ZA200307095B - Pyrazole derivatives for treating HIV. - Google Patents

Pyrazole derivatives for treating HIV. Download PDF

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ZA200307095B
ZA200307095B ZA200307095A ZA200307095A ZA200307095B ZA 200307095 B ZA200307095 B ZA 200307095B ZA 200307095 A ZA200307095 A ZA 200307095A ZA 200307095 A ZA200307095 A ZA 200307095A ZA 200307095 B ZA200307095 B ZA 200307095B
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South Africa
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pyrazol
methyl
diethyl
dichlorophenoxy
alkyl
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ZA200307095A
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Jones Lyn Howard
Mowbray Charles Eric
Price David Anthony
Selby Matthew Duncan
Stuppel Paul Anthony
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Pfizer
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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

PYRAZOLE DERIVATIVES FOR TREATING HIV
This invention relates to pyrazole derivatives and to processes for the preparation thereof, intermediates used in their preparation of, compositions containing them and the uses of such derivatives.
The compounds of the present invention bind to the enzyme reverse transcriptase and are modulators, especially inhibitors thereof. Reverse transcriptase is implicated in the infectious lifecycle of HIV, and compounds which interfere with the function of this enzyme have shown utility in the treatment of conditions including AIDS. There is a constant need to provide new and better modulators, especially inhibitors, of HIV reverse transcriptase since the virus is able to mutate, becoming resistant to the effects of known modulators.
The compounds of the present invention are useful in the treatment of a variety of disorders including those in which the inhibition of reverse transcriptase is implicated. Disorders of interest include those caused by Human
Immunodificiency Virus (HIV) and genetically related retroviruses, such as
Acquired Immune Deficiency Syndrome (AIDS).
European patent application EP 0 786 455 A1 discloses a class of imidazole compounds which inhibit the growth of HIV. A class of N-phenylpyrazoles which act as reverse transcriptase inhibitors are disclosed in J. Med. Chem., 2000, 43, 1034. Antiviral activity is ascribed to a class of N-(hydroxyethyi)pyrazole derivatives in US patent number 3,303,200.
According to the present invention there is provided a compound of the formula
R* R \ : _/ . N
Rr? or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein: either R' is H, C4-Cs alkyl, Cs-C; cycloalkyl, phenyl, benzyl, halo, -CN, -OR’, {
-CO:R™, -CONR®R"’, R® or R’, said C4-Cs alkyl, Cs-C, cycloalkyl, phenyl and benzyl being optionally substituted by halo, -CN, -OR™, S(O),R°, -CO,R", -CONR’R", -OCONR®R', -NR°CO:R'", -NR'R"", -NR°COR'®, -SO,NR°R"°, -NR°CONR®R®, -NR°SO,R' or R'; and
R? is H, Ci-Cs alkyl, Cs-Cs alkenyl, Cs-Cs alkynyl, Cs-C, cycloalkyl, Ca-Cr cycloalkenyl, phenyl, benzyl, R? or R®, said C4-Cg alkyl, C3-C7 cycloalkyl, phenyl and benzyl being optionally substituted by halo, -OR®, -OR'?, -CN, -CO.R’, -OCONR’R’, -CONR®R®, -C(=NR®)NR°OR®, -CONR’NR°R®, -NR°R?, -NR°R™2, -NR°COR’, -NR°COR?, -NR°COR", -NR°CO,R’, -NR°CONR®R?®, -SO,NR°R®, -NR°SO:R®, -NR*SO,NR°R®, R® or R®; or, R' and R? when taken together, represent unbranched Cs-C, alkylene, optionally substituted by oxo, optionally wherein one methylene group of said Cs-
C4 alkylene is replaced by an oxygen atom or a nitrogen atom, said nitrogen atom being optionally substituted by R'°;
R%is H, C1-Cs alkyl, Ca-C; cycloalkyl, phenyl, benzyl, halo, -CN, -OR’, -CO,R°, -CONR’R®, R® or R®, said C4-Cs alkyl, Cs-C; cycloalkyl, phenyl and benzyl being optionally substituted by halo, -CN, -OR?®, -CO.R®, -CONR®R®, -OCONRR®, -NR°CO2R®, -NR°R®, -NR°COR®, -SO.NR°R®, -NR°CONR®R®, -NR°SO,R®, R® or
RY
R* is phenyl, naphthyl or pyridyl, each being optionally substituted by R®, halo, -
CN, C4Cs alkyl, Ci-Cg haloalkyl, C3-C; cycloalkyl, C-Cs alkoxy, -CONR°R®,
OR", So,R®, O-(C1-GCs alkylene)-CONR®R®, O-(C+-Cs alkylene)-NR°R®, or O-(Cs-
Cs alkylene)-OR; each R’ is independently either H, C4-Cs alkyl or Cs-C; cycloalkyl or, when two R® groups are attached to the same nitrogen atom, those two groups taken together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl or morpholinyl, said azetidinyi, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl and morpholinyl being optionally substituted by C,-Cs alkyl or ’ 35 C3-Cy cycloalkyl; each R’ is independently either H, C-Cg alkyl or C3-C7 cycloalkyl;
R” is C4-Cs alkyl or C4-C; cycloalkyl:
Fi
R? is a five or six-membered, aromatic heterocyclic group containing (i) from 1 to ] 4 nitrogen heteroatom(s) or (ii) 1 or 2 nitrogen heteroatom(s) and 1 oxygen or 1 sulphur heteroatom or (ii) 1 or 2 oxygen or sulphur heteroatom(s), said . 5 heterocyclic group being optionally substituted by halo, oxo, -CN, -COR®, -CONR’R®, -SO:NR°R®, -NR’SO,R®, -OR®, -NR°R®, -(C+-Cs alkylene)-NR°R®, C;-
Cs alkyl, fluoro(C4-Cg)alkyl or C5-C7 cycloalkyl;
R® is a four to seven-membered, saturated or partially unsaturated heterocyclic group containing (i) 1 or 2 nitrogen heteroatom(s) or (ii) 1 nitrogen heteroatom and 1 oxygen or 1 sulphur heteroatom or (iii) 1 oxygen or sulphur heteroatom, said heterocyclic group being optionally substituted by oxo, C-Cg alkyl, Cs-C; cycloalkyl, -SO;R®, -CONR’R®, -COOR?®, -CO-(C;-Cs alkylene)-OR® or -COR® and optionally substituted on a carbon atom which is not adjacent to a heteroatom by halo, -OR®, -NR°R®, -NR°COR?®, -NR*COOR?®, -NR*CONR’R?®, -NR°SO,R°® or -CN;
R' is H, R®, R®, R"®, C-Cs alkyl, Cs-C; cycloalkyl or ~(C1-Cs alkyl)-(Cs-C7 cycloalkyl), said C4-Cs alkyl and C3-C7 cycloalkyl being optionally substituted by -ORS, -OR", R®, R®, R"® or -COR'®;
R'" is H, C4-Cs alkyl or C3-C; cycloalkyl, said C-Cs alkyl and Cs-C; cycloalkyl being optionally substituted by -OR®, -NR°R®, -NR°COR®, -CONR®R®, R® or R®:
R'? is C1-Cs alkyl substituted by R®, R%, -OR®, -CONR®R®, -NR*COR® or -NR°R®;
R' is phenyl optionally substituted by halo, CN, -COR®, -CONR®R®, -SO,NR°R?, -NR°SO.R®, -OR®, -NR°R®, -(C+-Cs alkylene)-NR°R®, C4-C alkyl, halo(C+-Ce)alkyl or C3-C7 cycloalkyl; and xis0,1o0r2; with the proviso that (a) when R' and R® are both phenyl, R? is not methyl; and (b) when R' is ethoxy and R® is ethoxycarbonyl, R? is not phenyl.
In the above definitions, halo means fluoro, chloro, bromo or iodo. Unless otherwise stated, alkyl, alkenyl, alkynyl, alkylene and alkoxy groups containing the requisite number of carbon atoms can be unbranched or branched chain.
Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec- butyl and t-butyl. Examples of alkenyl include ethenyl, propen-1-yl, propen-2-yl, i propen-3-yl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl, 2- buten-2-yl, 2-methylpropen-1-yl or 2-methylpropen-3-yl. Examples of alkynyl include ethynyl, propyn-1-yl, propyn-3-yl, 1-butyn-1-yl, 1-butyn-3-yl, 1-butyn-4-yl, 2-butyn-1-yl. Examples of alkylene include methylene, 1,1-ethylene, 1,2- ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene and 1,3-propylene. ' Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i- butoxy, sec-butoxy and t-butoxy. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Where R' and R? are taken together, they form, along with the nitrogen atom and the carbon atom of the pyrazole ring to which they are attached, a 5- or 6-membered ring. Where a heterocyclic group R® or R® is attached to an oxygen, sulphur or nitrogen heteroatom the heterocyclic group R® or R® must be linked through a ring carbon atom. Further, where a heterocyclic group R® is attached to an oxygen, sulphur or nitrogen heteroatom the heterocyclic group R® must be linked through a ring carbon atom that is not adjacent to a ring heteratom.
The pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, para- toluenesulphonate and pamoate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples are the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine sals.
For a review on suitable salts see Berge et al, J. Pharm. Sci., 66, 1-19, 1977. ) The pharmaceutically acceptable solvates of the compounds of the formula (1) include the hydrates thereof. ) 35
Also included within the present scope of the compounds of the formula (I) are polymorphs thereof.
The compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds.
Examples of such derivatives are described in: Drugs of Today, Volume 19,
Number 9, 1983, pp 499 — 538; Topics in Chemistry, Chapter 31, pp 306 — 316; . 5 and in “Design of Prodrugs” by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference) and include: esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, sulphonamides, carbamates, azo-compounds, : phosphamides, glycosides, ethers, acetals and ketals.
A compound of the formula (I) may contain one or more asymmetric carbon atoms and therefore exist in two or more stereoisomeric forms. The present invention includes the individual stereoisomers of the compounds of the formula (1) together with, where appropriate, the individual tautomers thereof, and mixtures thereof.
Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or high performance liquid chromatography (HPLC) of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (1) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by HPLC of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
Preferably, R, when taken separately, is H, C;-Cs alkyl, C3-C7 cycloalkyl or OR’, said C4-Cs alkyl and C5-C; cycloalkyl being optionally substituted by halo, -CN, -OR™, S(0)R™, -CO.R', -CONR®R'’, -OCONR’R'’, -NR°CO,R", -NR'°R"", -NRP°COR'™, -SO.NR°R', -NR’CONR’R', -NR°SO.R" or R™.
Preferably, R', when taken separately, is H, C1-Cs alkyl, Cs-C7 cycloalkyl or -OR?, said C4-Cs alkyl being optionally substituted by halo, -OR™, -NR'R!', -NR°COR'® or R'.
Preferably, R', when taken separately, is H, C4-C4 alkyl, cyclopropyl, or -OCH,, said Cy-C, alkyl being optionally substituted by bromo, -OH, -O(C;-C; alkyl), -NR'°R"", -NHCOR" or R™,
Preferably, R', when taken separately, is H, -CHs, -CH2CHa, ~CH(CHa)s, ~C(CHs)s, cyclopropyl, -OCHs, -CH.OH, -CH2OCH3, -CH2OCH,CHa, -CH.Br, ~CHzNH,, -CH2NHCH3, -CHaN(CH),, -CHNHCHx(cyclopropyt),
-CH>NHCH,CH>0CHs3, -CHoNHCH>CHoNHCOCHS, -CH:NHCO(4-cyanophenyl), -CH2NHCO(3-cyanophenyl), -CH,NHCH;(4-cyanophenyl), ~CH,NHCH,(4- fluorophenyl), -CH,NHCH3(4-methoxyphenyl), -CH2NHCH2(4- aminosulphonylphenyl), -CH,NHCH,(4-aminocarbonylphenyl), -CH,NHCH.(pyrid- . 5 3-yb, -CH2N(CHj3)(4-cyanophenylmethyl), ~-CH2N(CH>CH,OH})(4- cyanophenylmethyl), 4-methoxypiperidin-1-yimethyl, 4-aminocarbonylpiperidin-1- ylmethyl, 4-methylcarbonylaminopiperidin-1-ylmethyl, piperazin-1-yimethyl, 4- methylpiperazin-1-yimethyl, 4-methylcarbonyipiperazin-1-yimethyl, 4- methoxymethylcarbonylpiperazin-1-ylmethyl, 4-methoxycarbonylpiperazin-1- yimethyl, 4-methylsulphonylpiperazin-1-ylmethyl, morpholin-4-yimethyl, 2- methylimidazol-1-yimethyl, pyrazol-1-ylmethyl or 1,2,4-triazol-1-yimethyi.
Preferably, R', when taken separately, is, -CHas, -CH2CHa, cyclopropyi, -CH,NHCH,(4-cyanophenyl), -CHaNHCH(4-fluorophenyl), -CHoNHCHx(4- methoxyphenyl), -CH:NHCHz(4-aminosulphonylphenyl) or -CH,NHCH,(4- aminocarbonylphenyl).
Preferably, R?, when taken separately, is H, C4-Cs alkyl, C3-Cs alkenyl or R°, said
C1-Cs alkyl being optionally substituted by halo, -OR®, -OR'2, -CN, -CO,R’, -OCONR’R®, -CONR’R®, -C(=NR®*)NR°OR®, -CONR°NR°R®, -NR°R®, -NR°R "2, -NR°COR’, -NR°COR’, -NR°COR'", -NR*CO,R®, -NR°*CONR’R®, -SO.NR°R®, -NR°SO,R®, R® or R®,
Preferably, R?, when taken separately, is H, C;-Cs alkyl, Cs-Cs alkenyl or R®, said
C4-Cs alkyl being optionally substituted by -OR®, -OR'?, -CN, -CO.R’, -CONR°R®, -C(=NR®)NR°OR®, -CONR®NRR’, -NR°R®, -NR°R'?, -NR°COR?®, -NR°COR'?, -NR°CO2R°, R®or R®.
Preferably, R?, when taken separately, is H, C-Cs alkyl, propenyl or R®, said C4-
C3 alkyl being optionally substituted by -OH, -OCHjs, -OCH,CH,NH,, -CN, -CO2CHs, -CO,CH,CHjs, -CONH,, -C(=NH)NHOH, -CONHNH,, -NH,, -NHCHj, -N(CH3)2, -NHCHCH,NHCOCH;, -NHCH,CH,OCH3, -NHCH,R®, -NHCORS®, -NHCOCH,OCH;z, -NHCO,C(CHs)s, R® or R®.
Preferably, R?, when taken separately, is H, methyl, -CH,CH=CH,, -CH-CN, -CH20CH3, -CH2CONH,, -CH,CONHNH;, -CH>CO,CHg, -CH.CO>CH-CHs, -CH2C(=NH)NHOH, -CH,CH,0OH, -CH2CH>0OCHS3;, -CH>CH,NHo, -CH2CH2NHCOCH,0CHs, -CH2CH2NHCO,C(CHj)s, 2-(pyrid-2- ) 35 ylcarbonylamino)eth-1-yl, 2-(pyrazin-2-ylcarbonylamino)eth-1-yl, -CH2CH20OCH,;CH,NH,, -CH,CH2NHCHs, -CH2CH2N(CHg),, -CH,CHNHCH,CH2NHCOCHS;, -CHCH,NHCH,CH,OCHa, -CH,CH(OH)CHj;, (3-hydroxypyrazol-5-yl)methyl, 2-hydroxy-1,3,4-oxadiazol-5- yimethyl, 2-amino-1,3,4-oxadiazol-6-yl, 5-hydroxy-1,2,4-oxadiazol-3-yimethyl, 6- i hydroxy-2-methylpyrimidin-4-yimethyl, 6-hydroxy-2-aminopyrimidin-4-ylmethyl, 2- (morpholin-4-yl)eth-1-yl, 2-(4-methylcarbonylpiperazin-1-yl)eth-1-yl, morpholin-3- ylmethyl, (2-(tetrahydrofuran-2-ylmethylamino)eth-1-yl, 1-methylazetidin-3-yl or azetidin-3-yl.
Preferably, R?, when taken separately, is H, -CH,CH,OH or -CH;CH,NH,
Preferably, R' and R? when taken together, represent unbranched C;-C, alkylene, optionally substituted by oxo, wherein one methylene group of said Ca-
C, alkylene is replaced by an oxygen atom or a nitrogen atom, said nitrogen atom being optionally substituted by R'°.
Preferably, R' and R? when taken together, represent unbranched propylene wherein one methylene group is replaced by an oxygen atom or unbranched butylene wherein one methylene group is replaced by a nitrogen atom, said propylene and butylene being optionally substituted by oxo and said nitrogen atom being optionally substituted by R'°.
Preferably, R' and R?, when taken together, represent >-OCH-CH,-", “CONHCH.CH,-¥, “CHoNHCH.CH,-Y, *CH2N(CH3)CH,CH,-, “CH,N(4- cyanophenylmethyl)CH.CHz-Y or *CH,N(4-methoxyphenylmethyl)CH.CH,-Y wherein xX’ represents the point of attachment to the carbon atom of the pyrazole ring and 'y’ represents the point of attachment to the nitrogen atom of the pyrazole ring.
Preferably, R® is H or C4-Cs alkyl, said C-Cg alkyl being optionally substituted by halo, -CN, -OR®, -CO,R®, -CONR’R®, -OCONR°R®, -NR°*CO.R®, -NR°R, -NR°COR®, -SO.NR’R®, -NR’*CONR’R®, -NR®SO,R®, R® or R°.
Preferably, R® is H or C4-Cs alkyl.
Preferably, R% is H or C1-C, alkyl.
Preferably, R® is H, -CHa, -CH2CHa, -CH(CHa)2 or -C(CHa)s.
Preferably, R® is CHa, -CHa2CHj, -CH(CHa), or cyclopropyl.
Preferably, R* is phenyl optionally substituted by R®, halo, -CN, C;-Cs alkyl, C1-Cs haloalkyl, Cs-C7 cycloalkyl or C4-Cs alkoxy.
Preferably, R* is phenyl substituted by R®, halo, -CN, C4-Cs alkyl, C4-Cg haloalkyl,
Cs-C; cycloalkyl or C4-Cg alkoxy. ) 35 Preferably, R* is phenyl substituted by halo, -CN or C4-Cg alkyl.
Preferably, R* is phenyl substituted by fluoro, chloro, -CN or methyl.
Preferably, R*is 3-cyanophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-fluorophenyl, 2-fluorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 2,3- dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-
difluorophenyl, 2,3-diflucrophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl, 3,5- dicyanophenyl, 3,5-dimethylphenyl, 4-fluoro-3-methylphenyl, 3-cyano-4- fluorophenyl, 3-cyano-5-fluorophenyl, 2-chloro-4-cyanophenyl, 3-chloro-5- ] cyanophenyl, 3-cyano-5-methylphenyl or 4-cyano-2,6-dimethylphenyl.
Preferably, R* is 3,5-dicyanophenyl, 3-cyano-5-fluorophenyl, 3-chloro-5- cyanophenyl or 3-cyano-5-methylphenyl.
In an alternative set of preferences:
Preferably, R* is phenyl optionally substituted by R®, halo, -CN, C+-Cs alkyl, C4-Cs haloalkyl, C5-C; cycloalkyl, C4-Cs alkoxy, -CONR’R®, OR", So.R®, O-(Ci-Cs alkylene)-CONR°R®, O-(C;-C; alkylene)-NR°R®, or O-(C:-Cs alkylene)-OR®: or naphthyl.
Preferably, R* is phenyl substituted by R®, halo, -CN, C;-Cs alkyl, C1-Cs haloalkyl,
Cs-C; cycloalkyl, C1-Cs alkoxy, -CONR’R®, OR, So,R®, O-(C:-Cs alkylene)-
CONR°R®, O-(C4-Cs alkylene)-NR°R®, or O-(C;-Cs alkylene)-ORE.
