AU2004218260A1 - N-aryl heteroaromatic products, compositions containing same and use thereof - Google Patents

N-aryl heteroaromatic products, compositions containing same and use thereof Download PDF

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AU2004218260A1
AU2004218260A1 AU2004218260A AU2004218260A AU2004218260A1 AU 2004218260 A1 AU2004218260 A1 AU 2004218260A1 AU 2004218260 A AU2004218260 A AU 2004218260A AU 2004218260 A AU2004218260 A AU 2004218260A AU 2004218260 A1 AU2004218260 A1 AU 2004218260A1
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pyrazol
methyl
piperazin
methanone
phenyl
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AU2004218260A
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Alain Le-Brun
Patrick Mailliet
Joseph M Salvino
Fabienne Thompson
Gilles Tiraboschi
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Aventis Pharma SA
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Aventis Pharma SA
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Priority claimed from FR0300894A external-priority patent/FR2850379B1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Description

IN THE MATTER OF an Australian Application corresponding to PCT Application PCT/FR2004/000168 RWS Group Ltd, of Europa House, Marsham Way, Gerrards Cross, Buckinghamshire, England, hereby solemnly and sincerely declares that, to the best of its knowledge and belief, the following document, prepared by one of its translators competent in the art and conversant with the English and French languages, is a true and correct translation of the PCT Application filed under No. PCT/FR2004/000168 Date: 7 June 2005 C. E. SITCH Deputy Managing Director - UK Translation Division For and on behalf of RWS Group Ltd WO 2004/078732 1 PCT/FR2004/000168 N-ARYL HETEROAROMATIC PRODUCTS, COMPOSITIONS CONTAINING SAME AND USE THEREOF The present invention relates to novel chemical compounds, particularly novel N-arylheteroaromatic products, to compositions containing them and to their 5 use as medicinal products. More particularly, the invention relates to novel N-arylheteroaromatic products with anticancer activity, and in particular inhibitory activity on tubulin polymerization. The N-arylheteroaromatic products concerned herein correspond to the 10 following general formulae (la), (Ib) or (Ic): R3 R4 R5 R1 R3 R4 R 5 R3 R4 R 5 R9 NN X N .,. NR R1 / R6 I R6 N R6 R2 R2 R2 General formula (la) General formula (Ib) General formula (Ic) Van Wijngaarden et al. (US 4 772 604, US 4 874 770, EP 0 241 053) claim piperazine derivatives with antipsychotic properties. These patents have also been recalled in Chem. Abs., Vol. 108 (1988), p. 576, 221717q, in which they 15 form the subject of the citation of two products, neither of which is disclosed in the abovementioned patents. These are N \/ o HO and N N/ -I 0 / CI \/ o 2 As may be seen on reading the patents from Van Wijngaarden et al., the products described and claimed are either 2,5-disubstituted pyrroles or 1,3- or 3,5-disubstituted pyrazoles. Thus, the two products described above, which are 1,5-disubstituted pyrazoles, can neither be found nor deduced from the 5 content of these documents. Patent application WO 01/19798 claims heterocyclic compounds that are useful as Factor Xa inhibitors for the treatment, for example, of thrombosis and for inhibiting the coagulation of biological samples. The products described are not included in the definition of the products according to the 10 invention, with the exception of the following compound: Ermondi et al., in Farmaco, 53, 519 (1998), discloses prazosine analogs, which are potential adrenoreceptor-al inhibitors. Only one prazosine analog is a 5-(4-heteroarylpiperazinocarbonyl)-1-phenylpyrazole: HNOMe N N 0 N
O
15 Baxtermondi et al. (WO 01/5782) claim piperidine compounds prazosing the anformulalogs, below, for the treatmial adrent of diseasesptor-l in hibitors.ch modulate on of thprazose chemokinealog is a 5-(4-heteroarylpiperazinocarbonyl)-1 -phenylpyrazole: H2N Me N~~ W~e N N NJ N 0 15 Baxter et al. (WO 01/5782) claim piperidine compounds having the formula below, for the treatment of diseases in which modulation of the chemokine 3 receptors may be beneficial, such as pulmonary obstructions or rheumatoid arthritis. RN,Y U V Q(Rn Ri NW (R 3 )n R2 I R4 In no case can Q represent a single bond therein, and thus the products 5 described in WO 01/5782 cannot be included in the present invention. Now, surprisingly, it has been found that products corresponding to the general formula (I) below have considerable inhibitory activity on tubulin polymerization: R3 R4 R5 R R3 R4 R5 Ri R3 R4 R5 R9 X L, NR X L, R1XI R 1 (1) N N' \i N NI L N L N, N L R6L SR6 / R6 / R6 R2 R2 R2 General formula (la) General formula (Ib) General formula (Ic) 10 in which: 1) R1 and R2 are selected independently from the group consisting of aryl, heteroaryl, substituted aryl and substituted heteroaryl; R2 may also be chosen from the group C5-C7 cycloalkyl; 2) L is selected from the group consisting of C(R7)(R8), C=O, C=S, and 15 C=N(R7); 3) R3 is selected from the group consisting of H, halogen, CF3, alkyl, substituted alkyl, alkylene, substituted alkylene, alkynyl, substituted alkynyl, cycloalkyl, cycloalkylene, heterocyclyl, substituted heterocyclyl, CO-R7, C(R7)=N-O(R8), COOH, CONH-aryl, CONH-heteroaryl, 20 CONH-R7, CON(R7)(R8), CO-N(R7)-aryl, CO-N(R7)-heteroaryl, C(OR7)=NH, C[N(R7)(R8)]=NH, NH2, NH-aryl, NH-heteroaryl, NH(R7), N(R7)(R8), NH-CO-R7, N(R7)-CO-aryl, N(R7)-CO-heteroaryl, NH SO2-R7, NH-SO2-aryl, NH-SO2-heteroaryl, NH-CH2-CO2(R7), NH CH2-aryl, NH-CH2-heteroaryl, NH-COO-(C1-C4)alkyl, NH-CH2-(C2 25 C3)alkylene, NH-CH2-(C2-C3)alkynyl, N(R7)-N(R8)(R12), 4 N-N=C(R7)(R8), CN, O-R7, O-CH2-aryl, O-CH2-heteroaryl, S-R7, SO R7, SO 2 -R7, aryl, heteroaryl, substituted cycloalkyl, substituted aryl and substituted heteroaryl; 4) R4 is selected from the group consisting of H, (C1-C3)alkyl, 5 cyclopropyl, (C2-C3)alkylene, (C2-C3)alkynyl, O(C1-C3)alkyl, S-(C1 C3)alkyl, F, Cl and Br; 5) XisNorCH; 6) R5 and R6 are selected independently from the group consisting of H, (C1-C3)alkyl, oxo and halogen; 10 7) R7, R8 and R12 are independently selected from the group consisting of H, (C1-C3)alkyl and substituted (C1-C3)alkyl; 8) R9 is (C1-C3)alkyl; in racemic form, enriched in one enantiomer, enriched in one diastereoisomer, its tautomers, its prodrugs and its pharmaceutically 15 acceptable salts, with the proviso that the product of formula (I) is not one of the following compounds: N NJ OS 0 N 0-S N N 1 OMe N Pf fa OMe reaN N 0 Products of general formula (la) or (Ib) are preferred.
5 Products for which X is N are preferred. A preferred substituent R1 may be chosen from phenyl; phenyl substituted with at least one radical chosen from halogen, (C1-C3)alkyl, CON(R10)(R11), O-R10, S-R10 and N(R10)(R11), in which R10 and R11 are chosen 5 independently from H, (C1-C3)alkyl and halogenated (C1-C3)alkyl; pyridyl; pyridyl substituted with at least one radical chosen from halogen, (C1-C3) alkyl, CON(R10)(R11), O-R10, S-R10 and N(R10)(R11), in which R10 and R11 are chosen independently from H, (C1-C3)alkyl and halogenated (Cl C3)alkyl. 10 More preferably, R1 will be phenyl substituted with halogen or (C1-C3)alkyl, or (C1-C3)alkoxy, or carboxamide; 2- or 3-pyridyl; 2- or 3-pyridyl substituted with halogen or (C1-C3)alkyl. Very preferably, R1 is phenyl substituted with a chloro radical, one or two methoxy radicals or a carboxamide radical. 15 When R1 is substituted phenyl, preferred substitution combinations may be chosen from 2,3-disubstituted phenyl, 2,5-disubstituted phenyl, 3-substituted phenyl, 3,5-disubstituted phenyl and 3,4-disubstituted phenyl, and more preferably from 3-substituted phenyl, 3,5-disubstituted phenyl and 3,4 disubstituted phenyl. 20 When R1 is substituted 2-pyridyl, preferred substitutions are chosen from 4 or 6-substituted 2-pyridyl or 4,6-disubstituted 2-pyridyl. When R1 is substituted 3-pyridyl, preferred substitutions are 2- or 5-substituted 3-pyridyl. A preferred substituent R2 may be chosen from phenyl, 3-pyridyl, phenyl 25 substituted with at least one radical chosen from halogen, alkyl, O-R10, S-R10 and N(R10)(R11), in which R10 and R11 are independently chosen from H, (Cl-C3)alkyl and halogenated (C1-C3)alkyl. A preferred substituent R2 is chosen from unsubstituted phenyl and 3-pyridyl. Unsubstituted phenyl is more preferred. 30 Preferably, R3 is H or (Cl-C3)alkyl, CF3, hydroxymethyl, amino, azetidino or pyrrolidino.
6 More preferably, R3 is H or a methyl, hydroxymethyl, CF3 or amino radical. R4 is preferably H. In general, products of general formula (la), (Ib) or (Ic) in accordance with the 5 invention in which L is C(O) may be prepared by coupling a 1-aryl(heteroaryl) pyrrole-2-carboxylic acid, or a 2-aryl(heteroaryl)pyrazole-3-carboxylic acid, of general formula (11), in which R2, R3 and R4 are defined as above, with, respectively, a piperazine derivative of general formula (lila) or a 1,2,3,6 tetrahydropyridine derivative (Illb), in which R1 is defined as above, or a 10 piperidine derivative of general formula (IlIc), in which R1 and R9 are defined as above, according to Scheme 1: R5 R5
HO
2 C R4 R5 + Ri-N NH Ri-N N R4 N ' R 3 (IIa)-(la) (II) R6 R6 R2. N. X/ R3 R2 X
HO
2 C R4 R5 R5 S R3 + R1 H R1 N (b) R2,N7x/" R3 (c R.2 'X (111b) - (Ib (11) R6 R6 R2,N X R3 R2 X Scheme 1 The coupling may be performed using the coupling methods known to those 15 skilled in the art, in particular those consisting in activating the acid of general formula (11) in the form of chloride or anhydride, or any of the coupling methods developed for peptide synthesis. In general, products of general formula (la), (Ib) or (lc) in accordance with the invention in which L is C(O) may be prepared by coupling a methyl or ethyl 20 ester of a 1-aryl(heteroaryl)pyrrole-2-carboxylic acid or of a 2-aryl(heteroaryl) pyrazole-3-carboxylic acid, of general formula (11), in which R2, R3 and R4 are defined as above, with, respectively, a piperazine derivative of general 7 formula (lila) or a 1,2,3,6-tetrahydropyridine derivative (lllb), in which R1 is defined as above, or a piperidine derivative of general formula (lllc), in which R1 and R9 are as defined above according to Scheme 1(a): C2 R4 R5 R5 Me(Et)-CO R4 / O + R1 -N NH -- Ri-N -N R4 R2N / R3 (Iia) (la) R2' X a)Ia (II) R6 R6 ,N../ R3 R2 X Me(et)C R4 R5 R5 R.Nii' R3 RNH - R N1 Me(Et) (llib) (Ib) R4 R9 R9 R2+EN)- /... R1 NH R1 N N R3 + (lllc) R (Ic) ) R6 6 N / R3 R2 X 5 Scheme 1 a The coupling may be performed using the coupling methods known to those skilled in the art, in particular by activating the amine (lila), (lllb) or (lllc) with trimethylaluminum under the conditions described in Organic Synthesis 59, 49-53 (1980). 10 The acids or the methyl or ethyl esters of 1-aryl(heteroaryl)pyrrole-2 carboxylic or 2-aryl(heteroaryl)pyrazole-3-carboxylic acids of general formula (11) may be obtained according to the methods known to those skilled in the art, in particular the ortho-carboxylation of a pyrrole or pyrazole derivative, followed by the N-alkylation or N-arylation of the pyrrole or pyrazole according 15 to Scheme 2; in the case of the pyrazoles, a readily separable mixture of N-1 and N-2 substituted products is generally obtained.
8 1-BuLi or R4 other base R'O C R4 Cleavage of oDG R4 - 2-CO 2 or H(CI)CO 2 R' 2 R' 2 C oDG. R3 oDG'N x'/ R3 HN R3 oDG- x oD Xx arylation oDG = ortho-directing group arylation such as Boc, Ac or COCF 3 R'= H, Me or Et R'0 2 C R4 R2,N /R3 (ll) R2' X Scheme 2 When X represents a nitrogen atom, the arylation, advantageously performed by Suzuki coupling, may be performed by working under the conditions 5 described in Tetrahedron, 55, 12757 (1999). When X represents a nitrogen atom, the arylation may very advantageously be performed by working under the conditions described by Buchwald in J. Amer. Chem. Soc., 123, 7727 (2001), with an aryl halide R2-Hal, by catalysis with cuprous iodide in the presence of cesium carbonate and 1,2 10 diaminocyclohexane. In the case where R2 represents a phenyl radical, X represents a CH group and R4 represents a hydrogen atom, it is possible to perform the ortho carboxylation of 1-phenylpyrrole-2-carboxylic acid directly, by working according to Tetrahedron, 49, 10278 (1993). 15 The groups R3 and/or R4, which are other than a hydrogen atom, the 1-aryl(heteroaryl)pyrrole-2-carboxylic or 2-aryl(heteroaryl)pyrazole-3-car boxylic acids of general formula (II) may also be introduced into 1-aryl(heteroaryl)pyrrole-2-carboxylic or 2-aryl(heteroaryl)pyrazole-3-car boxylic acids of general formula (11), in which R3 and/or R4 represent a 20 hydrogen atom, by any of the conventional methods known to those skilled in the art.
9 Among these methods, mention may be made of the regioselective halogenation of the 1-aryl(heteroaryl)pyrrole-2-carboxylic or 2-aryl(hetero aryl)pyrazole-3-carboxylic acids, followed by substitution. In the context of the invention, when X represents a nitrogen atom, the 5 substitution of a halogen in position 3 of a 1-aryl-1H-pyrazole-5-carboxylic acid ester is found to be a method that is particularly advantageous for preparing a derivative of general formula (la) in which X represents a nitrogen atom, R4 represents a hydrogen atom and R3 represents alkylene, substituted alkylene, alkynyl, substituted alkynyl, aryl, substituted aryl, 10 heteroaryl, substituted heteroaryl, NH2, NH-aryl, NH(R7), N(R7)(R8), NH-CO R7, NH-CO-aryl, NH-SO2-aryl, NH-CH2-CO2R7, NH-CH2-aryl, N(R7) N(R7)(R8), N-N=C(R7)(R8), CN, OR7, SR7, SO-R7 or SO2-R7, according to Scheme 2a. 1) NBS (NIS) 2) base H OR' H R2 ,N 0 RO 2 C substitution R'2 %OH N R OR2,N Br(I) R2' N (II) (II) R' = Me or Et 15 Scheme 2a In the context of the invention, the substitution of ethyl 3-bromo-1-phenyl-1H pyrazole-3-carboxylate, which may be prepared according to Tetrahedron Lett., 40, 2605 (1999), will be used in particular. 20 In the context of the invention, the substitutions of the bromine atom will advantageously be performed by heating for a few minutes at 120-150 0 C in a microwave reactor, more particularly Suzuki and Heck carbon-carbon couplings or Buchwald aminations. In the context of the invention, when X represents a nitrogen atom or a CH 25 radical, the substitution of the bromine atom of a bromomethyl radical in position 3 of a 1-aryl-1 H-pyrazole(pyrrole)-5-carboxylic acid ester is found to 10 be a method that is particularly advantageous for preparing a derivative of general formula (la) in which X represents a nitrogen atom or a CH radical, R4 represents a hydrogen atom and R3 represents an alkyl radical, according to Scheme 2b. NBS/AIBN R'O2C substitution R'O 2 C a'o 2 c cci 4 -- XR* N= 2,/ N / N. / CR2N R2N NX ' - R2 X Br + + (ll)
R'O
2 C X'= O, S, NH, N(R7)) R'= Meor Et - Br R'3= R8 N'Y R2 ' X Br CaCO3 microwave
R'O
2 c reductive R'O 2C R N amination 2, R'3 N- R'3 N'-N' R2' x R2 "x 5 O Scheme 2b In the context of the invention, the substitutions of the bromine atom will advantageously be performed by heating for a few minutes at 120-1500C in a microwave reactor. 10 In the case where X represents a nitrogen atom, R3 represents a hydrogen atom or a C1-C3 alkyl radical and R4 represents a hydrogen atom, it is advantageous to use the method for synthesizing 2-aryl(heteroaryl)pyrazole 3-carboxylic acids described in J. Het. Chem., 30, 307 (1993), starting with aryl(heteroaryl)hydrazines, by working according to Scheme 3: H
N
" 1) AcOH HO 2 R2NNH2 + reflux , R4 1 R4 CO 2 Et 2) NaOH R2 N 1 5 2) NaOH Scheme 3 Starting with aryl(heteroaryl)hydrazines, it is also advantageously possible to prepare 2-aryl(heteroaryl)pyrazole-3-carboxylic esters, by working according to J. Het. Chem., 36, 217 (1999), which will then be saponified to the 20 corresponding acids.
11 Another method for synthesizing 2-aryl(heteroaryl)pyrazole-3-carboxylic esters that is particularly advantageous in the context of the invention uses cycloaddition reactions, followed by oxidation of the intermediate adduct obtained with chloranil, of aryl(heteroaryl)hydrazones with a propionate, by 5 working according to Tetrahedron, 36, 887 (1980). Another method for synthesizing 1-aryl(heteroaryl)pyrrole-5-carboxylic acid esters that is particularly advantageous in the context of the invention uses the reaction of an aryl(heteroaryl)amine with 2,5-dimethoxytetrahydrofuran, by working according to Heterocycles, 53, 2160 (2000). 10 The piperazine derivatives of general formula (lila), in which R1, R5 and R6 are defined as above are either commercially available or are prepared according to the standard methods known to those skilled in the art. Among these methods, the Nl-aryl(heteroaryl)ation, according to Scheme 4, of piperazines bearing a protecting group on the nitrogen in position 4, is 15 particularly advantageous in the context of the invention: R5 arylation R5 cleavage of GP R5 HN N-GP - R1-N N-GP - R1-N NH R6 R6 R6 (lila) GP = Boc, Ac, Cbz, Bn ... Scheme 4 The aryl(heteroaryl)ation reaction of piperazines, generally of Hartwig/ 20 B0chwald type, may be performed by working under the conditions described in Biorg. Med. Chem. Lett., 11, 1375 (2001) or in Biorg. Med. Chem., 10, 3817 (2002). Another method for synthesizing aryl(heteroaryl)piperazines that is particularly advantageous in the context of the invention, when R5 and R6 25 represent hydrogen-atoms, consists in reacting an aryl(heteroaryl)amine with a bis(2-hydroxy- or 2-haloethyl)amine, at a temperature above 100-120 0 C, according to Scheme 5: 12 OH(Hal) R1-NH2 + 2 NH R1-N NH (Illa) OH(Hal) Scheme 5 It is particularly advantageous to perform the process in the presence of microwaves under the conditions described in Synth. Comm., 28, 1175 5 (1998), or in Tetrahedron Lett, 38, 6875 (1997). The 1,2,3,6-tetrahydropyridine derivatives (Illb), in which R1, R5 and R6 are defined as above, are either commercially available or are prepared according to the conventional methods known to those skilled in the art. Among these methods, the action according to Scheme 6, of an 10 organometallic aryl(heteroaryl) derivative, such as an organomagnesium reagent, an organolithium reagent or an organocerium reagent, on a piperid 4-one derivative in which the nitrogen atom is substituted with a protecting group, is particularly advantageous. O= NGPR1-M RH OI N-GP ---- R1 N-GP - R1 NH HO GP = Boc, Ac, Cbz, Bn ... (lb) 15 M = MgCI(Br), CeCl 2 ... Scheme 6 The process may be performed in particular under the conditions described in J. Med. Chem., 38, 1998 (1995) or in EP 306764 or in J. Med. Chem., 28, 311 (1985). 20 When R5 and R6 represent hydrogen atoms, Suzuki coupling of the pinacol ester of N-Boc-1,2,3,6-tetrahydropyridyl-4-boronic acid with an aryl or hetero aryl halide, preferably a bromide or an iodide, under the conditions described in Tetrahedron Lett, 41, 3705 (2000), according to Scheme 7, is particularly advantageous in the context of the invention. It is understood that the Boc 25 protecting group may be replaced with any other protecting group that is compatible with the reaction conditions and that the pinacol boronic ester may 13 also be replaced with any other boronic, acid or ester derivative that is compatible with said conditions. R1-Hal + B - N-boc - R1 - N-boc R1 NH (lllb) 5 Scheme 7 The piperidine derivatives, in which R1, R6, R7 and R9 are defined as above, are prepared according to the conventional methods known to those skilled in the art. Among these methods, the action, according to Scheme 8, of an 10 organometallic alkyl derivative, such as an organomagnesium reagent, an organolithium reagent or an organocerium reagent, on a piperid-4-one derivative in which the nitrogen atom is substituted with a protecting group, followed by the action of an aryl or heteroaryl derivative, in the presence of an acid catalyst, of Lewis acid or superacid type according to Olah, is particularly 15 advantageous in the context of the invention. R9-M R9.. R9-H R9, R9 OH N-GP -MRO N-GP R N-GP NH acid cat. Ri GP = Boc, Ac, Cbz, Bn .... (IlIc) M = MgCI(Br), CeCI 2 ... Scheme 8 The process may be performed in particular under the conditions described in 20 J. Med. Chem., 41, 5320 (1998) or in Tetrahedron Lett., 41, 8853 (2000). In general, products of general formula (la), (Ib) or (Ic) in accordance with the invention in which L is CH 2 may be prepared by reducing a compound of general formula (la), (Ib) or (Ic), respectively, in which L is C(0), by any of the reduction methods known to those skilled in the art, for instance the 25 Clemmensen or Wolff-Kishner methods, by working according to Scheme 9: 14 R5 R5 R1-N N R (la) R1-N N R4 (la) R 6 N/ ' R 3 ( a R2 X R6 N' R3 R2 X R5 0 R5 R1 N R4 (Ib) Ri N R4 (lb) R6 NR2Nx/ R3 R2 X R6 .N' R3 R2 X R5 R9 R5 R1 R (Ic) . R N Rc) R6 N-- ' /RR3 R2 X R6 ,Nx' R3 R2 X Scheme 9 In general, products of general formula (la), (Ib) or (Ic) in accordance with the invention in which L is CH 2 may also be prepared from the esters of the 5 products of general formula (11), by using the various methods known to those skilled in the art, according to the reaction sequences of Scheme 10: O R5 R4 OH R1-N N R4 RR~ N I)R~~, (1a) R3 ,NR2 (llia) R6 (l. )/ R3 R2 X 1- esterification 2- reduction R5 (3- LG) R4 OH (LG) (Ilib) R1 NR4 (Ib) R3 ~OH (L-G)R6R3 R6 .Nx' R3 R3 .N- R2 X X R2 (lc) LG = Hal, OTs, OMs ... R9 R5 R1 N R4 R6 R2N7 ' R3 (c) R2 X Scheme 10 In general, products of general formula (la), (Ib) or (Ic) in accordance with the 10 invention in which L is CR7R8, with R7 and/or R8 other than a hydrogen atom, may also be prepared from the products of general formula (11), or 15 esters thereof, using the various methods known to those skilled in the art, according to-the reaction sequences of Scheme 11: O R5 R4 OH(Oalk) R7 R8 R1-N N - R 4 (la) R3 X I- R2 (lla) R6 .N / R3 R6 -, R3 R2 X R5 R7 R 8 (lllb) R1 N R (Ib)
R
4
R
7 OH (LG) R6 ~N' R3 R3 N-R2 R2' X X R2 (Illc) R5 LG = Hal, OTs, OMs .... R9 R7 R8 RI N R4 .(Ic) R6 R2. N'~' R3 Scheme 11 5 In general, products of general formula (la), (Ib) or (Ic) in accordance with the invention in which L is C(S) may be prepared by thionation of a compound of general formula (la), (Ib) or (Ic), respectively, in which L is C(0), by any of the reduction methods known to those skilled in the art, by working according to Scheme 12: R5 R5 RlN \OHR R4 (la) R-N N (la) R6 ,N R36 R3 R2 X R6 , 2 N / R3 R2' X R5 0 R5 R1 N R4 (Ib) R1 (Ib) R1 N R (lb) R6 N R3 R2 X R6 WN R3 R2 X R5 R9 o R5 R IV N 4 (Ic) - R ( - N R4 (Ic) R6 N R3
S
R2 X R6 R2,N, R3 Scheme10 R2 X12 Scheme 12 16 It is particularly advantageous in the context of the invention to perform the thionation using a Lawesson reagent, by working according to Bull. Soc. Chim. Belg., 87, 293 (1978). In general, products of general formula (la), (Ib) or (Ic) in accordance with the 5 invention in which L is C(NH) may be prepared from the nitriles derived from the products of general formula (11), using the various methods known to those skilled in the art, according to the reaction sequences of Scheme 13: O R5 R4 OH R1-N -kN NH R4 (a) R 3 1 X ,N,. I)(a X R2 (lia) R6 N R3 R2 X N R5 R4 /N (Ilib) R1 NH (b) R3 ' N R6 N R3 R25 X R2 R6 RN,' R3 R2 X R4 Br f RI- NI R4 (Ic R BrR9 I NH Scheme 13 10 It is generally necessary to activate the nitrile, which is relatively unreactive, either with aluminum chloride, by working according to J. Chem. Soc. 1947, 1110; or with cuprous iodide, by working according to Tetrahedron Lett., 34, 6395 (1993); or by converting the nitrile into an imino ether prior to the reaction with the piperazine - or 1,2,3,6-terahydropyridine or piperidine 15 derivative, by working according to Eur. J. Med. Chem., 24, 427 (1989). In general, products of general formula (la) or (Ic) in accordance with the invention in which L is C(NR7), with R7 identical to or different than a hydrogen atom, may be prepared from the products of general formula (la) or (Ic), respectively, in which L is C(O) and/or C(S), by using the various 20 methods known to those skilled in the art, according to the reaction sequences of Scheme 14: 17 R5 R5 R5 xY -\ N-R7 R1-N N R4 Ri-N N. R4 Ri-N N R4 'R6 N,' R3R6 N' 3 (Ia) R6 R2.,N'X R3 R6 N R3 R6 R2 N X R3 R N4 RRN4 3 R % N R 4 (a) ( R , a) R5 R3 R9R9 Y R9y R5 _V N_ R4 _V N _ R4 R/i- NR4 RI A. 3 6 N' R3 -- - R 6 .N iR (Ic) R2 XR2 R2 X (Ic) Scheme 14 In the context of the invention, when X is an oxygen atom, it is particularly advantageous to successively react oxalyl chloride, which leads to an 5 intermediate in which Y is a chlorine atom, and then an amine R7-NH 2 , by working according to PoL. J. Chem., 58, 117 (1984), and in the case where X is a sulfur atom, to first react methyl iodide, which leads to an intermediate in which Y is a methylthio radical, and then an amine R7-NH 2 , by working according to Eur. J. Med. Chem, 12, 365 (1977). 10 More specifically and more advantageously in the context of the invention, products of general formula (la) in accordance with the invention in which L is C(O), X is N, R3 is methyl, R6 and R7 are H and R1 and R2 are defined as above, may be prepared by coupling between a 1-phenylpyrazole-3 carboxylic acid and a piperazine derivative according to Reaction Scheme 15: H 0 N' 0 1) AcOH HO2c 1) (COCI) 2 , CH 2
C
2 /-- 0 ,N + 2 reflux R1-N N R1 NH 2 CO Et- 2 2) NaOH R2 N N 2) R2-N NH N 15 THF, TEA Scheme 15 In this scheme, a phenylhydrazine, optionally in salified form, is condensed with an a-methyloxime of an a,y-diketo ester in acidic medium to give a mixture of 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic and 5-methyl-I 20 phenyl-1 H-pyrazole-3-carboxylic acids. The 5-methyl-2-phenyl-2H-pyrazole-3 carboxylic acid is isolated and then used in an amidation reaction between 18 the preactivated carboxylic function of the pyrazole and an amine such as a 4-arylpiperazine in basic medium to give a product in accordance with the invention. The 5-alkyl-2-phenyl-2H-pyrazole-3-carboxylic and 5-alkyl-1l-phenyl-1H 5 pyrazole-3-carboxylic acids may be obtained and isolated under the conditions described by Ashton, in J. Het. Chem., 30, 307 (1993). More specifically and more advantageously in the context of the invention, products in accordance with the invention may also be prepared on a solid phase, according to Reaction Scheme 16: 0 F R2 R2 R2-N \-O NH or-n NOH - N1O 0 NFNN R1-N N HDMAP H F FO0 DMF F FDMF 16h I 20h 10 Scheme 16 More specifically and more advantageously in the context of the invention, products of general formula (la) in accordance with the invention in which L is C(O), X is N, R3 is other than H or methyl, R6 and R7 are H and R1 and R2 15 are as defined above, may be prepared from a product of general formula (la) in which R3 is a bromine atom or a bromomethyl radical or a formyl radical, according to Reaction Schemes 17, 18 and 19: R1-N N EtO 2 c 0 r:Ri-N N: _ 0IN/- R2 BN r AIMe 3 N Br R NN - R3 R2NR2' NNR R3 = alkenyl, alkynyl, aryl, heteroaryl N(R7)(R8), OR8, SR8 ... Scheme 17 19 RI-N N EtO 2 c Ri-N N Ri-N N '/ - 1-R1 R2 N AIMe 3 R'Br 32 N-, 2 N, '" SBr X' R'3 X' = O, S, N(R7) R'3= R8 Scheme 18 R1-N N EtO2c \_/ 0 R2Ri AIMez R1-N N Ri-N N X=N (R7) R2 N, -l - R'3 = R8 RN 0 Ae 3 N'N O X'- R'3 0_ 0 0 RI-N N R1-N N H R1-N N X' = O, N(R7)O R'3 = R8 - OH R1-N N--/ N NN' R NR2.NN
N-
0 R2NR2' N X 0 X' = O, N(R7)N(R7) SR'3 = R8 0 R i- N N / - 3 'N 0 X= 0, N(R7) R'3 = R8 Scheme 19 5 It is also advantageous, in the content of the invention, to modify, at the final stage(s) of the synthesis, the substituents borne by the radicals R1 and/or R2, which represent substituted aryl or heteroaryl groups, via standard methods known to those skilled in the art, for instance, in a nonlimiting manner, the reduction of a nitro radical to an amino radical, the alkylation of a phenol or 10 thiophenol radical to a phenyl ether or thioether, the hydrolysis of a cyano radical to a carboxyl or carboxamide radical, the acylation of an amino radical to an amide, the esterification or amidation of a carboxyl radical. The general synthetic methods presented in Schemes 1 to 16 illustrate, in a nonlimiting manner, the possible preparations of the compounds of the 20 invention. Many other synthetic routes may be used, in particular those described in: Comprehensive Heterocyclic Chemistry, 5 (Part 4A), by A. Katritsky et al. (Pergamon Press); 5 Advanced Organic Chemistry 'Progress in Pyrazole Chemistry", 6, 347-429 (1966) by A.N. Kost et al.; Journal of Heterocyclic Chemistry "Synthesis of Pyrazoles and condensed Pyrazoles", 36, 321-332 (1999) by M. Kenzi et al.; Organic Chemistry 'The Chemistry of pyrroles", 34 (1977) by A.R. 10 Jones et al. (Academic Press); Organic Chemistry in Monographs "Chemistry of Pyrroles, 15 (1974) by A. Gossauer (Springer Verlag). The examples below illustrate, in a nonlimiting manner, the products of the invention. 15 General conditions: 1. The reactions using microwaves were performed on a Personal Chemistry EmrysTM Optimizer machine in EmrysTM process vials of 0.5 2.0 ml or 2.0-5.0 ml. 2. With the exception of particular conditions explicitly described - for 20 instance for the Example 3 library products - the LC/MS analyses are performed under the conditions below: - X Terra RP 18 2.1x50 mm 3.5 pm - oven at 400C, flow rate = 0.7 ml/min, injection volume V = 10 p1 - eluent A: H 2 0 + 0.1% HCOOH pH = 2 B: CH 3 CN 25 time (min) A% B% 0.0 95 5 5.0 5 95 6.5 5 95 7.0 95 5 30 9.0 95 5 - MS/ES positive and negative mode detection CV = 50V, m/z 50-1500 DAD X = 200 to 400 nm ELSD T evaporation = 75°C, T nebulization = 80'C, flow rate = 35 1 1/min 21 3. With the exception of particular conditions explicitly described, the purifications by preparative LC/MS are performed under the conditions below: - X Terra RP 18 30x100 mm 5 pm column 5 - eluents: i) pH = 5 A: aqueous 20 mM solution of ammonium hydrogen carbonate + HCOOH (up to pH = 5) / B: CH 3 CN, or ii) pH = 9 A: aqueous 20 mM solution of ammonium hydrogen carbonate + aqueous ammonia (up to pH = 9) 10 B: CH 3 CN - time (min) flow rate (ml/min) A% B% 0.0 10 70 30 3.0 30 50 50 4.0 30 40 60 15 11.0 30 0 100 12.5 30 0 100 12.9 20 0 100 - detection: positive and negative mode MS/ES CV = 20V, m/z 100-1100 20 Example 1 [4-(3-Chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)meth anone A solution of 250 pl of oxalyl chloride in 1 ml of dichloromethane is added at 00C to a solution of 387 mg of 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic 25 acid, which may be obtained according to J. Het. Chem., 30, 307 (1993), in 4 ml of dichloromethane. One drop of dimethylformamide is added to this reaction mixture. After stirring for 3 hours at a temperature close to 20 0 C, the reaction mixture is concentrated to dryness, taken up in 5 ml of tetrahydrofuran and then added slowly to a solution of 413 mg of 1-(3 30 chlorophenyl)piperazine and 402 pl of triethylamine in 5 ml of tetrahydrofuran. After stirring for 18 hours at room temperature, the reaction mixture is concentrated to dryness. The brown paste obtained is taken up in 20 ml of ethyl acetate and then washed three times with 10 ml of distilled water. The organic phase is dried over magnesium sulfate and then concentrated to 35 dryness under reduced pressure. After purification on silica (eluent: 22 cyclohexane/ethyl acetate), 402 mg of [4-(3-chlorophenyl)piperazin-1-yl](5 methyl-2-phenyl-2H-pyrazol-3-yl)methanone are collected in the form of a white powder, the characteristics of which are as follows: IR spectrum (KBr): 2835; 1634; 1593; 1500; 1445; 1236; 1003; 944; 5 762 and 692 cm -1 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 6 in ppm): 2.30 (s: 3H); 2.88 (mt: 2H); 3.17 (mt: 2H); 3.36 (mt: 2H); 3.69 (mt: 2H); 6.53 (s: 1H); 6.83 (dd, J = 8 and 1.5 Hz: 1H); 6.86 (dd, J = 8 and 1.5 Hz: 1H); 6.92 (t, J = 1.5 Hz: 1H); 7.23 (t, J = 8 Hz: 1H); 7.36 (tt, J = 7 and 2 Hz: 1H); from 7.40 to 7.55 10 (mt: 4H). Example 2 [4-(3,4-Dimethylphenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone By working in a manner similar to that for the synthesis of [4-(3 15 chlorophenyl)piperazin- 1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone, but replacing the 1-(3-chlorophenyl)piperazine with 400 mg of 1-(3,4 dimethylphenyl)piperazine, 285 mg of [4-(3,4-dimethylphenyl)piperazin-1-yl] (5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone are obtained in the form of a pale yellow solid, the characteristics of which are as follows: 20 IR spectrum (CCI 4 ): 2921; 2862; 2819; 1646; 1504; 1473; 1446; 1365; 1236; 1002 and 692 cm 1 1 H NMR spectrum (300 MHz, (CD3)2SO d6, 5 in ppm): 2.12 (s: 3H); 2.17 (s: 3H); 2.30 (s: 3H); 2.71 (mt: 2H); 3.01 (mt: 2H); from 3.25 to 3.40 (mt: 2H); 3.68 (mt: 2H); 6.52 (s: 1H); 6.59 (dd, J = 8 and 2 Hz: 1H); 6.70 (d, J = 2 25 Hz: 1H); 6.97 (d, J = 8 Hz: 1H); 7.36 (tt, J = 7 and 2 Hz: 1H); from 7.40 to 7.55 (mt: 4H). Example 3 Example 3 below shows an application of the use of the general synthetic route presented in Scheme 16. In this case, N-phenylpiperazine and 30 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid may be substituted with radicals as defined above, to obtain products in accordance with the invention.
