DESCRIPTION A20LSCARBOXAMIDE DERIVATIVE
Technical Field
The present invention relates to an azolecarboxamide
derivative which is useful as a medicine, particularly as an agent for treating urinary frequency, urinary urgency, urinary incontinence, lower urinary tract pain, which are associated with various lower urinary tract diseases including overactive bladder, and various diseases accompanied by pain.
Background Art
Overactive bladder refers to a clinical condition complaining urinary urgency regardless of incontinence, which is usually accompanied by urinary frequency and nocturia (Non-Patent Document 1). Currently, an anticholinergic agent is mainly used for the treatment thereof, and certain therapeutic outcome has been shown. However, it is known to cause side-effects such as dry mouth, constipation and blurred vision and it has been reported that the anticholinergic agent is difficult to be used for patients with prostatic hypertrophy or elderly patients because of a risk of urinary retention. In addition, there are patients showing no improvement with the anticholinergic agent. From the above facts, there is a great expectation for a drug with new mechanism of action against overactive bladder.

Nerve Growth Factor (NGF) is one of humoral factors named generically as a neurotrophic factor, which plays an important role in the development, differentiation and function maintenance of neurons in an organism. As the receptor of NGF, the high-affinity trkA receptor (receptor tyrosine kinase} and the low-affinity p75 receptor have been known. It has been reported that p75 binds to all of nerve growth factors, and is involved in apoptosis in the process of neuron development, but its role has not yet been fully elucidated. It has been known that NGF and trkA receptor-knockout mice show the same phenotype (Non-Patent Document 1), and it is believed that a physiological action of NGF is exhibited mainly through the trkA receptor.
It has been known that the NGF level in bladder is
high in a patient with overactive bladder or interstitial cystitis (Non-Patent Document 2), and it has been reported that an intravesical instillation of NGF reduces a bladder capacity of rat and that an inhibition of NGF improves urinary functions in the urinary frequency model rat (Non-Patent Document 3). In addition, there have been reported that the inhibition of NGF improved urinary freguency or incontinence in patients with interstitial cystitis (Non-Patent Document 4), and thus it is believed that a trkA receptor inhibitor is useful as an agent for treating urinary frequency/urinary urgency, and urinary incontinence which are associated with overactive bladder, and lower urinary tract diseases such as interstitial cystitis and prostatitis.

Moreover, a trkA receptor inhibitor has a different mechanism of action, and thus side effects which are characteristic to the anticholinergic agent are expected to be avoided and also an effect on patients who showed no improvement with the anticholinergic agent is expected. In addition, this agent is expected to show more potent effects on subjective symptoms by acting on sensory nerves. Furthermore, this agent has been reported to exhibit an effect of improving morbid conditions without lowering the urinary pressure in the urinary frequency model rat (Non-Patent Document 5), and thus it is expected that this agent can be administered safely to a patient with prostatic hypertrophy or an elderly patient.
It has been also known that administration of NGF to human or rat induces pain, and that algesthesia in the trkA knockout mice is lost. Consequently, NGF is believed to be strongly related in expression of pain. An NGF inhibition shows efficacy to the model animals with neuropathic pain or inflammatory pain, such as a model with pain induced by injury to sciatic nerve (Non-Patent Document 6) and a model with pain induced by damage to knee joint (Non-Patent Document 7), and the trkA receptor inhibitor is believed to be useful as an agent for treating a lower urinary tract disease accompanied by lower urinary tract pain and various kinds of pains such as an osteoarthritis.
As the compound mentioned above, there have been known an indolocarbazole derivative (Non-Patent Document S), a pyrrolocarbazole derivative (Patent Document 1), a pyrazolone derivative (Patent Document 2), an oxyindole

derivative (Patent Document 3 and 4), an azaoxyindole derivative (Patent Document 5), a pyrazolyl condensed ring compound (Patent Document 6), a pyrazole derivative (Patent Document 7 and 8), a tricyclic derivative (Patent Document 9) and ALE-0540 (Patent Document 10).
In addition to the above Non-Patent Document 8 and Patent Documents 1 to 10, as the compound having relatively similar structure, a compound represented by the following general formula (XV) is disclosed as a c-fms kinase inhibitor in Patent Document 11. However, a trkA receptor-inhibitory activity in the present invention is not mentioned at all. Furthermore, in this publication, there is no specific disclosure in Examples and so forth as for the-compound having thiazole or oxazole skeleton wherein 2 position is substituted.
[Chem. 12]

(In the formula, A is phenyl, naphthyl, or biphenyl which may respectively be substituted; or a 5 to 7-membered aromatic monoheterocyclic group or a 8 to 10-membered aromatic biheterocyclic group which may respectively be substituted and have 1 to 4 N, 0, or S; Ri is -H, aryl, or the like; X is -CO-, -C(=NH)-, -CS-, or the like; R2 and R3 are each independently -H, C1-6 alkyl, aryl, cycloalkyl, or the like, while R2 and R3 may, together with the nitrogen.

to which R2 and R3 are bonded, form a 5 to 7-membered heterocyclic group or aromatic heterocyclic group, and the heterocyclic group may be substituted and contain 1 to 3 N, 0 or S; W is phenyl, naphthyl or biphenyl which may respectively be substituted, or a 5 or 6-membered monocyclic or 8 to 10-membered bicyclic heterocyclic group or aromatic heterocyclic ring/ which may respectively be substituted and contain 1 to 4 N, 0 or S. For details, refer to the publication).
Non-Patent Document 1: "Reviews in the Neurosciences', (England], 1997, vol 8, p.13 to 27
Non-Patent Document 2: "British Journal of Urology', (England), 1997, vol 79, p.572 to 7
Non-Patent Document 3: "Neuroscience', (U.S.A'.), 1997, vol. 78, No. 2, p.449 to 59
Non-Patent Document 4: "General Outline preliminarily-described for the 99"h American Urology Association' , (San-Francisco) , 2004, #363
Non-Patent Document 5: "The Journal of Urology', (U.S.A.), 2005, vol 173, p.1016 to 21
Non-Patent Document 6: 'Pain', (U.S.A.), 1999, vol 81, p.245 to 55
Non-Patent Document 7: "Pain', (U.S.A.), 2005, vol 116, p.8 to 16
Non-Patent Document 8: 'Cancer Research', 1999, vol 59, p.2395 to 2401
Patent Document 1: International Publication pamphlet WO01/14380

Patent Document 2: International Publication pamphlet WO01/32653
Patent Document 3: International Publication pamphlet WO02/20479
Patent Document 4: International Publication pamphlet WO02/20513
Patent Document 5: International Publication pamphlet WO03/027111
Patent Document 6: Japan Patent Application Publication 2003-231687
Patent Document 7: International Publication pamphlet WO2005/049033
Patent Document 8: International Publication pamphlet WO2005/103010 "
Patent Document 9: International Publication pamphlet WC2005/076695
Patent Document 10; International Publication pamphlet WO01/78698
Patent Document 11: International Publication pamphlet WO2004/096795
DISCLOSURE OF THE INVENTION
PROBLEMS TO BE SOLVED BY THE INVENTION
As described above, existing agents for treating urinary frequency, urinary urgency, urinary incontinence which are associated with overactive bladder, and various lower urinary tract diseases accompanied by pain in the lower urinary tract such as interstitial cystitis and chronic prostatitis, are not satisfactory in the points of

efficacy, safety, etc. Thus, an agent for treating lower urinary tract disease which is excellent in efficacy and safety has been demanded.
MEANS FOR SOLVING THE PROBLEMS
As described above, a trkA receptor inhibitor is expected to be a highly safe therapeutic agent with few side effects such as dry mouth and urinary retention, for a lower urinary tract disease. The inventors of the present invention made extensive studies on a compound having a trkA receptor-inhibitory activity in order to provide a novel compound useful for treating a lower urinary tract disease and so forth. As a result, they found that an azolecarboxamide derivative represented by the "following general formula (I) exhibits potent trkA receptor-inhibitory activity, thus they completed the invention.
That is, the present invention relates to a novel azolecarboxamide derivative or a salt thereof, the derivative represented by the following general formula (I) :
[Chem. 13]

(In the formula, symbols have the following meanings; X: S or 0,

A: phenylene which may be substituted, pyridinediyl which may be substituted, pyrimidinediyl which may be substituted, thiophenediyl which may be substituted, pyrazolediyl which may be substituted, or pyridonediyl which may be substituted,
Q: a monocyclic or bicyclic alicyclic nitrogen-containing heterocyclic group which may be substituted,
R~: halogen, lower alkylcarbonyl, C1-C7 alkyl which may be substituted, lower cycloalkyl which may be substituted, lower alkoxy which may be substituted, aryl which may be substituted, heteroaryl which may be substituted, a group represented by the general formula (II), the general formula fill), or the general formula (IV) :
[Chem. 14]

(II) (III) (IV)
Rla and RlD: each independently -H, lower alkyl which may be substituted, lower cycloalkyl, a saturated heterocyclic group which may be substituted, lower alkylcarbonyl, lower alkoxycarbonyl, aryl, or heteroaryl,
Ric: -H or lower alkyl,
Y1: lower alkylene which may be substituted in which -0-, -S-, -SO-, -S02-, or -N(-Rld>- may be contained between carbons thereof,

Rid: -H, lower alkyl, lower alkylcarbonyl, lower
alkoxycarbonyl, or aryl-lower alkyl,
Y2: lower alkylene in which -0-, -S-, -SO2-,
-N(-Rle)-, -N(-CO-Rlf)-, -N (-CO-NH-R19)--, -N (~CS-NH-Rlg) -, or
-N (-S02-Rlh) - may be contained between carbons thereof, Rle: -H or lower alkyl which may be substituted, Rlf: lower alkyl which may be substituted, lower
cycloalkyl, lower alkoxy, aryl which may be substituted,
heteroaryl which may be substituted, or aryl-lower alkenyl, Rlg: -H, lower alkyl, aryl, or aryl-lower alkyl, Rlh: lower alkyl, lower cycloalkyl, lower cycloalkyl-
lower alkyl, aryl which may be substituted, heteroaryl, or
aryl-lower alkyl,
" R2 is -H, halogen, or a nitrogen-containing saturated
heterocyclic group. The same shall be applied
hereinafter).
EFFECTS OF THE INVENTION
The compound of the present invention has a potent trkA receptor-inhibitory activity, urinary symptom-improving action, and analgesic action, and thus is useful as. an agent for treating or preventing, for example, urinary frequency, urinary urgency, urinary incontinence which are associated with various lower urinary tract diseases including overactive bladder, and various lower urinary tract diseases accompanied by pain in the lower urinary tract such as interstitial cystitis and chronic prostatitis, as well as various diseases accompanied by pain.

Since the compound of the present invention has different mechanism of action from the anticholinergic agent, an effect on patients who showed no improvement with the anticholinergic agent can be expected, and it is expected to be served as a very safe agent for treating a lower urinary tract disease by avoiding side effects which are characteristic to the anticholinergic agent.
BEST .MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the present invention will be described in more detail.
As used in the definition of the general formulae in the present specification, the term "lower" means a linear or branched carbon chain having 1 to 6 carbon atoms " (hereinafter simply referred to as Ci-e) , unless otherwise specifically mentioned. Accordingly, the "lower alkyl" is Ci-6 alkyl, preferably linear alkyl such as methyl, ethyl, n-propyl, and n-butyl groups, and a branched alkyl such as isopropyl, isobutyl, tert-butyl, and neopentyl groups. Mere preferred is C^ alkyl, and particularly preferred are methyl, ethyl, n-propyl, isopropyl, and tert-butyl groups. The "lower alkylene" is a divalent group of Ci_e alkyl, preferably C1-3 alkylene, such as methylene, ethylene, methyl methylene, ethyl methylene, and trimethylene. ■
The "lower alkenyl" means C2-e alkenyl, preferred are vinyl and ally!, and particularly preferred is allyl.
The "lower alkoxy" means -O-lower alkyl, preferred is C1-4 alkoxy, and particularly preferred are methoxy, ethoxy, and tert-butoxy.

The "halogen" means F, CI, Br, and I. The "halogeno-lower alkyl" means C-L_6 alkyl substituted with one or more halogen, preferred is Ci-6 alkyl substituted with one or more F or CI, and more preferred are chloropropyl, fluoroethyl, trifluoromethyl, trifluoroethyl, and trifluoropropyl groups.
The "cycloalkyl" is a C3-10 saturated hydrocarbon ring group, which may have bridge (s) . Preferred is C3_8 cycloalkyl, and particularly preferred are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
The "aryl" is a Ce-14 mono- to tricyclic aromatic hydrocarbon ring group, preferred are phenyl and naphthyl groups. More preferred is phenyl. The aryl may be condensed with monocyclic; oxygen-containing, saturated ' '" heterocyclic or monocyclic cycloalkyl. The "aryi-lower alkyl", the "aryl-iower aikenyl", the "aryloxy", the "arylamino", and the "arylcarbonyl" represent "lower alkyl substituted with aryl", "lower aikenyl substituted with aryl", "oxy substituted with aryl", "amino substituted with aryl", and "carbonyl substituted with aryl", respectively.
The "heteroaryl" collectively means a 5 to 8-membered, preferably 5- to 6-membered monocyclic aromatic ring group (monocyclic heteroaryl) each of which has 1 to 3 heteroatom(s) selected from 0, S, and N, or a bicyclic or tricyclic heteroaryl having the monocyclic heteroaryl groups condensed with each other, having a benzene ring condensed with the monocyclic heteroaryl group, or having a benzene ring condensed with the heterocyclic group. Preferable examples of the monocyclic heteroaryl include

pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazoiyl, triazolyl, thienyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isooxazolyl, and oxadiazolyi groups, and more preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, thienyl, and furyl groups. Preferable examples of the bicyclic heteroaryl include dihydrobenzofuranyl,
In the"heteroaryl", the ring atom S may be oxidized to form an oxide or dioxide, and N may be oxidized to form an oxide. The "heteroaryl-lower alkyl" means "lower alkyl substituted with heteroaryl".
The "saturated heterocyclic group" means a 4- to 8-membered, preferably 5- to 6-membered saturated heterocyclic group containing one heteroatom of W or'O, and a 5- to 8-membered saturated heterocyclic group containing one N atom, and one heteroatom selected from N, 0, and S. Preferred are azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, diazepanyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, oxazepanyl, and thiomorpholinyl groups.
In the "saturated heterocycle", the ring atom S may be oxidized to form an oxide or dioxide, and N may be oxidized to form an oxide.
The "alicyclic heterocyclic group" means a corresponding heterocyclic group having double bonds in the above-mentioned saturated heterocyclic group or its structure. Preferred are azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, diazepanyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl,

oxazepanyl, thiomorpholinyl, pyrrolinyl, and tetrahydropyridyi groups.
The "monocyclic or bicyclic, alicyclic nitrogen-conraining heterocyclic group" means a saturated or partially unsaturated 4- to 8-membered, preferably 5- to 6-membered monocyclic nitrogen-containing heterocyclic group, or a 4- to 8-membered, preferably 5- to 6-membered nitrogen-containing heterocyclic group having one bridge. More preferred are azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, diazepanyl, morpholinyl, thiomorpholinyl, 2,5-diazabicycloheptyl, and tetrahydropyridyi groups.
Preferred embodiments in the compound of the present invention represented" by the general formula (I) are described in the following.
1) The compound, wherein X is S or 0, and the general formula (I) is represented by the following formula:
[Chem. 15]


2} The compound as described in 1), wherein A is a divalent group represented by the following formula: A: [Chem. 16]

(The symbols in the formula have the following meanings:
R3: -H, halogen, lower alkyl, cyano, cyano lower alkyl, hydroxy-lower alkyl, lower alkoxy, halogeno-lower alkoxy, lower alkoxy-lower alkyl, lower alkenyl, cyano lower alkenyl, carboxy, carbamoyl, lower alkoxy-carbonyl, carboxy-lower alkyl, lower alkoxy-carbonyl-lower alkyl, carbamoyl-lower alkyl, lower alkyl-aminocarbonyl-lower alkyl, lower alkyl-sulfonyl, aminosulfonyl, or lower alkylsulfinyl,
R4: -H, halogen, or lower alkoxy,
R3 and R4 in combination may be bridged as -O-lower alkylene,
R=: -H or halogen.

