PROCESS FOR THE PREPARATION OF INDAZOLYL UREAS THAT INHIBIT VANILLOID SUBTYPE 1 (VR1) RECEPTORS
Related Applications
This application claims priority to U.S. Provisional Application Serial No. 60/792,099, filed April 14, 2006.
Field of the Invention
The invention relates to the process of preparing indazoly) ureas that are useful as Vanilloid subtype 1 receptor (VRl) inhibitors. The invention also relates to the intermediates in the process that generates the indazolyl ureas and uses thereof.
Background
Compounds of general formula (1) that are antagonists of the Vanilloid subtype 1 receptor (VRl) were originally prepared via a synthetic route described in USSN:10/864,068. The synthetic route in this invention relied upon treating a nitroanaline with sodium nitrite to form a nitroindazole intermediate. Recent developments have afforded a new highly efficient synthetic pathway, which generates fewer impurities and presents a more cost effective process for generating this valuable compound. The new route also incorporates the following innovative chemical methods: a new method for the preparation of 4-haloindazoles via condensation of the corresponding halogenated benzaldehydes or certain halogenated ketone substituted benzene rings with hydrazine; a method for the selective protection of halomdazoles at the Nl or N2 position and a method for the conversion of haloindazoles into indazoyl ureas.
Compounds of general formula (I) that are antagonists of the Vanilloid subtype 1 receptor (VRl) are useful in treating disorders associated with overactivity of the Vanilloid subtype 1 receptor a described in USSN: 10/864,068.
Detailed Description of the Invention
The present invention discloses a novel process to make compounds of formula (1),
(Formula Removed)
wherein, R1 is selected from the group consisting ot hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkvl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxvalkyl, cvano, cyanoalkyl, cycloalkyl, cycloalkyialkyl, formyl, formvlalkyl, haloalkoxv, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF3)2(HO)C-, RB(SO)2RAN-, RAO(SO)2-, RBO(SO)2-, ZAZBN-, (ZAZBN)alkyl, (ZAZBX)carbonyl, (ZAZBN)carbonylalkyl, and (ZAZBN)sulfonyl;
R9, R10 R11, and R12 arc each independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, aryl, carboxy, carboxvalkyl, cyano, cyanoalkyl, tormyl, tormylalkvl, haloalkoxy, haloalkyl, haloalkylthio, halogen, heteroaryl, heterocycle, hydroxy, hydroxyalkyl, mercapto, mercaptoalkvl, nitro, (CF3)2(HO)C-,RB(SO),RAN-, RAQ(SO)2-, RBO(SO)2-, ZAZBN-, (ZAZBN)alkyl, (ZAZBN)carbonyl, (ZAZBN)carbonylalkyl, and (ZAZBX)sulfonyl;
RA is hydrogen or alkyl;
RB is alkyl, aryl, or arvlalkyl; and
ZA and ZB are each independently hydrogen, alkyl, alkylcarbonyl, tormyl, aryl, or arvlalkyl, comprising the steps of:
(a) heating a mixture of a compound of formula (111), a base selected from the group consisting or sodium hydroxide, potassium phosphate and cesium carbonate, and a composition comprising a compound of formula (I la), a compound of formula (IIb) or a mixture thereof, wherein P is selected from the group consisting of alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, arylalkyl, arylcarbonyl and aryloxycarbonvl, R1 is defined under the compound of formula (I) and Y is chloro or bromo, in the presence of palladium catalyst and a phosphine based ligand,
(Formula Removed)
to provide a composition consisting of a compound or formula (IVa), a compound of formula (IVb) or a mixture thereof, wherein R1 R9, R10„ R11, and R12 are defined under the compound of formula (1),
(Formula Removed)
followed by
(b) treating the composition consisting of the compound of formula (IVa), the
compound of formula (IVb) or the mixture thereof, to conditions that will provide the
compound of formula (I). Compounds of formula (I) are useful for controlling pain and
urinary disorders in mammals by inhibiting the VR1 receptor.
It is understood that the process of this invention can be carried out in an inert atmosphere, preferably nitrogen. Contained within the scope of this invention, it is understood that there are several palladium catalysts which may be utilized in step (a) which include but are not limited to palladium acetate and Pd3(DBA),. It is understood that within the scope of this invention, the phosphine based ligand may include phosphine ligands that are utilized by one skilled in the art of coupling reactions of this type. Most preferred phosphine ligands include but are not limited to Xantphos, 2-di-t-butvlphosphino-l-l'-binaphthyl and 5-(di-t-butylphosphanyl)-1 ',3',5'-triphenvl-17 /-(1,4']bipvrazolyl. It is also understood that in the process of this invention, the base of step (a) can be potassium 1 phosphate, potassium carbonate or cesium carbonate, preferably cesium carbonate.
It is also understood that in the process of this invention, the mixture of step (a) is heated to reflux for 2-20 hours, in an organic solvent including but not limited to Tl IF, toluene, DMF, \MP or ethylene glycol dimethyl ether, preferably ethylene glycol dimethyl ether. In certain embodiments, wherein Y is bromo, the mixture of step (a) is generally heated tor about 2 to about 10 hours in ethylene glycol dimethyl ether. In some instances, when Y is bromo, the mixture ot step (a) is heated tor about 5 hours. In certain

embodiments, wherein Y is bromo, the prefered conditions include the use of Pd2(DBA),, Xantphos and cesium carbonate in step (a).
In other embodiments, wherein Y is chloro, the mixture or step (a) is generally heated for about 5 to about 20 hours in ethylene glycol dimethyl ether. When Y is chloro the preferred palladium catalyst is palladium acetate. In certain embodiment of the present invention wherein Y is chloro, there is disclosed the use of palladium acetate, 2-di-t-butylphosphino-l-l'-binaphthyl and potassium phosphate in step (a). These steps are generally followed by filtration and/or precipitation to provide the composition consisting of the compound of formula (IVa) or (IVb) or a mixture thereof.
The present invention also includes a process to prepare compound of formula (IIa) and compound of formula (IIb) as described in Scheme 1. Contained within an embodiment describing the process for the preparation of the compound of formula (I Ia) and the compound of formula (IIb) outline the step (a), wherein the treatment of a meta-chloro or meta-bromo fluorobenzene with a base such as but not limited to lithium diisopropvlamide, lithium dicyclohexyamide or lithium bis(trimethylsilyl)amide in a solvent is carried out between a temperature of about -5(1 0C to about -78 "C for about 1 to about 3 hours. The process further comprises treating the cold mixture with a compound ot formula R1C(=O)-X, wherein R1 is hydrogen, alkenyl or alkyl, and X is chloro, (( CH3,) 2N -, phenoxv, or nitrophenoxy, to provide a compound of formula (V),
(Formula Removed)
The process of the present invention further comprises the treatment of the compound of formula (V) with hydrazine in a solvent including but not limited to DM1 , DMSO, or THF', preferably DMSO to obtain compounds of formula (VI),
(Formula Removed)
The process further comprises treating the compound of formula (VI) with a reagent P Z, wherein P is selected from the group consisting of alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, arylalkyl, arylcarbonyl find aryloxycarbonvl, such as but not limited to acetyl
chloride, acetic anhydride, benzyl bromide, benzyl chloroformate and di-tert-butyl dicarbonate, to provide the composition consisting of the compound or formula (IIa), the compound of formula (IIb) or a mixture of the compound of formula (I la) and the compound of formula (IIb),
(Formula Removed)
In one embodiment of the invention is disclosed the process which further comprises heating and stirring the mixture of the compound of formula (VI) and benzyl bromide in organic solvent, e.g N,N-dimethyl formamide, DMA, NMP, preferably DM1', to a temperature of about 40 "C to about 120 0C for the period of between about 4 hours and about 30 hours to introduce a benzyl protecting group onto one of the nitrogen atoms.
In another preferred embodiment, the process further includes treating the compound of formula (VI) with benzyl bromide in N,N--dimethyl formamide to a temperature of about 105 0C to about 115 0C for a period between about 20 hours to about 24 hours, to provide the compound of formula (VI lb).