23 Synthesis of the library 100 pl of a molar solution of N,N-diisopropylcarbodiimide in DMF, 100 pl of a decimolar solution of N-dimethylaminopyridine in DMF and then finally 200 pl of a solution at 0.5 mol/I in DMF of the corresponding pyrazole acids are 5 added to a suspension of 50 mg of tetrafluorophenyl resin (IRORI, unisphere 200; substitution 0.99 mmol/g) in 0.6 ml of dimethylformamide. The reaction mixtures are stirred at room temperature for 18 hours and then filtered. The resins are then washed three times with 1 ml of DMF and then alternatively four times with 1 ml of CH 2
CI
2 and 4 times with 1 ml of methanol, and then 10 finally twice with 1 ml of CH 2
CI
2 . The resins are dried in ambient air. A solution containing 0.5 mol/I of substituted phenylpiperazine and 0.75 mol/I of triethylamine is added to a suspension of 50 mg of resin obtained beforehand in 0.9 ml of dimethylformamide. The reaction medium is stirred for 18 hours and then filtered. The residual resin is washed twice with 0.5 ml of 15 dimethylformamide. The filtrate is concentrated to dryness and the oils obtained are purified by high performance liquid chromatography coupled to a mass spectrometer (LC/MS). Purification by LC/MS The products were purified by LC/MS using a Waters FractionLynx system 20 composed of a Waters model 600 gradient pump, a Waters model 515 regeneration pump, a Waters Reagent Manager dilution pump, a Waters model 2700 autoinjector, two Rheodyne LabPro model valves, a Waters model 996 diode array detector, a Waters model ZMD mass spectrometer and a Gilson model 204 fraction collector. The system was controlled by the 25 Waters FractionLynx software. The separation was performed alternately on two Waters Symmetry columns (C 18 , 5 pm, 19x50 mm, catalogue reference 186000210), one column undergoing regeneration with a 95/5 (v/v) water/acetonitrile mixture containing 0.07% (v/v) of trifluoroacetic acid, while the other column was performing separation. The columns were eluted using 30 a linear gradient of from 5% to 95% of acetonitrile containing 0.07 % (v/v) of trifluoroacetic acid in water containing 0.07% (v/v) of trifluoroacetic acid, at a flow rate of 10 ml/min. At the separation column outlet, a thousandth of the effluent is separated out using an LC Packing Accurate device, diluted with methanol at a flow rate of 0.5 ml/min and sent to the detectors, in a proportion 35 of 75% to the diode array detector and the remaining 25% to the mass spectrometer. The rest of the effluent (999/1000) is sent to the fraction 24 collector where the flow is discarded as long as the mass of the expected product is not detected by the FractionLynx software. The molecular formulae of the expected products are supplied to the FractionLynx software, which initiates collection of the product when the detected mass signal corresponds 5 to the [M+H] and/or [M+Na]* ion. In certain cases, depending on the analytical LC/MS results, when an intense ion corresponding to [M+2H] was detected, the value corresponding to half the calculated molecular mass (MW/2) is also supplied to the FractionLynx software. Under these conditions, collection is also initiated when the mass signal of the [M+2H] and/or 10 [M+Na+H] ion is (are) detected. The products were collected in tarred glass tubes. After collection, the solvents were evaporated off, in a Savant AES 2000 or Genevac HT8 centrifuge evaporator and the masses of products were determined by weighing the tubes after evaporation of the solvents. The LC/MS analyses were performed on a Micromass model LCT machine 15 connected to an HP 1100 machine. The abundance of the products was measured using an HP G1315A diode array detector over a wavelength range of 200-600 nm and a Sedex 65 light-scattering detector. The mass spectra were acquired over a range from 180 to 800. The data were analyzed using the Micromass MassLynx software. The separation was performed on a 20 Hypersil BDS C18, 3 pm (50 x 4.6 mm) column, eluting with a linear gradient of from 5% to 90% of acetonitrile containing 0.05% (v/v) of trifluoroacetic acid (TFA) in water containing 0.05% (v/v) of TFA, over 3.5 minutes at a flow rate of 1 ml/min. The total analysis time, including the volume reequilibration period, is 7 minutes. 25 The products of Examples 3/1 to 3/153 were obtained using a protocol according to Example 3. Example 4 (4-Phenyl-1,2,3,6-tetrahydropyridin-1 -yl)(5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone 30 316 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 20 mg of 1-hydroxybenzotriazole hydrate (HOBT) are added to a solution of 300 mg of 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid, which may be obtained according to J. Het. Chem., 30, 307 (1993) in 15 ml of dichloromethane. After stirring for 10 minutes at room temperature, 230 p/1 of 35 triethylamine (TEA) and 323 mg of 4-phenyl-1,2,3,6-.tetrahydropyridine hydro- 25 chloride are added and this reaction mixture is then stirred for 36 hours at room temperature. After addition of 10 ml of water, the organic phase is separated out by settling of the phases, and then washed with water, dried over magnesium sulfate and concentrated under reduced pressure. After 5 purification by flash chromatography on a column of silica (60; 35-70 pm), eluting with a mixture of cyclohexane and ethyl acetate (75/25 by volume), 300 mg of (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)(5-methyl-2-phenyl-2H pyrazol-3-yl)methanone are obtained in the form of a white foam, the characteristics of which are as follows: 10 Melting point (Kofler) = 68 0 C Mass spectrum (El): m/z = 343 (M ) Example 5 [4-(3-Chlorophenyl)piperazin-1 -yl](2-phenyl-2H-pyrazol-3-yl)methanone The process is performed in a manner similar to that of Example 1, but 15 starting with 500 mg of 2-phenyl-2H-pyrazol-5ylcarboxylic acid, which may be prepared according to Heterocycles, 23, 943 (1985), of 575 mg of 1-(3 chlorophenyl)piperazine and 342 pl of oxalyl chloride in 20 ml of dichloro methane, to give, after purification by flash chromatography on a column of silica (60; 35-70 pm), eluting with a mixture of dichloromethane and methanol 20 (98/2 by volume), 680 mg of [4-(3-chlorophenyl)piperazin-1-yl](2-phenyl-2H pyrazol-3-yl)methanone in the form of a very viscous pale yellow oil, the characteristics of which are as follows: Mass spectrum (El): m/z = 366 (M') Example 6 25 [4-(3-Chlorophenyl)piperazin-1-yl](1-phenyl- 1H-pyrrol-2-yl)methanone The process is performed in a manner similar to that of Example 1, but starting with 187 mg of 1-phenyl-1 H-pyrrol-2ylcarboxylic acid, which may be prepared according to Tetrahedron, 49, 10271 (1993), 216 mg of 1-(3 chlorophenyl)piperazine and 128 pl of oxalyl chloride in 20 ml of dichloro 30 methane, to give, after purification by flash chromatography on a column of silica (60; 35-70 pm), eluting with a mixture of dichloromethane and methanol (98/2 by volume) followed by recrystallization from diisopropyl ether, 200 mg of [4-(3-chlorophenyl)piperazin-1 -yl](1-phenyl-1 H-pyrrol-2-yl)methanone in the form of white crystals, the characteristics of which are as follows: 35 Mass spectrum (El): m/z = 365 (M') 26 Melting point (Kofler) = 105 0 C Example E2 [4-(3,5-Dichlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone 5 By performing the process in a manner similar to that for the synthesis of [4 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Examplel), but replacing the 1-(3-chlorophenyl)piperazine with 486 mg of 1-(3,5-dichlorophenyl)piperazine, 147 mg of [4-(3,5-dichlorophenyl)piperazin 1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone are obtained in the form 10 of a white solid, the characteristics of which are as follows: IR spectrum (KBr): 2924; 2852; 1629; 1587; 1554; 1502; 1463; 1288; 1241; 982; 963; 794; 764; 691 and 672 cm -1 1 H NMR spectrum (400 MHz, (CD 3
)
2 SO d6, 8 in ppm): 2.31 (s: 3H); 2.98 (unresolved complex: 2H); 3.25 (unresolved complex: 2H); 3.37 15 (unresolved complex: 2H); 3.67 (unresolved complex: 2H); 6.54 (s: 1H); from 6.85 to 7.00 (mt: 3H); 7.37 (tt, J = 7.5 and 1.5 Hz: 1H); 7.45 (broad d, J = 7.5 Hz: 2H); 7.50 (broad t, J = 7.5 Hz: 2H). Example E3 [4-(3-Dimethylaminophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3 20 yl)methanone. Step 1: 1.6 g of bis-(2-chloroethyl)amine hydrochloride and 2.86 g of sodium carbonate are added to a solution of 1.2 g of N,N-dimethylbenzene-1,3 diamine, which may be obtained according to J. Org. Chem., 57, 5254 (1992), in 15 ml of n-butanol. After refluxing for 18 hours, 50 ml of dichloromethane 25 and 40 ml of water are added, the organic phase is separated out by settling of the phases and is then washed with 40 ml of water, dried over magnesium sulfate and concentrated under reduced pressure. 2.35 g of dimethyl-(3 piperazin-1-ylphenyl)amine are thus obtained in the form of a viscous brown oil, which is used without further purification in the following step, and the 30 characteristics of which are as follows: Mass spectrum IC m/z=206 MH base peak Step 2: 316 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro chloride (EDCI), 20 mg of 1-hydroxybenzotriazole hydrate (HOBT) and 0.48 g of dimethyl(3-piperazin-1-ylphenyl)amine are added to a solution of 303 mg of 27 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid, which may be obtained according to-J. Het. Chem., 30, 307 (1993) in 15 ml of dichloromethane, and this reaction mixture is stirred for 36 hours at room temperature. After adding 20 ml of water, the organic phase is separated out by settling of the phases 5 and is then washed with water, dried over magnesium sulfate and concen trated under reduced pressure. After purification by flash chromatography on a column of silica (60; 35-70 pm), eluting with a mixture of cyclohexane and ethyl acetate (60/40 by volume), 140 mg of [4-(3-dimethylaminophenyl) piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone are obtained in 10 the form of a white foam, the characteristics of which are as follows: 1 H NMR spectrum (400 MHz, (CD 3
)
2 SO d6, 8 in ppm): 2.31 (s: 3H); 2.76 (unresolved complex: 2H); 2.87 (s: 6H); 3.08 (unresolved complex: 2H); 3.33 (unresolved complex: 2H); 3.70 (unresolved complex: 2H); 6.18 (t, J = 2 Hz: 1H); 6.22 (dd, J = 8.5 and 2 Hz: 1H); 6.26 (dd, J = 8.5 and 2 Hz: 1H); 6.54 15 (s: 1H); 7.02 (t, J = 8.5 Hz: 1H); 7.38 (tt, J = 7.5 and 1.5 Hz: 1H); from 7.45 to 7.55 (mt: 4H). Example E4 [4-(6-Chloropyrid-2-yl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone 20 By performing the process in a manner similar to that for the synthesis of [4 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 745 mg of 1-(6-chloro-2-pyridyl)piperazine, which may be obtained according to patent US 4078063, 900 mg of [4-(6-chloropyrid-2-yl)piperazin-1-yl](5-methyl-2 25 phenyl-2H-pyrazol-3-yl)methanone are obtained in the form of a white foam, the characteristics of which are as follows: 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO. d6, 8 in ppm): 2.31 (s: 3H); 3.22 (unresolved complex: 2H); 3.36 (unresolved complex: 2H); 3.51 (unresolved complex: 2H); 3.66 (unresolved complex: 2H); 6.54 (s: 1H); 6.71 30 (d, J = 7.5 Hz: 1H); 6.76 (d, J = 8 Hz: 1H); 7.36 (broad t, J = 7 Hz: 1H); from 7.40 to 7.55 (mt: 4H); 7.58 (broad dd, J = 8 and 7 Hz: 1H). Example E5 [4-(3-Nitrophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone 28 By performing the process in a manner similar to that for the synthesis of [4 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 683.8 mg of 1-(3-nitrophenyl)piperazine, which may be obtained according to J. Med. 5 Chem., 32, 1052 (1989), 500 mg of [4-(3-nitrophenyl)piperazin-1-yl](5-methyl 2-phenyl-2H-pyrazol-3-yl)methanone are obtained in the form of a yellow solid, the characteristics of which are as follows: Melting point (Kofler): 142 0 C 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 8 in ppm): 2.31 (broad s: 10 3H); 3.00 (unresolved complex: 2H); 3.28 (unresolved complex: 2H); 3.42 (unresolved complex: 2H); 3.73 (unresolved complex: 2H); 6.56 (s: 1H); from 7.30 to 7.65 (mt: 9H). Example E6 [4-(3-Bromophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methan 15 one By performing the process in a manner similar to that for the synthesis of [4 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 1.25 g of 1-(3-bromophenyl)piperazine, which may be obtained according to Chem. 20 Pharm. Bull. 50, 453 (2002), 1.65 g of [4-(3-bromophenyl)piperazin-1-yl](5 methyl-2-phenyl-2H-pyrazol-3-yl)methanone are obtained in the form of a white solid, the characteristics of which are as follows: Melting point (Kofler): 138 0 C 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 8 in ppm): 2.30 (s: 3H); 25 2.87 (unresolved complex: 2H); 3.17 (unresolved complex: 2H); 3.38 (unresolved complex: 2H); 3.69 (unresolved complex: 2H); 6.54 (s: 1H); 6.89 (dd, J = 8.5 and 2 Hz: 1 H); 6.97 (broad dd, J = 8.5 and 1.5 Hz: 1 H); 7.06 (broad s: 1H); 7.17 (t, J = 8.5 Hz: 1H); 7.37 (tt, J = 7.5 and 1.5 Hz: 1H); from 7.40 to 7.55 (mt: 4H). 30 Example E7 [4-(3-Chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanethione. 212 mg of Lawesson's reagent are added to a solution of 0.2 g of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone, 35 obtained in Example 1, in 10 ml of toluene. After refluxing for 1 hour 30 29 minutes and adding 10 ml of ethyl acetate, the organic phase is separated out by settling of the phases and is then washed with 30 ml of saturated sodium bicarbonate solution and dried over magnesium sulfate, and then concentrated under reduced pressure. After purification by flash 5 chromatography on a column of silica (60; 35-70 pm), eluting with a mixture of cyclohexane and ethyl acetate (80-20 by volume), 130 mg of [4-(3-chloro phenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanethione are obtained in the form of a white foam, the characteristics of which are as follows: 10 Melting point: (Kofler) = 95-980C 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6 with addition of a few drops of CD 3 COOD d4, 6 in ppm): 2.29 (broad s: 3H); from 2.80 to 3.70 (broad unresolved complex: 6H); from 4.00 to 4.50 (broad unresolved complex: 2H); 6.42 (broad s: 1H); from 6.70 to 6.90 (mt: 3H); 7.21 (broad t, J = 8 Hz: 1H); 15 7.33 (broad t, J = 7 Hz: 1H); from 7.40 to 7.55 (mt: 4H). Example E8 [4-(6-Methoxypyrid-2-yl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone 169 mg of sodium methoxide are added to a solution of 300 mg of [4-(6 20 chloropyrid-2-yl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methan one, described in Example E4, in 10 ml of methanol. After refluxing for 48 hours and concentrating under reduced pressure, the crude mixture is purified by flash chromatography on a column of silica (60; 35-70 pm), eluting with a mixture of cyclohexane and ethyl acetate (70-30 by volume), to give 9 mg of 25 [4-(6-methoxypyrid-2-yl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone in the form of a white solid, the characteristics of which are as follows: 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 5 in ppm): 2.30 (broad s: 3H); 3.20 (unresolved complex: 2H); 3.33 (unresolved complex: 2H); 3.49 30 (unresolved complex: 2H); 3.66 (unresolved complex: 2H); 3.77 (s: 3H); 6.08 (d, J = 7.5 Hz: 1 H); 6.30 (d, J = 8 Hz: 1H); 6.54 (s: 1H); 7.37 (broad t, J = 7.5 Hz: 1H); from 7.40 to 7.55 (mt: 5H). Example E9 [4-(3-Aminophenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methan 35 one 30 9.5 mg of 10% of palladium-on-charcoal are added to a solution of 350 mg of [4-(3-nitrophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methan one, described in Example E5, in 10 ml of absolute ethanol, and hydrogen is introduced at a pressure of about 1 bar and at a temperature in the region of 5 2000. After reaction for 20 hours, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography on a column of silica (60; 35-70 pm), eluting with a mixture of cyclohexane and ethyl acetate (30/70 by volume), and 265 mg of [4-(3 aminophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone 10 are thus obtained in the form of a white solid, the characteristics of which are as follows: Melting point (Kofler): 1580C Mass spectrum (El): m/z = 361 (M+) 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 6 in ppm): 2.30 (broad s: 15 3H); 2.69 (unresolved complex: 2H); 2.98 (unresolved complex: 2H); 3.33 (unresolved complex: 2H); 3.67 (unresolved complex: 2H); 4.90 (broad s: 2H); from 6.00 to 6.10 (mt: 3H); 6.52 (s: 1H); 6.85 (broad t, J = 8 Hz: 1H); 7.37 (tt, J =7 and 1.5 Hz: 1H); from 7.30 to 7.55 (mt: 4H). Example E10 20 [4-(3-Cyanophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone 69 mg of sodium cyanide, 285 mg of tetrakis(triphenylphosphine)palladium and 140 mg of aluminum oxide are added to a solution of 0.5 g of [4-(3 bromophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone, 25 described in Example E6, in 20 ml of toluene. After refluxing for 20 hours and adding 50 ml of ethyl acetate, the organic phase is separated out by settling of the phases and then washed with twice 50 ml of water and dried over magnesium sulfate. After purification by flash chromatography on a column of silica (60; 35-70 pm), eluting with a mixture of cyclohexane and ethyl acetate 30 (60/40 by volume), 125 mg of [4-(3-cyanophenyl)piperazin-1-yl](5-methyl-2 phenyl-2H-pyrazol-3-yl)methanone are thus obtained in the form of a white solid, the characteristics of which are as follows: Melting point (Kofler): 1360C Mass spectrum (El): m/z = 371 (M+) 31 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 6 in ppm): 2.31 (s: 3H); 2.96 (unresolved complex: 2H); 3.24 (unresolved complex: 2H); 3.37 (unresolved complex: 2H); 3.70 (unresolved complex: 2H); 6.54 (s: 1H); from 7.15 to 7.55 (mt: 9H). 5 Example Ell [4-(3-Trifluoromethyloxyphenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol 3-yl)methanone By performing the process in a manner similar to that for the synthesis of [4 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone 10 (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 462 mg of 1-(3-trifluoromethyloxyphenyl)piperazine, which may be obtained according to J. Med. Chem., 22, 554 (1979), 425 mg of [4-(3-trifluoromethyloxyphenyl) piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone are obtained in the form of a white solid, the characteristics of which are as follows: 15 Melting point (Kofler): 107 0 C Mass spectrum (El): m/z = 430 (M+) Example E12 [4-(1,3-Benzodioxol-5-yl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone 20 By performing the process in a manner similar to that for the synthesis of [4 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 606 mg of 1-(1,3-benzodioxol-5-yl)piperazine, which may be obtained according to Tetrahedron Lett., 39, 617 (1998), 920 mg of [4-(1,3-benzodioxol-5-yl) 25 piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone are obtained in the form of a white solid, the characteristics of which are as follows: Melting point (Kofler): 128 0 C Mass spectrum (El): m/z = 390 (M+) Example E13 30 [4-(3-Hydroxyphenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone By performing the process in a manner similar to that for the synthesis of [4 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 171 mg of 32 1-(3-hydroxyphenyl)piperazine, 258 mg of [4-(3-hydroxyphenyl)piperazin-1 yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone are obtained in the form of a solid, the characteristics of which are as follows: 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 6 in ppm): 2.30 (s: 3H); 5 2.73 (unresolved complex: 2H); 3.03 (unresolved complex: 2H); from 3.25 to 3.40 (unresolved complex: 2H); 3.67 (unresolved complex: 2H); from 6.20 to 6.30 (mt: 2H); 6.32 (broad d, J = 8.5 Hz: 1H); 6.52 (s: 1H); 6.98 (t, J = 8.5 Hz: 1H); 7.36 (tt, J = 7 and 1.5 Hz: 1H); from 7.40 to 7.55 (mt: 4H); 9.17 (s: 1H). Example E14 10 [4-(3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methane Step 1:195 mg of O,N-dimethylhydroxylamine hydrochloride and 300 pl of triethylamine are added to a solution of 404 mg of 5-methyl-2-phenyl-2H pyrazole-3-carboxylic acid, 360 mg of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride and 270 mg of 1-hydroxybenzotriazole in 10 ml of 15 dichloromethane. After stirring for 96 hours at a temperature in the region of 20 0 C, the medium is diluted with 20 ml of dichloromethane, the phases are separated by settling and the organic phase is washed with 20 ml of 1N hydrochloric acid solution and then three times with 15 ml of distilled water. After drying over magnesium sulfate, concentrating under reduced pressure 20 and purifying by flash chromatography on a column of silica (60; 35-70 pm), eluting with a mixture of dichloromethane and methanol (gradient of from 100% to 90% dichloromethane by volume), 360 mg of N-methoxy-N-methyl-5 methyl-2-phenyl-2H-pyrazole-3-carboxamide are obtained, and used directly in the following step. 25 Step 2: A solution of 350 mg of N-methoxy-N-methyl-5-methyl-2-phenyl-2H pyrazole-3-carboxamide in 1.2 ml of ethyl ether is added, at a temperature in the region of -60 0 C, to a suspension of 69 mg of lithium aluminum hydride in 3.2 ml of ethyl ether. After the temperature has risen by about 50C, a solution of 315 mg of sodium hydrogen sulfate in 1.1 ml of distilled water is added. 30 After dilution with 20 ml of ethyl ether, the organic phase is separated out by settling of the phases and then washed twice with 1N hydrochloric acid solution, at a temperature in the region of 00C, twice with saturated sodium hydrogen carbonate solution, once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The 35 concentrate is dissolved in 5 ml of dichloromethane and 200 mg of 33 manganese dioxide are added. After stirring for 18 hours at a temperature in the region of-20 0 C, the medium is concentrated under reduced pressure and then taken up in 20 ml of ethyl acetate, filtered in the presence of Celite and then concentrated under reduced pressure to give 266 mg of 5-methyl-2 5 phenyl-2H-pyrazole-3-carboxaldehyde in the form of a foam, which is used without further purification in the following step after control by LC/MS analysis. Step 3: 55.8 mg of 5-methyl-2-phenyl-2H-pyrazole-3-carboxaldehyde, 17 pl of acetic acid and 380 mg of powdered 3 A molecular sieves are added to a 10 solution of 39 mg of 1-(3-chlorophenyl)piperazine in 10 ml of acetonitrile. After stirring for 2 hours at a temperature in the region of 200C, 18.9 mg of sodium cyanoborohydride are added. After stirring for 48 hours at a temperature in the region of 20 0 C, 200 pl of distilled water are added. After filtration, concentration under reduced pressure and then purification by LC/MS, 13 mg 15 of [4-(3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methane trifluoroacetate are obtained in the form of a white solid, the characteristics of which are as follows: IR spectrum: 1679; 1596; 1502; 1456; 1206; 1137; 945; 800; 721 and 699 cm 1 20 1H NMR spectrum (400 MHz, (CD 3
)
2 SO d6, at a temperature of 373 K, 8 in ppm): 2.27 (s: 3H); 2.69 (unresolved complex: 4H); from 3.10 to 3.35 (unresolved complex: 4H); 3.75 (broad s: 2H); 6.33 (s: 1H); 6.80 (broad d, J = 8 Hz: 1H); 6.88 (dd, J = 8 and 2 Hz: 1H); 6.92 (mt: 1H); 7.22 (t, J = 8 Hz: 1H); 7.42 (broad t, J = 7.5 and 1.5 Hz: 1H); 7.52 (broad t, J = 7.5 Hz: 2H); 7.62 25 (broad d, J = 7.5 Hz: 2H). Example E15 [4-(Isoquinolin-1 -yl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl ) methanone hydrochloride By performing the process in a manner similar to that for the synthesis of [4 30 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 100 mg of 1-(piperazin-1-yl)isoquinoline, which may be obtained according to patent WO 2002002568, 93 mg of [4-(isoquinolin-1-yl)piperazin-1-yl](5-methyl-2 phenyl-2H-pyrazol-3-yl)methanone hydrochloride are isolated in the form of a 35 white solid, the characteristics of which are as follows: 34 Melting point (Kofler): 128"C Mass spectrum (El): m/z = 433 (M+) Example E16
[
4
-(
4 -Chloro-3-methylphenyl)piperazin-l -yl](5-methyl-2-phenyl-2H-pyrazol-3 5 yl)methanone By performing the process in a manner similar to that for the synthesis of [4
(
3 -chlorophenyl)piperazin-1 -yl]( 5 -methyl- 2 -phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-( 3 -chlorophenyl)piperazine with 99.8 mg of 1-( 4 -chloro-3-methylphenyl)piperazine, which may be obtained from (4 10 chloro-3-methylphenyl)amine by working as described in Step 1 of Example E3, 70 mg of [ 4
-(
4 -chloro-3-methylphenyl)piperazin-1-yl](5-methyl-2-phenyl 2 H-pyrazol-3-yl)methanone are obtained in the form of a white solid, the characteristics of which are as follows: Melting point (Kofler): 110'C 15 Mass spectrum (El): m/z = 394 (M+) Example E17
(
5 -Methyl-2-phenyl-2H-pyrazol-3-yl)(4-quinolin-4-ylpiperazin- 1 -yl)methanone By performing the process in a manner similar to that for the synthesis of [4 (3-chlorophenyl)piperazin-1 -yl]( 5 -methyl-2-phenyl-2H-pyrazol-3-yl)methanone 20 (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 100 mg of 4 -(piperazin-1-yl)quinoline, which may be obtained according to J. Het. Chem., 33, 415 (1996), 100 mg of (5-methyl-2-phenyl-2H-pyrazol-3-y)[4 (quinolin-4-yl)piperazin-1-yl]methanone are obtained in the form of a white foam, the characteristics of which are as follows: 25 Mass spectrum (El): m/z = 397 (M+) Example E18 N-{3-[4-(5-methyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1-yl]phenyl} acetamide By performing the process in a manner similar to that for the synthesis of [4 30 ( 3 -chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 800 mg of N-(3-piperazin-1 -ylphenyl)acetamide, which may be obtained according to Tetrahedron Lett., 35, 7331 (1994), 1 g of N-{3-[4-(5-methyl-2-phenyl-2H pyrazole-3-carbonyl)piperazin-1-yl]phenyl}acetamide is obtained in the form 35 of an amorphous beige-colored solid, the characteristics of which are as follows: Mass spectrum (El): m/z = 403 (M+) 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 6 in ppm): 2.03 (s: 3H); 5 2.31 (s: 3H); 2.76 (unresolved complex: 2H); 3.05 (unresolved complex: 2H); 3.33 (unresolved complex: 2H); 3.71 (unresolved complex: 2H); 6.53 (s: 1H); 6.58 (broad dd, J = 8 and 2 Hz: 1H); 7.03 (broad d, J = 8 Hz: 1H); 7.13 (t, J = 8 Hz: 1H); 7.18 (broad s: 1H); from 7.40 to 7.55 (mt: 4H); 7.36 (tt, J = 7 and 1.5 Hz: 1H); 9.79 (broad s: 1H). 10 Example E19 (5-Methyl-2-phenyl-2H-pyrazol-3-yl)(2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-yl) methanone By performing the process in a manner similar to that for the synthesis of [4 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone 15 (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 51 mg of 2,3,5,6-tetrahydro[1,2']bipyrazine, which may be obtained according to J. Med. Chem., 21, 536 (1978), 70 mg of (5-methyl-2-phenyl-2H-pyrazol-3-yl) (2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-yl)methanone are obtained in the form of a white solid, the characteristics of which are as follows: 20 Mass spectrum (El): m/z = 348 (M+) Melting point (Kofler): 1290C Example E20 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone 25 By performing the process in a manner similar to that for the synthesis of [4 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 467 mg of 1-(3,5-dimethoxyphenyl)piperazine, 727 mg of [4-(3,5-dimethoxyphenyl) piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone are obtained in 30 the form of a solid, the characteristics of which are as follows: 1 H NMR spectrum (300 MHz, (0D 3
)
2 SO d6, 5 in ppm): 2.31 (s: 3H); 2.80 (unresolved complex: 2H); 3.10 (unresolved complex: 2H); from 3.25 to 3.40 (unresolved complex: 2H); 3.68 (unresolved complex: 2H); 3.71 (s: 6H); from 5.95 to 6.05 (mt: 3H); 6.53 (s: 1H); 7.38 (broad t, J = 35 7 Hz: 1H); from 7.40 to 7.55 (mt: 4H).
36 Example E21 (5-Methyl-2-pyrid-2-yl-2H-pyrazol-3-yl)(4-phenylpiperazin-1 -yl)methanone Step 1: 2.26 ml of diisopropylethylamine, 2.96 g of HATU and 1.19 ml of 1-phenylpiperazine are added to a solution of 818mg of 5-methyl-1H 5 pyrazole-3-carboxylic acid in 10 ml of DMF. After stirring for 2 hours at room temperature, the reaction mixture is poured into 100 ml of saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (40-63 pm), 10 eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5 by volume), 3.30 g of an orange oil are obtained. The product is taken up in 210 ml of dichloromethane in the presence of 22 g of Dowex® 50WX8 50-100 mesh resin, and the suspension is stirred for 1 hour at room temperature, filtered, rinsed with dichloromethane and suction-filtered. The 15 resin is then taken up in 200 ml of a 9/1 mixture of methanol and aqueous ammonia, left in contact overnight and then filtered and rinsed. Concentration of the filtrate gives 1.39 g of (5-methyl-1H-pyrazol-3-yl)(4-phenylpiperazin-1 yl)methanone in the form of a pale yellow solid, the characteristics of which are as follows: 20 Mass spectrum (ES): m/z = 343 (MH') Step 2:100 mg of product from Step 1, 14 mg of cuprous iodide, 2.0 ml of 1,4-dioxane, 38 mg of trans-1,2-diaminocyclohexane, 169 mg of cesium carbonate, 88 mg of 2-bromopyridine and 20 mg of 1-ethyl-3 methylimidazolium chloride are placed in a microwave reactor and then 25 subjected to the microwave field for 15 minutes at 140 0 C. 60 mg of cuprous iodide and 40 mg of 2-bromopyridine are added and the mixture is subjected to the microwave field for a further 15 minutes at 1400C. The reaction mixture is poured into 50 ml of water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced 30 pressure. After purification by flash chromatography on a column of silica (30 60 pm), eluting with a mixture of toluene, ethyl acetate and triethylamine (80/20/0.1 by volumee, 52 mg of (5-methyl-2-pyrid-2-yl-2H-pyrazol-3-yl)(4 phenylpiperazin-1-yl)methanone are obtained in the form of a pale yellow solid, the characteristics of which are as follows: 35 Mass spectrum (El): m/z = 347 (M') 37 1 H NMR spectrum (400 MHz, (CD 3
)
2 SO d6, 8 in ppm): 2.63 ppm (s, 3H); 3.20 ppm (m, 4H); 3.80 ppm (m, 2H); 4.08 ppm (m, 2H); 6.62 ppm (s, 1H); 6.81 ppm (bt, J=8 Hz, 1H); 6.97 ppm (bd, J=8 Hz, 2H); 7.23 ppm (bt, J=8 Hz, 2H); 7.44 ppm (ddd, J=1.5- 7.5- 8.5 Hz, 1H); 7.85 ppm (bd, J= 8.5 Hz, 5 1H); 8.03 ppm (ddd, J= 2- 7.5- 8.5 Hz, 1H); 8.54 ppm (dm, J= 5 Hz). Example E22 [4-(3-Chlorophenyl)piperazin-1 -yl](5-methyl-2-pyrid-2-yl-2H-pyrazol-3-yl) methanone Step 1:14.7 ml of a 2M solution of trimethylaluminum in toluene are added, at 10 250C, to a solution of 4.325 g of 1-(3-chlorophenyl)piperazine in 60 ml of toluene, followed by addition, after 10 minutes, of 2.26 g of ethyl 5-methyl-1H pyrazole-3-carboxylate. The reaction mixture is stirred for 6 hours at 600C and then poured into 100 ml of aqueous 1M sodium potassium tartrate solution and extracted with ethyl acetate. The organic phase is dried over magnesium 15 sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (40-63 pm), eluting with a mixture of ethyl acetate and triethylamine (98/2 by volume), 3.22 g of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2H-pyrazol-3-yl)methanone are obtained in the form of a pale yellow solid, the characteristics of which are as 20 follows: Mass spectrum (El): m/z = 304 (M ) Step 2: The process is performed in a manner similar to that of Step 2 of Example E21, starting with 100 mg of the product of Step 1 of the present example, to give, after purification by flash chromatography on a column of 25 silica (30-60 pm), eluting with a mixture of toluene, ethyl acetate and triethylamine (80/20/0.1 by volume), 24 mg of [4-(3-chlorophenyl)piperazin-1 yl](5-methyl-2-pyrid-2-yl-2H-pyrazol-3-yl)methanone in the form of a yellow oil, the characteristics of which are as follows: LC/MS analysis: tr = 4.12; m/z = 382 (MH ) 30 1 H NMR spectrum (400 MHz, CDCI 3 , 6 in ppm): 2.37 (s, 3H); 3.08 ppm (m, 2H); 3.31 ppm (m, 2H); 3.45 ppm (m, 2H); 3.94 ppm (m, 2H); 6.28 ppm (s, 1H); 6.71 ppm (dd, J= 2.5-8.5 Hz, 1H); 6.84 ppm (m, 2H); 7.15 ppm (m, 2H); 7.78 ppm (td, J=8-1.5 Hz, 1H); 7.88 ppm (bd, J= 8Hz, 1H); 8.26 ppm (bd, J= 5Hz, 1H).