R6: -H or lower alkyl. The same shall be applied hereinafter.)
3) More preferably, the compound as described in 2),
wherein A is a divalent group represented by the following
formula:
[Chem. 17]

4) Even more preferably, the compound as described in
3), wherein A is as described in 3) and the symbols in the
formula have the following meanings:
R23: -H, fluoro, chloro, bromo, methyl, ethyl, vinyl, cyano, cyanomethyl, cyanoethyl, cyanovinyl, hydroxymethyl, methoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methoxycarbonyl, carboKy, carbamoyl, mesyl, aminosulfonyl, methylsulfinyl, or
-Alk-CO-R23a,
-Aik-: methylene or ethylene,
R23a: hydroxy, amino, tert-butylamino, methoxy, or ethoxy,
R"4: -K, fluoro, chloro, bromo, or methoxy,

R23 and R24 in combination may be bridged as a -0-ethylene,
R25: -H or bromo,
R26: -H or methyl) .
5) The compound as described in 2), wherein Q is a cyclic group selected from the groups represented by the general formulae (V), (VI), (VII), (VIII), and (IX):
[Chem. 18]

(VIII) (IX)
(The symbols in the formula have the following meanings:
V1, V2: each independently Ci_3 alkylene,
V3: methylene or ethylene,
W: -CH(-R9)~, -N(-R9)-, -0-, -S-, -SO-, or -S02-,
R7 and R8: each independently -H, halogen, hydroxy, lower alkyl, hydroxy-lower alkyl, carboxy, lower alkoxycarbonyl, lower alkylcarbonyloxy, carbamoyl, aryl, aryl-iower alkyl, a saturated heterocyclic group which may

be substituted with lower aikyl, or an -Alk-saturated heterocyclic group,
-Alk~: lower alkylene, and
two of R7, R8, and R9 in combination may be bridged as a lower alkylene,
R7 and Ra may be substituted with the same carbon atoms, or in combination may form an oxo group, or a nitrogen-containing saturated heterocyclic group having spiro bonds,
wherein the nitrogen-containing saturated heterocyclic group may be substituted with a lower aikyl or oxo group,
R9: -H, lower alkyl, cyano, hydroxy, lower alkoxy, lower alkenyl, lower alkoxycarbonyl-lower alkenyi, lower alkyisulfonyl, -Alk-R9*, -CO-R9b, -Alk-CO-R9b, -CO-Alk-R5', -NR9dR3e, aryl, aryloxy, or a saturated heterocyclic group, wherein the saturated heterocyclic group may be substituted with a lower alkyl, hydroxy, or oxo group*
-Alk-: lower alkylene,
R9a: cyano, hydroxy, lower alkoxy, mono- or dihydroxy lower alkyl, aryl, aryloxy, arylcarbonyloxy, amino which may be substituted with lower alkyl, lower alkoxy-carbonylamino, heteroaryl, or saturated heterocyclic group, wherein the heteroaryl may be substituted with a lower alkyl or oxo group, and the saturated heterocyclic group may be substituted with a lower alkyl group,
R9b: lower alkyl, hydroxy, lower alkoxy, -NR9fR9e or alicyclic heterocyclic group, wherein the alicyclic heterocyclic group may be substituted with lower aikyl,

hydroxy, carboxy, lower alkoxycarbonyl, mono- or di-lower alkylamino, a saturated heterocyclic group, or an -Alk-saturated heterocyclic group,
-Alk-: lower alkylene,
R9f and RSg: each independently -H, lower alkyl, hydroxy-lower alkyl, lower cycloalkyl which may be substituted with amino, lower alkoxy-lower alkyl, mono- or di-lower alkyl-amino-lower alkyl, lower alkylsulfonyl, heteroaryl, a saturated heterocyclic group,
wherein the saturated heterocyclic group may be substituted with lower alkyl or aryl-lower alkyl, or
an -Alk-saturated heterocyclic group,
-Alk-: lower alkylene,
R9c: lower alkoxy, lower alkylcarbonyloxy or saturated heterocyclic group, wherein the saturated heterocyclic group may be substituted with a lower alkyl or oxo group, and
RSd and R9e: each independently -H, lower alkyl, lower alkylcarbonyl, or carbamoyl-lower alkyl) .
6) More preferably, the compound as described in 5), wherein Q is a cyclic group represented by the following formula:


(The symbols in the formula have the following meanings:
R27 and R28: each independently -H, fluoro, hydroxy, oxo, methyl, hydroxymethyl, carboxy, carbamoyl, acetoxy, methoxycarbonyl, phenyl, benzyl, pyrrolidinylmethyl, or piperidinyl which may be substituted with methyl,
R27 and R28 in combination may be bonded with the same Q ring-constituting carbon atom to form a pyrrolidine ring which may be substituted with methyl and oxo, and thus may have a spiro bond.
R29: -H, hydroxy, cyano, methyl, ethyl, isopropyl, isopentyl, allyl, methoxy, methoxycarbonyiallyl, ethoxycarbonylallyl, phenyl, phenoxy, piperidinyl which may be substituted with a methyl group, piperazinyl which may

be substituted with a methyl group or an oxo group, morpholinyl, methylsulfonyl, tetrahydrofuryl which may be substituted with hydroxy, -Alk-R29*, -CO-R29b, -Alk-CO-R29b, -CO-Aik-R29c, or -NR29dR29e,
~Alk-: methylene, ethylene, methylmethylene, trimethylene, tetramethylene, or pentamethylene,
R29a: methoxy, cyano, hydroxy, phenyl, phenoxy, benzoyloxy, pyridyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl which may be substituted with oxo, imidazolyl which may be substituted with methyl, pyrrolidinyl which may be substituted with methyl, piperidinyl which may be substituted with methyl, morpholinyl, oxazepanyl, 1,2-dihydroxyethyl, 1-hydroxypropyl, amino, dimethylamina, diethylamiho, or tert-butoxycarbonylamino,
R2Sb: methyl, hydroxy, methoxy, ethoxy, butoxy, pyrrolidinyl which may have a substituent selected from the following Group G5.lt pyrrolinyl, piperidinyl which may have a substituent selected from the following Group GE_2, piperazinyl which may have a substituent selected from the following Group G5_3, diazepanyl which may be substituted with methyl, morpholinyl, tetrahydropyranyl, or -NR29fR 9,
R29~: -H, methyl, ethyl, hydroxyethyl, methoxyethyl, tetrahydropyranyl, morpholinylethyl, dimethylaminoethyl, mesyl, pyridyl, cyclohexyl which may be substituted with amino, piperidinyl which may be substituted with methyl, or pyrrolidinyl which may have a substituent selected from the following Group G5-4,
R29g: -H, methyl, or ethyl,

Group G5-1: hydroxy, methyl, dimethyl amino, and pyrrolidinylmethyl.
Group G5^2: methyl, carboxy, ethoxycarbonyl, and pyrrolidinyl.
Group G5-3: methyl and propyl.
Group G5-4: methyl and benzyl,
R29c: methoxy, acetoxy, pyrrolidinyl, piperazinyl which may be substituted with methyl, morpholinyl, or thiomorpholinyl which may be substituted with oxo,
R29d and R29e: each independently -H, methyl, ethyl, acetyl, or carbamoylmethyl).
7) The compound as described in 5), wherein R1 is represented by the following formula:
R": 'halogen, lower alkylcarbonyl, lower cycloalkyl which may be substituted with hydroxy, or lower alkoxy which may be substituted with lower alkoxy, C1-C7 alkyl which may have a substituent selected from the following Group Gs-i, aryl, heteroaryl, a group represented by the general formula (X), (XI), (XII), (XIII), or (XIV),
wherein the aryi and the heteroaryl may have one or two substituents selected from the following Group Gs.2, and the two substituents in combination may form a cyclic structure,
Group Ge-i: hydroxy., lower alkoxy, N-lower alkyl-N-lower alkoxy-lower alkyl-amino, mono- or di-lower alkyl amino, a saturated heterocyclic group, aryl, and aryloxy,
wherein the aryl or the aryloxy may be substituted with halogen or halogeno-lower alkyl,

Group Gg-2: halogen, hydroxy, oxo, lower alkyl, halogeno-lower alkyl, lower alkoxy, cyano, carboxy, carbamoyl, and -NR1:LR"J,
R11 and R13: each independently -R, lower alkyl, lower alkoxy-lower alkyl, or lower alkoxycarbonyl,
[Chem. 20]

Rlp, Riq: each independently -H, lower cycloalkyl, lower alkylcarbonyl, lower alkoxycarbonyl, aryl, heteroaryl, a saturated heterocyclic group, or lower alkyl which may have a substituent selected from the following Group Gs-3,
wherein the saturated heterocyclic group may have a substituent selected from the group consisting of lower alkyl which may be substituted with one or two aryl, and aryl-lower alkoxycarbonyl,
Group G6-3: halogen, hydroxy, cyano, lower alkoxy, lower alkoxy-lower alkoxy, aryl, heteroaryl, a saturated

heterocyclic group, carboxy, lower alkoxycarbonyl, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, carbamoyl which may be substituted with lower alkyi, and -NRl*Ru,
Ru and R11: each independently -H, lower alkyi, lower alkylcarbonyl, lower alkoxycarbonyl, or lower alkylsulfonyl,
k: 0, 1, or 2,
Y3: single bond, -CH2~, -0-, -H(-R1m) -, -S-, -SO-, or -S02-
Rlm: -H, lower alkyi, lower alkylcarbonyl, lower alkoxycarbonyl, or aryl-lower alkyi,
Rlr, Rls: each independently -H, halogen, hydroxy, lower alkyi, lower alkoxy, hydroxy-lower alkyi, lower alkoxy-lower alkyi, lower alkylcarbonyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkyl-amino-lower alkyi, aryl, or -CO-NH-Alk-Rln,
-Alk-: lower alkylene,
Rln: hydroxy or a saturated heterocyclic group,
wherein Rlr and Rls in combination may be bridged as a lower alkylene, and RlE and RlE may be substituted with the same carbon atom, and may form an oxo group,
m=0, 1, or 2, and n=l, 2, 3, or 4,
preferably, m=0, 1, or 2, and n= 2 or 3,
more preferably, in a case of m=0, n=3, in a case of m=l, n=3, and in a case of m=2, n=2,
R": -H or lower alkyi,
Rlu: -H, lower alkyi, -Aik-Rlw, -CO-R1", -S02-Rly, or -CS-NH-R1',

-Alk-: lower alkylene,
Riw: lower cycloalkyl, lower alkoxy, carboxy, carbamoyl, a saturated heterocyclic group, aryl, or heteroaryl,
wherein the aryl may have a substituent selected from the group consisting of lower alkyl, lower alkoxy, and carboxy groups,
Rix: lower alkyl, lower cycloalkyl, hydrcxy-Iower alkyl, lower alkoxy, lower alkoxy-lower alkyl, amino, lower alkyl-amino, arylamino, aryl-lower alkyl amino, mono- or di-lower alkyl-amino-lower alkyl, aryl, aryl-lower alkyl which may be substituted with halogen, aryl-lower alkenyl, heteroaryl, heteroaryl-lower alkyl,
wherein the aryl or the heteroaryl may have a substituent selected from the group consisting of halogen, lower alkyl, lower alkoxy, and aryl,
RJy: lower alkyl, lower cycloalkyl, lower cycloalkyi-lower alkyl, aryl, aryl-lower alkyl, heteroaryl,
wherein the aryl may have a substituent selected from the group consisting of halogen and aryl,
Riz: lower alkyl, aryl, aryl-lower alkyl,
Rlv: -H or lower alkoxycarbonyl,
Y^: -0-, -S- or -S02-,
h: 0 or 1) .
8) More preferably, the compound as described in 7), wherein R1 is a group represented by the following (a) to (1) :

(a) bromo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclopentyi, cyclohexyl which may be substituted with hydroxy, acetyl, or methoxyethoxy,
(b) lower alkyl having a substituent selected from the following Group GT-I,
Group G7-1: hydroxy, methoxy, propoxy, phenoxy which may be substituted with butyl, phenyl which may be substituted with chloro or trifluoro methyl, morpholinyl, dimethylamino, and methoxyethyl(methyl)amino,
(c) phenyl, pyridyi, or pyrazolyl,
wherein these groups may be substituted with one or two groups selected from the following Group G-7-2,
Group G7-2: fluoro, chloro, bromo, hydroxy, oxo, methyl, trifiuoroinethyi, methoxy, cyano, carboxy, " carbamoyl, amino, methylamino, dimethylamino, methoxyethyl(methyl)amino, and tert-butoxycarbonylamino,
(d) pyrimidinyl, pyrazinyi, pyridazinyl which may be substituted with methoxy, oxodihydropyridyl, pyrrolyl, furyl, thienyl, or dihydrobenzofuranyl,
(e) -NRllpRllq
Rllp: -H, methyl, ethyl, propyl, isopropyl, cyclobutyl, trifluoromethyl, or methoxyethyl,
Rllq: -H, cyclopropyl, cyclobutyl, acetyl, tert-butoxycarbonyl, phenyl, pyridyi, tetrahydropyranyl, tetrahydrofuryl, oxetanyl, pyrrolidinyl, methylpyrrolidinyl, benzyloxycarbonylpyrrolidinyl, diphenylmethylazetidinyl, or C1-C4 alkyl which may have a substituent selected from the following Group G7-3,

Group G^_3: fluoro, chloro, hydroxy, cyano, methoxy, ethoxy, methoxyethoxy, amino, methylamino, dimethylamino, acetyiamino, mesylamino, tert-butoxycarbonylamina, carboxy, carbamoyl, dimethylaminocarhonyl, methoxycarhonyl, phenyl, pyridyl, furyl, tetrahydrofuryl, methylthio, methylsulfinyl, and mesyl,
(f) 4-morpholinyl,
wherein the morpholinyl may have a substituent selected from the following Group G7_4,
Group G-y-4: methyl, hydroxymethyl, methoxymethyl, and dimethylaminomethyl,
(g) 1-piperazinyl or 1-diazepanyl,
wherein these groups may be substituted with a group selected from the following Group G7-5 for a nitrogen atom, and may have a group selected from the following Group G7-6,
Group G7-5: methyl, propyl, acetyl, benzyl, or tert-butoxycarbonyl,
Group G7-6: fluoro, hydroxy, hydroxymethyl, methoxy, methoxymethyl, cxo, methylamino, or phenyl,
(h) 1-piperidin.yi,
wherein the piperidinyl may be substituted with one or two group selected from the following G7-T,
Group G7_7: fluoro, hydroxy, hydroxymethyl, methoxy, ethoxy, acetyloxy, oko, carboxy, carbamoyl, ethoxycarbonyl, hydroxypropyicarbamoyl, or tetrahydrofurylmethylcarbamoyl,
(i) 1-pyrrolidinyl or 1-azetidinyl
wherein these groups may be substituted with one or two groups selected from nhe following Group G7_8,

Group G7-s: fluoro,. hydroxy, hydroxymethyl, methoxy, methoxymethyl, oxo, raethylamino, or phenyl,
(j) 3-morpholinyl, 3-piperidinyl, 2-pyrroiidinyl, or 3-pyrrolidinyl,
wherein these groups may be substituted with a group selected the following G7-9 for a nitrogen atom,
Group 67-9: acetyl, tert-butoxycarbonyl, or benzyl,
(k) 4-oxazepanyl, 4-thiomorpholinyl, 1-oxothiomorpholin-4-yl, l,l-dicxothiomorpholin-4-yl, 2,5-diazabicycloheptan-1-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, tetrahydrofuryl, tetrahydropyranyl, thiacyclohexyl, or 1,1-dioxothiacyclohexyl,
(1) a group represented by the following formula:
[Chem." 21]

(The symbols in the formula have the following meanings:
Rzlt: ~H or methyl,
-Alk-: methylene, ethylene, trimethylene, tetramethyiene, pentamethylene, methyltrimethylene,
R21w: -H, cyclopropyl, methoxy, carboxy, carbamoyl, tetrahydrofuryl, pyridyl, or phenyl,

wherein the phenyl may have a substituent selected from the group consisting of methyl, methoxy, and carboxy,
R2 z: methyl, ethyl, propyl, butyl, pentyl, isopropyl, ethylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl which may be substituted with methyl, pyridyl, pyridazinyl, pyrimidinyl, thienyl, phenyl, tert-butoxy, amino, isopropylamino, phenylamino or benzylamino, phenylvinyl, phenylpropenyl, or -Alk3lK-R31*,
wherein the phenyl may have a substituent selected from the group consisting of fluoro, methyl, methoxy, and phenyl,
-Alk3lK-: methylene, ethylene, trimethylene, or tetramethylene,
R31*: phenyl or pyridyl, each of which may be substituted with hydroxy, methoxy, dimethylamino, or fluoro,
R^17: methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, or thienyl,
wherein the phenyl may have a substituent selected from the group consisting of fluoro and phenyl,
R2iz: methyl, isopropyl, phenyl, or benzyl).
9) The compound as described in 7), wherein R2 is a
group represented by the following:
R2: -H, halogen, or a nitrogen-containing saturated heterocyclic group.
10) More preferably, the compound as described in 9),
wherein R2 is as follows:
R2; -H, bromo, or a pyrrolidinyl group.