Preferably, R® is pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each being optionally substituted by halo, -CN, -COR?®, -CONR®R®, -SO,NR°R?, -NR°SO,R’, -OR’, -NR°R®, -(C4-Cs alkylene)-NR°R®, C-Cs alkyl, fluoro(Cs-
Ce)alkyl or C3-C; cycloalkyl.
Preferably, R? is imidazolyl, pyrazolyl, 1,24-triazolyl, 1,2,4-oxadiazoly!, 1,3,4- oxadiazolyl, pyridinyl, pyrazinyl or pyrimidinyl, each being optionally substituted by halo, -CN, -COR®, -CONR’R®, -SO.NR°R?, -NR°SO,R?, -OR®, -NR°R’, -(C1-Cs alkylene)-NR°R®, C4-Cs alkyl, fluoro(C+-Cg)alkyl or Cs-C; cycloalkyi.
Preferably, R® is imidazolyl, pyrazolyl, 1,24-triazolyl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, pyridinyl, pyrazinyl or pyrimidinyl, each being optionally substituted by -OR®, -NR°R® or C;-Cs alkyl.
Preferably, R® is imidazolyl, pyrazolyl, 1,24-triazolyl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, pyridinyl, pyrazinyl or pyrimidinyl, each being optionally substituted by -OH, -NH. or methyl.
Preferably, R® is pyrazol-1-yl, 2-methylimidazol-1-yl, 1,2,4-triazol-1-yl, 3- hydroxypyrazol-5-yl, 2-hydroxy-1,3,4-oxadiazol-5-yl, 2-amino-1,3,4-oxadiazol-5-yl, : 35 5-hydroxy-1,2,4-oxadiazol-3-yl, 2-methyl-4-hydroxypyrimidin-6-yl, 2-amino-4- hydroxypyrimidin-6-yl, pyridin-3-yl, pyridin-2-yl or pyrazin-2-yl.
Preferably, R® is azetidinyl, tetrahydropyrrolyl, piperidinyl, azepinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepinyl, morpholinyl, piperazinyl or diazepinyl, each being optionally substituted by oxo, C4-Cg alkyl, C3-C cycloalkyl, -SO,R®, -CONR°R?®, -COOR?®, -CO-(C1-Cs alkylene)-OR® or -COR?® and optionally substituted on a carbon atom which is not adjacent to a heteroatom by halo, -OR®, -NR°R®, -NR°COR’, -NR°COOR?, -NR°CONRR®, -NR*SO.R’ or -CN.
Preferably, R° is azetidinyl, piperidinyl, tetrahydrofuranyl, piperazinyl or morpholinyl, each being optionally substituted by oxo, C1-Cs alkyl, Cz-C; cycloalkyl, -SO;R°®, -<CONR’R®, -COOR?®, -CO-(C+-C; alkylene)-OR® or -COR® and optionally substituted on a carbon atom which is not adjacent to a heteroatom by halo, -OR®, -NR°R®, -NR°COR?®, -NR’COOR?®, -NR°CONR®R®, -NR*SO,R® or -CN.
Preferably, R® is azetidinyl, piperidinyl, tetrahydrofuranyl, piperazinyl or morpholinyl, each being optionally substituted by C;-Cs alkyl, -SO,R®, -CONR®R®, -COOR®, -CO-(C+-Cs alkylene)-OR® or -COR’ and optionally substituted on a’ carbon atom which is not adjacent to a heteroatom by -OR® or -NR°COR®.
Preferably, R® is azetidinyl, piperidinyi, tetrahydrofuranyl, piperazinyl or morphoninyl, each being optionally substituted by -CHj3, -SO>CH3;, -CONH,, -COOCHs3, -COCH,OCH; or -COCH3; and optionally substituted on a carbon atom which is not adjacent to a heteroatom by -OCH3; or -NHCOCHs.
Preferably, R® is 4-methoxypiperidin-1-yl, 4-aminocarbonylpiperidin-1-yl, 4- methylcarbonylaminopiperidin-1-yl, piperazin-1-yi, 4-methylpiperazin-i-yl, 4- methylcarbonylpiperazin-1-yl, 4-methoxymethylcarbonyipiperazin-1-yl, 4- methoxycarbonylpiperazin-1-yl, 4-methylsulphonyipiperazin-1-yl, morpholin-4-yl, tetrahydrofuran-2-yl, morpholin-3-yl, azetidin-3-yl or 1-methylazetidin-3-yl.
Preferably, R'is H, R®, R®, R'®, C-Cs alkyl or -(C+-Cs alkyl)-(Cs-C7 cycloalkyl), said C4-Cs alkyl being optionally substituted by -OR®, -OR", R®, R®, R™ or -COR™,
Preferably, R'® is H, R®, R®, R"®, C4-Cs alkyl or -(C4-Cs alkyl)-(Cs-C; cycloalkyl), said C4-Cs alkyl being optionally substituted by -OR® or R*2,
Preferably, R" is H, R®, R®, R"®, -CHs, -CHyCH; or -CHa(cyclopropyl), said -CHs; and -CH.CHjs being optionally substituted by -OCH; or R'.
Preferably, R'is H, R®, R®, R"®, -CHg, -CHyCHs, -CH.CH,OCH3 -CHy(cyclopropyl), 4-cyanophenylmethyl, 4-fluorophenylmethyl, 4- methoxyphenyimethyl, 4-aminosulphonylphenyimethyl or 4- aminocarbonylphenylmethyl. } 35
Preferably, R'is H or C4-Cs alkyl, said C4-Cs alkyl being optionally substituted by -OR®, -NR°R®, -NR°COR®, -CONR°R®, R® or R’.
Preferably, R"" is H or C-Cg alkyl, said C4-Cs alkyl being optionally substituted by -OR® or -NR°COR’.

Claims (43)

  1. 279 B CLAIMS
    : 1. A compound of the formula (I) . Rr R' \ 2 i A Cm re or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein: either R' is H, C;-C; alkyl, C3-C; cycloalkyl, phenyl, benzyl, halo, -CN, -OR’, -CO:R'", -CONR’R™, R® or R®, said C,-Cs alkyl, C5-C; cycloalkyl, phenyl and benzyl being optionally substituted by halo, -CN, -OR', S(O),R'°, -CO,R'", -CONR°R', -OCONR’RY, -NR°CO:R'", -NR'R', -NR’COR'", -SO,NR°R™, -NR°CONR°R'’, -NR°SO:R'® or R™; and R? is H, Ci-Cs alkyl, Cs-Cs alkenyl, Cs-Cs alkynyl, Cs-C; cycloalkyl, Cs-C; cycloalkenyl, phenyl, benzyl, R® or R®, said C;-Cs alkyl, Cs-C; cycloalkyl, phenyl and benzyl being optionally substituted by halo, -OR®, -OR'?, -CN, -CO,R’, -OCONR®R®, -CONR’R®, -C(=NR°)NR°OR®, -CONR®NR®R®, -NR°R®, -NR°R'2, -NR°COR®, -NR°COR®, -NR°COR', -NR°CO,R®, -NR*CONR®R®, -SO,NR°R’, -NR°SO.R®, -NR°SONR°R’, R® or R®; or, R' and R? when taken together, represent unbranched Cs-C, alkylene, optionally substituted by oxo, optionally wherein one methylene group of said : Cs-C4 alkylene is replaced by an oxygen atom or a nitrogen atom, said nitrogen : atom being optionally substituted by R'®; ; : R% is H, C4-Cs alkyl, C3-C; cycloalkyl, phenyl, benzyl, halo, -CN, -OR’, -CO.R®, -CONR®R®, R® or R®, said C4-Cs alkyl, Cs-C7 cycloalkyl, phenyl and benzyl being optionally substituted by halo, -CN, -OR®, -CO.R®, -CONR®R®, -OCONR®R®, -NR°CO,R®, -NR°R®, -NR®COR®, -SO.NR°R®, -NR°CONR’R®, -NR°SO.R®, R® or RY R* is phenyl, naphthyl or pyridyl, each being optionally substituted by R®, halo, ! -CN, C1-Cs alkyl, C4-Cg haloalkyl, C3-C7 cycloalkyl, C;-C¢ alkoxy, -CONR®R®, i
    OR™, SoR®, O-(C1-Cs alkylene)-CONR®R®, O-(Ci-Cs alkylene)-NR°R®, or 0-(C+-Cs alkylene)-OR®; - each R® is independently either H, C4-Cs alkyl or C5-C; cycloalkyl or, when two R® groups are attached to the same nitrogen atom, those two groups taken together : with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl or morpholinyl, said azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyi, homopiperazinyl and morpholinyl being optionally substituted by C+-Cs alkyl or Cs-C; cycloalkyl; each R® is independently either H, C1-Cg alky! or C5-C7 cycloalkyl; R’ is C-Cs alkyl or C3-C7 cycloalkyl;
    R® is a five or six-membered, aromatic heterocyclic group containing (i) from 1 to 4 nitrogen heteroatom(s) or (ii) 1 or 2 nitrogen heteroatom(s) and 1 oxygen or 1 sulphur heteroatom or (iii) 1 or 2 oxygen or sulphur heteroatom(s), said heterocyclic group being optionally substituted by halo, oxo, -CN, -COR® -CONR’R®, -SO,NR°R°, -NR’SO.R’, -OR®, -NR°R®, -(Ci-Cs alkylene)-NR°R®, C4-Ce alkyl, fluoro(C+-Ce)alkyl or Cs-Cy cycloalkyl; R® is a four to seven-membered, saturated or partially unsaturated heterocyclic group containing (i) 1 or 2 nitrogen heteroatom(s) or (ii) 1 nitrogen heteroatom and 1 oxygen or 1 sulphur heteroatom or (ji) 1 oxygen or sulphur heteroatom, said heterocyclic group being optionally substituted by oxo, C;-Cs alkyl, C5-C; cycloalkyl, -SO2R®, -CONR®R®, -COOR®, -CO-(C+-Cs alkylene)-OR® or -COR® and optionally substituted on a carbon atom which is not adjacent to a heteroatom by halo, -OR®, -NR°R®, -NR®*COR®, -NR°COOR?®, -NR°CONR®R®, -NR°SO,R°® or -CN;
    R" is H, R® R% R', C;-Cs alkyl, Cs-C7 cycloalkyl or -(C-Cs alkyl)-(Cs-Cy cycloalkyl), said C¢-Cs alkyl and C3-C; cycloalkyl being optionally substituted by -OR?®, -OR", R®, R%, R"® or -COR"™; : 35 R'" is H, C+-Cs alkyl or C5-C; cycloalkyl, said C1-Cs alkyl and Cs-C; cycloalkyl being optionally substituted by -OR®, -NR°R®, -NR*COR®, -CONR®R®, R® or R®; R'? is C4-Cs alkyl substituted by R®, R®, -OR®, -CONR®R®, -NR°COR® or -NR°R®;
    R' is phenyl optionally substituted by halo, -CN, -COR®, -CONR®R?®, -SO.NR°R?, -NR°SO,R’, -OR®, -NR°R®, -(C4-Cs alkylene)-NR°R®, C;-C; alkyi, halo(C1-Ce)alkyl or C3-C7 cycloalkyl; and xis0,1o0r2; with the proviso that (a) when R' and R® are both phenyl, R? is not methyl; and (b) when R' is ethoxy and R? is ethoxycarbonyl, R? is not phenyl.
