On 512, 459 513 75, 5 A OZON 0 OH Tablet Melting Point Example No. Structure MW MS (M+1 °r LC Activity retention time class frit a / N-N HaC Example 1-123 ci 511, 475 512 61, 4 A 0 nu, ci ci s cl Exainple 1-124 581, 565 582 82, 3 A O N N oh Q M-N \ or N-N Example 1-125 555, 527 556 53 A 0 N'/H H ci N-W \ - N H, cNs'i Sg1., 565 582 56, 4 A Example 1-126, XI zu o o Table 1 Melting Point Example No. Structure MW MS (M+1 r LC Activity retention time class H s16 cl N-N Hz Example 1-127 N 541, 5 541, 1 Rt=2. 36 (method A) 0 cul MY CL N-N ci Example 1-128 527, 52 527, 11 (RCthVd7A) A Pizza Fi3CNOH CL N-N H C' Example 1-129 A"" 527, 47 527, 04 Rt =2. 42 (method A) cul NH OH cl HIC Cul I F o c' Ti w I, OH H, C' CH3 Table 1 Melting Point Example No. Structure MW MS (M+1) or lIPLC Activity retention time class rRf) F N 4 Example 1-131 579, 52 579, 09 Rt =2. 82 A (method A) cri I H3C OH a p N-N 7 ci Example 1-132 579, 48 579, 09,.. A (Method A) N H O HIC a Han3 C ^/N/-N\\ C_ N/S Example 1-133 1 0 cici 776, 613 777, 01 Rt =3. 46 (method A) H, C- CH3 ci CI F N-N p N-N Example l-'134 N 550, 409 551 247-249 A ci COOH Table 1 Melting Point Example No. Structure W7 MS (Nl+l) or IIPLC Activity retention time class (roi ci N-N \ N Example 1-135 599, 58 600 44, 8 B zou OH ci Cl w HC<Ñ, $ SCI cl Example 1-136 622, 618 623 100, 4 B ° roi nu ; 0 cri choral 4 s Hz Ci GI Example 1-1 i I 595, 592 596 58, 9 A zu OH cri OU HA N-N HO ci 485, 44 485, 1 205. 2-210 zu Table 1 Melting Point Example No. Structure 11'MS (M+1) r LC Activity retention time class (ru ci i \ N-N NN X Example 1-139 567, 54 568 122 A ce zu N OH C Cf i Example 1-140 619, 54 620 87 A ci 0 N cl a " Example 1-141 ci 581, 57 582 86 A N C\ h/O OH Ci CL S Example 1-142 g c 633, 57 A zu OH Table 1 Melting Point Example No. Structure MW MS (M+1 r LC Activity retention time class ce a N-N Example 1-143 N ci 569, 5144 570 83. 6-86. 1 A Example 1-143 o 0 ci ci H N-N Y Example 1-144 N 583, 5415 584 61. 1-62. 9 A w N°cH ci ci \, N-N H G' : S Example 1-145 3 N ci 555, 4873 556 110-113 B o u'OH 0 CI 0 cri Example 1-146 H3Cz NXS <-CI 569, 5144 570 95-98 A / Zoo 0 0 I I 0 0 Table ! Melting Point Example No. Structure MW MS (M+1 or SPLC Activity retention time class cri Cl HO bN N-N \-N Example 1-147 43 cl 554, 54 555 66. 7-72-3 A zu /N l Example 1-148 N 420, 49 421 177. 5-178. 4 sa I /\ Example 1-149 N Rt=4. 44 (method 2C) N-N f N-N F j'-S Rut=5. 01 Example 1-150 (method 2A) '' \ (method2A) Table 1 Melting Point ,--., . < orHPLC Activity Example No. Structure MW MS (M+1 r LC Activity retention time class (gon ZON I , --s Example 1-151 N -s Rt--4. 52 (method 2B) N Cl, o \ \ I F Rt=4. 48 N-F (method 2D) o N O CH, O-CH3 0 \/ Example 1-153 s Rt--4. 25 B (method 2D) N O < s Rt=4. 64 0 CH, CL, CRI Example 1-154)/-N (Method 2D) B H, G, 0 0 N-N O \ zozo 0 Nw :' CH3 WS I \ NwCHs R3. 61 Example 1-155 (method 2D) D N Table 1 Melting. Point or HPLC Activity Example No. Structure MW MS \i+1 or HPLC Activity retention time class (ru HC CH3 N-CH3 . Rn O i-cHt H3CW ° N N<F Example 1-156 \s/ j\ A (method 2D) o -0 0 F /CH, 0 O-CH, Example 1-157 s Q Rt--4. 08 A H, C'0 N (method 2D) 0 N, N 7 O HaC N °\ H, c N-CH 3 Rt--4. 1. 9 -158 Example I H3c, s N' (method 2D) A 3 a N, rH CH, oCH3 N-CH3 0 Example 1-159 s N Rt=4. 35 (method 2D) HaC, i 0 N. ;, l O CH 0-C 3 l7 i 11 T" C Rt=4. 47 (method D) H C, 'Q N, NF zu Table 1 Melting Point Example No. Structure MW MS (M+I) or RPLC Activity retention time class (ru- I CH, O-CH3 Example 1-161 s Rt--4. 43 A (method 2D) o Nr ci cl, /CH3 0 ! \ Rt=4. 35 Example 1-162 HOC 0 F (method 2D) A N '"v CL, zea C ( Example 1-163 ci Rt--4. 3 7 (method 2D) yY t H3C, r N CH3 CH3 0 Example 1-164 Rt--4. 06 s (method 2D) /o C'V \ cl cri Rt=4. 40 Example 1-165 (method 2D) B [03 N Table Table 1 Melting Point Example No. Structure MW MS (M+1 orxIPLC Activiiy retention time class o z3 0 F Rt=4. 07 Example 1-166 tSo<F (method 2D) D F N-F F 0---F N F Example 1-167 S ' R4. y7 yl-N (method 2D) Cl.. cri [Example2-l] Method B 3- [3- (2, 2-diphenylethyl)-5- (3-fluorophenyl)-4H-1, 2, 4-triazol-4-yl] benzoic acid