38 Example E23 3-[4-(5-Methyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin- 1 -yl]benzamide By working in a manner similar to that for the synthesis of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone 5 (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 11.13 g of 3-(piperazin-1-yl)benzamide, which may be obtained according to patent WO 98/00400, 11.5 g of 3-[4-(5-methyl-2-phenyl-2H-pyrazole-3-carbonyl) piperazin-1-yl]benzamide are obtained in the form of an off-white solid, the characteristics of which are as follows: 10 Mass spectrum (El): m/z = 389 (M+) Melting point (Kofler): 186 0 C 1H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 8 in ppm): 2.31 (s: 3H); 2.89 (unresolved complex: 2H); 3.17 (unresolved complex: 2H); 3.38 (unresolved complex: 2H); 3.72 (unresolved complex: 2H); 6.54 (s: 1H); 7.04 15 (broad d, J = 8 Hz: 1H); from 7.20 to 7.55 (mt: 9H); 7.89 (unresolved complex: 1 H). Example E24 [4-(Biphenyl-3-yl)piperazin-1 -yl)(5-methyl-2-phenyl-2H-pyrazol-3-yl)meth anone 20 The process is performed in a manner similar to that for the synthesis of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 250.9 mg of 1-(biphenyl-3-yl)piperazine, which may be prepared according to patent WO 01/021604. 93 mg of [4-(biphenyl-3-ylpiperazin-1-yl)(5-methyl-2-phenyl 25 2H-pyrazol-3-yl)methanone are obtained in the form of a white lacquer, the characteristics of which are as follows: Mass spectrum (El): m/z = 422 (M+) Example E25 [4-(3-Phenylmethyloxyphenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3 30 yl)methanone By working in a manner similar to that for the synthesis of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 149 mg of 1-(3-benzyloxyphenyl)piperazine, which may be obtained from 35 (3-phenylmethyloxyphenyl)amine by working as described in Step 1 of 39 Example E3, 121 mg of [4-(3-phenylmethyloxyphenyl)piperazin-1-yl]( 5 methyl-2-phenyl-2H-pyrazol-3-yl)methanone are obtained in the form of a white solid, the characteristics of which are as follows: Mass spectrum (El): m/z = 452(M+) 5 1H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 5 in ppm): 2.31 (s: 3H); 2.81 (unresolved complex: 2H); 3.11 (unresolved complex: 2H); 3.33 (unresolved complex: 2H); 3.68 (unresolved complex: 2H); 5.07 (s: 2H); from 6.40 to 6.55 (mt: 3H); 6.53 (s: 1H); 7.13 (t, J= 8 Hz: 1H); from 7.25 to 7.55 (mt: 10H). 10 Example E26 [4-(3-Methanesulfonylphenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone By working in a manner similar to that for the synthesis of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone 15 (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 150.2 mg of 1-(3-methanesulfonylphenyl)piperazine, which may be obtained according to patent WO 01/046145, 18 mg of [4-(3-methanesulfonylphenyl)piperazin-1 yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone are obtained in the form of a white solid, the characteristics of which are as follows: 20 Mass spectrum (El): m/z = 424 (M+) Examples E27 and E28 tert-Butyl and ethyl esters of 3-[4-(5-methyl-2-phenyl-2H-pyrazole-3 carbonyl)piperazin-1-yl]benzoic acid By working in a manner similar to that for the synthesis of [4-(3 25 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 1.5 g of a mixture (20/80) of the tert-butyl and ethyl esters of 3-(piperazin-1-yl)benzoic acid, which may be obtained according to patent WO 98/02432, 0.3 g of tert butyl 3-[4-(5-methyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1-yl]benzoate 30 is obtained in the form of an off-white solid, the characteristics of which are as follows: Mass spectrum (El): m/z = 446 (M+) Melting point (Kofler): 144°C 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 8 in ppm): 1.54 (s: 9H); 35 2.30 (s: 3H); 2.84 (unresolved complex: 2H); 3.15 (unresolved complex: 2H); 40 3.38 (unresolved complex: 2H); 3.71 (unresolved complex: 2H); 6.54 (s: 1H); 7.14 (mt: 1H); from 7.35 to 7.55 (mt: 8H). and 1 g of the ethyl ester of 3-[4-(5-methyl-2-phenyl-2H-pyrazole-3 carbonyl)piperazin-1-yl]benzoic acid are obtained in the form of a white solid, 5 the characteristics of which are as follows: Mass spectrum (El): m/z = 418 (M+) Melting point (Kofler): 1340C Example E29 [4-(1,3-Benzodioxol-4-yl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) 10 methanone By working in a manner similar to that for the synthesis of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 0.5 g of 1-(1,3-benzodioxol-4-yl)piperazine, which may be obtained according to J. 15 Med. Chem., 45, 4128 (2002), 0.59 g of [4-(1,3-benzodioxol-4-yl)piperazin-1 yl])(5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone is obtained in the form of a white solid, the characteristics of which are as follows: Mass spectrum (El): m/z = 390 (M+) Melting point (Kofler): 1310C 20 Example E30 [4-(1,3-Benzodioxol-4-yl)piperazin-1 -yl](5-methyl-2-m-tolyl-2H-pyrazol-3 yl)methanone By working in a manner similar to that for the synthesis of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone 25 (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 0.5 g of 1-(1,3-benzodioxol-4-yl)piperazine, which may. be obtained according to J. Med. Chem., 45, 4128 (2002), and replacing the 5-methyl-2-phenyl-2H pyrazole-3-carboxylic acid with 5-methyl-2-m-tolyl-2H-pyrazole-3-carboxylic acid, which may be obtained according to J. Het. Chem., 30, 307 (1993), 30 0.73 g of [4-(1,3-benzodioxol-4-yl)piperazin-1 -yl](5-methyl-2-m-tolyl-2H pyrazol-3-yl)methanone is obtained in the form of a white solid, the characteristics of which are as follows: Mass spectrum (El): m/z = 404 (M+) Melting point (Kofler): 1320C 41 Example E31 (5-Methyl-2-phenyl-2H-pyrazol-3-yl)[4-(4-methylpyrid-2-yl)piperazin- 1 yl]methanone By working in a manner similar to that for the synthesis of [4-(3 5 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 287 mg of 1-(4-methylpyrid-2-yl)piperazine, 154 mg of (5-methyl-2-phenyl-2H-pyrazol-3 yl)[4-(4-methylpyrid-2-yl)piperazin-1-yl]methanone are obtained in the form of a yellow gum, the characteristics of which are as follows: 10 Mass spectrum (El): m/z = 361 (M+) Example E32 [4-(3-Phenylmethylaminophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H pyrazol-3-yl)methanone hydrochloride. Step 1: 0.93 ml of triethylamine and 0.78 ml of benzoyl chloride are added, in 15 the region of 00C, to a solution of 1.6 g of 3-(4-phenylmethylpiperazin-1 yl)phenylamine, which may be obtained according to patent WO 02/090327, in 50 ml of dichloromethane. After 72 hours in the region of room temperature and addition of 50 ml of water, the organic phase is separated out by settling of the phases, washed with twice 50 ml of water, with 50 ml of saturated 20 sodium chloride solution and dried over magnesium sulfate and then concentrated under reduced pressure. After purification by flash chromatography on a column of silica (60; 35-70 pm), eluting with a mixture of cyclohexane and ethyl acetate (70-30 by volume), 1.2 g of N-(3-(piperazin-1 yl)phenyl]benzamide are obtained in the form of an amorphous brown solid, 25 the characteristics of which are as follows: Mass spectrum IE m/z=281 M m/z=239 (M - C 2
H
4
N)*
" base peak m/z=105 CzHsO + m/z=77 C6H5 30 Step 2:106 mg of lithium aluminum hydride are added to a solution of 0.5 g of N-[3-(piperazin-1-yl)phenyl]benzamide in 20 ml of tetrahydrofuran, and the mixture is refluxed for 20 hours. After addition of 1 ml of ethyl acetate, 1 ml of water, 1 ml of 1N sodium hydroxide and 1 ml of water, is thus obtained; the insoluble material is removed by filtration and, after separation of the phases 35 by settling, washing with 25 ml of saturated aqueous sodium chloride solution 42 and drying over magnesium sulfate, 0.5 g of phenylmethyl-[3-(piperazin-1 yl-)phenyl]amine in the form of an orange-colored oil, the characteristics of which are as follows: Mass spectrum IC m/z=282 M 1 H 5 m/z=268 MH m/z=178 Co 10
H
16
N
3 + base peak Step 3: By working in a manner similar to that for the synthesis of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 0.5 g of 10 phenylmethyl-[3-(piperazin-1-yl)phenyl]amine, 200 mg of [4-(3-phenylmethyl aminophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone hydrochloride are isolated in the form of an amorphous white solid, the characteristics of which are as follows: Mass spectrum (El): m/z = 451(M+) 15 Example E33 [4-(5-Chloro-3-pyridyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)meth anone Step 1: A suspension of 0.74 g of 3,5-dichloropyridine, 2.98 g of 1-tert butoxycarbonylpiperazine, 7.33 g of cesium carbonate, 0.687 g of 20 tris(dibenzylideneacetone)dipalladium (0) and 1.96 g of 2-dicyclohexyl phosphino-2'-(N,N-dimethylamino)biphenyl in 450 ml of 1,2-dimethoxyethane is maintained at 90'C for 100 hours. The medium is concentrated under reduced pressure and then taken up in 50 ml of dichloromethane and filtered in the presence of Celite. After concentration under reduced pressure and 25 purification by flash chromatography on a column of silica (60; 35-70 pm), eluting with a mixture of cyclohexane and ethyl acetate (gradient of from 100% to 50% of cyclohexane by volume), 715 mg of 1-tert-butoxycarbonyl-4 (5-chloro-3-pyridyl)piperazine are obtained in the form of an oil, the characteristics of which are as follows: 30 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 5 in ppm): 1.43 (s: 9H); 3.26 (broad t, J = 5-Hz: 4H); 3.47 (broad t, J = 5 Hz: 4H); 7.45 (mt: 1H); 8.01 (d, J = 2 Hz: 1H); 8.29 (d, J = 2.5 Hz: 1H). Step 2: A suspension of 680 mg of 1-tert-butoxycarbonyl-4-(5-chloro-3 pyridyl)piperazine in 1.8 ml of 5N hydrochloric acid solution is heated at 60 0
C
43 for 3 hours. The medium is concentrated under reduced pressure and then diluted with 20 ml of dichloromethane. After addition of 5 ml of normal sodium hydroxide solution, the organic phase is separated out by settling of the phases and then washed with water, dried over magnesium sulfate and 5 concentrated under reduced pressure to give 450 mg of 1-(5-chloro-3 pyridyl)piperazine, which is used without further purification in the following step. Step 3: By working in a manner similar to that for the synthesis of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone 10 (Examplel), but replacing the 1-(3-chlorophenyl)piperazine with 429 mg of 1-(5-chloro-3-pyridyl)piperazine, 286 mg of [4-(5-chloro-3-pyridyl)piperazin-1 yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone are obtained in the form of a solid, the characteristics of which are as follows: IR spectrum (KBr): 2921; 2853; 1641; 1574; 1502; 1445; 1363; 1234; 15 1002; 996; 946; 763 and 693 cm 1 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 6 in ppm): 2.31 (s: 3H); 3.01 (unresolved complex: 2H); 3.28 (unresolved complex: 2H); 3.40 (unresolved complex: 2H); 3.70 (unresolved complex: 2H); 6.54 (s: 1H); from 7.35 to 7.55 (mt: 4H); 7.37 (tt, J = 7.5 and 1.5 Hz: 1H); 7.41 (mt: 1H); 8.02 (d, 20 J = 2 Hz: 1H); 8.23 (d, J = 2.5 Hz: 1H). Example E34 [4-(3-Methylaminophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone Step 1: 0.93 ml of triethylamine and 0.54 ml of methyl chloroformate are 25 added, in the region of 000C, to a solution of 1.6 g of 3-(4-phenylmethyl piperazin-1-yl)phenylamine, which may be obtained according to patent WO 02/090327, in 50 ml of dichloromethane. After 72 hours in the region of room temperature and addition of 50 ml of water, the organic phase is separated out by settling of the phases, washed with twice 50 ml of water and 30 with 50 ml of saturated sodium chloride solution and then dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (60; 35-70 pjm), eluting with a mixture of cyclohexane and ethyl acetate (70-30 by volume), 0.6 g of methyl [3-(4-phenylmethylpiperazin-1 -yl)phenyl]carbamate is 44 obtained in the form of an orange-colored oil, the characteristics of which are as follows: Mass spectrum (El): m/z = 325(M+) Step 2: By working in a manner similar to that of Step 2 of Example E34, but 5 replacing the N-[3-(piperazin-1-yl)phenyl]benzamide with 1.5 g of [3-(4 phenylmethylpiperazin-1-yl)phenyl]carbamate, 1.3g of [3-(4-phenylmethyl piperazin-1-yl)phenyl]methylamine are obtained in the form of an orange colored oil, the characteristics of which are as follows: Mass spectrum IE m/z=281 M* base peak 10 m/z=266 (M - CH 3
)
+ m/z=190 (M - C 7 H7) m/z=135 C 8
H
11
N
2 + m/z=91 C7H7 + Step 3: 1.16 g of ammonium formate and 53 mg of 20% palladium-on 15 charcoal are added to a solution of 1.3 g of [3-(4-phenylmethylpiperazin-1 yl)phenyl]methylamine in 65 ml of methanol under an inert atmosphere. After refluxing for 4 hours, the catalyst is filtered off on Celite and the filtrate is concentrated under reduced pressure. 20 ml of water and 1 ml of 1N sodium hydroxide are added, and the mixture is then extracted with 3 times 25 ml of 20 ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. After purification by flash chromatography on a column of silica (60; 35-70 pm), eluting with a mixture of dichloromethane and methanol (90-10 by volume), 0.8 g of methyl-[3-(piperazin-1-yl)phenyl]amine is obtained in the form of an 25 orange-colored oil, the characteristics of which are as follows: Mass spectrum IE m/z=191 M m/z=149 (M - C 2
H
4 N)- base peak Step 4: By working in a manner similar to that for the synthesis of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone, 30 but replacing the 1-(3-chlorophenyl)piperazine with 0.5 g of methyl[3 (piperazin-1-yl)phenyl])amine, 0.31 g of [4-(3-methylaminophenyl)piperazin-1 yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone is obtained in the form of a beige-colored foam, the characteristics of which are as follows: Mass spectrum (El): m/z = 375(M+) 45 Example E35 Methyl 3-hydroxy-2-{3-[4-(5-methyl-2-phenyl-2H-pyrazole-3-carbonyl)piper azin-1 -yl]benzoylamino}propionate Step 1: 763 mg of potassium hydroxide pellets are added to a solution of 5 4.4 g of ethyl 3-[4-(5-methyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1 -yl] benzoate, described in Example E28, in 75 ml of distilled water and 150 ml of methanol. After 20 hours at room temperature, the reaction mixture is concentrated under reduced pressure and the residue is acidified with 5N hydrochloric acid to pH 5. After filtration of the solid formed, 3.9 g of 3-[4-(5 10 methyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1-yl]benzoic acid are thus obtained in the form of a pale yellow solid, the characteristics of which are as follows: Melting point (Kofler): 206 0 C 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 8 in ppm): 2.30 (s: 3H); 15 2.86 (unresolved complex: 2H); 3.15 (unresolved complex: 2H); 3.38 (unresolved complex: 2H); 3.71 (unresolved complex: 2H); 6.54 (s: 1H); 7.14 (broad d, J = 8.5 Hz: 1H); from 7.25 to 7.55 (mt: 8H); from 12.60 to 13.20 (very broad unresolved complex: 1H). Step 2: 316 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 20 hydrochloride (EDCI) and 223 mg of 1-hydroxybenzotriazole hydrate (HOBT) are added to a solution of 586 mg of 3-[4-(5-methyl-2-phenyl-2H-pyrazole-3 carbonyl)piperazin-1-yl]benzoic acid in 25 ml of dichloromethane. After stirring for 10 minutes at room temperature, 211 pl of triethylamine (TEA) and 233 mg of methyl D,L-2-amino-3-hydroxypropionate hydrochloride are added and this 25 reaction mixture is then stirred for 20 hours at room temperature. After addition of 50 ml of dichloromethane and 50 ml of water, the organic phase is separated out by settling of the phases and then washed with water, dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (60; 35-70 pm), 30 eluting with pure ethyl acetate, 520 mg of methyl 3-hydroxy-2-{3-[4-(5-methyl 2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1-yl]benzoylamino}propionate are obtained in the form of a beige-colored foam, the characteristics of which are as follows: Mass spectrum (El): m/z = 491 (M') 46 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 8 in ppm): 2.31 (s: 3H); 2.90 (unresolved complex: 2H); 3.19 (unresolved complex: 2H); 3.40 (unresolved complex: 2H); 3.67 (s: 3H); 3.73 (unresolved complex: 2H); 3.80 (broad t, J = 5.5 Hz: 2H); 4.55 (mt: 1H); 5.06 (very broad t, J = 5.5 Hz: 1H); 5 6.54 (s: 1H); 7.08 (mt: 1H); from 7.25 to 7.55 (mt: 8H); 8.51 (d, J = 7.5 Hz: 1 H). Example E36 [4-(3-Chlorophenyl)piperazin-1 -yl](5-methyl-2-pyrazin-2-yl-2H-pyrazol-3-yl) methanone 10 The process is performed in a manner similar to that of Step 2 of Example E22, starting with 150 mg of product from Step 1 of Example E22 and 85 mg and then 39 mg of 2-chloropyrazine, to give, after purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of dichloromethane, methanol and aqueous ammonia (98/2/0.1 by volume), 15 4 mg of [4-(3-chlorophenyl)piperazin-1-yl](5-methyl-2-pyrazin-2-yl-2H-pyrazol 3-yl)methanone in the form of a yellow resin, the characteristics of which are as follows: LC/MS analysis: tr = 3.90; m/z = 383 (MH ) 1 H NMR spectrum (400 MHz, CDCl 3 , 6 in ppm): 2.40 ppm (s, 3H); 3.11 20 ppm (m, 2H); 3.21 ppm (m, 2H); 3.50 ppm (m, 2H); 3.97 ppm (m, 2H); 6.32 ppm (s, 1H); 6.80 ppm (bd, J= 8.5 Hz, 1H); 6.89 ppm (m, 2H); 7.19 ppm (t, J=8.5Hz, 1H); 8.23 ppm (bs, 1H); 8.44 ppm (d, J= 2.5 Hz, 1H); 9.24 ppm (bs, 1H) Example E37 25 [4-(3-Chlorophenyl)piperazin-1 -yl](5-methyl-2-thiazol-2-yl-2H-pyrazol-3-yl) methanone The process is performed in a manner similar to that of Step 2 of Example E22, starting with 150 mg of the product from Step 1 of Example E22 and 121 mg and then 56 mg of 2-bromothiazole, to give, after purification by flash 30 chromatography on a column of silica (30-60 pm), eluting with a mixture of toluene, ethyl acetate and triethylamine (80/20/0.1 by volume), 5 mg of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2-thiazol-2-yl-2H-pyrazol-3-yl)methan one in the form of a yellow oil, the characteristics of which are as follows: LC/MS analysis: tr = 4.16; m/z = 388 (MH*) 47 1 H NMR spectrum (400 MHz, CDCl 3 , 8 in ppm): 2.36 ppm (s, 3H); 3.08 ppm (m, 2H); 3.32 ppm (m, 2H); 3.43 ppm (m, 2H); 3.97 ppm (m, 2H); 6.30 ppm (s, 1H); 6.78 ppm (bd, J=8.5 Hz, 1H); 6.87 ppm (m, 2H); 7.06 ppm (d, J= 3.5 Hz, 1H); 7.18 ppm (t, J= 8.5 Hz, 1H); 7.45 ppm (d, J= 3.5 Hz, 1H) 5 Example E38 2-{5-[4-(3-Chlorophenyl)piperazine-1 -carbonyl]-3-methylpyrazol-1 -yl}nicotino nitrile The process is performed in a manner similar to that of Step 2 of Example E22, starting with 150 mg of the product from Step 1 of Example E22 and 10 68 mg and then 32 mg of 2-chloro-3-cyanopyridine, to give, after purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of toluene, ethyl acetate and triethylamine (80/20/0.1 by volume), 7 mg of 2-{5-[4-(3-chlorophenyl)piperazine-1l-carbonyl]-3-methylpyrazol-1-yl} nicotinonitrile in the form of a white solid, the characteristics of which are as 15 follows: LC/MS analysis: tr = 4.03; m/z = 408 (MH ) 1 H NMR spectrum (400 MHz, CDCl 3 , 6 in ppm): 2.43 ppm (s, 3H); 3.19 ppm (m, 2H); 3.29 ppm (m, 2H); 3.66 ppm (m, 2H); 3.91 ppm (m, 2H); 6.38 (s, 1H); 6.82 ppm (bd, J=8.5Hz, 1H); 6.89 ppm (m, 2H); 7.21 ppm (t, J = 8.5 Hz, 20 1H); 7.31 ppm (dd, J= 5-7.5 Hz, 1H); 8.13 ppm (dd, J= 2-7.5 Hz, 1H); 8.52 ppm (dd, J= 2-5 Hz, 1H). Example E39 {4-[3-(1-Hydroxyethyl)phenyl]piperazin-1 -yl}(5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone hydrochloride 25 Step 1: 2.99 g of 3-bromoacetophenone, 317 mg of (R)(+)-2,2'-bis(diphenyl phosphino)-1,1'-binaphthyl, 114 mg of palladium acetate and 1.59 g of sodium tert-butoxide are added to a solution of 2.78 g of N-phenylmethylpiperazine in 100 ml of toluene. After heating at 80'C for 20 hours, the insoluble material is filtered off, 25 ml of ethyl acetate and 25 ml of 30 water are added and the organic phase is separated out by settling of the phases and then washed with water, dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (60; 35-70 pm), eluting with a mixture of cyclohexane and ethyl acetate (20-70 by volume), 0.4 g of 1-[3-(4- 48 phenylmethylpiperazin-1-yl)phenyl]ethanone is obtained in the form of an orange-colored oil, the characteristics of which are as follows: Mass spectrum (El): m/z = 294(M+) Step 2: By working in a manner similar to that of Step 3 of Example 34, but 5 replacing the [3-(4-phenylmethylpiperazin-1-yl)phenyl]methylamine with 0.7 g of 1-[3-(4-phenylmethylpiperazin-1 -yl)phenyl]ethanone, 0.3 g of 1-[3 (piperazin-1-yl)phenyl]ethanol is obtained in the form of an orange-colored oil, the characteristics of which are as follows: Mass spectrum (El): m/z = 294(M+) 10 Step3: By working in a manner similar to that for the synthesis of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 0.3 g of 1-(3 (piperazin-1-yl)phenyl]ethanol, 0.15 g of {4-[3-(1-hydroxyethyl)phenyl] piperazin-1-yl}-(5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone hydrochloride 15 is isolated in the form of an amorphous off-white solid, the characteristics of which are as follows: Mass spectrum (El): m/z = 390(M+) Example E40 N-(2-Hydroxyethyl)-3-[4-(5-methyl-2-phenyl-2H-pyrazole-3 20 carbonyl)piperazin-1-yl]benzamide Working in a manner similar to that for the synthesis of methyl 3-hydroxy-2-{3 [4-(5-methyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1 -yl]benzoylamino} propionate of Step 2 of Example E35, but replacing the D,L-2-amino-3 hydroxypropionic acid with 62 pl of ethanolamine, 0.36 g of N-(2-hydroxy 25 ethyl)-3-[4-(5-methyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1 -yl]benz amide is obtained in the form of a beige-colored foam, the characteristics of which are as follows: Mass spectrum (El): m/z = 433(M+) 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 5 in ppm): 2.31 (s: 3H); 30 2.87 (unresolved complex: 2H); 3.17 (unresolved complex: 2H); 3.33 (mt: 2H); 3.39 (unresolved complex: 2H); 3.52 (mt: 2H); 3.73 (unresolved complex: 2H); 4.73 (t, J = 5.5 Hz: 1H); 6.54 (s: 1H); 7.04 (mt: 1H); from 7.20 to 7.55 (mt: 8H); 8.37 (broad t, J = 5.5 Hz: 1H).
49 Example E41 [4-(Isoquinolin-4-yl)piperazin-1 -yl)](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone By working in a manner similar to that for the synthesis of [4-(3 5 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 213.3 mg of 4-piperazin-1-ylisoquinoline, which may be obtained according to patent DE 19900544, 320 mg of [4-(isoquinolin-4-yl)piperazin-1-y])(5-methyl-2 phenyl-2H-pyrazol-3-yl)methanone are obtained in the form of a white solid, 10 the characteristics of which are as follows: Melting point (Kofler): 166°C Mass spectrum (El): m/z = 397(M+) Example E42 [4-(3-Chlorophenyl)piperazin-1 -yl][2-(2,4-difluorophenyl)-5-methyl-2H-pyrazol 15 3-yl]methanone Step 1: 3.35 g of methyl hydroxylamine hydrochloride are added to a solution of- 5.28 g of ethyl 2,4-dioxovalerate in 35 ml of DMF and 35 ml of ethanol, followed by addition of 9.99 g of sodium acetate trihydrate. After stirring for 2 hours at 600C, the reaction mixture is filtered and the filtrate concentrated. 20 The oil obtained is taken up in isopropyl ether and the organic phase is washed with saturated aqueous sodium dihydrogen phosphate solution, dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (40-63 pm), eluting with a mixture of heptane and ethyl acetate (60/40 by volume), 2.13 g of ethyl 25 2,4-dioximinovalerate A are obtained in the form of a colorless liquid, the characteristics of which are as follows: Mass spectrum (El): m/z = 216 (M') Step 2: 5.6 ml of a 2M solution of trimethylaluminum in toluene are added, at 250C, to a solution of 1.65 g of 1-(3-chlorophenyl)piperazine in 45 ml of 30 toluene, followed by addition, at 600C, of a solution of 1.21 g of dioxime A (Step 1 of the present example) in 10 ml of toluene. The reaction medium is stirred for 1 hour at 750C and then poured into 100 ml of aqueous 1M sodium potassium tartrate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced 35 pressure. After purification by flash chromatography on a column of silica (40- 50 63 pm), eluting with a mixture of heptane and ethyl acetate (80/20 by volume), 1.1-5g of N-[4-(3-chlorophenyl)piperazinyl]-2,4-dioximinovaleramide B are obtained in the form of a yellow oil, the characteristics of which are as follows: 5 Mass spectrum (ES): m/z = 367 (MH') Step 3:108 mg of 2,4-difluorophenylhydrazine hydrochloride are added, at 250C, to a solution of 110 mg of amide B in 0.6 ml of acetic acid and 0.3 ml of methylglycol. The reaction medium is stirred for 3.5 hours at 1000C and then concentrated. After purification by flash chromatography on a column of silica 10 (40-63 pm), eluting with a mixture of heptane and ethyl acetate (70/30 by volume), 101 mg of [4-(3-chlorophenyl)piperazin-1-yl][2-(2,4-difluorophenyl) 5-methyl-2H-pyrazol-3-yl]methanone are obtained in the form of a pale yellow solid, the characteristics of which are as follows: LC/MS analysis: tr = 4.34; m/z = 417 (MH') 15 1 H NMR spectrum (400 MHz, (CD 3
)
2 SO d6, 5 in ppm): 2.29 ppm (s, 3H); 3.18 ppm ( m, 4H); 3.66 ppm (m, 4H); 6.60 ppm (s, 1H); 6.82 (dd, J = 2 8.5 Hz, 1H); 6.91 ppm (dd, J= 2- 8.5 Hz, 1H); 6.97 ppm (t, J= 2 Hz, 1H); 7.22 ppm (m, 2H); 7.45 ppm (ddd, J= 2.5-9- 11 Hz, 1H); 7.61 ppm (dt, 6- 9Hz, 1H). Example E43 20 [4-(3-Chlorophenyl)piperazin-1 -yl][5-methyl-2-(2,3,5,6-tetrafluorophenyl)-2H pyrazol-3-yl]methanone The process is performed in a manner similar to that of Example E42, starting with 75 mg of amide B, obtained from Step 2 of Example E42, and 109 mg of 2,3,5,6-tetrafluorophenylhydrazine in the presence of 76 mg of para 25 toluenesulfonic acid monohydrate, for 9 hours at 1000C, to give, after purification by flash chromatography on a column of silica (40-63 pm), eluting with a mixture of heptane and ethyl acetate (80/20 by volume), 14 mg of [4-(3 chlorophenyl)piperazin-1 -yl][5-methyl-2-(2,3,5,6-tetrafluorophenyl)-2H pyrazol-3-yl]methanone in the form of a yellow solid, the characteristics of 30 which are as follows: LC/MS analysis: tr = 4.51; m/z = 453 (MH ) 1 H NMR spectrum (400 MHz, (CD 3
)
2 SO d6, 5 in ppm): 2.32 ppm (s, 3H); 3.22 ppm (m, 4H); 3.66 ppm (m, 2H); 3.77 ppm (m, 2H); 6.79 ppm (s, 1H); 6.83 ppm (dd, 2.5 -8.5 Hz, 1H); 6.92 ppm (dd, J= 2.5- 8.5 Hz, 1H); 6.98 35 ppm (t, J= 2.5 Hz, 1H); 7.24 ppm (t, J= 8.5 Hz, 1H); 8.10 ppm (m, 1H) 51 Example E44 [4-(3-Chlorophenyl)piperazin-1 -yl][2-(2,5-dichlorophenyl)-5-methyl-2H pyrazol-3-yl]methanone 184 mg of 2,5-dichlorophenylhydrazine and 197 mg of para-toluenesulfonic 5 acid monohydrate are added, at 250C, to a solution of 190 mg of amide B, obtained in Step 2 of Example E42, in 1.5 ml of acetic acid. The reaction medium is stirred for 1.5 hours at 100'C and then concentrated. After purification by flash chromatography on a column of silica (60; 40-63 pm), eluting with a mixture of heptane and ethyl acetate (80/20 by volume), 84 mg 10 of [4-(3-chlorophenyl)piperazin-1 -yl][2-(2,5-dichlorophenyl)-5-methyl-2H pyrazol-3-yl]methanone are obtained in the form of a yellow solid, the characteristics of which are as follows: LC/MS analysis: tr = 4.62; m/z = 449 (MH') 1 H NMR spectrum (400 MHz, (CD 3
)
2 SO d6, 8 in ppm): 2.29 ppm (s, 15 3H); 3.20 ppm (m, 4H); 3.65 ppm (m, 2H); 3.76 ppm (m, 2H); 6.64 ppm (s, 1H); 6.82 ppm (dd, J= 2.5- 8.5 Hz, 1H); 6.91 ppm (dd, J= 2.5- 8.5 Hz, 1H); 6.97 ppm (t, J= 2.5 Hz, 1H); 7.23 ppm (t, J= 8.5 Hz, 1H); 7.56 ppm (dd, 2.5 8.5 Hz, 1H); 7.62 ppm (d, J= 2.5 Hz, 1H); 7.63 ppm (d, J= 8.5 Hz). Example E45 20 [4-(3-Chlorophenyl)piperazin-1 -yl](5-methyl-2-o-tolyl-2H-pyrazol-3-yl)methan one 55 mg of ortho-tolylhydrazine hydrochloride are added at 250C to a solution of 106 mg of amide B, obtained in Step 2 of Example E42 in 1.0 ml of acetic acid. The reaction medium is stirred for 2 hours at 1000C and then 25 concentrated. After purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of heptane and ethyl acetate (80/20 by volume), 22mg of [4-(3-chlorophenyl)piperazin-1-yl](5-methyl-2-o-tolyl-2H pyrazol-3-yl)methanone are obtained in the form of a white solid, the characteristics of which are as follows: 30 LC/MS analysis: tr = 4.31; m/z = 495 (MH') Example E46 (1-Phenyl- 1 H-pyrrol-2-yl)[4-(pyrid-3-yl)piperazin-1-yl]methanone hydro chloride The process is performed in a manner similar to that for the synthesis of [4-(3 35 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone 52 (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 65.4 mg of 1-(pyrid-3-yl)piperazine, which may be obtained according to Chem. Pharm. Bull., 49, 1314 (2001), and replacing the 5-methyl-2-phenyl-2H-pyrazole-3 carboxylic acid with 75 mg of 1-phenyl-1H-pyrrole-2-carboxylic acid, which 5 may be obtained according to Synth. Commun., 28, 443 (1998). 77 mg of (1 phenyl-1 H-pyrrol-2-yl)[(4-(pyrid-3-yl)piperazin-1 -yl]methanone hydrochloride are thus isolated in the form of a yellow solid, the characteristics of which are as follows: Melting point (Kofler): 180 0 C 10 Mass spectrum (El): m/z = 332 (M+) Example E47 [4-(3-Chlorophenyl)piperazin-1 -yl][2-(2,5-dimethylphenyl)-5-methyl-2H pyrazol-3-yl]methanone The process is performed in a manner similar to that of Example E45, starting 15 with 106 mg of amide B, obtained in Step 2 of Example E42, and 60 mg of 2,5-dimethylphenylhydrazine hydrochloride, to give, after purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of heptane and ethyl acetate (80/20 by volume), 46 mg of [4-(3 chlorophenyl)piperazin-1-yl][2-(2,5-dimethylphenyl)-5-methyl-2H-pyrazol-3 20 yl]methanone in the form of a white solid, the characteristics of which are as follows: LC/MS analysis: tr = 4.48; m/z = 409 (MH ) Example E48 [4-(3-Chlorophenyl)piperazin-1 -yl](2-cyclohexyl-5-methyl-2 H -pyrazol-3-yl) 25 methanone The process is performed in a manner similar to that of Example E45, starting with 106 mg of amide B, obtained in Step 2 of Example E42, and 74 mg of cyclohexylhydrazine hydrochloride, for 6 hours at 100 0 C, to give, after purification by flash chromatography on a column of silica (30-60 p/m), eluting 30 with a mixture of heptane and ethyl acetate (80/20 by volume), 70 mg of [4-(3 chlorophenyl)piperazin-1 -yl](2-cyclohexyl-5-methyl-2H-pyrazol-3-yl)methan one in the form of a white solid, the characteristics of which are as follows: LC/MS analysis: tr = 4.51; m/z = 387 (MH') 53 Example E49 [4-(3-Chlorophenyl)piperazin-1l-yl][5-methyl-2-(4-nitrophenyl)-2H-pyrazol-3-yl] methanone The process is performed in a manner similar to that of Example E45, starting 5 with 165 mg of amide B, obtained in Step 2 of Example 42, and 105 mg of 4-nitrophenylhydrazine in the presence of 104 mg of para-toluenesulfonic acid monohydrate, for 4 hours at 1000C, to give, after purification by flash chromatography on a column of silica (40-63 pm), eluting with a mixture of heptane and ethyl acetate (80/20 by volume), 148 mg of [4-(3-chloro 10 phenyl)piperazin-1 -yl][5-methyl-2-(4-nitrophenyl)-2H-pyrazol-3-yl]methanone in the form of a yellow solid, the characteristics of which are as follows: LC/MS analysis: tr = 4.36; m/z = 426 (MH ) 1 H NMR spectrum (400 MHz, (CD 3
)
2 SO d6, 6 in ppm): 2.31 ppm (s, 3H); 3.11 ppm (m, 2H); 3.28 ppm (masked, 2Hz); 3.53 ppm (m, 2H); 3.74 15 ppm (m, 2H); 6.66 ppm (s, 1H); 6.81 ppm (dd, J= 2.5- 8.5 Hz, 1H); 6.88 ppm (dd, J= 2.5- 8.5 Hz, 1H); 6.94 ppm (t, J= 2.5 Hz, 1H); 7.22 ppm (t, J = 8.5 Hz, 1H); 7.70 and 8.33 ppm (AA'BB' system, 4H). Example E50 [4-(3-Chlorophenyl)piperazin-1-yl][5-methyl-2-(4-trifluoromethylphenyl)-2H 20 pyrazol-3-yl]methanone The process is performed in a manner similar to that of Example E45, starting with 165 mg of amide B, obtained in Step 2 of Example E42, and 120 mg of 4-(trifluoromethyl)phenylhydrazine in the presence of 104 mg of para toluenesulfonic acid monohydrate, for 5 hours at 1000C, to give, after 25 purification by flash chromatography on a column of silica (40-63 pm), eluting with a mixture of heptane and ethyl acetate (80/20 by volume), 98 mg of [4-(3 chlorophenyl)piperazin-1 -yl][5-methyl-2-(4-trifluoromethylphenyl)-2H-pyrazol 3-yl]methanone in the form of a white solid, the characteristics of which are as follows: 30 LC/MS analysis: tr = 4.61; m/z = 449 (MH') 1 H NMR spectrum (400 MHz, (CD 3
)
2 SO d6, 8 in ppm): 2.31 ppm (s, 3H); 3.01 ppm (m, 2H); 3.23 ppm (m, 2H); 3.48 ppm (m, 2H); 3.72 ppm (m, 2H); 6.61 ppm (s, 1H); 6.82 ppm (dd, J= 2.5- 8.5 Hz, 1H); 6.87 ppm (dd, J= 2.5- 8.5 Hz, 1H); 6.93 ppm (t, J= 2.5 Hz, 1H); 7.22 ppm (t, J= 8.5 Hz, 1H); 35 7.66 and 7.85 ppm (AA'BB' system, 4H).
54 Example E51 [4-(3,5-Dimethoxyphenyl)piperazin-1-yl](1-phenyl-1 H-pyrrol-2-yl)methanone hydrochloride By working in a manner similar to that for the synthesis of [4-(3 5 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 89 mg of 1-(3,5-dimethoxyphenyl)piperazine and replacing the 5-methyl-2-phenyl-2H pyrazole-3-carboxylic acid with 75 mg of 1-phenyl-1H-pyrrole-2-carboxylic, acid, which may be obtained according to Synth. Comm., 28, 443 (1998), 10 30 mg of [4-(3,5-dimethoxyphenyl)piperazin-1 -yl](1 -phenyl-1H-pyrrol-2 yl)methanone hydrochloride are isolated in the form of an amorphous white solid, the characteristics of which are as follows: Mass spectrum (El): m/z = 391 (M+) Example E52 15 [4-(3-Chlorophenyl)piperazin-1 -yl][5-methyl-2-(pyrid-3-yl)-2H-pyrazol-3 yl]methanone By working in a manner similar to that for the synthesis of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic 20 acid with 203 mg of 5-methyl-2-(pyrid-3-yl)-2H-pyrazole-3-carboxylic acid, which may be obtained according to J. Het. Chem., 36, 217 (1999), 290 mg of [4-(3-chlorophenyl)piperazin-1 -yl][5-methyl-2-(pyrid-3-yl)-2H-pyrazol-3 yl]methanone are obtained in the form of a beige-colored solid, the characteristics of which are as follows: 25 Melting point (Kofler): 1240C Mass spectrum (El): m/z = 381 (M+) Example E53 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl][5-methyl-2-(pyrid-3-yl)-2H-pyrazol-3 yl]methanone 30 By working in a manner similar to that for the synthesis of [4-(3 chlorophenyl)piperazin-1 -yl][5-methyl-2-(pyrid-3-yl)-2H-pyrazol-3 yl]methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 602 mg of 1-(3,5-dimethoxyphenyl)piperazine, and 5-methyl-2-phenyl 2H-pyrazole-3-carboxylic acid with 600 mg of 5-methyl-2-pyrid-3-yl-2H 35 pyrazole-3-carboxylic acid, which may be obtained according to J. Het.