In the specification, the substituent acceptable by the term "may be substituted" may be any of the groups that are usually used in the technical field as a substituent of a respective group, and each of the groups may have at least one substituent.
In A of the general formula (I), examples of the substituent of the "phenylene which may be substituted, pyridinediyl which may be substituted, or pyrimidinediyl which may be substituted" include halogen, lower alkyl, cyano, cyano-lower alkyl, hydroxy-lower alkyl, lower alkoxy, halogeno-lower alkoxy, lower alkoxy-lower alkyl, lower alkenyl, cyano-lower alkenyl, carboxy, carbamoyl, lower alkoxycarbonyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, lower alkylaminocarbonyl-lower alkyl, lower alkylsulfonyl, aminosulfonyl, or lower alkylsulfinyl.
Examples of the substituent of the "thiophenediyl which may be substituted, pyrazoldiyl which may be substituted, or pyridonediyl which may be substituted" in A of the general formula (I), in which two substituents in combination may be bridged as -O-lower alkylene, include halogen and lower alkyl.
Examples of the substituent of the "monocyclic or bicyclic, alicyclic nitrogen-containing heterocyclic group which may be substituted" in Q of the general formula (I) include halogen, hydroxy, oxo, cyano, lower alkyl, lower alkenyl, lower alkoxycarbonyl-lower alkenyl, lower aikylcarbonyloxy, lower alkylsuifonyi, aryl, aryloxy, a saturated heterocyclic group, and groups represented

by -Alk-R9a, -CO-R9b, -Alk-CO-R9b, -CO-Alk-R9c, and -NR9dRSe. Here, the saturated heterocyclic group may be substituted with a lower alkyl, hydroxy, or oxo group, or may have a spiro bond.
The symbols in the formula have the following meanings:
-Alk-: lower alkylene,
Ra: cyano, hydroxy, lower alkoxy, mono- or dihydroxy-lower alkyl, aryl, aryloxy, arylcarbonyloxy, amino which may be substituted with lower alkyl, heteroaryl, or a saturated heterocyclic group, wherein the heteroaryl may be substituted with a lower alkyl or oxo group, and the saturated heterocyclic group may be substituted with lower alkyl,
QV
R : lower alkyl, hydroxy, lower alkoxy, an alicyclic heterocyclic group, or -NR9fR9g, wherein the alicyclic heterocyclic group may be substituted with lower alkyl, hydroxy, carboxy, lower alkoxycarbonyl, mono- or di-lower alkyiamino, a saturated heterocyclic group, or an -Alk-saturated heterocyclic group,
-Alk-: lower alkylene,
R9f and R5s: each independently -H, lower alkyl, hydroxy-lower alkyl, lower cycloalkyl which may be substituted with amino, lower alkoxy-lower alkyl, mono- or di-lower alkyl-amino-lower alkyl, lower alkylsulfonyl, heteroaryl, a saturated heterocyclic group, wherein the saturated heterocyclic group may be substituted with lower alkyl or aryl-lower alkyl, or an -Alk-saturated heterocyclic group,

■ -Alk-: lower alkylene,
R c: lower alkoxy, lower aikylcarbonyloxy, or a saturated heterocyclic group, wherein the saturated heterocyclic group may be substituted with lower alkyl or oxo,
R9d and R9e:.each independently -H, lower alkyl, lower alkylcarbonyl, or carbamoyl-lower alkyl).
Examples of the substituent of the "C1-C7 alkyl which may be substituted" in R1 of the general formula (I) include hydroxy, lower alkoxy, N-lower alkyl-N-lower alkoxy lower alkyl-amino, mono- or di-lower alkylamino, a saturated heterocyclic group, aryl, and aryloxy.
Here, the aryl or aryloxy may be substituted with halogen or halogeno-lower alkyl.
Examples of the substituent of the "lower cycloalkyl which may be substituted" in R: of the general formula (I) include hydroxy.
Examples of the substituent of the "lower alkoxy which may be substituted" in R: of the general formula fl) include lower alkoxy.
Examples of the substituent of the "aryl which may be substituted" and the "heteroaryl which may be substituted" in R1 of the general formula (I) include halogen, hydroxy, oxo, lower alkyl, halogeno-lower alkyl, lower alkoxy, cyano, carboxy, carbamoyl, and -NR1:LRlj.
The symbols in the formula have the following meanings:
R11 and Rlj: each independently ~H, lower alkyl, lower alkoxy-lower alkyl, or lower aikoxycarbonyl].

Examples of the substituent of the "lower alkyl which may be substituted" in Ria and Rlb in rhe general formula (II) include halogen, hydroxy, cyano, lower alkoxy, lower alkoxy-lower alkoxy, aryl, heteroaryl, a saturated heterocyclic group, carboxy, lower alkoxycarbonyl, lower alkylsulfanyl, lower alkylsuifinyl, lower alkylsulfonyl, carbamoyl which may be substituted with lower alkyl, and -NRlkRn.
The symbols in the formula have the following meanings:
Rlk and R11: each independently -H, lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl or lower alkylsulfonyl).
Examples"of the substituent of the "saturated heterocyclic group which may be substituted" in R13 and Rlb in the general formula (II) include lower alkyl which may be substituted with aryl, and aryl-lower alkoxycarbonyl.
Examples of the substituent of the "lower alkylene which may be substituted" in Y in the general formula (III) include halogen, hydroxy, cxo, lower alkyl, lower alkoxy, hydroxy-lower alkyl, lower alkoxy-lower alkyl, aryl, aryl-lower alkyl, carboxy, lower alkylcarbonyl, lower alkoxycarbonyloxy, lower alkoxycarbonyl, carbamoyl, mono-or di-lower alkyl-amino-lower alkyl, and -CO-NH-Alk-Rln. Here, two substituents in combination may be bridged as lower alkylene, and two substituents may be substituted on the same carbon atom.
The symbols in the formula have the following meanings:

-ftlk-: lower alkylene,
Rlr": hydroxy or a saturated heterocyclic group) .
Examples of the substituent of the "lower alkyl which may be substituted" of Rle in Z of the general formula (IV) include lower cycloalkyl, lower alkoxy, carboxy, carbamoyl, a saturated heterocyclic group, aryl, and heteroaryl,
wherein the aryl may have a substituent selected from the group consisting of lower alkyl, lower alkoxy, and carboxy groups,
Examples of the substituent of the "lower alkyl which may be substituted" of Rlf in Z of the general formula (IV) include hydroxy, lower alkoxy, mono- or di-lower alkyl amino, aryl which may be substituted with halogen, and heteroaryl.
Examples of the substituent of the "aryl which may be substituted" and the "heteroaryl which may be substituted" of Rlf in Z of the general formula (IV) include halogen, lower alkyl, lower alkoxy, and aryl.
Examples of the substituent of the "aryl which may be substituted" of Rlh in 1 of the general formula (IV) include halogen and aryl.
The compound of the present invention represented by the general formula (I) may have asymmetric carbons depending on the kind of the substituents, and thus optical isomers may be present. The present invention includes the isolated counterparts of either of a mixture of these optical isomers, and an isolated form thereof. The compound of the present invention may have tautomers, and the present invention also encompasses isolated isomers or

a mixture thereof. Examples of these tautomers include a tautomer of 2-hydroxypyridine and 2-pyridone. Also, the labeled compounds, that is, the compounds having at least one element in the compounds of the present invention substituted with radioactive isotopes or non-radioactive isotopes are also included in the present invention.
Furthermore, the "pharmaceutically acceptable prodrugs" of the compounds represented by the general formula (I) are also included in the present invention. The "pharmaceutically acceptable prodrug" is a compound having a group which is converted into a group such as CO2H, NH2, and OH by solvolysis or under a physiological condition to produce the compound (I) of the present invention. Examples of the group capable of forming a " prodrug include those as described in "Prog. Med., 5, 2151-2161 (1985), and "lyakuhin no Kaihatsu (Development of Drugs) (Hirokawa Shoten, 1990), vol. 7, Bunshi Sekkei (Molecular Design)", 163-198.
The salt of compounds (I) of the present invention are the pharmaceutically acceptable salts, and specific examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesuifonic acid, aspartic acid, and glutamic acid. Depending on the kind of substituents, the compounds may

form, a salt with a base, and examples thereof include salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and lithium, and with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, and ammonium salts.
In addition, the compound (I) of the present invention and a salt thereof also include various hydrates and solvates, and polymorphic substances thereof. (Preparation Methods)
The compound according to the present invention and a pharmaceutical^ acceptable salt thereof can be prepared by applying various known synthetic methods, utilizing characteristics based on their basic skeltons or the type of the substituents. Representive preparation methods are exemplified hereinafter. Further, depending on the type of the functional groups, it is in some cases effective from the viewpoint of the preparation techniques to protect the functional group with an appropriate protecting group, or to replace it by a group which may be easily converted into the functional group, during the steps of from starting materials to intermediates. Thereafter, if desired, the protecting group may be removed to obtain a desired compound. Examples of such a functional group include a hydroxyl group, a carboxyl group, and an amino group, and examples of a protecting group thereof include those as described in "Protective Groups in Organic Synthesis", edited by T.W. Greene and P.G.M. Wuts, (USA), 3rd edition, 1999, which may be optionally selected and used in response to the reaction conditions. In such a method, the desired

compound can be obtained by introducing the protecting group to carry out the reaction, and then, if desired, removing the protecting group or converting it into a desired group.
In addition, a prodrug of the compound (I) or a salt thereof can be prepared by introducing a specific group during the stage of from starting materials to intermediates, similar to the aforementioned protecting groups, or by carrying out the reaction using the obtained compound (I) . The reaction can be carried out by employing a method conventionally known to a person skilled in the art, such as common esterification, amidation, and acylation.
(First Preparation Method)
[Chem. 22]

(wherein X, A, Q, R1, and R2 have the same meanings as defined above, respectively. The same shall be applied hereinafter.)
(Step 1)
This step is a process for preparing a compound (I) by subjecting a compound (2) or a reactive derivative thereof, and a compound (1) or a salt thereof to amidation

. by a conventional method, and then if desired, removing the protecting group.
Examples of the reactive derivative of the compound (2) include a common ester such as methyl ester, ethyl ester, and tert-butyl ester; an acid halide such as acid chloride and acid bromide; an acid azide; an active ester with 1-hydroxybenzotriazole, p-nitrophenol, N-hydroxysuccinimide, or the like; a symmetric acid. anhydride; a mixed acid anhydride of a halocarboxylic acid alky ester such as an alkyl halocarbonate, a pivaloyl halide, a p-toluenesulfonyl chloride, and the like; and a mixed acid anhydride such as a phosphoric mixed acid anhydride obtained by the reaction of diphenylphosphoryl chloride with N-methylmorpholine.
If the compound (2) is reacted as a free acid, or is reacted without isolation of an active ester, or the like, amidation that can be usually used by a person skilled in the art can be used, but a method in which a condensing agent such as l-ethyI-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC-HC1) , or dicyclohexylcarbodiiraide (DCC) , carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA], diethylphosphorylcyanide (DEPC), 0-(7-azabenzotriazol-l-yl)-W,N,N', N'-tetramethyluronium hexafluorophosphate (HATU) are allowed to undergo the reaction in the presence of 1-hydroxybenzotriazole (HOBt) , a method in which phosphorus oxychloride is allowed to undergo the reaction in a pyridine solvent, or a condensing agent-carrying polystyrene resin such as a PS-carbodiimide [Argonaut

Technologies, Inc., USA) or a PL-DCC resin {Polymer . Laboratories, UK) are appropriately used.
Also, in some cases, it is preferable to use an isocyanate-carrying polystyrene resin, such as PS-Isocyanate (Argonaut Technologies, Inc., USA), in order to remove an excessive amount of amine after completion of the reaction. In addition, it is preferable in some cases to use a quaternary ammonium salt-carrying polystyrene resin, such as MP-Carbonate (Argonaut Technologies, Inc., USA), in order to remove an excessive amount of carboxylic acid, and the aforementioned additive such as HOBt after completion of the reaction.
Particularly, in the present invention, an acid chloride method, and a method for performing a reaction in the coexistence of an active esterifying agent and a condensing agent are convenient.
The reaction varies depending on the reactive derivatives, condensing agents, or the like to be used, but usually, this is carried out under cooling, from under cooling to at room temperature, or from at room temperature to under heating, in a solvent inert to the reaction, such as halogenated hydrocarbons such as dichlorometahane, dichloroethane and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as ether and tetrahydrofuran (THF); esters such as ethyl acetate (EtOAc); acetronitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), and dimethyl sulfoxide (DMSO).
Furthermore, in the reaction, it is in some cases advantageous in advancing the reaction smoothly to carry

out the reaction with an excess amount of the compound (I) or in the presence of a base such as N-methylmorphoIine, trimethylamine, triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, picoline, and lutidine. Also, a salt formed from a w^ak base and a strong acid, such as pyridine hydrochloride, pyridine p-toluenesulfonate, and N,N-dimethylaniline hydrochloride, may be used. Pyridine may be used as a solvent.
Particularly, it is preferable to carry out the reaction in the presence of a base such as triethylamine in a solvent such as THF and DMF.
(Second Preparation Method)
(Chem." 23]


(wherein Z1 represents halogen, SMe, SOMe, SO£Me, S03H, or OTf. 1/ represents hydrogen or methyl. RA can be any one of the substltuents that are usually used, preferably lower alkyl, and more preferably lower alkoxy-lower alkyl. 1% Rla, and Rlb have the same meanings as defined above, respectively. The same shall be applied hereinafter)
The nucleophilic substitution reaction of this step can be carried out in a solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, alcohols such as methanol, ethanol, and isopropanol, acetonitrile, DMF, DMA, and DMSO, in the presence of an organic base such as triethylamine and diisopropylethylamine, and/or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, and sodium hydride, by allowing the compound (4), (S) , or HO-R1A to undergo the reaction with the compound {3). Further, in order to accelerate the reaction, a catalyst such as dimethylaminopyridine may be added. Also, instead of the organic base and/or the inorganic base, the compound (4) or (5) may be used in an excessive amount. The reaction varies depending on the base to be used, but it can be carried out from under cooling to at room temperature, from at room temperature to under heating, or from at room temperature to under reflux.
Also, in some cases, it is preferable to use an isocyanate-carrying polystyrene resin, such as PS-Isocyanate (Argonaut Technologies, Inc., USA), in order to

remove an excessive amount of amine after completion of the reaction.
(Third Preparation Method)
[Chem. 24]

(wherein L1 represents lower alkyl. R7 and R9 have the same meanings as defined above, respectively. The same shall be applied hereinafter.)
The 1,3-dipolar cycloaddition reaction of this step is a step for carrying out cycloaddition by azomethine ylide generated in the reaction system for the compound (6). For various alkoxymethylsilyl methylamine, the reaction can be carried out by allowing the compound (6) to undergo the reaction in the presence of an organic acid such as trifluoroacetic acid, or a Lewis acid such as trimethylsilyl trifluoromethane sulfonate, cesium fluoride, lithium fluoride, tetrabutylammonium fluoride, and zinc chloride, in an organic solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, acetonitrile, DMF, DMA, and DMSO. The reaction varies depending on the acid or the solvent to be used, but it can be carried out from under cooling to at room temperature, from at room temperature to under heating, or from at room temperature to under reflux.

(Fourth Preparation Method)
Furthermore, the compound of the present invention having various functional groups represented, in the formula (1} can be prepared from the compound of the present indention obtained by First Preparation Method, Second Preparation Method, or Third Preparation Method, by any combination of well-known processes that can be usually employed by a person skilled in the art, such as alkylation, acylation, substitution reaction, oxidation, reduction, and hydrolysis. This step is not limited to a one-step reaction, but it may be consisted of a multi-step reaction. Further, the processes that can be usually employed by a person skilled in the art are not limited to the application for the compound of the present invention, but they may be used in the application for the preparation intermediates -
Representative reactions are exemplified hereinafter.
(1) Amidation
A compound having an amide group among the compounds (I) of the present invention can be prepared by reacting a compound having an amino group as a starting material with a carboxylic acid and a reactive derivative thereof, or by reacting a compound having carboxylic acid as a starting material with an amine. The reaction can be carried out in accordance with Step A of First Preparation Method, for . example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", vol. 22 (I9S2) (Maruzen), or "Compendium of' Organic Synthetic Methods", vols. 1 to 3, or the like.

