CA2542682A1 - 5-substituted 2-(phenylmethyl) thio-4-phenyl-4h-1,2,4-triazole derivatives and related compounds as gaba-agonists for the treatment of urinary incontinence and related diseases - Google Patents

Abstract

This invention relates to phenyltriazole derivatives of the formula (I) and salts thereof which is useful as an active ingredient of pharmaceutical preparations : (I) wherein R1 represents alkyl optionally substituted or 3-8 membered saturated or unsaturated ring optionally substituted, R2 represents -COR21, -(CH2)n-R21 or tert-butyl, X represents CR10R11, NR12, S, O, SO2, or SO
wherein R10, R11 and R12 independently represent hydrogen or methyl. The other substituents are as defined in the claims. The phenyltriazole derivatives of the present invention have an excellent activity as GABAb agonist and are useful for the prophylaxis and treatment of diseases associated with GABAb activity, in particular for the treatment of overactive bladder, urinary incontinence such as urge urinary incontinence, benign prostatic hyperplasia (BPH), chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, or nerve injury.

Description

5-SUBSTITUTED 2-(PHENYLMETHYL)THIO-4-PHENYL-4H-1,2,4-TRIA20LE DERIVATIVES AND
RELATED COMPOUNDS AS GABA-AGONISTS FOR THE TREATMENT OF URINARY INCONTINENCE
AND
RELATED DISEASES
DETAILED DESCRIPTION OF INVENTION
TECH1~ICAL 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 y-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 t<vo receptor subt~~pes has been.demonstrated to be necessazy for normal-function (Jones et a/., Nature, (1998) 396, 674- 679); Kaupmami et al., Nature, (1998) 396, 683-687;
Kuner et a/., Science, (1999) 283, Z4-77). Currently there are two GABAB receptor subtypes lalown, GABABRl 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 GABABR1 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 variet~~ 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 GABA$ agonists and antagonists are lrnown and have been proposed for use in therapy including pain, spasticity and motor conh~ol, 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, Tanalca, 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 ~ii'ethral resistance and detrusor overactivity associated with spasticity (Steers et al.; J. Unol., 148, 1849-1855,1992; Mertens et al., Acta Neuroclzir., 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 et al. .I. Ur~ol., 150, 537-542, 1993; Pehrson et al. J. Urol., 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 GABAR 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 (SLTI~ 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 detz-usor 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.

_3_ Benin 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 unlrnown 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 bloclting dihydrotestosterone have been used to reduce the size of the.
prostate. Sa-reductase inhibitors such as finasteride are prescribed for BPH. These agents selectively inhibit Sa-reductase which mediates conversion of testosterone to dihydrotestosterone, thereby reducing plasma dihydrotestosterone levels and thus prostate growth. The Sa-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:
N-N
~N Ra D
A

wherein A repz:esents optionally substituted aryl, etc;
B and D independently represent optionally substituted aryl, carbocyeles, 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-[Alk2]n-YP-RlP;
wherein RlP represents H, optionally substituted aryl, etc;
Xr 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:
Rb~
Rb3 N
Rb2 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 ha~~ing GABAB receptor agonistic activit~r.

The development of a compound which has effective GABAg agonistic activity and can be used for the prophylaxis and treatment of diseases associated with GABA$ receptor activit~~, 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:
N-N Rz s R
R
R5 Rs wherein R' represents alkyl optionally substituted by one or tlvo substituents selected from the group consisting of alkoxy, amino, alkylamino, di(alkyl)amino, alkanoyloxy, hydroxy, carboxy, alkoxycarbonyl, cycloalkylphenyloxy, halogen, morpholino, carbamoyl, alkylsulfonyl-amimo, phenyloxy optionally substituted by cycloalkyl, and 3- R membered saturated ring optionally having one or two N atom which ring optionally substituted by hydroxy or alkanoyl, or 3-~u 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 rizono-, di-, or tri- halogen substituted allyl;
R' represents -CORZ', -(CH~)~ R'' or tert-butyl, wherein Rz' is alkoxy, hydroxy, mono-, di-, or tri- halogen substituted alkyl, or 3-8 membered saturated or unsaturated ring optionally having one o'r 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-(allyl)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;
nis0orl;
R3 and R~ independently represent hydrogen, halogen, cyano, hydroxy, amino, alkylamino, di(alkyl)amino, cycloalkylamino, carboxy, alkoxycarbonyl, sulfamoyl, alkylaminosulfonyl, di(alkyl)aminosulfonyl; alkanoyl, alkanc~ylamino, 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 hydxogen, hydroxy, vitro, cyano, halogen, sulfamoyl, allrylsulfonyl, alkyl-aminosulfonyl, di(allryl)aminosulfonyl, -(CHz)",-CO-Rs°, -(CHz)m Rs', -NRszRs3, or -ORsa, wherein m is 0, 1, 2, or 3 Rs° is hydroxy, hydrogen, alkoxy, moipholino, di(phenyl)methyloxy, di(halogen substituted phenyl)methyloxy, -NRs°'Rsoz (,herein said Rs°' and Rsoz independently represent hydrogen, alkoxyalkyl, alkyl, hydroxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl or Rs°' and Rs°z 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 all'yl optionally substituted by halogen, Rs' is hydrogen, hydroxy,. or -NRs"Rs'z (wherein said Rs" and Rs'z independently represent hydrogen, alkoxyalkyl, alkyl, hydroxyalkyl, alkox)~carbonylallyl, or _ '7 _ carboxyalkyl, or RS" and RS'Z together forni 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 RSZ 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 moipholino, amino, di(alkyl)amino, carboxy, alkoxycarbonyl, or mono-, di-, or tri- halogen, or piperazino substituted by carboxy;
R6 and R' independently represents hydrogen, morpholino, hydroxypyrrolidinylcarbonyl, hydroxyalkylaminocarbonyl, cyano, hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, alkylamino, di(alkyl)amino, cycloalkylanuno, alkoxycarbonyyl, sulfamoyl, alkylaminosulfonyl, di(alkyl)aminosulfonyl, alkanoyl, alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, alkylcarbamoyl, di-(alkyl)carb-amoyl, alkylsulfonyl, alkyl optionally substituted by alkoxyalkyl(alkyl)amino, di(alkyl)anuno, 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 R' together form phenyl fused to adjacent phenyl; and X represents GR'°R", NR'2, S, O, SO~, or SO
wherein~R'°, R", and R'' independently represent hydrogen or methyl.
. The phenyltriazole derivatives of formula (1), their tautomeric and stereoisomeric form, and salts thereof surprisingly show excellent GABA$ agonistic acti~nty. 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 _8_ pain, rheumatoid artlwitic pain, neuralgia, neuropathies, algesia, or nerve injury inducefi' 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 GA.BAB receptor activity.
In another embodiment, the phenyltriazole derivatives of formula (~ are those wherein;
wherein R' represents all'yl optionally substituted by one or two substituents selected from the group consisting of alkoxy, amino, alk~~lamino, 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 tlvo substituents selected from the group consisting of alkyl, halogen, alkoxy, nitro, amino, cyano, alkylamino, di(allyl)amino, 4-7 membered saturated cyclic amine optionally substituted by hydroxy, and mono-, di-, or tri- halogen substituted allyl;
R'' represents -COR''' or -(CHz)"-R'', wherein R'' is alkoxy, hydroxy, mono-, di-, or tri- halogen substituted alkyl, or 3-8 membered saturated or unsaturated ring optionally having one or hvo heteroatoms selected from the group consisting of N, 0, and S and which ring is optionally substituted by one or t<vo substituents independently selected from the group consisting of alkanoyl, halogen, benzyl, alkoxycarbonyl, haloalkyloxy-carbonyl, cyano, hydroxy, ari~ino, alkylamino, di(allyl)amino, cycloalkylamino, alkoxycarbonyl, sulfamoyl, alkylaminosulfon~rl, di(all'yl)aminosulfonyl, alkanoyl, alkanoylamino, carbamoyl, alkylcarbamoyl, di-(alkyl)carbamoyl, alkylsulfonyl, alkyl optionally substituted by alkoxycarbonyl or mono-, di-, or tl~i-halogen, alkoxy optionally substituted by mono-, di-, or tri- halogen, and alkylthio optionally substituted by mono-, di-, or tri- halogen;
nis0orl;

R' and R4 independently represent hydrogen, halogen, cyano, hydroxy, amino, alkyrarnino, di(allcyl)amino, cycloalkylamino, alkoxycarbonyl, sulfamoyl, allcylaminosulfonyl, 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;
Rs represents hydrogen, hydroxy, nitro, cyano, halogen, sulfamoyl, alkylsulfonyl, alkyl-aminosulforlyl, di(alkyl)aminosulfonyl, -(CH~)m CO-Rs°, -(CHz)m Rs', -NR52R53~ or -ORs4, wherein mis0, 1,2,or3 Rs° is hydroxy, hydrogen, alkoxy, morpholino, di(phenyl)methyloxy, di(halogen substituted phenyl)methyloxy, -NRs°'Rs°z (wherein said Rs°' and Rsoz independently represent hydrogen, alkoxyalleyl, alkyl, hydroxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl or Rs°' and Rsoz together form with the adjuscent N atom, rnorpholino, or 4-7 membered saturated cyclic anuno optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl) or alkyl optionally substituted by halogen, Rs' is hydrogen, hydroxy, or -NRs"Rs'z (wherein said Rs" and Rs'z independently represent hydrogen, alkoxyalkyl, alkyl, hydroxyalkyl, alkoxycarbonylalkyl, or carboxyalkyl, ox 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), Rsz and Rs3 independently represent hydrogen, alkyl, hydroxy, cycloalkylcarbonyl, or hydroxyalkyl, or Rsz and Rs3 together form with adjuscent N atom, morpholino, cyclic anuno optionally substiW ted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl, Rs~ represents alkyl optionally substituted by morpholino, amino, di(alkyl) anuno, or mono-, di-, or tri- halogen;