(Formula Removed)
In another embodiment, the process also discloses the heating and stirring the mixture of the compound of formula (VI) and benzyl bromide in \,N-dimethyl formamide to a temperature of about 50 "('. to about 60 "('. for a period between about 20 hours to about 24 hours to provide the compound of formula (VIIa),
(Formula Removed)
The process of the present invention also discloses treating a compound of formula (VIII) as described in Scheme 3 to obtain a compound of formula (III),
(Formula Removed)
The process also describes treating the composition consisting of the compound of formula (VIIa), the compound of formula (Vllb) or the mixture thereof, wherein R1 is defined under the compound of formula (I) and Y is chloro or bromo, with a compound of formula (III), a base selected from the group consisting of sodium carbonate, potassium carbonate and cesium carbonate, in the presence of palladium catalyst and a phosphine based ligand to provide a composition consisting of a compounds of formula (I Va), a compound of formula (IVb) or a mixture thereof, wherein the P group is benzyl. The process further describes treating the composition consisting of the compound of formula (IVa), the compound of formula (IVb) or the mixture thereof, wherein the P group is benzyl with a palladium catalyst comprising palladium on carbon, palladium hydroxide or palladium on barium sulfate, preferably palladium hydroxide, more preferably 20% palladium hydroxide and a hydrogen donor comprising an atmosphere of hydrogen, formic acid, or cyclohexadiene, preferably formic acid, in a solvent comprising an alcoholic solvents, tetrahydrofuran or ethyl acetate; preferably tetrahydroturan to provide the compound of formula (I).
The present invention further includes a process for preparing the compound of formula (IX),
(Formula Removed)
(IX), comprising the steps of heating, preferably for 5-10 hours, a mixture of a compound of formula (XI), a base consisting of potassium phosphate, potassium carbonate or cesium carbonate, preferably cesium carbonate, and a composition consisting of the compound of formula (Xa), a compound of formula (Xb) or a mixture thereof, wherein Y is chloro or bromo, in the presence of a catalyst such as but not limited to Pd2(DBA)3 and a phosphine
based ligand, including but not limited to Xantphos, 2-di-t-butylphosphino- 1-1'-binaphthyl and 5-(di-t-butylphosphanyl)-t',3',5'-triphenyl-1'H-[l,4]bipyrazolyl under an atmosphere of nitrogen,
(Formula Removed)
to provide the composition consisting or"a compound of formula (XI la), a compound of formula (XIlb) or a mixture thereof",
(Formula Removed)
followed by treating the composition consisting ot the compound ot formula (XIla), the compound of formula (XI lb) or the mixture thereof, with a palladium catalyst comprising palladium on carbon, palladium hydroxide or palladium on barium sulfate, preferably palladium hydroxide, more preferably 20% palladium hydroxide and a hydrogen donor comprising an atmosphere ot hydrogen, formic acid, or cyclohexadiene, preferably formic acid, in a solvent comprising an alcoholic solvents, tetrahydrofuran or ethyl acetate; preferably tetrahydrofuran to provide the compound ot formula (IX). The present invention includes a composition consisting of the compound ot formula (11a), the compound of formula (IIb), or the mixture thereof,
(Formula Removed)
wherein Y is chloro or bromo; and R, is selected from the group consisting ot hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkvl, alkoxvcarbonvl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkvlcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy,
haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mcrcaptoalkyl, nitro, (CF5)2(HO)C-, RB(SO)2RAN-, RAO(SO)2-, RBO(SO)2-, ZAZBN-, (ZAZBN)alkyl, (ZAZBN)carbony), (ZAZBN)carbonylalkyl, or (ZAZBN)sulfonyl.
The present invention also includes a compound of formula (III),
(Formula Removed)
wherein R9 R10„ R11, and R12 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, aryl, carboxy, carboxyalkvl, cyano, cyanoalkyl, formyl, rormylalkvl, haloalkoxy, haloalkyl, haloalkylthio, halogen, heteroaryl, heterocvcle, hydroxy, hydroxyalkyl, mercapto, mcrcaptoalkyl, nitro, ((CF)2(HO)C-, RB(SO)2RAN- R,O(SO)2, RBC)(SO)2, ZAZBN-, (ZAZBN)alkyl, (ZAZBN)carbonyl, (ZAZBN)carbonylalkyl, and (ZAZHN)sulfonyl.
The present invention also includes a composition, comprising a compound of formula (Xa), a compound of formula (Xb), or a mixture thereof, wherein Y is chloro or bromo,
(Formula Removed)
which is useful in the process of preparing a compound of formula (IX). The present invention further includes a compound ot formula (XI),
(Formula Removed)
which is useful in the process of preparing a compound of formula (IX).It is understood
that the compounds of formula (IIa), (IIa,), (IIb), (IIb2) and (III), are useful in the process of preparing a compound of formula (I), which is representative of compounds of the present
invention, and which is useful for the treatment of a disorder bv inhibiting vanilloid receptor
subtype 1 in a mammal comprising administering a therapeutically effective amount of a
compound of formula (I) or a pharmaceuticall) acceptable salt or prodrug thereof. It is
understood that the disorder includes pain, inflammatory hyperalgesia, urinary incontinence
and bladder overreactivity. It is also understood that the compounds of formula (Xa),
(Xb), (Xc), (Xd) and (XI), are useful in the process of preparing a compound of formula (IX), which is useful for the treatment of a disorder bv inhibiting vanilloid receptor subtype 1 in a mammal comprising administering a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt or prodrug thereof. It is understood that the disorder includes pain, inflammatory hyperalgesia, urinary incontinence and bladder overreactivity. Definitions
As used throughout this specification and the appended claims, the following terms have the following meanings:
The term "alkenyl" as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenvl include, but are not limited to, ethenyi, 2-propenyl, 2-methvl--2-propcnyl, .vbutenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
The term "alkoxy" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples ot alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
The term "alkoxvalkoxy" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkoxv group, as defined herein. Representative examples of alkoxvalkoxy include, but are not limited to, methoxvmethoxv, ethoxymethoxy and 2-ethoxvethoxv.
The term "alkoxyalkyl" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples ot alkoxvalkvl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxvmethvl.
The term "alkoxycarbonyl" as used herein, means an alkoxv group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl,
ethoxycarbonyl, and tert-butoxycarbonyl.
The term "alkoxycarbonylalkyl" as used herein, means an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkvl group, as defined herein. Representative examples ot alkoxycarbonylalkyl include, but are not limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and 2-tert-butoxycarbonylethyl.
The term "alkyl" as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexvl, 3-methylhexyl, 2,2 dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
The term "alkylcarbonvl" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonvl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyi-l-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
The term "alkylcarbonylalkyi" as used herein, means an alkylcarbonvl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylcarbonylalkyi include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.
The term "alkylcarbonvloxy" as used herein, means an alkylcarbonvl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative-examples of alkylcarbonyloxy include, but are not limited to, acetvloxy, ethylcarbonyloxy, and tert-butylcarbom loxy.
The term "alkylsulfonyl" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethyls ulfonyl.
The term "alkvlthio" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moietv through a sulfur atom. Representative examples ot alkvlthio include, but are not limited, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, and hexvlsulfanyl.
The term "alkynyl" as used herein, means a straight or hranched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1 -propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1 -butynyl.
The term "aryi" as used herein, means a phenyl group, or a bicyclic or a tricyclic fused ring system wherein one or more of the fused rings is a phenyl group. Bicyclic fused ring systems are exemplified by a phenyl group fused to a cycloalkyl group, as defined herein, or another phenyl group. Tricyclic fused ring systems are exemplified by a bicyclic fused ring system fused to a cycloalkyl group, as defined herein, or another phenyl group. Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indenyl, naphthyl, phenyl and tetrahvdronaphthyl.
The aryi groups of this invention are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from alken\1, alkoxy, alkoxyalkoxv, alkoxyalkvl, alkoxycarbonyl, alkoxycarbonvlalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulronyl, alkylthio, alkynyl, carboxy, carboxyalkyl, cvano, cvanoalkyl, cycloalkyl, cvcloalkylalkyl, ethylenedioxv, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxy alkyl, methylenedioxy, mercapto, mercaptoalkyl, nitro, ZCZDN-, (ZcZDN)alkyl, (ZCZDN)carbonyl, (ZcZDN')carbomialkyl, (ZcZDN)sulfomi, -NRAS(O)2RB, -S(O)2ORA and -S(O)2RA wherein RA and RB are as defined herein.