  2. 2. A compound according to claim 1 wherein R', when taken separately, is H, C+-Cs alkyl, Cs-C; cycloalkyl or -OR’, said C4-Cs alkyl and C3-C; cycloalkyl being optionally substituted by halo, -CN, -OR", S(O)R", -CO.R', -CONR’R', -OCONR®R"™, -NR°CO-R', -NR'R"", -NR’*COR", -SO.NR°R®, -NR*CONR’R", -NR°SO.R™ or R™.
  3. 3. A compound according to claim 1 or 2 wherein R', when taken separately, is H, C-Cs alkyl, C5-C; cycloalkyl or -OR’, said C-Cs alkyl being optionally substituted by halo, -OR™, -NR'"R"!, -NR* COR" or R'°.
  4. 4. A compound according to any preceding claim wherein RZ, when taken
    . separately, is H, C4-Cg alkyl, Cs-Cs alkenyl or R®, said C4-Cs alkyl being optionally substituted by halo, -OR°, -OR", -CN, -CO.R’, -OCONR°R®, -CONR°R’, -C(=NR°)NR°OR®, -CONR’NR°R®, -NR°R®, -NR°R'?, -NR°COR®, -NR°COR®, -NR°COR", -NR’CO:R®, -NR°CONR’R®, -SO,NR°R’, -NR°SO,R®, R® or R®.
  5. 5. A compound according to any preceding claim wherein R?, when taken separately, is H, C1-Cs alkyl, C3-Cs alkenyl or R®, said C;-Cg alkyl being optionally substituted by -OR’, -OR', -CN, -CO;R’, -CONR°R’, -C(=NR°)NR°OR’ -CONR®NR®R®, -NR°R®, -NR°R'?, -NR°COR®, -NR°COR'2, -NR°CO.R®, R® or R®.
  6. 6. A compound according to claim 1 wherein R' and R?, when taken together, represent unbranched Cs-C4 alkylene, optionally substituted by oxo, wherein one methylene group of said Cs-C4 alkylene is replaced by an oxygen atom or a nitrogen atom, said nitrogen atom being optionally substituted by R*°, - 35
  7. 7. A compound according to claims 1 or 6 wherein R' and R?, when taken together, represent unbranched propylene wherein one methylene group is replaced by an oxygen atom or unbranched butylene wherein one methylene group is replaced by a nitrogen atom, said propylene and butylene being optionally substituted by oxo and said nitrogen atom being optionally substituted by R'.
  8. : 8. A compound according to any preceding claim wherein Ris H or C1-Ce alkyl, said C4-Cg alkyl being optionally substituted by halo, -CN, -OR®, -CO,R5, : -CONR®R®, -OCONR°R®°, -NR’CO.R’, -NRR®, -NRP°COR®, -SO.NR°R’, -NR°CONR’R®, -NR°SO:R’, R® or R®.
  9. 9. A compound according to any preceding claim wherein R® is H or Ci-Cs alkyl.
  10. 10. A compound according to any preceding claim wherein R* is phenyl optionally substituted by R®, halo, -CN, C-Cs alkyl, C:-Cg haloalkyl, Cs-C; cycloalkyl, C4-Cs alkoxy, -CONR®R®, OR", So,R°®, O-(C4-Cs alkylene)-CONR®R®, O-(C4-Cs alkylene)-NR°R®, or O-(C4-Cs alkylene)-OR®; or naphthyl.
  11. 11. A compound according to any preceding claim wherein R* is phenyl substituted by R®, halo, -CN, C,-Cs alkyl, C4-Cg haloalkyl, C3-C; cycloalkyl, C1-Cs alkoxy, -CONR°R®, OR", SoR® 0-(Ci-Cs alkylene)-CONR’R®, O-(C-Cs alkylene)-NR®R®, or O-(C4-Ce alkylene)-OR®.
  12. 12. A compound according to any preceding claim wherein R* is phenyl substituted by RE, halo, -CN, C¢-Cs alkyl, C1-Cs haloalkyl, C3-C; cycloalkyl! or C1 -Cs alkoxy.
  13. 13. A compound according to any preceding claim wherein R* is phenyl substituted by halo, -CN or C4-Cs alkyl.
  14. 14. A compound according to any preceding claim wherein R® is pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each being optionally substituted by halo, -CN, -COR®, -CONR°R®, -S0:NR°R®, -NR°SO,R®, -OR®, -NR°R®, -(C1-Cs alkylene)-NR®R®, C;-Cg alkyl, fluoro(C1-Cg)alkyl or C3-C7 cycloalkyl. :
  15. 15. A compound according to any preceding claim wherein R® is imidazolyl, pyrazolyl, 1,2 4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrazinyl or pyrimidinyl, each being optionally substituted by halo, -CN, -COR®,
  16. -CONR°R®, -SO.NR°R’, -NR°SO.R®, -OR®, -NR°R’, -(C,-Cs alkylene)-NR°R®, C1-Cs alkyl, fluoro(C4-Ce)alkyl or Cs-C7 cycloalkyl. : 16. A compound according to any preceding claim wherein R® is imidazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrazinyl : or pyrimidinyl, each being optionally substituted by -OR®, -NR°R® or C4-Cs alkyl.
  17. 17. A compound according to any preceding claim wherein R® is azetidinyl, tetrahydropyrrolyl, piperidinyl, azepinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepinyl, morpholinyl, piperazinyl or diazepinyl, each being optionally substituted by oxo, C;-Cs alkyl, Cs-C; cycloalkyl, -SO,R®, -CONR®R®, -COOR?®, -CO-(C+-Cs alkylene)-OR® or -COR® and optionally substituted on a carbon atom which is not adjacent to a heteroatom by halo, -OR®, -NR°R®, -NR’COR?®, -NR°COOR?®, -NR°*CONR®R®, -NR®SO,R® or -CN.
  18. 18. A compound according to any preceding claim wherein R® is azetidinyl, piperidinyl, tetrahydrofuranyl, piperazinyl or morpholinyl, each being optionally substituted by oxo, C:-Cs alkyl, Cs-C; cycloalkyl, -SO;R®, -CONR®R?, -COOR?, -CO-(C4-Cs alkylene)-OR® or -COR® and optionally substituted on a carbon atom which is not adjacent to a heteroatom by halo, -OR®, -NR°R®, -NR°COR, -NR°COOR?, -NR*CONR®RS, -NR°SO,R° or -CN.
  19. 19. A compound according to any preceding claim wherein R® is azetidinyl, piperidinyl, tetrahydrofuranyl, piperazinyl or morpholinyl, each being optionally substituted by C-Cs alkyl, -SO:R®, -CONR’R®, -COOR®, -CO-(C;-Cs alkylene)- OR?® or -COR® and optionally substituted on a carbon atom which is not adjacent to a heteroatom by -OR® or -NR°*COR®.
  20. 20. A compound according to any preceding claim wherein R'is H, R®, R®, R"®, C4-Cs alkyl or -(C4-Cs alkyl)-(Cs-C7 cycloalkyl), said C;-Cs alkyl being optionally substituted by -OR®, -OR™, R®, R°, R" or -COR™, :
  21. 21. A compound according to any preceding claim wherein R'® is H, R?, R®, R'®, C1-Cs alkyl or -(C4-Cg alkyl)-(Cs-C cycloalkyl), said C;-Cs alkyl being optionally : 35 substituted by -OR® or R™.
  22. 22. A compound according to any preceding claim wherein R" is H or C1-Cs alkyl, said C4-Cs alkyl being optionally substituted by -OR®, -NR®RS5, -NR*COR, -CONR°RS, R® or R®.
  23. 23. A compound according to any preceding claim wherein R'is H or C4-Cq alkyl, said C,-Cs alkyl being optionally substituted by -OR® or -NR’COR®.
  24. 24. A compound according to any preceding claim wherein R% is C4-C, alkyl substituted by R®, R®, -OR®, -CONR’R®, -NR°COR?® or -NR°R°.
  25. 25. A compound according to any preceding claim wherein R'? is C-C, alkyl substituted by R®, -OR®, -NR*COR® or -NR°R®,
  26. 26. A compound according to any preceding claim wherein R™ is phenyl substituted by halo, -CN, -COR®, -CONR’R®, -SO,NR®R®, -NR°SO,R°, -OR®, -NR°R®, -(C;-Cs alkylene)-NR°R®, C4-Cs alkyl, halo(Ci-Cg)alkyl or Cs-C; cycloalkyl.
  27. 27. A compound according to any preceding claim wherein R' is phenyl substituted by halo, -CN, -CONR’R?, -SO,NR°R® or -OR>.