R6 and R' independently represents hydrogen, morpholino, hydroxypyrrolidinylcafhonyl, hydroxyalkylaminoearbonyl, cyano, hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, vitro, amino, alhylamino, di(alkyl)amino, cycloalkylanuno, alkoxycarbonyl, .sulfamoyl, alhylaminosulfonyl, di(alkyl)aminosulfonyl, alkanoyl, alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, alhylcarbamoyl, di-(alkyl)carb-amoyl, alkylsulfonyl, al)'yl 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 C,_6 allc~~lthio optionally substituted by mono-, di-, or tri- halogen or R6 and R' together form phenyl fused to adj acent phenyl; and X represents CR'°R", NR'2, S, O, SO~, or SO
wherein R'°, R", and R'z independently represent hydrogen or methyl.
Yet another embodiment of formula ()7 can be those wherein:
X represents CHI, NH, S, O, SOz, or SO;
R' represents C3 to C$ cycloalkyl, C~-Cb alkyl optionally substituted by one or W o substituents selected from the group consisting of CI-C6 alkoxy, amino, C~-C6 alkylamino, di(C~-C6 alkyl)amino, C~-alkanoyloxy, hydroxy, C3-C8 cycloall'yl, carboxy, C~-C6 alkoxycarbonyl, C3-C$
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, C~-C6 alkoxy, .vitro, amino, cyano, C~-Cbalkylanuno, di(C~-Cbalkyl)amino, and mono-, di- or tri-halogen substituted C,-Ctiall'yl, R' represents -COR'' or -(CH~)"-R'', wherein RZ' represents mono-, di-, tri-halogen sub-stituted C,-C6 all..yl, morpholino, C,-C6 alkoxy, hydroxy, C3 to C8 cycloalkyl, pyridyl, furanyl, thiophenyl, pyrrolidinyl, piperidinyl optionally substituted by one substituent selected from the group consisting of benzyl, C~-Cn alkoxycarbonyl, and halo alkyloxycarbonyl, or phenyl optionally substituted by one substituent selected fi~om the group consisting of C~-Cb alkyl, halogen, C~-C6 alkoxy, and mono-, di-, or tri-halogen substituted C~-C6alkyl;

nis0orl;
R3 and R'' independently represent hydrogen, halogen, cyano, hydroxy, amino, C1_6 alkylamino, di(C~_6 alkyl)amino, C3_$ cycloalkylamino, Cl_6 alkoxycarbonyl, sulfamoyl, Cl_ti all'yl-aminosulfonyl, di(C~_6 alkyl)aminosulfonyl, C~_6 alkanoyl, C1_b alkanoylamino, carbamoyl, C,_b alkylcarbamoyl, di-(C~_6 alkyl)carbamoyl, C~_6 alkylsulfonyl, C~_6 alkyl optionally substituted by C,_6 alkoxycarbonyl or mono-, di-, or tri-halogen, C~_6 alkoxy optionally substituted by mono-, di-, or tri- halogen, or C,_6 alkylthio optionally substituted by mono-, di-, or tri- halogen;
Rs ' represents hydrogen, nitro, cyano, hydroxy, halogen, sulfamoyl, C1-C6alkylsulfonyl, CI
C6alhylaminosulfonyl, di(C~-C6a11'yl)aminosulfonyl, -(CHz)m-CO-Rs°, -(CHz)m Rs', -~szRsa or -ORsa, wherein m is 0, 1, 2, or 3 Rs° is hydraxy, hydrogen, C~-Cbalkoxy, morpholino, diphenylmethyloxy, -NRs°'Rs°z (wherein said Rs°' and Rs°z independently represent hydrogen, CI-C6alkoxyalkyl, C~-C6alkyl, hydroxy C~-Cballyl, C~-C6alkoxycarbonyl C~-C6allyl, or carboxy C~-Cbalkyl or Rs°' and Rs°'' 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, Rs' is hydrogen, hydroxy, or -NRsi'Rsiz (,herein said Rs" and Rs''' independently represent hydrogen, C~-C6 alkoxyalk~~l, C~-C6 alkyl, hydroxyalkyl, C~-C6 alkoxy-carbonylalkyl, or carboxyalkyl or Rs" and Rs'z together form with the adjacent N
atom, 4-7 membered saturated cyclic anuno optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl) Rsz and Rs3 independently represent hydrogen, C~-C6 allyl, hydroxy, C3-CSCycloalkyl-carbonyl, or hydroxy C,-C6 all.~~l or Rsz and Rs3 together forni with adjacent N
atom, rnorpholino, 4-7 membered saturated cyclic amino optionally substituted by one substituent selected from the group consisting of carboxy, hydroxyalkyl, hydroxy, and carbamoyl Rs4 represents alkyl optionally substituted by morpholino, amino, or di(alkyl) amino, or mono-, di-, or tri- halogen; and R6 and R' independently represent hydrogen, morpholino, .
hydroxypyrrolidinylca~ljonyl, hydroxyC~-C6alkylaminocarbonyl, cyano, hydroxy, hydroxyC,-G6alkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, anuno, C,_~ alkylamino, di(C1_6 alkyl)anuno, C3_g cycloalkylamino, C1_6 alkoxycarbonyl, sulfamoyl, C~_6 alkylaminosulfonyl, di(C~_6 alkyl)anunosulfonyl, C,_6 alkanoyl, C~_a alkanoylamino, carbamoyl, diphenylmeth yloxycarbonyl, C,_6 alkylcarbamoyl, di-(C~_6 allcyl)carbamoyl, C~_a alkylsulfonyl, C,_6 alkyl optionally substituted by alkoxyall'yl(alkyl)amino, di(alkyl)amino, C1_E
alkoxycarbonyl, carboxy, or mono-, di-, or tri-halogen, C1._6 alkoxy optionally substituted by morpholino, di(alkyl)amino, or mono-, di-, or tri- halogen, or C~_ti alkylthio optionally substituted by mono-, di-, or tri- halogen or R6 and R' together form phenyl fused to adjacent phenyl.
Yet another embodiment of formula (1~ can be those wherein:
X represents CHz, NH, S, or SO;
R' represents cyclopropyl, pyridyl, phenyl optionally substituted by halogen, C1-Cbalkoxy, nitro, amino, cyano, C~-Ctiallylamino, di(Cl-C6alkyl)amino, or halogen substituted C1-Coalkyl, C,-C6 alkyl optionally substituted by one or two substituents selected from the group con sisting of C~-G6alkoxy, amino, C~-C6 alhylamino, di(C~-C6 alkyl)amino, C~-Cb alkanoyloxy, hydroxy, C3-C$ cycloallyl, carboxy, C~-C6 alkoxycarbonyl, C3-Cs cycloalhylphenyloxy, halogen, morpholino, and pywolidinyl, pyrrolidinyl, or piperidinyl optionally substituted by methyl;
R' represents -COR''' or -(CHI)"-Rz', wherein R'' represents mono-, di- or tri-halogen substi-tuted alkyl, morpholino, C,-Ctialkoxy, hydroxy, C3 to C$ cycloalkyl, pyridyl, furanyl, thiophenyl, pyrrolidinyl, piperidinyl optionally substituted by one selected from the group consisting from benzyl, C,-C6alkoxycarbonyl, and haloC,-Ctialkyloxycarbonyl, or phenyl optionally substituted by one selected from the group consisting of C,-C6 allyl, halogen, C~-Cd alkoxy, and mono-, di- or tri- halogen substituted C~-C6alhyl;
nis0orl;
R3 and R4 independently represent hydrogen, halogen, methyl, or amino;

RS represents hydrogen, morpholino, hydroxypyrrolidinylcarbonyl, hydroxyalkylaminocaflionyl, cyano, hydroxy, hydroxyall'yl, hydroxyamino, carboxy, fluoro, chloro, bromo, vitro, amino, C~_6 alkylamino, di(Cl_6 all'yl)amino, C3_$ cycloalkylamino, CI_6 alkoxycarbonyl, sulfamoyl, .Cl_6 alkylaminosulfonyl, di(C~_~ alkyl)aminosulfonyl, C1_6 alkanoyl, Cl_6 alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, C~_6 alkylcarbamoyl, di-(C,_6 all'yl)carbamoyl, C1_6 alkylsulfonyl, Gl_6 alkyl optionally substituted by alkoxy-alkyl(allyl)ami.no, di(allyl)amino, C~_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 C~_6 alkylthio optionally substituted by mono-, di-, or tri-halogen; and R6 and R' represent hydrogen, or R° and R' together fornl phenyl fused to adj acent phenyl.
Yet another embodiment of fornmla (I) can be those wherein:
X represents CHz, NH, or S;
R' represents cyclopropyl, pyridyl, phenyl optionally substituted by halogen, alkoxy, vitro, amino, cyano, alkylamino, di(alkyl)amino, or halogen substituted allyl, C,-C6 all'yl optionally substituted by one or t~~~o substituents selected from the group consisting of alkoxy, amino, C~-C6 alkylamino, di(C~-C6 alkyl)amino, C,-C6 alkanoyloxy, hydroxy, C3-C8 cycloalkyl, carboxy, Cl-C6 alkoxycarbonyl, C~-CR
cycloalkylphenyloxy, halogen, moipholino, and pyrrolidinyl, pyrrolidiny, or piperidinyl optionally substituted by methyl.
Further, another embodiment of formula (~ can be those wherein:
X represents CHI, NH, or S;
RZ represents -COR''', -(CHZ)"R''', wherein RZ' is phenyl optionally substituted by C~-Cb alkyl, halogen, halogen substituted alkyl or alkoxy and n is 0 or 1.
Additional embodiment of formula (n can be those wherein:
X represents CH2, NH, or S;
R3 and R4 independently represent hydrogen, halogen, methyl, amino; and RS represents hydrogen, morpholino, hydroxypyrrolidinylcarbonyl, hydroxyalkyfamino-carbonyl, cyano, .hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, vitro, amino, C,_6.alkylamino, di(C,_b alkyl)amino, C3_8 cycloalkylainino, C,_ti alkoxy-carbonyl, sulfamoyl, C,_6 alkylaminosulfonyl, di(Cl_6 alkyl)aminosulfonyl, Cl_6 alkanoyl, S C,_b alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, C~_ti alkylcarbamoyl, di-(C~_6 alkyl)carbamoyl, C,_6 alkylsulfonyl, C1_d alkyl optionally substituted by alkoxy-alkyl(alkyl)amino, di(all'yl)amino, C~_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 C~_6 alkylthio optionally substituted by mono-, di-, or tri-halogen; and R° and R' represents hydrogen.
More preferably, said phenyltriazole derivative of the formula (I) is selected from the group consisting of:
(4-{3-cyclopropyl-5-[(diphenyhnethyl)thio)-4H-1,2,4-triazol-4-yl}
phenyl)dimethylamine;
( .4-{3-[(diphenylmethyl)thioJ-5-ethyl-4H-1,2,4-triazol-4-yl}phenyl)dimethylanune;
(4-{3-[(diphenylmethyl)thio]-5-propyl-4H-1,2,4-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]thin} -5-cyclopropyl-4H-1,2,4-triazol-4-yl)phenyl]dimethyl-30 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}-S-cyclopropyl-4H-1,2,4-triazol-4-yl)phenyl]dimethyl-amore;
[4-(3-{[(.4-chlorophenyl)(phenyl)methyl]thio~-5-cyclopropyl-4H-1,2,4-triazol-4-yl)phenylJdimeth-ylamine;
(4-{3-cyclobutyl-5-[(diphenylmethyl)thio]-4H-1,2,4-triazol-4-yl}phenyl)dimethylamine;
(4-{3-buyl-5-[(diphenylmethyl)thin]-4H-1,2,4-ti-iazol-4-yl}
phenyl)dimethylamine;

[4-(3- f [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-y1]phen-yl} dimethylamine;
[4-(3-{[(4-chlorophenyl)(cycloheayl)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-[3-{[bis(4-chlorophenyl)methyl]thio}-5-(3-fluorophenyl)-4H-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]thin}-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-triazol-4-yl]-phenyl } -piperidine-3-carboxylic acid or the salt thereof.
Further, the present invention pro~~ides a medicament, tvhich includes one of the compounds, described above and optionally pharmaceutically acceptable e.xcipients.