The term "arylalkyl" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylcthyl, 3-phenylpropyl, and 2-naphth-2-vlefhyl.
The term "carboxy" as used herein, means a -CO2H group.
The term "carboxyalkyl" as used herein, means a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl), 2-carboxyethvl, and 3-carboxypropyi.
The term "cvano" as used herein, means a -CN group.
The term "cvanoalkyl" as used herein, means a cvano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cvanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoyethvl, and 3-cyanopropvl.
The term "cycloalkyl" as used herein, means a saturated monocyclic ring system containing from 3 to 8 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloocty 1.
The tenn "cvcloalkylalkyl" as used herein, means a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
The term "ethylenedioxy" as used herein, means a -O(CH2)2O- group wherein the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through one carbon atom forming a 5 membered ring or the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through two adjacent carbon atoms forming a six membered ring.
The term "rormyl" as used herein, means a -C(O)H group.
The term "tormylalkyl" as used herein means a formyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
The term "halo" or "halogen" as used herein, means -C1, -Br, -I or -1;.
The term "haloalkoxy" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, 2-chloro-3~fluoropentyloxv, and pentafluoroethoxy.
The term "haloalkyl" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl tritluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
The term "haloalkylthio" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkvithio group, as defined herein. Representative examples of haloalkylthio include, but are not Limited to, trifluorornethylthio.
The term "heteroaryl," as used herein, means a monocyclic heteroaryl or a bicvcLic heteroaryl. The monocyclic heteroaryl is a 5 or 6 membered ring containing at least one heteroatom independently selected from the group consisting ot O, N, and S. The 5 membered ring contains two double bonds may contain one, two, three or four nitrogen atoms, one nitrogen atom and one oxygen atom, one nitrogen atom and one sulfur atom, or one oxygen atom or one sulfur atom. The 6 membered ring contains three double bonds may contain one, two, three or four nitrogen atoms, one nitrogen atom and one oxygen atom, one nitrogen atom and one sulfur atom, one or two oxygen atoms or one or two suliur atoms. The 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryl include, but are not limited to, funyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxa/olyl, pyridinyl, pyridazinvl, pyrimidinvl, pyra/inyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyi, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl
fused to a cycloalkyl, or a monocyclic heteroaryl fused to a cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl. The bicyclic heteroaryl is connected to the parent molecular moiety through any carbon atom or any substitutable nitrogen atom contained within the bicyclic heteroaryl. Representative examples of bicyclic heteroarvl include, but are not limited to, benzimidazolyl, benzofuranvl, benzothienyl, benzoxadiazolyl, cinnolinyl, dihydroquinolinyl, dihydroisoquinolinyl, furopyridinyl, indazohl, mdolyl, isoquinolmyl, naphthyndinyl, quinolinyl, tetrahydroquinolinyl, and thienopyridinyl.
The heteroaryl groups of this invention are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from alkenvl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkvlcarbonyl, alkylcarbom lalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl, carboxy, carboxyalkvl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, ethylenedioxy, tormyl, formylalkyl, haloalkoxy, haloalkvl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, methylenedioxy, mercapto, mercaptoalkyl, nitro, Zc ZDN-, (ZcZDN)alkyl, (ZcZnN)carbonvl, (ZcZDN)carbonylalkvl, (ZC ZDN)sulfonvl, -NRAS(O)2RB, -S(O)2ORA and -S(O)2RA wherein RA and RB are as defined herein.
The term "heterocycle," as used herein, refers to a three, tour, five, six, seven, or eight membered ring containing one or two heteroatoms independently selected from the group consisting ot nitrogen, oxygen, and sulfur. The three membered ring has zero double bonds. The four and five membered ring has zero or one double bond. The six membered ring has zero, one, or two double bonds. The seven and eight membered rings have zero, one, two, or three double bonds. The heterocycle groups of the present invention can be attached to the parent molecular moiety through a carbon atom or a nitrogen atom. . Representative examples of heterocycle include, but are not limited to, azabicyclo[2.2. 1]heptanyl, azabicyclo|2.2.1.|octanyl, azetidiyl, hexahydro-lH-azepinyl, hexahydroazocm-(2H)-yl, indazohl, morpholinyl, octahvdroisoquinoline, piperazim 1, piperidinyl, pvridinyl, pyrrolidinyl, and thiomorpholinyl.
The heterocycles of the present invention are optionally with substituted with 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxv, alkoxyalkvl, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkvlcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkvl, halo, hydroxy, hydroxvalkyl, mercapto, nitro, piperidinyl, and oxo.
The term "hydroxy" as used herein, means an -OH group.
The term "hydroxyalkyl" as used herein, means at least one hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.

Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyi, 3-hydroxypropyl, 2,3-dihvdroxypentyl, and 2-cth\T4-hvdroxyheptvl.
The term "mercapto" as used herein, means a -SI 1 group.
The term "mercaptoalkyl" as used herein, means a mercapto group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of mercaptoalkyl include, but are not limited to, 2-mercaptoethyl and 3-mercaptopropyl.
The term "methylenedioxy" as used herein, means a -OCH,O- group wherein the oxygen atoms of the methyienedioxy are attached to the parent molecular moietv through two adjacent carbon atoms.
The term "nitro" as used herein, means a NO, group.
The term "nitrogen protecting group" as used herein, means those groups intended to protect an ammo group against undesirable reactions during synthetic procedures. Preferred nitrogen protecting groups are acetyl, benzoyl, benzyl, benzvloxycarbonyl (Cbz), formyl, phenylsulfonyl, tert-butoxycarbonyl (Boc), tert-butylacetyl, trifluoroacetyl, and triphenylmethyl (trityl). Methods describing how to introduce or remove such groups are outlined in Protecting Groups In Organic Synthesis, 3rd Ed. Theodora W. Greene and Peter CM. Wuts, John Wiley & Sons, Inc., or as known to one skilled in the art.
The term "oxo" as used herein, means =O.
The term "P-Z," as used herein, means a nitrogen protecting group, selected irom the group consisting of alkoxyalkyl, alkvlcarbonyl, alkoxycarbonvl, arvlalkyl, arylcarbonyl and arvloxvcarbonyl. Preferred P groups include but are not limited to alkvlcarbonyl, alkoxycarbonyl, arvlalkyl and aryloxvcarbonvl.
The term "RA," as used herein, means a substituent that is selected from the group consisting of hydrogen and alk\l.
The term "RB," as used herein, means a substituent that is selected from the group consisting of alkyl, aryl, and arvlalkyl.
The term "sulfonyl" as used herein, means a S(O)r group.
The term "ZAZBN-" as used herein, means two groups, ZA and ZB which are appended to the parent molecular moiety through a nitrogen atom. ZA and ZB are each independently selected from hydrogen, alkyl, alkvlcarbonyl, formyl, aryl and arylalkyl. Representative examples of" ZXZBN- include, but are not limited to, amino, methylammo, acetylamino, benzylamino, phenylamino, and acetylmethylamino.
The term "(ZAZBN,)alkyl" as used herein, means a ZAZBX- group, as defined herein,
appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (ZAZBN)alkyl include, but are not limited to, aminomethyl, 2-(methylamino)ethyl, 2-(dimethylamino)ethvl and (ethvlmethylamino)methyl.
The term "(ZAZBN)carbonyl" as used herein, means a ZAZBN- group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (ZAZBN)carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl and (ethylmcthylamino)carbonyl.
The term "(ZAZBN')carbonylalkyl " as used herein, means a (ZAZBN)carbonyl group, as defined herein, appended to the parent molecular moiety" through an alkvl group, as defined herein. Representative examples of (ZAZBN)carbonvlalkvl include, but are not limited to, (aminocarbonyl)methyl, 2-((methylamino)carbonyl)ethyl and ((dimethylamino)carbonyl)methyl.
The term "(ZAZBN)sultonyl as used herein, means a ZXZ,BN group, as defined herein, appended to the parent molecular moietv through a sulfonyl group, as defined herein. Representative examples of (ZAZBN)sulfonyl include, but are not limited to, aminosulfonyl, (methylamino)sulfonyl, (dimethylamino)sultonyl and (ethylmethvlamino)sulfonyl.