55 Chem., 36, 217 (1999), 800 mg of [4-(3,5-dimethoxyphenyl)piperazin-1-yl][5 methyl-2-(pyrid-3-yl)-2H-pyrazol-3-yl]methanone are obtained in the form of a white solid, the characteristics of which are as follows: Melting point (Kofler): 600C 5 Mass spectrum (El): m/z = 407 (M+) Example E54 [4-(4-Fluoro-3-pyridyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone By working, in 3 steps, in a manner similar to that for the synthesis of [4-(5 10 chloro-3-pyridyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 33), but replacing in Step 1 of the synthesis the 3,5-dichloropyridine with 3.52 g of 5-bromo-2-fluoropyridine, 433 mg of [4-(4-fluoro-3-pyridyl) piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone are obtained, in Step 3 of the synthesis, in the form of a solid, the characteristics of which are 15 as follows: 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 6 in ppm): 2.31 (s: 3H); 2.85 (unresolved complex: 2H); 3.13 (unresolved complex: 2H); 3.39 (unresolved complex: 2H); 3.72 (unresolved complex: 2H); 6.54 (s: 1H); 7.05 (dd, J = 9 and 3 Hz: 1H); 7.37 (tt, J = 7 and 1.5 Hz: 1H); from 7.35 to 7.60 (mt: 20 5H); 7.79 (dd, J = 3 and 1.5 Hz: 1H). Example E55 3-{5-[4-(3-Chlorophenyl)piperazine-1 -carbonyl]-3-trifluoromethylpyrazol-1 yl}benzonitrile By working in a manner similar to that for the synthesis of [4-(3-chloro 25 phenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid with 100 mg of 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3 carboxylic acid, which may be obtained according to patent WO 02/000647, 72 mg of 3-{5-[4-(3-chlorophenyl)piperazine-1-carbonyl]-3 30 trifluoromethylpyrazol-1-yl}benzonitrile are obtained in the form of a white foam, the characteristics of which are as follows: Mass spectrum (El): m/z = 459 (M+) 56 Example E56 3-{5-[4-(3,5-Dimethoxyphenyl)piperazine-1 -carbonyl]-3-trifluoromethylpyrazol 1-yl}benzonitrile By working in a manner similar to that for the synthesis of [4-(3 5 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 79 mg of 1-(3,5-dimethoxyphenyl)piperazine and replacing the 5-methyl-2-phenyl-2H pyrazole-3-carboxylic acid with 100 mg of 2-(3-cyanophenyl)-5 trifluoromethyl-2H-pyrazole-3-carboxylic acid, which may be obtained 10 according to patent WO 02/000647, 118 mg of 3-{5-[4-(3,5 dimethoxyphenyl)piperazine-1 -carbonyl]-3-trifluoromethylpyrazol-1 -yl}benzo nitrile are obtained in the form of a white foam, the characteristics of which are as follows: Mass spectrum (El): m/z = 485 (M+) 15 Example E57 3-[4-(1-Phenyl-1 H-pyrrole-2-carbonyl)piperazin-1-yl]benzamide By working in a manner similar to that for the synthesis of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Examplel), but replacing the 1-(3-chlorophenyl)piperazine with 113.2 mg of 20 3-piperazin-1-ylbenzarnide, which may be obtained according to patent WO 98/00400, and replacing the 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid with 75mg of 1-phenyl-1H-pyrrole-2-carboxylic acid, which may be obtained according to Synth. Comm., 28, 443 (1998), 65 mg of 3-[4-(1 phenyl-1lH-pyrrole-2-carbonyl)piperazin-1-yl]benzamide are obtained in the 25 form of an amorphous beige-colored solid, the characteristics of which are as follows: Mass spectrum (El): m/z = 374 (M+) Example E58 [2-(3-Fluorophenyl)-5-methyl-2H-pyrazol-3-yl](4-pyrid-3-ylpiperazin- 1 30 yl)methanone By working in a manner similar to that for the synthesis of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone, but replacing the 1-(3-chlorophenyl)piperazine with 214 mg of 1-pyrid-3 ylpiperazine, which may be obtained according to Chemical and 35 Pharmaceutical Bulletin, 49, 1314 (2001) and replacing the 5-methyl-2- 57 phenyl-2H-pyrazole-3-carboxylic acid with 288.7 mg of 2-(3-fluorophenyl)-5 methyl-2H-pyrazole-3-carboxylic acid, which may be obtained according to J. Het. Chem., 30, 304 (1993), 280 mg of [2-(3-fluorophenyl)-5-methyl-2H pyrazol-3-yl](4-pyrid-3-ylpiperazin-1-yl)methanone are obtained in the form of 5 a white powder, the characteristics of which are as follows: Melting point (Kofler): 132oC Mass spectrum (El): m/z = 365 (M+) Example E59 [4-(4-Bromo-3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3 10 yl)methanone 140 mg of N-bromosuccinimide and 6.5 mg of 2,2'-azobis(2 methylpropionitrile) are added to a solution of 300 mg of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2 H-pyrazol-3-yl)methanone (Example 1) in 6 ml of carbon tetrachloride. The reaction mixture is refluxed 15 under irradiation from a 250 W lamp (white light) for 3 hours and then filtered and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (40-63 pm), eluting with a mixture of toluene and ethyl acetate (80/20 by volume), 350 mg of [4-(4-bromo-3 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone 20 are obtained in the form of a pale yellow oil, the characteristics of which are as follows: LC/MS analysis: tr = 4.49; m/z = 458 (MH ) 1 H NMR spectrum (400 MHz, (CD 3
)
2 SO d6, 6 in ppm): 2.29 ppm (s, 3H); 2.89 ppm (m, 2H); 3.17 ppm (m, 2H); 3.34 ppm (m, 2H); 3.66 ppm (m, 25 2H); 6.51 ppm (s, 1H); 6.80 ppm (bd J= 8.5 Hz, 1H); 7.09 ppm (bs, 1H); 7.35 ppm (bt, J= 8Hz, 1H); from 7.41 to 7.52 ppm (m, 5H). Example E60 (5-Hydroxymethyl-2-phenyl-2H-pyrazol-3-yl)[4-(3-chlorophenyl)piperazin-1 yl]methanone 30 The process is performed in a manner similar to that of Step 3 of Example E73, starting with 0.3 g of ethyl 3-benzoyloxymethyl-1-phenyl-1-H-pyrazole-5 carboxylate, obtained in Step 2 of Example 73, and 537 mg of 1-(3-chloro phenyl)piperazine to give, after purification by flash chromatography on a column of silica (40-63 pm), eluting with a mixture of dichloromethane and 35 ethyl acetate (80/20 by volume), 253 mg of (5-hydroxymethyl-2-phenyl-2H- 58 pyrazol-3-yl)[4-(3-chlorophenyl)piperazin-1-yl]methanone in the form of a white solid, the characteristics of which are as follows: Mass spectrum(ES): m/z = 422 (MH ) Example E61 5 (5-Benzyloxy-2-pyrid-2-yl-2H-pyrazol-3-yl)[4-(3-chlorophenyl)piperazin-1 yl]methanone Step 1: A solution of 4.58 g of N-tert-butoxycarbonyl anhydride (Boc 2 0) in 40 ml of dichloromethane is added to a solution of 3.12 g of ethyl 5-hydroxy 1H-pyrazole-3-carboxylate, which may be prepared according to Chem. 10 Pharm. Bull. 31(4) 1228 (1983), using toluene instead of benzene, in 40 ml of dichloromethane and 3.1 ml of triethylamine, cooled to 0 0 C. The reaction medium is stirred for 3 hours at room temperature and then washed with saturated aqueous sodium dihydrogen phosphate solution. The organic phase is dried over magnesium sulfate and concentrated under reduced 15 pressure. After purification by flash chromatography on a column of silica (40 63 pm), eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume), 3.26 g of 1-tert-butyl 3-ethyl 5-hydroxypyrazole-1,3-dicarboxylate are obtained in the form of a white solid, the characteristics of which are as follows: 20 Mass spectrum (ES): m/z = 257 (MH ) Step 2: A solution of 0.37 ml of benzyl bromide in 3 ml of DMF is added to 796 mg of the product of Step 1 of the present Example and 1.11 g of cesium carbonate in 15 ml of DMF at -5 0 C. The reaction medium is stirred for 3 hours at 0 0 C and then poured into saturated aqueous sodium dihydrogen phosphate 25 solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (40-63 pm), eluting with a mixture of heptane and ethyl acetate (90/10 by volume), 117 mg of 1-tert-butyl 3-ethyl 5-benzyloxypyrazole-1,3-dicarboxylate are obtained in the 30 form of a white solid, the characteristics of which are as follows: Mass spectrum (ES): m/z = 347 (MH ) Step 3: 3 ml of trifluoroacetic acid are added to 1.50 g of the product of Step 2 of the present Example in 12 ml of dichloromethane at room temperature. The reaction medium is stirred for 1 hour at room temperature, concentrated 59 under reduced pressure and then purified by flash chromatography on a column of silica (40-63 pm), eluting with a mixture of dichloromethane and ethyl acetate (97/3 by volume), to give 340 mg of ethyl 5-benzyloxy-2H pyrazole-3-carboxylate in the form of a white solid, the characteristics of 5 which are as follows: Mass spectrum (ES): m/z = 247 (MH ) Step 4: The process is performed in a manner similar to that of Step 2 of Example E42, starting with 320 mg of the product of Step 3 of the present example and 537 mg of 1-(3-chlorophenyl)piperazine to give, after purification 10 by flash chromatography on a column of silica (40-63 pm), eluting with a mixture of dichloromethane and ethyl acetate (80/20 by volume), 173 mg of (5-benzyloxy-1 H-pyrazol-3-yl)[4-(3-chlorophenyl)piperazin-1 -yl]methanone in the form of a white solid, the characteristics of which are as follows: Mass spectrum(ES): m/z = 397 (MH ) 15 Step 5:100 mg of the product from Step 4 of the present example, 10 mg of cuprous iodide, 2.0 ml of 1,4-dioxane, 30 p/1 of trans-1,2-diaminocyclohexane, 115 mg of cesium carbonate, 37 pl of 2-bromopyridine and 30 pl of 1-hexyl-3 methylimidazolium pentafluorophosphate are placed in a microwave reactor and then subjected to the microwave field for 15 minutes at 140 0 C. The 20 mixture is filtered, rinsed with 0.5 ml of 1,4-dioxane, a further 10 mg of cuprous iodide, 30 pl of trans-1,2-diaminocyclohexane, 115 mg of cesium carbonate, 37 p/1 of 2-bromopyridine and 30 pl of 1-hexyl-3-methylimidazolium pentafluorophosphate are added and the mixture is then subjected to the microwave field for a further 15 minutes at 140 0 C. The reaction mixture is 25 poured into 20 ml of water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (40 63 pm), eluting with a mixture of dichloromethane and ethyl acetate (80/20 by volume), 62 mg of (5-benzyloxy-2-pyrid-2-yl-2H-pyrazol-3-yl)[4-(3 30 chlorophenyl)piperazin-1-yl]methanone are obtained in the form of an orange gum, the characteristics of which are as follows: LC/MS analysis: tr = 4.77; m/z = 474 (MH') 1 H NMR spectrum (400 MHz, (CD 3
)
2 SO d6, 6 in ppm): 3.08 ppm (m, 2H); 3.31 ppm (masked, 4H); 3.74 ppm (m, 2H); 5.30 ppm (s, 2H); 6.25 ppm 35 (s, 1H); 6.81 ppm (dd, J= 2.5- 8.5 Hz, 1H); 6.88 ppm (dd, J=2.5- 8.5 Hz, 1H); 60 6.94 ppm (t, J= 2.5 Hz, 1H); 7.21 ppm (t, J= 8.5 Hz, 1H); 7.26 ppm (ddd, J=1 5- 7.5 Hz, 1H); 7.36 ppm (bt, J=8.5 Hz, 1H); 7.41 ppm (bt, J= 8.5 Hz, 2H); 7.51 ppm (bd, J= 8.5 Hz, 2H); 7.76 ppm (td, J= 1- 8.5 Hz, 1H); 7.96 ppm (ddd, J= 2- 7.5- 8.5 Hz, 1H); 8.30 ppm (ddd, J= 1- 2- 5 Hz, 1H). 5 Example E62 (5-Methyl-2-phenyl-2H-pyrazol-3-yl)[4-(2-nitrophenyl)piperazin-1 -yl]methan one By working in a manner similar to that for the synthesis of [4-(3 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone 10 (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 414.5 mg of 1-(2-nitrophenyl)piperazine, 490 mg of (5-methyl-2-phenyl-2H-pyrazol-3-yl)[4 (2-nitrophenyl)piperazin-1-yl]methanone are obtained in the form of a yellow solid, the characteristics of which are as follows: Melting point (Kofler): 127 0 C 15 Mass spectrum (El): m/z = 391(M+) Example E63 [4-(3,5-Dimethylphenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone By working in a manner similar to that for the synthesis of [4-(3 20 chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 380.6 mg of 1-(3,5-dimethylphenyl)piperazine, 450 mg of [4-(3,5-dimethylphenyl)piperazin 1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone are obtained in the form of a white solid, the characteristics of which are as follows: 25 Melting point (Kofler): 109 0 C Mass spectrum (El): m/z = 374(M+) Examples E64 and E65 [5-Bromo-2-(4-bromophenyl)-2H-pyrazol-3-yl][4-(3-chlorophenyl)piperazin-1 yl]methanone (Example E64) and 30 (5-Bromo-2-phenyl-2H-pyrazol-3-yl)[4-(3-chlorophenyl)piperazin-1 -yl] methanone (Example E65) Step 1: The synthesis of ethyl 5-bromo-2-phenyl-2H-pyrazole-3-carboxylate, according to Tetrahedron Lett., 40, 2605 (1999), starting with 1.64 g of (phenylhydrazono)acetic acid and 3.56 g of N-bromosuccinimide in 40 ml of 61 DMF, followed by addition of 5.1 ml of ethyl propionate and 1.4 ml of triethylamine gives, after 2 successive purifications by flash chromatography on a column of silica (40-63 pm), eluting, respectively, with a mixture of heptane and ethyl acetate (90/10 by volume) and, for the fractions that are 5 still impure, with another mixture of cyclohexane and acetone (95/5 by volume): 57 mg of ethyl 5-bromo-2-(4-bromophenyl)-2H-pyrazole-3-carboxylate, in the form of an orange-colored solid, the characteristics of which are as follows: 10 Mass spectrum (ES): m/z = 374 (MH') 1 H NMR spectrum (400 MHz, (CD 3
)
2 SO d6, 5 in ppm): 1.16 ppm (t, J= 7 Hz, 3H); 4.18 ppm (q, J= 7 Hz, 2H); 7.24 ppm (s, 1H); 7.47 and 7.70 ppm (AA'BB' system, 4H). and 15 520 mg of ethyl 5-bromo-2-phenyl-2H-pyrazole-3-carboxylate, in the form of an orange-colored solid, the characteristics of which are in accordance with those given in the literature. Step 2: The process is performed in a manner similar to that of Step 2 of Example E42, starting with 192 mg of ethyl 5-bromo-2-phenyl-2H-pyrazole-3 20 carboxylate, containing 10 to 20% of ethyl 5-bromo-2-(4-bromophenyl)-2H pyrazole-3-carboxylate, and 256 mg of 1-(3-chlorophenyl)piperazine, to give, after purification by flash chromatography on a column of silica (40-63 pm), eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume): 8 mg of [5-bromo-2-(4-bromophenyl)-2H-pyrazol-3-yl][4-(3-chloro 25 phenyl)piperazin-1-yl]methanone (Example E64) in the form of a pale yellow solid, the characteristics of which are as follows: LC/MS analysis: tr = 4.78; m/z = 523 (MH ) 1 H NMR spectrum (400 MHz, CDCI 3 , 6 in ppm): 2.84 ppm (m, 2H); 3.14 ppm (m, 2H); 3.32 ppm (m, 2H); 3.84 ppm (m, 2H); 6.58 ppm (s, 1H); 30 6.72 ppm (dd, J= 2.5-8.5 Hz, 1H); 6.82 ppm (t, J= 2.5 Hz, 1H); 6.90 ppm (dd, J = 2.5-8.5 Hz, 1H); 7.18 ppm (t, J= 8.5 Hz, 1H); 7.42 and 7.59 ppm (AA'BB' system, 4H). and 108 mg of (5-bromo-2-phenyl-2H-pyrazol-3-yl)[4-(3-chlorophenyl) 35 piperazin-1-yl]methanone (Example E65) in the form of a white solid, the characteristics of which are as follows: 62 LC/MS analysis: tr = 4.51; m/z = 445 (MH ) Example E66 [4-(3-Chlorophenyl)piperazin-1 -yl](2,5-diphenyl-2H-pyrazol-3-yl)methanone 22 mg of tetrakis(triphenylphosphine)palladium(0) and 0.5 ml of water are 5 added to 90 mg of the product of Example E65, 35 mg of phenylboronic acid and 42 mg of sodium carbonate in 2 ml of DMF in a microwave reactor. The reaction mixture is subjected to the microwave field for 5 minutes at 1400C and then poured into 10 ml of saturated aqueous sodium dihydrogen phosphate solution and extracted with ethyl acetate. The organic phase is 10 dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of cyclohexane and acetone (80/20 by volume), 50 mg of [4-(3-chlorophenyl)piperazin-1 -yl](2,5-diphenyl-2H-pyrazol-3-yl)methanone are obtained in the form of a yellow resin. 15 LC/MS analysis: tr = 4.77; m/z = 443 (MH ) Example E67 [4-(3-Chlorophenyl)piperazin-1 -yl][2-phenyl-5-(pyrid-3-yl)-2H-pyrazol-3 yl]methanone The process is performed in a manner similar to that of Example E66, starting 20 with 74 mg of the product of Example E65 and 29 mg of pyridyl-3-boronic acid, to give, after purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of dichloromethane and ethyl acetate (80/20 by volume), 35 mg of [4-(3-chlorophenyl)piperazin-1-yl][2-phenyl-5 (pyrid-3-yl)-2H-pyrazol-3-yl]methanone in the form of a white solid, the 25 characteristics of which are as follows: LC/MS analysis: tr = 4.08; m/z = 444 (MH ) Example E68 [4-(3-Chlorophenyl)piperazin-1 -yl][2-phenyl-5-(thiophen-3-yl)-2H-pyrazol-3 yl]methanone 30 The process is performed in a manner similar to that of Example E66, starting with 74 mg of the product of Example E65 and 30 mg of thienyl-3-boronic acid, to give, after successive purifications by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of heptane and ethyl acetate (90/10 by volume) and then by preparative HPLC/MS (H 2 0 pH=5 / 63
CH
3 CN), 20.5 mg of [4-(3-chlorophenyl)piperazin-1-yl][2-phenyl-5-(thiophen 3-yl)-2H-pyrazol-3-yl])methanone in the form of a white powder, the characteristics of which are as follows: LC/MS analysis: tr = 5.04; m/z = 449 (MH') 5 Example E69 [4-(3-Chlorophenyl)piperazin-1 -yl][2-phenyl-5-(thiophen-2-yl)-2H-pyrazol-3 yl]methanone The process is performed in a manner similar to that of Example E66, starting with 67 mg of the product of Example E65 and 27 mg of thienyl-2-boronic 10 acid, to give, after successive purifications by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of heptane and ethyl acetate (90/10 by volume) and then by preparative HPLC/MS (H 2 0 pH=5 /
CH
3 CN), 27 mg of [4-(3-chlorophenyl)piperazin-1-yl][2-phenyl-5-(thiophen-2 yl)-2H-pyrazol-3-yl]methanone in the form of a white powder, the 15 characteristics of which are as follows: LC/MS analysis: tr = 5.07; m/z = 449 (MH ) Example E70 5-[4-(3-Chlorophenyl)piperazine-1-carbonyl]-1-phenyl-1 H-pyrazole-3 carboxaldehyde 20 Ste 1: 2.50 g of calcium carbonate are added at room temperature to 9.68 g of ethyl 5-dibromomethyl-2-phenyl-2H-pyrazole-3-carboxylate, obtained in Step 1 of Example E73, in 260 ml of water. The reaction mixture is stirred at reflux for 7 hours, cooled, acidified to pH 1 by controlled addition of concentrated hydrochloric acid and extracted with ethyl acetate. The organic 25 phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (40 63 pm), eluting with a mixture of dichloromethane and heptane (70/30 by volume), 5.06 g of ethyl 5-formyl-2-phenyl-2H-pyrazole-3-carboxylate are obtained in the form of a white powder, the characteristics of which are as 30 follows: Mass spectrum (ES): m/z = 245 (MH') Step 2: The process is performed in a manner similar to that of Step 1 of Example E22, starting with 63 mg of ethyl 5-formyl-2-phenyl-2H-pyrazole-3 carboxylate and 101 mg of 1-(3-chlorophenyl)piperazine, to give, after 64 purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of heptane and ethyl acetate (70/30 by volume), 60 mg of 5-[4 (3-chlorophenyl)piperazine-1-carbonyl]-1-phenyl-1 H-pyrazole-3-carbox aldehyde in the form of a colorless oil, the characteristics of which are as 5 follows: LC/MS analysis: tr = 4.47; m/z = 395 (MH*) Example E71 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl](5-isopropyl-2-phenyl-2H-pyrazol-3 yl)methanone 10 By performing the process in a manner similar to that for the synthesis of [4 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 193.2 mg of 1-(3,5-dimethoxyphenyl)piperazine and by replacing the 5-methyl-2-phenyl 2H-pyrazole-3-carboxylic acid with 200 mg of 5-isopropyl-2-phenyl-2H 15 pyrazole-3-carboxylic acid, 300 mg of [4-(3,5-dimethoxyphenyl)piperazin-1 yl](5-isopropyl-2-phenyl-2H-pyrazol-3-yl)methanone are obtained in the form of a white powder, the characteristics of which are as follows: Melting point (Kofler): 116 0 C Mass spectrum (El): m/z = 434 (M+) 20 Example E72 [4-(3-Chloro-4-fluorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone By performing the process, in 3 steps, in a manner similar to that for the synthesis of [4-(3-chloro-3-pyridyl)piperazin-1-yl](5-methyl-2-phenyl-2H 25 pyrazol-3-yl)methanone (Example 33), but replacing in Step 1 of the synthesis of the 3,5-dichloropyridine with 404 mg of 3-chloro-4-fluorobromobenzene, 213 mg of [4-(3-chloro-4-fluorophenyl)piperazin-1-yl](5-methyl-2-phenyl-2H pyrazol-3-yl)methanone are obtained, in Step 3 of the synthesis, in the form of a solid, the characteristics of which are as follows: 30 IR spectrum IR: 2924; 2839; 1647; 1501; 1221; 1003; 996; 771; 730 and 693 cm' 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 8 in ppm): 2.31 (s: 3H); 2.82 (unresolved complex: 2H); 3.118 (unresolved complex: 2H); from 3.25 to 3.40 (unresolved complex: 2H); 3.69 (unresolved complex: 2H); 6.53 (s: 1H); 65 6.89 (dt, J = 9 and 3.5 Hz: 1H); 7.05 (dd, J = 6 and 3 Hz: 1H); 7.26 (t, J = 9 Hz: 1H); 7.36 (broad t, J = 7.5 Hz: 1H); from 7.40 to 7.55 (mt: 4H). Example E 73 [4-(3,5-Dimethoxyphenyl)piperazin-1-yl](3-hydroxymethyl-1-phenyl-1 H 5 pyrazol-5-yl)methanone Step 1: 13 g of ethyl 3-methyl-l-phenyl-1lH-pyrazole-5-carboxylate, which may be obtained according to J. Het Chem 1999, 36(1), 217-220, are dissolved in 250 ml of carbon tetrachloride in a 2 L photochemical reactor, followed by successive addition of 12.45 g of N-bromosuccinimide and 0.65 g 10 of 2,2'-azobis(2-methylpropionitrile). The mixture is irradiated for 4 hours using a Hanovia lamp, 2.67 g of N-bromosuccinimide are then added and the mixture is irradiated for a further 2 hours. After cooling to room temperature, the insoluble material formed is filtered off, washed twice with 50 ml of carbon tetrachloride, and the combined filtrates are concentrated under reduced 15 pressure. The orange oil obtained is purified by flash chromatography on a column of silica (60; 35-70 pm), eluting with toluene, to give, by collecting the fractions eluted between 600 and 1200 ml, 8 g of ethyl 3-bromomethyl-1 phenyl-1 H-pyrazole-5-carboxylate in the form of a yellow powder, which is used without further purification in the following step. 20 Step 2:14.22 g of ethyl 3-bromomethyl-1 -phenyl-1 H-pyrazole-5-carboxylate, obtained as in the preceding step, are dissolved in 170 ml of dimethylformamide in a 500 ml three-necked flask under an argon atmosphere, followed by addition of 7.95 g of sodium benzoate, and the mixture is heated at 50 0 C for 3 hours. After cooling and concentrating under 25 reduced pressure, the residue is poured into 200 ml of water and then extracted with 3 times 100 ml of ethyl acetate. The combined organic phases are washed with saturated aqueous ammonium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. 15.5 g of ethyl 3-benzoyloxymethyl-1 -phenyl-1 H-pyrazole-5-carboxylate are thus obtained in 30 the form of a beige-colored powder, which is used without further purification in the following step. Step 3: 2.1 g of (3,5-dimethoxyphenyl)piperazine are dissolved in 8 ml of dry toluene at 300C, in a 500 ml three-necked flask under an argon atmosphere, followed by dropwise addition of 4.5 ml of a 2M solution of trimethylaluminum 66 in toluene, and the mixture is stirred for 30 minutes. After cooling to about 200C, 1.06 g-of ethyl 3-benzoyloxymethyl-1 -phenyl-1 H-pyrazole-5-carboxylate obtained in the preceding step, dissolved in 20 ml of toluene, are added. After heating at 600C for 7 hours, the reaction medium is poured into 70 ml of 5 aqueous 1M sodium potassium tartrate solution and then extracted with 3 times 50 ml of ethyl acetate. The combined organic phases are washed with 50 ml of aqueous 1M sodium potassium tartrate solution, dried over magnesium sulfate and concentrated under reduced pressure. The orange oil obtained is purified by flash chromatography on a column of silica (60; 35 10 70 pm), eluting with a mixture of dichloromethane and of methanol (99.5/0.5 by volume), and 0.8 g of [4-(3,5-dimethoxyphenyl)piperazin-1-yl](5-hydroxy methyl-2-phenyl-2H-pyrazol-3-yl)methanone is thus obtained in the form of a pale beige-colored foam, the characteristics of which are as follows: Mass spectrum (El): m/z = 422 (M') 15 Example E74 [4-(3-Difluoromethoxyphenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone hydrochloride. Stepl: A mixture of 500.1 mg of 1-boc piperazine and 598.8 mg of commercial 3-difluoromethoxybromobenzene is placed in 20 ml of toluene in 20 a 50 ml three-necked flask under an inert atmosphere of argon, followed by addition of 56.85 mg of (R)(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 20.4 mg of palladium(ll) acetate. The reaction mixture is stirred at reflux for 16 hours. After cooling to 200C, the reaction mixture is diluted with water (20 ml) and then extracted with ethyl acetate (2 x 30 ml). The organic extracts are 25 combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The compound obtained is purified by chromatography on silica gel (AIT cartridge, ref. FC-25 Si-BP-SUP, 20-40 pm, dichloromethane eluent, flow rate of 20 mI/min). The fractions containing the expected compound are combined and then evaporated under reduced pressure. 30 253 mg of tert-butyl 4-(3-difluoromethoxyphenyl)piperazine-1l-carboxylate are thus isolated, the characteristics of which are as follows: LC/MS: RT=4.18 min, M+H' 329.31 (Micromass machine, LCT model, connected to an HP 1100 machine, HP G1315A diode array detector (200 600 nm), Sedex 65 light-scattering detector; data analyzed with the 35 Micromass MassLynx software; separation on a Hypersil BDS C18, 3 pm (50 67 x 4.6 mm) column, eluting with a linear gradient of from 5% to 90% of acetonitrile containing 0.05 % (v/v) of trifluoroacetic acid (TFA) in water containing 0.05 % (v/v) TFA, over 3.5 minutes at a flow rate of 1 mI/min). Step 2: A solution of 253 mg of tert-butyl 4-(3-difluoromethoxyphenyl) 5 piperazine-1-carboxylate in a mixture of 1016 pl of dioxane and 963 pl of hydrochloric acid is placed in a 10 ml round-bottomed flask. The reaction mixture is stirred at 20 0 C for 48 hours. The solid formed is filtered off, washed with 10 ml of diisopropyl ether and dried under reduced pressure. 189 mg of 1-(3-difluoromethoxyphenyl)piperazine hydrochloride are thus isolated, and 10 are used without purification for the following step. Step 3: A solution of 144.4 mg of 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid, which may be obtained according to J. Het. Chem., 30, 307 (1993), in 11 ml of dichloromethane is placed in a 50 ml three-necked flask under an inert atmosphere of argon, followed by successive addition of 189 mg of 1-(3 15 difluoromethoxyphenyl)piperazine hydrochloride, 106.1 mg of 1-hydroxy benzotriazole, 150.6 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and then 331 pl of triethylamine (331 pl). The reaction mixture is stirred at 20 0 C for 48 hours and then diluted with dichloromethane (20 ml) and water (20 ml), the phases are separated by settling and the organic 20 phase is extracted (30 ml of dichloromethane). The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The compound obtained is purified by chromatography on silica gel (AIT cartridge, ref. FC 25-Si-HP, 15-35 pm, eluent: 80/20 to 60/40 cyclohexane/ethyl acetate over 60 minutes, flow rate of 7 ml/min). The 25 fractions containing the expected compound are combined and then evaporated under reduced pressure. The evaporation residue is taken up in a mixture of ethyl ether (12 ml) and 2N hydrochloric acid/ethyl ether (500 p1) and then triturated until a solid is obtained, which is filtered off, washed (5 ml) and dried under reduced pressure. 199 mg of [4-(3-difluoromethoxy 30 phenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone hydro chloride are thus isolated in the form of a white powder, the characteristics of which are as follows: Melting point (Kofler): 127 0
C
68 Example E75 [4-(3-Chlorophenyl)piperazin-1 -yl][5-(2-methylimidazol-1 -ylmethyl)-2-phenyl 2H-pyrazol-3-yl]methanone Step 1: 133mg of 2-methylimidazole are added to 100 mg of ethyl 5 5-bromomethyl-2-phenyl-2H-pyrazole-3-carboxylate, obtained in Step 1 of Example E73, in 1.5 ml of THF in a microwave reactor. The reaction mixture is subjected to the microwave field for 10 minutes at 120 0 C, poured into 20 ml of saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and 10 concentrated under reduced pressure. After purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of ethyl acetate and triethylamine (90/10 by volume), 74 mg of ethyl 5-(2 methylimidazol-1-ylmethyl)-2-phenyl-2H-pyrazole-3-carboxylate are obtained in the form of a colorless oil, the characteristics of which are as follows: 15 Mass spectrum (ES): m/z = 311 (MH) Step 2: The process is performed in a manner similar to that of Step 1 of Example E22, starting with 114 mg of the product of Step 1 of the present example and 145 mg of 1-(3-chlorophenyl)piperazine, to give, after purification by flash chromatography on a column of silica (30-60 pm), eluting 20 with a mixture of ethyl acetate and triethylamine (90/10 by volume), 21 mg of [4-(3-chlorophenyl)piperazin-1 -yl][5-(2-methylimidazol-1 -ylmethyl)-2-phenyl 2H-pyrazol-3-yl]methanone in the form of a yellow oil, the characteristics of which are as follows: LC/MS analysis: tr = 2.85; m/z = 461 (MH ' ) 25 Example E76 [4-(3-Chlorophenyl)piperazin-1 -yl](2-phenyl-5-phenylaminomethyl-2H-pyrazol 3-yl)methanone Step 1: The process is performed in a manner similar to that of Step 1 of Example E75, starting with 100 mg of the product of Step 1 of Example E73 30 and 151 mg of aniline, to give, after purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of toluene, ethyl acetate and triethylamine (80/20/0.1 by volume), 79 mg of ethyl 2-phenyl-5 phenylaminomethyl-2H-pyrazole-3-carboxylate in the form of a pale pink oil, the characteristics of which are as follows: 69 Mass spectrum (ES): m/z = 322 (MH') Step 2: The process is performed in a manner similar to that of Step 2 of Example E75, starting with 79 mg of the product of Step 1 of present example and 170 mg of 1-(3-chlorophenyl)piperazine, to give, after purification by flash 5 chromatography on a column of silica (30-60 pm), eluting with a mixture of toluene, ethyl acetate and triethylamine (70/30/0.1 by volume), 39 mg of [4-(3 chlorophenyl)piperazin-1 -yl](2-phenyl-5-phenylaminomethyl-2H-pyrazol-3-yl) methanone in the form of a pale yellow oil, the characteristics of which are as follows: 10 LC/MS analysis: tr = 4.51; m/z = 472 (MH ) Example E77 [4-(2-Bromo-5-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone The process is performed in a manner similar to that of Example E59, starting 15 with 300 mg of [4-(3-chlorophenyl)piperazin-1-yl](5-methyl-2-phenyl-2H pyrazol-3-yl)methanone in 3 ml of carbon tetrachloride, 210 mg of N-bromosuccinimide, 15 mg of benzoyl peroxide and 65 mg of potassium carbonate, to give, after successive purifications by flash chromatography on a column of silica (40-63 pm), eluting with a mixture of toluene and ethyl 20 acetate (8/2 by volume) and then by preparative HPLC/MS (H 2 0 pH=9 /
CH
3 CN), 16 mg of [4-(2-bromo-5-chlorophenyl)piperazin-1-yl](5-methyl-2 phenyl-2H-pyrazol-3-yl)methanone in the form of a cream-colored solid, the characteristics of which are as follows: LC/MS analysis: tr = 4.45; m/z = 459 (MH ' ) 25 1 H NMR spectrum (400 MHz, (CD 3
)
2 SO d6, 5 in ppm): 2.28 ppm (s, 3H); 2.68 ppm (m, 2H); 2.93 ppm (m, 2H); 3.40 ppm (m, 2H) ; 3.70 ppm (m, 2H); 6.53 ppm (s, 1H); 7.40 ppm (tl, J= 8 Hz, 1H); 7.44 ppm (dl, J= 8 Hz, 2H); 7.50 ppm (bt, J= 8 Hz, 2H); 7.62 ppm (d, J= 8.5 Hz, 1H); 7.05 ppm (d, J= 2.5 Hz, 1H); 7.09 ppm (dd, J= 2.5- 8.5 Hz, 1H). 30 Example E 78 [4-(3,5-Dimethoxyphenyl)piperazin-1-yl](3-dibromomethyl-1-phenyl-1 H pyrazol-5-yl)methanone Step 1: By working as in Step 1 of Example 73, but collecting the fractions eluted between 150 and 550 ml, 9 g of ethyl 3-dibromomethyl-1-phenyl-1H- 70 pyrazole-5-carboxylate are obtained in the form of an orange-colored oil, which is used without further purification for the following step. Step 2: 0.52 ml of a 2M solution of trimethylaluminum in toluene is added, at 250C, to a solution of 195 mg of 1-(3,5-dimethoxyphenyl)piperazine in 2 ml of 5 toluene, followed by addition, at 600C, of a solution of 162 mg of the product of Step 1 of the present example in 4 ml of toluene. The reaction medium is stirred for 2.5 hours at 650C and then for 1.5 hours at 800C, after which is it poured into 10 ml of aqueous 1M sodium potassium tartrate solution and extracted with ethyl acetate. The organic phase is dried over magnesium 10 sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (40-63 pm), eluting with a mixture of dichloromethane and ethyl acetate (90/10 by volume), 235 mg of (5 dibromomethyl-2-phenyl-2H-pyrazol-3-yl)[4-(3,5-dimethoxyphenyl)piperazin 1-yl]methanone are obtained in the form of a pale yellow solid, the 15 characteristics of which are as follows: LC/MS analysis: tr = 4.36; m/z = 563 (MH') 1 H NMR spectrum (400 MHz, (CD 3
)
2 SO d6, 8 in ppm): 2.83 ppm (m, 2H); 3.10 ppm (m, 2H); 3.37 (masked, 2H); 3.66 ppm (m, 2H); 3.68 ppm (s, 6H); 5.99 ppm (bs, 1H); 6.02 ppm (bs, 2H); 6.99 ppm (s, 1H); 7.42 ppm (s, 20 1H); 7.46 ppm (m, 3H); 7.54 ppm (bt, J=8Hz, 2H). Example E79 [4-(2,4-Dibromo-5-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol 3-yl)methanone The product is obtained at the same time as that of Example E77 after 25 preparative HPLC/MS purification, in the form of a pale yellow oil, the characteristics of which are as follows: LC/MS analysis: tr = 4.74; m/z = 537 (MH) 1 H NMR spectrum (400 MHz, (CD 3
)