(2) Sulfonylation
A compound having a sulfonamide group among the compounds (I) of the present invention can be prepared by-reacting a compound having an amino group as a starting material with a reactive derivative of sulfonic acid. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 24 (1992) (Maruzen).
(3) Synthesis of Carbamate
A compound having a carbamate group among the compounds (I) of the present invention can be prepared by reacting a compound having an amino group as a starting material with a carbonate derivative. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 20 (1992) (Maruzen).
(4) Synthesis of Urea and thiourea
A compound having an urea group among the compounds (I) of the present invention can be prepared by reacting a compound having an amino group as a starting material with an isocyanate compound, an aminocarbonyl halide, or the like.
A compound having a thiourea group among the compounds (1} of the present invention can be prepared by reacting a compound having an amino group as a starting material with a thioisocyanate compound, etc.

The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4zn edition}", edited by The Chemical Society of Japan, vol. 20 (1992) (Maruzen).
(5) O-acylation
A compound having an ester group among the compounds (I) of the present invention can be prepared by reacting a compound having an alcohol group as a starting material with a carboxylic acid derivative. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 22 (1992) (Maruzen).
(6) N-alkylation
A compound having a secondary amine or a tertiary amine among the compounds (1} of the present invention can have an alkyl group introduced thereinto by reacting a compound having a primary amino group or a secondary amine group as a starting material with another alkylating agent or an epoxy derivative. As the alkylating agent, alkyl halide, an organic sulfonic ester of alcohol, and the like sre preferred.
The reaction is carried out by mixing the materials from under cooling to under heating in a solvent inert to the reaction, such as aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones such as acetone and 2-butanone, acetonitrile, ethyl acetate, DMF, DMA, and NMP. It is sometimes advantageous in smoothly advancing the

reaction to carry out "he reaction in the presence of an organic base or an inorganic base. (7) Reductive alkyiation
A compound having a secondary amine or a tertiary amine among the compounds (I) of the present invention can have an alkyl group introduced thereinto by reacting a compound having a primary amino group or a secondary amino group as a starting material with an aldehyde and a ketone for performing reductive alkyiation, in the presence of an reducing agent such as sodium borohydride and sodium triacetoxy borohydride, or under a catalytic reduction condition by palladium-carbon under a hydrogen atmosphere. This can exemplified by a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 20 (1992) (Maruzen), or the like. It is sometimes preferable to use a reducing agent-carrying polystyrene resin, such as MP-Triacetoxybcrohydride (Argonaut Technologies, Inc., USA) as a reducing agent. {8) oxidation
A compound having a sulfonyl group or a sulfenyl group among the compounds (I) of the present invention can be prepared by subjecting a compound having a sulfide group to an oxidation reaction. The compound having an adjacent diol can be prepared by subjecting a corresponding olefin product to an Os oxidation, etc. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental

Chemistry) {4th edition)", edited by The Chemical Society of Japan, vol. 23 (1992) (Maruzen).
(9) Reduction reaction
A compound having a primary alcohol group among the compounds (I) of the present invention can be prepared by subjecting a corresponding compound having a carboxyl group to a reduction reaction. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 26 (1992) (Maruzen).
(10) Catalytic reduction reaction
In the synthesis of the compound of the present invention, a corresponding reduced product can be prepared Dy subjecting a compound having double bonds, and a compound having a halogen group as starting materials to catalytic reduction reaction. The reaction can be carried sut, for example, with reference to a method as described Ln "Jikken Kagaku Ko2a (Courses in Experimental Chemistry! (4th edition)", edited by The Chemical Society of Japan, rol. 26 (1992) (Maruzen).
(11) ipso substitution reaction
A compound having an alkoxypyridine or aminopyridine ;kelton among the compounds (I) of the present invention :an be prepared by reacting a corresponding compound having . chioropyridyl group as a starting material with an .lkoxides, an amine, or the like. The reaction can be :arried out, for example, with reference to Step A of econd Preparation Method. Further, under the same

condition, an azide group can be once introduced by sodium azide, and then a catalytic reduction, or the like can be carried out to convert the group to a primary amino group.
(12) Palladium coupling reaction
A compound having a cyanoaryl group among the compounds (I) of the present invention can be prepared by cross-coupling a corresponding compound having a halogenated aryl group as a starting material with zinc cyanide, or the like in the presence of a palladium catalyst. Further, a compound having an alkenylaryl group or an alkylaryl group can be prepared by cross-coupling a corresponding compound having a halogenated aryl group as a starting material with an organic tin reagent, boric acid, or the like in the presence of a palladium catalyst. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition}", edited by The Chemical Society of Japan, vol. 25 (1992) (Maruzen).
(13) Addition reaction via lithiation
A compound having a carboxylphenyl group among the compounds (I) of the present invention can be prepared by subjecting a compound having a bromophenyl group as a starting material to a lithium-halogen exchange reaction by allowing alkyl lithium to undergo the reaction, and then reacting the resultant with carbon dioxide. The reaction -can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4tt! edition}", edited by The Chemical Society of Japan, vol. 20 (1992) (Maruzen).

(14) Hydrolysis reaction
A compound having a carboxyl group or an amide group among the compounds (I) of the present invention can be prepared by subjecting a corresponding compound having an ester group, an amide group, or a cyano group to hydrolysis. The reaction can be carried out, for example, with reference to a method as described in "Protective Groups in Organic Synthesis (3rd edition)" as described above, or "Jikken Kagaku Koza {Courses in Experimental Chemistry) (4th edition)", edited-by The Chemical Society of Japan, vol. 22 {1992) (Maruzen).
(15) Dehydration reaction
A compound having a cyano group among the compounds {I) of the present invention can be prepared by subjecting a compound having a carboxamide group to a dehydration reaction. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4tn edition)", edited by The Chemical Society of Japan, vol. 20 (1992) (Maruzen).
In various reactions as described above, it is in some cases preferable to use a primary amine-carrying polystyrene resin, such as PS-Trisamine (Argonaut Technologies, Inc., USA), or the like, in order to remove an electrophilic. reagent (acid chloride, sulfonyl chloride, isocyanate, or the like), or to use a strong cationic exchanger, such as BondElut® SCX (Varian Ltd., USA) to purify basic substances, or the like.

The starting materials used in .the preparation of the compounds of the present invention can be prepared, for example, by using the methods described in Reference Examples as described below, well-known methods, or methods apparent to a person skilled in the art, or variations thereof.
(Starting Material Synthesis 1)
[Chem. 25]

(wherein Z2 represents halogen or -0-S02CF3. L2 represents hydrogen or methyl. The ring of Q1 has a nitrogen atom as a ring-forming atom, and represents an alicyclic hetexocycie that bonds with the ring oi A at the nitrogen atom. R7, R8, and R9 have the same meanings as defined above, respectively. The same shall be applied hereinafter.}

This step is a process for preparing a compound (10) by carrying out a substitution reaction at an ortho position of the nitro group of the compound (8). The substitution reaction of this step can be carried out in the same manner as in Step 2 of Second Preparation Method.

.
This step is a process for preparing a compound (la) by subjecting the nitro compound (10) to reduction. The reduction reaction of this step can be carried out by using a reduction reaction for a nitro group, which can be usually employed by a person skilled in the art. For example, it can be exemplified by a reduction reaction using an reducing agent such as reduced iron and tin chloride, and a hydrogenation reaction using palladiiim-carbon, rhodium-carbon, or the like as a catalyst. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Coursed in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 26 (1992) (Maruzen).
(Starting Material Synthesis 2)
[Chem. 2 6]

(wherein Z3 represents halogen or -0-SO-2CF3, and 2^ represents -B(OH)2, dialkylboron, dialkoxyboron, or trialkyltin. Alternatively, Z3 may represent -B(OH)2, dialkyl boron, dialkoxyboron, or trialkyltin, and Z4 may represent halogen or -0-S02CF3. The rings of QZ and Q" represent aliphatic nitrogen-containing heterocycies that

bond with the ring of A at the carbon atom, respectively. The same shall be applied hereinafter.)

This step is a reaction of two cyclic skeltons comprising a combination of the compound (11} and the compound (12), preferably in the presence of a transition metal catalyst and a suitable additive to form a carbon-carbon bond. Representative methods thereof include a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 25 {1992) (Maruzen). As the transition metal catalyst, various palladium complexes such as tetrakis(triphenylphosphine)palladium, and various nickel complexes such as
dibromobis(triphenylphosphine)nickel can be preferably used. As the additive, various iigands such as triphenylphosphine, sodium carbonate, and zinc can be preferably used, but it is preferable to suitably select an additive depending on the employed methods. Usually, this reaction is carried out in a solvent from at room temperature to under heating.

This step is a process for preparing a compound (14) by subjecting the nitro compound (13) to reduction. The reduction of the nitro group in this step can be carried out in the same manner as in Step Bj. of Starting Material Synthesis 1, but particularly preferred is a reduction reaction using a reducing agent such as reduced iron and tin chloride.

This step is a process for preparing a compound (lb) by subjecting the double bonds of the compound (14) to reduction. For the reduction reaction of this step, a reduction reaction that can be usually employed by a person skilled in the art can be used. For example, the reaction can be exemplified by a catalytic reduction reaction using palladium-carbon, or the like as a catalyst under a hydrogen atmosphere.
(Starting Material Synthesis 3)
[Chem. 27]

(wherein ZD represents halogen or hydrogen, and L" represents a protecting group for amine. Q2 and Q3 have the same meanings as defined above, respectively. The same shall be applied hereinafter.)

This step is a process for preparing a compound (16) by allowing alkyl lithium to undergo the reaction with the compound {15} for a lithium-halogen exchange or deprotonation reaction to produce aryl lithium, and then subj ecting the ketone to an addition reaction. A method as

described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) {4th edition)", edited by The Chemical Society of Japan, vol. 25 (1992) (Maruzen) , and an equivalent method.

This step is a process for preparing a compound (17) by subjecting a substituent L3 on nitrogen of the compound (16) to deprotection. For the reaction, a deprotection condition by a conventional method corresponding to the substituent L3 can be used, and for example, a method as described in the deprotection reaction of an amino group in "Protective Groups in Organic Synthesis (3rd edition)", or the like can be applied.

This step is a method for preparing an olefinic product by subjecting a hydroxy group of the compound (17) to a hydroxy group-elimination reaction. The reaction can be carried out under a basic condition via halogenation and sulfonation in addition to an acid catalyst dehydration reaction. A method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4tb edition)", edited by The Chemical Society of Japan, vol. 19 (1992) (Maruzen) or an equivalent method can be employed.

This step is a process for preparing a compound (lb) by subjecting the double bonds of the compound (18) to reduction. The reduction reaction of this step can be carried out in the same manner as in Step C2 of Starting Material Synthesis 2.

Furthermore, these Steps B3-to D3 can be carried out in varying order depending on the need. For example, a method in which from the compound (16), a dehydration reaction is carried out in Step C3, deprotection of the substituent L3 on nitrogen is carried out in Step B3, and then reduction of the double bonds carried out in Step D3, or other methods can be exemplified.
(Starting Material Synthesis 4)
[Chem. 28]

(1 9) (20) (2a)
(wherein L4 represents a protecting group for carboxylic acid. The same shall be applied hereinafter.)

This step is a method for constructing a thiazole ring by allowing an a-fraloketone,. representatively such as bromopyruvic ester, to undergo the reaction with a thioamide or thiourea. Those methods as described "Comprehensive Organic Chemistry", vol. 4, or an equivalent method can be employed. In addition, it is in some cases preferable to add trifluoroacetic anhydride in order to promote a cyclization reaction.

This step is a process for preparing a carboxylic acid derivative (2a) by subjecting a carboxylic acid ester derivative (20) to hydrolysis. For this reaction, a hydrolysis condition by a conventional method can be used,

and for example, a method as described in the deprotection reaction of a carboxyl group in "Protective Groups in Organic Synthesis (3rd edition)" as described above, or the like can be applied.
(Starting Material Synthesis 5)
[Chem. 29]

<21> (2a)

This step is a method for constructing a thiazole ring by allowing an cc-haloketone, representatively such as bromopyruvic acid, to undergo the reaction with a thioamide or thiourea. The reaction can be carried out in the same manner as in Step M of Starting Material Synthesis 4.
(Starting Material Synthesis 6)
[Chem. 30]

(22) (23) (2a)

This step is a process for preparing a compound (23) by carrying out a substitution reaction of the compound (22) at a 2 position of the thiazole. The substitution reaction of this step can be carried out in the same manner as in Step 2 of Second Preparation Method.

This step is a process for preparing a compound (2a) by subjecting the carboxylic acid ester derivative (23) to hydrolysis. The hydrolysis reaction of this step can be carried out in the same manner as in Step B4 of Starting Material Synthesis 4,
(Starting Material Synthesis 7)
[Chem. 31]

(24) (25) (2 b)

This step is a method for constructing an oxazoie ring by allowing an a-haloketone, representatively such as bromopyruvic acid ester, to undergo the reaction with an amide or urea. A method as described in "Heterocyclic Compounds" edited by Turchi, vol. 45, or "Heterocyclic Compounds" edited by Palmer, vol. 60, Part A, or an equivalent method can be employed.

This step is a process for preparing a compound (2b) by subjecting the carboxylic acid ester derivative (25) to hydrolysis. The hydrolysis reaction of this step can be carried out in the same manner as in Step 34 of Starting Material Synthesis 4.

(Starting Material Synthesis 8) [Chem. 32]

This step is a process for carrying out an amidation reaction from the compound (26) and the compound (27). The reaction can be carried out in accordance with Step 1 in First Preparation Method, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry} (4th edition)", edited by The Chemical Society of Japan, vol. 22 (1992) (Maruzen), or "Compendium of Organic Synthetic Methods" as described above, vols. 1 to 3, or the like.

This step is a method for constructing an oxazoline ring by carrying out a dehydration-cyclization reaction from the compound (28). The cyclization of this step can be carried out, for example, with reference to a method as described in Phillips, A. J.; Wipf, P.; Williams, D. R.; et al., Org Lett, 2000, 2 (Si, 1165-1168, "Heterocyclic Compounds" as described above, vol. 60, Part A, Part B, etc.

This step is a method for constructing an cxazole ring by carrying out an oxidation reaction from the compound (29) . The cyclization of this step can be carried out, for example, with reference to a method as described in Phillips, A. J.; Wipf, P.; Williams, D. R.; et al., Org Lett, 2000, 2(8), 1165-1168, or "Heterocyclic Compounds" as described above, vol. 60, Part A, or the like.

This step is a process for preparing a compound {2c} by subjecting the carboxylic acid ester derivative (30) to hydrolysis. The hydrolysis reaction of this step can be carried out in the same manner as in Step B4 of Starting Material Synthesis 4.
(Starting Material Synthesis 9)
i'Chem. 33]

(wherein Ar represents aryl which may be substituted, or heteroaryl which may be substituted, and bonds with an oxazole ring at the carbon atoms on the ring. Z3 and Z4 have the same meanings as defined above, respectively. The same shall be applied hereinafter.)

This step is a method for synthesizing a biaryl compound from the compound (31) and the compound (32). The reaction of this step can be carried out, for example, in

accordance with HODGETTS, K. J.; KERSHAW," M. T. ; Org Lett, 2002, 4(17), 2905-2907.

This step is a process for preparing a compound {2d) by subjecting the carboxylic acid ester derivative (33) to hydrolysis. The hydrolysis reaction of this step can be carried out in the same manner as in Step B4 of Starting Material Synthesis 4.
Furthermore, in Starting Material Syntheses 1 to 9, the substituents to bond with the compound (I) of the present invention can be converted in a suitable period of time in the above-described step for proceeding in the next step. Examples of the method for the aforesaid conversion include a method in which of Starting Material Synthesis 3, a Boc group is introduced to the position of R9, and an alkylation reaction is carried out at a suitable periods of time, before Step B3, before Step C3, or before Step V3, and after deprotection of the Boc group, to conversion into a partial structure Rs of the compound according to the present invention.
The reaction products obtained by each of Preparation Methods can be isolated and purified as their free compounds, and salts or various solvates thereof, such as hydrates. The salts can be prepared after carrying out a conventional salt formation treatment.
The isolation and purification can be carried out by employing common chemical operations such as extraction, concentration, removal by distillation, crystallization, filtration, recrystallization, and various chromatography.