  28. 28. 2-[4-(3,5-Dichlorophenoxy)-3,5-dimethyl-1H-pyrazol-1-yljethanol; 2-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yljethanol; 4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazole; [4-~(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllacetonitrile; 5-{{4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yijmethyl}-1 H-pyrazol-3-ol; 6-{[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljmethyl}-2-methyl-4(3H)- pyrimidinone; 2-Amino-6-{[4-(3,5-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljmethyl}-4(3H)- pyrimidinone; 2-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yl]-N- hydroxyethanimidamide; Methyl [4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yljacetate; 2-[4-(3,5-Dichlorophenoxy)-3,5-diethyl- 1 H-pyrazol-1-yljacetamide; 2-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllacetohydrazide; Co 5-{[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-ylimethyl}-1,3,4-oxadiazol- 2(3H)-one; - 35 2-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllethylamine; 3-{{4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljmethyl}-1,2 4-oxadiazol- 5-0; 5-{[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljmethyl}-1,3,4-oxadiazol- 2-amine;
    285 | oT N-{2-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljethyl}-2- methoxyacetamide; N-{2-[4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]ethyl}-2- : pyridinecarboxamide;
    N-{2-[4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yllethyl}-2- pyrazinecarboxamide; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylloxy}benzonitrile; 4-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylJoxy}-3,5-dimethylbenzonitrile; 3-chloro-4-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylloxy}benzonitrile;
    5-{3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylloxy}-2-fluorobenzonitrile; 2-[4-(4-chlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yl]ethanol; 2-[4-(3-chlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllethanol; 2-[4-(2-chlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljethanol; 2-[4-(2,6-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllethanol;
    156 2-[4-(2,3-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllethanol; 2-[4-(2,4-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllethanol; 2-[3,5-diethyl-4-(2-fluorophenoxy)-1H-pyrazol-1-yllethanol; 2-[3,5-diethyl-4-(3-fluorophenoxy)-1H-pyrazol-1-yllethanol; 2-[4-(3,5-dimethylphenoxy)-3,5-diethyl-1 H-pyrazol-1-yl]ethanol;
    2-[3,5-diethyl-4-(4-fluoro-3-methylphenoxy)-1H-pyrazol-1-yllethanol; 2-[4-(2,5-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljethanol; 2-[4-(2,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-ylJethanol; 2-[4-(3,4-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yilethanol; 2-[4-(2,6-difluorophenoxy)-3,5-diethyl-1H-pyrazol-1-yllethanol;
    2-[4-(2,5-difluorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllethanol; 2-[4-(3,5-difluorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllethanol; 4-(3,5-Dichlorophenoxy)-3,5-diethyl-1-(2-methoxyethyl)-1 H-pyrazole; 4-(3,5-dichlorophenoxy)-3,5-diethyl-1-(methoxymethyl)-1 H-pyrazole; 4-(3,5-dichlorophenoxy)-3,5-diethyl-1-methyl-1H-pyrazole;
    4-(3,5-Dichlorophenoxy)-3-ethyl-1H-pyrazole; 4-{2-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yllethyl}morpholine; N-{2-[4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]ethyl}-N-(2-
    methoxyethyl)amine; 1-(1-{2-[4-(3,5-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yl]ethyl}-4- : 35 piperidinyl)ethanone; N-{2-[4-(3,5-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljethyl}-N,N- dimethylamine; N-[2-({2-[4-(3,5-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1- yllethyl}Jamino)ethyl]lacetamide;
    N-{2-[4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yllethyl}-N-methylamine; N-{2-[4-(3,5-dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljethyl}- N-(tetrahydro-2- furanylmethyl)amine; 3-{[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-ylimethyl}morpholine;
    1-(3-Azetidinyl)-4-(3,5-dichlorophenoxy)-3,5-diethyl-1 H-pyrazole;
    : 7-(3,5-Dichiorophenoxy)-6-ethyl-2,3-dihydropyrazolo[5,1-b][1,3]oxazole; 4-(3,5-Dichlorophenoxy)-3,5-dimethyl-1H-pyrazole; 1-[4-(3,5-Dichlorophenoxy)-3,5-diethyl-1 H-pyrazol-1-yl}-2-propanol; 2-{2-[4-(3,5-Dichlorophenxoy)-3,5-diethyl-1H-pyrazol-1-yl)ethoxy}ethanamine;
    4-{[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-ylimethylimorpholine; 4-(3,5-Dichlorophenoxy)-3-methyl-5-[(2-methyl-1 H-imidazol-1-yl)methyl]-1 H- pyrazole; 2-[4-(3,5-Dichlorophenoxy)-3-ethyl-5-methoxy-1H-pyrazol-1-yl}ethanol; 1-{[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yljmethyl}-1H-1,2,4-triazole;
    3-[(3,5-Diethyl-1H-pyrazol-4-yl)oxylbenzonitrile; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1 H-pyrazol-4-yljoxy}benzonitrile; 2-[4-(3-Cyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yllacetamide;
    Ethyl [4-(3-cyanophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllacetate; 1-Allyl-4-(3,5-dichlorophenoxy)-3,5-diethyl-1 H-pyrazole;
    N-{[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yljmethyl}-N-(4- methoxybenzyl)amine; N-(cyclopropylmethyl)[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5- yllmethanamine;
    [4-(3,5-dichiorophenoxy)-3-methyl- 1 H-pyrazol-5-yl}-N, N-dimethylmethanamine;
    [4-(8,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]-N-methylmethanamine; 1-{[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yllmethyl}-4-methylpiperazine; 1-{[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yljmethyl}-4- piperidinecarboxamide;
    N-{[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5-ylimethyl}-2-
    methoxyethanamine; 1-acetyl-4-{[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yllmethyl}piperazine; N-[2-({[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5-
    yllmethyl}amino)ethyllacetamide; N-(1-{[4-(3,5-dichlorophenoxy)-3-methyi-1H-pyrazol-5-ylimethyl}-4-
    ’ 35 piperidinyl)acetamide; 1-{[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yllmethyl}-4- methoxypiperidine; 3-Chloro-5-[(3,5-dimethyl-1 H-pyrazol-4-yl)oxyjbenzonitrile; 3-{[5-(Aminomethyl)-3-methyl-1H-pyrazol-4-ylJoxy}-5-chlorobenzonitrile;
    3-Chloro-5-{[3-methyl-5-(1-piperazinylmethyl)-1 H-pyrazol-4-ylJoxy}benzonitrile; 3-Chloro-5-[(5-{[(4-cyanobenzyl)amino]methyl}-3-methyl- 1 H-pyrazol-4- yl)oxylbenzonitrile;
    : 3-Chloro-5-[(3-methyl-5-{[4-(methylsulfonyl)-1-piperazinyljmethyl}-1 H-pyrazol-4-
    yloxylbenzonitrile;
    3-Chloro-5-[(5-{[4-(methoxyacetyl)-1-piperazinyllmethyl}-3-methyl-1 H-pyrazol-4- yl)oxy]benzonitrile; Methyl 4-{[4-(3-chloro-5-cyanophenoxy)-3-methyl-1H-pyrazol-5-yljmethyl}-1- piperazinecarboxylate;
    4-[({[4-(3-Chloro-5-cyanophenoxy)-3-methyl-1H-pyrazol-5- yllmethyl}amino)methyllbenzenesulfonamide; 4-(3,5-Dichlorophenoxy)-5-(methoxymethyl)-3-methyl-1 H-pyrazole; 3-tert-Butyl-4-(3,5-dichlorophenoxy)-5-methyl-1 H-pyrazole; 4-(3,5-Dichlorophenoxy)-3-ethyl-5-methyl-1 H-pyrazole;
    4-Cyano-N-{[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5- yllmethyl}benzamide;
    ~3-Cyano-N-{[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5- yljmethyl}benzamide; N-{{4-(3,5-Dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yljmethyl}-N-(3-
    pyridinylmethyl)amine; 3-({5-[(4-Acetyl-1-piperazinyl)methyl]-3-methyl-1 H-pyrazol-4-yl}oxy)-5- chlorobenzonitrile; 3-Chloro-5-[(5-{[(4-cyanobenzyl)(methyl)amino]methyl}-3-methyi-1 H-pyrazol-4- yl)oxylbenzonitrile;
    3-Chloro-5-[(5-{[(4-cyanobenzyl)(2-hydroxyethyl)amino]methyl}-3-methyl-1 H- pyrazol-4-yl)oxylbenzonitrile;