Alkyl per se and "alk" and "allyl" in alkenyl, alkynyl, alkoxy, alkanoyl, alhylamino, allylamino carbonyl, alkylanunosulphonyl, 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, S 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, text-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 alkylanuno radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylamino, ethylamino, n-propylamino, isopropylamino, tort-butylannino, n-pentylamino, n-hexyl-amino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-pxopylamino, 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, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, h-iazolyl, 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'~'ork 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]
N~N Rz H R~ ~ ~X~ W Ra R N h Rz N
~ R~ 1 \ R3 ~ / R7 Ra L
-r Ra _I
R5 Rs Rs Rs (I-a) (II) (III) S The compound of the formula (I-a) (wherein R', Rz, R3, Ra, RS, R6 and R' are the same as defined above and X' represents O, S or NR''') can be prepared by reacting the compound of the formula (II) (wherein R', R5, R6 and R' are the same as defined above) with the compound of the formula (~ (wherein Rz, R3 and Ra are the same as defined above and L, represents a leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom; Cti_lo arylsulfonyloxy group such as benzenesulfonyloxy, or p-toluenesulfonyloxy; and C~-a 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, sodi~.un bicarbonate, or potassium bicarbonate, and others.

R5, R6, and/or R' of compound of the formula (n can be further modified using conventional methods.
X' is further modified to be converted to SO or SO2.
Preparation of intermediate (lQ-a) [Method (i)J
s N-N
N-NHa NCS N-H~NH
R N SH
R~~p + R~ ~ R ~ ~ R~ Step i-2 5 Rs Step i-1 ~ R~
R s Rs R
(VI) R5 Rs (IV) (V) ( I I-a ) The compound of the formula (II-a) (wherein R', R5, R6 and R' 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 R' 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) (wherein R5, R6 and R' are the same as defined above).
The reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichlorome.thane, chloroform and 1,2-dichloroethane; ethers such. as diethyl ether, iso-propyl ether, dioxane and tetrahydrofuran (TI-iF) 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-dimethylacetanude (DMAG) and N-methylpyrrolidone (NI\~IP);
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 linuted to, about room temperature to 100°C. The reaction may be conducted for, usually, 30 minutes to 4S hours and preferably 1 to 24 hours.

In Step i-2, the compound of the formula (lI-a) (wherein R', R5, R6 and R' are the same as Refined 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, die.thylaniline, 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 conunercially available or can be. prepared by the use of known techniques.
Preparation of intermediate (1~
[Method (ii)]
O
HZN-NHS ~ NHS
R'~N
Rv L2 ~ H
Step ii-1a (IV) (VII) Step ii-1b Step ii-2b O
HzN~N~Ls R~~N~N~L
H a (VIII) (IX) In step ii-1a, the compound of the formula (IV) (wherein R' is the same as defined above) can be prepared by reacting the compound of the formula (VIl) (wherein R' is the same as defined above and L~ represents a leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom, hydroxy and C~_6 alkoxy) with hycu~azine (free base, its salt or its hydrate).

The reaction can be carried out in a solvent including, for instance, alcohots such as me'tnanol, ethanol, 1-propanol, isopropanol and tert-butariol, 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 prefei-ablyy 2 hours to 24 hours.
Alternatively, the compound of the fornmla (N) 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 (\TIn (wherein R' and L~ are the same as defined above) with the compomd .of the fomnula (VJT~ (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, hatogenate.d 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; nitrites 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 (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 ii-2b, the compound of the fornmla (N) (wherein R' is the same as defined above) can be prepared by removing the protecting group L3 of the compound of the. formula (LY) (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 tritluoroacetic acid and hydrochlaric acid.
The reaction may be earned .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; niti-iles 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-in>idazolidinone (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 (V)~ and (VIII are commercially available or can be prepared by the use of lrnown techniques.
Alternative procedures for the preparation of intermediate (VT) [Method (iii)]
NCS ~ S S
3\ 3 _ L N-NHS ~ R~ H H~NH H~N-H~NH
H + ---t Rs Rs Step iii-1 / R~ Step iii-2 / R~
(Vlll) (V) R5 Rs Rs Rs (X) (XI) S
l_" H
N-H~NH
R1.~ (vli) , Step iii-3 Rs Rs (VI) 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) (vs~herein wherein L3, R5, R6 and R' are the same as defined above) can be prepared by reacting the compound of the formula (VDT
(wherein L3 is the -~2-same as defined above) with the compound of the formula (V) (wherein R5, R6 and R' are th'e 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 (X17, (wherein R5, R6 and R' are the same as defined above) can be prepared by removing the protecting group L3 of the compound of the formula (.k) (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 (N).
In Step iii-3, the compound of the formula (VIA (wherein R', R5, R° and R' are the same as defined above) can be prepared by reacting the compound of the formula (.'~ (wherein R5, R6 and R' are the same as defined above) with the compound of the formula (Vff) (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 (N).
Preparation of intermediate (II-b) [Method (iv)]

(VII) R~ N R~N
HZN R ~ \ ~ R
\ R~ O ~ I R _ GI
O Step iv-2 s Rs Rs Rs Step iv-1 Rs Rs R
(fill I) (XIV) , (XII) N-N
HZN-NH2 R~ N Br~N R~ N NH

I R Step iv-4 ~ R~
Srep iv-3 HZN~N Rs Rs s s R R
(I I-b) 1 s (xv) The compound of the formula (II-b) (wherein R', R5, R6 and R' are the 'same as defined above) can be prepared by the following procedures.
In Step iv-1, the compound of the formula (XI~ (wherein R', R5, R° and R' are the same as defined above) can be prepared by reacting the compound of the formula (XII) (wherein R5, R6 and R' are the same as defined above) with the compound of the formula (VII) (wherein R' and LZ are the same as defined above).

When LZ is hydroxy, the reaction can be done 'using a coupling agent including, for ir(stance, carbodiimides such as N, N-dicyclohexylcarbodiimide and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide, benzophenyltriazole-1-yl-oxy-Iris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide. N-hydroxysuccininude, 1-hydroxybenzotiazole monohydrate (HOBt), and the like can be used as an accelerator of the reaction.
The reaction maybe 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; nitTiles such as acetonitrile; amides such as N, N-dimethyl-formamide (DMF), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMl');
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 fox, usually, 30 minutes to 48 hours and preferably 2 hours to 12 hours.
In Step iv-2, the compound of the formula (XIV) (where.in R', R5, Rb and R' are the same as defined above) can be prepared by reacting the compound of the .formula (XI>~
(wherein R', RS, R6 and R' are the same as defined above) with an appropriate halogenating reagent including, for instance, SOC12, POCK, 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 rnay 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, R6 and R' are the same as defined above) can be prepared by reacting the compound of the formula (XIV) (wherein R', R5, R6 and R' are the same as defined above) with hydrazine (free base, its salt or its hydrate).

-24_ The reaction may be carried out in a solvent including, for instance, halogenated hyydro6arbons 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; nitrile,s such as acetonitrile;
amides such as N, N-di-S methylformamide (DMF), N, N-dimethylacetanude (DMAC) and N-methylpyrrolidone (NMP);
urea such as 1,3-dimethyl-2-imidazolidinone (DMII; 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 fox, 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, R6 and R' are the same as defined above) can be prepared by reacting the compound of the formula (XV) (wherein R', R$, 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 hyd~~o 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 tent-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 (XI~ is commercially available or can be prepared by the use of laiown techniques.

_ 25 _ Preparation of intermediate (~
[Method (v)]
H / Rs R? Lq \ q \ (XVII) R R' R
(XVI) Step v-1 ~. R3 Step v-2 ~ Rs HO 1 ~ L~
q R4 R
(XVIII) (III) R \~R3 Step v'-1 \ 4 R
(XIX) The compound of the fornmla ()T~ (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 (XVII17 (wherein wherein RZ, R~ and R4 are the same as defined above) can be prepared by reacting the compound of the formula (XVfj (wherein R3 and R~ are the same as defined above) with the compound of the formula (.XVII) (wherein RZ 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 (XVIB) (wherein wherein Rz, R3 and R4 are the same as def'med above) can be alternatively prepared by reacting the compound of the formula (.~) (wherein R2, R3 and R'' 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 fonnula (lII) (wherein L~, R'', R3 and R4 are the same as defined above) can be prepared by reacting the compound of the formula (XVIIl~
(wherein wherein Rz, R3 and R4 are the same as defined above) with an appropriate halogenating reagent including, for instance, POCl3, PC13, SOCK, 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 I~ydrocarbons 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), (XVIl~ 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]

- 27 _ Rz ' R_ N-N
H w Rs ~ ~ w s R~~N ~ . R7 ~a R~° Rya ~ Ra ~ Ro N ,° ~ R
Ray H NON ~ s (~) / R Ra z Rs R ~ R~
(XV) Rs Rs The compound of the formula (I-b) (wherein R', R', R3, Ra, R5, R6, R', R'° and R" are the same as defined above) can be prepared by reacting the compound of the formula (XV) (wherein R', R5, Rb and R' are the same as defined above) with the compound of the formula (~'.~i) (wherein Rz, R3, Ra, R'° and R" are the same as defined above and La 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, t<vo 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 (X~.) is conunercially, available or can be prepared by the use. of lrno~m techniques..
When the compound shown by the formula (n or a salt thereof has an asymmetl-ic carbon in the structure, their optically active compounds and racenuc 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 hase. Such salts are la~own 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.

_7g_ 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 forni lower alkylesters or lmown 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, intrape.ritoneal, subcutaneous, uitramuscular, and the like forms, well-known 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-known 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 axe 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 malting 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 earner .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 cawier, 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, fox example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, .sodium benzoate, sodium acetate, sodium chloride, talc, 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 fornmlation may be in unit dosage form, 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/lcglday to 30 mgll;g/day, and most preferably from about 0.5 mgllcg/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 /lcg/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.