Various isomers can be isolated in the standard method making use or the differences in physicochemical properties among isomers. For example, optical isomers can be separated by general optical resolution, for example, by fractional crystallization, chromatography, or the like. In addition, the optical isomers can also be prepared from appropriate optically active starting material compounds.
The effects of the compounds of the present invention were confirmed by the following pharmacological tests.
1. Experiment to measure a receptor inhibitory activity using cells expressing a nerve growth factor receptor
The nerve growth factor receptor inhibitory activity was measured by using the increase in a ligand-dependent """ calcium concentration in cells as an index. HEK293 cells (American Type Culture Collection) that stably expressed Human nerve growth factor receptor were dispensed onto a 96-well poiy-D~lysine-coated plate (Product Name: Biocoat, PDL96W black/clear, by Nippon Becton Dickinson) to a 2*104 cells/well at the day before the experiment, and incubated overnight at 37DC under 5% carbon dioxide (C02) in a culture medium containing 10% fetal bovine serum (FBS) (Product Name: DMEM, Invitrogen Corporation). The culture medium was replaced by a washing solution: a Hank's balanced salt solution)(HBSS), containing a 1.5 uM loading buffer (fluorescent indicator (Product Name: Fluo4-AM, Tong Ren Tang Technologies Co, Ltd.)), 20 mM 2-[4-(2-hydroxyethyl)-1-piperazinyi]ethanesulfonic acid (HEPES)-sodium hydroxide (NaOH), 2.5 mM Probenecid, 0.1% bovine

serum albumin (BSA), and left to stand at room temperature for 3 hours,- and the cells were washed using a plate washer (Product Name: ELx405, BIO-TEK instrument Corporation)in which a washing solution had been set up. The compound that had been preliminarily dissolved and diluted in a washing solution was added thereto, and set up in a system for measuring a calcium (Ca) concentration in a cell (Product Name: FLIPR, Molecular Devices Corporation). After 5 minutes, a nerve growth factor (NGF, mouse derived 2.5S, Alomone) corresponding on 80% stimulation of a maximum response was added (to a final concentration of about 100 to 150 ng/ml) to measure the change in Ca concentrations in cells. A difference between a maximum value and a minimum value in'Ca" concentrations in cells was determined, and kept as measurement data. With a response upon addition of NGF being set at 0%, and a response upon addition of a buffer being set at 100%, the concentration causing 50% inhibition was determined as an IC5Q value. The results are shown in the following Table 1. In the table, Ex represents Compound No. of Examples as described later. From the results of this test, it was confirmed that the compound of the present invention has a nerve growth factor receptor inhibitory activity.

2. Evaluation of the inhibitory activity of the compound on enhanced vascular permeability caused by NGF in rat
The in vivo trkA receptor inhibitory activity of the compound was examined. A Wistar female rat (SLC) were forced to be orally administered with the compound (0.5% methylceliulose solution) 10 mg/3 ml/kg or a vehicle (0.5% methylcellulose solution) 3 mi/kg. Under ether anesthesia performed at 60 min after administration, physiological saline or 1 ug/ml NGF (NGF, mouse derived 2.5S, Alomone) was intracutaneously administered to the back at 50 ul/site, and then immediately a 1% Evans blue solution (dissolved in physiological saline) was administered through caudal vein at 3 ml/kg. At a time point of 10 min after the administration, the skin on the back was taken,

and shaken in formamide for 16 hours. After shaking, an absorption of Evans blue extracted with formamide was measured by an absorption meter (wavelength: 620 nm}, and the concentration was determined by a calibration curve method. A value obtained by subtracting the concentration of Evans blue at a site administered with physiological saline from the concentration of Evans blue at a site administered with NGF has a function dependent on NGF, and an inhibitory rate of the compound group was determined with a group administered with vehicle being set at 100%. The results are shown in the following Table 2. In this test, it was confirmed that the compound of the present invention has an excellent inhibitory activity on enhanced vascular permeability caused by NGF 'in rat.


3. Effects of the compound on the cyclophosphamide (CPA)-induced urinary frequency in rat;
CPA (150 mg/5 ml/kg) was intraperitoneally administered to a Wistar female rat (Charles river laboratories), and after two days, the experiment was carried out. It was forced to be orally administered with distilled water (30 ml/kg), and then placed in a metabolic cage, and the voided urine weight and the urination frequency were continuously measured for 1 hour. The compound (0.5% methylcellulose solution) 3 or 10 mg/5 ml/kg, or a vehicle (0.5% methylcellulose solution) 5 ml/kg was orally administered, and after 5 to 30 min, the urinary functions were measured after loading water in the same manner as described above. A total voided urine weight was divided by the total urination frequency to determine an effective bladder capacity. Winn the value before administration of the compound being set at 100%, a rate of change in the effective bladder capacity caused by administration of the compound was determined. The results are shown in the following Table 3.
In this test, at 2 days after CPA treatment, the effective bladder capacity was decreased (about 0.5 ml), indicating urinary frequency condition. On the other hand, the compound of the present invention improved the urinary frequency condition. For example. Example 492 increased the effective bladder capacity up to 177%.


A . Effects of the compound on acetic acid-induced painful behaviors in rat
1% Acetic acid {99% distilled water) was intraperitoneaily administered to a Wistar male rat (Charles river laboratories), and the frequency of pain behavior (writhing) between 10 min and 20 min after administration was measured. The compound (10 mg/5 ml/kg) or a vehicle(0.5% methylcellulose solution) was orally administered 5 mins before the administration of 1% acetic acid. With the frequency of the group administered with the vehicle being set at 100%, the inhibition rate of the writhing behavior frequency by the compound administration was determined. The results are shown in the following Table 4. In this test, the compound of the present invention exhibited an excellent analgesic action.


From the results as described above, it was
demonstrated that the compound of the present invention has
a potent in vitro and in vivo trkA receptor inhibitory
activity, and has a urinary symptom-improving action and an
analgesic action. Accordingly, it can be expected that the
compound of the present invention is useful as a _
therapeutic or prophylactic drug for various lower urinary tract diseases accompanied by urinary symptoms, and various pain diseases.
A pharmaceutical composition containing the compound (I) of the present invention or a salt thereof is prepared by using a carrier, an excipient or other additives that are usually used in the preparation of drugs.
Administration may be made in any one form for either oral administration by tablets, pills, capsules, granules, powders, and liquids, or for parenteral administration by injections for intravenous injection, and intramuscular injection, suppositories, percutaneous preparations, transnasal preparations, inhalations or the like. The dose is appropriately decided in response to an individual case by taking the symptoms, age and sex of the subject and the like into consideration, but is usually from about 0.001

mg/kg to about 100 mg/kg per day per adult in the case of oral administration, and this is administered in one portion or dividing it into 2 to 4 portions. Also, in the case of intravenous administration according to the symptoms, this is administered usually within the range of from 0.0001 mg/kg to 10 mg/kg per day per adult, once a day or two or more times a day. In addition, in the case of inhalation, this is administered generally within the range of from 0.0001 mg/kg to 1 mg/kg per adult, once a day or two or more times a day.
Regarding the solid composition of the present invention for oral administration, tablets, powders, granules, or the like are used. In such a solid composition, one or more active substances are mixed with at least one inactive excipient(s) such as lactose, mannitol, glucose, hydroxypropylcellulose, microcryst&Hine cellulose, starch, polyvinyl pyrrolidone, and magnesium aluminometasilicate. In a conventional method, the composition may contain inactive additives such as lubricants such as magnesium stearate, disintegrators such as carboxymethylstarch sodium, and solubilization assisting agents. As occasion demands, tablets or pills may be coated with a sugar coating, or a gastric or enteric coating agent.
The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like, and contains a generally used inert solvent such as purified water ot ethanol. In addition to the inert solvent, this

composition may contain auxiliary agents such as solubilization assisting agents, moistening agents, and suspending agents, sweeteners, correctives, aromatics and antiseptics.
Injections for parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions and emulsions. As the aqueous solvent, for example, distilled water for injection and physiological saline are included. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, plant oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (Pharmacopeia). Such a composition may further contain tonicity agents, antiseptics, moistening agents, emulsifying agents, dispersing agents, stabilizing agents, and solubilization assisting agent. These are sterilized, for example, by filtration through bacteria retaining filter, blending of germicides or irradiation. In addition, these can also be used by producing sterile solid compositions, and dissolving or suspending it in sterile water or a sterile solvent for injection prior to their use.
Regarding transmucosal agents such as inhalers and transnasal agents, those in a solid, liquid or semi-solid state are used, and may be produced in accordance with conventionally known methods. For example, excipients such as lactose and starch, and also pH adjusting agents, antiseptics, surfactants, lubricants, stabilizers, thickeners, and the like may be optionally added thereto. For their administration, an appropriate device for

inhalation or insufflation can be used. For example, a compound may be administered alone or as a powder of prescribed mixture, or as a solution or suspension by combining it with a pharmaceuticaily acceptable carrier, using conventionally known devices or sprayer, such as metered-dose inhalers. The dry powder inhaler or the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule can be used. Alternatively, this may be in a form such as a high pressure aerosol spray which uses an appropriate propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, and carbon dioxide.
In the preparation of the suppositories, a low melting point wax such as a mixture of fatty acid glycerides, or cocoa butter is dissolved, and an active ingredient is added thereto, followed by uniformly dispersing under stirring. Thereafter, it was poured into an appropriate mold and cooled for solidification. The liquid preparation includes solutions, suspensions, oil retention enemas, and emulsions, such as a solution in water or propyleneglycol.
EXAMPLES
Hereinafter, the compounds of the present invention will be described in more detail with reference to Examples. Also, the preparation methods of the starting material compounds are shown in Reference Examples. Further, the preparation methods of the compounds of the present invention are not limited to the preparation

methods of the specific Examples .as below, and any combination of the preparation methods or well-known preparation methods can be used for preparation.
The following abbreviations are used in Reference Examples and Examples.
Me: methyl, Et: ethyl, Ac: acetyl, Ms: mesyl, Ph: phenyl, Boc: tert-butoxycarbonyl, TBS: tert-butyldimethylsilyl, Tf: trifluoromethanesulfonyl, HOBt: 1-hydroxybenzotriazole, WSOHC1: l-ethyl-3- {3-dimethylaminopropyl)carbodiimide hydrochloride, DCC: dicyclohexylcarbodiimide, CDI: carbonyldiimidazole, DPPA: diphenylphosphorylazide, DEPC: diethylphosphorylcyanide, THF: tetrahydrofuran, EtOAc: ethyl acetate, DMF: N,N-dimethylformamide, DMA: N,N-dimethylacetamide, DMSO: dimethylsulfoxide.
Reference Example 1
2,4-Difluoro-6-nitrophenol was allowed to undergo the reaction with trifluorometnanesulfonic anhydride in pyridine to prepare 2,4-difluoro-6-nitrophenyl trifiuoromethane sulfonic acid ester.
Reference Example 8
4-Chloro-3-nitrophenyl methylsulfide was allowed to undergo the reaction with m-chloroperbezoic acid in chloroform for performing oxidation of sulfide to prepare 4-chloro-3-nitrophenyl methylsulfoxide.
Reference Example 9
1,2,3-Trifluoro-4-nitrobenzene was allowed to undergo the reaction with potassium hydroxide and ethyl cyanoacetate in DMSO, and then with acetic acid and

hydrochloric acid to prepare (2,3-difluoro-4~ nitrophenyl)acetonitfile .
Reference Example 10
3-Chloro-2,6-difluorophenylacetonitrile was allowed to undergo the reaction with tetramethylammonium nitrate and trifluoromethanesulfonic anhydride in methylene chloride to prepare (3-chloro-2,6~difluoro-5-nitrophenyi)acetonitrile.
Reference Example 11
4-Chloro-3-nitirophenol was allowed to undergo the reaction with sodium chlorodifluoroacetate and cesium carbonate in DMF-water to prepare l-chloro-4-(dif luoromethoxy) -2-fi.itrobenzene.
Reference Examples 12 and 13
4-Chloro-5-nitropyridin-2(1H)-one was allowed to undergo the reaction with silver carbonate and methyl iodide in methylene chloride to prepare 4-chloro-2-methoxy-5-nitropyridine and 4-chloro-l-methyl-5-nitropyridin-2(1H)-one.
Reference Example 14
(2R,5S)-2,5-Dimethylpiperazine-l-carboxylic acid tert-butyl ester was allowed to undergo the reaction with potassium carbonate and bromoacetamide in DMF to prepare (2R,5S)-4-(2-amino-2-oxoethyl)-2, 5-dimethylpiperazine-l-carboxylic acid tert^butyl ester.
Reference Example 15
4-0xopiperidine-l-carboxylic acid tert-butyl ester was allowed to undergo the reaction with N-methylglycinamide and sodium triacetoxyborohydride in

dichloroethane to prepare 4-[{2-amino-2~
oxoethyl)(methyl)amino]piperidine-1-carboxylic acid tert-
butyl ester.
Reference Example 19
4-0xoazepane-l-carboxylic acid tert-butyl ester was allowed to undergo the reaction with sodium cyanide in an aqueous sodium hydrogen sulfite solution to prepare 4-cyaiio-4-hydroxyazepane~l-carbcxylic acid tert-butyl ester.
Reference Example 20
4-Cyano-4-hydroxyazepane-1-carboxylie acid tert-butyl ester was allowed to undergo the reaction with 10% hydrogen chloride/methanol to prepare 4-hydrosyazepane-4-carboxylic acid methyl ester hydrochloride.
Reference Example 21
4-(2-Amino-2-oxoethyl)piperazine-1-carboxylic acid tert-butyl ester was allowed to undergo the reaction with 4 M hydrogen chloride/dioxane to prepare 2-piperazin-l-ylacetamide dihydrochloride.
Reference Example 27
2,4-Difluoronitrobenzene was allowed to undergo the reaction with 2-piperazin-l-ylacetamide and triethylamine in acetonitrile to prepare 2-[4-f5-fluoro-2-nitrophenyl)piperazin-l-yl]acetamide.
Reference Example 130
4-0xoazepane-l-carboxylic acid tert-butyl ester was allowed to undergo the reaction with lithium diisopropylamide and 1,1,1-trifluoro-N-phenyl-N-[ (trifiuoromeTihyl) sulfonyi]methanesulfonamide in THF to

prepare 4~{ [(trifluoromethyli sulfonyl]oxo}-2,3,6,7-"cetrahydro-IH-azepine-1-carboxylic acid tert-butyl ester.
Reference Example 132
(4-Aminophenyl) acetonitrile was allowed to undergo the reaction with bis(pyridine)iodonium tetrafluoroborate in methylene chloride to prepare (4-amino-3-iodophenyl)acetonitrile.
Reference Example 135
2-Fiuoro~6-nitrophenyl-trifluoromethane sulfonic acid ester was allowed to undergo the reaction with [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium (II), potassium phosphate, and 4-(4,4,5,5-tetramethyl-l,3,2-dioxabororan~2-yl)-3,6-dihydropyridine-l(2H)-carboxylic acid tert-butyl ester in DMF to prepare 4-(2-fluorO-6- "' nitrophenyl)-3,6-dihydropyridine-l(2H)-carboxylic acid tert-butyl ester.
Reference Example 14 0
4-Amino-3~bromobenzonitrile was allowed to undergo the reaction with triethylamine, palladium acetate, 2-(dicyciohexylphosphino) biphenyi, and bis (pir.acolato) ciiboron in dioxane, and then with 4-
{ [ (trifluoromethyl) sulfonyl] cxo}-3, 6-dihydropyridine--l (2H) -carboxylic acid tert-butyl ester, barium hydroxide arid water to prepare 4-(2-amino-5-cyanophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester.
Reference Example 171
1-(2-Nitrophenyl)-2,5-dihydro-lH-pyrrole was allowed to undergo the reaction with N-rnethylmorphoiine-N-oxi.de,

and a catalytic amount of osmium tetroxide in THF-water to prepare cis-1-(2-nitrophenylipyrrolidine-3,4-diol.
Reference Example 173
2- [4- (2-Bromo-4-f luarQ-6-nitropheriyl} piperazin-1-yl]acetamide was allowed to undergo the reaction with zinc cyanide and tetrakistriphenylphosphinepalladium in DMF to prepare 2-[4-(2-cyano-4-fluoro-6-nitrophenyl)piperazin-1-yl]acetamide.
Reference Example 174
1-(5-Bromo-2-nitrophenyl)-4~hydroxypiperidine-4-carboxylic acid methyl ester was allowed to undergo the reaction with phosphorus oxychloride in pyridine to prepare 1-(5-bromo-2-nitrophenyl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid methyl ester".
Reference Example 175
2-[4-(4-Formyl-2~nitrophenyl) piperazin-1-yl]acetamide was allowed to undergo the reaction with ethyl diethylphosphonoacetate and potassium carbonate in DMF to prepare ethyl (2E)-3-{4-[4-(2-amino-2-oxoethyl)piperazin-1-yl]-3-nitrophenyl}aerylate.
Reference Example 17 6
1-(3-Nitropyridine-2-yl)piperidine-4-carboxamide was allowed to undergo the reaction with palladium-carbon in a methanol-THF mixed solution, under a hydrogen atmosphere for performing reduction of a nitro group to prepare l-{3-aminopyridine-2-yl}piperidine-4-carboxamide.
Reference Examples 276 and 277
2-[4-{6-Chlcro-3-nitropyridine~2-yl)piperazin-1-yl]acetamide was allowed to undergo the reaction with