The term " Zc ZDN-" as used herein, means two groups, ZCand ZD, which are appended to the parent molecular moietv through a nitrogen atom. ZC and ZD are each independently selected from hydrogen, alkyl, alkylcarbom 1, formyl, aryl and arvlalkyl. Representative examples of ZCZDN- include, but are not limited to, amino, methylammo, acetylamino, benzylamino, phenylamino, and acetvlmethylamino.
The term "(Zc ZDN)alkyl" as used herein, means a -NZCZD group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (ZCZnN)alkyl include, but are not limited to, aminomethyl, 2-(methvlammo)ethyl, 2-(dimeth\iamino)ethvl and (ethvlmethylamino)methyl.
The term "(ZrZDN)carbonvl" as used herein, means a ZCZDN- group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (ZcZDX)carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbon\ 1 and (ethvlmethylamino)carbonyl.
The term "(ZCZDN)carbonylalkyl " as used herein, means a (ZCZDN)carbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (ZCZDN)carbonylalkyl include, but are not limited to, (aminocarbonyl)methyl, 2-((methylamino)carbonyl)ethyl and ((dimethylamino)carbonvl)methyl.
The term "(ZCZDN)sulfonyl" as used herein, means a ZC-ZDN- group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of (ZcZnN)sultonyl include, but are not limited to, aminosulfonyl, (methylamino)sulfonyl, (dimethylamino)sulfonyl and (ethylmethylamino)sulfonyl.
Compounds of the present invention were named h\ ACD/ChemSketch version 5.0 (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada) or were given names that appeared to be consistent with ACD nomenclature.
Schemes
The compounds of the invention can be better understood in connection with the following synthetic schemes and following methods that illustrate a means bv which the compounds can be prepared.
Abbreviations which have been used in the descriptions of the schemes and the examples that follow are: DMK tor 1,2-dimethoxvethane or ethylene glycol dimethyl ether, DMF for N,N-dimethylfotrnamide, DMSO for dimethyl sulfoxide, I.DA tor lithium diisopropylamide which can be prepared by the slow addition of 2.5 X butyllithium in hexanes to a solution ot diisopropylamine in THF' between 0 °C and -75 0C, MTBE for methvl tert-butylether, THF for tetrahydroturan, rt tor "room temperature" or ambient temperature suitably ranging from about 20 0C to about 30 0C
(Formula Removed)
As shown in Scheme 1, halofluorobenzene, wherein the halo ot halofluorobenzene, Y, is either chloro or bromo, when treated with base including, but not limited to, lithium
diisopropylamide (1 .DA), lithium dicyclohexyamidc or an equivalent as known to one skilled in the art, in a solvent such as but not limited to tetrahydroturan, methyl tert-butyl ether or ciiethyl ether, between the temperature of about -50 "C to about -78 0C for about 1 to about 3 hours; followed by treatment with compounds of formula R1C(=O)-X, wherein R1 is hydrogen, alkenyl or alkyl, and X is chloro, (CH,)2N, phenoxy, or nitrophenoxy, will provide compounds of formula 1. In the instance where X is (C113)2N-, the workup is generally accompanied by the addition of an acid such as acetic acid or a dilute aqueous mineral acid. More preferred conditions include, the use of lithium diisopropylamide in tetrahydroturan at a temperature between about -70 0C to about -78 °C for about 1 hour, followed by the addition of R1C(=O)-X, followed by the addition of an acid such as acetic acid or a dilute acjueous mineral acid, allowing the mixture to come to ambient temperature, followed by partitioning between an aqueous and organic solvent, followed bv separation of the organic solution and concentration. Compounds of formula 1 when treated with anhydrous hydrazine, or hydazine hydrate under heated conditions will provide indazoles of formula 2. Conditions for the cyclization include heating to between about 50 "C to about 100 "C, a mixture of the compound of formulal_ with anhydrous hydrazine or hydrazine hydrate in a solvent including but not limited to DMP, DM SO or THF. Alternatively, compounds of formula 1 containing a hydrogen atom in the R1, may be complexed with hydroxylamine or O-alkylated hydroxylamine to form the corresponding oxime. The oxime may stabilize the formyl group of compounds of formula 1. The oxime may be utilized directly, to form the indazole by heating in the presence of hydrazine to provide compounds of formula 2. Compounds of formula 2 when treated with reagents which will react with nitrogen atoms to protect them from further reactions, for example P-Z, which include acetyl chloride, acetic anhydride, benzyl chlorotormate, di-tert-butyl dicarbonate or 9-fluorenylmcthyl chloroformate, wall provide either the compound of formula (3), the compound of formula (4) or a mixture of both the compound of formula (3} and the compound of formula (4) depending on the conditions utilized. Often a mixture containing a majority of one product versus the other may be obtained, which can be further purified to isolate one compound from the other or at least obtain a mixture which has been enriched in one of the compounds. A preferred protecting group for the nitrogen atom of the compounds of formula 2 is benzyl or a substituted benzyl (F, OMe etc.). Compounds of formula 2 when treated with benzyl bromide under specific heated conditions will provide high yields ot either compound of formula 3 or compound of formula 4, wherein P is benzyl, depending on conditions utilized. Recrystalization of the mixtures of products will reduce the quantity of the one of the
compounds to provide a highly enriched or pure sample of the either the N-l protected isomer (compound of formula 4) or X-2 protected isomer (compound of formula 3), depending on the conditions and product desired. In general, the compound of formula 4 is obtained by heating the mixture of compound of formula 2 with benzyl bromide to the temperature between about 105 "C to about 115 0C for between 20 -24 hours, whereas the compound of formula 3 is obtained by heating the mixture of compound of formula 2 with benzyl bromide to the temperature between about 50 0C to about 60 "C for about 20-24 hours. The reaction is typically conducted in a solvent such as but not limited to DM1;.
(Formula Removed)
Similarly, compounds of formula 7 and 8 can be obtained according to Scheme 2. The use of N,N-dimethyl formamide as the compound of formula R1C.(=O))-X, followed bv an acidic workup, such as stirring in the presence of acetic acid will provide the compound of formula 1, wherein the R, group is formyl. When halofluorobenzenc, wherein the halo Y is chloro or bromo, is treated with IDA, followed bv the addition of DM1.;, optionally followed by an acidic workup will provide compounds ot formula 5. Compounds ot formula 5 when treated with hydrazine hydrate under heated conditions will provide mdazoles of formula 6. Alternatively, compounds of formula 5 when treated with hydroxvlamme or O- substituted hydroxylamine will provide the corresponding oxime, which may be then treated with hydrazine under heated conditions will provide indazoles of formula 6. Compounds of formula 6 when treated with benzyl bromide under specific heated conditions, as outlined in Scheme 1, will provide high yields of either compound of formula 7 or compound of formula
8 depending on conditions. Recrystalization of the products will reduce the quantity of the undesired isomers depending on the conditions and product desired.
(Formula Removed)
As outlined in Scheme 3, compounds of' formula 9, wherein R1, R10 R11 and R12R9, Rl0 R11 and R12 are each independentyl selected from the group consisting of hydrogen, alkenvl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkvl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, aryl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, heteroaryl, heterocycle, hydroxy, hydroxyalkvl, mercapto, mercaptoalkyl, nitro, (CF3)2(HO)C-, RBSO)2RAN-, RAO(SO)2 , RBO(SO)2-, ZAZBN-, (ZAZBN)alkyl, (ZAZBN)carbonyl, (ZAZBN)carbonylalkyl, and (ZAZBN)sulfonyl, which are made according to the procedure previously reported in US 2005/0043351.A1, when treated with phenyl carbamate or a similar reagent will provide compounds of formula 10. Preferred conditions include the treatment of compounds of formula 9 with phenyl carbamate in the presence of a base such as but not limited to triethylamine, diisopropylethylamme, N-methyl morpholine, sodium carbonate or potassium carbonate in a solvent such as but not limited to THF, acetonitnle or DMF'. More preferred conditions are when a mixture ot a compound ot formula 9, phenyl carbamate and diisopropylethylamine are refluxed together in THF tor between about 2 hours to about 10 hours.