2 SO d6, 8 in ppm): 2.28 ppm (s,3H); 2.71 ppm (m, 2H); 2.94 ppm (m, 2H); 3.40 ppm (m, 2H); 3.70 ppm (m, 30 2H); 6.53 ppm (s, 1H); 7.23 ppm (s, 1H); 7.40 ppm (bt, J= 8, 1H); 7.44 ppm (bd, J= 8 Hz, 2H); 7.51 ppm (bt, J= 8 Hz, 2H); 8.01 ppm (s, 1H). Example E80 (5-Benzyloxymethyl-2-phenyl-2H-pyrazol-3-yl)[4-(3-chlorophenyl)piperazin-1 yl]methanone 71 Step 1: 35 mg of 50% sodium hydride in oil are added to a solution of 87 mg of benzyl alcohol in 0.5 ml of DMF. The reaction mixture is stirred for 30 minutes at room temperature, followed by addition of a solution of 200 mg of ethyl 5-bromomethyl-2-phenyl-2H-pyrazole-3-carboxylate, obtained in Step 1 5 of Example E73, in 1.5 ml of DMF. The reaction mixture is stirred for 4 hours at room temperature and then poured into 50 ml of saturated aqueous sodium dihydrogen phosphate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (30 10 60 pm), eluting with a mixture of ethyl acetate and triethylamine (90/10 by volume), 52 mg of ethyl 5-benzyloxymethyl-2-phenyl-2H-pyrazole-3 carboxylate are obtained in the form of a colorless oil, the characteristics of which are as follows: Mass spectrum (ES): m/z = 337 (MH ) 15 Step 2: The process is performed in a manner similar to that of Step 2 of Example E75, starting with 52 mg of the product of Step 1 of the present example and 122 mg of 1-(3-chlorophenyl)piperazine, for 1.5 hours at 60 0 C, to give, after purification by flash chromatography on a column of silica (30 60 pm), eluting with a mixture of dichloromethane and ethyl acetate (95/5 by 20 volume), 54 mg of (5-benzyloxymethyl-2-phenyl-2H-pyrazol-3-yl)[4-(3-chloro phenyl)piperazin-1-yl]methanone in the form of a pale yellow oil, the characteristics of which are as follows: LC/MS analysis: tr = 4.63; m/z = 487 (MH ) Examples E81 and E82 25 [5-Bromo-2-(4-bromophenyl)-2H-pyrazol-3-yl][4-(3,5-dimethoxyphenyl) piperazin-1-yl]methanone (Example E81) and (5-Bromo-2-phenyl-2H-pyrazol-3-yl)[4-(3,5-dimethoxyphenyl)piperazin-1 -yl] methanone (Example E82) The process is performed in a manner similar to that of Step 2 of Examples 30 E64 and E65, starting with 1.18 g of ethyl 5-bromo-2-phenyl-2H-pyrazole-3 carboxylate, obtained in Step 1 of Examples E64 and E65 and containing 10% to 20% of ethyl 5-bromo-2-(4-bromophenyl)-2H-pyrazole-3-carboxylate, and 1.87 g of 1-(3,5-dimethoxyphenyl)piperazine, to give, after purification by flash chromatography on a column of silica (40-63 pm), eluting with a mixture 35 of cyclohexane and ethyl acetate (70/30 by volume): 72 58 mg of [5-bromo-2-(4-bromophenyl)-2H-pyrazol-3-yl][4-(3,5 dimethoxyphenyl)piperazin-1-yl]methanone (Example E81), in the form of an ochre-colored solid, the characteristics of which are as follows: LC/MS analysis: tr = 4.47; m/z = 549 (MH') 5 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 5 in ppm): 2.95 ppm (m, 2H); 3.14 ppm (m, 2H); 3.44 ppm (m, 2H); 3.65 ppm (m, 2H); 3.70 ppm (s, 6H); 6.00 ppm (t, J=2 Hz, 1H); 6.05 ppm (d, J= 2 Hz, 2 H); 6.98 ppm (s, 1H); 7.42 and 7.77 ppm (AA'BB' system, 4H). and 10 1.80 g of (5-bromo-2-phenyl-2H-pyrazol-3-yl)[4-(3,5-dimethoxyphenyl) piperazin-1-yl]methanone (Example E82), in the form of an orange-colored resin, the characteristics of which are as follows: LC/MS analysis: tr = 4.17; m/z = 471 (MH*) Example E83 15 Methyl N-{3-[4-(5-methyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1 -yl] phenyl}succinamate 424 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 297 mg of 1-hydroxybenzotriazole hydrate (HOBT) and 264 mg of succinic acid monomethyl ester are added to a solution of 726 mg of [4-(3 20 aminophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone, described in Example E9, in 35 ml of dichloromethane. The reaction mixture is stirred for 20 hours at room temperature. After addition of 50 ml of dichloromethane and 50 ml of water, the organic phase is separated out by settling of the phases and then washed with water, dried over magnesium 25 sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (60; 35-70 pm), eluting with pure ethyl acetate, 650 mg of methyl N-{3-[4-(5-methyl-2-phenyl-2H-pyrazole-3 carbonyl)piperazin-1-yl]phenyl}succinamate are obtained in the form of a white foam, the characteristics of which are as follows: 30 Mass spectrum (El): m/z = 475 (M') Example 84 Parallel synthesis of Examples E84, E105, E108 and 109 E84 [4-(3-lsopropoxyphenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone 73 E105 Methyl {3-[4-(5-methyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1l-yl] phenoxy}acetate hydrochloride E108 [4-(3-Butoxyphenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone hydrochloride 5 E109 [4-(3-Ethoxyphenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone hydrochloride A solution of 100 mg of [4-(3-hydroxyphenyl)piperazin-1-yl](5-methyl-2 phenyl-2H-pyrazol-3-yl)methanone, prepared in Example 13, in 1000 pl of dimethylformamide (1000 pl) is placed in 4 glass reactors (13 x 100 mm) 10 identified from 1 to 4, equipped with a magnetic stirrer and placed under an inert atmosphere of argon, followed by addition of 12.4 mg of sodium hydride to each reactor. Each tube is stirred at 200C for 1.5 hours, followed by addition of the halo derivatives, i.e., respectively, 38.87 pl of 2-bromopropane to tube, 39.19 pl of methyl bromoacetate to tube 2, 44.67 pl of 1-bromobutane 15 to tube 3 and 26.7 pl1 of iodoethane to tube 4. After 1 hour at 200C, analysis by thin-layer chromatography (1/1 cyclohexane/ethyl acetate) shows that reactions 2, 3 and 4 are complete, whereas the reaction in tube 1 no longer proceeds. A further 12.4 mg of sodium hydride and 38.87 pl of 2-bromopropane are thus added to reactor 1. After reaction for a further 30 20 minutes, analysis by thin layer chromatography (1/1 cyclohexane/ethyl acetate) shows that reaction 1 is complete. The contents of reactors 1 to 4 are transferred into 4 glass tubes of 36 x 100, each reactor tube being rinsed with ethyl acetate (15 ml) and water (15 ml), and then transferred onto the liquid-liquid extraction platform. The following protocol is applied to the three 25 reaction mixtures: decantation of the two phases, separation of the heavy and light extracts and then extraction of the heavy phases with ethyl acetate (2 x 10 ml), reunification of the organic extracts. After drying and evaporating, the compounds are isolated and are purified by chromatography on silica gel (prefilled cartridge, diameter 26 mm, height 135 mm, SiO 2 15-40 pm), eluting 30 with mixtures of cyclohexane and ethyl acetate (E84: 90-10 by volume at 10 ml/min; E105: 80-20 by volume at 10 ml/min, E108: 80-20 by volume at 10 ml/min; E109: 75-25 by volume at 10 ml/min). After evaporation of the fractions containing the expected compound, 74 - either the expected compound is isolated directly, and 80.3 mg of [4-(3 isopropoxyphenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone E84 are thus obtained, the characteristics of which are as follows: 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, chemical shift in ppm): 5 1.25 (d, J = 6.5 Hz: 6H); 2.30 (s: 3H); 2.80 (unresolved complex: 2H); 3.09 (unresolved complex: 2H); 3.33 (unresolved complex: 2H); 3.68 (unresolved complex: 2H); 4.57 (mt: 1H); from 6.30 to 6.40 (mt: 2H); 6.45 (broad d, J = 8.5 Hz: 1H); 6.53 (s: 1H); 7.10 (t, J = 8.5 Hz: 1H); 7.36 (broad t, J = 7 Hz: 1H); from 7.40 to 7.55 (mt: 4H). 10 - or the compound obtained is taken up in a mixture of ethyl ether (10 ml) and 2N hydrochloric acid/ethyl ether (150 pl) and is triturated until a solid appears. After filtration, washing with ethyl ether (5 ml) and drying, the corresponding hydrochlorides are isolated, and the following are thus obtained: 81.4 mg of methyl {3-[4-(5-methyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin 15 1-yl]phenoxy}acetate hydrochloride E105, the characteristics of which are as follows: 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, chemical shift in ppm): 2.30 (s: 3H); 2.82 (unresolved complex: 2H); 3.12 (unresolved complex: 2H); 3.35 (unresolved complex: 2H); 3.69 (unresolved complex: 2H); 3.71 (s: 3H); 20 4.75 (s: 2H); 6.37 (broad dd, J = 8.5 and 2 Hz: 1H); 6.44 (broad t, J = 2 Hz: 1H); 6.52 (broad dd, J = 8.5 and 2 Hz: 1H); 6.53 (s: 1H); 7.12 (t, J = 8.5 Hz: 1H); 7.37 (broad t, J = 7 Hz: 1H); from 7.40 to 7.55 (mt: 4H). 81.4 mg of [4-(3-butoxyphenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol 3-yl)methanone hydrochloride E108, the characteristics of which are as 25 follows: 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, chemical shift in ppm): 0.95 (t, J = 7 Hz: 3H); 1.44 (mt: 2H); 1.68 (mt: 2H); 2.31 (s: 3H); 2.81 (unresolved complex: 2H); 3.10 (unresolved complex: 2H); 3.35 (unresolved complex: 2H); 3.69 (unresolved complex: 2H); 3.93 (t, J = 6.5 Hz: 2H); from 30 6.35 to 6.45 (mt: 2H); 6.47 (broad d, J = 8.5 Hz: 1H); 6.53 (s: 1H); 7.11 (t, J = 8.5 Hz: 1H); from 7.35 to 7.55 (mt: 4H); 7.37 (broad t, J = 7 Hz: 1H). Melting point (Kofler) = 125 0
C
75 75.5 mg of [4-(3-ethoxyphenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol 3-yl)methanone hydrochloride E109, the characteristics of which are as follows: 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, chemical shift in ppm): 5 1.32 (t, J = 7 Hz: 3H); 2.31 (s: 3H); 2.81 (unresolved complex: 2H); 3.10 (unresolved complex: 2H); from 3.25 to 3.45 (mt: 2H); 3.69 (unresolved complex: 2H); 3.99 (q, J = 7 Hz: 2H); from 6.35 to 6.45 (mt: 2H); 6.47 (broad d, J = 8.5 Hz: 1H); 6.53 (s: 1H); 7.11 (t, J = 8.5 Hz: 1H); from 7.35 to 7.55 (mt: 4H); 7.37 (broad t, J = 7 Hz: 1H). 10 Example E85 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl][2-phenyl-5-(thiophen-3-yl)-2H pyrazol-3-yl]methanone The process is performed in a manner similar to that of Example E66, starting with 150 mg of the product of Example E82 and 57.5 mg of thienyl-3-boronic 15 acid, by microwave reaction for 3 minutes at 140 0 C, to give, after purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of heptane and ethyl acetate (70/30 by volume), 126 mg of [4-3,5 dimethoxyphenyl)piperazin-1 -yl][2-phenyl-5-(thiophen-3-yl)-2H-pyrazol-3-yl] ethanone in the form of an ochre-colored solid, the characteristics of which 20 are as follows: LC/MS analysis: tr = 4.36; m/z = 475 (MH ) Example E86 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl][2-phenyl-5-(E-propen-2-yl)-2H pyrazol-3-yl]methanone 25 The process is performed in a manner similar to that of Example E66, starting with 150 mg of the product of Example E82 and 39 mg of trans-propenyl boronic acid, by microwave reaction for 3 minutes to 140 0 C, to give, after purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of heptane and ethyl acetate (70/30 by volume), 85 mg of [4 30 (3,5-dimethoxyphenyl)piperazin-1 -yl][2-phenyl-5-(E-propen-2-yl)-2H-pyrazol 3-yl]methanone in the form of a pale yellow solid, the characteristics of which are as follows: LC/MS analysis: tr = 4.15; m/z = 433 (MH ) 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 5 in ppm): 1.88 ppm (d, 35 J=5Hz, 3H); 2.79 ppm (m, 2H); 3.09 ppm (m, 2H); 3.33 (masked, 2H); 3.65 76 ppm (m, 2H); 3.68 ppm (s, 6H); 5.99 ppm (t, J= 2 Hz, 1H); 6.01 ppm (d, J= 2Hz, 2H); 6.42 ppm (m, 2H); 6.86 ppm (s, 1H); 7.37 ppm (m, 1H); from 7.42 to 7.53 ppm (m, 5H). Example E87 5 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl]-{5-[E-2-(4-fluorophenyl)vinyl]-2 phenyl-2H-pyrazol-3-yl}methanone The process is performed in a manner similar to that of Example E66, starting with 150 mg of the product of Example E82 and 75 mg of trans-2-(4 fluorophenyl)vinylboronic acid, by microwave reaction for 3 minutes at 1400C, 10 to obtain, after purification by flash chromatography on a column of silica (30 60 pm), eluting with a mixture of heptane and ethyl acetate (70/03 by volume), 118 g of [4-(3,5-dimethoxyphenyl)piperazin-1-yl]-{5-[E-2-(4-fluoro phenyl)vinyl]-2-phenyl-2H-pyrazol-3-yl}methanone are obtained in the form of a pale yellow solid, the characteristics of which are as follows: 15 LC/MS analysis: tr = 4.60; m/z = 513 (MH') 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 6 in ppm): 2.83 ppm (m, 2H); 3.10 ppm (m, 2H); 3.38 ppm (masked, 2H); 3.68 ppm (m, 2H); 3.69 ppm (s, 6H); 5.99 ppm (t, J= 2 Hz, 1H); 6.03 ppm (d, J= 2Hz, 2H); 7.05 ppm (s, 1H); 7.23 ppm (t, J= 8.5 Hz, 2H); 7.20 ppm (d, J= 16.5 Hz, 1H); 7.34 ppm (d, 20 J= 16.5 Hz, 1H); 7.40 ppm (m, 1H); 7.50 ppm (m, 4H); 7.68 ppm ( dd, J= 5 8.5 Hz, 2H). Example E88 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl][5-(4-fluorophenyl)-2-phenyl-2H pyrazol-3-yl]methanone 25 The process is performed in a manner similar to that of Example E66, starting with 150 mg of the product of Example E82 and 66 mg of 4-fluorophenylboronic acid, by microwave reaction for 3 minutes at 140 0 C, to obtain, after purification by flash chromatography on a column of silica (30 60 pm), eluting with a mixture of heptane and ethyl acetate (70/30 by 30 volume), 133 mg of [4-(3,5-dimethoxyphenyl)piperazin-1-yl][5-(4 fluorophenyl)-2-phenyl-2H-pyrazol-3-yl]methanone in the form of a beige colored solid, the characteristics of which are as follows: LC/MS analysis: tr = 4.51; m/z = 487 (MH ) 77 Example E89 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl][2-phenyl-5-(4-trifluoromethylphenyl) 2H-pyrazol-3-yl]methanone The process is performed in a manner similar to that of Example E66, starting 5 with 150 mg of the product of Example E82 and 86 mg of 4-(trifluoro methyl)phenylboronic acid, by microwave reaction for 3 minutes at 1400C, to obtain, after purification by flash chromatography on a column of silica (30 60 pm), eluting with a mixture of heptane and ethyl acetate (70/30 by volume), 147 mg of [4-(3,5-dimethoxyphenyl)piperazin-1-yl][2-phenyl-5-(4 10 trifluoromethylphenyl)-2H-pyrazol-3-yl]methanone in the form of a yellow solid, the characteristics of which are as follows: LC/MS analysis: tr = 4.76; m/z = 537 (MH ) Example E90 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl][5-(furan-3-yl)-2-phenyl-2H-pyrazol-3 15 yl]methanone The process is performed in a manner similar to that of Example E66, starting with 150 mg of the product of Example E82 and 51 mg of furyl-3-boronic acid, by microwave reaction for 3 minutes at 140 0 C, to obtain, after purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture 20 of heptane and ethyl acetate (70/30 by volume), 137 mg of [4-(3,5 dimethoxyphenyl)piperazin-1 -yl][5-(furan-3-yl)-2-phenyl-2H-pyrazol-3-yl] methanone in the form of a pale yellow solid, the characteristics of which are as follows: LC/MS analysis: tr = 4.17; m/z = 459 (MH*) 25 Example E91 [4-(3,5-Dimethoxyphenyl)piperazin-1-yl][2-phenyl-5-(1 H-pyrrol-2-yl)-2H pyrazol-3-yl]methanone The process is performed in a manner similar to that of Example E66, starting with 153 mg of the product of Example E82 and 105 mg of 1-(t 30 butoxycarbonyl)pyrrole-2-boronic acid, by microwave reaction for 3 minutes at 1400C, to obtain, after purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of heptane and ethyl acetate (70/30 by volume), 68 mg of [4-(3,5-dimethoxyphenyl)piperazin-1 -yl][2-phenyl-5-(1H pyrrol-2-yl)-2H-pyrazol-3-yl]methanone in the form of a pale yellow solid, the 35 characteristics of which are as follows: 78 LC/MS analysis: tr = 4.11; m/z = 458 (MH') 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 5 in ppm): 2.80 ppm (m, 2H); 3.10 ppm (m, 2H); 3.36 ppm (masked, 2H); 3.67 ppm (m, 2H); 3.68 ppm (s, 6H); 5.99 ppm (t, J= 2 Hz, 1H); 6.02 ppm (d, J= 2 Hz, 2 H); 6.12 ppm (m, 5 1H); 6.51 ppm (m, 1H); 6.83 ppm (m, 1H); 6.92 ppm (s, 1H); 7.39 ppm (m, 1H); 7.52 ppm (m, 4H); 11.35 ppm (bs, 1H). Example E92 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl](2-phenyl-2H-pyrazol-3-yl)methanone 36 p1 of pyrrolidine, 11 mg of sodium tert-butoxide and 0.20 ml of THF are 10 added to 50 mg of the product of Example E82, 10.5 mg of tris(dibenzylideneacetone)dipalladium(0) and 42 mg of 2-dicyclohexyl phosphino-2'-(N,N-dimethylamino)biphenyl in 0.30 ml of THF in a microwave reactor. The reaction mixture is subjected to the microwave field for 10 minutes at 80 0 C and then poured into 10 ml of saturated aqueous sodium 15 dihydrogen phosphate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by preparative HPLC/MS (H 2 0 pH=9 / CH 3 CN), 6 mg of [4-(3,5-dimethoxyphenyl)piperazin-1 -yl](2-phenyl-2H-pyrazol-3 yl)methanone are obtained in the form of a pale yellow powder, the 20 characteristics of which are as follows: LC/MS analysis: tr = 3.65; m/z = 393 (MH ) 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 6 in ppm): 2.78 ppm (m, 2H); 3.08 ppm (m, 2H); 3.31 ppm (masked, 2H); 3.69 ppm (m, 2H); 3.70 ppm (s, 6H); 5.99 ppm (t, J=2 Hz, 1H); 6.01 ppm (d, J= 2 Hz, 2H); 6.73 ppm (d, J= 25 2 Hz, 1H); 7.40 ppm (m, 1H); from 7.46 to 7.55 ppm (m, 4H); 7.81 ppm (d, J= 2 Hz, 1H). Example E93 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl][2-phenyl-5-(pyrrolidin-1 -yl)-2H pyrazol-3-yl]methanone 30 36 p1 of pyrrolidine, 11 mg of sodium tert-butoxide and 0.20 ml of THF are added to 50 mg_ of the product of Example E82, 10.5 mg of tris(dibenzylideneacetone)dipalladium(0) and 42 mg of 2-(di-tert-butyl phosphino)biphenyl in 0.30 ml of THF in a microwave reactor. The reaction mixture is subjected to the microwave field for 10 minutes at 80'C and then 35 poured into 10 ml of saturated aqueous sodium dihydrogen phosphate 79 solution and extracted with ethyl acetate. The organic phase is dried over magnesium - sulfate and concentrated under reduced pressure. After purification by preparative HPLC/MS, (H 2 0 pH=9 / CH 3 CN), 23 mg of [4-(3,5 dimethoxyphenyl)piperazin-1 -yl][2-phenyl-5-(pyrrolidin-1 -yl)-2H-pyrazol-3 5 yl]methanone are obtained in the form of a pale yellow powder, the characteristics of which are as follows: LC/MS analysis: tr = 4.13; m/z = 462 (MH ) Example E94 5-[4-(3,5-Dimethoxyphenyl)piperazine-1-carbonyl]-1-phenyl-1 H-pyrazole-3 10 carboxaldehyde oxime E The process is performed in a manner similar to that of Step 1 of Example E95, starting with 440 mg of the product of Example El00 and 80 mg of hydroxylamine hydrochloride, to give 401 mg of 5-[4-(3,5-dimethoxy phenyl)piperazine-1l-carbonyl]-1l-phenyl-1 H-pyrazole-3-carboxaldehyde oxime 15 E in the form of a white foam, the characteristics of which are as follows: LC/MS analysis: tr = 3.99; m/z = 436 (MH ) 1 H NMR spectrum (400 MHz, (CD 3
)
2 SO d6, 5 in ppm): 2.81 ppm (m,2H); 3.12 ppm (m, 2H); 3.36 ppm (m, 2H); 3.68 ppm (m, 2 H); 3.70 ppm (s, 6H); 5.98 ppm (t, J= 2Hz, 1H); 6.02 ppm (d, J= 2Hz, 2H); 6.92 ppm (s, 1H); 20 from 7.38 to 7.46 ppm (m, 5H); 8.15 ppm (s, 1H); 11.46 ppm (bs, 1H). Example E95 5-[4-(3,5-Dimethoxyphenyl)piperazine-1-carbonyl]-1-phenyl-1 H-pyrazole-3 carboxaldehyde oxime Z Step 1: 94 mg of hydroxyamine hydrochloride are added, at 00C, to 300 mg of 25 the product of Step 1 of Example E70 in 4 ml of ethanol and 120 pl of pyridine. The reaction mixture is stirred for 1 hour at room temperature, poured into 10 ml of saturated aqueous sodium dihydrogen phosphate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After 30 purification by flash chromatography on a column of silica (40-63 pm), eluting with a mixture of dichloromethane and ethyl acetate (90/10 by volume), 115 mg of ethyl 5Z-oximino-2-phenylpyrazole-3-carboxylate are obtained in the form of a white solid, the characteristics of which are as follows: 80 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 8 in ppm): 1.17 ppm (t, J= 7Hz, 3H); 4.19 (q, J= 7Hz, 2H); 7.63 ppm (s, 1H); 7.50 ppm (m, 5Hz);7.60 ppm (s, 1H); 11.90 ppm (bs, 1H). Step 2: The process is performed in a manner similar to that of Step 1 of 5 Example E22, starting with 183 mg of the product of Step 1 of the present example and 330 mg of 1-(3,5-dimethoxyphenyl)piperazine, for 5 hours at 800C, to give, after purification by preparative HPLC/MS (H 2 0 pH=9 /
CH
3 CN), 37 mg of 5-[4-(3,5-dimethoxyphenyl)piperazine-1l-carbonyl]-l phenyl-1H-pyrazole-3-carboxaldehyde oxime Z, in the form of a white powder, 10 the characteristics of which are as follows: LC/MS analysis: tr = 3.63; m/z = 436 (MH) 1H NMR NMR spectrum (400 MHz, (CD 3
)
2 SO d6, 8 in ppm): 2.94 ppm (m, 2H); 3.10 ppm (m, 2H); 3.37 ppm (masked, 2H); 3.68 ppm (m, 2H); 3.69 ppm (s, 6H); 5.99 ppm (bs, 1 H); 6.02 ppm (bs, 2H); from 7.42 to 7.57 ppm (m, 15 5H); 7.28 ppm (s, 1H); 7.60 ppm (s, 1H); 11.8 ppm (bs, 1H). Example E96 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl][5-(morpholin-4-yl)-2-phenyl-2H pyrazol-3-yl]methanone The process is performed in a manner similar to that of Example E93, starting 20 with 100 mg of the product of Example E82 and 116 p/1 of morpholine in 1,2 dimethoxyethane (DME), by microwave reaction for 10 minutes at 800C, to give, after purification by preparative HPLC/MS (H 2 0 pH=9 / CH 3 CN), 91 mg of [4-(3,5-dimethoxyphenyl)piperazin-1 -yl][5-(morpholin-4-yl)-2-phenyl-2H pyrazol-3-yl]methanone in the form of a pale yellow solid, the characteristics 25 of which are as follows: LC/MS analysis: tr = 3.80; m/z = 478 (MH ) Example E97 3-[4-(5-Methyl-2-pyrid-3-yl-2H-pyrazole-3-carbonyl)piperazin-1 -yl]benzamide By performing the process in a manner similar to that for the synthesis of [4 30 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 278 mg of 3-(piperazin-1-yl)benzamide, which may be obtained according to patent WO 98/00400 and 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid, with 223.5 mg of 5-methyl-2-pyrid-3-yl-2H-pyrazole-3-carboxylic acid, which may 81 be obtained according to J. Het. Chem., 36, 217 (1999), 300 mg of 3-[4-(5 methyl-2-pyrid-3-yl-2H-pyrazole-3-carbonyl)piperazin-1 -yl]benzamide are obtained in the form of a pale yellow foam, the characteristics of which are as follows: 5 Mass spectrum (El): m/z = 390 (M+) Example E98 (5-Benzylamino-2-phenyl-2H-pyrazol-3-yl)[4-(3,5-dimethoxyphenyl)piperazin 1-yl]methanone The process is performed in a manner similar to that of Example E93, starting 10 with 100 mg of the product of Example E82, 21 mg of tris(dibenzylideneacetone)dipalladium(0), and 64 mg of 2-(di-tert-butyl phosphino)biphenyl in 0.60 ml of DME, to which are added 116 pl of benzylamine, 30.5 mg of sodium tert-butoxide and 0.40 ml of DME. The reaction mixture is subjected to the microwave field for 5 minutes at 90 0 C, 15 10 mg of tris(dibenzylideneacetone)dipalladium(0) are added and the mixture is subjected to the microwave field for a further 3 minutes at 100 0 C. After work-up and purification by preparative HPLC/MS (H 2 0 pH=9 / CH 3 CN), 38 mg of (5-benzylamino-2-phenyl-2H-pyrazol-3-yl)[4-(3,5-dimethoxyphenyl) piperazin-1-yl]methanone are obtained in the form of a white powder, the 20 characteristics of which are as follows: LC/MS analysis: tr = 4.19; m/z = 498 (MH ) Example E99 (5-Amino-2-phenyl-2H-pyrazol-3-yl)[4-(3,5-dimethoxyphenyl)piperazin-1 yl]methanone 25 Step 1: The process is performed in a manner similar to that of Example E98, starting with 100 mg of the product of Example E82 and 142 pl of benzophenoneimine. The reaction mixture is subjected to the microwave field for 12 minutes at 80 0 C, 10 mg of tris(dibenzylideneacetone)dipalladium(0) and 100 pl of DME are added and the mixture is subjected to the microwave 30 field for a further 2 minutes at 90°C. After work-up and purification by flash chromatography on a column of silica (40-63 pm), eluting with a mixture of heptane and ethyl acetate (70/30 by volume), 66 mg of [5-(benzhydrylidene amino)-2-phenyl-2H-pyrazol-3-yl][4-(3,5-dimethoxyphenyl)piperazin-1 -yl]- 82 methanone are obtained in the form of a yellow solid, the characteristics of which are as follows: Mass spectrum (El): m/z = 571 (M') Step 2: 131 mg of ammonium formate and 60 mg of 10% palladium-on 5 charcoal are added to 66 mg of the product of Step 1 of the present example in 2.5 ml of methanol, in a microwave reactor. The reaction mixture is subjected to the microwave field for 3 minutes at 1000C, filtered, concentrated under reduced pressure and then purified by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of dichloromethane and 10 ethyl acetate (70/30 by volume), to give 29 mg of (5-amino-2-phenyl-2H pyrazol-3-yl)[4-(3,5-dimethoxyphenyl)piperazin-1-yl]methanone in the form of a pale yellow solid, the characteristics of which are as follows: LC/MS analysis: tr = 3.30; m/z = 408 (MH) Example E100 15 5-[4-(3,5-Dimethoxyphenyl)piperazine-1 -carbonyl]-1l-phenyl-1H-pyrazole-3 carboxaldehyde 27 mg of calcium carbonate and 2 ml of water are added to 150 mg of the product of Example E78 in 2 ml of 1,4-dioxane, in a microwave reactor. The reaction mixture is subjected to the microwave field for 10 minutes at 1200C, 20 acidified to pH 5 by controlled addition of aqueous 1M hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of dichloromethane and ethyl acetate (95/5 by volume), 98 mg 25 of 5-[4-(3,5-dimethoxyphenyl)piperazine-1l-carbonyl]-1l-phenyl-1lH-pyrazole-3 carboxaldehyde are obtained in the form of a white solid, the characteristics of which are as follows: LC/MS analysis: tr = 3.73; m/z = 421 (MH') Example E101 30 [4-(3-Chlorophenyl)piperazin-1 -yl](5-phenoxymethyl-2-phenyl-2H-pyrazol-3 yl)methanone Step 1: 0.58 ml of 1M sodium hydroxide is added to a solution of 68 mg of phenol in 1.5 ml of acetone. The reaction mixture is stirred for 45 minutes at room temperature and then treated with a solution of 150 mg of ethyl 83 5-bromomethyl-2-phenyl-2H-pyrazole-3-carboxylate, obtained in Step 1 of Example E73, in 1.5 ml of acetone. The reaction mixture is stirred for 5 hours at room temperature and then poured into 20 ml of saturated aqueous sodium dihydrogen phosphate solution and extracted with ethyl acetate. The organic 5 phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (30 60 pm), eluting with a mixture of dichloromethane and heptane (70/30 by volume) and then with a mixture of dichloromethane, ethyl acetate and acetic acid (70/30/1 by volume), 73 mg of ethyl 5-phenoxymethyl-2-phenyl-2H 10 pyrazole-3-carboxylate are obtained in the form of a colorless oil, the characteristics of which are as follows: Mass spectrum (ES): m/z = 323 (MH') Step 2: The process is performed in a manner similar to that of Step 2 of Example E75, starting with 73 mg of the product of Step 1 of the present 15 example and 179 mg of 1-(3-chlorophenyl)piperazine, for 3 hours at 600C, to give, after purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of dichloromethane and ethyl acetate (95/5 by volume), 78 mg of [4-(3-chlorophenyl)piperazin-1-yl](5-phenoxymethyl-2 phenyl-2H-pyrazol-3-yl)methanone in the form of a white solid, the 20 characteristics of which are as follows: LC/MS analysis: tr = 4.59; m/z = 473 (MH') Example E102 [4-(3-Chlorophenyl)piperazin-1 -yl](2-phenyl-5-phenylsulfanylmethyl-2H pyrazol-3-yl)methanone 25 Step 1: A solution of 73 mg of potassium tert-butoxide in 1 ml of THF is added to a solution of 66 pl of thiophenol in 2 ml of THF, cooled to 50C. The reaction mixture is stirred for 10 minutes at 100C and then treated with a solution of 200 mg of ethyl 3-bromomethyl-1 -phenyl-1 H-pyrazole-5-carboxylate, obtained in Step 1 of Example E73, in 2 ml of THF. The reaction mixture is stirred for 30 16 hours at room temperature and then poured into 50 ml of saturated aqueous sodium dihydrogen phosphate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (40-63 pm), eluting with a mixture of 35 toluene and ethyl acetate (97/3 by volume), 235 mg of ethyl 2-phenyl-5- 84 phenylsulfanylmethyl-2H-pyrazole-3-carboxylate are obtained in the form of a pale yellow oil, the characteristics of which are as follows: Mass spectrum (ES): m/z = 339 (MH') Step 2: The process is performed in a manner similar to that of Step 2 of 5 Example E75, starting with 100 mg of the product of Step 1 of the present example and 232 mg of 1-(3-chlorophenyl)piperazine, for 2 hours at 600C, to give, after purification by flash chromatography on a column of silica (30 60 pm), eluting with a mixture of dichloromethane and ethyl acetate (98/2 by volume), 114 mg of [4-(3-chlorophenyl)piperazin-1-yl](2-phenyl-5-phenyl 10 sulfanylmethyl-2H-pyrazol-3-yl)methanone are obtained in the form of a pale yellow solid, the characteristics of which are as follows: LC/MS analysis: tr = 4.65; m/z = 489 (MH') Example E103 {4-[3-(2-Hydroxyethylamino)phenyl]piperazin-1 -yl}-(5-methyl-2-phenyl-2H 15 pyrazol-3-yl)methanone Starting with 361 mg of [4-(3-aminophenyl)piperazin-1-yl](5-methyl-2-phenyl 2H-pyrazol-3-yl)methanone, described in Example 9, in 2 ml of toluene, 211 pl of triethylamine and 158 p/l of 2-iodoethanol are added. After refluxing for 20 hours, 25ml of ethyl acetate and 25 ml of water are added and the 20 organic phase is separated out by settling and then washed with twice 25 ml of water, dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (60; 35-70 pm), eluting with a mixture of cyclohexane and ethyl acetate (80-20 by volume), 0.2 g of {4-[3-(2-hydroxyethylamino)phenyl]piperazin-1-yl}-(5-methyl 25 2-phenyl-2H-pyrazol-3-yl)methanone is obtained in the form of an orange colored foam, the characteristics of which are as follows: Mass spectrum (El): m/z = 405 (M') 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 5 in ppm): 2.31 (s: 3H); 2.71 (unresolved complex: 2H); 3.02 (unresolved complex: 2H); 3.06 (q, 30 J = 6 Hz: 2H); 3.32 (unresolved complex: 2H); 3.54 (broad q, J = 6 Hz: 2H); 3.68 (unresolved complex: 2H); 4.65 (broad t, J = 6 Hz: 1H); 5.28 (t, J = 6 Hz: 1H); from 6.05 to 6.15 (mt: 3H); 6.52 (s: 1H); 6.91 (broad t, J = 8 Hz: 1 H); 7.38 (broad t, J = 7.5 Hz: 1H); from 7.40 to 7.55 (mt: 4H).
85 Example E104 (5-Methyl-2-phenyl-2H-pyrazol-3-yl)[4-(thiophen-3-yl)piperazin-1 -yl] methanone Step 1: 5.2 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 5 (EDCI), 3.3 g of 1-hydroxybenzotriazole hydrate (HOBT) and 5 g of 5-methyl 2-phenyl-2H-pyrazole-3-carboxylic acid are added to a solution of 4.6 g of tert-butyl piperazine-1-carboxylate in 100 ml of dichloromethane. The reaction mixture is stirred for 20 hours at room temperature. After addition of 50 ml of dichloromethane and 50 ml of saturated aqueous sodium bicarbonate 10 solution, the organic phase is separated out by settling of the phases, and then dried over magnesium sulfate and concentrated under reduced pressure. 8.1 g of tert-butyl 4-(5-methyl-2-phenyl-2H-pyrazole-3 carbonyl)piperazine-1-carboxylate are thus obtained in the form of a white solid, the characteristics of which are as follows: 15 Melting point (Kofler): 150 0 C 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 6 in ppm): 1.40 (s: 9H); 2.29 (s: 3H); 3.03 (unresolved complex: 2H); 3.23 (unresolved complex: 2H); 3.32 (unresolved complex: 2H); 3.54 (unresolved complex: 2H); 6.50 (s: 1H); from 7.30 to 7.55 (mt: 5H). 20 Step 2: 27 ml of a 4N solution of hydrochloric acid in dioxane are added dropwise to a solution of 8 g of tert-butyl 4-(5-methyl-2-phenyl-2H-pyrazole-3 carbonyl)piperazine-1-carboxylate in 50 ml of dichloromethane. After reaction for 20 hours and concentration under reduced pressure, the residue is taken up in 1N sodium hydroxide solution to pH 10, extracted with 50 ml of ethyl 25 acetate, dried over sodium sulfate and concentrated under reduced pressure. 2.96 g of (5-methyl-2-phenyl-2H-pyrazol-3-yl)(piperazin-1-yl)methanone are thus obtained in the form of a white solid, the characteristics of which are as follows: Melting point (Kofler): 138 0 C 30 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 6 in ppm): from 2.20 to 2.35 (mt: 2H); 2.29 (s: 3H); 2.60 (broad t, J = 4.5 Hz: 2H); 3.06 (broad t, J = 4.5 Hz: 2H); 3.48 (broad t, J = 4.5 Hz: 2H); 6.45 (s: 1H); from 7.30 to 7.55 (mt: 5H). Step 3: 121 mg of 3-bromothiophene, 46 mg of (R)(+)-2,2'-bis(diphenyl 35 phosphino)-1,1'-binaphthyl, 17 mg of palladium acetate and 71 mg of sodium 86 tert-butoxide are added to a solution of 200 mg of (5-methyl-2-phenyl-2H pyrazol-3-yl)(piperazin-1-yl)methanone in 6 ml of toluene. After heating at 90 0 C for 20 hours, the insoluble material is filtered off, 50 ml of ethyl acetate and the organic phase is separated out by settling of the phases and then 5 washed with 3 times 10 ml of water, dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (60; 35-70 pm), eluting with a mixture of cyclohexane and ethyl acetate (70-30 by volume), 18 mg of (5-methyl-2 phenyl-2H-pyrazol-3-yl)[4-(thiophen-3-yl)piperazin-1 -yl]methanone are 10 obtained in the form of an amorphous yellow solid, the characteristics of which are as follows: 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 8 in ppm): 2.31 (s: 3H); 2.74 (unresolved complex: 2H); 3.01 (unresolved complex: 2H); 3.34 (unresolved complex: 2H); 3.69 (unresolved complex: 2H); 6.33 (dd, J = 3 15 and 1.5 Hz: 1H); 6.52 (s: 1H); 6.93 (dd, J = 5.5 and 1.5 Hz: 1H); 7.37 (tt, J = 7.5 and 1.5 Hz: 1H); from 7.40 to 7.55 (mt: 4H); 7.42 (dd, J = 5.5 and 3 Hz: 1H). Example E105 This example is described with Example E84. 20 Example E106 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl][5-(3-hydroxypyrrolidin-1 -yl)-2-phenyl 2H-pyrazol-3-yl]methanone The process is performed in a manner similar to that of Example E98, starting with 100 mg of the product of Example E82 and 90 pl of 3-pyrrolidinol, by 25 microwave reaction for 5 minutes at 90 0 C, to give, after purification by preparative HPLC/MS (H 2 0 pH=9 / CH 3 CN), 48 mg of [4-(3,5-dimethoxy phenyl)piperazin-1 -yl][5-(3-hydroxypyrrolidin-1 -yl)-2-phenyl-2H-pyrazol-3-yl] methanone in the form of a white powder, the characteristics of which are as follows: 30 LC/MS analysis: tr = 3.47; m/z = 478 (MH ) Example E107 1-{3-[4-(5-Methyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1 yl]phenyl}ethanone 87 By performing the process in a manner similar to that for the synthesis of [4 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 82 mg of 1-[3-(piperazin-1-yl)phenyl]ethanone, which may be obtained according to 5 patent WO 02/088107, 21.8 mg of 1-{3-[4-(5-methyl-2-phenyl-2H-pyrazole-3 carbonyl)piperazin-1-yl]phenyl}ethanone are obtained in the form of a white solid, the characteristics of which are as follows: Melting point (Kofler): 1340C Mass spectrum (El): m/z = 388 (M+) 10 Example E108 This example is described with Example E84 Example E109 This example is described with Example E84 Example E1 10 15 N-(2-Methyla minoethyl)-3-[4-(5-methyl-2-phenyl-2H-pyrazole-3 carbonyl)piperazin-1-yl]benzamide Step 1: 763 mg of potassium hydroxide pellets are added to a solution of 4.4 g of ethyl 3-[4-(5-methyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1-yl] benzoate, described in Example E28, in 75 ml of distilled water and 150 ml of 20 methanol. After 20 hours at room temperature, the reaction mixture is concentrated under reduced pressure and the residue is acidified to pH 5 with 5N hydrochloric acid. After filtering off the solid formed, 3.9 g of 3-[4-(5 methyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1-yl]benzoic acid are thus obtained in the form of a pale yellow solid, the characteristics of which are as 25 follows: Melting point (Kofler): 206'C Mass spectrum (El): m/z = 390 (M') Step 2: 211 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 148 mg of 1-hydroxybenzotriazole hydrate (HOBT) and 30 175 mg of tert-butyl- (2-aminoethyl)methylcarbamate are added to a solution of 390.5 mg of 3-[4-(5-methyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1 yl]benzoic acid in 17 ml of dichloromethane. The reaction mixture is stirred for 72 hours at room temperature. After addition of 25 ml of dichloromethane and 88 25 ml of water, the organic phase is separated out by settling of the phases and then washed with 25 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (60; 5 35-70 pm), eluting with a mixture of cyclohexane and ethyl acetate (70-30 by volume), 500 mg of tert-butyl methyl(2-{3-[4-(5-methyl-2-phenyl-2H-pyrazole 3-carbonyl)piperazin-1 -yl]benzoylamino}ethyl)carbamate are obtained in the form of a beige-colored foam, the characteristics of which are as follows: Mass spectrum (El): m/z = 546 (M') 10 Step 3: 1 ml of a 4N solution of hydrochloric acid in dioxane is added dropwise to a solution of 440 mg of tert-butyl methyl-(2-{3-[4-(5-methyl-2 phenyl-2H-pyrazole-3-carbonyl)piperazin-1 -yl]benzoylamino}ethyl)carbamate in 1 ml of dioxane. After reaction for 20 hours and concentration under reduced pressure, 440 mg of N-(2-methylaminoethyl)-3-[4-(5-methyl-2 15 phenyl-2H-pyrazole-3-carbonyl)piperazin-1-yl]benzamide are thus obtained in the form of an amorphous yellow solid, the characteristics of which are as follows: Mass spectrum (El): m/z = 446 (M+) 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 5 in ppm): 2,32 (s: 3H); 20 2,60 (t, J = 5 Hz: 3H); 2,93 (unresolved complex: 2H); 3,09 (mt: 2H); 3,20 (unresolved complex: 2H); 3,40 (mt: 2H); 3,58 (unresolved complex: 2H); 3,73 (unresolved complex: 2H); 6,55 (s:-1H); 7,08 (broad d, J = 8 Hz: 1H); from 7,25 6 7,55 (mt: 8H); 8,77 (broad t, J = 5 Hz: 1H); 8,89 (unresolved complex: 2H). 25 Example Elll (5-Methyl-2-phenyl-2H-pyrazol-3-yl)[4-(3,4,5-trifluorophenyl)piperazin-1 yl]methanone By performing the process in a manner similar to that for the synthesis of [4 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone 30 (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 200 mg of 1-(3,4,5-trifluorophenyl)piperazine, which may be obtained from 3,4,5 trifluorobromobenzene by working in a manner similar to that for the synthesis of 1-[3-(4-benzylpiperazin-1-yl)phenyl]ethanone of Step 1 of Example E39 and the characteristics of which are as follows: 1 H NMR spectrum (300 MHz, 35 (CD 3
)
2 SO d6, 8 in ppm): 3.19 (unresolved complex: 4H); 3.43 (broad t, J = 5.5 89 Hz: 4H); 6.96 (dd, J = 12 and 6.5 Hz: 2H); 9.23 (unresolved complex: 2H).-, 115 mg of (5-methyl-2-phenyl-2H-pyrazol-3-yl)[4-(3,4,5-trifluorophenyl)piper azin-1-yl]methanone are obtained in the form of a white solid, the characteristics of which are as follows: 5 Melting point (Kofler): 2040C Mass spectrum (El): m/z = 400 (M+) Example E112 Ethyl E-3-{5-[4-(3,5-dimethoxyphenyl)piperazine-1 -carbonyl]-1 -phenyl-1 H pyrazol-3-yl}acrylate 10 195 mg of (carbethoxymethylene)triphenylphosphorane are added, at room temperature, to a solution of 196 mg of 5-[4-(3,5-dimethoxyphenyl)piperazine 1-carbonyl]-1l-phenyl-1lH-pyrazole-3-carboxaldehyde, obtained in Example E100, in 3 ml of THF. After stirring for 12 hours at 500C, the reaction mixture is concentrated under reduced pressure and purified by flash chromatography 15 on a column of silica (40-63 pm), eluting with a mixture of dichloromethane and ethyl acetate (95/5 by volume), to give 130 mg of ethyl E-3-{5-[4-(3,5 dimethoxyphenyl)piperazine-1l-carbonyl]-1l-phenyl-l1H-pyrazol-3-yl}acrylate in the form of a white solid, the characteristics of which are as follows: LC/MS analysis: tr = 4.16; m/z = 491 (MH ) 20 Example E113 3-[4-(5-Methoxymethoxymethyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1 yl]benzamide Step 1: 455 mg of sodium hydride at 60% in liquid petroleum jelly and 1.15 g of chloromethoxymethane are added, in the region of 00C, to a solution of 25 1.4 g of ethyl 5-hydroxymethyl-2-phenyl-2H-pyrazole-3-carboxylate, which is obtained as a side product in the synthesis of Example 71, in 35 ml of tetrahydrofuran. After reaction for 20 hours at room temperature, 50 ml of water and 50 ml of ethyl acetate are added and the organic phase is separated out by settling of the phases, washed with water, dried over 30 magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (60; 35-70 pm), eluting with pure dichloromethane, 1.1 g of ethyl 5-methoxymethoxymethyl-2 phenyl-2H-pyrazole-3-carboxylate are obtained in the form of an orange colored oil, the characteristics of which are as follows.