potassium carbonate and ethyl cyanoacetate in DMF, and then with trifluoroacetic acid. This was allowed to undergo the reaction with 10% palladium-carbon and hydrogen in methanol to prepare 2-{4-[3-amino-6-(cyanomethyl)pyridin-2-yl]piperazin-l-yl}acetamide and 2-{5-amino-6-[4-(2-amino-2-oxoethyl)piperazin-1-yl]pyridin-2-yl}-N-tert-butylacetamide.
Reference Example 27 8
2-[4-f4-Bromo-2-nitrophenyi}piperazin-l-yl]acetamide was allowed to undergo the reaction with rhodium-carbon in a methanol-THF mixed solution under a hydrogen atmosphere for performing reduction of a nitro group to prepare 2-[4-(2-amino-4-bromophenyl)piperasin-l-yl]acetamide. ■ ■ Reference Example 284
2- [4-(6-Amino-3-chloro-2-cyanophenyl)piperazin-1-yl]acetamide was allowed to undergo the reaction with palladium-carbon in methanol under a hydrogen atmosphere for performing dechlorination to prepare 2-[4-(2-amino-6-cyanophenyl)piperazin-1-ylJ acetamide hydrochloride.
Reference Example 286
2- [4- (4-Chloro-2-nitrophenyl)piperazin-1-yl]acetamide was allowed to undergo the reaction with reduced iron in acetic acid for performing reduction of a nitro group to prepare 2~[4-(4-chloro-2-aminophenyl)piperazin-1-yl]acetamide.
Reference Example 303
1- (4-Nitro-l-oxidepyridin-3-yl)piperidine-4-carboxamide was allowed to undergo the reaction with

reduced iron in acetic acid to prepare 1- (4-aminopyridir.-3-ylipiperidine-4-carboxamide.
Reference Example 304
l-Benzyl-3- (2-nitrophenyl) pyrrolidine was allowed to undergo the reaction with palladium-carbon in methanol under a hydrogen atmosphere for performing reduction of a nitro group, and then ammonium formate was added thereto for performing debenzylation. This was allowed to undergo the reaction with di-tert-butyl dicarbonate to prepare 3-(2-aminophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester.
Reference Example 305
1-(2-Aminophenyl)-3-pyrrolidinecarboxylic acid methyl ester was allowed to undergo the reaction with formaniide and sodium methoxide in DMF under an argon atmosphere to prepare i-(2-aminophenyli-3-pyrroiidine carboxamide.
Reference Example 308
2-Bromopyridine-3-amine was allowed to undergo the reaction with trifluoroacetic anhydride in TKF to prepare N-(2-bromopyridin-3-yl)-2,2,2-trifluoroacetamide.
Reference Example 309
Methyliithium and butyllithium were added to a solution of N-(2-Bromophenyl)-2,2,2-trifluoroacetamide in THE, followed by allowing to undergo the reaction with 4-oxo-1-piperidinecarboxylic acid tert-butyl ester to prepare 4-hydroxy-4-[2-[{trifluoroacetyl)amino]phenyl]-1-piperidinecarboxylic acid tert-butyl ester.

Reference Example 312
A THF-menhanol solution of 4-hydroxy-4-{2-[(trifiuoroacetyl)amino]phenyl}-1-piperidinecarbcxyiic acid tert-butyi ester was allowed to undergo the reaction with a 15% aqueous sodium hydroxide solution to prepare 4-(2~ aminophenyl)-4-hydroxy-l-piperidinecarboxylic acid te^t-butyl ester.
Reference Example 316
A solution of 4-(2-Aminophenyl)-4-hydroxy-l-piperidinecarboxylic acid tert-butyl ester in ethanol was allowed to undergo the reaction with a 4 M hydrogen chloride/dioxane solution to prepare 2-(1, 2, 3,6-tetrahydro-4-pyridinyl)aniline dihydrochloride.
Reference Example 318
A solution of N-(3-methoxyphenyl)-2,2-dimethylpropanamide in tetrahydrofuran was allowed to undergo the reaction with butyllithium, and then 4-oxo-l-piperidinecarboxylic acid tert-butyl ester was added thereto. The reaction solution was concentrated, and the residue was allowed to undergo the reaction with sulfuric scid to prepare 3-methoxy-2-(1,2,3, 6-tetrahydropyridin-4-yi)aniline.
Reference Examples 322 and 323
4-f3-Aminopyridine-2-yl)piperidin-4-ol hydrochloride was allowed to undergo the reaction with 20% sulfuric acid. This was allowed to undergo the reaction with potassium carbonate and 2-bromoacetamide in acetonitrile to obtain 2-(3-amino-3',6'-dihydro-2,4'-bipyridine-1'(2'H)-yl)acetamide

and 2-[4-(3-aminopyridine-2-yl)-4-hydroxypiperidin-l-yl]acetamide.
Reference Example 324
A solution of 5-fluoro-2-(1,2,3,6-tetrahydro-4-pyridinyl)aniline dihydrochloride in pyridine was allowed tc undergo the reaction with 4-morpholinecarbonylchloride to prepare 5-fluoro~2-[1-(4-morpholinylcarbonyl)-1,2,3,6-tetrahydro-4-pyridinyl]aniline.
Reference Example 325
A 4 M hydrogen chloride/EtOAc solution was added to a solution of 2-[4-(2-aminophenyl)-3, 6-dihydro-l(2H)-pyridinyl]acetamide in ethanol, and followed by reacting with palladium-carbon under a hydrogen atmosphere for performing reduction of double bonds to prepare 2-[4-(2- "" " aminophenyl)-1-piperidinyl]acetamide dihydrochloride.
Reference Example 333
3-_Methyldihydrofuran-2 (3H) -one was allowed to undergo the reaction with aqueous ammonia to prepare 4-hydroxy-2-methylbutanamide.
Reference Example 334
Triethyiamine and 4-dimethylaminopyridine were added to a solution of 2-methylbutanamide in dichloromethane, and followed by reacting with benzoyl chloride to prepare 4-amino-3-methyl-4-oxobutylbenzoate.
Reference Example 335
A solution of [(1R)-2-hydroxy-l-methylethyl]carbamic acid tert-butyl ester in acetonitrile was allowed to undergo the reaction with methyl -iodide in the presence of

silver oxide (I) for alkylation to prepare [(1R)-2-methoxy-i-methyiethyi]carbamic acid tert-butyl ester.
Reference Example 336
A solution of (S)-1-methoxy-2-propylamine in tetrahydrofuran was allowed to undergo the reaction with ethyl chloroforraate in the presence of triethylamine to obtain [(IS)-2-methoxy-l-methylethyl]carbamic acid ethyl ester.
Reference Example 337
[(1R)-2-methoxy-l-methylethyl]carbamic acid tert-butyl ester was allowed to undergo the reaction with lithium aluminum hydride in tetrahydrofuran to obtain (2R)-l-methoxy-N-methylpropane-2-amine hydrochloride.
Reference-Example 339 -.-.-. - - -
A 4 M hydrogen chloride/EtOAc solution was added to 2-methoxynicotinonitrile, and followed by reacting with dithiophosphoric acid 0,0-diethyl ester to prepare 2-hydrcxythionicotinamide.
Reference Example 34 0
4-(Benzyloxy)butanamide was allowed to undergo the reaction with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide in THF to prepare 4-(benzyloxy)butanethioamide.
Reference Example 34 7 ■ A 4 M hydrogen chloride/EtOAc solution was added to 6-methoxypyridazine-3~carbonitrile, and followed by reacting with dithiophosphoric acid 0,0-diethyl ester to prepare 6-methoxypyridazine-3-carbothioamide.

Reference Example 349
(S) -3-Hydroxypiperidine hydrochloride was subject ro thioamidation using benzoylthioisocyanate in toluene to prepare N-{[(3S)-3-hydroxypiperidin-l-yl] carbonothioyl }ben?amide.
Reference Example 3 64
N-{ [(3S)-3-hydfoxypiperidin-l-yl] carbonothioyl )ben£amide was reacted with a methyl amine-methanol solution in methanol to prepare (3S)-3-hydroxypiperidine-1-carbothioamide.
Reference Example 381
Furan-3-carbothioamide was allowed to undergo the reaction with 3-brom■■■.,:•- ■■-
Example 698
To a solution of 46 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-(2-cyano-4-pyridinyl)-1,3-thiazole-4-carboxamide in 1 ml of DMSO were added 71 mg of powdered potassium carbonate and 0.015 ml of 30% aqueous hydrogen peroxide at 0°C. The mixture was stirred at room temperature for 1.5 hours, and then at 120°C for 24 hours, to the mixture was added water,, and then the precipitate was collected, filtered, and then dried. To the residue was added a 4 M hydrogen chloride/EtOAc solution in a mixed, solution of methanol and chloroform, and the solution was concentrated. The residue was washed with a mixed solvent of methanol and isopropyl ether to prepare 44 mg of 4-{4-[({2-([4-(2-amino-2-oxoethyl)-l-

piperazinyl]phenyl}amino)carbonyl]-1, 3-thiazol-2-yl}-2-pyridinecarboxamide hydrochloride.
Example 703
A solution of 203.6 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-bromo-l,3-thiazole-4-carboxamide and 687.1 mg of 1,4-dioxa-8-azaspiro[4.5]decane in 1.02 ml of DMA was stirred overnight at 100°C, and then the mixture was concentrated and dried under reduced pressure. To the residue was added 30 ml of water, and stirred at room temperature for 2 hours. The precipitate was collected by filtration, dried under reduced pressure at 50°C, and purified by preparative TLC to obtain 200 mg of a solid. To a solution of the resulting product in 30 ml of acetone was added 228 mg of p-t'oluenesulfonic acid hydrate. The mixture was stirred at room temperature for 4 hours, and then at 40CC for 3 days, and then to the mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by preparative TLC, and dissolved in a mixed solution of methanol and chloroform, and a 4 M hydrogen chloride/EtOAc solution was added thereto. The solution was concentrated, and the residue was washed with a mixed solvent of ethanol and isopropyl . ether, and dried under reduced pressure to prepare 170.6 mg of N-{2-[4-(2-amino-2-oxomethyl)-1-piperazinyl]phenyl}-2-(4-oxo-l-piperidinyl)-1,3-thiazole-4-carboxamide hydrochloride.

Examples 718 and 7 34
A solution of 151 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-bromo-1,3-thiazole-4-carboxamide, 333 mg of azetidine hydrochloride, and 0.5 ml of triethylamine in 1.02 ml of DMA was stirred overnight at 100°C, and then the mixture was concentrated and dried under reduced pressure. To the residue was added 30 ml of water, and then the aqueous layer was extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated. The residue was purified using preparative TLC, and then a 4 M hydrogen chloride/EtOAc solution in a mixed solution of methanol and chloroform was added thereto. The solution was concentrated, and the obtained residue was washed with mixed solvent of ethaiiol' "■' " ' and isopropyl ether, and dried under reduced pressure to obtain a mixture of two kinds of compounds. To this was added a saturated aqueous sodium hydrogen carbonate solution for neutralization, and then extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, concentrated, and isolated using preparative TLC.
The upper fraction was washed with a mixed solvent of ethanol and isopropyl ether to prepare 17.2 mg of N-{2-[4~ (2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-(1-azetidinyl)-1,3-thiazole-4-carboxamide.
The lower fraction was dissolved in ethyl acetate, and a 4 M hydrogen chloride/EtOAc solution was allowed to act thereon, followed by washing with a mixed solvent of ethanol and isopropyl ether to prepare 82.3 mg of N-{2-[4-

(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-[(3-ch'loropropyl)amino]-1,3-thiazole-4-carboxamide hydrochloride.
Example 723
To a solution of 296 mg of 2-(l-oxidethiomorpholin-4-yl)-1,3-thiazole-4-carboxylic acid in 10.0 ml of THF was added 260 jil of 4-methylmorpholine and 170 \xl of isobutylchloridecarbonate under ice-cooling at 0°C for 5 min, followed by warming to room temperature, and stirring for 15 min. The reaction liquid was ice cooled again, and a solution of 281 mg of 2-[4-(2-aminophenyl)piperazin-1-yl]acetoamide in 8.00 ml of THF was added dropwise thereto, followed by stirring at 0°C for 1 hour, and then warmed at room temperature, followed by stirring for 8 hours. To the reaction liquid was added an aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. At this time, the insolubles partitioned between the aqueous layer and the organic layer were separated by filtration. The organic layer was washed with saturated brine, and then dried over magnesium sulfate. A solvent was evaporated under reduced pressure, the residue was mixed with the above-described insolubles, and this was subject to a recrystallization operation using ethanol to precipitate a solid, which was collected by filtration. This was suspended in ethanol, a 4 M hydrogen chloride/EtOAc solution was added thereto, and the solid was collected by filtration to prepare 281 mg of iV— {2- [4 — (2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-(1-

oxidothiomorpholin-4-yl)-1,3-thiazole-4-carboxamide hydrochloride.
Example 7 92
269 mg of 2-methoxyethanol was dissolved in 6 ml of DMF, and 141 mg of 60% sodium hydride was added thereto under ice-cooling, followed by stirring for 30 min. A solution of 300 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-bromo-l,3-thiazole-4-carboxamide in DMF was added thereto, followed by stirring at 60°C for 30 min. To the reaction liquid was added an aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1). This was dissolved in ethanol, a 4 M hydrogen chloride/EtOAc solution was added thereto, and then the precipitated solid was collected by filtration to prepare 137 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-(2-methoxyethoxy)-1,3-thiazole-4-carboxamide hydrochloride.
Example 7 93
155 mg of N-{2-[4-(2-airtino-2-oxoethyl)piperazin-1-yl]phenyl}-2-piperazin-l-yl-l,3-thiazole-4-carboxamide and 26 \xl of propionaldehyde were suspended in 2 ml of methylene chloride, and 62 \xl of acetic acid was added thereto, followed by stirring at room temperature for 1 hour. 7 6 mg of sodium triacetoxyborohydride was added thereto, followed by further stirring for 15 min. To the reaction liquid was added an aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform,

and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methano1=20:1). This was dissolved in ethanol, a 4 M hydrogen chloride/EtOAc solution was added thereto, and then the precipitated solid was collected by filtration to prepare 96 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-(4-propylpiperazin-l-yl) -1, 3-thiazole-4-carboxamide hydrochloride.
Example 815
28 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-[(3S)-4-benzyl-3-(methoxymethyl)piperazin-1-yl]-1,3-thiazole-4-carboxamide was dissolved in 1 ml of methanol, and 28 mg of 10% palladium-carbon and 57 \il of formic acid were added thereto, followed by stirring at room temperature for 7 hours. The reaction liquid was filtered through celite, and the mother liquor was evaporated under reduced pressure. To the residue was added an'aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform:2-propanol=3:1, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (chlorof orm:.methanol=300 :1) . This was dissolved in ethanol, a 4 M hydrogen chloride/EtOAc solution was added thereto, and then the precipitated solid was collected by filtration to prepare 7 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-[(3S)-3-(methoxymethyl)piperazin-1-yl]-1,3-thiazole-4-carboxamide hydrochloride.