(Formula Removed)
As shown in Scheme 4, the treatment of a mixture or'a compound of formula H),, a base consisting or potassium phosphate, potassium carbonate or cesium carbonate and a compound of formula 3, a compound of formula 4 or a mixture or both, wherein Y is chloro or bromo, in the presence of a catalyst prepared from a palladium compound, preferably palladium acetate or Pd,(DBA), and a phosphine based Itgand, including but not limited to Xantphos, 2-di-t-butylphosphino-l-1-binaphthvl, 5-(di-t-butylphosphanyl)-l',3',5'-triphenyl-1'H-[1,4']bipyrazolyl, will provide either the compound or formula11, the compound of formula 12, or a mixture of both compounds of formula 11. and compound of formula 12. The reaction is usually conducted in a solvent such as but not limited to ethylene glycol dimethyl ether. Preferably, the reaction is carried out using cesium carbonate as the base and heated to reflux for about 3 to about 20 hours. More preferably, the reaction is heated to reflux for 5-10 hours. The reaction may be filtered to remove insoluble material to simplify the isolation of the product, and often following concentrating the volume of the mixture under reduced pressure, the product may be isolated following dilution with another solvent such as hexane, heptane and the like followed by filtration of the compounds of formula 11 and/or 12.
(Formula Removed)
As shown in Scheme 5, either the compounds of formula H, the compounds of formula 12 or a mixture ot both when treated according to conditions known to remove the nitrogen protecting group, or as outline in Protecting Groups In Organic Synthesis, 3rd Ed. Theodora W. Greene and Peter G.M. Wuts, John Wiley & Sons, Inc., will provide the compound of formula 13 which is representative of compounds of formula (I). For example, when the protecting group is benzyl, the removal may be effected by treatment with a palladium catalyst in the presence of a hydrogen donor comprising an atmosphere ot hydrogen, formic acid, or cyclohexadiene in a solvent comprising alcoholic solvents, tetrahydroturan or ethyl acetate; to provide the compound of formula13. Examples of palladium catalyst include but are not limited to 5-20 % palladium on carbon, palladium hydroxide or palladium on barium sulfate. Typical solvents include methanol, ethanol, te trahydrofuran, ethyl acetate and the like. Often acetic acid may be utilized to increase the rate of reaction. Preferably, 20% palladium hydroxide and formic acid in tetrahydrofuran effects the transformation. More preferably, the heating of the compounds of formula .11 and/or 12 in the presence of 20% palladium hydroxide and formic acid in tetrahydrofuran to 60 °C for about 1-5 hours will provide the compound of formula 13.
Examples
The following Examples are intended as an illustration of and not a limitation upon the scope of the invention as defined in the appended claims.
(Formula Removed)
Example 1 2-Bromo-6-fluorobenzaldehyde l-Bromo-3-fluorobenzene (17.3 g, 0.1 M) was added over 5 minutes to a solution of lithium diisopropylamide (prepared from 11.5 g, 0.1 IY1 diisopropylamine and 40 ml., 2.5 X butyllithium in hexanes) in THF between -70 and -75 0C .After stirring for 1 hour at - 75 °C, DMF (8 ml.) was added to the mixture over 10 minutes. The stirring was continued cold for additional 40 minutes atter which the mixture was quenched by addition or acetic acid (26 g). The mixture was allowed to warm to ambient temperature and transferred into the mixture of 200 mL MTBK, 200 ml, water and 150 ml. hydrochloric acid (~- 4 X). The organic layer was separated and concentrated in vacuo to provide the desired bromofluorobenzaldehyde (19.2 g, 95 %): 1H XMR (CDC1,, δ, ppm) 7.14 (t, 1H,.J = 7.6 I Iz), 7.39 (m, 111), 7.48 (d, 1H, J= 7.5 Hz), 10.34 (s, 111).
(Formula Removed)
Example 2 4-Bromoindazole Direct preparation.
To a stirred solution of bromofluorobenzaldehvde (20.3 g, 0.1 mol) in DMSO (20 ml.) at room temperature is added hydrazine monohvdrate (100 mL) while maintaining the internal temperature less than 35 °C. The mixture is then heated to 70 -750C tor 22 hours after which the internal temperature is adjusted to 25 0C. The mixture was diluted with water (125 ml.) followed by heptanes (25 ml.) while maintaining the internal temperature less than 40 "C. The mixture was stirred at ambient temperature for 1 hour and the product slurry was filtered to collect the solids. The wet cake was washed with 4:1 HO)/MeOH (2 x 20 ml.), then dried at 50 0C in a vacuum oven to provide 14.7 g (75 %) of the titled compound: 1H XMR (DMSO-d6, δ, ppm) 7.28 (t, 1H, J= 7.6 Hz), 7.34 (d. 1H.J = 7.4 Hz), 7.59 (d. 1H,J= 7.5 Hz), 8.05 (s, 1H), 13.46 (s, 111, -Ml).
Preparation via oxime intermediate.
Hydroxvlamine (50 % in water, 7 g, O.lmol) was added to a solution of bromofluorobenzaldehyde (20.3 g, 0.1 mol) in dioxane (50 mL) while maintaining an internal temperature less than 30 °C After 30 minutes, hydrazine monohvdrate (50 ml,) was added to the mixture and the mixture was heated to reflux (85°C) for 24 hours. The mixture was cooled to 25 0C and concentrated under reduced pressure to a volume of about 50 ml.. The mixture was diluted with water (100 mL) while maintaining the internal temperature less than 40 °C. The mixture was stirred at ambient temperature for at least 1 hour. The product slurry was filtered to collect the solids. The wet cake was washed with 4:1 H2O/MeOH (2 x 20 mL), dried in at 50 °C in a vacuum oven to provide 14.9 g (76 %) of the titled compound.
(Formula Removed)
i Lxample 3 4-Chloroindazolc 4-Chloromdazole could be prepared according to the procedure of Lxample 2 substituting 2-chloro-6-fluorobenzaldehyde tor 2-bromo-6-fluorobenzaldehyde as a starting material. Isolated yield 70 - 74 %: '] 1HNMR (CDCl3, δ ppm) 7.15 (d, 111,.J= 7.4 Hz), 7.30 (t, 1H,J= 7.6 Hz), 7.40 (d, 1H,J= 7.5 Hz), 8.16 (s, 1H), 10.61 (s. 111, -NH).
(Formula Removed)
Example 4 2-N-bcnzyl-4-bromoindazolc. 4-Bromoindazolc of Example 2 (17.4 g, 0.088 M), benzyl bromide (22.7 g, 0.132 M) and DML (35 ml,) were heated to about 50 °C for 25 hours (HPLC: 15:1 ratio of 2-N and 1-N isomers). The mixture was cooled to ambient temperature and diluted with ethyl acetate (160 mL) and water (100 ml.). The organic layer was separated, washed with aqueous sodium bicarbonate (5 %, 100 mL ). The organic layer was separated and concentrated under reduced pressure. The residue was diluted with isopropanol (160 mL) and concentrated under reduced pressure to a volume of about 120 mL. The mixture was heated to 50 0C to dissolve
the solid and diluted with water (70 ml) to precipitate the product. The slum was cooled to 0 °C and the precipitate was filtered off. The solid was washed with a mixture of IPA and Water (1: 1, 50 mL), and dried at 50 0C to provide the titled compound (16.5 g, 77 %, which contained less than 2% of EN-isomer by HPI.C): 1H NMR (CDC1,, δ, ppm) 5.56 (s, 2 H), 7.11 (m, IN), 7.21 (d, J= 7.2 11/., 1 11,), 7.24 - 7.39 (m, 5 11), 7.65 (d, J=■■ 8.6 1 lz, 1H), 7.88 (s,lH).
(Formula Removed)
Example 5 2~N-benzyl-4-chloromdazole. 2-N-benzyl-4-chloroindazole is prepared according to the procedure of Example 4 bv substituting Example 3 for Example 4 (62 % yield), 1HNMR (CDCI;, δ, ppm) 5.69 (s, 2 11), 7.06 (d, J= 7.3 1 lz 1H), 7.21 (d,d J= 7.2, 8.6 I lz, 111,), 7.30 - 7.40 (m, 5 11), 7.62 (d, J= 8.6 Ilz, 111), 7.95 (s, 111).