EXA1~ZPLES
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 pm)) 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, Ine., Watanabe Chemical lnd. 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 ~L
Gradient (Time ) : (water / acetonitrile) 01\~Iinutes : 9 / 1 0.2 Minutes: 9 / 1 2.0 Minutes: 1 / 9 3.5 Minutes: 1 / 9 4.0 Minutes: 9 / 1 3~ _ 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.
~0 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 C1S 60*2 at 30 °C; injection volume: 1.00 ~1;
flowrate: 0.75 ml/min; eluent:
A= 0.01 M H3P0~ in HzO, 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 ~,1;
flowrate: 0.75 ml/min;
eluent: A= 0.01 M H3P04 in HzO, B= CH3CN; gradient [t(min): AB]: 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 ~1; flowrate:
0.75 ml/nun; eluent: A=
5ml 70% HC104/1L H20, B= CH3CN; gradient [t(min): A/B]: 0.0: 98/2; 0.5: 98/2;
4.5: 10/90; 6.5:
10190; 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: I'MC-ODS-AQ, 50 mm x 2.0 mm, 3.0 Vim; 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 nun 10%A ~ 4.51 min 100%A-j 6.5 min 100%A; oven: 40°C; flow rate: 0.8 mllmin; 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 Vim; 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%B~ 5.5 min 90%B; oven:
45°C; flow rate: 0.0 min 0.75 ml/min -~ 4.5 min 0.75 mllmin~ 5.5 min 1.25 ml/min; UV-detection: 210 nm.
'H NMR spectra were recorded using either Bruker DRX-300 (300 1\~iz for 'H) spectrometer or Brucker 500 UltraShieled~ (S00 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 determinations 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 exanuned 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~~a~, GABAB~~ba and GABAB~2~ receptor subunits were cloned into pcDNA3 .(Invitrogen) as previously described (White J. H. et al., Nature 1998, 396(6712):679-S2). 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 transfe.ction (mammalian transfection kit; Stratagene) cells were grown at 20000 cells per well at 35 °C with 3% CO~ for 24 h with 0.1 ml per well. DNA
suspension: 10 pg expression plasmid DNA of each human GABAB~~aa and human GABAB~Z~ in pcDNA3 was dissolved in 450 p,l of water with 50 ml CaClz (2.5 M) + 500 pl 2x phosphate buffered saline (PBS, pH 6.95) and incubated for 10 to 20 nun at room temperature. In the meantime cell medium was aspirated and cells were washed twice with 200 pl PBS
per well and then 200 ~.1 medium plus 5% MBS was added. For transfection 20 p.l of suspended DNA was added and incubated for 3 h at 35 °C with 3% CO~, cells were washed with PBS and 200 ~1 of growth medium was added and cells were grown for days. Cells were then trypsinized and diluted 1:10 in fibronectin coated.
wells and incubated with growth medium supplemented with 1 mg/n~l G41 S (Gibco BRL) and grown under selection pressure for 10 days with 2-3 medium changes. After 6418 selection cells were grown until colonies had formed.
(2) Folskolin-stimulated luciferase-reporter gene assay GABAByniz>-HEK293/CRE-luc cells were seeded into poly-D-lysine-coated 3S4-well white/opaque plates (BD BIOCOAT) at 4000 cells/well in 40 p.l DMEM/F12 medium i0 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 pllwell. 10 minutes after the test compound addition, forskolin prepared in a manner similar to the test compounds was added at 5 pl/well (1.6 p.M 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 ~l/well of 1:1 mixture of Steady-GIoTT' 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 (200250 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.S) to facilitate respiration; and a cannula (BECTON DIChTNSON, 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 inti~avesical pressure to approximately 15 cm HzO.
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 mean~S.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=)O.l~M<B(<or=)0.5 ~M<C(<or=) 1 pM<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 wethane (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-~XA.D) 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 PowexLab 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-S-cyclopropyl-[1,2,4]triazol-4-yl)-benzoic acid Br OH
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 nunol) 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 HCl 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, lOH), 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) ,,O
O O I/~(~/N
SCN .~ O~CH~ H

"-CHI
A mixture of cyclopropanecarbohydrazide (255 mg, 2.55 mmol) and methyl 3-isothiocyanato-benzoate (492 mg, 2.55 minol) 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)hydrazine]carbonothioyl~ amino) benzoate (399 mg).1H NMR
(DMSO-dti) 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
n~/z 294 (1\~+1).
Next, a solution of methyl 3-({[2-(cyclopropylcarbonyl)hydrazine]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 1N aqueous solution of HCI. The mixture was extracted with ethylacetate, dried over NazS04, altered, and concentrated under reduced .pressure to obtain 3-(3-cyelopropyl-5-thioxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)benzoic acid (355 mg).'H NMR (DMSO-d6) S 0.77-0.92 (m, .4H), 1.47-1.52 (m, 1H), 7.70-7.77 (m, 2H), 8.01 (s, 1H), 5.09 (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) cyclopropanecarbohydrazide O H , O
,N O CH3 N O CH
CI + HZN ~ ~ Ni ~ s GH3 Hs H ~ ! HCH3 O
---~ N~NH
H
To a solution of tert-butyl hydrazinecarboxylate (6.38 g, 48.3 mmol) and triethylamine (7.26 g, 71.5 nunol) in dichloromethane (10 mL) was added cyclopropanecarbonyl chloride (5.00 g, 47.8 mrnol) at 0 °C. The mixture was stirred for 16 hours at ambient temperature, and the resulting suspension eras filtered and washed with dichloromethane. The filtrate was concentrated under reduced pressure to provide tert-butyl 2-(cyclopropylcarbonyl)hydrazinecarboxylate (13.0 g). 1H
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 tent-butyl 2-(cyclopropylcarbonyl)hydrazinecarboxylate (3.00 g, 15.0 mrnol) in 1,4-dioxane (50 mL) was added 4N HCl 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 v,~ashed with saturated sodium bicarbonate aqueous solution and brine, dried over NazS04, 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 o / I o H~N
CI I \ F --.~. \ y F
/ H ~ /
\ I / I F / I I NHz \ F
N
N I / H I /
F N-N
/ N~NHz i /I
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 nunol) 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 Na2S04, filtered, and concentrated i.mder reduced pressure to obtain 3-fluoro-N-phenylbenzanude (2.45 g). 'H NMR (DMSO-db) 8: 7.09-7.15(m, 1H), 7.33-7.40 (m, ZH), 7.41-7.49 (m, 1H), 7.55-7.64(m, 1H), 7.73-7.84 (m, 4H); m/z 216.15 (M++11.
Next, a nvxture of 3-fluoro-N-phenylbenzamide (1.OO 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, 54.9 mmol) in benzene (15 mL) was added 3-fluora-N-phenylbenzenecarboxinudoyl chloride (0.800 g, 3.39 mmol) at 0 °C. After ha~~ing 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 houxs.
After having cooled to ambient temperature, the mixture was concentrated under reduced pressure, and the obtained residue was purified by preparative TLC (eluent:
dichloromethane -/ methanol =
95 / 5) to provide 5-(3-fluorophenyl)-4-phenyl-4H-1,2,4-triazol-3-amine (lOS
mg).. 'H NMR
(DMSO-do) b: 5.82 (s, 2H), 6.90 (t, ,I--7.3Hz, 1H), 6.98-7.27 (W , 3H), 7.28-7.42 (m, 3H), 7.52-7.54 (m, 2H); m/z 255.25 (M~+1).
Preparation of intermediates Method (v)-1 Phenyl(pyridin-3-yl)methanol O H
MgBr NI \ ~H + ~ \ ~ i \ ~ \
/ / /
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 MgSO,,, altered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / diethylether = 4 l 1) to provide phenyl(pyridin-3-yl)methanol (1.07 g).'H NMR (CDC13-d): c~ 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), 8.51 (1H, d, J = 2.5 Hz); MS m/z 186 (M+1).
Method (v°)-1 cyclobutyl(phenyl)methanol O OH
\ \
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 Iayer was dried over MgS04, filtered, and concentrated under reduced pressure to obtain cyclobutyl(phenyl)methanol (1.03 g). '~P NMR
(CDCl3-c~: 8 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 (SH, m).
Method (v)-2 1,1'-(chloromethylene)bis(4-chlorobenzene) OH Cl \ \ \ \
CI ~ / ~ / . CI CI ~ / ~ / CI
To a solution of 4,4'-dichlorobenzhydrol (4.7S 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 Na~SO~, filtered, and concentrated under reduced pressure to provide 1,1'-(chloromethylene)bis(4-chlorobenzene) (5.14 g). 'H NMR (CDCl3-a~: 8 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 11~'V MS (M+l) or PLC Activity retention time class '_J
O N
/-~. w S
Example 1-2 ~N 1 , 463,603 464 189,1 D
i ) N
HaCi wCHs Example 1-3 ~ ~ N~"S ~ ~ 531,721 (m tho'd2C) D
..
N-~ ~._%
m r Example 1-4 I ~ N ~ \ 420,538 (m thod 2B) B
NON
S
w N Rt=4.41 Example 1-5 ~ / 420,538 B
N \ (method 2B) w l, N.. N
Rt=4.49 Example 1-6 F ~ ~ N ' ~ 481,549 B
(method 2A) Table 1 Melting Point Example No. Structure MVV MS (M+1 or HPLC . Activity retention time class H3C ~ N~.CH3 \ ..
_ ~2 Example 1-7 N S ~ 426,SS5 427 (method A) '~
N-N
\
N~N
j S \
Rt=4.52 Example 1=8 ~ ~ N I ~ 481,549 (method 2A) A

OH
~.
s Exam le 1-9 'N~N~ ~ '' 443 6185 444 Rt = 2,75 p ~ ~ ' (method A) ~N' i J _~s ! ~ 7 Example 1-10 / ~ \ ' 480,6118 481 (method A) I

Table 1 Melting Point Example Structure MW MS (M+1or HPLC Activity No. , retention class time Ht \
, ~
CIW / -N
~ N ~ ~-N S \ /

Example ~ ~ 516,5405444 207,8 B

~ N.~

CIH

~O~-~ w ~ Rt= 2 Example ~ N 458,55 459,2 . A
1-12 ~' (method w 1 B) /N\

w N-N

Example N S ~ ~ 414,57 415,2 82.1-86.5 A

/N~

H0~ ~ , w.

S
Example N 1 ~ 416,55 417,2 214.4-215.2B ' /N~

w N S U
Example 428,6 429,3 81.2-84.6 A
1-15 i w ,N~

Table 1 Melting Point or HPLC Activity Example Structure MW MS (M+1) No.

retention class time / \

F ~ ~ / N
l ~~~ S 437 25 156-157 A

E

- ~ \ , , , w xamp e ~' GH3 N- N
/ ~ w ~ S
' Example '' 440,612441 48,7 A
1-17 " N

w H3G.N.GH3 w N-N

E '~s 476 57 l ~

xamp ,, ~~ , , e 1- N

8 , i ~

H3G.N.G N3 N-N
E w 440 441 60 A

l - r , .
xamp N , e w H~C~N~CH3 _ 47 _ Table 1 Melting Point or HPLC Activit Example Structure MVO' MS (M+1 y No.