90 Mass spectrum (El): m/z = 290 (M+) Step 2: 6 ml of water and 250 mg of potassium hydroxide are added to a solution of 1.1 g of ethyl 5-methoxymethoxymethyl-2-phenyl-2H-pyrazole-3 carboxylate in 12 ml of ethanol. After 20 hours at room temperature, the 5 mixture is concentrated under reduced pressure, taken up in aqueous 1N hydrochloric acid solution to pH 1 and extracted with 3 times 25 ml of dichloromethane. The organic phase is separated out by settling of the phases, washed with 25 ml of water, dried over magnesium sulfate and concentrated under reduced pressure. 500 mg of 5-methoxymethoxymethyl 10 2-phenyl-2H-pyrazole-3-carboxylic acid are thus obtained in the form of an orange-colored oil, the characteristics of which are as follows: Mass spectrum (El): m/z = 262 (M+) Step 3: By performing the process in a manner similar to that for the synthesis of [4-(3-chlorophenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)meth 15 anone, but replacing the 1-(3-chlorophenyl)piperazine with 556mg of 3-piperazin-1-ylbenzamide, which may be obtained according to patent WO 98/00400, and by replacing the 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid with 525 mg of 5-methoxymethoxymethyl-2-phenyl-2H-pyrazole-3 carboxylic acid, 900 mg of 3-[4-(5-methoxymethoxymethyl-2-phenyl-2H 20 pyrazole-3-carbonyl)piperazin-1-yl]benzamide are obtained in the form of an amorphous beige-colored solid, the characteristics of which are as follows: Mass spectrum (El): m/z = 449 (M+) Example E114 3-{5-[4-(3,5-Dimethoxyphenyl)piperazine-1-carbonyl]-1-phenyl-1 H-pyrazol-3 25 yl}thiophene-2-carboxaldehyde The process is performed in a manner similar to that of Example E66, starting with 86 mg of the product of Example E82 and 40 mg of 2-formyl-3 thiopheneboronic acid. After microwave reaction for 3 minutes at 1400C, 6 mg of tetrakis(triphenylphosphine)palladium(0) and 0.2 ml of DMF are added and 30 the mixture is subjected to the microwave field for a further 1 minute at 140 0 C, to give, after work-up and successive purifications by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of heptane and ethyl acetate (6/4 by volume) and then by preparative HPLC/MS (H 2 0 pH=9 /
CH
3 CN), 33mg of 3-{5-[4-(3,5-dimethoxyphenyl)piperazine-1l-carbonyl]-l- 91 phenyl-1 H-pyrazol-3-yl}thiophene-2-carboxaldehyde in the form of a pale yellow powder, the characteristics of which are as follows: LC/MS: tr = 4.63; m/z = 503 (MH') Example E116 5 N-Methyl-3-[4-(5-methyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1 -yl] benzamide Step 1: A solution of 0.86 ml of oxalyl chloride is added, at 0oC, to a solution of 3.1 g tert-butyl 4-(3-carboxyphenyl)piperazine-1-carboxylate, which may be obtained according to patent GB 2 327 609, in 15 ml of dioxane. One drop of 10 dimethylformamide is added to this reaction mixture. After stirring for 2 hours at a temperature in the region of 20'C, the reaction mixture is added dropwise to 50 ml of aqueous 40% methylamine solution. After stirring for 1 hour at room temperature, the reaction mixture is taken up in 200 ml of dichloromethane and then washed twice with 50 ml of distilled water. The 15 organic phase is dried over magnesium sulfate and then concentrated to dryness under reduced pressure. 1.5 g of tert-butyl 4-(3-methylcarbamoyl phenyl)piperazine-1-carboxylate are thus obtained in the form of an orange colored oil, the characteristics of which are as follows: 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 6 in ppm): 1.45 (s: 9H); 20 2.78 (d, J = 4.5 Hz: 3H); 3.16 (broad t, J = 5.5 Hz: 4H); 3.49 (broad t, J = 5.5 Hz: 4H); 7.11 (broad dt, J = 7.5 and 2 Hz: 1H); from 7.20 to 7.35 (mt: 2H); 7.39 (broad s: 1 H); 8.32 (broad q, J = 4.5 Hz: 1 H). Step 2: 5.9 ml of a 4N solution of hydrochloric acid in dioxane are added dropwise to a solution of 1.5 g of tert-butyl 4-(3-methylcarbamoylphenyl) 25 piperazine-1-carboxylate in 5.8 ml of dioxane. After reaction for 6 hours at room temperature and concentration under reduced pressure, 950 mg of N-methyl-3-(piperazin-1-yl)benzamide hydrochloride are thus obtained in the form of an amorphous brown solid, the characteristics of which are as follows: 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 8 in ppm): 2.79 (d, J = 4.5 30 Hz: 3H); 3.15 (unresolved complex: 4H); 3.44 (broad t, J = 5.5 Hz: 4H); 7.15 (mt: 1H); from 7.25 to 7.40 (mt: 2H); 7.44 (broad s: 1H); 8.42 (broad q; J = 4.5 Hz: 1H); 9.17 (unresolved complex: 2H). Step 3: By performing the process in a manner similar to that for the synthesis of [4-(3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)- 92 methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 584 mg of N-methyl-3-(piperazin-1-yl)benzamide, 450 mg of N-methyl-3-[4-(5 methyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1 -yl]benzamide are obtained in the form of a beige-colored solid, the characteristics of which are 5 as follows: Melting point (Kofler): 1800C Mass spectrum (El): m/z = 403 (M+) Example E117 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl](2-phenyl-5-trifluoromethyl-2H 10 pyrazol-3-yl)methanone By performing the process in a manner similar to that for the synthesis of [4 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine by 244.5 mg of 1-(3,5-dimethoxyphenyl)piperazine and replacing the 5-methyl-2-phenyl-2H 15 pyrazole-3-carboxylic acid with 256 mg of 2-phenyl-5-trifluoromethyl-2H pyrazole-3-carboxylic acid, which may be obtained according to patent WO 03/024222, 340 mg of [4-(3,5-dimethoxyphenyl)piperazin-1 -yl](2-phenyl 5-trifluoromethyl-2H-pyrazol-3-yl)methanone are obtained in the form of a white solid, the characteristics of which are as follows: 20 Melting point (Kofler): 840C Mass spectrum (El): m/z = 460 (M+) Example E118 [4-(3-Chlorophenyl)piperazin-1 -yl](2-phenyl-5-trifluoromethyl-2H-pyrazol-3-yl) methanone 25 By performing the process in a manner similar to that for the synthesis of [4 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid with 256 mg of 2-phenyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid, which may be obtained according to patent WO 03/024222, 240 mg of [4-(3 30 chlorophenyl)piperazin-1 -yl](2-phenyl-5-trifluoromethyl-2H-pyrazol-3-yl)meth anone are obtained in the form of a white solid, the characteristics of which are as follows: Melting point (Kofler): 1600C Mass spectrum (El): m/z = 434 (M+) 93 Example E119 3-[4-(2-Phenyl-5-trifluoromethyl-2H-pyrazole-3-carbonyl)piperazin-1 -yl]benz amide By performing the process in a manner similar to that for the synthesis of [4 5 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 306 mg of 3-(piperazin-1-yl)benzamide, which may be obtained according to patent WO 98/00400, and replacing the 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid with 256 mg of 2-phenyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid, 10 which may be obtained according to patent WO 03/024222, 260 mg of 3-[4 (2-phenyl-5-trifluoromethyl-2H-pyrazole-3-carbonyl)piperazin-1 -yl]benzamide are obtained in the form of a white solid, the characteristics of which are as follows: Melting point (Kofler): 1600C 15 Mass spectrum (El): m/z = 443 (M+) Example E120 (5-Aminomethyl-2-phenyl-2H-pyrazol-3-yl)[4-(3,5-dimethoxyphenyl)piperazin 1-yl]methanone Step 1: 32 mg of sodium azide are added to a solution of 150 mg of ethyl 20 5-bromomethyl-2-phenyl-2H-pyrazole-3-carboxylate, obtained in Step 1 of Example E73, in 2 ml of DMSO at room temperature. The reaction mixture is stirred for 2 hours at room temperature and then for 1 hour at 500C, and is finally poured onto 50 ml of water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under 25 reduced pressure to give 135 mg of ethyl 5-azidomethyl-2-phenyl-2H pyrazole-3-carboxylate in the form of a pale yellow oil, the characteristics of which are as follows: TLC analysis: 7/3 heptane / EtOAc, Rf = 0.35 Mass spectrum (ES): m/z = 272 (MH+) 30 Step 2: The process is performed in a manner similar to that of Step 2 of Example E94, starting with 135 mg of the product of Step 1 of the present example and 221 mg of 1-(3,5-dimethoxyphenyl)piperazine, for 6 hours at 600C, to give, after purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of dichloromethane and ethyl acetate (95/5 35 by volume), 129 mg of (5-azidomethyl-2-phenyl-2H-pyrazol-3-yl)[4-(3,5- 94 dimethoxyphenyl)piperazin-1-yl]methanone in the form of a white solid, the characteristics of which are as follows: Mass spectrum (ES): m/z = 448 (MH ) Step 3: 90 mg of triphenylphosphine are added to a solution of 129 mg of the 5 product of Step 2 of the present example in 3 ml of THF at room temperature. The reaction mixture is stirred for 6 hours at room temperature, 0.6 ml of water is then added and the resulting mixture is stirred for 40 hours at room temperature, concentrated to dryness under reduced pressure and taken up in dichloromethane. The organic phase is washed with aqueous 1M 10 hydrochloric acid solution and then with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated under reduced pressure to give 84 mg of (5-aminomethyl-2-phenyl-2H-pyrazol-3 yl)[4-(3,5-dimethoxyphenyl)piperazin-1-yl]methanone in the form of a white solid, the characteristics of which are as follows: 15 LC/MS analysis: tr = 2.63; m/z = 422 (MH ) Example E121 Allyl {5-[4-(3,5-Dimethoxyphenyl)piperazine-1l-carbonyl]-1l-phenyl-1 H-pyrazol 3-ylmethyl}carbamate 23 pl of allyl isocyanate are added, at 5 0 C, to a solution of 100 mg of (5 20 aminomethyl-2-phenyl-2H-pyrazol-3-yl)[4-(3,5-dimethoxyphenyl)piperazin-1 yl]methanone, obtained in Example 120, in 1 ml of dichloromethane and 33 pl of triethylamine. The reaction mixture is stirred for 1.5 hours at 500C and then for 18 hours at 20 0 C, after which it is poured into 50 ml of saturated aqueous sodium dihydrogen phosphate solution and extracted with ethyl acetate. The 25 organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (30-60 p/m), eluting with a mixture of dichloromethane and ethyl acetate (60/40 by volume), 48 mg of allyl {5-[4-(3,5-dimethoxyphenyl)piperazine-1 carbonyl]-1l-phenyl-1 H-pyrazol-3-ylmethyl}carbamate are obtained in the form 30 of a white solid, the characteristics of which are as follows: LC/MS analysis: tr = 4.71; m/z = 506 (MH ) Example E122 Ethyl {5-[4-(3,5-Dimethoxyphenyl)piperazine-1-carbonyl]-1-phenyl-1 H pyrazol-3-ylmethyl}carbamate 95 The process is performed in a manner similar to that of Example E121, starting with 100 mg of (5-aminomethyl-2-phenyl-2H-pyrazol-3-yl)[4-(3,5 dimethoxyphenyl)piperazin-1-yl]methanone, obtained in Example 120, and 21 pl of ethyl isocyanate, to give, after purification by flash chromatography 5 on a column of silica (30-60 pm), eluting with a mixture of dichloromethane and ethyl acetate (60/40 by volume), 74 mg of ethyl {5-[4-(3,5 dimethoxyphenyl)piperazine-1-carbonyl]-1-phenyl-1 H-pyrazol-3-ylmethyl} carbamate, in the form of a white solid, the characteristics of which are as follows: 10 LC/MS analysis: tr = 4.62; m/z = 494 (MH ) Example E123 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl][5-(2-fluoroethoxymethyl)-2-phenyl 2H-pyrazol-3-yl]methanone Step 1: The process is performed in a manner similar to that of Step 1 of 15 Example E80, starting with 34 p1l of 2-fluoroethanol and 150 mg of ethyl 5-bromomethyl-2-phenyl-2H-pyrazole-3-carboxylate, obtained in Step 1 of Example E73, to give, after purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of heptane and ethyl acetate (80/20 by volume), 66 mg of ethyl 5-(2-fluoroethoxymethyl)-2-phenyl-2H-pyrazole-3 20 carboxylate in the form of a pale yellow oil, the characteristics of which are as follows: Mass spectrum (ES): m/z = 293 (MH ) Step 2: The process is performed in a manner similar to that of Step 2 of Example E80, starting with 66 mg of the product of Step 1 of the present 25 example and 151 mg of 1-(3,5-dimethoxyphenyl)piperazine for 4 hours at 600C, to give, after purification by flash chromatography on a column of silica (30-60 p/m), eluting with a mixture of dichloromethane and ethyl acetate (60/40 by volume), 86 mg of [4-(3,5-dimethoxyphenyl)piperazin-1-yl][5-(2 fluoroethoxymethyl)-2-phenyl-2H-pyrazol-3-yl]methanone in the form of a pale 30 yellow oil, the characteristics of which are as follows: LC/MS analysis: tr = 3.70; m/z = 469 (MH') Example E124 [5-(Cyclopentylhydroxymethyl)-2-phenyl-2H-pyrazol-3-yl][4-(3,5-dimethoxy phenyl)piperazin-1 -yl]methanone 96 A solution of 100 mg of 5-[4-(3,5-dimethoxyphenyl)piperazine-1-carbonyl]-1 phenyl-lH-pyrazole-3-carboxaldehyde, obtained in Example E100, in 1.5 ml of THF is added, at room temperature, to 0.24 ml of a 1N solution of cyclopentylmagnesium bromide in THF, at room temperature. After stirring for 5 two hours at room temperature, the reaction mixture is poured into 5 ml of saturated aqueous ammonium chloride solution and extracted with ether. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of dichloromethane and ethyl acetate 10 (60/40 by volume), 18.5 mg of [5-(cyclopentylhydroxymethyl)-2-phenyl-2H pyrazol-3-yl][4-(3,5-dimethoxyphenyl)piperazin-1-yl]methanone are obtained in the form of a colorless resin, the characteristics of which are as follows: LC/MS analysis: tr = 3.27; m/z = 423 (MH ) Example E125 15 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl][5-(1-hydroxypropyl)-2-phenyl-2H pyrazol-3-yl]methanone The process is performed in a manner similar to that of Example E124, starting with 0.595 ml of a 1N solution of ethylmagnesium bromide in THF and 100 mg of 5-[4-(3,5-dimethoxyphenyl)piperazine-1l-carbonyl]-1-phenyl-1H 20 pyrazole-3-carboxaldehyde, obtained in Example E100, in 1.5 ml of THF, to give, after purification by flash chromatography on a column of silica (30 60 pm), eluting with a mixture of dichloromethane and ethyl acetate (60/40 by volume), 36 mg of [4-(3,5-dimethoxyphenyl)piperazin-1-yl][5-(1-hydroxy propyl)-2-phenyl-2H-pyrazol-3-yl]methanone in the form of a colorless resin, 25 the characteristics of which are as follows: LC/MS analysis: tr = 3.53; m/z = 451 (MH') Example E126 Methyl E-3-{5-[4-(3,5-dimethoxyphenyl)piperazine-1l-carbonyl]-1l-phenyl-1lH pyrazol-3-yl}acrylate 30 0.205 ml of a 1N solution of lithium aluminum hydride in THF is added, at room temperature, to a solution of 100 mg of 5-[4-(3,5 dimethoxyphenyl)piperazine-1-carbonyl]-1 -phenyl-1 H-pyrazole-3 carboxaldehyde, obtained in Example E100, in 1 ml of THF and 1 ml of methanol. After stirring for 6 hours at room temperature, the reaction mixture 35 is poured into 50 ml of saturated aqueous sodium dihydrogen phosphate 97 solution and extracted with ethyl acetate. The organic phase is dried over magnesium - sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (30-60 pum), eluting with a mixture of dichloromethane and ethyl acetate (95/5 by volume), 49 mg 5 of methyl E-3-{5-[4-(3,5-dimethoxyphenyl)piperazine-1l-carbonyl]-1l-phenyl 1H-pyrazol-3-yl}acrylate are obtained in the form of a white solid, the characteristics of which are as follows: LC/MS analysis: tr = 3.95; m/z = 477 (MH ) 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 8 in ppm): 2.81 ppm (m, 10 2H); 3.08 ppm (m, 2H); 3.33 ppm (masked, 2H); 3.67 ppm (m, 2H); 3.68 ppm (s, 6H); 3.75 ppm (s, 3H); 5.99 ppm (bs, 1H); 6.02 ppm (bs, 2H); 6.70 ppm (d, J= 16 Hz, 1H); 7.28 ppm (s, 1H); from 7.40 to 7.58 ppm (m, 6H). This product may also be obtained in a manner similar to that of Example El 12 with (carbomethoxymethylene)triphenylphosphorane. 15 Example E127 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl][5-(1 -hydroxyethyl)-2-phenyl-2H pyrazol-3-yl]methanone 0.5 ml of THF and a solution of 50 mg of 5-[4-(3,5-dimethoxyphenyl) piperazine-1 -carbonyl]- 1 -phenyl-1 H-pyrazole-3-carboxaldehyde, obtained in 20 Example E100, in 1 ml of THF are added at room temperature to 87 pl of a 1.5M solution of methyllithium in THF. After stirring for 20 hours at room temperature, the reaction mixture is poured into 5 ml of saturated aqueous ammonium chloride solution and extracted with ether. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. 25 After purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of dichloromethane and ethyl acetate (60/40 by volume), 6 mg of [4-(3,5-dimethoxyphenyl)piperazin-1-yl][5-(1-hydroxyethyl) 2-phenyl-2H-pyrazol-3-yl]methanone are obtained in the form of a pale yellow solid, the characteristics of which are as follows: 30 LC/MS analysis: tr = 3.38; m/z = 437 (MH') Example E128 3-Hydroxy-N-{3-[4-(5-methyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1 -yl] phenyl}propionamide 98 1 ml of a 1M solution of diethylaluminum chloride in hexane and 72 mg oxetan-2-one are added, at 00C, to a solution of 362 mg of [4-(3-amino phenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone, described in Example E9, in 20 ml of dichloromethane. After 20 minutes at 5 0 0 C and 3 hours at room temperature, the mixture is cooled again to about 0oC and 1 ml of 1N hydrochloric acid solution is added. The reaction mixture is then neutralized with saturated sodium bicarbonate solution, extracted with 3 times 50 ml of dichloromethane and washed with 50 ml of water. After drying over magnesium sulfate and concentrating under reduced pressure, 10 followed by purification by flash chromatography on a column of silica (60; 35 70 pm), eluting with a mixture of dichloromethane and methanol (90-10 by volume), 20 mg of 3-hydroxy-N-{3-[4-(5-methyl-2-phenyl-2H-pyrazole-3 carbonyl)piperazin-1-yl]phenyl}propionamide are obtained in the form of an amorphous beige-colored solid, the characteristics of which are as follows: 15 Mass spectrum (El): m/z = 433 (M ) 1 H NMR spectrum (300 MHz, (CD 3
)
2 SO d6, 6 in ppm): 2.32 (s: 3H); 2.45 (t, J = 6.5 Hz: 2H); 2.76 (unresolved complex: 2H); 3.06 (unresolved complex: 2H); 3.36 (unresolved complex: 2H); 3.70 (mt: 4H); 4.65 (unresolved complex: 1H); 6.53 (s: 1H); 6.58 (broad d, J = 8 Hz: 1H); 7.04 (broad d, J = 8 20 Hz: 1H); 7.12 (t, J = 8 Hz: 1H); 7.24 (broad s: 1H); 7.36 (broad t, J = 7.5 Hz: 1H); from 7.40 to 7.55 (mt: 4H); 9.75 (broad s: 1H). Example E129 [5-(Azetidin-1 -yl)-2-phenyl-2H-pyrazol-3-yl][4-(3,5-dimethoxyphenyl)piperazin 1-yl]methanone 25 The process is performed in a manner similar to that of Example E98, starting with 100 mg of the product of Example E82 and 72 p1 of azetidine, by microwave reaction for 5 minutes at 900C, to give, after purification by preparative HPLC/MS (H 2 0 pH=9 / CH 3 CN), 23.5 mg of [5-(azetidin-1-yl)-2 phenyl-2H-pyrazol-3-yl][4-(3,5-dimethoxyphenyl)piperazin- 1 -yl]methanone in 30 the form of a white powder, the characteristics of which are as follows: LC/MS analysis: tr = 4.05; m/z = 448 (MH*) Example E130 (5-Allylamino-2-phenyl-2H-pyrazol-3-yl)[4-(3,5-dimethoxyphenyl)piperazin-1 yl]methanone 99 The process is performed in a manner similar to that of Example E98, starting with 100 mg of the product of Example E82 and 80 pl of allylamine, by microwave reaction for 3 minutes at 100 0 C. 10 mg of tris(dibenzylidene acetone)dipalladium(0), 80 p1 of allylamine and 0.20 ml of DME are added 5 and the mixture is subjected to the microwave field for a further 3 minutes at 1000C, to give, after purification by preparative HPLC/MS (H 2 0 pH=9 /
CH
3 CN), 33mg of (5-allylamino-2-phenyl-2H-pyrazol-3-yl)[4-(3,5-dimethoxy phenyl)piperazin-1-yl]methanone in the form of a pale yellow powder, the characteristics of which are as follows: 10 LC/MS analysis: tr = 4.22; m/z = 448 (MH ) Example E131 [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl][5-(hydroxyphenylmethyl)-2-phenyl 2H-pyrazol-3-yl]methanone The process is performed in a manner similar to that of Example E124, 15 starting with 0.36 ml of a 1N solution phenylmagnesium bromide in THF and 100 mg of 5-[4-(3,5-dimethoxyphenyl)piperazine-1l-carbonyl]-1l-phenyl-1lH pyrazole-3-carboxaldehyde, obtained in Example E100, in 1.5 ml of THF, to give, after purification by flash chromatography on a column of silica (30 60 pm), eluting with a mixture of dichloromethane and ethyl acetate (60/40 by 20 volume), 81 mg of [4-(3,5-dimethoxyphenyl)piperazin-1-yl][5-(hydroxyphenyl methyl)-2-phenyl-2H-pyrazol-3-yl]methanone in the form of a white solid, the characteristics of which are as follows: LC/MS analysis: tr = 3.86; m/z = 499 (MH*) Example E132 25 [4-(3-Hydroxymethylphenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone Step 1: 3.6 ml of a 4N solution of hydrochloric acid in dioxane are added dropwise to a solution of 850 mg of tert-butyl 4-(3-hydroxymethyl phenyl)piperazine-1-carboxylate, which may be obtained according to patent 30 WO 00/015609, in 4 ml of dioxane. After reaction for 20 hours, the precipitate formed is filtered off and then washed with 20 ml of petroleum ether. 770 mg of [3-(piperazin-1-yl)phenyl]methanol hydrochloride are thus obtained in the form of an amorphous brown solid, the characteristics of which are as follows: Mass spectrum (El): m/z = 192 (M+) 100 Step 2: By performing the process in a manner similar to that for the synthesis of [4-(3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone, but replacing the 1-(3-chlorophenyl)piperazine with 265 mg of [3 (piperazin-1 -yl)phenyl]methanol hydrochloride, 250 mg of [4-(3-hydroxy 5 methylphenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone are obtained in the form of a beige-colored foam, the characteristics of which are as follows: Mass spectrum (El): m/z = 376 (M+) Example E133 10 3-[4-(2-Phenyl-2H-pyrazole-3-carbonyl)piperazin-1 -yl]benzamide By performing the process in a manner similar to that for the synthesis of [4 (3-chlorophenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone (Example 1), but replacing the 1-(3-chlorophenyl)piperazine with 556 mg of 3-(piperazin-1-yl)benzamide, which may be obtained according to patent 15 WO 98/00400 and replacing the 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid with 376.4 mg of 2-phenyl-2H-pyrazole-3-carboxylic acid, 530 mg of 3-[4 (2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1 -yl]benzamide are obtained in the form of an amorphous white solid, the characteristics of which are as follows: 20 Mass spectrum (El): m/z = 375 (M+) Example E134 3-[4-(5-Hydroxymethyl-2-phenyl-2H-pyrazole-3-carbonyl)piperazin-1 -yl]benz amide 1.17 ml of a 4N solution of hydrochloric acid in dioxane are added to a 25 solution of 840 mg of 3-[4-(5-methoxymethoxymethyl-2-phenyl-2H-pyrazole-3 carbonyl)piperazin-1-yl]benzamide, obtained in Example El113, in 30 ml of absolute ethanol. After reaction for 20 hours at room temperature and concentration under reduced pressure, the residue is taken up in 20 ml of water and aqueous 10% sodium bicarbonate solution to pH 8. The solid 30 formed is filtered off and washed with twice 25 ml of water and then with 2 ml of absolute ethanol. 555 mg of 3-[4-(5-hydroxymethyl-2-phenyl-2H-pyrazole 3-carbonyl)piperazin-1-yl]benzamide are thus obtained in the form of an off white solid, the characteristics of which are as follows: Melting point (Kofler): 2160C 35 Mass spectrum (El): m/z = 405 (M+) 101 Example E135 (5-Cyanomethyl-2-phenyl-2H-pyrazol-3-yl)[4-(3,5-dimethoxyphenyl)piperazin 1-yl]methanone Step 1: 32 mg of potassium cyanide are added to a solution of 150 mg of 5 ethyl 5-bromomethyl-2-phenyl-2H-pyrazole-3-carboxylate, obtained in Step 1 of Example E73, in 2 ml of DMSO at room temperature. The reaction mixture is stirred for 4 hours at 200C and then poured into 50 ml of saturated aqueous sodium dihydrogen phosphate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under 10 reduced pressure. After purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of heptane and ethyl acetate (70/30 by volume), 102 mg of ethyl 5-cyanomethyl-2-phenyl-2H-pyrazole-3 carboxylate are thus obtained in the form of a colorless oil, the characteristics of which are as follows: 15 Mass spectrum (ES): m/z = 256 (MH ) Step 2: The process is performed in a manner similar to that of Step 2 of Example E80, starting with 100 mg of the product of Step 1 of the present example and 174 mg of 1-(3,5-dimethoxyphenyl)piperazine, for 4 hours at 60 0 C, to give, after purification by flash chromatography on a column of silica 20 (30-60 pm), eluting with a mixture of dichloromethane and ethyl acetate (80/20 by volume), 106 mg of (5-cyanomethyl-2-phenyl-2H-pyrazol-3-yl)[4 (3,5-dimethoxyphenyl)piperazin-1-yl]methanone in the form of a colorless oil, the characteristics of which are as follows: LC/MS analysis: tr = 3.64; m/z = 432 (MH') 25 Example E136 [4-(3-Difluoromethoxyphenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone hydrochloride Step 1: 4-(3-Difluoromethoxyphenyl)piperazine-1l-carboxylic acid tert-butoxide A mixture of commercial 1-boc piperazine (500.1 mg, 2.685 mmol) and of 30 commercial 3-difluoromethoxybromobenzene (598.8 mg, 2.685 mmol) in toluene (20 ml) is -placed in a 50 ml three-necked flask under an inert atmosphere of argon, followed by addition of the ligand (R)(+)-2,2' bis(diphenylphosphino)-1,1'-binaphthyl (56.850 mg, 91.2 pmol) and palladium(ii) acetate (20.4 mg, 91.2 pmol). The reaction mixture is stirred and 102 refluxed for 16 hours. After cooling to 2000, the reaction mixture is diluted with water (20 ml) and then extracted with ethyl acetate (2 x 30 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The compound obtained is purified by 5 chromatography on silica gel (AIT cartridge, ref. FC-25 Si-BP-SUP, 20-40 pm, dichloromethane eluent, flow rate of 20 ml/min). The fractions containing the expected compound are combined and then evaporated under reduced pressure. The expected 4-(3-difluoromethoxyphenyl)piperazine-1l-carboxylic acid tert-butoxide (253 mg) is isolated, the characteristics of which are as 10 follows: LC/MS analysis: tr = 4.18 min, M+H 329.31 Step 2: 1-(3-Difluoromethoxyphenyl)piperazine hydrochloride A solution of 4-(3-difluoromethoxyphenyl)piperazine-1l-carboxylic acid tert butoxide (253 mg, 3.8 mmol) is placed in a mixture of dioxane (1016 pl) and 15 hydrochloric acid (963 pl) in a 10 ml round-bottomed flask. The reaction mixture is stirred at 200C for 48 hours. The solid formed is filtered off, washed (diisopropyl ether, 10 ml) and dried under reduced pressure. The 1-(3 difluoromethoxyphenyl)piperazine hydrochloride (189 mg) is isolated, identified, characterized and used without further purification for the following 20 step. Step 3: [4-(3-Difluoromethoxyphenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H pyrazol-3-yl)methanone hydrochloride A solution of 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid, which may be obtained according to J. Het. Chem., 30, 307 (1993), (144.4 mg, 714 pmol) in 25 dichloromethane (11 ml) is placed in a 50 ml three-necked flask under an inert atmosphere of argon, followed by successive addition of 1-(3-difluoro methoxyphenyl)piperazine hydrochloride (189mg, 714 pmol), 1-hydroxy benzotriazole (106.1 mg, 785 pmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (150.6 mg, 785 pmol) and then triethylamine 30 (331 pl1). The reaction mixture is stirred for 48 hours at 200C and then diluted with dichloromethane (20 ml) and water (20 ml), the phases are separated by settling and the aqueous phase is extracted (30 ml of dichloromethane). The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The compound obtained is purified by 35 chromatography on silica gel (AIT cartridge, ref. FC 25-Si-HP, 15-35 pm, 103 80/20 to 60/40 cyclohexane/ethyl acetate eluent over 60 minutes, flow rate of 7 ml/min). The fractions containing the expected compound are combined and then evaporated under reduced pressure. The evaporation residue is taken up in a mixture of ethyl ether (12 ml) and 2N hydrochloric acid/ethyl 5 ether (500 pl) and then triturated until a solid is obtained, which is filtered off, washed (5 ml) and dried under reduced pressure. The [4-(3-difluoromethoxy phenyl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methanone hydrochloride (199 mg) is isolated, the characteristics of which are as follows: Melting point 1270C (Kofler). 10 Example E137 N-{{3-{[4-(3,5-Dimethoxyphenyl)piperazin-1 -yl]carbonyl}-2-phenyl-2H-pyrazin 5-yl}glycine tert-butyl ester The process is performed in a manner similar to that of Example E98, starting with 100 mg of the product of Example E82 and 145 pl of glycine tert-butyl 15 ester, by microwave reaction for 5 minutes at 1000C. 21 mg of tris (dibenzylideneacetone)dipalladium(0), 145 pl of glycine tert-butyl ester and 0.20 ml of DME are added and the mixture is then subjected to the microwave field for a further 5 minutes at 12000 and then for 5 minutes at 1400C, to give, after purification by preparative HPLC/MS (H 2 0 pH=9 / CH 3 CN), 2.2 mg of 20 tert-butyl ester of N-{{3-{[4-(3,5-dimethoxyphenyl)piperazin-1-yl]carbonyl}-2 phenyl-2H-pyrazin-5-yl}glycine in the form of a white powder, the characteristics of which are as follows: LC/MS analysis: tr = 4.23; m/z = 476 (MH*) Example E138 25 [4-(3,5-dimethoxyphenyl)piperazin-1 -yl][5-(piperid-1 -yl)-2-phenyl-2H-pyrazol 3-yl)methanone The process is performed in a manner similar to that of Example E98, starting with 100 mg of the product of Example E82 and 105 pl of piperidine, by microwave reaction for 5 minutes at 900C, to give, after purification by 30 preparative HPLC/MS (H 2 0 pH=9/CH 3 CN), 12 mg of [4-(3,5-dimethoxy phenyl)piperazin-1 -yl][5-(piperid-1 -yl)-2-phenyl-2H-pyrazol-3-yl)methanone in the form of a white powder, the characteristics of which are as follows: LC/MS analysis: tr = 4.57; m/z = 522 (MH') 104 Example E139 [4-(3,5-dimethoxyphenyl)piperazin-1 -yl](4,5-difluoro-2-phenyl-2H-pyrazol-3 yl)methanone 0.30 ml of a 1.7N solution of tert-butyllithium in THF is added to a solution of 5 100 mg of (5-bromo-2-phenyl-2H-pyrazol-3-yl)[4-(3,5-dimethoxyphenyl)-l yl]methanone ester (Example E82) in 2 ml of THF, cooled to -780C. The reaction medium is stirred for 30 minutes at -78 0 C and then treated with a solution of 87 mg of N-fluorobenzenesulfonimide in 1 ml of THF. The reaction medium is stirred for 1.5 hours at -78 0 C and then for 16 hours at room 10 temperature, poured into 50 ml of saturated aqueous sodium dihydrogen phosphate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (30-60 pm), eluting with a mixture of toluene and ethyl acetate (90/10 by volume), 15 mg 15 of [4-(3,5-dimethoxyphenyl)piperazin-1-yl](4,5-difluoro-2-phenyl-2H-pyrazol-3 yl)methanone are obtained in the form of a yellow oil, the characteristics of which are as follows: LC/MS analysis: tr = 4.26; m/z = 429 (MH ) Example E140 20 [4-(5-hydroxypyrid-3-yl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone Step 1: 3-Benzyloxy-5-bromopyridine A solution of 5-bromopyrid-3-ol (1 g, 5.74 mmol) in dimethylformamide (15 ml) is placed in a 50 ml three-necked flask under an inert atmosphere of argon, 25 followed by addition, at 20 0 C, of potassium carbonate (794.3 mg, 5.74 mmol) and benzyl bromide (687 pl, 5.74 mmol). The reaction mixture is stirred at 20 0 C for 16 hours and then diluted with ethyl acetate (150 ml) and water (150 ml). After separation of the phases by settling, the organic phase is extracted with 2 portions of ethyl acetate (50ml). The organic extracts are 30 combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The compound obtained is purified by chromatography on silica gel (FC-50-Si-BP-Support cartridge, 20-40 pm, dichloromethane eluent, flow rate of 20 ml/min). The fractions containing the expected compound are combined and then evaporated under reduced pressure to give 350 mg of 35 3-benzyloxy-5-bromopyridine, the characteristics of which are as follows: 105 Mass spectrum: (IE) m/z=263 M'; m/z=91 C 7
H
7 ' base peak Step 2: tert-Butyl 4-(5-benzyloxypyrid-3-yl)piperazine-l-carboxylate A mixture of 1-boc piperazine (246.8 mg, 1.325 mmol) and of 3-benzyloxy-5 bromopyridine (350 mg, 1.325 mmol) in toluene (10 ml) is placed in a 50 ml 5 three-necked flask under an inert atmosphere of argon, followed by addition of the ligand (R)(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (28.05 mg, 45.05 pmol) and palladium(ii) acetate (10.10 mg, 45.05 pmol). The reaction mixture is stirred and refluxed for 16 hours. After cooling to 20 0 C, the reaction mixture is diluted with water (30 ml) and then extracted with ethyl acetate (2 x 10 30 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crystalline compound obtained is taken up in ethyl ether (20 ml) and then triturated, filtered off and dried under reduced pressure. The tert-butyl 4-(5-benzyloxypyrid-3 yl)piperazine-1-carboxylate, 280.1 mg, is isolated, the characteristics of which 15 are as follows: LC/MS analysis: tr = 3.04 min.; m/z=370.34, (M+H ) Step 3: 1-(5-Benzyloxypyrid-3-yl)piperazine hydrochloride A solution of tert-butyl 4-(5-benzyloxypyrid-3-yl)piperazine- 1 -carboxylate (280.1 mg, 0.758 p/mol) in dioxane (1 ml) is placed in a 50 ml round-bottomed 20 flask and is then stirred at 22 0 C while adding hydrochloric acid (948 pl). The reaction mixture is stirred at 220C for 16 hours. The yellow solid formed is filtered off, rinsed with diisopropyl ether (15 ml) and then dried under reduced pressure. The 1-(5-benzyloxypyrid-3-yl)piperazine hydrochloride (280 mg, 98%) is isolated and used without further purification for the following step. 25 Step 4: [4-(5-Benzyloxypyrid-3-yl)piperazin-1 -yl](5-methyl-2-phenyl-2H pyrazol-3-yl)methanone A solution of 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid, which may be obtained according to J. Het. Chem., 30, 307 (1993), (150 mg, 742 pmol) in dichloromethane (11 ml) is placed in a 50 ml three-necked flask under an 30 inert atmosphere of argon, followed by successive addition of 1-(5 benzyloxypyrid-3-yl)piperazine hydrochloride (226.9 mg, 742 pmol), 1-hydroxybenzotriazole (110.3 mg, 816 pmol), 1-(3-dimethylaminopropyl)-3 ethylcarbodiimide hydrochloride (156.5 mg, 742 pmol) and then triethylamine (344 pl). The reaction mixture is stirred at 200C for 16 hours and is then 35 diluted with dichloromethane (20 ml) and water (10 ml), the phases are 106 separated by settling and the aqueous phase is extracted (30 ml of dichloromethane). The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The compound obtained is purified by chromatography on silica gel (AIT cartridge, ref. FC 25 5 Si-HP, 15-35p/m, eluent: 100% dichloromethane to 90/10 dichloro methane/methanol over 60 minutes, flow rate of 7 ml/min). The fractions containing the expected compound are combined and then evaporated under reduced pressure and [4-(5-benzyloxypyrid-3-yl)piperazin- 1 -yl](5-methyl-2 phenyl-2H-pyrazol-3-yl)methanone (268 mg) is isolated, the characteristics of 10 which are as follows: LC/MS analysis: tr = 2.90 min; m/z=454.24 (M+H* Step 4: [4-(5-Hydroxypyrid-3-yl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol 3-yl)methanone A solution of [4-(5-benzyloxypyrid-3-yl)piperazin-1-yl](5-methyl-2-phenyl-2H 15 pyrazol-3-yl)methanone (268 mg; 591 pmol) in ethanol (22.5 ml) is placed in a 50 ml round-bottomed flask, ammonium formate (231.1 mg, 3.664 mmol) and palladium-on-charcoal (94.3 mg, 88.6 pmol) are then added and the reaction mixture is maintained at 80 0 C for 3.5 hours. After cooling to 20 0 C, the catalyst is removed by filtration through Celite and the filtrate is then evaporated under 20 reduced pressure. The compound obtained is purified by chromatography on silica gel (cartridge 26 mm in diameter, height 135 mm, 20 g of 15-40 pm silica, eluent of 100% dichloromethane to 80/20 dichloromethane/methanol over 60 minutes, flow rate of 10 ml/min). The fractions containing the expected compound are combined and then evaporated under reduced 25 pressure, to give a compound that is purified again by chromatography on silica gel (cartridge 26 mm in diameter, height 135 mm, 20 g of 15-40 pm silica, eluent of 100% ethyl acetate to 80/20 ethyl acetate/methanol over 60 minutes, flow rate of 10 ml/min). The fractions containing the expected compound are combined and then evaporated under reduced pressure to 30 give [4-(5-hydroxypyrid-3-yl)piperazin-1 -yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone (154 mg), the characteristics of which are as follows: Melting point: 128 0 C (Kofler). Among the products obtained, the products that are particularly preferred are: - [4-(3-Chlorophenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)meth 35 anone (Example 1) 107 - [4-(3,4-Dimethylphenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone (Example 2) - [4-(3,5-Dichlorophenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone (Example E2) 5 - [4-(Quinolin-4-yl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)methan one (Example E17) - [4-(3-Chlorophenyl)piperazin-1-yl](5-hydroxymethyl-2-phenyl-2H-pyrazol-3 yl)methanone (Example E60) - [4-(3,4-Methylenedioxyphenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol 10 3-yl)methanone (Example E30) - [4-(3,5-Dimethoxyphenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone (Example E20) - [4-(3,5-Dimethylphenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone (Example E63) 15 - [4-(3-Difluoromethoxyphenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol 3-yl)methanone (Example E74) - [4-(3-Chlorophenyl)piperazin-1-yl][5-(2-methylimidazol-1-yl-methyl)-2 phenyl-2H-pyrazol-3-yl]methanone (Example E75) - [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl][5-(1 H-pyrrol-2-yl)methyl-2-phenyl 20 2H-pyrazol-3-yl]methanone (Example E91) - [4-(3,5-Dimethoxyphenyl)piperazin-1-yl][5-(pyrrolidin-1-yl)methyl-2-phenyl 2H-pyrazol-3-yl]methanone (Example E93) - [4-(3-Carboxamidophenyl)piperazin-1-yl](5-trifluoromethyl-2-phenyl-2H pyrazol-3-yl)methanone (Example E1 19) 25 - [5-(Azetidin-1-yl)-2-phenyl-2 H-pyrazol-3-yl][4-(3,5-dimethoxyphenyl)piper azin-1 -yl]methanone (Example E129) - [4-(3-Carboxamidophenyl)piperazin-1-yl](2-phenyl-2H-pyrazol-3-yl)meth anone (Example E133) - [4-(3-Carboxamidophenyl)piperazin-1-yl](5-hydroxymethyl-2-phenyl-2H 30 pyrazol-3-yl)methanone (Example E134) - [4-(3-Carboxamidophenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone (Example E23) - [4-(3,5-Dimethoxyphenyl)piperazin-1-yl](5-hydroxymethyl-2-phenyl-2H pyrazol-3-yl)methanone (Example E73) 35 - (5-Amino-2-phenyl-2H-pyrazol-3-yl)[4-(3,5-dimethoxyphenyl)piperazin-1-yl] methanone (Example E99).