    ~ 3-Chloro-5-({3-methyl-5-[(2-methyl-1 H-imidazol-1-yl)methyl]-1 H-pyrazol-4- yl}oxy)benzonitrile; 2-(4-(3,5-Dichlorophenoxy)-3-methyl-5-{[(3-pyridinyimethyl)amino]methyl}-1 H- pyrazol-1-ylhethanol; 5-[(3-Isopropyl-5-methyl-1 H-pyrazol-4-yl)oxylisophthalonitrile; 5-{[1-(2-Hydroxyethyl)-3-isopropyl-5-methyl-1 H-pyrazol-4-ylJoxylisophthalonitrile;
    : 3-(3,5-Dichlorophenoxy)-2-ethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one; 3-(3,5-Dichlorophenoxy)-2-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine; 3-(3,5-Dichlorophenoxy)-2-ethyl-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5- alpyrazine; 4-[(3-(3,5-Dichlorophenoxy)-2-ethyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4 H)- yymethyllbenzonitrile; ]
    3-(3,5-Dichlorophenoxy)-2-ethyl-5-(4-methoxybenzyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine; [1-(2-Aminoethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1 H-pyrazol-5-yljmethanol; : 2-[4-(3,5-Dichlorophenoxy)-5-(ethoxymethyl)-3-ethyl-1H-pyrazol-1-yllethylamine; 2-[4-(3,5-dichlorophenoxy)-3-ethyl-5-(1 H-pyrazol-1-ylmethyl)-1H-pyrazol-1-
    : yllethylamine;
    N-{[1-(2-aminoethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1 H-pyrazol-5-yljmethy}-N- (4-methoxybenzyl)amine; 4-[({[1-(2-aminoethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1 H-pyrazol-5-
    yljmethyl}amino)methyllbenzonitrile; 2-[5-[(4-Acetyl-1-piperazinyl)methyl]-4-(3,5-dichiorophenoxy)-3-ethyl-1 H-pyrazol- 1-yllethylamine;
    N-[2-({[1-(2-Aminoethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1 H-pyrazol-5- yllmethyl}amino)ethyllacetamide;
    [4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yllmethanamine hydrobromide; N-{[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yllmethyl}-N-(4- fluorobenzyl)amine; } 4-[({[4~(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5- ylJmethyl}amino)methyl]benzonitrile;
    3-Chloro-5-[(1,3,5-trimethyl-1 H-pyrazol-4-yl)oxy]benzonitrile; 3-Chloro-5-[(5-{[(4-cyanobenzyl)amino]methyl}-1,3-dimethyl-1 H-pyrazol-4- yl)oxylbenzonitrile; 3-Chloro-5-{[1-(2-hydroxyethyl)-3,5-dimethyl-1 H-pyrazol-4-yljoxy}benzonitrile; 3-Chiloro-5-{[5-{[(4-cyanobenzyl)amino]methyl}-1-(2-hydroxyethyl)-3-methyi-1H-
    pyrazol-4-ylJoxy}benzonitrile; 4-[({[4-(3-Chloro-5-cyanophenoxy)-3-methyi-1H-pyrazol-5- ylimethyl}amino)methyljbenzamide; 3-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}-5-fluorobenzonitrile;
    - 3-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylJoxy}-5-methylbenzonitrile;
    5-{[3,5-diethyl-1-(2-hydroxyethyl)- 1 H-pyrazol-4-ylloxy}isophthalonitrile; 3-chloro-5-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylloxy}benzonitrile; 3-[(3,5-diethyl-1H-pyrazol-4-yl)oxy]-5-fluorobenzonitrile;
    5-[(3,5-diethyl-1H-pyrazol-4-yl)oxylisophthalonitrile; 3-[(3,5-diethyl-1H-pyrazol-4-yl)oxy]-5-methylbenzonitrile;
    : 35 3-chloro-5-[(3,5-diethyl-1H-pyrazol-4-yl)oxylbenzonitrile; 3-{[1-(2-aminoethyl)-3,5-diethyl-1 H-pyrazol-4-ylloxy}-5-methylbenzonitrile; 3-{[1-(2-aminoethyl)-3,5-diethyl-1 H-pyrazol-4-ylloxy}-5-chlorobenzonitrile; 5-{[1-(2-aminoethyl)-3,5-diethyl-1 H-pyrazol-4-yljoxy}isophthalonitrile; 3-{[1-(2-aminoethyt)-3,5-diethyl-1 H-pyrazol-4-ylJoxy}-5-fluorobenzonitrile;
    5-[(3-cyclopropyl-5-ethyl-1H-pyrazol-4-yl)oxyjisophthalonitrile; 5-[(3-tert-butyl-5-methyl-1 H-pyrazol-4-yl)oxylisophthalonitrile; 5-[(5-ethyl-3-isopropyl-1H-pyrazol-4-yl)oxyJisophthalonitrile; : 4-(3,5-Dichlorophenoxy)-3,5-diethyl-1-(1-methyl-3-azetidinyl)-1 H-pyrazole; 2-4-(3,5-Dichlorophenoxy)-3-ethyl-1H-pyrazol-1-yljethylamine; 2-[4-(3,5-Dichlorophenoxy)-5-ethyl-1 H-pyrazol-1-yllethylamine; tert-Butyl 2-[4-(3,5-dichlorophenoxy)-3-ethyl-5-(hydroxymethyl)-1 H-pyrazol-1- yllethylcarbamate; tert-Butyl 2-[4-(3,5-dichlorophenoxy)-5-(ethoxymethyl)-3-ethyl-1 H-pyrazol-1-
    yllethylcarbamate; tert-Butyl 2-[5-(bromomethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1 H-pyrazol-1- yllethyicarbamate; tert-Butyl 2-[5-(aminomethyl)-4-(3,5-dichlorophenoxy)-3-ethyl-1 H-pyrazol-1- yllethylcarbamate;
    tert-Butyl 2-[5-[(4-acetyl-1-piperazinyl)methyl]-4-(3,5-dichlorophenoxy)-3-ethyl-
    1 H-pyrazol-1-yllethylcarbamate;
    tert-Butyl 2-[4-(3,5-dichlorophenoxy)-3-ethyl-5-(1H-pyrazol-1-yimethyl)-1 H- pyrazol-1-yijethylcarbamate; :
    tert-Butyl 2-[5-({[2-(acetylamino)ethyljamino}methyl)-4-(3,5-dichlorophenoxy)-3- ’
    ethyl-1H-pyrazol-1-yljethylcarbamate; tert-Butyl 2-(4-(3,5-dichlorophenoxy)-3-ethyl-5-{[(4-methoxybenzyl)aminojmethyl}- 1 H-pyrazol-1-yl)ethylcarbamate; tert-Butyl 2-[5-{[(4-cyanobenzyl)amino]methyl}-4-(3,5-dichlorophenoxy)-3-ethyl-
    1 H-pyrazol-1-yllethylcarbamate;
    3-{[5-(Bromomethyl)-1,3-dimethyl-1 H-pyrazol-4-ylloxy}-5-chiorobenzonitrile; 3-[(3,5-Diethyl-1-methyl-1 H-pyrazol-4-yl)oxy]benzonitrile; 3-{[3,5-Diethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yljoxy}benzonitrile; 3-({5-[2-(Benzyloxy)ethyl]-3-ethyl-1 H-pyrazol-4-yljoxy)-5-fluorobenzonitrile; 3-{[3-Ethyl-5-(2-hydroxyethyl)-1 H-pyrazol-4-yl]oxy}-5-fluorobenzonitrile;
    3-({5-[2-(4-Cyanophenoxy)ethyl]-3-ethyl-1 H-pyrazol-4-yl}oxy)-5-fluorobenzonitrile; 3-[(3-Ethyl-5-{2-[(2-methyl-3-pyridinyl)oxylethyl}-1 H-pyrazol-4-yl)oxy]-5- fluorobenzonitrile;
    : 3-({3-Ethyl-5-[2-(3-pyridinyloxy)ethyl]-1 H-pyrazol-4-yl}oxy)-5-fluorobenzonitrile; 3-[(5-{2-[(2-Amino-3-pyridinyl)oxylethyl}-3-ethyl-1 H-pyrazol-4-yl)oxy]-5-
    - 35 fluorobenzonitrile; 5-({5-[2-(benzyloxy)ethyl]-3-ethyl-1 H-pyrazol-4-yl}oxy)isophthalonitrile; 5-{[3-Ethyl-5-(2-hydroxyethyl)-1 H-pyrazol-4-ylJoxy}isophthalonitrile; 3-{[5-(Aminomethyl)-1-(2-hydroxyethyl)-3-methyl-1 H-pyrazol-4-yljoxy}-5- chlorobenzonitrile;
    5-[(1-Allyl-3-tert-butyl-5-methyl-1 H-pyrazol-4-yl)oxyJisophthalonitrile; 5-{[3-tert-Butyl-1-(2-hydroxyethyl)-5-methyl-1 H-pyrazol-4-yljoxy}isophthalonitrile; 5-{[1-(2-Aminoethyl)-3-tert-butyl-5-methyl-1H-pyrazol-4-ylJoxy}isophthalonitrile; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylloxy}-5-(1 H-1,2,4-triazol-1- ylbenzonitrile;
    : 3-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylloxy}-5-(4-oxo-1(4 H)- pyridinyl)benzonitrile; 3-{[3,5-diethyl-1-(2-hydroxyethyl)- 1 H-pyrazoi-4-ylloxy}-5-(1H-1,2,3-triazol-1- ybenzonitrile;
    3-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylJoxy}-5-(2H-1,2,3-triazol-2- yl)benzonitrile; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-yljoxy}-5-fluorobenzamide; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylJoxy}-5-(1 H-pyrazol-1- yl)benzamide;
    3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylloxy}-5-(2-oxo-1(2H)- pyridinyl)benzamide; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylloxy}-5-(6-oxo-1(6H)- pyridazinyl)benzamide; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylloxy}-5-(2,3-dimethyl-5-0x0-2,5-
    dihydro-1H-pyrazol-1-yl)benzamide; 5-{[3-Cyclopropyl-5-ethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylloxy}isophthalonitrile; 5-{[5-Cyclopropyl-3-ethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yljoxy}isophthalonitrile; 5-{[5-Ethyl-1-(2-hydroxyethyl)-3-isopropyl-1H-pyrazol-4-yl]oxy}isophthalonitrile; 5-{[3-Ethyl-1-(2-hydroxyethyl)-5-isopropyl-1H-pyrazol-4-ylloxy}isophthalonitrile;
    2-[4-(3,5-Dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yllethyl carbamate; N-{2-[4-(3,5-Dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yllethyl}sulfamide; N-{2-[4-(3,5-Dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yljethyl}-2- methoxyacetamide; 5-{[1-(3-Azetidinyl)-3,5-diethyl-1H-pyrazol-4-yijoxy}isophthalonitrile; :
    5-{[3,5-Diethyl-1-(3-hydroxypropyl)-1H-pyrazol-4-ylJoxy}lisophthalonitrile; 5-[(3,5-Diethyl-1-methyl-1H-pyrazol-4-yl)oxylisophthalonitrile; 5-{[3,5-Diethyl-1-(2-methoxyethyl)-1 H-pyrazol-4-ylJoxy}isophthalonitrile;
    ’ 5-{[1-(3-Aminopropyl)-3,5-diethyl-1 H-pyrazol-4-ylJoxy}isophthalonitrile; methyl [4-(3,5-Dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yljacetate;