• Example 821
A solution of 100 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-bromo-l,3-thiazole-4-carboxamide ■ and 180 mg of 3-(methoxymethyl)azetidine in 2 ml of DMA was stirred at 100°C for 48 hours, to the mixture was added water, and then the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, and then dried over sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography (chloroform:methanol=99:1 to 20:1), the obtained residue was dissolved in methanol, diethyl ether was added thereto, and the precipitated solid was collected by filtration, and dried under reduced •pressure to prepare'55-"mg of N-{2- [4- (2-amino-2-oxoethyl)piperazin-l-yl]phenyl}-2-{[3-methoxy~2-(methoxymethyl)propyl]amino}-1,3-thiazole-4-carboxamide.
Example 835
A solution of 370 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-bromo-l,3-thiazole-4-carboxamide, 524 mg of 3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester, and 0.76 ml of ethyldiisopropylamine in 1.85 ml of DMA was stirred overnight at 100°C. To the reaction liquid was added 200 ml of water, followed by extraction with chloroform. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by preparative TLC to obtain an oily substance. To a solution of this oily substance in 2 ml of methanol was added 8 ml of a 4 M aqueous hydrogen chloride/dioxane

solution for reaction overnight at room temperature, and a
saturated aqueous sodium hydrogen carbonate solution was
added thereto, followed by extraction with chloroform. The
organic layer was washed with saturated brine, dried over
anhydrous magnesium sulfate, concentrated under reduced
pressure, and purified by preparative TLC to obtain an oily
substance. To a solution of this oily substance in 0.33 ml
of methanol was added 3.3 ml of aqueous ammonia for
overnight reaction. The obtained mixture was concentrated
under reduced pressure, and purified by preparative TLC,
and then a 4 M hydrogen chloride/EtOAc solution was added ;
thereto to prepare 135 mg of N-{2-[4-(2-amino-2-
oxoethyl)piperazin-l-yl]phenyl}-2-[methyl(pyrrolidin-3- ;
yl") amino] -1, 3-thiazole—4-carboxamide dihydrochlor-ide. -
Example 8 37 '
To a solution of 50 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-bromo-1,3-thiazole-4-carboxamide, 47.2 mg of 3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester, and 0.041 ml of ethyldiisopropylamine in 0.5 ml of l-methyl-2-pyrrolidone was radiated with microwave at 200°C for 30 min. To the mixture was added 100 ml of water, followed by extraction with chloroform, and the organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified using preparative TLC, and a 4 M hydrogen chloride/EtOAc solution was added thereto to prepare 18.4 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-[3-(methylamino)pyrrolidin-1-yl] -1,3-thiazole-4-carboxamide dihydrochloride.'

Example 850
A solution'of 147 mg of N-{2-[4-(2-amino-2-oxoethyl)-
1-piperazinyl]phenyl}-2-(2-chloro-4-pyridinyl)-1,3-
thiazole-4-carboxamide, 434 mg of methylamine
hydrochloride, and 0.9 ml of triethylamine in 2 ml of DMSO
was radiated with microwave at 200°C for 70 min. To the
obtained mixture was added water, followed by extraction
with chloroform. The organic layer was combined, washed
with water and saturated brine in this order, dried over
magnesium sulfate, and concentrated under reduced pressure.
The residue was purified using preparative TLC, and a 4 M
hydrogen chloride/EtOAc solution was added thereto to ;
prepare 32.1 mg of N-{2-[4-(2-(methylamino)-2-oxoethyl)-1- >
pipera2inyl] phenyl}-2-l'2^(methylamino)-4-pyridinyl]-1, 3- **• • - ; thiazole-4-carboxamide hydrochloride.
Example 8 64
To a solution of 84 mg of 2-[1-(tert-butoxycarbonyl)-lH-pyrrol-2-yl]-1,3-oxazole-4-carboxylic acid ethyl ester in 2.1 ml of ethanol was added 0.17 ml of a 4 M aqueous lithium hydroxide solution, followed by stirring at room temperature for 3 hours. To the mixture was added 0.68 ml • of a 1 M aqueous hydrochloric acid solution, followed by adjustment of its pH to 5 to 6 with a 1 M aqueous sodium hydroxide solution, and then concentration under reduced pressure. A solution of the concentrated residue, 64.25 mg of 2-[4-(2-aminophenyl)-1-piperazinyl]acetoamide, 236.7 mg of WSC-HC1, and 166.7 mg of HOBt in 2.52 ml of DMF was stirred overnight at room temperature. To the mixture was added 30 ml of a solution of a saturated aqueous sodium

hydrogen carbonate solution, followed by extraction with EtOAc. The organic layer was saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC to prepare 32 mg of N-{2-[4-(2-amino-2-oxomethyl)-l-piperazinyl]phenyl}-2-(lH-pyrrolo-2-yl)-1,3-oxazole-4-carboxamide.
Example 952
To a solution of 120 mg of sodium 2-(4-ethoxypiperidin-1-yl)-1,3-oxazole-4-carboxylate in 3 ml of DMF were added 209 mg of 0-(7-azabenzotriazol-l-yl)-N,N,N', N'-tetramethyluronium hexafluorophosphate and 104 mg of 1-(3-aminopyridin-2-yl)piperidine-4-carboxamide, followed by stirring at room temperature for 3 days. Water
was added thereto, and the precipitated solid was washed'-
with water and then collected by filtration, followed by dryness to prepare 48 mg of 1-f3-({ [2-(4-ethoxypiperidin-l-yl)-1,3-oxazol-4-yl]carbonyl}amino)pyridin-2-yl]piperidine-4-carboxamide.
Example 98 0
To a solution of 4.4 mg of 2-piperidin-l-ylaniline, 5.1 mg of 2-phenyl-l,3-thiazole-4-carboxylic acid, and 3.4 mg of HOBt in 1.00 ml of N,N-dimethylformamide were added 100 mg of PS-Carbodiimide (Argonaut Technologies, Inc.) at room temperature, followed by stirring overnight. To the reaction liquid was added 50 mg of MP-Carbonate (Argonaut Technologies, Inc.) and 50 mg of PS-Isocyanate (Argonaut Technologies, Inc.) at room temperature, followed by stirring for 4 hours, the insolubles were filtered, and the filtrate was concentrated under reduced pressure to prepare

7.3 mg of 2-phenyl-N-(2-piperidin-l-ylphenyl)-1,3-thiazole-4-carboxamide. In the same manner as in Example 980, the compounds of Examples 978 to 1000 and Examples 1092 to 1112 were prepared using the corresponding substituted aniline and carboxylic acid as starting materials.
Example 1029
To a solution of 14.1 mg of 1-fluoro-2-nitrobenzene in 100 \xl of acetonitrile was added a solution of 21.91 mg of 4- (piperazin-l-ylcarbonyl)morpholine in 220 u,l of 1-methylpyrrolidin-2-one at room temperature, followed by stirring at 80 °C for 4 hours. To the reaction liquid were added 700 (J,l of N, N-dimethylf ormamide and 100 mg of PS-Isocyanate (Argonaut Technologies, Inc.) at room temperature", followed by stirring"overnight, the insolubles were filtered, the filtrate was concentrated under reduced pressure, and to the obtained residue was added a solution of 112.8 mg of tin chloride (II) dihydrate in 500 fil of ethanol and 50 \xl of concentrated hydrochloric acid, followed by stirring at 70°C for 4 hours. The reaction liquid was concentrated under reduced pressure, and 1.5 ml' of a 2 M aqueous sodium hydroxide solution was added thereto, followed by extraction with chloroform. A solvent was evaporated under reduced pressure, and to the residue was added a solution of 10.3 mg of 2-phenyl-l,3-thiazole-4-carboxylic acid and 6.8 mg of HOBt in 1.00 ml of N,N-dimethylformamide, and 7 5 mg of PL-DCC Resin (Polymer Laboratories Ltd.) at room temperature, followed by stirring overnight. To the reaction liquid were added 50 mg of MP-Carbonate (Argonaut Technologies, Inc.) and 50 mg

of PS-Isocyanate (Argonaut Technologies, Inc.) at room temperature, followed by stirring overnight, the insolubles were filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative high performance liquid chromatography (methanol-0.1% aqueous formic acid solution) to prepare 3.0 mg of N-{2-[4-(morpholin-4-ylcarbonyl)piperazin-1-yl]phenyl}-2-phenyl-l,3-thiazole-4-carboxamide.
From l-fluoro-2-nitrobenzene, 2-phenyl-l,3-thiazole-4-carboxylic acid, and each corresponding starting material, in the same manner as in Example 1029, the compounds of Examples 1001 to 1044 were prepared.
Example 104 8
To a''solution of 7.4 mg of l-(2-aminophenyl)piperidine-4-carboxylic acid ethyl ester, 7.4 mg of 2-(2-thienyl)-1,3-thiazole-4-carboxylic acid, and 4.1 mg of HOBt in 1.00 ml of N,N-dimethylformamide solution was added 100 mg of PS-Carbodiimide (Argonaut Technologies, Inc.) at room temperature, followed by stirring overnight. To the reaction liquid were added 50 mg of MP-Carbonate (Argonaut Technologies, Inc.) and 50 mg of PS-Isocyanate (Argonaut Technologies, Inc.) at room temperature, followed by stirring for 4 hours, and the insolubles were filtered. The filtrate was concentrated under reduced pressure, the obtained residue was dissolved in 0.5 ml of ethanol and 0.5 ml of tetrahydrofuran, and 0.5 ml of a 2 M aqueous sodium hydroxide solution was added dropwise thereto at room temperature, followed by stirring at 60°C for one day. To the reaction liquid was added dropwise 1.0 ml of a 1M

aqueous hydrochloric acid solution, followed by extraction with chloroform. A solvent was evaporated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (methanol-0.1% aqueous formic acid solution) to prepare 2.4 mg of 1-[2-({ [2-(2-thienyl)-1, 3-thiazol-4-yl]carbonyl}amino) phenyl]piperidine-4-carboxylic acid.
From 1-(2-aminophenyl)piperidine-4-carboxylic acid ethyl ester and each corresponding starting material, in the same manner as in Example 104 8, the compounds of Examples 1045 to 1052 were prepared.
Example 1065
To a solution of 10.9 mg of 2-phenyl-N-(2-piperidin-4-ylphenyl)-1,3-thiazole-4-carboxamide in"0.5 ml of N,N-dimethylformamide were added 4.0 mg of 3-bromopropanenitrile and 12.4 mg of potassium carbonate, followed by stirring overnight at 60°C. To the reaction liquid was added water, followed by extraction with chloroform. A solvent was evaporated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (methanol-0.1% aqueous formic acid solution) to prepare 3.6 mg of N-{2-[l-(2-cyanoethyl)piperidin-4-yl]phenyl}-2-phenyl-l,3-thiazole-4-carboxamide.
From 2-phenyl-N-(2-piperidin-4-ylphenyl)-1, 3-thiazole-4-carboxamide and each corresponding starting material, in the same manner as in Example 10 65, the compounds of Examples 1053 to 1091 were prepared.

Example 1116
To a solution of 2.2 mg of propionic acid in 60 jul of l-methylpyrrolidin-2-one were added 12.5 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-piperidin-4-yl-1,3-thiazole-4-carboxamide dihydrochloride, 10.4 p.1 of triethylamine, a solution of 3.4 mg of HOBt in 1.00 ml of N,N-dimethylformamide, and 100 mg of PS-Carbodiimide (Argonaut Technologies, Inc.) at room temperature, followed by stirring overnight. To the reaction liquid were added 50 mg of MP-Carbonate (Argonaut Technologies, Inc.) and 50 mg of PS-Isocyanate (Argonaut Technologies, Inc.) at room temperature, followed by stirring for 4 hours, and the insolubles were filtered. The filtrate was concentrated under reduced"pressure to prepare 10.4 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl-}2-(1-propionylpiperidin-4-yl)-1,3-thiazole-4-carboxamide.
In the sa'me manner as in Example 1116, the compounds of Examples 1116 to 1161 were prepared using the corresponding carboxylic acid as a starting material.
Example 1162
To a solution of 1.7 mg of propionaldehyde, 12.5 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-piperidin-4-yl-l,3-thiazole-4-carboxamide dihydrochloride, and 6.9 jal of triethylamine in 0.50 ml of N,N-dimethylformamide were added 50 |LX1 of acetic acid and 75 mg MP-Triacetoxyborohydride (Argonaut Technologies, Inc.) at room temperature, followed by stirring overnight. To the reaction liquid was added 50 mg of PS-Isocyanate (Argonaut Technologies, Inc.) at room temperature, followed by

stirring for 4 hours, and the insolubles were filtered. The filtrate was purified by solid phase extraction using BondElut® SCX (Varian, Inc., USA) (eluent, concentrated aqueous ammonia:methanol=l:9) to prepare 0.9 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-(1-propylpiperidin-4-yl)-1,3-thiazole-4-carboxamide.
In the same manner as in Example 1162, the compounds of Examples 1162 to 1177 were prepared using the corresponding aldehyde as a starting material.
Example 1178
To 3.4 mg of methanesulfonylchloride was added a mixed solution of 12.5 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-l-yl]phenyl}-2-piperidin-4-yl-l,3-thiazole-4-carboxamide dihydrochloride and 10.4 fxl of triethylamine in 0.50 ml dichloroethane and 0.50 ml of N,N-dimethylformamide at room temperature, followed by stirring overnight. To the reaction liquid were added 50 mg of PS-Isocyanate (Argonaut Technologies, Inc.) and 50 mg of PS-Trisamine (Argonaut Technologies, Inc.) at room temperature, followed by stirring for 4 hours, and the insolubles were filtered. The filtrate was purified by solid phase extraction using BondElut® SCX (Varian, Inc., USA) (eluent, concentrated aqueous ammonia:methanol=l:9) to prepare 11.4 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-(1-(methylsulfonyl)piperidin-4-yl)-1,3-thiazole-4-carboxamide.
In the same manner as in Example 1178, the compounds of Examples 1178 to 1195 were prepared using the corresponding sulfonyl chloride as a starting material.

Example 1196
To - 2.6 mg of isopropylisocyanate was added a solution of 12.5 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-piperidin-4-yl-l,3-thiazole-4-carboxamide dihydrochloride and 10.4 fo.1 of triethylamine in 0.50 ml of N,N-dimethylformamide at room temperature, followed by stirring overnight. To the reaction liquid were added 50 mg of PS-Isocyanate (Argonaut Technologies, Inc.) and 50 mg of PS-Trisamine (Argonaut Technologies, Inc.) at room temperature, followed by stirring for 4 hours, and the insolubles were filtered. The filtrate was purified by solid phase extraction using BondElut® SCX (Varian, Inc., USA) (eluent, concentrated aqueous ammonia:methanol=l:9) to prepare 11.9 mg of 4-{4-[({2-[4-(2-amino-2-
oxoethy1)piperazin-1-yl]phenyl}amino)carbonyl]-1,3-thiazol-2-yl}-N-isopropylpiperidine-1-carboxamide.
In the same manner as in Example 1196, the compounds of Examples 1196 to 1202 were prepared using the corresponding isocyanate or isothiocyanate as a starting material.
The structures and the physiochemical data of the compounds of Examples 1 to 1202 are shown in Tables 6 to 68. In addition to the description on the preparation methods in Examples as above, the compounds of the Example Nos. were prepared in the same manner as the methods of Examples of the numbers shown in Syn of Tables, using each corresponding starting material.
In the tables as described below in Examples, the following abbreviations are used.

Ex in the left-hand columns in-the Tables represents Example Nos., and the cells in the middle columns except for the top cell of each table show the structural formulae corresponding to the substituents of the compounds of the present invention represented by the general formulae. The structural formulae marked with * in the cells of the tables indicate that the compounds are optically active. Example Nos. with reference to the preparation methods with Syn are shown at the tops of the right-hand columns. The materials horizontally described in the right hand of Syn, that is, (Sal) indicate salts, and the materials without such a description represents free compounds.
(HCl) represents hydrochloride, and (Na) represents a sodium salt. The values by mass analysis as Dat (physiochemical data) are shown at the bottoms in the right-hand columns.

NMR data of several Example compounds are shown in the following Table 69. For the data, tetramethylsilane was used as an internal standard, and unless otherwise specifically mentioned, 6 (ppm) cf the Deaks in 1H-NMR using DMSO-dg as a measurement solvent is shown.
(CDCI3) : 5 (ppm) of the peaks in 1H-NMR in CDC13. [Table 69]

Industrial Applicability
The compound o.f the present invention has a potent trkA receptor inhibitory activity, and is useful as a medicine, particularly as an agent for treating urinary frequency, urinary urgency, urinary incontinence, lower urinary tract pain, which are associated with various lower urinary tract diseases including overactive bladder, and various diseases accompanied by pain.