, retention class time F

N-N
w ~
S ~

Example N 462,566463 41,3 A

i I

H3G.N.CH

f N- N
~
~ w ~

Example S 485,6998484 Rt = 2.58 B
1-21 ~~N

(method A) ~N~

f HO~~ .
w 54 S ~ ~t - 2 Example N 446,6192445 . A
1-22 f (method A) ~N~

~ /

N-N
w S
Example ~~N ~ ' 558,6217484 203,8 B

CIH

H C

GIH
,N~

- 48 _ Table 1 Melting Point Example No. Structure M'Vi' MS (M+~) or HPLC Activity retention time class N-N
/ ~ w Example 1-24 ~N S 1 ~ ci 461,031 462 56,2 A
w H C N CH
w !, N-N
Example 1-25 ~N S ' ~' 428,6 429,3 135.8-138.6 A
~ ~
i ~N~
N-N
Example 1-26 ~N S 1 ' 440,61 441,3 150.8-151.7 A
~. N ~
/ \
F I \ N_N~ .~
S
Exa le 1-27 ~ / \ 467 57 468 2 169-170 A
mp ~ -~ ' ' (method B) s Example 1-28 i ~' N / \ 467,5? 468,2 Rt =3.21 A
i I ~- (method B) w OH

Table 1 Melting Point Example No. Structure MW MS (M+1) °r PLC Activity retention time class m / ~
v Example 1-29 ~ ~ ~N ~ ~ 453,54 454,06 69-70 A
OH
F ~~- S \
Example 1-30 ~ ~' '~ ~ 519,65 ~.2 (-38[ >300 A
~ ~ 1 ~o K
GOOEt ~Ph \ N S
Example 1-31 ~ . / 463,53 464 method C) D
\
OMe _ COOEt ~Ph \ N S
r Example 1-32 r I 447,54 448 141-142 D
Me Table 1 Melting Point or HI'LC Activity Eaaznple No. Structure MW MS (l~~I+~) retention time class N-N COOH , \ ~ ~ ~Ph ~N
Example 1-33 / ' 435,48 436 110-111 D
OMe _ COOH
/ ~ .,,~Ph N S
Example 1-34 ~ I 419,48 420 88-89 D
Me Ph N
Example 1-35 ~ 397,55 398 Rt ~ 5.08 (method C) Me i s Example 1-36 I i 482,693 483 146,8 A
.
w ,N~

Table 1 Melting Point or HPLC Activity Example No. Structure MW MS (M+1) retention time class I w HO'~~~
N S Rt = 2.2 Example 1-37 ~ I i 444,557 445 (method A) B
N
I
o i "
"o~_~
Example 1-3S ~ I i 472,61 473 (method A) ~I
iNy Example 1-39 ~ ~N S / \. 4S2,54 483,07 79-80 B
NN~
Example 1-40 ~ S ~ ~ 480,57 481,12 81-82 A .
i ~ ~ o N HZ
Example 1-41 N r '1 442,63 443,3 59.5-62.4 A
I
~N~

Table 1 Melting Point or HPLC Activity Example Structure 11'IW MS (M+1 No.

retention class tune N-N
~S
~N, ~ '' Example 442,63 443,3 194-198.8 B

w ~N~

N- N _ ~S y Example ~N 456,66 457,3 108.2-109.1D

~I

w ~N~

~S

' Example 486,64 487,3 149.5-155.2A
1-44 ' I

w /NW

w / N_~ w N S ~

Example 456,66 457,3 126.4-127.2B

w /N~

N-N
S

Example 432,633433 47,1 A
1-46 ~f H3C~N~CH3 Table 1 Melting Point Example No. Structure ~ MS ~+1 or HPLC Activity retention time class N-N
, S _ Example 1-47 ~ 390,552 391 (method B) C
H3C~N~CH3 w N-N
~ w Example 1-48 " N \ ° 416,547 417 Rt = 3.03 ~ (method B) H3C~N~CH3 w N-N
Example 1-49 ~ ~N 427,574 428 46,9 D
I
NaCiNwCHs ~°~,CH3 ~N~S
Example 1-50 ° 422,55 423 50,9 D
w H3C~N~°H3 Table 1 Melting Point Example No. Structure ~ MS (~+1~ or HPLC Activity retention time class ,OH
N S o 394,497 395 114,6 D
Example 1-51 I
N
H3G~ ~CH3 N-N
Rt = 3.48 Example 1-5? ~ N 404,579 405 (method B) A
N
H3C~ ~GH3 w N-N
Example 1-53 ~ ~ 418,606 419 (method B) A
H3C~N~GH3 H
Example 1-54 ~N~S~ ~ \: cH3 454,639 455 46,6 A
I
H~C~N~GH~

Table 1 Melting Point or PLC Actis~ity Example Structure M'VV MS retention class No. (M+1 time R

N-N
\

\
Example N S 432,614433 45 A

I

H,C~N'CH3 \

I

N

~

Example ~ , , method A) 1-56 ~
/

\ I o ~ ~%

/ \

N-N

N~ 56 08 ~

Example / \ , , method A) 1-57 ~
I

NHZ

F \ % _~
S
/
/

Example ' I ~ 495,58 496,08method A) O OH

i ,i N-N
~, ~I. ~S. w F A
' Example f 494,583495 54,2 "
/ F
I

H~C~N'CH3 _ 56 _ Table 1 llZelting Point Example No. Structure MVV MS (M+1 or HPLC Acti~~ity retention time class n1 .
i-~
Example 1-60 " N 440,612 441 54,8 B
I
w H3C~N~CH~
N-N _ / N~S, ~
Example 1-61 ~ N~' 427,574 42S 79,9 A
H3C~N~CH3 ,\ /
Example 1-62 ~N s ~ ~ 493,589 494 201,5 B
w ~ o OH
o_ ~ 1 .+
s Example 1-63 ~ ~ 1 ~ 508,56 509 211,1 B
i w ~ o OH

-.57._ Table 1 Melting Point Example Structure NIW MS or HPLC Activity No. (M+1 retention class time ,,.

N-N
Example. N* ~ ~ N , %' 508,56 509 98,7 A

w I o OH

,i -N ~ w Example ,~c, ~ ~ ~ NHS' \ ~ 506,6313507,15229.8-232.0B
1-65 N i hf~C
OH

f N-N ~w Example c~N~sr 1 ,1 401,4908402,09158.0-160.2D

, oN

,, r~
1 ~

N 427,574428 45,8 A
Example 7 w H~C~N~CH3 i N
=7 ~ N

Example F 418,485419 (Rethod B
1-68 I B) F~aC~NvCHa __Sg _ Table 1 Melting Point Example Structure MW MS (1~~+1)or HPLC Activity No. retention class time ci N-N
~ i 46S 52 A
~ 7 S

69 i 467,078 , Example -I

w H3e'N~cH, Ph S- 'Ph Et N

413,59 414 Rt = 5.64 A
Example (method 1-70 C) f F \ / _~ w S ~ .2 f /

Example ~ ~ 468,56 469,09 (method A
1-71 I A) NH
i OH

I
F \ N
N I
~

Example ~ 462,55 463,09 62-63 A
1-72 ~
I

fl N

/ ~

i ~ ~ N~S 538 27 l B

Example ~ ~ , , (method 1-73 B) CH3 i I

\ N\/~O~CHa Table 1 Melting Point or HPLC Acti~~ity Example Structure MW MS (11Z+1retention class No. time \ , F
w I -~--\
~N S \
~

Example ~ ~ 494,64 495,11 method B
1-74 I A) HaCiNwCHa CI

N-N

Example N S ~ 546,519547 126-127 B

cl w OBn CI~
N S ~~ 126 B

Example 434,99 435,2 .

.

/N~

~N

~
N S
~

Example 485,65 486,3 54.0-57.9 B

~N~

-6~-Table 1 Melting Point -Example No. Structure ~ MS ~+1 or HPLC Activity retention time class t N-N
~~ ~N~S~ ; ~ Rt = 3.17 B
Example 1-78 ( 469,65 470,3 (method B) I
,N~
N_\ w Example 1-79 l ~ N~S~ '~ 464,547 465,07 196-198 D
i w I off ° N N
Example 1-80 ~ \ / N~S/ ~ 492,65 493 Rt = 2.96 A
(method A) /N~
r -N~~ _ \ / ~S.
Example 1-81 °~~N* ~ -~ N ' ~~ 507,62 508 179,1 A
/N~

Table 1 Melting Point Example Structure MW MS (M+1or HPLC Activity No. retention class time I
/

~N ~ ~~~
. w \ ~S~ 506 507 177 C
~N. I ~., 63 3 Example ~ , , 1-S? i N-N _ 1 \ / ~ , f 477 47S 1 A
83 N S ~ :' 59 l ~
E

- ~ , (meth d e i A) xamp CI

N-N
HO~
~

Example S ~ ' CI 514,431515 114,4 D

~

OH
O

F N _ Example / ~ ~ N~S ~ f c~ 549,499550 69,5 A

I

H3C~N~CH3 ~- 62-Table I
Melting Point Example Structure MW MS (M-~-1r PLC Activity No. retention class time cl 1, Example N-N 497,491498 53,7 A
1-86 H'~~'N~S ~~c~

I

H,C~N~CH~

CI

~ N
Example H~~~ ~S' ~ 498,432499 201,6 A
1-87 N ~ /

CI
I

OH
\
O

CI

/, N-N
Example ~ / N~S ~,~ 496,416497 139,4 A

el I

off F \ N-~ w S \
f /

Example ' I ~ 520,63 521,2 95-96 A

'NH
O

90 N S ~ \ 44 05 61-62 A
l ~ 516 518 E

e , , -xamp ~
/

Br ~- 63 -.Ta- ble 1 lVlelting Point or HPLC Acti~~ity Example Structure ~ MS retention class No. ~+1 time cl f H0, N S ~ ~ 49 514 4 A

Example cl , , H C'N~CH3 a CI

i , S ~~ 530 58 A
~ 1 92 cl 529,92 , Example N .

cl H3C'N~CH3 CI

N-N
le 1-93 iw 529,92 530 67,2 A
Exam ~N S 1 ~

p cl cl H3C'N~CH~

CI

-N
Example F / ~ / N~S~ 1 \; cl 550,439551 235,4 A

I

.
OH
O

._ 64 _ Table 1 Melting Point Example No. Structure ~~ MS ~+1 or HPLC Activity retention time class ;' N-N
Exam le 1-95 ~ ~ ~ ' ' ~~ 522,429 523 212 A
p ~ N S 1'~ci OH
, w f HO %~
Example 1-96 0~ ~N '~ 458,58 459,2 98.7-103.7 B
w /N~
CI
HC ;
S
Example 1-97 N 1 ' e' 536,522 499 95,7 A
I
o-K
CI
i N- N
Example 1-98 ~N~S r / CI 534,506 467 127,2 A
i w I O_ O
K

._ 65 Table 1 Melting Point r PLC Acti~~ity Example Structure MW MS (l~Z+1retentionclass No. time CI

1 fJ

F N'N , 99 ~ ~ ~ NO'S ICI 635,588636 51,2 A
Example -i ~O

-~NJ

N-N
Example ~ ~ v / N~S~ ~~ 593,551594 48,5 A
1-100 ci N
O~ ~CH3 CI

w Example 564,466567 90,4 A
1-101 N S l~ci I

0 off cl' HO, ~~

Example N S 485,093486 53,4 A

H3C~N~CH3 Table 1 Melting Point Example No. Structure ~ MS ~+1) or HPLC Activity retention time class cl ,, N-N
HC
Example 1-103 N 470,034 471 89,3 A
OH
O
CI

HO~ //
Example 1-104 ~N>'Sf 1 ; ~ cl 527,474 528 109,5 D
I -w N
H~C~ ~CH3 CI
/~
"a°~ ~ -' ' ~~ Rt = 6.13 Example 1-105 N S ~~cl 482,48 482 (method C) A
I
H,c cH, Cl 1 ;
F N- N
Example 1-106 / ~ ~N~S ~ / CI 588,529 551 164,5 A
O K

.~ 67;
Table 1 Melting Point or HPLC Activity Example Structure NIW MS (1~~I+1retention class No. time ci N-N ! _ ' Example ~s \ 470,42 470,06 1-107 "3~