    2-[4-(8,5-Dicyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yljacetamide; 5-{[3,5-Diethyl-1-(hydroxymethyl)-1 H-pyrazol-4-ylJoxy}isophthalonitrile; 3-[({[4-(3-cyano-5-fluorophenoxy)-3-methyl-1 H-pyrazol-5- ylimethyl}amino)methyllbenzamide;
    4-{({[4-(3-Cyano-5-fluorophenoxy)-3-methyi-1H-pyrazol-5- yllmethyl}amino)methyllbenzamide; 4-[({[4-(8,5-Dicyanophenoxy)-3-methyl-1 H-pyrazol-5- ylimethyl}amino)methyllbenzamide; 3-[({[4-(3-Chloro-5-cyanophenoxy)-3-methyl-1H-pyrazol-5-
    : ylimethyl}amino)methyl]benzamide; 4-[({[4-(3-Cyano-5-methylphenoxy)-3-methyl-1H-pyrazol-5- yllmethyl}amino)methyl]benzamide; 4-[({[4-(3-Cyanophenoxy)-3-methyl-1H-pyrazol-5-
    yljmethyl}amino)methyllbenzamide; 5-[(3,5-Dicyclopropyl-1H-pyrazol-4-yl)oxylisophthalonitrile; 5-{[3,5-Dicyclopropyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-yljoxylisophthalonitrile; 5-{[1-(2-Aminoethyl)-3,5-dicyclopropyl-1H-pyrazol-4-yljoxylisophthalonitrile; 3-{[3-cyclopropyl-1-(2-hydroxyethyl)-5-methyl-1 H-pyrazol-4-ylloxy}-5-
    methylbenzonitrile; 3-{[5-cyclopropyl-1-(2-hydroxyethyl)-3-methyl-1 H-pyrazol-4-yljoxy}-5- methylbenzonitrile; 3-[3-Cyclopropyl-1-(2-amino-ethyl)-5-methyl-1H-pyrazol-4-yloxy]-5-methyl- benzonitrile;
    3-[(3-Cyclopropyl-5-methyl-1H-pyrazol-4-yl)oxy]-5-methylbenzonitrile; 3-{[1-(3-Aminopropyl)-3,5-diethyl-1 H-pyrazol-4-ylloxy}-5-methylbenzonitrile; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)- 1 H-pyrazol-4-yiJoxy}-4-methoxybenzonitrile; 2-[3,5-Diethyl-4-(1-naphthyloxy)-1H-pyrazol-1-yllethanol; 2-[3,5-Diethyl-4-(2-naphthyloxy)-1 H-pyrazol-1-yllethanol,
    2-{4-[3,5-Di(1H-pyrazol-1-yl)phenoxy]-3,5-diethyl-1 H-pyrazol-1-yl}ethanol; 2-{3,5-Diethyl-4-[3-fluoro-5-(1 H-pyrazol-1-yl)phenoxy]- 1 H-pyrazol-1-yl}ethanol; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylloxy}-5-methoxybenzonitrile; 2-{4-(3,5-Difluorophenoxy)-3,5-diethyl-1H-pyrazol-1-yllethylamine; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1 H-pyrazol-4-ylJoxy}-5-fluorobenzamide;
    3-[(3-Isopropyl-5-methyl-1 H-pyrazol-4-yl)oxy]-5-methylbenzonitrile; 3-{[1-(2-Aminoethyl)-3-isopropyl-5-methyl-1 H-pyrazol-4-ylJoxy}-5- methylbenzonitrile;
    2-{4-(3,5-Dichlorophenoxy)-3,5-diethyl-1H-pyrazol-1-yl}-N-(2- pyridinylmethyl)acetamide;
    ) 35 [4-(3,5-Dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yllacetonitrile; 1-{[4-(3,5-Dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yllacetyl}piperidine; (3R)-1-{[4-(3,5-Dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yl]acetyl}-3-piperidinol; N-(2,4-Dichlorobenzyl)-2-[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5- yllacetamide;
    292 PTT
    2-[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]-N-(6-methyl-2-
    pyridinyl)acetamide;
    2-[4-(3,5-Dichlorophenoxy)-3-methyl-1H-pyrazol-5-yl]-N-[4- (trifluoromethyl)benzyl]acetamide;
    N-(3-Chlorobenzyl)-2-{4-(3,5-dichlorophenoxy)-3-methyl-1H-pyrazol-5-
    yllacetamide;
    2-[4-(3,5-Dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yl}-N-[2-
    (trifluoromethyl)benzyllacetamide;
    2-[4-(3,5-Dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yl]-N-(4-
    fluorobenzyl)acetamide; N-Benzyl-2-[4-(3,5-dichlorophenoxy)-3-methyl-1 H-pyrazol-5-yl}-N- methylacetamide; 3-chloro-5-[(5-{[(2-chlorobenzyl)amino]methyl}-3-methyl-1 H-pyrazol-4- yl)oxy]benzonitrile;
    3-({5-[(Benzylamino)methyli}-3-methyl-1 H-pyrazol-4-yl}oxy)-5-chlorobenzonitrile; 3-[(5-{[Benzyl(methyl)amino]methyi}-3-methyl-1 H-pyrazol-4-yl)oxy]-5- chlorobenzonitrile; 3-Chloro-5-{[5-({[(5-chloro-2-pyridinyl)methyl]Jamino}methyl)-3-methyl-1 H-pyrazol- 4-ylloxy}benzonitrile;
    3-Chloro-5-[(3-methyl-5-{[(4-pyridinylmethyl)amino]methyl}-1 H-pyrazol-4- yl)oxylbenzonitrile; 3-Chloro-5-[(3-methyl-5-{[(4-methylbenzyl)amino]methyl}- 1 H-pyrazol-4- yl)oxylbenzonitrile; 3-Chloro-5-[(5-{[(3-methoxypropyl)amino]methyl}-3-methyl-1 H-pyrazol-4-
    yl)oxylbenzonitrile; 4-[2-({[4-(3-Chloro-5-cyanophenoxy)-3-methyl-1 H-pyrazol-5- ylimethyl}amino)ethyilbenzenesulfonamide; 3-Chloro-5-{[3-methyl-5-({[(1S)-1-phenylethyllamino}methyl)-1H-pyrazol-4- yljoxy}benzonitrile;
    3-Chloro-5-[(5-{[(4-chiorobenzyl)amino]methyl}-3-methyl-1 H-pyrazol-4- yl)oxy]benzonitrile; 3-Chloro-5-{(3-methyl-5-{[methyl(2-phenylethyl)amino]methyl}-1 H-pyrazol-4-
    yloxy]benzonitrile; 3-Chloro-5-({3-methyl-5-[(1 H-pyrazol-3-ylamino)methyl]-1 H-pyrazol-4- ’ 35 ylloxy)benzonitrile; N-[2-({[4-(3-Chloro-5-cyanophenoxy)-3-methyl-1 H-pyrazol-5- yllmethyl}amino)ethyljacetamide; . : 3-Chloro-5-[(5-{[(3-chlorobenzyl)amino]methyl}-3-methyl-1 H-pyrazol-4- yloxylbenzonitrile; {
    3-Chioro-5-{[5-({[3-fluoro-5-(trifluoromethyl)benzyllamino}methyl)-3-methyl-1 H- pyrazol-4-ylloxy}benzonitrile; 3-Chloro-5-[(3-methyl-5-{[(6-methyl-2-pyridinyl)amino]methyl}-1H-pyrazol-4- : yl)oxylbenzonitrile; 3-Chloro-5-{(5-{[(4-hydroxy-6-methyl-2-pyrimidinyl)amino]methyl}-3-methyl-1 H- : pyrazol-4-yl)oxy]benzonitrile; 3-Chloro-5-[(5-{[(4-fluorobenzyl)amino]methyl}-3-methyl-1 H-pyrazol-4- yl)oxy]benzonitrile; 3-Chloro-5-{[5-({[(1 R)-2-hydroxy-1-phenylethyllamino}methyl)-3-methyl- 1 H-
    pyrazol-4-yljoxy}benzonitrile; 3-({5-[(Benzylamino)methyl]-3-methyl-1H-pyrazol-4-yl}oxy)-5-chlorobenzonitrile; 3-Chloro-5-[(5-{[(3-methoxybenzyl)amino]jmethyl}-3-methyl-1 H-pyrazol-4- yhoxylbenzonitrile; 3-Chloro-5-{[3-methyl-5-({[4- (trifluoromethyl)benzyllamino}methyl)-1 H-pyrazol-4-
    ylloxy}benzonitrile; 3-Chloro-5-{[5-({[(1 R)-1-(hydroxymethyl)-2-methylpropyl]lamino}methyl)-3-methyl-
    1 H-pyrazol-4-yljoxy}benzonitrile; 3-Chloro-5-[(5-{[(2-methoxybenzyl)amino]methyl}-3-methyl-1 H-pyrazol-4- yl)oxylbenzonitrile;
    3-Chloro-5-{[3-methyl-5-({[2-(2-thienyl)ethyl]Jamino}methyl)-1 H-pyrazol-4- ylloxy}benzonitrile; : 3-Chloro-5-[(3-methyl-5-{[(3-pyridinylmethyl)amino]methyl}-1 H-pyrazol-4- yl)oxylbenzonitrile; 3-Chloro-5-{[3-methyl-5-({[2-(irifluoromethyl)benzyllamino}methyl)-1 H-pyrazol-4-
    ylloxy}benzonitrile; 3-Chloro-5-[(5-{[(2,4-dichlorobenzyl)aminolmethyl}-3-methyl-1H-pyrazol-4- yl)oxylbenzonitrile; 3-Chloro-5-[(3-methyl-5-{[(2-pyridinylmethyl)amino]methyl}-1 H-pyrazoi-4- yl)oxylbenzonitrile; 3-Chloro-5-[(5-{[(3,4-dichlorobenzyl)amino]methyl}-3-methyl-1H-pyrazol-4- yl)oxylbenzonitrile; 3-Chloro-5-[(3-methyl-5-{[(3-phenylpropyl)amino}methyl}-1 H-pyrazol-4-
    : yl)oxylbenzonitrile; 3-Chloro-5-[(5-{[(4-methoxybenzyl)amino]methyl}-3-methyl-1 H-pyrazol-4- - 35 yloxylbenzonitrile; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylJoxy}-5- (methylsulfanyl)benzonitrile; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yljoxy}-5- (methylsulfinyl)benzonitrile;
    3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yljoxy}-5- (methylsulfonyl)benzonitrile; 3-{[8,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylJoxy}-5-{2- : (dimethylamino)ethoxy]benzonitrile;
    3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yljoxy}-5-[2- (methylamino)ethoxy]benzonitrile; 2-(3-Cyano-5-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4- ylloxy}phenoxy)acetamide; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylloxy}-5-(2-
    methoxyethoxy)benzonitrile; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1 H-pyrazol-4-ylloxy}-5-methoxybenzonitrile; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-ylloxy}-5-(1 H-pyrazol-1- yl)benzonitrile; 3,5-Dichlorophenyl-3-methyl-5-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl}-1 H-
    pyrazol-4-yl ether; 3-Fluoro-5-{[1-(2-hydroxyethyl)-5-methyl-3-(trifluoromethyl)-1 H-pyrazol-4- ylloxy}benzonitrile; 5-[(3,5-Diethyl-1-{2-[(2-methoxyethoxy)methoxylethyl}-1 H-pyrazol-4- yl)oxylisophthalonitrile; 3-Cyano-5-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-yljoxy}benzamide; 5-{[5-Ethyl-3-(1-hydroxyethyl)-1 H-pyrazol-4-yl]oxylisophthalonitrile; 5-{[5-Ethyl-3-(1-hydroxyethyl)-1-(2-hydroxyethyl)-1H-pyrazol-4- ylloxylisophthalonitrile; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylloxy}-5-(5-trifluoromethyi-1,2,4-