CLAIMS
1. An azolecarboxamide derivative represented by following the general formula (I) or a salt thereof: [Chem. 1]

(wherein symbols have the following meanings: • X: S .or ,0.,
A: phenylene which may be substituted, pyridinediyl which may be substituted, pyrimidinedi'yl which may be substituted, thiophenediyl which may be substituted, pyrazolediyi which may be substituted, pyridonediyl which may be substituted,
Q: a monocyclic or bicyclic alicyclic nitrogen-containing heterocyclic group which may be substituted,
R1: halogen, lower alkylcarbonyl, C1-C7 alkyl which may be substituted, lower cycloalkyl which may be substituted, lower alkoxy which may be substituted, aryl which may be substituted, heteroaryl which may be substituted, a group represented by the general formula (II), the general formula (III), or the general formula (IV);

[Chem. 2]

Rla and Rlb: each independently -H, lower alkyl which may be substituted, lower cycloalkyl, a saturated heterocyclic group which may be substituted, lower alkylcarbonyl, lower alkoxycarbonyl, aryl, or heteroaryl,
Rlc: -H or lower alkyl,
Yl: lower alkylene which may be substituted in which -0-, -S-, -SO-, -S02~r or -N(-Rld)- may be contained between carbons thereof,
Rla: -H, lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl, or aryl-lower alkyl,
Y2: lower alkylene in which -0-, -S-, -S02-, -N(-Rle)-, -N(-CO-Rlf)-, -N(-CO-NH-Rlg)-, -N (-CS-NH-R19) ~, or -N (-S02-R~n) - may be contained between carbons thereof,
Rle: -H or lower alkyl which may be substituted,
Rlf: lower alkyl which may be substituted, lower cycloalkyl, lower alkoxy, aryl which may be substituted, heteroaryl which may be substituted, or aryl-lower alkenyl,
Rlg: -H, lower alkyl, aryl, or aryl-lower alkyl,
Rlh: lower alkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl which may be substituted, heteroaryl, or aryl-lower alkyl, and

R2: ~H, halogen, or a nitrogen-containing saturated heterocyclic group).
2. The derivative according to claim 1, wherein A, Q or R1 have the following meanings, or a salt thereof, A: [Chem. 3]

R3: -H, halogen, lower alkyl, cyano, cyano-lower alkyl, hydroxy-lower alkyl, lower alkoxy, halogeno-lower alkoxy, lower alkoxy-lower alkyl, lower alkenyl, cyano-lower alkenyl, carboxy, carbamoyl, lower alkoxycarbonyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, lower alkylaminocarbonyl-lower alkyl, lower alkylsulfonyl, aminosulfonyl, or lower alkylsulfinyl,
R4: -H, halogen, or lower alkoxy,
R3 and R4 in combination may be bridged as -O-lower alkylene,
R5: -H or halogen,
R5: -H or lower alkyl,

Q: a group represented by the general formula (V), (VI), (VII), (VIII) or (IX): [Chem. 4]

(VIII) (IX)
V1 and Vz: each independently Ci_3 alkylene,
V3: methylene or ethylene,
W: -CH(-R5)-, -N(-R9)-, -0-, -S-, -SO-, or-S02-,
R7 and R8: each independently -H, halogen, hydroxy, lower alkyl, hydroxy-lower alkyl, carboxy, lower alkoxycarbonyl, lower alkylcarbonyloxy, carbamoyl, aryl, aryl-lower alkyl, a saturated heterocyclic group which may be substituted with lower alkyl, or an -Alk-saturated heterocyclic group,
-Alk-: lower alkylene,
two substituents of R7, R8 and R5 in combination may be bridged as lower alkylene,
R7 and R8 may be substituted with the same carbon atoms, or in combination may form an oxo group, or a

nitrogen-containing saturated heterocyclic group having . spiro bonds, wherein the nitrogen-containing saturated heterocyclic group may be substituted with lower alkyl or an oxo group,
R9: -H, lower alkyl, cyano, hydroxy, lower alkoxy, lower alkenyl, lower alkoxycarbonyl-lower alkenyl, lower alkylsulfonyl, -Alk-R9a, -COR9b, -Alk-CO-R9b, -CO-Alk-R9c, -NR9dR9e, aryl, aryloxy, or a saturated heterocyclic group, wherein the nitrogen-containing saturated heterocyclic group may be substituted with lower alkyl, hydroxy, or an oxo group,
-Alk-: lower alkylene,
R9a: cyano, hydroxy, lower alkoxy, mono- or dihydroxy-lower alkyl, aryl, aryloxy, arylcarbonyloxy, amino which may be substituted with lower alkyl, lower alkoxycarbonylamino, heteroaryl, or a saturated heterocyclic group, wherein the heteroaryl may be substituted with lower alkyl or an oxo group, and the saturated heterocyclic group may be substituted with a lower alkyl group,
R9b: lower alkyl, hydroxy, lower alkoxy, -NR9fR9g or an alicylic heterocyclic group, wherein the alicyclic heterocyclic group may be substituted with lower alkyl, hydroxy, carboxy, lower alkoxycarbonyl, mono- or di-lower alkyiamino, a saturated heterocyclic group, or an -Alk-saturated heterocyclic group,
-Alk-: lower alkylene,
R9f and R9g: each independently -H, lower alkyl, hydroxy-lower alkyl, lower cycloalkyl which may be

substituted with amino, lower alkoxy-lower alkyl, mono- or di-lower alkylamino-lower alkyl, lower alkylsulfonyl, heteroaryl, or a saturated heterocyclic group,
wherein the saturated heterocyclic group may be substituted with lower alkyl or aryl-lower alkyl,
or an -Alk-saturated heterocyclic group,
-Alk-: lower alkylene,
R9c: lower alkoxy, lower alkylcarbonyloxy, or a saturated heterocyclic group, wherein the saturated heterocyclic group may be substituted with lower alkyl or an oxo group,
R9d and R9e: each independently -H, lower alkyl, lower alkylcarbonyl, or carbamoyl-lower alkyl,
R1: halogen, lower alkylcarbonyl, lower cycloalkyl which may be substituted with hydroxy, lower alkoxy which may be substituted with lower alkoxy, C:-C7 alkyl which may have a substituent selected from the following Gi group, aryl, heteroaryl, a group represented by the general formula (X), (XI), (XII), (XIII), or (XIV),
wherein the aryl or heteroaryl may have one or two substituent(s) selected from the following G2 group, and the two substituents in combination may form a cyclic structure,
Gi group: hydroxy, lower alkoxy, N-lower alkyl-N-lower alkoxy-lower alkylamino, mono- or di-lower alkylamino, a saturated heterocyclic group, aryl or aryloxy,
Wherein the aryl or aryloxy may.be substituted with, halogen, and halogeno-lower alkyl,

G2 group: halogenr hydroxy, oxo, lower alkyl, halogeno-lower alkyl, lower alkoxy, cyano, carboxy, carbamoyl, and -NR11Rlj,
R11 and Rlj: each independently -H, lower alkyl, lower alkoxy-lower alkyl, or lower alkoxycarbonyl,
[Chem. 5]

(XIII) (XIV)
Rlp and Riq: each independently -H, lower cycloalkyl, lower alkylcarbonyl, lower alkoxycarbonyl, aryl, heteroaryl, a saturated heterocyclic group, or lower alkyl which may have a substituent selected from the following G3 group,
wherein the saturated heterocyclic group may have.a substit.uent selected from the group consisting of lower alkyl which may substituted with one or two aryl(s), and aryl-lower alkoxycarbonyl,
G3 group: halogen, hydroxy, cyano, lower alkoxy, lower alkoxy-lower alkoxy, aryl, heteroaryl, a saturated heterocyclic group, carboxy, lower alkoxycarbonyl, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl,

carbamoyl which may be substituted with lower alkyl,. and -NRlkRn,
Rlk and R11: each independently -H, lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl, or lower alkylsulfonyl,
k: 0, 1 or 2,
Y3: a single bond, -CH2-, -0-, -N(-Rlm)-, -S-, -SO-, or -S02-,
Rlm: -H, lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl, or aryl-lower alkyl,
Rir and Rls: each independently -H, halogen, hydroxy, lower alkyl, lower alkoxy, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkylcarbonyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkylamino-lower alkyl, aryl or -CO-NH-Alk-Rln,
-Alk-: lower alkylene,
Rln: hydroxy or a saturated heterocyclic group,
wherein Rir and Rls in combination may be bridged as lower alkylene, and Rlr and Rls may be substituted with the same carbon atom, and may form an oxo group,
m: 0, 1, or 2,
n: 1, 2, 3, or 4,
R11: -H or lower alkyl,
Rlu: -H, lower alkyl, -Alk-Rlw, -C0-Rlx, -S02-Rly, or -CS-NH-Rlz,
-Alk-: lower alkylene,
Rlw: lower cycloalkyl, lower alkoxy, carboxy, carbamoyl, a saturated heterocyclic group, or aryl, . heteroaryl, .

wherein the aryl may have a substituent selected from the group consisting of lower alkyl, lower alkoxy and a carboxy group,
Rlx: lower alkyl, lower cycloalkyl, hydroxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl, amino, lower alkylamino, arylamino, aryl-lower alkylamino, mono- or di-lower alkylamino-lower alkyl, aryl, aryl-lower alkyl which may be substituted with halogen, aryl-lower alkenyl, heteroaryl, or heteroaryl-lower alkyl,
wherein the aryl or heteroaryl may have a substituent selected from the group consisting of halogen, lower alkyl, lower alkoxy, and aryl,
Rly:. lower alkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl, aryl-lower alkyl, or heteroaryl,
wherein the aryl may have a substituent selected from the group consisting of halogen and aryl,
Rlz: lower alkyl, aryl, aryl-lower alkyl,
Rlv: -H or lower alkoxycarbonyl,
Y4: -0-, -S-, or -SO2-, and
h: 0 or 1.
3. The derivative according to claim 1 or 2, wherein A has the following meaning,or a salt thereof, A:

[Chem. 6]

R13: -Hf halogen, lower alkyl, cyano, cyano-lower alkyl, hydroxy-lower alkyl, lower alkoxy, halogeno-lower alkoxy, lower alkoxy-lower alkyl, lower alkenyl, cyano-lower alkenyl, carboxy, carbamoyl, lower alkoxycarbonyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, mono- or di-lower alkylaminocarbonyl-lower alkyl, lower alkylsulfonyl, aminosulfonyl or lower alkylsulfinyl,
R14: -H, halogen or lower alkoxy.
4. The derivative according to any one of claims 1 to 3, wherein Q has the following meaning, or a salt thereof,
Q:
[Chem. 7]

R17 and R1S: each independently -H, halogen, hydroxy, lower alkyl, hydroxy-lower alkyl, carboxy, lower

alkoxycarbonyl, lower aikylcarbonyloxy, carbamoyl, aryl or aryl-lower alkyl,
R19: ~H, lower alkyl, cyano, hydroxy, lower alkoxy, lower alkenyl, lower alkoxycarbonyl-lower alkenyl, lower alkylsulfonyl, ~Alk-R9a, -CO-R19b, -Alk-CO-R19b, -CO-Alk-R9c, -NR9dR9e, aryl, aryloxy, or a saturated heterocyclic group, wherein the saturated heterocyclic group may be substituted with lower alkyl, hydroxy or an oxo group,
-Alk-: lower alkylene,
R9a' R9c, R9d, and R9e have the same meanings as described above,
R19b: lower alkyl, hydroxy, lower alkoxy, -NR19fR19g or an alicylic heterocyclic group,
wherein the alicyclic heterocyclic group may be substituted with lower alkyl, hydroxy, carboxy, lower alkoxycarbonyl, or mono- or di-lower alkylamino,
R19f and R19g: each independently -H, lower alkyl, hydroxy-lower alkyl, lower cycloalkyl which may be substituted with amino,, lower alkoxy-lower alkyl, mono- or di-lower alkylamino-lower alkyl, lower alkylsulfonyl, heteroaryl, or a saturated heterocyclic group which may be substituted with lower alkyl.
5. The derivative according to any one of claims 1 to 4, wherein R1 has the following meaning, or a salt thereof, R1:

[Chem. 8]

-Alk-: lower alkylene,
Rlla: -H or lower alkyl,
Rllb: -H, lower alkyl, lower cycloalkyl, hydroxy-lower alkyl, or lower alkoxy-lower alkyl,
R1±c: -H, hydroxy, lower alkyl, hydroxy-lower alkyl, or lower alkoxy-lower alkyl,
Rlld: -H, hydroxy, lower alkoxy, a saturated heterocyclic group, or aryl,
wherein the aryl may have a substituent selected from the group consisting of halogen and halogeno-lower alkyl,
Rlle: -H, lower alkyl, -Alk-Rlw, -CO-Rllx, or -S02-RUy
-Alk-: lower alkylene,
Rlw has the same meaning as described above,
RllK: lower alkyl, lower cycloalkyl, hydroxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl, amino, lower

alkylamino, aryiamino, aryl-lower alkylamino, di-lower alkylamino-lower alkyl, aryl, aryl-lower alkyl, aryl-lower alkenyl, heteroaryl, or heteroaryl-lower alkyl,
wherein the aryl may have a substituent selected from the group consisting of halogen, lower alkyl, and lower alkoxy,
RUy: lower alkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl which may be substituted with halogen, aryl-lower alkyl, or heteroaryl,
RUf: -H or hydroxy,
Rllg: -H, halogen, hydroxy, oxo, lower alkyl, halogeno-lower alkyl, lower alkoxy, cyano, carboxy, carbamoyl, or -NRuiRUj,
R111 and Rnj: each independently -H, lower alkyl, lower alkoxy-lower alkyl, or lower alkoxycarbonyl,
Rllh: -H or lower alkyl.
6. The derivative according to Claim 5, wherein A, Q, Rx and R2 have the following meanings, or a salt thereof,
A: [Chem. 9]


Q: [Chem. 10]

R2: -H,
R13 and R14: the same as in claim 3,
R17, R18, and R19: the same as in claim 4,
Rlla, Rllb, Rllc, and Rllg: the same as in claim 5.
7. The derivative according to Claim 6, wherein R13 is -H, halogen or lower alkoxycarbonyl-lower alkyl; R14, R17 and R18 are each -H; R19 is -H, hydroxy, carbamoyl or aminocarbonyl-lower alkyl; Rlla is lower alkyl; RUb is lower alkoxy-lower alkyl; and Rllc and R115 are each -H, or a salt thereof.

8. The compound according to claim 1, which is selected from the group consisting of:
methyl (3-[4-(2-amino-2-oxoethyl)piperazin-1-yl]-4-{[(2-phenyl-l,3-thiazol-4-yl)carbonyl]amino}phenyl)acetate,
N-[2-(3-carbamoylpyrrolidin-l-yl)phenyl]-2-phenyl-1, 3-thiazole-4-carboxamide,
N-{2-[4-(2-amino-2-oxoethyl)piperazin-l-yl]phenyl}-2-morpholin-4-yl-l,3-thiazole-4-carboxamide,
N-{2-[4-(2-amino-2-oxoethyl)piperazin-l-yl]-3-fluorophenyl}-2-(4-hydroxypiperidin-l-yl)-1,3-thiazole-4-carboxamide,
N-{2-[4-(2-amino-2-oxoethyl)piperazin-l-yl]phenyl}-2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazole-4-carboxamide,
l-{3-[ ({2-[(2-methoxyethyl) (methyl)amino]-1,3-thiazol~4-yl}carbonyl)amino]pyridin-2-yl}piperidine-4-carboxamide,
" N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]pyridin-3-yl}-2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazole-4-carboxamide,
N-[2-(4-hydroxypiperidin-l-yl)phenyl]-2-phenyl-l, 3-oxazole-4-carboxamide,
1- (2-{[(2-morpholin-4-yl-l,3-oxazol-4-yl)carbonyl]amino}phenyl)piperidine-4-carboxamide,
l-(3-{[(2-morpholin-4-yl-l,3-oxazol-4-yl)carbonyl]amino}pyridin-2-yl)piperidine-4-carboxamide, and
N-{2-[4-(2-amino-2-oxoethyl)piperazin~i-yl]phenyl}-2-(3-furyl)-1,3-oxazoie-4-carboxamide , or a salt thereof.

9. A pharmaceutical composition, comprising the
azolecarboxamide derivative according to claim 1 or a
pharmaceutically acceptable salt thereof, as an active
ingredient.
10. An agent for treating or preventing disease related to NGF or trkA receptor, comprising the azolecarboxamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof, as an active ingredient.
11. An agent for treating or preventing urinary frequency, urinary urgency, urinary incontinence, lower urinary tract pain, which are associated with various lower urinary tract diseases, or various diseases accompanied by pain, which comprises the azolecarboxamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
12. The prophylactic or therapeutic agent according to Claim 9, wherein the lower urinary tract disease is overactive bladder, interstitial cystitis or chronic prostatitis.
13. The prophylactic or therapeutic agent according to claim 9, wherein the disease accompanied by pain is osteoarthritis.

14. A method for treating or preventing urinary
frequency, urinary urgency, urinary incontinence, lower
urinary tract pain, which are associated with various lower
urinary tract diseases, or various diseases accompanied by
a pain, which comprises administrating an effective amount
of the azolecarboxamide derivative according to claim 1 or
a pharmaceutically acceptable salt thereof to a patient.
15. A trkA receptor inhibitor, comprising the
azolecarboxamide derivative according to claim 1 or a
pharmaceutically acceptable salt thereof.