(Formula Removed)
Example 6 1 N-benzyl-4-bromoindazole 4-Bromoindazole of Example 2 (14.8 g, 0.075 M), benzyl bromide (14.8 g, 0.086 M) and DMF (30 ml.) were heated to 110 °C for 22 hours (HPI.C: 19:1 ratio of 1-N and 2-N isomers). The mixture was cooled to ambient temperature and diluted with ethyl acetate (75 ml.), heptanes (75 ml.) and water (75 ml). The organic layer was separated and washed with aqueous sodium bicarbonate (5 %, 75 ml.). The organic layer was separated and concentrated under reduced pressure. The residue was dissolved in methanol (100 ml.) and the product was precipitated with water (100 ml.). Filtration and drying under reduced pressure at 50 °C provided the 1- N isomer (15.0 g, 70 %, less than 5 % of 2-N isomer by HPLC):1HNMR (CDCl3 δ, ppm) 5.56 (s, 2 11), 7.10 - 7.18 (m, 3H), 7.23 ■- 7.32 (m, 511), 8.04 (s, 1H).
(Formula Removed)
Example 7 l-N-benxyl-4-chloroindazole. l-N-benzyl-4-chloroindazole is prepared according to the procedure of Example 6 by substituting Example 3 for Example 2 (68 % yield), 1HNMR (CDC13, δ, ppm) 5.58 (s, 2H), 7.07 - 7.14 (m, 1 H) 7.15 - 7.20 (m, 2H), 7.20 - 7.33 (m, 5 H), 8.1 1 (s, 1 H)
(Formula Removed)
Example 8 (R)-l-(5-tert-butyl-2.3-dihydro-1H-indan- l-yl)urea t-Butyl-indanylamine tosylate (26.5 g, 0.072 M) (as previously reported in US 2005/0043351 Al), phenylcarbamate (9.57 g, 0.07 M) and dusopropylethylatnme (9.9 g, 0.076 M) in THF- (70 ml.) were heated to reflux for 15 hours. 'The mixture was cooled to ambient temperature, diluted with water (140 ml). The product was filtered ott and washed with water (100 ml). Drying under reduced pressure at 50 0C- 60 0C provided the titled compound (14.7 g, 88%): 1H NMR (DMSC)-d6 δ, ppm) 1.26 (s, 9H), 1.66 (m, 1H), 2.35 (m, 1 11), 2.73 (m, 111), 2.86 (m, 1 11), 4.99 (q, / - 7.9 Hz, 1H). 5.4 1 (s, 2 H), 6.21 (d, J= 8.4 Hz, 1H),7.13 (d,/= 8.0 Hz, 111), 7.19-7.23 (m, 211).
(Formula Removed)
Example 9 (R) l-(2- -benzyl-2H l-indazol-4-yl)-3-(5-tert-butyl-2.3-dihydro- lH-indan-1 -yl)urea A solution of 2-N-benzylbromoindazole, Example 4 ( 5.0 g, 17.4 mmol) in DIME (65 ml.) was added to a mixture of mdanylurea (3.6 g, 15.5 mmol), cesium carbonate (7.5 g), Pd,(DBA), (0.23 g) and Xantphos (0.42 g). The mixture was evacuated and purged with
nitrogen two times and then refluxed for 5 hours. The mixture was cooled to 70 °C and filtered hot, the solids were washed with hot DMK (50 ml.). Combined filtrates were concentrated under reduced pressure to about a volume of 50 ml. and the product was precipitated by addition ot heptane (80 ml,). The mixture was filtered, and the wet cake was slurried in ethanol (25 mL). The product was collected bv filtration and dried under reduced pressure to provide 5.3g (70 %) of the titled compound: 1HNMR (DMSO-d6, δ, ppm) 1.27 (s, 9H), 1.80 (m, 1H), 2.44 (m, 1 H), 2.80 (m, 1H), 2.93 (m, 1 H), 5.13 (q, J= 7.9 Hz, 1H), 5.64 (s, 2 H), 6.53 (d, J= 8.4 Hz, 1H), 7.09 - 7.15 (m, 211), 7.23 (s, 2H), , 7.28 - 7.37 (m, 5H), 7.50 (d, J= 6.6 Hz, 1H), 8.23 (s, 1H), 8.43 (s. 1H).
(Formula Removed)
Kxamplc 10 An alternatiye method of obtaining (R)-l-(2-bcnzyl-2l l-indazol-4-yl)-3-(5-tcrt-butyl-2.3-dihydro-1H-indan-l-yl)urea prepared from 2-N'-ben/ylchloroindazole In a pressure reactor palladium acetate (29 mg) and 2-di-t-butylphosphino-1-1'-binaphthyl (102 mg) were mixed in dichloromethane (14 ml) at 85°C tor 30 mm under inert atmosphere. Atter the solvent removal by evaporation the reactor was charged with 2-X-benzyl-4-chloroindazole, Kxample 5 ( 1.14 g, 4.7 mmol), potassium phosphate (1.36 g ,1.5 eq.), indanylurea (1.0 g, 0.9 eq.), and DME(15 ml.) The mixture was evacuated and purged with nitrogen and then heated at 85 °C tor 18 hours. The mixture was cooled to 70 0O, diluted with DME (50 ml.) and filtered hot, the solids were washed with hot DMK (50 ml.). Combined filtrates were concentrated under reduced pressure to about a volume ot 14 ml, and the product was precipitated by addition of heptane (22 ml.). The product was collected by filtration and dried under reduced pressure to provide 1.6g (85 %) ot the titled compound. '3
(Formula Removed)
Kxample 11 (R)-l-(l-benzyl-H:l-indazol-4-yl)-3-(5-tcrt-butyl-2.3-dihydro-lH-indan-2-yl)urea The titled compound was prepared according to the procedure outlined in Example 9, substituting KN-benzyl-4-bromoindazole for 2-N-benzylbromoindazole (60 % yield). 1H NMR (CDCl3 δ, ppm) 1.29 (s, 9H), 1.80 (m, 1H), 2.63 (m, 1 H), 2.83 (m, 1H), 2.92 (m, 1 H), 5.25 (d, J = 8.3 Hz, 1H), 5.40 (q, J= 7.9 Hz, 1H), 5.55 (s, 2 H), 6.80 (s, 1H), 7.07 (d, J= 7.7 1 lz, 1H), 7.15 - 7.29 (in, 9f I), 8.02 (s, 1 H),.
(Formula Removed)
Eample 12 l-((R)-5-tert-butyl-23-dihydro-lH-inden-1-yl)-3-(3a,7a-dihydro-lH-indazol-4-yl)urea
Kxample 10 (3.0 g), 20% palladium hydroxide on carbon (1.5 g) and formic acid (10 ml.) were mixed in THF (100 ml.) at 60 °C under nitrogen atmosphere for 3 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was combined with ethanol (50 ml.) and activated carbon (0.5 g). The mixture was refluxed for lhour, then filtered. The filtrate was concentrated a volume of 23 ml. under reduced pressure and the product was precipitated by the addition of water (8.6 mi,). The title compound was filtered and dried to 1.91 g (80% yield).
Alternatively, the title compound could be prepared according to the procedure outlined in Eample 12 substituting Eample 11 for Eample 9.

What is claimed is
1. A process for preparing a compound having structural formula (I),
(Formula Removed)
wherein, R1 is selected from the group consisting or hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonvloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF3)2(HO)C-, RB(SO)2RAN-, RAO(SO)2-, RBO(SO)2-, ZAZBN-, (ZAZBN)alkyl, (ZAZBN)carbonyl, (ZAZBN)carbonyIalkyl, and (ZAZBN)sulfonyl;
R9, R10, R11, and R12 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonvloxy, alkylthio, alkynyl, aryl, carboxy, carboxyalkyl, cyano, cyanoalkvl, formy], formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, heteroaryl, heterocycle, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF3)2(HO)C-, RB(SO)2RAN-, RAC)(SC))2, RBC)(SO))2-, ZAZBN-, (ZAZBN)alkyl, (ZAZBN)carbon\i, (ZAZBN)carbonylalkvl, and (ZAZBN,)sulfonyl;
RA is hydrogen or alkyl;
RB is alkyl, aryl, or arylalkyl; and
ZA and ZB are each independently hydrogen, alkyl, alkylcarbonyl, formyl, aryl, or arylalkyl, comprising the steps of:
(a) heating a mixture ot a compound of formula (111), a base selected from the group consisting ot sodium hydroxide, potassium phosphate and cesium carbonate, and a composition consisting of a compound of formula (Ha), a compound of formula (IIb) or a
mixture thereof, wherein P is selected from the group consisting of alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, arylalkyl, arylcarbonyl and aryloxycarbonyl, R1 is defined under the compound of formula (I) and Y is chloro or bromo, in the presence of palladium catalyst and a phosphine based ligand,
(Formula Removed)
to provide a composition consisting or a compound or" formula (I Va), a compound of formula (IVb) or a mixture thereof, wherein R1, R9, R10, R11, and R12 are defined under the compound of formula (1),
(Formula Removed)
followed by
(b) treating the composition consisting of the compound of formula (lVa), the compound of formula (IVb) or the mixture thereof, to conditions that will provide the compound of formula (I).