, c~ (method N A) I
~oH

ci N-N
"3C

N
/

Example ~ 539,53 539,11 60-61 B

c~
I

Cy ,, S

~

Example '~ I 591,54 591,11 84-85 B
1-109 ci CI

F NN

Example / ~ ~N~S ~ ! CI 549,455550 204 A

NHZ
O

:- 6s_ Table 1 Melting Point -Example No. Structure MW MS (M+1 or HPLC Acti~~ity retention time class cr Example 1-111 N S N 558,19 559 57,6 A
'f 1 Cf N-N
Example 1-112 ~N S ,NH 468,066 469 146,5 D
~I
w N
H3C \CH3 Cr /.
Example 1-113 ~N~S ~ ~~ 526,102 527 59,4 A
O.~CH

N
HyC~ ~CH3 Cf N-N
Example 1-114 H'e~N~'S l ~ef 567,535 568 60,5 A
i ('~
N' j-OH
'~'0 6~
Table 1 Melting Point Example Structure MW MS (M+1 or HPLC Activity No. l retention c time ass cl HOC' '~
Example N S 1 ~cl 541,5 54 70,3 A
1-115 i H
N~OH

CI
I i HOC '~
l S l~ 448 49S 90 A

e N , , Examp cl - i N Hz CI

H3C~ r N-N

N S \
117 ~ ~ ~ ' 539,53539,09 84-85 A
Example .

cl OH

CI
/ \

p / \ N~
S \

Example ' ~ 591,54591,06 108-109 A
1-118 ~

I
cl OH

_'70:_ Table 1 Melting Point Example No. Structure MW MS (M+1) or HFLC Activity retention time class cl 1 , N~ ,N-N _ ~N~S, I~cl 526,49 526(Ivl~, 204 4 A
Example 1-119 0 528(M+2) ' I
/N~
CI

Example 1-120 ~N~s '~ c 510,103 511 74,6 B
/ I CHa N
H3~s \CH3 CI
F
Example 1-121 ~ ~ NHS 1 / CI 563,482 564 75,5 A
I
O N H., a ,.;
%\
Example 1-122 ~'°~N'~s~ 1 , cl 512,459 513 75,5 A
I
O OH

Tabled Melting Point Example Structure MW MS (M+1~or PLC Activity No. retention class time a ,r~

~/

N-N
H
C ~

Example a 511,475512 61,4 A
1-123 N S ' r~c, I

0 NH, ci "'~N~S/ 1~

~~
Example ~ ~ 581,565582 82,3 A

O N
[
/

~
OH

CI
~r N-N
H / ~

Example.l-125N , ' ci 555,527556 53 A
I

0 N'~/OH

H

ci ' -N
H,c~N~~s ~

oi 581,565582 56,4 A
Example , 1-126 ~I
w o ~

o Table 1 Melting Point or HPLC Activity Example Structure ~ MS ~+1 retention class No. time cl \

i HOC Rt=2 S

E:~ample ~ \ 541,5 541,1 . A
1-127 N (method A) I /, C CI

H3C~N~CH~H

CI
\

/

c'~ Rt =2 ~ i~
H

Example 3 527,52 527,11 . A
1-128 - (method s A) N / \

I ~ a H3C~N~OH

CI

/
N-N
H C' Example 3 N S / \ 527,47 527,04 Rt =2.42 A
1-129 w (method A) O GI

,NH OH

Cl i F 51 08 Rt =2.49 A
/ \ N~S 3 593 Example \ , , ) 1-130 ~ / 9 ( w ~ method A

I , o a H3C~N~CH~H

_ 73 ._ _Ta- ble 1 Melting Point Example No. Structure MW MS (M+1 or HPLC Activity retention time class a / \
Exam le 1-131 ~ I~S 579,52 579,09 Rt =2.82 A
p / \ (method A) w I ~ cl H3C~N~OH
CI
/ \
Example 1-132 / ~ N~S / \ 579,48 579,09 (method A) '~
I ~ o cl ,NH OH

a ~ /N/-N\\
~C~N~S
/ \
Example 1-133 ~ ~ o ~ ~Im 776,613 777,01 Rt =3.46 (method A) H~C~N1CH~
CI
C~
/~
Example 1-134 / N S ~ 550,409 551 247-249 A
ci COOH

~- 74-Table 1 Melting Point Example Structure MVV MS (l~Z+1)or HPLC Activity No.

retention class time cl 1, N-N _ H C
/ ' N
Example S 1 / CI 599,58 600 44,8 B
1-135 ~ I

~oH

OH

CI
w -N
C
H

O
N S 1 ~ CI

Example ~ ~ 622,618623 100,4 B

O N
~~-~I
/NH;

~

CI Chiral w 1 f HOC
N 1 , CI

Example i I 595,592596 58,9 A

OH

CI

N-N
HO~
~

Example N S ~ 485,44 485,1 205.2 L10 1-138 cl ,Ny - .75.~
Table 1 llZelting Point Example Structure 11~' MS (M+1or HPLC Activity No.

retention class time t ci i \

N-N
H3C~
~

N
Example S 567,54 568 122 A
I-139 ., / ~

ci N
'~OH

Cf ~N" i ~~S

Example -' ~ \ 619,54 620 87 A

cl ,N
~OH

CI

H

N ~ \

Example I ~ ~ cl 581,57 582 86 A

N
~~O
'''' O~rH

CI
/ \

S

Example I ~ " 'ol 633,57 A

OH

-'76 _ Table 1 Melting Point Example No. Structure MW MS (M+1 or HPLC Activity retention time class Ht cl , N-N
H,c~ ~~s ~~cl 569 5144 570 33.6-86.1 A
Example 1=143 N

\ ~ N~o~c~

cl . -, _ / -, Example 1-144 H3°~N' S l~cl 583,5415 584 61.1-62.9 A
\ ~ N~°'cH

O O
CI
, N-N
H G~ ~S~
Example.l-145 3 N ~ ~ cl 555,4873 556 110-113 B

\ ~ N~OH

CI
, ,.
Example 1-146 H3c~N~s~ ~~cl 569,5144 570 95-98 A
N~OH
1~ ~f\

-.77_ Table ~1.:
Melting Point Example No. Structure MW MS (M+11 or HPLC Activity retention time class ci I
~N~ ~ , w.
Example 1-147 '~~N S \ .~' c~ 554,54 555 66.7-72-3 A
i /N~
l N,N
Example 1-148 / ~ N'~'~N ~ 420,49 421 177.5-178.4 H3C~N~CH3 Example 1-149 N ~ Rt=4.44 N S (method 2C) N-N
f N-N
~>'-S
N Rt=5.01 Example 1-150 ~ , / 1 / \ (method 2A) ~g._, Table l Melting Point Example No. Structure MW MS (M+1 or HPLC Activity retention time class f ~N
I ~,~--s Example 1-151 ~ N Rt=4.52 / ~ (method 2B) N

o \ \
I
S N F Rt=4.48 Example 1-152 ~ 11 , ~ ~ F (method ZD) \ I ~ N F
O

O
\ /
Example 1-153 ~ S Rt=4.25 B
~N ~ ~ (method 2D) N~ ~ O
H~O~O \ I O N CHI

O _ GI
Exam le 1-154 ~ S N Rt=4.64 B
p ~ 1j . ~/ (method 2D) H3C~ / O N~N~~~CI
O ~~\
~O
0 ~N~ CH3 WS I \ NwCHs Rt=3.61 D
Example 1-155 ~ ~,~ N,~N (method 2D) -~79~--Table 1 Melting.Point Example No. Structure 1\'IW MS (11~I+1) or HPLC Activity retention time class O
Example 1-156 ~ \ s \ ~ Rt=4.56 A
~N ~ \ F (method 2D) H30,0 \ ' O N.N~F

O
~-CH3 Example 1-157 s ,~ ~ Rt=4.08 A
HaCO - ~-N (method 2D) O N~N

O HaC
/ \ N-CH3 ' " Rt=4.19 Exam le 1-158 p H3~ - S\- (method 2D) o \ / N
o N~ ~~
N
CHI H3C~N_CH~
O _ \ /
Exam le 1-159 ~ s Rt=4.35 A
p rN (method 2D) HOC, ~ / O N~N; ~ O
0 \ CH

O
Exam le 1-160 ~ ~ ~ ~ Rt=4.47 A
p s~N ~ \ (method 2D) H C ~ ' O N,N~ F F
~0 _ g0.~
Table 1 Melting Point Example No. Structure MW MS (M+1) or HPLC Activity retention time class O H' O_CH3 Example 1-16I ~- S ~ ~ Rt=4.43 N (method 2D) H3o. ~ ~ O Nr r ~ ~ ci O \

O
!\
Rt=4.35 Example 1-162 H~o S ~ (method 2D) O ~ ~ O N// N, N
C Ha C( I
Example 1-163 ~ ~ c~ Rt=4.37 E
(method 2D) H3C, r ~N
O ~ I O N~i O
Exam le 1-164 ~ ~ ~ Rt=4.06 (method 2D) / o c~
G~ .
N
Rt=4.40 Example 1-165 o S N /
11 ~ F (method 2D) N,N

_ g~ _ Table l _,_ _ Melting Point Example No. Structure MW MS (M+1 °r PLC Activity retention time class ~~CHa COQ
N F Rt=4.07 Example 1-166 o s~N ~ \ F (method 2D) N_N F
O
O~F
F
O
Example 1-167 S \ '~ Rt~4.y7 _ ~ N (method 2Dj N~N
'' CI

8~_ [Example' 2-1]
Method B
3-[3-(2,2-diphenylethyl)-5-(3-fluorophenyl)-4H-1,2,4-triazol-4-yl]benzoic acid o / o HZN \ O~CH3 CI \ F HsC~O \ I N \ F
/ I / O H I /
I CI F
H3C~0 \ \ F
N
H
o I/
O
F
To solution of ethyl m-anunobenzoate (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~SO~, 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- f [(IE,Z)-chloro(3-fluorophenyl)methyl ene] amino ] benzoate (1.11 g).
Next, to a solution of ethyl 3-{[(IE,Z)-chloro(3-fluorophenyl)methylene]amino]benzoate (320 mg, 1.04 xnmol) 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 - 83._ ' iiiixture was concentrated under reduced pressure. The obtained residue was purified t~~ice by preparative TLC (eluent: dichloromethane / methanol = 95 /.5 and then with ethylacetate / hexane 1 / T) toprovide ethyl 3-[3-(2,?-diphenylethyl)-5-(3-fluorophenyl)-4H-1,2,4-triazol-4-yl]benzoate (78.0 mg). 'H NMR (DMSO-d6) 8: 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--l.9Hz, 1H), 7.72 (t, J--7.9Hz, 1H), 8.15 (d, J--7.9Hz, 1H); mlz 492.2 (M"+1).
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 1N aqueous sodium hydroxide solution at room temperature and stirred for 16 hours. The mixture was concentrated under reduced pressure, neutralized with 1N HCl aqueous solution, and extracted with ethylacetate. The organic layer was dried over Na~S04, 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).
'H NMR (DMSO-d6) 8: 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, .l--7.9Hz, 1H), 7.67-7.72 (m, 2H), S.l 1 (d, J--7.9Hz, 1H).
mp 233-234 °C;
Molecular weight : 463.51 MS (M+H): 464 Activity Class : D

s4..
In the siiriilar 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 Example 2-2. I \ 419,5 420,3 128-129 D
i F I ~ I,N~ \
Example 2-3. w 491,56 492,2 Rt =2.92 D
1 (method B) v r y,, ~I

Example 3-1 (4-{3-cyclopropyl-5-[(diphenylmethyl)sulfinyl]-4H-1,2,4-triazol-4-yhphenyl)dimethylamine 1 ~1 1 N-N N-N
~ w / ~ , V N/ 'S I N S I
O
,N
H3C~N~CH3 H3C ~CH3 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 nunol) 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 NaZS04, filtered, and concentrated under reduced pressure to 85 ~-obtain (4-{3-cyclopropyl-5-[(diphenylmethyl)sulfinyl]-4H-1,3,4-triazol-4-yl}phenyl)dimethyl-amine (326 rng), 1H NMR (DMSO- .d6) 8 0.83-0.90 (m, 4H), 1.49-1.54 (m, 1H), 3.54(s, 6H), 5.87 (s, 1H), 7.?2-7.31(m, lOH), 7.44 (d, J= 8.6 Hz, 2H), 8.30 (d, J= 5.6 Hz, ?H).
Molecular weight : 44?.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.