To solution of ethyl m-aminobenzoate (5.36 g, 32.4 mmol) in tetrahydrofuran (100 mL) was added 1-hydroxybenzotriazole (7.67 g, 56.8 mmol), triethylamine (3.61 g, 35.7 mmol), 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide (10.9 g, 56.8 mmol), and m-fluorobenzoic acid (5.00 g, 35.7 rnmol) at room temperature and stirred for 4 hours. After water was added, the mixture was ex- tracted with ethylacetate. The organic layer was washed with brine, dried over Na'S04, filtered, and concentrated under reduced pressure to obtain ethyl 3- [ (3-fluorobenzoyl) amino] benzoate.

Next, a mixture of ethyl 3- [ (3-fluorobenzoyl) amino] benzoate (1.11 g, 3.86 mmol) and thionyl chloride was heated at 80 °C for 16 hours. After cooled to room temperature, the excess of thionyl chloride was removed underreduced pressure and obtained ethyl 3-{[(lE, Z) -chloro (3- fluorophenyl) methylene] amino} benzoate (1.11 g).

Next, to a solution of ethyl 3- { [ (lE, Z) -chloro (3-fluorophenyl) methylene] amino} benzoate (320 mg, 1.04 mmol) in acetonitrile (5 mL) was added 3, 3-diphenylpropanohydrazide (300 mg, 1.25 mmol) and the mixture was heated to 90 °C for 16 hours. After having cooled to ambient temperature, the mixture was concentrated under reduced pressure. The obtained residue was purified twice-by preparative TLC (eluent: dichloromethane/methanol = 95/. 5 and then with ethylacetate/hexane = 1 / 1) to provide ethyl 3- [3- (2, 2-diphenylethyl)-5- (3-fluorophenyl)-4H-1, 2, 4-triazol-4- (78.0 mg).'H NMR (DMSO-d6) 5 : 1.31 (t, J=7. 3Hz, 3H), 3.36 (d, J=7. 6Hz, 2H), 4.32 (q, J=7. 3Hz, 2H), 4.45 (t, J=8. 2Hz, 1H), 7.04 (d, J=7. 9Hz, 1H), 7. 08-7. 24 (m, 12H), 7.33-7. 35 (m, 1H), 7.57- 7.59 (m, 1H), 7.68 (t, J=1. 9Hz, 1H), 7.72 (t, J=7. 9Hz, 1H), 8.15 (d, J=7. 9Hz, 1H) ; m/z 492.2 (M"+l).

To a solution of ethyl 3- [3- (2, 2-diphenylethyl)-5- (3-fluorophenyl)-4H-1, 2, 4-triazol-4-yl] benzoate (72.0 mg, 0.15 mmol) in ethanol (2 mL) was added IN aqueous sodium hydroxide solution at room temperature and stirred for 16 hours. The mixture was concentrated under reduced pressure, neutralized with IN HCl aqueous solution, and extracted with ethylacetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by preparative TLC (eluent: dichloromethane/methanol = 95/5) to provide 3- [3- (2, 2-di- phenylethyl)-5- (3-fluorophenyl)-4H-1, 2, 4-triazol-4-yl] benzoic acid (37.0 mg).