108 Among the products that are particularly preferred, the following products are preferred: - [4-(3-Carboxamidophenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone (Example E23) 5 - [4-(3,5-Dimethoxyphenyl)piperazin-1-yl](5-hydroxymethyl-2-phenyl-2H pyrazol-3-yl)methanone (Example E73) - (5-Amino-2-phenyl-2H-pyrazol-3-yl)[4-(3,5-dimethoxyphenyl)piperazin-1 yl]methanone (Example E99). A product in accordance with the invention may be used for the manufacture 10 of a medicinal product that is useful for treating a pathological condition, in particular a cancer. The present invention also relates to therapeutic compositions containing a compound according to the invention, in combination with a pharmaceutically acceptable excipient depending on the chosen mode of administration. The 15 pharmaceutical composition may be in solid or liquid form or in the form of liposomes. Among the solid compositions that may be mentioned are powders, gelatin capsules and tablets. Among the oral forms, solid forms protected against the acidic medium of the stomach may also be included. The supports used for 20 the solid forms consist in particular of mineral supports such as phosphates or carbonates, or organic supports such as lactose, celluloses, starch or polymers. The liquid forms consist of solutions, suspensions or dispersions. They contain, as dispersive support, either water or an organic solvent (ethanol, NMP or the like) or mixtures of surfactants and solvents or of 25 complexing agents and solvents. The liquid forms will preferably be injectable and, as a result, will have a formulation that is acceptable for such a use. 30 Acceptable routes- of administration by injection include intravenous, intraperitoneal, intramuscular and subcutaneous routes, the intravenous route being preferred.
109 The administered dose of the compounds of the invention will be adapted by the practitioner depending on the route of administration to the patient and the condition of said patient. The compounds of the present invention may be administered alone or as a 5 mixture with other anticancer agents. Among the possible combinations, that may be mentioned are: * alkylating agents and especially cyclophosphamide, melphalan, ifosfamide, chlorambucil, busulfan, thiotepa, prednimustine, carmustine, lomustine, semustine, steptozotocin, decarbazine, 10 temozolomide, procarbazine and hexamethylmelamine; * platinum derivatives especially such as cisplatin, carboplatin or oxaliplatin; * antibiotic agents especially such as bleomycin, mitomycin or dactinomycin; 15 * antimicrotubule agents especially such as vinblastine, vincristine, vindesine, vinorelbine or taxoids (paclitaxel and docetaxel); * anthracyclines especially such as doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone or losoxantrone; * group I and II topoisomerases such as etoposide, teniposide, 20 amsacrine, irinotecan, topotecan and tomudex; * fluoropyrimidines such as 5-fluorouracil, UFT or floxuridine; * cytidine analogues such as 5-azacytidine, cytarabine, gemcitabine, 6-mercaptomurine or 6-thioguanine; * adenosine analogs such as pentostatin, cytarabine or fludarabine 25 phosphate; * methotrexate and folinic acid; * various enzymes and compounds such as L-asparaginase, hydroxyurea, trans-retinoic acid, suramin, dexrazoxane, amifostine, herceptin and estrogen and androgen hormones; 30 * antivascular agents such as combretastatin or colchicine derivatives and prodrugs thereof.
110 It is also possible to combine the compounds of the present invention with a radiation treatment. These treatments may be administered simultaneously, separately or sequentially. The treatment will be adapted to the patient to be treated by the practitioner. 5 A product of the invention may be useful for inhibiting the in vitro polymerization of tubulin. Evaluation of the inhibition of tubulin polymerization Tubulin is purified from pig brain according to published methods (Shelanski et al., 1973, Proc. Natl. Acad. Sci. USA, 70, 765-768. Weingarten et al., 1975, 10 Proc. Natl. Acad. Sci. USA, 72, 1858-1862). Briefly, the brains are ground and centrifuged in an extraction buffer. The tubulin contained in the supernatant of the extract undergoes two successive cycles of polymerization at 37 0 C and depolymerization at 40C, before being separated from the MAPs (Microtubule Associated Proteins) by chromatography on a phosphocellulose P11 column 15 (Whatman). The tubulin thus isolated is more than 95% pure. It is stored in a buffer known as RB/2 30% glycerol, the composition of which is 50 mM MES-NaOH [2-(N-morpholino)ethanesulfonic acid], pH 6.8; 0.25 mM MgCI 2 ; 0.5 mM EGTA; 30% glycerol (v/v), 0.2 mM GTP (guanosine-5'-triphosphate). The polymerization of tubulin to microtubules is monitored by turbidimetry as 20 follows: the tubulin is adjusted to a concentration of 10 pIm (1 mg/ml) in RB/2 30% glycerol buffer to which 1 mM GTP and 6 mM MgCI 2 are added. The polymerization is triggered by an increase in temperature from 60C to 37 0 C in a cuvette with an optical path length of 1 cm, placed in a UVIKON 931 spectrophotometer (Kontron) equipped with a thermostatically maintained 25 cuvette holder. The increase in the turbidity of the solution is monitored at 350 nm. The products are dissolved at 10 mM in DMSO and added at variable concentrations (0.5 to 10 gm) to the tubulin solution before polymerization. The IC50 value is defined as the concentration of product that inhibits the rate 30 of polymerization by 50%. A product whose ICo50 value is less than or equal to 25 prm is considered as being very active. A product in accordance with the invention may be useful for inhibiting the in vitro proliferation of tumoral cells.
111 Test for determining the inhibition of proliferation of the human colon tumor line HCT116 The proliferation of HCT116 cells is evaluated by measuring the incorporation of [ 1 4 C]-thymidine in the following manner. The HCT116 cells (obtained from 5 the ATCC) are cultured in a DMEM medium (Gibco) containing 10 % fetal calf serum and antibiotics (1 % penicillin, 1 % streptomycin). To perform the proliferation test, the cells are inoculated in cytostar 96-well microplates (Amersham), at a rate of 5000 cells per well. [ 1 4 C]-thymidine (0.1 pCi/well) and the products to be evaluated are then added. Variable concentrations of 10 products up to 10 pm are used; the DMSO (solvent used to dissolve the products) should not exceed 0.5 % in the medium. 48 hours after incubation at 370C, the radioactivity incorporated into the cells is measured by counting the plate in a TRI-LUX counter (Wallac). The IC50 is defined as the concentration of product that reduces the radioactivity by 50 % compared with 15 an untreated control. A product whose ICo50 is less than 3 pm is considered cytotoxic. Test for determining the inhibition of vascularization A test for determining the detachment of the endothelial cells was developed in order to select the products with regard to their "in vitro" activity. This test 20 for determining the detachment of endothelial cells is characterized in that the endothelial cells, inoculated into plates whose bottom is covered with a binder preferably chosen from gelatin, fibronectin and vitronectin, after culturing, are supplemented with a medium containing the test compound, and the cells are then labeled with a fluorescent substance, the cells which have become 25 detached are removed by washing and the fluorescence of the remaining cells is counted in a fluorimeter. This test consists in measuring the detachment of endothelial cells cultured on substrata based on a binder preferably chosen from fibronectin, vitronectin and gelatin. Preferably, a day after the inoculation of the cells in plates 30 containing, for example, 96 wells, the culture medium is replaced with a medium containing -the test compound in the absence of serum. The same preparation is prepared six times at three different concentrations (0.1, 0.3 and 0.6 pm) and the control six times without addition of antivascular product. After two hours of treatment with the test substance, the cells are labeled with 112 calcein-AM (1.6 pg/mi) in the culture medium supplemented with 0.1% BSA. The cells that have become detached are removed by washing with the culture medium containing 0.1% bovine serum albumin; 100 pl of medium are added to each well. The fluorescence of the remaining cells is counted in a 5 fluorimeter. The data obtained are expressed relative to the control (untreated cells). The evaluation of the detachment of the endothelial cells in vitro is determined in the following manner. HDMEC cells (Human Dermal Microvascular Endothelial Cells, Promocell, c-122102) are cultured in an 10 ECGM-MV medium that contains 5% fetal calf serum, growth factors (EGF 10 ng/ml, hydrocortisone 1 ptg/ml, 0.4% growth supplement with heparin) and antibiotics (amphotericin 50 ng/ml, gentamycin 50 pg/ml). For the detachment test, the HDMECs are inoculated at a rate of 5 000 cells in clear-bottomed 96-well plates (Costar) precoated with fibronectin (10 pg/ml), vitronectin 15 (1 pig/ml) or gelatin. Twenty-four hours later, the culture medium is replaced with ECGM-MV 0.1% BSA medium containing the products indicated. The concentrations tested are 0.1-0.3 and 1 piM for each product. After two hours of treatment, the cells are labeled for one hour with calcein (1.6 pg/ml, Molecular Probes) in ECGM-MV 0.1% BSA medium. The detached cells are 20 then removed by washing with ECGM-MV 0.1% BSA medium; 100 jl of medium is added to each well. The fluorescence of the cells that remain attached to the substratum of the well is counted using a fluorimeter, Spectrafluor Plus (Tecan excitation 485 nm, and emission 535 nm). The data are the mean of six different samples and are expressed as the percentage of 25 the control (untreated cells). A cell detachment effect of greater than or equal to 15% is considered as significant.
113 Biological results Inhibition of Inhibition of Percentage Ex. Molar tubulin HCT116 detachment No. Structure mass polymerization proliferation of HDMEC at IC 50 (pm) IC 50 (pm) 1 pm O N N-N N N 3/1 376.457 20 O / O 0 N N-N N N 3/2 O 404.511 0.312 0 0 N N-N N 3/3 0 390.49 1.8 0.087 0 N N-N N N Cl 3/4 O 424.93 1.8 0.389 0 N N-N N Cl 3/5 00 c, l 440.93 3 0.238 I N N 3/6 0 346.44 4.5 0.177 114 N O 3/7 0O N / N6 376.46 5.6 0.040 FF N F N N N 3/8 \ 414.43 6.5 0.841 N Cl N N N O 0 N N-N N 3/10 376.46 2 0.025 0 N 3/11 360.46 3 0.036 0 N N- N 3/12 392.53 3 0.145 115 O N N-N N 3/13 396.5 6 0.466 0 N- N ON 3/14 O 404.47 15 0.352 0 3/15 394.45 2 0.0040 0O O N N-N N 3/16 F 378.45 6 0.224 o. oo 0 N N-N N 3/17 F 392.48 3.5 0.159 0 N N-N N 3/18 F 398.87 2 0.028 Cl 116 O IN N- N N-N N 3/19 F 378.45 1.8 0.017 0 N-N N 3/20 F 414.49 3 1.846 O
I
0 - N N-N N Cl 3/21 - F 412.9 1.8 0.469 0 N N- N C 3/22 F 0 428.9 1.5 0.046 0 N NN N 3/23 432.419 3 0.434 F F F 3/24 N 398.87 5 0.239 F
II
117 CI N \-NQ N 3/25 N, 0- 410.902 1.8 0.040 CI N N N 3/26 N S 426.969 1.5 0.090 0 3/27 N, Cl 394.903 4.5 0.217 0 N N N N * 374.485 7 0.269 3/28 N N N 3/29 NP 388.512 5 0.452 0 \ N N 3/30 N' 388.512 2.9 0.729 118 N N N 3/31 N , CI 394.903 1.3 0.140 N N N 3/32 N \ / 410.518 3 0.556 N N, N 3/33 O N - 394.903 3 0.170 CI Cl o N - - N - 3/34 N CI 415.322 2.5 0.526 N N3/35-N N 3/36 C 415.322 1.8 0.119 CIl 119 O N NN N 3/37 F 398.867 20 1.436 CI 0 IN N N N-N N 3/38 398.867 6 0.338 F Cl 0 N N-N N 3/39 410.902 25 0.734 0 Cl / Cl N N N 3/40 N. 380.876 3 0.775 N N N F 3/41 0 - 364.421 6.5 0.2940 N NN N 3/42 0 360.458 5 0.0850 N N N 3/43 0 N N- 390.484 9 0.2290 120 N N N 3/44 360.458 2 0.0470 N N N 3/45 N' O 390.484 3 0.0730 N N / N\ L 3/46 N F FF 428.455 8 0.1970 0F F N N \ /_ F N 3/47 N, 378.448 8 0.3120 0 N N /- 3/48 N 374.485 5 0.1180 0 -- 3/49 Ns O- 390.484 1 0.0079 121 N0 -- N N N N- 3/50 N 374.485 1.5 0.0061 0 N N 3/51 N S 406.551 2 0.0370 0 \N N -C 3/52 N 394.903 13 0.2560 Cl N N 3/53 N N-. '408.930 1.2 0.0520 CI 0 N N N 3/54 N0 0 424.929 1 0.1170 0 N N N 3/55 N F 428.455 5.5 1.3500
-FF
122 0 N N - N 0 N N N-N N 3/57 378.448 4 10.514 4.5 3.9370 F 0 N N N-N N 3/58 S 414.481 5.7 4.9750 F 0 N N-N KN 3/59 41428.892 1 .3 0.00869750 F N N-N N C 3/60 O428.892 1.3 0.0086 F F o N N N 3/61 N. F 432.419 25
FF
123 F N 3/62 N 422.457 6 0.0710 0 N N-N N 3/63 394.447 0.9 0.0190 F O CI 3/64 N 408.930 25 Cl N N- / CI N 3/65 N Cl 449.767 1.3 0.0730 Cl 0 N - N N 3/66 N 408.930 2 0.0730 Cl N N 3/67 Ns 394.903 2.7 0.1270 124 CI N N 3/68 N, ... / N 408.930 1.5 0.0360 CI N N N / Cl N 3/69 N, 415.322 18 0.3470 CI Cl N N N 3/70 N N N0 429.348 12.5 CI O N N \/NP 3/71 N 424.929 2.5 0.2200 Cl CI O N N N 3 F 3/72 N-,. FF 448.874 7 0.1430 Co 0 N N 3/73 0-.. 410.902 2.5 0.1110 125 CI - 0 N/-\
N
N N N 3/74 N 394.903 7.5 0.2980 NO N N 3/75 N 445.347 17 0.4680 N N Cl 3/76 N- CI 429.348 3 1.0810 0 N 3/77 N 388.512 25 -0 N / \ N NN N 3/78 N . 374.485 25 N N 3/79 N 388.512 25 126
-
0 N
--
\ N N N ~O 3/80 N 390.484 5 0.0780 0 N 3/81 N-N N cl 0 N00 3/8 445.347 3.5 0.2950 CI 0 N N 3/82 N 406.483 1.2 0.0083 N OF N 3/83 O 39410.902 1.5 0.190066 I O N N N-.. F 3/84 F F 414.428 5.5 0.1760 0 '- N NNN 3/85 F O 394.447 3 0.1890 127 O 0 '-N N-N N 3/86 F 392.475 12.5 0.385 0 NN 3/87 F 378.448 15 0.2380 0 N N N N Cl 3/88 F O 428.892 6 0.0605 I N N-N N 3/89 F 364.421 2.2 0.0140 0 N N-N N 3/90 \ FO ," 394.447 3 0.0330 I 0 O N N-N N 3/91 F 432.419 1.5 0.0140 F F 0 N-NN 3/92 F -F 382.412 12.5 0.1580 128 0 N- N O N-N N 3/93 F - Cl 433.312 1.7 0.0320 CI O N N-N N 3/94 F 392.475 0.8 0.0320 0 N N-N N 3/95 F 392.475 3 0.1640 0 N N-N N 3/96 F 3/96 F 394.447 1.8 0.0036 O 0 N N- N N 3/97 \ F S -'"I: 410.514 3 0.0830 I 0 N- N N- N N 3/98 F 0408.474 7 0.1570 129 0 N N-N N 3/99 FC 1 433.312 2 0.0410 CI 0 N N-N N 3/100 F O 422.457 < 25 0 O0 0 N-N N 3/101 364.421 5 0.5690 F 0 N N-N N 3/102 0 394.447 13 0.1810 F 0 N N-N N 3/103 392.475 21 F 0 -- N NKN 3/104 392.475 5 0.2850
F
130 -o 0 \ N\ 0 3/105 406.483 4.5 0.1180 O N N-N N 3/106 cl 445.347 7 0.9850 0 Cl / 0 N N- N N 3/107 N 347.419 12.5 0 N N-N \ N 3/108 N 374.485 3.5 O N N N 3/109 N ' 374.485 8 4.3300 Cl QONN C N /_ C 3/110 N, 415.322 0.2987 131 N - N 2 N374.485 0.6 0.1600 16 F N N N N 3/111 N' 364.421 12.5 CI O N N N 3/112 N 380.876 15 1.5240 N N. d cl N N CI N 3/113 N '429.348 1.2 0.0750 O N N N- 3881 3/114 N' 388.512 0.8 I I 132 0 - 0 1 N N 3/115 N N \ 404.511 20 ICI C 3/116 I' , 429.348 3 0.1410 N-.. F Cl OOp N N N " 3/117 - 412.893 7 F 3/118 N
-
408.474 25 N--. F CI Cl O N N N 3/119 1. 433.312 3.1 0.5620 Cl 0 N N~~ \-- / 3/120 / 0 410.910 0.040 ,o "£ .
x ,~ooN 133 Cl 0 N N 3/121 F 448.874 3.3 0.0510 F F Cl O N N \ 3/122 N 408.930 7.5 Cl N N \/ 3/123 1 394.903 3.3 0.051 N N \ CI 0 \N / \ / N O N N 3/125 N 449.767 12.5 0.1480 N N 3/126 N, 448.874 25 8.7350 134 CI CI N N N N~ N \-/ N-0 3/127 N, -o 445.347 1.8 Cl O N N N \- N 3/128 \ F 448.874 12 0.9010 FF Cl C C ON N 0 o\ /-- \ N 3/129 N ~ 449.767 < 25 2.5580 N N N / \ -0 3/130 N, O 390.484 < 25 o I
I
N \ - N- F N N 3/131 NF 428.455 3.1 0.1350 0 N N N 3/132 N'\ 429.348 20 3.0980 135 0O" 0 N N N \-- / 3/133 / F 444.454 6.2 0.2140 FF 0"I O N N 3/134 / 390.484 4.3 N\ 0 0 N N 3/135 \ 404.511 6 0.3210 O"" o NN N/3 NN-/N 3/136 1 404.511 12.5 0.9320 N N N 0~ 3/137 422.550 4.2 N N N 3/138 \ 426.517 < 25 19.9550
N
136 0O 3/139 N cl Cl 445.347 < 25 1.3490 0 ~ N O"I 3/140 N o 434.500 < 25 2.9680 / N N N 3/141 392.475 7 0.0660 N N F/ N 3/142 392.475 3.8 0.1100 O N N F I 3/143 414.481 2.5 0.1400 0 F N-o 3/144 394.45 9.5 0.2550 0 IP N N \/N F N 3/145 F F 432.419 10 1.5060 137 F N N c Ns cl 3/146 433.312 1.3 0.0430 F o, - , . N N \/NP 3/147 N 378.448 7 1.2920 F O N N N 3/148 N 392.475 1.5 0.1980 / 0 O C cl 3/149 N 440.928 7.5 CI N 5 366.850 1.2 0.0041 CI 0N /-\N-d N 6 ' 2 365.862 1.2 0.0382 0 N N \ N 3/150 N. 361.446 1.1 0.0055 138 Cl N N N / NL 3/151 N 394.903 1.7 0.0221 F N N Ns 3/152 N 364.421 0.8 0.0063 N N N \- N N. 3/153 347.419 2.2 0.0224 Cl 0
N-
N N E2 N 415.32 1.5 0.0001
N
o N N N E3 \ 399.50 25 N CI 0 O N N- E4 N 381.87 1.3 0.0047 139 O N-N 0 NN \ / N \Z -< E5 / 391.43 0.8 0.0030 N\ Br 0 /__\ N N \/N Ns E6 N"- 425.33 0.9 0.0012 CI S N\-/ N Ns E7 N. 396.92 1.4 0.0110
O
ON N N. E8 N" 377.45 2 N 0 N N N E9 N' 361.45 3 0.0531 0 N N N _ E10 N 371.44 0.9 0.0049 Q 0 N / NN F El NN O+F 430.43 1 0.0120
F
140 O0 N , E12 390.44 2.3 0.0031 0 N N NO N E13 362.43 1 0.0142 CI cl N N N \- / NF E14 N 480.91 12 3.079 0 0 0 N N N Ns E15 cl 434.94 14 0.2387 cI 0 N
-
-
NO N N / Ns E16 N 394.90 1.5 0.0390 0 N N N) E17 397.48 1.5 0.0085 E4 80 N El18 0 403.48 1.2 0.0595 141 0N N \--/ N _-- N N N N E19 348.41 6 0.040
O
0 N NN-- N i \ 0 E20 N 406.48 0.29 0.0015 N N N E21 347.42 9.5 0.1982 N 0- / E22 381.87 1.9 0.0064 0 N N NN N x,__/_/ N E23 0 389.46 0.32 0.010 Q N /o.\ E24 - 422.53 1.7 0.3119 o E25 438.53 6 0.5602 142 0 N N N E26 424.52 6.4 0.1351 N O o o 0 E27 446.55 22.5 0o N- \-N \/ N 0 0 E28 418.49 3.4 0.0606 N N / N_ E29 390.44 0.46 0.0095 0 N N N E30 404.47 0.42 0.0021 0 Nl~ N N \- N N E31 361.45 1.5 0.0208 0 N /r
-
\-4 N N N N.N E32 451.47 3.1 0.5135 143 0 N N N / N CI E33 381.87 0.9 0.0089 0 N--\N _ O N N N E34 375.47 0.8 0.0140 0 o N NN-9 D N N 0 0 E35 477.52 5.5 N
-
N N N ' \ \c-I\ ° NC E37 387.89 2 0.0377 \N 0 N N / N 0/ N N E39 390.48 2.5 0.0719 144 0 -r
-
0 V/0\_/ N N N. E40 0 433.51 1.6 0.1185 N N N N\-/ \ / E41 397.48 4.5 0.0894 F N N Fcl E42 N 416.86 2.09 0.0502 F / \FO { F F, N N .
E43 F ci 452.84 2.17 1.4635 CI /\ o N N E44 cl cl 449.77 1.68 0.2357 z 0
N
N N Cl E45 394.90 0.99 0.0105 0E1 N N E46 332.41 14.5 1.2360 _ ____ 145 - N N E47 ci 408.93 1.55 NN ,-- __q N c E48 386.92 3.26 0.4895 0 0 I ONN C
N
N E49 N c 425.87 20.2 N Cl F F F /\o 0 N N N E50 / \ cl 448.87 25 - N N E51 0- 427.93 1.3 2.2980 NO N C E52 381.87 1.41 0.0102 146
O
00 N N N N E53 407.47 0.62 0.0111 0 N/ -F N N N\ N) N E54 365.41 14.2 1.0370 0 N- N N N / N C E55 F F 459.86 3.6 1.3370 F
O
N- 0
/---\N
N N N N
O
E56 F F 485.46 1.1 0.1450 F Q 0 NN E58 N N\ E58 365.41 1 0.0411 147 N N Br N C E59 459.77 2.1 0.1040 0 N N CI E60 396.88 1.37 0.0117 0 N N N N \-J N N CI E61 473.96 2.3 6.0900 0 NO N N/ N~ \ \--/ \ N O-N E62 o 391.43 13.5 Q 0
/\
N N l\\ E63 N374.49 0.6 0.0022 Br 0 N-- N _ N N E64 N cl 524.64 3.5 Br 0 N N CI E65 445.75 1.7 0.0106 Br 148 NI \l N CI E66 442.95 3.7 1.828 N N E67 443.94 2.3 0.2370 N /' \ \~ N N N CI E68 448.98 1.4 0.3390 S N N N CI E69 448.98 1.7 6.1540 s N / N \-j cI E70 394.86 1.3 0.0108 O
O
N O N N4 5 4 0N. E71 NN 434.54 3.74 0.2000 149 Cl N N N E72 398.87 1.55 0.0066
O
0 N N E73 N 422.48 0.99 0.0069 O 0 N N N 0 E74 H C F- 448.90 F 0 N N N N Cl E75 460.97 5.1 0.0612 N Br 0 0 \\ c a/ NE CI N E76 N ~ ~~~Br47.919035 0 -0 N N N -/ / E77 N c 466.76 0.7 0.0267 150
O
\ 0 N N \-/N E78 N 564.28 13.98 0.3180 Br Br Br N N Br N C E79 545.66 2.2 1.0380 0 N NN CI N E80 487.00 4.4 1.1260 0 Br 0 N N \ \ 0 N E81 550.25 17.1 Br 0 i 0 N N E82 N, 471.34 0.94 0.0018 Br o / N .N N o 0 0 N N0 E83 475.55 20 151 0 -/- _ N N O/ E84 426.94 0.65 0.0029
O
0 \ N- N /N i \ 0\ E85 N 474.58 1.39 0.1807 S
O
0 N N I \ 0 E86 N 432.52 0.87 0.0068
O
0 N NO E87 N 512.58 1.26 1.2830 F 0 0 N N E88 486.54 4.53 1.2570
F
152
O
0 N -0 N N N \ _ _ E89 N536.55 3.42 1.0980 F FF F
O
0 N N N 0-~ E90 458.53 1.73 0.0188
SO
0 N / \N E91 N N 457.53 1 0.0105 N 0 N N N \- / I \ 0 E92 N 392.46 1.16 0.0010 0 E93 N, O 461.56 2.02 0.0063
N
153
O
0
--
O -N N N 0 E94 435.48 0.9 0.0020 N I O 0 0 o
SO
E95 N 435.48 0.8 0.00017 NO
O
0 0 i \ 0 E96 N 477.56 11.37 0.0733 N 0 _ _ N J5 o /- / N N N E97 0 390.44 3.6 0.0811
O
EN N\/N N O0 / o\ I98\ 0 E98 497.60 1.4 0.2230
N-_,,
154
O
N N N /o__ i \ \ 0 E99 N 407.47 1 0.0024 N
O
S N N /._.0 E100 420.47 0.5 0.0041 0 0 E101 c 472.97 25 O 0 N N NN j/ N Cl E102 489.04 18 S N N N N N O E103 405.50 1 0.0167 N N Q\2I 's N ' E104 352.46 8 0.8389 EN, ON 6\ / N N N E105 404.51 3.6 1.6510 155
O
0 N N \-jN0 I \ 0 E106 N 0 477.56 10 0.1419 O 0 0 N N \ -jN N E107 0 388.47 1.4 0.0104 N N N O O %,J N E108 434.49 0.9 N O E109 418.54 5.2 8.0450 / o - /NN QJN N N N'-Cl E110 483.01 12 1.1661 F N N F \ F E111 N " 400.40 2.33
\I
156 0 0
-
I \ 0 N E112 490.56 3 0 O N N N N E113 0 449.51 9.2 0 O
O
0 /-\ 0 N N E114 502.59 12.9 0 o O N N N SDI N\ E115 353.45 < 25 3.2370 N N E16 403.48 2.07 0.0113 E116 403.48 2.07 0.0113 157 0 O 0 N N /' \ o-/ \ El 17 N 460.45 7.9 0.0284 F F F 0 N N E118 434.85 2.3 0.4030 F F F 0 E119 0 443.43 1.2 0.0103 F F F 0 0
--
N N i, -I \ 0 E120 421.50 17.9 N 0 0 SN
N-
N / \ 0 E121 o-. 505.57 0.9 158
O
0 /-- -0 0 N
\
E122 N o N 0 493.56 1.2
O
0 SN N o E123 468.53 2.5 -F o N N 0 E124 "490.60 < 25 /0 E125 N 450.54 4.1 0
O
0 N N \jN0 i \ -/0 E126 N 476.53 0.8 O O 159 0 0 N/ \ -O N N N / \ 0 E127 N 436.51 2.3 O N N E128 0 433.51 3.0 0.1196
O
0 N N / \ 0 E129 N447.54 0.9 N
O
N N S\ v\ 0 E130 N 447.54 1.5 N 0 N N N o E131 498.58 < 25 0
Q/
E132 / \ o 376.48 0.9
NI.
160 0 N N E133 0 375.43 1 0 N N N E134 / \ N 405.46 3.2 N 0 0 0 E135 N 0 - N o 431.95 0.5 N
O
lN 0 N NN '/- N 0 N N /o\_/ E137 N 537.66 3.2 N O 0 o Q 0 E138 N NN 475.59 22 _ 0_O
N
161 0 \// \o E139 428.43 2.9 N F O F 0 q N O N3 E140 363.41 16.5

Claims (9)

1. A product corresponding to Formula (I) below: R3 R4 / X N L, R1 R2 (1) in which: 5 R1 and R2 are selected independently from the group consisting of aryl, heteroaryl, substituted aryl and substituted heteroaryl; R2 may also be chosen from the group (C5-C7) cycloalkyl; L is selected from the group consisting of C(R7)(R8), C=0, C=S, and C=N(R7); 10 R3 is selected from the group consisting of H, halogen, CF3, alkyl, substituted alkyl, alkylene, substituted alkylene, alkynyl, substituted alkynyl, cycloalkyl, cycloalkylene, heterocyclyl, substituted heterocyclyl, CO-R7, C(R7)=N-O(R8), COOH, CONH-aryl, CONH-heteroaryl, CONH R7, CON(R7)(R8), CO-N(R7)-aryl, CO-N(R7)-heteroaryl, C(OR7)=NH, 15 C[N(R7)(R8)]=NH, NH2, NH-aryl, NH-heteroaryl, NH(R7), N(R7)(R8), NH CO-R7, N(R7)-CO-aryl, N(R7)-CO-heteroaryl, NH-SO2-R7, NH-SO2-aryl, NH-SO2-heteroaryl, NH-CH2-CO2(R7), NH-CH2-aryl, NH-CH2-heteroaryl, NH-COO-(C1-C4)alkyl, NH-CH2-(C2-C3)alkylene, NH-CH2-(C2 C3)alkynyl, N(R7)-N(R8)(R12), N-N=C(R7)(R8), CN, O-R7, O-CH2-aryl, 20 O-CH2-heteroaryl, S-R7, SO-R7, SO 2 -R7, aryl, heteroaryl, substituted cycloalkyl, substituted aryl and substituted heteroaryl; R4 is selected from the group consisting of H, (C1-C3)alkyl, cyclopropyl, (C2-C3)alkylene, (C2-C3)alkynyl, O(C1-C3)alkyl, S-(C1-C3)alkyl, F, CI and Br; 25 X is N or CH; R7, R8 and R12 are independently selected from the group consisting of H, (Cl-C3)alkyl and substituted (Cl-C3)alkyl; L-G-R1 is selected from the group consisting of: 163 R5 R5 R5 -/+-\R1 L-N N-R1 L-N / Ri L-N R9 R6 R6 R6 - L and R1 are as defined above; - R5 and R6 are selected independently from the group consisting of H, (C1-C3)alkyl, oxo and halogen; and
5- R9 is (C1-C3)alkyl; in racemic form, enriched in one enantiomer, enriched in one diastereoisomer, its tautomers, its prodrugs and its pharmaceutically acceptable salts, with the proviso that the product of formula (I) is not one of the following compounds: / N OMe NoN I o 0~ N 10 2. The product as claimed in claim 1, characterized in that X is N. 3. The product according to claim 1 or 2, characterized in that L-G-R1 is R5 L-N N-R1 R6 in which R5 and R6 are each H. 15 4. The product as claimed in any one of claims 1 to 3, characterized in that R1 is chosen from: - phenyl; - phenyl substituted with at least one radical chosen from halogen, (Cl C3)alkyl, CON(R10)(R11), O-R10, S-R10 and N(R10)(R11); 164 - pyridyl; - pyridyl substituted with at least one radical chosen from halogen, (Cl C3)alkyl, CON(R10)(R11), O-R10, S-R10 and N(R10)(R11), in which R10 and R11 are chosen independently from H, (C1-C3)alkyl and 5 halogenated (C1-C3)alkyl. 5. The product as claimed in claim 4, characterized in that R1 is chosen from: - phenyl substituted with halogen, (C1-C3)alkyl, (C1-C3)alkoxy or carboxamide, 10 - 2-pyridyl or 3-pyridyl, - 2-pyridyl or 3-pyridyl substituted with halogen or (C1-C3)alkyl.
6. The product as claimed in claim 5, characterized in that R1 is phenyl substituted with: - a chloro radical, or 15 - one or two methoxy radicals, or - a carboxamide radical.
7. The product as claimed in any one of claims 4 to 6, characterized in that R1 is chosen from 2,3-disubstituted phenyl, 2,5-disubstituted phenyl, 3-substituted phenyl, 3,5-disubstituted phenyl and 3,4-disubstituted phenyl. 20 8. The product as claimed in claim 5, characterized in that R1 is chosen from 4-substituted 2-pyridyl, 6-substituted 2-pyridyl, 4,6-disubstituted 2-pyridyl, 2- substituted 3-pyridyl and 5-substituted 3-pyridyl.
9. The product as claimed in claim 1, characterized in that R2 is chosen from phenyl, 3-pyridyl, phenyl substituted with at least one radical chosen 25 from halogen, alkyl, O-R10, S-R10 and N(R10)(R11), in which R10 and R11 are independently chosen from H, (C1-C3)alkyl and halogenated (Cl C3)alkyl.