2. The process according to claim 1, wherein
the palladium catalyst of step (a) consists ot palladium acetate or Pd2(DBA),.
3. The process according to claim 2, wherein step (a) is carried out in an inert atmosphere.
4. The process according to claim 3, wherein
the phosphine based ligand, is selected from the group consisting of Xantphos, 2-di-t-butylphosphino-l-l'-binaphthyl and 5-(di--t-butylphosphanyl)-r,3',5'-triphenyl-l'H-[1,4']bipyrazolyl.
5. The process according to claim 4, wherein
Y is bromo;
the palladium catalyst is Pd,(DBN)2; and the base of step (a) is cesium carbonate.
6. The process according to claim 5, wherein
the mixture of step (a) is heated to reflux for 2-10 hours in ethylene glycol dimethyl ether.
7. The process according to claim 6, wherein
P is benzyl, and
the conditions of step (b) further comprise:
treatment with palladium catalyst in the presence of a hydrogen donor selected from the group consisting of an atmosphere of hydrogen, formic acid, and cyclohexadiene in a solvent selected from the group consisting of an alcoholic solvent, tetrahvdroturan and ethyl acetate, to provide the compound of formula (1).
8. The process according to claim 1, wherein
Y is bromo;
the palladium catalyst of step (a) is Pd2(DBA2;
step (a) is carried out under an atmosphere of nitrogen;
the phosphine based ligand is Xantphos;
the base ot step (a) is cesium carbonate;
the mixture is heated to reflux for 5 hours;
the mixture is cooled to about 70 0('., then filtered;
the filtrates reduced in volume under reduced pressure;
to the filtrates is added heptane;
the formed precipitate is filtered to provide the composition consisting of the compound ot tormula (lVa), the compound ot formula (IVb) or the mixture thereof; and
treatment ot the composition consisting of the compound of formula (IVa), the compound of formula (IVb) or the mixture thereof, with 20 % palladium hydroxide and formic acid in a tetrahvdroturan to a temperature ot about 60 0C for about 3 hours, followed by filtration and concentration under reduced pressure to provide the compound of formula (I)-
9. The process according to claim 4, wherein
Y is chloro;
the palladium catalyst is palladium acetate; and the base of step (a) is potassium phosphate.
10. The process according to claim 9, wherein
the mixture ot step (a) is heated to reflux for 5-20 hours in ethylene glycol dimethyl ether.
11. The process according to claim 10, wherein
P is ben/vl, and
the conditions ot step (b) comprise:
treatment with palladium catalyst in the presence ot a hydrogen donor selected from the group consisting ot an atmosphere of hydrogen, formic acid, and cyclohexadiene in a solvent selected from the group consisting of an alcoholic solvent, tetrahvdrofuran and ethyl acetate, to provide the compound of formula (1).
12. The process according to claim 1, wherein
Y is chloro;
the palladium catalyst is palladium acetate;
step (a) is carried out under an atmosphere of nitrogen;
the phosphine based ligand, is 2-di-t-butvlphosphino-l-r-binaphthyl;
the base of step (a) is potassium phosphate;
the mixture is heated to reflux for 5 -20 hours;
the mixture is cooled to about 70 0C, then filtered;
the filtrates reduced in volume under reduced pressure;
to the filtrates is added heptane;
the formed precipitate is filtered to provide the composition consisting of the compound ot formula (IVa), the compound ot formula (I Vb) or the mixture thereof; followed by
the treatment of the composition consisting of the compound of formula (IVa), the compound of formula (1 Vb) or the mixture thereof, with 20 % palladium hydroxide and formic acid in a tetrahvdrofuran at about 60 '(". for about 3 hours, followed by filtration and concentration under reduced pressure to provide the compound of formula (I).
13. The process according to claim 1, wherein the composition consisting or" the compound of formula (IIa), the compound of formula (lIb), or a mixture thereof,
(Formula Removed)
are prepared comprising the steps of:
(a) treating a compound of formula (V), wherein the Y is chloro or bromo, with an
lithium reagent;
followed by
(b) treating the mixture with a compound of formula R1C(=O)-X, wherein R1 is
hydrogen, alkenyl or alkyl, and X is chloro, (C11,)2N-, phenoxy, or nitrophenoxy, to provide a
compound of formula (VI),
(Formula Removed)
followed by
(c) treating the compound of formula (VI) with hydrazine under heated conditions to
provide the compound of formula (VII),
(Formula Removed)
followed by
(d) treating the compound of formula (All) with a compound of formula P-Z wherein P is
selected from the group consisting of alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, arylalkyl,
arylcarbom 1 and aryloxvcarbonyl, to provide the composition consisting of the compound of
formula (IIa), the compound of formula (IIb) or a mixture of the compound of formula (I I a)
and the compound of formula (IIb),
(Formula Removed)
14. The process according to claim 13, wherein
step (a) comprises treating meta-bromofluoroben/ene with lithium diisopropylamide in THF between about —70 0(.'. and about -75 0('. tor about 1 hour.
15. The process according to claim 14, wherein
R1C(O)-X of step (b) is DMF; and
step (b) comprises the addition ot DM1 over the period of about 5 minutes to about 15 minutes; followed by the continued cold stirring of the mixture for the period of between about 30 minutes to about 1 hour; followed by the addition of acetic acid; followed by allowing the mixture to warm to ambient temperature; followed by diluting with a solvent comprising methvl tert-butyl ether or ethyl acetate followed by aqueous acid extraction; followed bv concentration to provide the compound of formula (VI), wherein R1 is hydrogen.
16. The process according to claim 15, wherein
step (c) comprises the addition ot hydrazine to a solution ot the compound of formula (VI) in DMSO while maintaining the internal temperature less than 35 0C, followed by heating the mixture to between about 70 "(7 and about 75 °C tor about 18 to about 24 hours after which the internal temperature is cooled to about 25 0C7 followed by diluting the mixture with water followed by heptanes while maintaining the internal temperature less than 40 °C; followed by stirring the mixture for about lhour, followed bv filtration to provide the compound of formula (VII), wherein R1is hvdrogen.
17. The process according to claim 16, wherein
the conditions of step (d) further comprise heating and stirring the mixture of the compound of formula (VII), wherein R1 is hvdrogen, and benzyl bromide in N,N-dimethyl formamide to a temperature of about 40 0C to about 120 (7 for the period of between about 4 hours and about 30 hours to provide the composition consisting of the compound, ot formula (IIa), the compound of formula (IIb) or a mixture thereof,
(Formula Removed)
18. The process according to claim 1", wherein
the conditions of step (d) further comprises heating and stirring the mixture of the compound of formula (VII) and benzyl bromide in N,N-dimethyl formamide to a temperature of about 105 0C', to about 115 0C. tor a period between about 20 hours to about 24 hours, to proyide the compound of formula (I la,),
(Formula Removed)
19. The process according to claim 18, \\ herein
Y is bromo.
20. The process according to claim 18, wherein
Y is chloro.
21. The process according to claim 17 wherein
the conditions of step (d) further comprises heating and stirring the mixture of the compound of formula (VI) and benzyl bromide in N,N-dimethyl formamide to a temperature of about 50 "C to about 60 '(. tor a period between about 20 hours to about 24 hours to provide the compound of formula (IIb2)
(Formula Removed)
22. The process according to claim 21, wherein

Y is bromo.