1H NMR (DMSO-d6) # : 3.36 (d, J=7. 8Hz, 2H), 4.44 (t, J=7. 9Hz, 1H), 7.03-7. 22 (m, 13H), 7.35 (q, J=7. 9Hz, 1H), 7. 52 (d, J=7. 9Hz, 1H), 7.67-7. 72 (m, 2H), S. 11 (d, J=7. 9Hz, 1H). mp 233-234 °C ; Molecular weight: 463.51 MS (M+H): 464 Activity Class: D

In the similar manner as described in Example 2-1, compounds in Example 2-2 to 2-3 as shown in Table 2 were synthesized.

Table 2 Example No. Structure MW MS (M+1) Melting Point Activity or HPLC class retention time (Ro Example 2-2., 419, 5 420, 3 128-129 D F N-N F I I, N \ NI Example 2-3./> 491, 56 492, 2 Rt =2. 92 D (method B) F N-N I N 1 o r° CH3

Example 3-1 (4-{3-cyclopropyl-5- [(diphenylmethyl) suliEmyl]-4H-1, 2, 4-triazol-4-yl} phenyl) dimethylamine

To a stirred suspension of (4-{3-cyclopropyl-5-[(diphenylmethyl)thio]-4H-1, 2, 4-triazol-4-yl}phen- yl) dimethylamine (370 mg, 0.87 mmol) in dichloromethane was added m-chloroperoxybenzoic acid (374 mg, 2. 17 mmol) at room temperature. After the mixture was stirred for 16 hours, it was filtered, and the filtrate was washed with sodium bicarbonate solution, water, and then with brine.

The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to

obtain (4-{3-cyclopropyl-5-[(diphenylmethyl)sulfinyl]-4H-1,2,4-tria zol-4-yl}phenyl)dimethyl- amine (326 mg).

'H NMR (DMSO-d6) 6 0.83-0. 90 (m, 4H), 1.49-1. 54 (m, 1H), 3.54 (s, 6H), 5.87 (s, 1H), 7.22- 7. 31 (m, 10H), 7.44 (d, J= 8. 6 Hz, 2H), 8.30 (d, J= 8. 6 Hz, 2H).

Molecular weight : 442. 58 MS (M+H) : 443 Activity Class: A In the similar manner as described above and with the use of intermediates described above, compounds in Example 4-1 to 4-73 as shown in Table 3 were synthesized.