:_ 86-Table 3 Example Structure MolecularActivity No.

Wei ht Class cl p !, 4_1 H~~N~S~ ~~cl 542,48 A

O. GH

O

GI

4-2 ~s~ ~1~GI 528,46 A
H3c'~-~

N
i OH

~
'IO

O

CI

CHI _ O=S.N~ 5 4-3 " N I ~ 576,57 A
GI
I

HaG.N.GH3 CI
\

/
N-N
H3C~\~, ~.S

4_4 N i \ 541, 50 A

cl HaC'N~OH

CI
\

/
N-N
H~C''~C~
~'S

4-5 N 583,54 A
i ~
~-~
o cl OH

OH

CI
\

/
N-N
H3C~~
~-.5 4-6 N 572,46 A
~ / \

GI

OH

O

87-_ Table 3 Example Structure MolecularActivity No.

Wei ht Class Cf HzN~_ ~~~, I~

cl 484,45 A

H3C~N'CH3 H C'~-L ~ i ~~, 3 N S l~

4_8 cl 527,47 A
~

I
NH
OOH

GI
w 1 f HC~

S I~

4-9 N 569,51 A
GI
~~

I
v 'NH
O~O~CH3 I I

O

N-N
4-10 "~~N~'S ~ ~ G, 597,56 A

\ ~ ~~O~CHa II

Fi O

CI
~

.

N-N _ 4-11 H3G~N~5 ~ ~~ 51 A

c, , w I N~oH

H ~~O

CI
i f N-N
HC~

4-12 ~ 585,55 A
~ GI
I
o \.
, N
HOI 'OH

gg._ Table 3 MolecularActivity Example Structure Wei Ht Class No.

cl l N-S ~
~

4-13 ~ cl 496,46 A
N
I

w H
C.N.CHa cl 4-14 "~~ 581 A
~S~ ~~ci 57 N , ~,.OH
~~'(N

O

CI

4-15 "~c~ 54 A
~'S~ ~ ~ 580 c, , N

~N~H
w N~O

O

_ CI

.~ ~NJ-N'\
H
C~
~

4-16 N 541,50 A
S
~ \

ci HN~OH
II

O

-- CI

N-N
H
C~
~

4-17 S j \ 513,49 A
' N
cl HN,fOH

CI
\

/
N-N
C'~C ~
H

~
4-18 S 571,53 A
N / \
r c ci "O~.N.CHOH

-, 89--'Table 3 MolecularActivity Example Structure Wei ht Class No.

cl 4-19 "3c'~ 51 A
~'s \~- 556 N , cl OH

fIO

O

C~

i H~C~
~S

N
4-20 I 533,95 A
~ ~ cl ~

w N.CH~
CHy CIN

CI
\

/
N-N
H3C'''~-~

S
4-21 N / \ 555,53 A
i I cl ~
NH O
C' v -OH
H

CI
\

/
N-N
H
C

4-22 N S 526,49 A
/ ~

CI

OH

O

OI
\

/
N-N
H

4-23 N / \ 499,42 A

~ I cl NOZ

CI

H
C
i N-N

4-24 3 579,59 A
s N / ~

o ci H30.N,OHO N' 'Table 3 Example No. Structure Molecular Activity Wei ht Class cl ~r N-N
4-25 ~N S N~.," cl 496,46 A
I
w H3G,N.CH3 CI
/ \
N-N
H3G'~.rC ~S
4-2g N / \ 469,44 A
cl NHZ
CI
/ \
N-N
H3C'~-C,N~S
4-27 / \ 528,46 A
o cl H C~O OH

GI
~ rNr-N\\
HsC~ ~S
4-28 N / ~ 528,46 A
cl CI
l \
N-N ' H~C'~,~N~S
4-29 / \ 484,45 A
~ I cl O.CH3 CI
i \
N-N
H~C''~ N ~ S
4-30 / \ 569,59 A
~ I cl 0~~
HN~O~CH3 IIO

:_:91-'Table 3 Example No. Structure Molecular Activity Wei ht Class cl / \
~ ~N~-N

4-31 N / \ 514,43 A
c cl OH OH
CI
/ \
~ /N/-N\\
HaC~ ~S
4-32 N ~ \ 514,43 A
cl OH
O DH
CI
/ \
~ /N/-N\\
H3G~ ~S
4-33 N / \ 470,42 A
I
cl OH
C!
N-N _ H3C'\~N~g' 4-34 °' 563,94 A
~ NH
~OH GIH
[~O
GI
- ~-N _ 4-35 H3G~N~~ ~ ,. cl 581,57 A

~N OH
CI
/ \
.~ jN~-N ' H3c~N~'S
4-36 ~ I ~ 527,47 A
cl HN~OH
IIO

._ 92-'Table 3 MolecularActivity Example Structure Wei ht Class No.

cl ~ !Nj-N
H
C~
~

N
S

4-37 ~ ~ 542,48 A

\ I
GI
~- o o~o CL
\

N-N
H~C~
~S

4-38 N 537,51 A
~
~ ~

I
cl w HN
flO

CI
\

i N-N
H3C~N'"S

4-39 ~ \ 547,53 A

cl HN. ,O

O CHa CI
\

/
~ /N/-N
C~
~
H

a 4-40 N 625,62 A
S
~ / ~

cl O~. ,N. .,O
s S' CH
H C' 3 O O ' GI

~ /N/-N
H
C~
~

4-41 N 528,46 A
S
/ \

I
GI
O

O~ OH

r F
N
-N

~ /
/
H
C~ ~

4-42 S 491, 67 B
N
r _ I

O
w K
O

..:93-'Table 3 MolecularActivity Example Structure Wei ht Class No.

\ F

I, N-N

H3C'~L -4-43 N 491,67 A
_ o Ky O

F

r N-N

4-44 H'~~N~S 491,67 A

p _ K.
O

I\

/ F
N-N
C ~''~, ~.
H

4-45 S 467,61 B
N
i \ I O.CH

a O

F

N-N S I
H3C'~C~ Y

4-46 N 467,61 A
/

I
\ .CH

O

F

N_N S I /
H C~~ y 4-47 467,61 A
I

\
.CHa O

\ F

/
N-N
H
C' 4-48 3 453,58 A
N
i \ I OH

O

-- F

N-N\\
H
C'~ ~

a 4-4g S 453,58 A
N

/
\ I OH

O

:_.94-'Table 3 Example No. Structure Molecular Activity Wei ht Class i F
~ jN~-N
H3C~ ~.S
4-50 N 453,58 B
i w I off H'C 1 O O
N-N i 4-51 N S 504,70 A
HyC~N~CH3 HO O
I w N-N
N S
4-52 ~ 513,10 B
H3C~N~CH3 CIH
CI
~ ~N~-N~~
HsC~ ~S
4-53 N / ~ 555,53 A
o cl H3C.N.C O.CH3 H3C~\~CN~S~
4-54 °' 513,49 A
OH

- 95=, Table 3 MolecularActivity Example Structure Weic Class No. ht ci ~ f N-N
H
C~
~
~.
~

a N

f , c~

4-55 ~- ~ 625,62 A

N
off ci s .
N-N
H3C~
~S
l-4-56 N 625,62 A
' ~
l w ~'~' N~ off h c i I
N-N

4-57 H3c'~N' I ~ 480,40 B

ci ~ j off F

~r H'~ 8 A
~'S ~

4-58 N 480,5 ' F
i I

W
HN~OH

H C
~
S 1~

4-59 ~. 506,62 A
F
l w OH

'Table 3 Example No. Structure Molecular Activity Wei ht Glass cl ~.
N-N _ H3C~N~~S~ ~ f CI
4-60 ~ ~ 581,57 A
N
O OH
F
N-N g H3C~NY
4-61 , H~c c,~Ha 427,54 A
~ ~ off F
N-N S
H3C~Ny 4-62 ~ H3c cH3H3 441,57 A
I °~cH

HO
N_N
N S
4-63 462,66 A
w H3C'N~CH3 F

N-N
H Cue, 4-64 3 N S ~ ' F 493,58 A
~I
OH
O
F
N-N
H C'' 4-65 ' N S ~ / F 494,61 A
~i H3C'N~OH

~- 97--Table 3 MolecularActivity Example Structure Wei ht Class No.

F

N-N
H C ~~
~-N
S
f' F

4-66 ~ ~ 548,66 A

N
~OH

[~O

F

N-N
HC~

4-67 3 N S , / F 538,62 A
~

w OH
HO~N'CH~

F

N-N
HC~

4-68 3 N S ~ / F 522,62 A
~~

I
~NH O
H~C~OH

F

N-N
H
e~
~.' ' 508,59 A

4 S ~ f F
-~

w OH
H3C.N.CHO

F

r N-N
HC~

4-70 ' N S ~ ' F 522,62 A
I

~' O'CH

H
C.N.CHO

N-N
c'~! ~-. ,, H

4-71 S 449,6 N

w ~ OH

O

'Table 3 Example Structure MolecularActivity No. Wei ht Cfass cl HC~

4-72 3 N S ~ '' ' 581,57 A
~

I
w ru OH

O

CI

N-N
H3c~
~s ~ ' N 563,98 A
' cl H CIH

N~O

Claims (18)

1. A phenyltriazole derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof:
wherein R1 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, alkylsulfonylamino, 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 O, and which ring is optionally substituted by one or two substituents selected from the group consisting of alkyl, halogen, alkoxy, nitro, amino, cyano, alkylanuno, di(alkyl)amino, 4-7 membered saturated cyclic amine optionally substituted by hydroxy, and mono-, di-, or tri-halogen substituted alkyl;
R2 represents -COR21, -(CH2)n-R21 or tert-buyl, 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, 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, alkyl-aminosulfonyl, 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;
R5 represents hydrogen, hydroxy, nitro, cyano, halogen, sulfamoyl, alkylsulfonyl, allylaminosulfonyl, di(alkyl)aminosulfonyl, -(CH2)m-CO-R50, -(CH2)m-R51, -NR52R53, or -OR54, wherein m is 0, 1, 2, or 3 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, hydroxy-alkyl, alkoxycarbonylalkyl, or carboxyalkyl or R501 and R502 together form with the adjuscent N atom, morpholino, piperazino optionally substituted by oxo, ar 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, R51 is hydrogen, hydroxy, or NR511R512 (wherein said R511 and R512 independently represent hydrogen, alkoxyalkyl, alkyl, hydroxyalhyl, alkoxycarbonyl-alkyl, or carboxyalkyl, or R511 and R512 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)carbamoyl, 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 alkylthio optionally substituted by mono-, di-, or tri- halogen or R6 and R7 together foam phenyl fused to adjacent phenyl; and X represents CR10R11, NR12, S, O, SO2, or SO
wherein R10, R11, and R12 independently represent hydrogen or methyl.