23. The process according to claim 21, wherein
Y is chloro.
24. The process according to claim 1, tor preparing the compound of formula (III),
(Formula Removed)
wherein R9 R10 R11 and R12 are defined in claim 1 comprising;
treating a compound of formula (VIII) with phenyl carbamate and a base selected trom the group consisting of triethylamine, diisopropyicthylamine, \ methylmorpholine, cesium carbonate, sodium carbonate and potassium carbonate under heated conditions to provide a compound of formula (III),
(Formula Removed)
25. The process according to claim 24, wherein
the base is diisopropvletln famine; the mixture is heated to reflux for a period of between about 12 hours to about 18 hours, after which the mixture was cooled to about 25 0C, diluted with water and filtered to provide the compound or" formula (III).
26. A process for preparing the compound ot formula (IX),
(Formula Removed)
comprising the steps of:
(a) heating a mixture of a compound of formula (XI), Pd2(DBA)i, Xantphos, a base
selected from the group consisting of sodium hydroxide, potassium phosphate and cesium
carbonate and a composition consisting of a compound ot formula (Xa), a compound of
formula (Xb) or a mixture thereof,
(Formula Removed)
to provide a composition consisting of a compound of formula (XI la), a compound of formula (XIlb) or a mixture thereof,
(Formula Removed)
followed by
(b) treating the composition of the compound of formula (XI la), the compound of
formula (XIlb) or the mixture thereof, with a palladium catalyst selected from the group
consisting of palladium on carbon, palladium hydroxide and palladium on barium sulfate and
a hydrogen donor selected from the group consisting of an atmosphere of hydrogen, formic
acid, and cyclohexadiene in a solvent selected from the group consisting of an alcoholic
solvents, tetrahydrofuran and ethyl acetate, to provide the compound of formula (IX).
27. A process for according to claim 26, wherein
step (a) is carried out under an atmosphere of nitrogen;
the base of step (a) is cesium carbonate;
the mixture is heated to reflux for 5 hours;
the mixture is cooled to about 70 °C then filtered;
the filtrates reduced in volume under reduced pressure;
to the filtrate is added heptane;
the precipitate is filtered to provide the compound of formula (XI la), the compound of formula (XI lb) or the mixture thereof;
treatment of die precipitate is filtered to provide the compound of formula (XIIa), the compound of formula (XI lb) or the mixture thereof, with 20 % palladium hydroxide and formic acid in a tetrahydrofuran at about 60 0C for about 3 hours, followed bv filtration and concentration under reduced pressure to provide the compound of formula (IX).
28. A process tor preparing the compound ol formula (IX),

(Formula Removed)
comprising the steps ol":
(a) heating a mixture of a compound ot formula (XI), palladium acetate, 2-di-t-
butylphosphmo-1-1'-binaphthyl, a base selected from the group consisting ot sodium
hydroxide, potassium phosphate and cesium carbonate and a composition consisting of a
compound of formula (Xc), a compound of formula (Xd) or a mixture thereof,
(Formula Removed)
to provide a composition consisting ot a compound ot formula (XIIa), a compound ot formula (XIIb) or a mixture thereof, followed In
(b) treating the composition consisting of the compound of formula (XIIa), the
compound of formula (Xllb) or the mixture thereof, with a palladium catalyst selected from the group consisting of palladium on carbon, palladium hydroxide and palladium on barium sulfate and a hydrogen donor selected from the group consisting of an atmosphere of hydrogen, formic acid, and cyclohexadiene in a solvent selected from the group consisting of an alcoholic solvents, tetrahydrofuran and ethyl acetate; to provide the compound of formula (IX).
29. The process according to claim 28, wherein
step (a) is carried out under an atmosphere of nitrogen;
the base of step (a) is potassium phosphate;
the mixture is heated to reflux for 5-2(1 hours;
the mixture is cooled to about 70 0C then filtered;
the filtrates reduced in volume under reduced pressure;
to the filtrate is added heptane;
the precipitate is filtered to provide the compound of formula (XI Ic), the compound of formula (XI Id) or the mixture thereof;
treatment of the compound of formula (XI In), the compound of formula (Xllb) or the mixture thereof, with 20 % palladium hydroxide and formic acid in a tetrahydrofuran at about 60 0 C tor about 3 hours, followed by filtration and concentration under reduced pressure to provide the compound of formula (IX).
30. A composition, comprising the compound of formula (I la), the compound of formula
(lib), or the mixture thereof,
(Formula Removed)
wherein Y is bromo or chloro, R1 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxvcarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hvdroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF2)z(HO)C-, RB(SO)2RAN: -, RAO(SO)2, RB( )(SO)2-, ZAZBN (ZA,ZB\)alkyl, (ZAZBN)carbonyl, (ZAZB)carbonylalkyl, or (ZAZB')sulfonvl;
which arc useful in the process of preparing a compound of formula (I).
31. The compound of claim 30, useful in the process of preparing a compound of formula (I), which are useful for the treatment of a disorder by inhibiting vanilloid receptor subtype 1 in a mammal comprising administering a therapeutically effective amount of a compound of formula (1) or a pharmaceutical acceptable salt or prodrug thereof.
32. The compound of claim 31, wherein the disorder is selected from the group consisting oi pain, inflammatory hyperalgesia, urinary incontinence and bladder oyerreactivity.
33. A compound of formula (III),
(Formula Removed)
wherein R9, R10 R11 and R12 are each independenth selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkvlcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, aryl, carboxy, carbox\alk\i, cyano, cyanoalkyl, tormvl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, heteroar\i, heterocvele, hulroxv, h\dro\yalk\l, mercapto, mercaptoalkyl, nitro, ((CF,)2(HO))O-, RB(SO)2RAN , RAO(SO)2-, RB( )(SO),-, ZAZBN'-, (ZAZBN:)alk\l, (ZAZBN)carbonvl, (ZAZBN)carbonylalkyl, and (ZAZB)sultonyl;
which is useful in the process of preparing a compound oi formula (I).
34. The compound of claim 33, useful in the process of preparing a compound oi formula (1), which are useful for the treatment of a disorder by inhibiting \anilloid receptor subtype 1 in a mammal comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceuticals acceptable salt or prodrug thereof.
35. The compound of claim 34, wherein the disorder is selected from the group consisting of pain, inflammatory hyperalgesia, urinary incontinence and bladder oyerreactivity.
36. A composition comprising a compound of formula (Xa), a compound of formula
(Xb), or a mixture thereof,
(Formula Removed)
which is useful in the process of preparing a compound of formula (IX).
37. The compound ot claim 36, useful in the process of preparing a compound of formula (IX), which is useful for the treatment ot a disorder by inhibiting vanilloid receptor subtvpc 1 in a mammal comprising administering a therapeutically effective amount of a compound of formula (IX) or a pharmaceutical acceptable salt or prodrug thereof.
38. The compound of claim 37, wherein the disorder is selected from the group consisting of pain, inflammatory hyperalgesia, urinary incontinence and bladder overrcactivity.
39. A composition comprising a compound ot formula (Xc), a compound of formula (Xd), or a mixture thereof,
(Formula Removed)
which is useful in the process of preparing a compound of formula IX).
40. The compound of claim 39, useful in the process of preparing a compound ot
formula (IX), which is useful tor the treatment of a disorder by inhibiting vanilloid receptor
subtype 1 in a mammal comprising administering a therapeutically effective amount of a
compound ot formula (IX) or a pharmaceutically acceptable salt or prodrug thereof.
11. The compound of claim 40, wherein the disorder is selected from the group)
consisting ot pain, mflammaton hyperalgesia, urinary incontinence and bladder overreactivity.
42. A compound ot formula (XI),
(Formula Removed)
which is useful in the process or preparing a compound ot formula (IX).
43. The compound of'claim 42, useful in the process of preparing a compound of formula (IX), which is useful for the treatment ot a disorder by inhibiting vamlloid receptor subtype 1 in a mammal comprising administering a therapeutically effective amount of a compound of formula (IX) or a pharmaceuticals acceptable salt or prodrug thereof.
44. The compound of claim 43, wherein the disorder is selected from the group consisting of pain, inflammatory hyperalgesia, urinary incontinence and bladder overreactivity.