Table 3 -,.,-.. Motecutar Act) V) ty Example No. Structure Molecular Activity Weight Class ci N-N 4-1 N ci 542, 48 A o. go 0 ci N-nif 4-2 N 528, 46 A OH 0 0 ci I Wot P"'N-N T 4-3 0 1 cl 576, 57 A cl Y HaC. N. H3 CI N-N H3C 4-4 H, C N-S 541, 50 A Cri N-N HaC'N-'OH Cl N-N H3C-N--/,/N-S 4-5 10 ci 583, 54 A NOH N OH OH ci N-N N-N H3C^N. S 4-6 Y S 512, 46 A cl OH 0 Table 3 . _ MoIecuIar Activity Example No. Structure Molecular Activity Weight Class Ct HzN//_ v\. ^, 4-7 ci 484, 45 A 4-7 H3CN'CH, ci N-N H C'-L i ^, 4-8 ci 527, 47 A xi NH ci GO W f H C 4-9 N ci 569, 51 A ZIZI v'NH OOCH, 0 ci N-N N-N 4-10 H3C tCH3 597, 56 A 0, CH, fut cl -cl 4-11 N ci 569, 51 A oh w N oH H ci i N-N H C -L 4-12 585, 55 A . I o 6-y- HO OH Table 3 Molecular Activity Molecular Activìty Example No. Structure Molecular Activity cl NN » Xa o N-nez N-N 4-13 N cri 496, 46 A ? w H3C CH3 ce 1 A-14 HcN--S : --ci 681, 57 A t, NS'OH 0 N cri CL 4-15 HN'S , 580, 54 A \7 fl NH o cri ci N-N e H3C 4-16 541, 50 A ci o cl O CI N-N t-N X 4-17 N j 513, 49 A ci H N OH ci C) N-N ''-c ! H3C (sN » St 4-18 571, 53 A cri ci . HO~NCHOH 'Table 3 -,.,,.-.. Moecutar ActtVtty . Molecular Activity Weight Class o N-N 4-19 H3C 1N ; Cl 556, 51 A [ ! i OH d - Cl i cl 4-20 CHz 533, 95 A 'CH, CHU CIL CI Ci H3C' 4-21 N 555, 53 A ci Nu 0 Nu O Cri Cul \ H3C J N S 4-22 526, 49 A ci OH 0 cri N-N N 4-23 3 s 499, 42 A ci NOS CL N-N N-N N3C' 4-24 N/ 579, 59 A . NO2 H3CNCH H 3 C' CH 3 K D 7 Q 5 0 A 'Table 3 Example No. Structure Molecular Activity Weight Class ce Zur N-N 4-25 N-S 496, 46 A N CRI H, C NCH, CL 4-'L'6 N 469, 44 A cri NH ci NHZ Cl N-N 4 X 1, Cl 4-27 628, 46 A 0 ci ci H, C 0 OH ci N-N y=- HIC t 4-28 528, 46 A ci 0OFFH O OHCH3 CI l ci N-N 4-29 N 484, 45 A cri ol CH, ci N-N r" cul k,"c. 0H, 0 II O 'Table 3 -,.,, .. Mo) ecu) ar Act) V) ty Molecular Activity Example No. Structure Molecular Activity Weight Class cl N-N 4-31 H3C/514, 43 A N-N e _ OH OH ci OH OU Cl HaC JS 4-32 N 514, 43 A ci OH OOH Cl N-N H3G lS 4-33 3 ¢ St 470, 42 A cl OH C) N-N -S 4-34 °'563, 94 A 6, NH kCH QH 0 ci Gui /l 4-35 Ha N cl 581, 57 A o OH ci CL jN-N NaC'IJ'S 4-36 H, C N 527, 47 A cl HN OH ICI o Table 3 -,.,-.. Mo) ecu) ar Act) V) ty Example No. Structure Molecular Activity Weight Class ci /V N-N' H3CNS 4-37 $ 542, 48 A ci cl, CH, CL N-N N-S 4-38 < (537, 51 A ci Hz cl CI N-N N 4-39 $^S ° 547, 53 A ci HN. ; O s, cl 0 cri N- N 4-40 625, 62 A Cri ON 0 H, C- CH, p- Ci N-N Hic 4-41 $> 528, 46 A cl GI OU v' H 4-42 N 491, 67 B F H3C 4-42 491, 67 B r w O_ o 0 Table 3 -,.,,-.. Moecuar ActtV'ty Molecular Activity Example No. Structure Molecular Activity Weight Class cr N-N H3C'L - 4-43"S A. 91, 67 A 0 F O F r N-N 4-44 H3C o Q 491, 67 A o _ K. 0 N-N F F NN N-N XF 4-45 467, 61 B i Y°'CH, 0 O F N-N S 1 N_N S / H3C'C Y 4-46 N 467, 61 A -cl, 0 mf CH N-N S HaCN 4-47 467, 61 A _ N-N ¢ o F N-N N-N N3C' 4-48 N 453, 58 A i oH o F / N-N H C 4-49 N o 453, 58 A on o 'Table 3 -,.,-.. Moecuar Act) V) ty Example No. Structure Molecular Activity Weight Class N-N F ^ JN-N H3C 4-50 N 453, 58 B 6-Y OH o H, C) 0C0 N-O N N-N i 4-51 s 504, 70 A NN3CAoSo HA O Ho 0 N-N . N S 4-52 J. 513, 10 B N. CIH OH . N-N N UQ\ 4-53 N 555, 53 A d. o Cri N H3CCN. . S 4-54 cl 513, 49 A OH OH Table 3 -,.. . Motecutar Acttvtty Example No. Structure Molecular Activity Weight Class ci N-N HaCNi'\S N-S. 1 c 4-55 [o) 625, 62 A 1 :.. N Zou 0 ci S. /N/-N H3C 4-56 N ci 625, 62 A wu 0 O-N'VOH ci N-N N-N 1 4-57 H3C-r, 480, 40 B Cri kOH 0 F N-N 4-58 C -s 480, 58 A i C) H . 0- -S H c 4-59 Jk 506, 62 A N OH OH 'Table 3 -,..-.. Motecuiar AcUvtty Example No. Structure Molecular Activity Weight Class ci zu N Cul Cl 4-60 581, 57 A N OOH F N-N g H 3C'-L N 4-61 X CH3 3 427, 54 A OH o F 3 Ñ f N 4-62 J6n 441, 57 A -°'CH 0 HO N-NI N S 4-63 462, 66 A W H, C' CH, N-N 1/ N-N H C, 4-64 F 493, 58 A N-N t_w OH F N-N N-S N-N 4-65'N S i 494, 61 A i H3C'OH Table 3 -,..-.. Moecuar Activity Molecular Activity Weight Class F N-N N N H C"Nis F 4-66 648, 66 A N 3 Ñ S t F OH 0 N-N N HC 4-67 soh 538, 62 A ou HO~ CH30 F \/ N-N H C 4-68 H3C (N 5 522, 62 A I v-NH O N-N 0 F N-N H go 4-69 N-_s F 508, 59 A AS OH H, C-N, CF F N-N N-N 4-70 N F 522, 62 A 'I °cH ))) C"3 H, N. CHO CH, / N-N 4-71 3 N S 449, 62 ou o 'Table 3 Molecular Activity Weight Class Cri 0 N-N 4-72 N cl 581, 57 A N-N t. ci Vil o CIL cl, N-N CH, 4-73 y NrOH CIH CH3