    oxadiazol-3-yl)benzonitrile; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylJoxy}-5-(5-methyl-1,2,4- oxadiazol-3-yl)benzonitrile; 3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-yljoxy}-5-(5-ethyl-1,2,4-oxadiazol- 3-yl)benzonitrile;
    3-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-yljoxy}-5-(5-isopropyl-1,2,4- oxadiazol-3-yl)benzonitrile; 5-[({[4-(3-Chloro-5-cyanophenoxy)-3-methyl-1H-pyrazol-5- ylimethyl}lamino)methyli]nicotinamide; 2-[({[4-(3-Chloro-5-cyanophenoxy)-3-methyl-1H-pyrazol-5-
    yllmethyl}amino)methyljisonicotinamide; Di(tert-butyl) 2-[4-(3,5-dicyanophenoxy)-3,5-diethyl-1 H-pyrazol-1-yljethyl phosphate; 2-[4-(3,5-Dicyanophenoxy)-3,5-diethyl-1 H-pyrazol-1-yllethyl dihydrogen phosphate;
    5-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-yljoxy}isophthalonitrile sulfate salt; 5-{[3,5-Diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylJoxy}isophthalonitrile ; 5-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]Joxy}isophthalonitrile tosylate salt; : 5-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrile mesylate salt; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1 H-pyrazol-4-ylJoxy}-5-methylbenzonitrile bis- mesylate salt; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1 H-pyrazol-4-ylJoxy}-5-methylbenzonitrile phosphate salt; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-ylJoxy}-5-methylbenzonitrile (L) tartrate salt; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}-5-methylbenzonitrile succinate salt; 3-{[1-(2-Aminoethyl)-3,5-diethyl-1 H-pyrazol-4-ylloxy}-5-methylbenzonitrile (L) citrate salt; or a pharmaceutically acceptable salt, solvate or derivative thereof.
  29. 29. 3-{[8,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-yljoxy}-5-fluorobenzonitrile; 3-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yiJoxy}-5-methylbenzonitrile; 5-{[3,5-diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-ylJoxy}isophthalonitrile; 3-chloro-5-{[3,5-diethyl-1-(2-hydroxyethyl)-1 H-pyrazol-4-ylJoxy}benzonitrile; 5-[(3,5-diethyl-1 H-pyrazol-4-yl)oxylisophthalonitrile; 3-[(3,5-diethyl-1 H-pyrazol-4-yl)oxy]-5-methylbenzonitrile; 3-chloro-5-[(3,5-diethyl-1 H-pyrazol-4-yl)oxy]benzonitrile; 3-{[1-(2-aminoethyl)-3,5-diethyl-1 H-pyrazol-4-ylJoxy}-5-methylbenzonitrile; 3-{[1-(2-aminoethyl)-3,5-diethyl-1 H-pyrazol-4-yljoxy}-5-chlorobenzonitrile; 5-{[1-(2-aminoethyl)-3,5-diethyl-1H-pyrazol-4-ylJoxy}isophthalonitrile; or a pharmaceutically acceptable salt, solvate or derivative thereof
  30. 30. A compound of the formula (1) R* R' L , 2 pa Rr’ ora pharmaceutically acceptable salt or solvate thereof, wherein:
    R' is H, Cy-Cs alkyl, -OC4-Cs alkyl, -OCs-C; cycloalkyl, said C4-Cg alkyl being optionally substituted by R'; R?is H, Ci-Cs alkyl, propenyl or C-linked R'™, said C;-C; alkyl being optionally ‘ substituted by -OH, -OCHs, -OCH5CHoNH,, -CN, -CO2CHs, -CONHo, -C(=NH)NH,, -CONHNH2, -NH,, -NHCHj; -N(CHaj)2, -NHCH>CH,NHCOCHS, -NHCH,CH,OCHj, -NHCH,R'", -NHCOR'®, -NHCOCH,OCHg, or R™ R%is C4-Cs alkyl; R* is phenyl optionally substituted by halo, -CN, C4-Cg alkyl, C;-Cs haloalkyl, C;-C7 cycloalkyl or C4-Cg alkoxy; and RY is azefidinyl, tetrahydrofuranyl, morpholinyi, piperazinyl, pyrazolyl, oxadiazolyl, pyridinyl or pyrimidinyl each being optionally substituted by -OH, -NHa, oxo or C4-Cg alkyl or -CO(C1-Cs alkyl).
  31. 31. A pharmaceutical composition including a compound of the formula (l) or a pharmaceutically acceptable salt, solvate or derivative thereof, according to any preceding claim, together with one or more pharmaceutically acceptable excipients, diluents or carriers.
  32. 32. A pharmaceutical composition according to claim 31 including one or more additional therapeutic agents.
  33. 33. A compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims 1 to 30, or a pharmaceutical composition according to claim 31 or 32, for use as a medicament.
  34. 34. A compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims 1 to 30, or a pharmaceutical composition according to claim 31 or 32, for use as a reverse transcriptase inhibitor or modulator.
  35. 35. A compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims 1 to 30, or a pharmaceutical composition according to claim 31 or 32, for use in the treatment
    © WO0 02085860 PCT/IB02/01234 of an HIV, or genetically-related retroviral, infection or a resulting acquired immune deficiency syndrome (AIDS).
  36. 36. The use of a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims 1 to 30, or a pharmaceutical composition according to claim 31 or 32, for the manufacture of a medicament having reverse transcriptase inhibitory or modulating activity.
  37. 37. The use of a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims i io 30, or a pharmaceutical composition according to claim 31 or 32, for the manufacture of a medicament for the treatment of an HIV, or genetically-related retroviral, infection or a resulting acquired immune deficiency syndrome (AIDS).
  38. 38. A process for preparing a compound of the formula (1) or a salt, solvate or pharmaceutically acceptable derivative thereof according to any of claims 1 to 30, which comprises: AMENDED SHEET ”
    (A) except where either R' or R® is halo, -OR® or CN, condensation of a compound of the formula (11), (VI) or (Vii) 4 4 R Rr’ R R' rR* 1 ONG 0 1 R L o | © To ar RO ROL 3 R= 0 VD or (vi)
    with a compound of the formula HNNHR? (V) or a salt or hydrate thereof; (B) for the preparation of a compound of the formula (I) in which R' or R® is -OR®, reaction of, respectively, a compound of the formulae (XI) or (XIV) 4 4 A ba Q 13 0) R! Daf (XH) Da (XIV) R N\ L N\ NR? or NS R2 with an alcohol of the formula (XXI) R®OH (XX)
    in the presence of a suitable palladium catalyst and carbon monoxide; (C) for the preparation of a compound of the formula (f) in which R' or R® is -OR®, reaction of, respectively, a compound of the formulae (XV) or (XVI),
    i 4 4 A J Q oH R! Da (XV) Daf (XVI) R= _N HO™X _N_ N~ ~R? or N~ R> y
    © Wo 2085860 PCT/IB02/01234 with a compound of the formula (XXI) ROH (xX) under dehydrating conditions; or (D) for the preparation of a compound of the formula (I) in which R' or R® is halo, reaction of, respectively, a compound of the formulae (XV) or (XVI) —4 4 a R =" R' ={ ow ={ ov RN No HON _N. N" TR? of NN“ R? with a halogenating agent; or (E) interconversion of a compound of formula (1) into another compound of formula (1); or (F) deprotecting a protected derivative of compound of formula (1); and optionally converting a compound of formula ()) prepared by any one of processes (A) to (F) into pharmaceutically acceptable salt, solvate or derivative thereof.
  39. 39. A compound of the formulae (If), (VI), (VII), (tl) or Xv).
  40. 40. A compound according to any one of claims 1, 30, 33, 34, 35 or 39, substantially as herein described and exemplified.
  41. 41. A pharmaceutical composition according to any one of claims 31, 33,34 0r 35, substantially as herein described and exemplified.
  42. 42. Use according to claim 36 or 37, substantially as herein described and exemplified.
  43. 43. A process according to claim 38, substantially as herein described and Co exemplified. oo AMENDED SHEET I B
ZA200307095A 2001-04-10 2003-09-10 Pyrazole derivatives for treating HIV. ZA200307095B (en)

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ECSP034800A (en) 2003-12-01
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TNSN03088A1 (en) 2005-12-23
HN2002000081A (en) 2003-11-15
UA75124C2 (en) 2006-03-15

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