2. The phenyltriazole derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1:
wherein X represents CH2, NH, S, O, SO2, or SO;
R1 represents C3 to C8 cycloalkyl, C1-C6 alkyl optionally substituted by one or two substituents selected from the group consisting of C1-C6 alkoxy, amino, C1-C6 allylamino, di(C1-C6 alkyl)amino, C1-alkanoyloxy, hydroxy, C3-C8 cycloalkyl, carboxy, C1-C6 alkoxycarbonyyl, 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(C1-C6alkyl)amino, and mono-, di- or tri- halogen substituted C1-C6alkyl, R2 represents -COR21 or -(CH2)n-R21, Wherein R21 represents mono-, di-, tri-halogen substituted C1-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, C1-C6 alkoxycarbonyl, and halo C1-C6 alkyloxycarbonyl, or phenyl optionally substituted by one substituent selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 alkoxy, and mono-, di-, or tri- halogen substituted C1-C6alkyl;
n is 0 or 1;
R3 and R4 independently represent hydrogen, halogen, cyano, hydroxy, amino, C1-6 alkyl-amino, di(C1-6 alkyl)amino, C3-8 cycloalkylamino, C1-6 alkoxycarbonyl, sulfamoyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, C1-6 alkanoyl, C1-6 alkanoylamino, carbamoyl, C1-6 alkylcarbamoyl, di-(C1-6 alkyl)carbamoyl, C1-6 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;
R5 represents hydrogen, nitro, cyano, hydroxy, halogen, sulfamoyl, C1-C6alkylsulfonyl, C1-C6alkylaminosulfonyl, di(C1-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, C1-C6alkyl, hydroxy C1-C6alkyl, C1-C6alkoxycarbonyl C1-C6alkyl, or carboxy C1-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 C1-C6 alkyl optionally substituted by halogen, R51 is hydrogen, hydroxy, or NR511R512 (wherein said R511 and R512 independently represent hydrogen, C1-C6 alkoxyalkyl, C1-C6 alkyl, hydroxyalkyl, C1-C6 alkoxycarbonylalkyl, 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 carb-oxy, hydroxyalkyl, hydroxy, and carbamoyl) R52 and R53 independently represent hydrogen, C1-C6 alkyl, hydroxy, C3-C8cycloalkylcarbonyl, or hydroxy C1-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, hydroxypyrrolidinyl-carbonyl, hydroxyC1-C6alkylaminocarbonyl, cyano, hydroxy, hydroxyC1-C6alkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C3-8 cycloalkylamino, C1-6 alkoxycarbonyl, sulfamoyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, C1-6 alkanoyl, C1-6 alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, C1-6 alkylcarbamoyl, di-(C1-6 alkyl)carbamoyl, C1-6 alkylsulfonyl, C1-6 alkyl optionally substituted by alkoxyalkyl(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 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.

3. The phenyltriazole derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1, wherein represents CH2, NH, S, or SO;
R1 represents cyclopropyl, pyridyl, phenyl optionally substituted by halogen, C1-C6alkoxy, nitro, amino, cyano, C1-C6alkylamino, di(C1-C6alkyl)amino, or halogen substituted C1-C6alkyl, C1-C6 alkyl optionally substituted by one or two substituents selected from the group consisting of C1-C6alkoxy, amino, C2-C6 alkylamino, di(C1-C6 alkyl)amino, C1-alkanoyloxy, hydroxy, C3-C8 cycloalkyl, carboxy, C1-C6 alkoxycarbonyl, C3-C8 cycloalkylphenyloxy, halogen, morpholino, and pyrrolidinyl, pyrrolidinyl, or piperidinyl optionally substituted by methyl;
R2 represents -COR21 or -(CH2)n-R21, wherein R21 represents mono-, di- or tri-halogen substituted alkyl, morpholino, C1-C6alkoxy, hydroxy, C3 to C8 cycloalkyl, pyridyl, furanyl, thiophenyl, pyrrolidinyl, piperidinyl optionally substituted by one selected from the group consisting from benzyl, C1-C6alkoxycarbonyl, and haloC1-C6alhyloxycarbonyl, or phenyl optionally substituted by one selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 alkoxy, and mono-, di- or tri-halogen substituted C1-C6alkyl;
n is 0 or 1;
R3 and R4 independently represent hydrogen, halogen, methyl, or amino;
R5 represents hydrogen, morpholino, hydroxypyrrolidinylcarbonyl, hydroxyalkylamino-carbonyl, cyano, hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C3-8 cycloalkylamino, C1-6 alkoxycarbonyl, sulfamoyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, C1-6 alkanoyl, C1-6 alkanoylamino, carbamoyl, diphenylmethyloxycarbonyl, C1-6 alkylcarbamoyl, di-(C1-6 alkyl)carbamoyl, C1-6 alkylsulfonyl, C1-6 alkyl optionally substituted by alkoxyalkyl(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 alkylthio optionally substituted by mono-, di-, or tri- halogen; and R6 and R7 represent hydrogen, or R6 and R7 together form phenyl fused to adjacent phenyl.

4. The phenyltriazole derivative of the formula (I), its tautomeric or stereoisomeric form, or a sah thereof as claimed in claim 1, wherein X represents CH2, NH, or S;
R1 represents cyclopropyl, pyridyl, phenyl optionally substituted by halogen, alkoxy, nitro, amino, cyano, alkylamino, di(alkyl)amino, or halogen substituted alkyl, C1-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, C1-alkanoyloxy, hydroxy, C3-C8 cycloalkyl, carboxy, C1-C6 alkoxycarbonyl, C3-C8 cycloalkylphenyloxy, halogen, morpholino, and pyrrolidinyl, pyrrolidiny, or piperidinyl optionally substituted by methyl.

5. The phenyltriazole derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1, wherein-X represents CH2, NH, or S;
R2 represents -COR21, -(CH2)n R21, wherein R21 is phenyl optionally substituted by C1-C6 alkyl, halogen, halogen substituted alkyl or alkoxy and n is 0 or 1.

6. The phenyltriazole derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1, wherein X represents CH2, NH, or S;
R3 and R4 independently represent hydrogen, halogen, methyl, amino; and R5 represents hydrogen, morpholino, hydroxypyrrolidinylcarbonyl, hydxoxyalkyl-aminocarbonyl, cyano, hydroxy, hydroxyalkyl, hydroxyamino, carboxy, fluoro, chloro, bromo, nitro, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C3-8 cyclo-alkylamino, C1-6 alkoxycarbonyl, sulfamoyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, C1-6 alkanoyl, C1-6 alkanoylamino, carbamoyl, diphenylmeth-yloxycarbonyl, C1-6 alkylcarbamoyl, di-(C1-6 alkyl)carbamoyl, C1-6 alkylsulfonyl, C1-6 alkyl optionally substituted by alkoxyalkyl(alhyl)amino, di(alkyl)amino, alkoxycaibonyl, 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 represents hydrogen.

7. The phenyltriazole derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1, wherein said phenyltriazole derivative of the fornmla (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-1,2,4-triazol-4-yl}phenyl)dimethylamine;
(4-{3-[(diphenylmethyl)thio]-5-propyl-4H-1,2,4-triazol-4-yl}phenyl)dimethylamine;
[4-(3-cyclopropyl-5-{[(2-methylphenyl)(phenyl)methyl]thio}-4H-1,2,4-triazol-4-yl)phenyl]dimethylamine;
[4-(3-{[bis(4-chlorophenyl)methyl]thio}-5-cyclopropyl-4H-1,2,4-triazol-4-yl)phen-y1]dimethylamine;
[4-(3-cyclopropyl-5-{[(4-methylphenyl)(phenyl)methyl]thin}-4H-1,2,4-triazol-4-yl)phenyl]dimethylamine;
[4-(3-{[bis(4-fluorophenyl)methyl]thio}-5-cyclopropyl-4H-1,2,4-triazol-4-yl)phen-yl]dimethylamine;
[4-(3-{[(4-chlorophenyl)(phenyl)methyl]thio}-5-cyclopropyl-4H-1,2,4-triazol-4-yl)phenyl]dimethylamine;
(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)dimethylamine;
[4-(3-{[bis(4-methylphenyl)methyl]thio}-5-cyclopropyl-4H-1,2,4-triazol-4-yl)phen-yl]dimethylamine;
{4-[3-cyclopropyl-5-({phenyl[4-(trifluoromethyl)phenyl]methyl}thio)-4H-1,2,4-triazol-4-yl]phenyl}dimethylamine;

[4-(3-{[(4-chlorophenyl)(cyclohexyl)methyl]thio}-5-cyclopropyl-4H-1,2,4-triazol-4-yl)phenyl]dimethylamine;
3-[(diphenylmethyl)thio]-5-ethyl-4-(4-isopropylphenyl)-4H-1,2,4-triazole;
{4-[3-{[bis(4-chlorophenyl)methyl]thio}-5-(3-fluorophenyl)-4H-1,2,4-triazol-4-yl]phen-yl}dimethylamine;
[4-(3-{[bis(4-chlorophenyl)methyl]thio}-5-propyl-4H-1,2,4-triazol-4-yl)phenyl]dimethyl-amine;
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-triazol-4-yl]-phenyl}-piperidine-3-carboxylic acid.

8. A medicament comprising a phenyltriazole derivative of the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1 in as an active ingredient.

9. The medicament as claimed in claim 8, further comprising one or more pharmaceutically acceptable excipients.

10. The medicament as claimed in claim 8, wherein said phenyltriazole derivative of the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof is a GABAb agonist.

11. The medicament as claimed in claim 8 for the treatment and/or prevention of an urological disorder or disease.

12. The medicament as claimed in claim 11, wherein said urological disorder or disease is urge urinary incontinence, overactive bladder, benign prostatic hyperplasia.

13. The medicament as claimed in claim 11 for the treatment and/or prevention of pain.

14. The medicament as claimed in claim 11 for the treatment and/or prevention of spasticity and motor control disorders, epilepsy, cognitive defects, psychiatric disorders, alcohol dependence and withdrawal, feeding behaviour, cardiovascular, respiratory disorders, or gastrointestinal disorders.

15. Use of a compound according to claim 1 for manufacturing a medicament for the treatment and/or prevention of an urological disorder or disease.

16. Use of a compound according to claim 1 for manufacturing a medicament for the treatment and/or prevention of pain.

17. Process for controlling an urological disorder or disease in humans and animals by administration of an GABAb-agonistically effective amount of a compound according to claim 1.

18. Process for controlling pain in humans and animals by administration of a GABAb-agonistically effective amount of a compound according to claim 1.