10. The product as claimed in claim 1, characterized in that R3 is chosen from H, (C1-C3)alkyl, CF3, hydroxymethyl, amino, azetidino and pyrrolidino. 30 11. The product as claimed in claim 10, characterized in that R3 is chosen from methyl, hydroxymethyl, CF3 and amino. 165
12. The product as claimed in claim 1, characterized in that R4 is H.
13. The product as claimed in claim 1, characterized in that it is chosen from: - (3,5-Dimethyl-1l-phenyl-1 H-pyrazol-4-yl)(4-phenylpiperazin-1-yl)methanone 5 - (3,5-Dimethyl-1 -phenyl-1 H-pyrazol-4-yl)[4-(2-methoxyphenyl)piperazin- 1 yl]methanone - (3,5-Dimethyl-1 -phenyl-1 H-pyrazol-4-yl)[4-(3-trifluoromethylphenyl)piper azin-1-yl]methanone - (3,5-Dimethyl-1 -phenyl-1 H-pyrazol-4-yl)[4-(4-fluorophenyl)piperazin-1 -yl] 10 methanone - 1-{4-[4-(3,5-Dimethyl-1 -phenyl-1 H-pyrazole-4-carbonyl)piperazin-1-yl] phenyl}ethanone - [4-(2,4-Dimethylphenyl)piperazin-1 -yl](3,5-dimethyl-1-phenyl-1 H-pyrazol-4 yl)methanone 15 - [4-(3,4-Dichlorophenyl)piperazin-1-yl](3,5-dimethyl- 1 -phenyl-1H-pyrazol-4 yl)methanone - [4-(3,4-Dimethylphenyl)piperazin-1 -yl](3,5-dimethyl-1-phenyl-1 H-pyrazol-4 yl)methanone - (3,5-Dimethyl-1 -phenyl-1 H-pyrazol-4-yl)(4-o-tolylpiperazin-1 -yl)methanone 20 - [4-(2,3-Dimethylphenyl)piperazin-1-yl](3,5-dimethyl-1l-phenyl-1H-pyrazol-4 yl)methanone - (3,5-Dimethyl-1 -phenyl-1 H-pyrazol-4-yl)[4-(2-ethylphenyl)piperazin-1-yl] methanone - [4-(3-Chlorophenyl)piperazin-1 -yl](3,5-dimethyl-1 -phenyl-1 H-pyrazol-4-yl) 25 methanone - (3,5-Dimethyl-1 -phenyl-1 H-pyrazol-4-yl)(4-m-tolylpiperazin-1-yl)methanone - (3,5-Dimethyl-1 -phenyl-1 H-pyrazol-4-yl)[4-(4-methoxyphenyl)piperazin-1 -yl] methanone - [4-(2,4-Dimethoxyphenyl)piperazin-1 -yl](3,5-dimethyl-1 -phenyl-1 H-pyrazol-4 30 yl)methanone - (3,5-Dimethyl-1 -phenyl-1 H-pyrazol-4-yl)[4-(2-methylsulfanylphenyl)piper azin-1-yl]methanone - [4-(4-Chlorophenyl)piperazin-1 -yl](3,5-dimethyl-1-phenyl-1 H-pyrazol-4-yl) methanone 166 - (3,5-Dimethyl-1 -phenyl-1 H-pyrazol-4-yI)(4-naphthalen-1 -ylpiperazin-1 -yi) methanone - [4-(5-Chloro-2-methylphenyl)piperazin-1 -yi](3,5-dimethyl-1 -phenyl-1 H pyrazol-4-yI)methanone 5 - (3 ,5-Dimethyl-1 -phenyl-1 H-pyrazol-4-yI )[4-(2-ethoxyphenyl )piperazin-1 -yI] methanone - [4-(2,3-Dichlorophenyl)piperazin-1 -yI](3,5-dimethyl-1 -phenyl-1 H-pyrazol-4 yI)methanone - (3 ,5-Dimethyl-1 -phenyl-1 H-pyrazol-4-yl)[4-(4-trifluoromethylphenyl)piper 10 azin-1 -yi]methanone - [4-(5-Chloro-2-methoxyphenyl)piperazin-1 -yI](3,5-d imethyl-1 -phenyl-1 H pyrazol-4-yI )meth anon e - [4-(4-Benzyloxyphenyl )piperazin-1 -yIJ(3 ,5-dimethyl-1 -phenyl-1 H-pyrazol-4 yI)methanone 15 - (3,5-Dimethyl-1 -phenyl-1 H-pyrazol-4-yI)[4-(2-trifl uoromethyl phenyl)pi per azin-1 -yI]methanone - 14-(2,3-Dihyd robenzo[1 ,4]dioxin-6-yI )piperazin- l-yI](3 ,5-d imethyl-1 -phenyl 1 H-pyrazol-4-yI)methanone - [2-(4-Methoxyphenyl)-5-methyl-2H-pyrazol-3-yI](4-phenylpiperazin-1 -yI) 20 methanone - [2-(4-M eth oxyp he nyl)-5-methyl-2 H-pyrazol1-3-yI] [4-(2-methoxyphe nyl)pi per azin-1 -yI]methanone - [2-(4-M eth oxyph enyl)-5-methyl-2 H-pyrazol -3-y] [4-(3-trifl uo rom ethyl phenyl) piperazin-1 -yljmethanone 25 - [4-(4-Fluorophenyl)piperazin-1 -yI][2-(4-methoxyphenyl)-5-methyl-2H pyrazol-3-yI]methanone - I -(4-{4-[2-(4-Methoxyphenyl)-5-methyl-2H-pyrazole-3-carbonyl]piperazin-1 yIlphenyl)ethanone - [4-(2,4-Dimethylphenyl )piperazin-1 -yII[2-(4-methoxyphenyl)-5-methyl-2H 30 pyrazol-3-yI] meth anone - [4-(3 ,4-Dichlorophenyl)piperazin-1 -yI][2-(4-methoxyphenyl)-5-methyl-2H pyrazol-3-yI]methanone - [4-(3 ,4-Dimethylphienyl)piperazin-1 -yI][2-(4-methoxyphenyl)-5-methyl-2H pyrazol-3-yI] meth anone 35 - [2-(4-Methoxyphenyl)-5-methyl-2H-pyrazol-3-yI](4-o-tolypiperazin-1 -yI) methanone 167 - [4-(2 ,3-Dimethylphenyl )piperazin-1 -yI][2-(4-methoxyphenyl)-5-methyl-2H pyrazol-3-yI]methanone - [4-(2-Ethylphenyl)piperazin-1 -yI][2-(4-methoxyphenyl )-5-methyl-2H-pyrazol 3-yI]methanone 5 - [4-(3-Chlorophenyl)piperazin-1 -yI][2-(4-methoxyphenyl )-5-methyl-2H pyrazol-3-yI]methanone - [2-(4-Methoxyphenyl)-5-methyl-2H-pyrazol-3-yI(4-m-tolylpiperazin- l-yI ) methanone - [2-(4-M eth oxyp hen yl)-5-methyl-2 H-pyrazol-3-yI] [4-(4- methoxyp he nyl ) 10 piperazin-1 -yI]methanone - [4-(2 ,4-Dimethoxyphenyl)piperazin-1 -yI][2-(4-methoxyphenyl)-5-methyl-2H pyrazol1-3-yI] metha none - [2- (4- Methoxyp henyl)-5-m ethyl -2 H-pyrazol-3-yiI [4-(2-meth ylsulfa nyl phenyl) piperazin-1 -yI]methanone 15 - [4-(4-Chlorophenyl)piperazin-1 -yI][2-(4-methoxyphenyl )-5-methyl-2H pyrazol-3-y] methanone - [2-(4-Methoxyphenyl)-5-methyl-2 H-pyrazol-3-yI](4-naphthalen-l1-ylpiperazin 1 -yl)methanone - [4-(5-Chloro-2-methylphenyl)piperazin-1 -yI][2-(4-methoxyphenyl)-5-methyl 20 2H-pyrazol-3-yI]methanone - [4-(2-Ethoxyphenyl)piperazin-1 -yI][2-(4-methoxyphenyl)-5-methyl-2H pyrazol-3-yI]methanone - [4-(2,3-Dichlorophenyl)piperazin-1 -yI][2-(4-methoxyphenyl)-5-methyl-2H pyrazol-3-y] meth anone 25 - [2-(4-Methoxyphenyl)-5-methyl-2H-pyrazol-3-y][4-(4-trifluoromethylphenyl) piperazin-1 -yI]methanone - [4-(5-Chloro-2-methoxyphenyl)piperazin-1 -yI][2-(4-methoxyphenyl)-5-methyl 2 H-pyrazol-3-yI]methanone - [4-(4-Benzyloxyphenyl )piperazin-1 -yI][2-(4-methoxyphenyl)-5-methyl-2H 30 pyrazol-3-yI] meth an one - [2-(4-Methoxyphenyl)-5-methyl-2H-pyrazol-3-yi4-(2-trifluoromethylphenyl) piperazin-1 -yI]methanone - [4-(2 ,3-Dihyd robenzo[1 ,4]dioxin-6-yI)piperazin-1 -yI][2-(4-methoxyphenyl)-5 methyl-2H-pyrazol-3-yllmethanone 35 - [2-(3-Methoxyphenyl)-5-methyl-2H-pyrazol-3-yI](4-phenylpiperazin-1 -yI) methanone 168 - [2-(3-Methoxyphenyl)-5-methyl-2 H-pyrazol-3-yl][4-(2-methoxyphenyl)piper azin-1-yl]methanone - [2-(3-Methoxyphenyl)-5-methyl-2H-pyrazol-3-yl][4-(3-trifluoromethylphenyl) piperazin-1 -yl]methanone 5 - [4-(4-Fluorophenyl)piperazin-1-yl][2-(3-methoxyphenyl)-5-methyl-2H pyrazol-3-yl]methanone - 1-(4-{4-[2-(3-Methoxyphenyl)-5-methyl-2H-pyrazole-3-carbonyl]piperazin-1 yl}phenyl)ethanone - [4-(2,4-Dimethylphenyl)piperazin-1-yl][2-(3-methoxyphenyl)-5-methyl-2H 10 pyrazol-3-yl]methanone - [4-(3,4-Dichlorophenyl)piperazin-1-yl][2-(3-methoxyphenyl)-5-methyl-2H pyrazol-3-yl]methanone - [4-(3,4-Dimethylphenyl)piperazin-1-yl][2-(3-methoxyphenyl)-5-methyl-2H pyrazol-3-yl]methanone 15 - [2-(3-Methoxyphenyl)-5-methyl-2H-pyrazol-3-yl](4-o-tolylpiperazin-1-yl) methanone - [4-(2,3-Dimethylphenyl)piperazin-1-yl][2-(3-methoxyphenyl)-5-methyl-2H pyrazol-3-yl]methanone - [4-(2-Ethylphenyl)piperazin-1-yl][2-(3-methoxyphenyl)-5-methyl-2H-pyrazol 20 3-yl]methanone - [4-(3-Chlorophenyl)piperazin-1-yl][2-(3-methoxyphenyl)-5-methyl-2H pyrazol-3-yl]methanone - [2-(3-Methoxyphenyl)-5-methyl-2H-pyrazol-3-yl](4-m-tolylpiperazin-1-yl) methanone 25 - [2-(3-Methoxyphenyl)-5-methyl-2H-pyrazol-3-yl][4-(4-methoxyphenyl)piper azin-1-yl]methanone - [4-(2,4-Dimethoxyphenyl)piperazin-1-yl][2-(3-methoxyphenyl)-5-methyl-2H pyrazol-3-yl]methanone -[2-(3-Methoxyphenyl)-5-methyl-2H-pyrazol-3-yl][4-(2-methylsulfanylphenyl) 30 piperazin-1 -yl]methanone - [4-(4-Chlorophenyl)piperazin-1-yl][2-(3-methoxyphenyl)-5-methyl-2H pyrazol-3-yl]methanone - [2-(3-Methoxyphenyl)-5-methyl-2H-pyrazol-3-yl](4-naphthalen-1-ylpiperazin 1-yl)methanone 35 - [4-(5-Chloro-2-methylphenyl)piperazin-1-yl][2-(3-methoxyphenyl)-5-methyl 2H-pyrazol-3-yl]methanone 169 - [4-(2-Ethoxyphenyl )piperazifl-1 -y] [2-(3-m ethoxyph efnl)-5-fl'ethylI-2H pyrazol-3-yI] meth anone - [4-(2 ,3-Dichlorophenyl)piperazifl-1 -y][2-(3-methoxyphenyI)-5-mlethyI-2H pyrazol-3-y] methanone 5 - [2(-ehxpey)5mty-Hprzl3y]4(-rfurmtypey) piperazin-1 -yI]methanone - [4-(5-Choro-2-methoxypheny)piperazil-1 -y][2-(3-methoxyphel)-5-methyI 2H-pyrazol-3-yI]methalofe - [4-(4-Benzyloxyphefl)piperazin-1 -y][2-(3-methoxyphefl)-5-methyl- 2 H 10 pyrazol-3-yI]methaflofe - [2(-ehxpey)5mty-Hprzl3y]4(-rfurmtypey) piperazin-1 -y]methanone - [4-(2,3-Dihyd robenzo[1 ,4]dioxin-6-yI)piperazifl-1 -yi[2-(3-methoxyphel)-5 methyl-2H-pyrazol-3-ylllmethaflofe 15 - (5-MethyI-2-phenyI-2H-pyrazoI-3-yI)(4-pheflpiperazifll -yI)methanone - [4-(2-Methoxyphenyl)piperazifl-1 -y](5-methyI-2-pheny-2H-pyrazoI-3-yi) methanone - (5Mty--hnl2-yao--l[4(-rfurmtypey ieai yllmethanone 20 - [4-(4-Fluorophelyl)piperazifl-1 -yl](5-methyI-2-phefl-2H-pyrazol-3-yl)meth anone - I 4[-5Mehl2peyl2-yaol--abnl ieai--yI]-phenyl} ethanone - [4-(2 ,4-Dimethylphenyl)piperazifl-1 -yII(5-methyI-2-pheny-2H-pyrazoI-3-yi) 25 methanone - [4-(3,4-Dichlorophenyl)piperazifl-1 -yII(5-methyI-2-pheny-2H-pyrazoI-3-yi) methanone - (5-MethyI-2-phenyI-2H-pyrazoI-3-yI)(4-o-toIyIpiperazifll -yI)methanone - [4-(2,3-Dimethylphenyl)piperazifl-1 -yi](5-methyl-2-phenyl-2H-pyrazoI-3-yI) 30 methanone - [4-(2-Ethylphenyl)piperazifl-1 y]5mty--hnl-Hprzl3y~eh anone - [4-(3-Chlorophenyl)piperazifl-1 -y](5-methyI-2-pheny-2H-pyrazoI-3-yI)methW anone 35 - [4-(3-Methoxyphenyl)piperazifl-1 -y](5-methyl-2-pheny-2H-pyrazoI-3-yi) methanone 170 (5--M ethypheny- Hpyrazonl -yi)(4-mtlyI pipe zn- y~mHpra oney ~( 4 -( 24 -DMethoxypheny)piperazin1 -y)( 5 -methyI-2,pheny2Hpyrazo 3 y) ( 5 m eth i 2 PenkHoaony)42 ehysea y ph fy~i e ai -[ 4 -(2 4 -hltoro phenyl)piperazin-1yU)( 5 -methy2pheny2Hpyrazo3) 5 anyone 10 - ( 5 -Methyi-2-phenyl;2H-pyrazol-3y)[(2-mhhi -faylphnpiperazin-lt aotne n - [ 4 -(4-Chlorn metylipezn-yl](ipei -I(-mety2HpheyzlHpylrazo aIomehnn 10 - f(-Ethoy2pheny2prazol-3yII(-meth2.pen1yi2Hprazoin-1 ) meth - [ 4 -(5~-DChoromyphenyipen - l( 5 -methy2-pheny2H-pyrazo 3 ylmethanone 20 [ 4 -(2-E~r.mthoxypheny in- pip]5etl -I(-ety2-phyraz Hp3yrazo, - [ 4 -(4,-enzyloyphenyl )piperazin-1 l-YI(5-methyI2-phenyI2 H-pyrazol-3y}. methanone - [4(2 -Dhyd robhenylo[1 py]dioxi-6.yI)pjperai-1 -YI](metheyl2-perny- 2 pyraoIlImethanone
20- N- 4 -(45-l.o2meth2pheny Hpyprazien3crbyl](petyn -y-phenyl-zl methanesuafonae - [4-(4 2 BFnuoroxphnyi)5..methyiHpyraI 3 IJ( *nyl2H- yImt-3-l anyone 30 - [4-(2,-Dihdroe nzo5 meth 2Hx n--lpY p ra3 1 -l 5mt l2pen2H - 2 ( 2 Fluorophenyl)-5.methy2H-pyraIol 3 -yj4-hn.Iprzi--lfeh azinhylyH netl-yI}- 171 - [4-(2 ,4-Dimethylphenyl )piperazin-1 -yI] [2-(2-fluorophenyl)-5-methyl-2 H pyrazol-3-yllmethanone - [4-(3,4-Dichlorophenyl)piperazin-1 -yI][2-(2-fluorophenyl)-5-methyl-2H pyrazol-3-yI]methanone 5 - [4-(3 ,4-Dimethyl phenyl )piperazin-1 -yI] [2-(2-fluorophenyl)-5-methyl-2H pyrazol1-3-yi] meth anone - [2-(2-Fluorophenyl )-5-methyl-2H-pyrazol-3-yi](4-o-toly piperazin-1 -yI ) methanone - [4-(2 ,3-Dimethylphenyl )piperazin-1 -yI][2-(2-fluorophenyl)-5-methyl-2H 10 pyrazol-3-yI]methanone - [4-(2-Ethylphenyl)piperazin-1 -yI][2-(2-fluorophenyi)-5-methyl-2H-pyrazol-3 yI] methanone - [4-(3-Chlorophenyl)piperazin-1 -yI][2-(2-fluorophenyl)-5-methyl-2H-pyrazol-3 yI]methanone 15 - [2-(2-Fl uorophenyl)-5-methyl-2 H-pyrazol-3-yl] [4-(3-methoxyphenyl)pi per azin-1 -yI]methanone - [2-(2-Fluorophenyl)-5-methyl-2H-pyrazol-3-yI](4-m-tolylpiperazin- 1-yl)meth anone - [2-(2-Fl uorophenyl)-5-methyl-2 H-pyrazol-3-yI] [4-(4-methoxyphenyl)pi per 20 azin-1 -yI]methanone - [4-(2,4-Dimethoxyphenyl)piperazin-1 -yI][2-(2-fluorophenyl)-5-methyl-2H pyrazol-3-yI]methanone - [2-(2-Fluorophenyl)-5-methyl-2H-pyrazol-3-yI][4-(2-methylsulfanylphenyl) piperazin-1 -yI]methanone 25 - [4-(4-Chlorophenyl)piperazin-1 -yI][2-(2-fluorophenyl)-5-methyl-2H-pyrazol-3 yI]methanone - [2-(2-Fluorophenyl)-5-methyl-2H-pyrazol-3-yI](4-naphthalen-1 -ylpiperazin-1 yl)methanone - [4-(5-Chloro-2-methylphenyl)piperazin-1 -yI][2-(2-fluorophenyl)-5-methyl-2H 30 pyrazol-3-yljmeth an one - [4-(2-Ethoxyphenyl)piperazin-1 -yI][2-(2-fluorophenyl)-5-methyl-2H-pyrazol-3 yI]methanone - [4-(2,3-Dichlorophenyl)piperazin-1 -yI][2-(2-fluorophenyl)-5-methyl-2H pyrazol-3-yI]methanone - [2-(2-Fluorophenyl)-5-methyl-2H-pyrazol-3-y][4-(4-trifluoromethylphenyl) piperazin-1 -yllmethanone 172 - [4-(5-Chloro-2-methoxyphenyl )piperazin-1 -yI] [2-(2-fl uo roph enyl )-5-m ethyl 2H-pyrazol-3-yllmethanone - [2-(2-Fluorophenyl)-5-methyl-2 H-pyrazol-3-yI][4-(2-trifluoromethylphenyl) piperazin-1 -yI]methanone 5 - [4-(2 ,3-Dihyd robenzo[1 ,4]d ioxin-6-yI)piperazin-1 -yi][2-(2-fluoropheny )-5 methyl-2H-pyrazol-3-yI]methanone - N-(4-{4-[2-(2-Fluorophenyl)-5-methyl-2H-pyrazole-3-carbonyl] piperazin-1 yI~phenyl)methanesulfonamide - [2-(3-Fluorophenyl )-5-methyl-2H-pyrazol-3-yI](4-phenylpiperazin-1 -yI )meth 10 anone - [2-(3-Fluorophenyl)-5-methyl-2H-pyrazol-3-yII[4-(2-methoxyphenyl)piper azin-1 -yI]methanone - [2-(3-FlIuo ro phe nyl)-5-methyl-2 H-pyrazol-3-y] [4-(3-trifl uoro meth yl phen yl) piperazin-1 -yI]methanone 15 - [2-(3-Fluorophenyl)-5-methyl-2H-pyrazol-3-yi][4-(4-fluorophenyl)piperazin-1 yI]methanone - I -(4-{4-[2-(3-Fluorophenyl)-5-methyl-2 H-pyrazole-3-carbonyl]piperazin-1 -yI} phenyl)ethanone - [4-(2 ,4-Dimethylphenyl)piperazin-1 -yI][2-(3-fluorophenyl)-5-methyl-2H 20 pyrazol-3-yi] meth anone - [4-(3,4-Dichlorophenyl)piperazin-1 -yI][2-(3-fluorophenyl)-5-methyl-2H pyrazol-3-yI]methanone - [4-(3 ,4-Dimethylphenyl )piperazin-1 -yI][2-(3-fluorophenyl )-5-methyl-2H pyrazol-3-yI]methanone 25 - [2-(3-Fluorophenyl)-5-methyl-2H-pyrazol-3-y](4-o-tolylpiperazin-1 -yI)meth anone - [4-(2,3-Dimethyiphenyl)piperazin-1 -yI][2-(3-fluorophenyl)-5-methyl-2H pyrazol-3-yll meth anone - [4-(2-Ethylphenyl)piperazin-1 -yI][2-(3-fluorophenyl)-5-methyl-2H-pyrazol-3 30 yljmethanone - [4-(3-Chlorophenyl)piperazin-1 -yi2-(3-fluorophenyl)-5-methyl-2H-pyrazol-3 yI]methanone - [2-(3-Fl uoro phenyl)-5-methyl-2 H-pyrazol-3-yI] [4-(3-methoxyphe nyl)pi per azin-1 -yI]methanone 35 - [2-(3-Fluorophenyl)-5-methyl-2H-pyrazol-3-yJ(4-m-tolylpiperazin-1 -yI)meth anone 173 - [2-(3-Fluorophenyl)-5-methyl-2 H-pyrazol-3-y] [4-(4-methoxyphenyl)pi per azin-1 -yI]methanone - [4-(2,4-Dimethoxyphenyl)piperazin-1 -yI][2-(3-fluorophenyl )-5-methyl-2 H pyrazol-3-yI]methanone 5 - [2-(3-FlIu oroph enyl)-5-methyl-2 H-pyrazol-3-yI] [4-(2-m ethyl su Ifa nyiph enyl ) piperazin-1 -y]methanone - [4-(4-Chlorophenyl)piperazin-1 -yI][2-(3-fluorophenyl)-5-methyl-2H-pyrazol-3 yI]methanone - [2-(3-Fluorophenyl)-5-methyl-2H-pyrazol-3-yI](4-naphthalen-1 -ylpiperazin-1 10 yI)methanone - [4-(5-Chloro-2-methylphenyl)piperazin-1 -yI][2-(3-fluorophenyl)-5-methyl-2H pyrazol-3-yl]methanone - [4-(2-Ethoxyphenyl)piperazin-1 -yII[2-(3-fluorophenyl)-5-methyl-2 H-pyrazol-3 yI]methanone 15 - 14-(2,3-Dichlorophenyl)piperazin-1 -yI]f2-(3-fluorophenyl)-5-methyl-2H pyrazol-3-yi] meth anone - [2-(3-Fluorophenyl)-5-methyl-2H-pyrazol-3-y][4-(4-trifluoromethylphenyl) piperazin-1 -yI]methanone - 14-(5-Chloro-2-methoxyphenyl)piperazin-1 -yl[2-(3-fluorophenyl)-5-methyl 20 2H-pyrazol-3-yI]methanone - [4-(4-Benzyloxyphenyl)piperazin-1 -yI] [2-(3-fluorophenyl)-5-methyl-2H pyrazol-3-yI]methanone - 12-(3-Fluorophenyl)-5-methyl-2H-pyrazol-3-yI][4-(2-trifluoromethylphenyl) piperazin-1 -y]methanone 25 - [4-(2,3-Dihyd robenzo[1 ,4Jd ioxin-6-yI)piperazin-1 -yI][2-(3-fluorophenyl)-5 methyl-2H-pyrazol-3-yI]methanone - N-(4-{4-[2-(3-Fluorophenyl)-5-methyl-2H-pyrazole-3-carbonyllpiperazin- yI~phenyl)methanesulfonamide - [2-(4-FluorophenyI)-5-methyI-2H-pyrazoI-3-yI](4-phenylpiperazin-1 -yI)meth 30 anone - [2-(4-Fl uorophenyl)-5-methyl-2 H-pyrazol-3-yI] [4-(2-methoxyphenyl)pi per azin-1 -ylllmethanone - [2-(4-Fluorophenyi)-5-methyl-2H-pyrazol-3-y][4-(3-trifluoromethylphenyl) piperazin-1 -y]methanone 35 - [2-(4-Fluorophenyl)-5-methyl-2H-pyrazol-3-y][4-(4-fluorophenyl )piperazin-1 yI]methanone 174 - 1-(4-{4-[2-(4-Fluorophenyl)-5-methyl-2H-pyrazole-3-carbonyl]piperazin-1-yl} phenyl)ethanone - [4-(2,4-Dimethylphenyl)piperazin-1-yl][2-(4-fluorophenyl)-5-methyl-2H pyrazol-3-yl]methanone 5 - [4-(3,4-Dichlorophenyl)piperazin-1-yl][2-(4-fluorophenyl)-5-methyl-2H pyrazol-3-yl]methanone - [4-(3,4-Dimethylphenyl)piperazin-1-yl][2-(4-fluorophenyl)-5-methyl-2H pyrazol-3-yl]methanone - [2-(4-Fluorophenyl)-5-methyl-2H-pyrazol-3-yl](4-o-tolylpiperazin-1-yl)meth 10 anone - [4-(2,3-Dimethylphenyl)piperazin-1-yl][2-(4-fluorophenyl)-5-methyl-2H pyrazol-3-yl]methanone - [4-(2-Ethylphenyl)piperazin-1-yl][2-(4-fluorophenyl)-5-methyl-2H-pyrazol-3 yl]methanone 15 - [4-(3-Chlorophenyl)piperazin-1-yl][2-(4-fluorophenyl)-5-methyl-2H-pyrazol-3 yl]methanone - [2-(4-Fluorophenyl)-5-methyl-2H-pyrazol-3-yl][4-(3-methoxyphenyl)piper azin-1-yl]methanone - [2-(4-Fluorophenyl)-5-methyl-2H-pyrazol-3-yl](4-m-tolylpiperazin-1-yl)meth 20 anone - [2-(4-Fluorophenyl)-5-methyl-2H-pyrazol-3-yl][4-(4-methoxyphenyl)piper azin-1-yl]methanone - [4-(2,4-Dimethoxyphenyl)piperazin-1-yl][2-(4-fluorophenyl)-5-methyl-2H pyrazol-3-yl]methanone 25 - [2-(4-Fluorophenyl)-5-methyl-2H-pyrazol-3-yl][4-(2-methylsulfanylphenyl) piperazin-1 -yl]methanone - [4-(4-Chlorophenyl)piperazin-1-yl][2-(4-fluorophenyl)-5-methyl-2H-pyrazol-3 yl]methanone - [2-(4-Fluorophenyl)-5-methyl-2H-pyrazol-3-yl](4-naphthalen-1-ylpiperazin-1 30 yl)methanone - [4-(5-Chloro-2-methylphenyl)piperazin-1-yl][2-(4-fluorophenyl)-5-methyl-2H pyrazol-3-yl]methanone - [4-(2-Ethoxyphenyl)piperazin-1-yl][2-(4-fluorophenyl)-5-methyl-2H-pyrazol-3 yl]methanone 35 - [4-(2,3-Dichlorophenyl)piperazin-1l-yl][2-(4-fluorophenyl)-5-methyl-2H pyrazol-3-yl]methanone 175 - [2-(4- FlIuo roph enyl )-5-m ethyl-2 H-pyrazol -3-yl] [4-(4-trifl uo rom ethyl ph enyl) piperazin-1 -yI]methanone - [4-(5-Chioro-2-methoxyphenyl)piperazin-1 -yI][2-(4-fluorophenyl)-5-methyl 2 H-pyrazol-3-yI]methanone 5 - [4-(4-Benzyloxyphenyl )piperazin-1 -yI]f2-(4-fluorophenyl)-5-methyl-2H pyrazol1-3-yi] meth anone - [2-(4-Fluorophenyl)-5-methyl-2H-pyrazol-3-y][4-(2-trifluoromethylphenyl ) piperazin-1 -yI]methanone - [4-(2 ,3-Dihydrobenzo[1 ,4]dioxin-6-yI)piperazin-1 -yI][2-(4-fluorophenyl )-5 10 methyl-2 H-pyrazol-3-yi] metha none - [2-(4-Methanesulfonylphenyl)-5-methyl-2H-pyrazol-3-yl](4-phenylpi perazin 1 -yI)metha none - [2-(4-M eth an esulIfo nyl phe nyl)-5-m ethyl -2 H- pyrazol1-3-yI] [4-(3-trifl uo romethyl phenyl)piperazin- 1 -yI]methanone 15 - 1 -(4-{4-[2-(4-Methanesulfonylphenyl)-5-methyl-2H-pyrazole-3-carbonyl] piperazin-1 -yIlphenyl)ethanone - [4-(2,4-Dimethylphenyl)piperazin-1 -yI][2-(4-methanesu Ifonylphenyl)-5 methyl-2H-pyrazol-3-yI]methanone - [2-(4-Methanesulfonylphenyl)-5-methyl-2H-pyrazol-3-y](4-o-tolyl piperazin-1 20 yI)methanone - [4-(3-Chlorophenyl)piperazin-1 -yI] [2-(4-meth an esulIfo nyl ph enyl)-5-m ethyl 2H-pyrazol-3-yI]methanone - [2-(4-Methanesulfonylphenyl )-5-methyl-2H-pyrazol-3-yI][4-(3-methoxy phenyl)piperazin-1 -yI]methanone 25 - [2-(4-Methanesulfonylphenyl)-5-methyl-2H-pyrazol-3-yI](4-m-tolylpiperazin 1 -yI)methanone - [4-(2,4-Dimethoxyphenyl)piperazin-1 -yI][2-(4-methanesulfonylphenyl)-5 methyl-2H-pyrazol-3-yllmethanone - [2-(4-Methanesulfonylphenyl)-5-methyl-2H-pyrazol-3-y][4-(2-methylsulfanyl 30 phenyl)piperazin-1 -yI] methanone - [4-(4-Chlorophenyl)piperazin-1 -y112-(4-methanesulfonylphenyl)-5-methyl 2 H-pyrazol-3-yI] meth anone - [4-(5-Chloro-2-methylphenyl)piperazin-1 -yI][2-(4-methanesulfonylphenyl)-5 m ethyl-2 H-pyrazol-3-yi] meth anone 35 - [4-(2-Ethoxyphenyl)piperazin-1 -yI][2-(4-methanesulfonylphenyl)-5-methyl 2H-pyrazol-3-yI]methanone 176 - [4-(2,3-Dichlorophenyl)piperazin-1 -yI][2-(4-methanesulfonylphenyl)-5 methyl-2 H-pyrazol-3-yI]methanone - [2-(4-Methanesulfonylphenyl)-5-methyl-2 H-pyrazol-3-y] [4-(4-trifluoromethyl phenyl)piperazin-1 -yI]methanone 5 - [4-(4-Benzyloxyphenyl )piperazin-1 -yI][2-(4-methanesu Ifonylphenyl)-5 methyl-2 H-pyrazol-3-yI]methanone - [2-(4-Methanesulfonylphenyl)-5-methyl-2H-pyrazol-3-yl] [4-(2-trifluoromethyl phenyl)piperazin-1 -yI]methanone - [4-(2 ,3-Dihydrobenzo[1 ,4]d ioxin-6-yI )piperazin-1 -yI][2-(4-methanesulfonyl 10 phenyl)-5-methyl-2H-pyrazol-3-yi]methanone - [2-(3-Chlorophenyl)-5-methyl-2H-pyrazol-3-yI](4-phenylpiperazin-1 -yI)meth anone - 12-(3-Chlorophenyl)-5-methyl-2H-pyrazol-3-yI][4-(2-methoxyphenyl)piper azin-1 -yI]methanone 15 - [2-(3-C hlIoro phe nyl)-5-methyl-2 H-pyrazol-3-y] [4-(3-trifl uo rom ethyl ph enyl) piperazin-1 -yI]methanone - [2-(3-C hlorophenyl)-5-methyl-2 H-pyrazol-3-y] [4-(2,4-d imethyl phenyl)pi per azin-1 -yI]methanone - [2-(3-C hlIoro phe nyl)-5-m ethyl-2 H-pyrazol1-3-yl 4-(3,4-d i methyl ph enyl)pi per 20 azin-1 -yI]methanone - [2-(3-Chlorophenyl)-5-methyl-2H-pyrazol-3-yII(4-o-tolylpiperazin-1 -yI)meth anone -[2-(3-C hlo roph enyl)-5-methyl-2 H-pyrazol-3-y] [4-(2 ,3-d methyl phe nyl) pi per azin-1 -yI]methanone 25 - [2-(3-Chlorophenyl)-5-methyl-2H-pyrazol-3-yI][4-(3-methoxyphenyl)piper azin-1 -yI]methanone - [2-(3-Chlorophenyl)-5-methyl-2H-pyrazol-3-yI](4-m-tolylpiperazin-1I-yI)meth anone - [2-(3-Chlorophenyl)-5-methyl-2H-pyrazol-3-y][4-(2 ,4-dimethoxyphenyl)piper 30 azin-1 -yI]methanone - [2-(3-Chlorophenyl)-5-methyl-2H-pyrazol-3-yI][4-(2-methylsulfanylphenyl) piperazin-1 -yI]methanone - 12-(3-Chloropheny)-5-methyl-2H-pyrazol-3-yI][4-(4-chlorophenyl)piperazin-1 yl]methanone 35 - [2-(3-Chlorophenyl)-5-methyl-2H-pyrazol-3-yI](4-naphthalen-1 -ylpiperazin-1 yI )methanone 177 - [2-(3-Chlorophenyl)-5-methyl-2H-pyrazol-3-yI][4-(2-ethoxyphenyl)piperazin 1 -yI]metha none - [2-(3-Chlorophenyl)-5-methyl-2 H-pyrazol-3-yI][4-(2,3-dichlorophenyl)piper azin-1 -yllmethanone 5 - [2-(3-C hlo ro phenyl)-5-methyl-2 H -pyrazol -3-yI] [4-(4-trifl uo ro methyl ph enyl ) piperazin-1 -yI]methanone - [4-(5-Chloro-2-methoxyphenyl)piperazin-1 -yII[2-(3-chlorophenyl )-5-methyl 2H-pyrazol-3-yI]methanone - [4-(4-Benzyloxyphenyl )piperazin-1 -yI] [2-(3-chlorophenyl )-5-methyl-2 H 10 pyrazol1-3-yI] meth anone -[2-(3-Chlorophenyl)-5-methyl-2H-pyrazol-3-y][4-(2-trifluoromethyphenyl) piperazin-1 -yI]methanone - [2-(3-Chlorophenyl)-5-methyl-2H-pyrazol-3-y][4-(2,3-dihyd robenzo[1 ,41 d ioxin-6-yl)piperazin-1 -yI]methanone 15 - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-yI](4-phenylpiperazin-1 -yI )meth anone - [2-(4-Ch lorophenyl)-5-methyl-2 H-pyrazol-3-y] [4-(2-methoxyphenyl)pi per azin-1 -yI]methanone - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-y][4-(3-trifluoromethylphenyl ) 20 piperazin-1 -yI]methanone - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-y][4-(4-fluoropheny)piperazin- yI]methanone - 1 -(4-{4-[2-(4-Chlorophenyl)-5-methyl-2H-pyrazole-3-carbonyl]piperazin-1 -yI} phenyl )ethanone 25 - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-y][4-(3,4-d ichlorophenyl)piper azin-1 -yI]methanone - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-yI][4-(3,4-dimethylphenyl)piper azin-1 -yI]methanone - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-y](4-o-tolyl piperazin-1 -yI )meth 30 anone - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-yI][4-(2,3-dimethylphenyl)piper azin-1 -yI]methanone - [2-(4-Chlorophenyi)-5-methyl-2H-pyrazol-3-yI][4-(2-ethylphenyl)piperazin-1 yI] methanone 35 - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-yIJ[4-(3-chlorophenyl)piperazin-1 yllmethanone 178 - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-yl](4-m-tolylpiperazin-1-yl)meth anone - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-yl][4-(4-methoxyphenyl)piper azin-1-yl]methanone 5 - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-yl][4-(4-chlorophenyl)piperazin-l1 yl]methanone - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-yl](4-naphthalen-1-ylpiperazin-1 yl)methanone - [4-(5-Chloro-2-methylphenyl)piperazin-1-yl][2-(4-chlorophenyl)-5-methyl-2H 10 pyrazol-3-yl]methanone - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-yl][4-(2,3-dichlorophenyl)piper azin-1-yl]methanone - [4-(5-Chloro-2-methoxyphenyl)piperazin-1-yl][2-(4-chlorophenyl)-5-methyl 2H-pyrazol-3-yl]methanone 15 - [4-(4-Benzyloxyphenyl)piperazin-1-yl][2-(4-chlorophenyl)-5-methyl-2H pyrazol-3-yl]methanone - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-yl][4-(2,3-dihydrobenzo[1,4] dioxin-6-yl)piperazin-1 -yl]methanone - (5-Methyl-2-p-tolyl-2H-pyrazol-3-yl)(4-phenylpiperazin-1-yl)methanone 20 - (5-Methyl-2-p-tolyl-2H-pyrazol-3-yl)[4-(3-trifluoromethylphenyl)piperazin-1 yl]methanone - 1-{4-[4-(5-Methyl-2-p-tolyl-2H-pyrazole-3-carbonyl)piperazin-1-yl]-phenyl} ethanone - [4-(3,4-Dichlorophenyl)piperazin-1-yl](5-methyl-2-p-tolyl-2H-pyrazol-3-yl) 25 methanone - (5-Methyl-2-p-tolyl-2H-pyrazol-3-yl)(4-o-tolylpiperazin-1-yl)methanone - [4-(2,3-Dimethylphenyl)piperazin-1-yl](5-methyl-2-p-tolyl-2H-pyrazol-3-yl) methanone - [4-(2-Ethylphenyl)piperazin-1-yl](5-methyl-2-p-tolyl-2H-pyrazol-3-yl)methan 30 one -[4-(3-Chlorophenyl)piperazin-1 -yl](5-methyl-2-p-tolyl-2H-pyrazol-3-yl)meth anone - [4-(3-Methoxyphenyl)piperazin-1-yl](5-methyl-2-p-tolyl-2H-pyrazol-3-yl)meth anone 35 - (5-Methyl-2-p-tolyl-2H-pyrazol-3-yl)(4-m-tolylpiperazin-1-yl)methanone 179 - [4-(4-Methoxyphenyl)piperazin-1-yl](5-methyl-2-p-tolyl-2H-pyrazol-3-yl)meth anone - [4-(2,4-Dimethoxyphenyl)piperazin-1-yl](5-methyl-2-p-tolyl-2H-pyrazol-3-yl) methanone 5 - [4-(2-Methylsulfanylphenyl)piperazin-1-yl](5-methyl-2-p-tolyl-2H-pyrazol-3 yl)methanone - [4-(4-Chlorophenyl)piperazin-1-yl](5-methyl-2-p-tolyl-2H-pyrazol-3-yl)meth anone - (5-Methyl-2-p-tolyl-2H-pyrazol-3-yl)(4-naphthalen- 1 -ylpiperazin-1-yl)meth 10 anone - [4-(5-Chloro-2-methylphenyl)piperazin-1-yl](5-methyl-2-p-tolyl-2H-pyrazol-3 yl)methanone - [4-(2-Ethoxyphenyl)piperazin-1-yl](5-methyl-2-p-tolyl-2H-pyrazol-3-yl)meth anone 15 - [4-(2,3-Dichlorophenyl)piperazin-1-yl](5-methyl-2-p-tolyl-2H-pyrazol-3-yl) methanone - (5-Methyl-2-p-tolyl-2H-pyrazol-3-yl)[4-(4-trifluoromethylphenyl)piperazin-1 yl]methanone - [4-(5-Chloro-2-methoxyphenyl)piperazin-1-yl](5-methyl-2-p-tolyl-2H-pyrazol 20 3-yl)methanone - [4-(4-Benzyloxyphenyl)piperazin-1-yl](5-methyl-2-p-tolyl-2H-pyrazol-3-yl) methanone - (5-Methyl-2-p-tolyl-2H-pyrazol-3-yl)[4-(2-trifluoromethylphenyl)piperazin-1 yl]methanone 25 - [4-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl](5-methyl-2-p-tolyl-2H pyrazol-3-yl)methanone - N-{4-[4-(5-Methyl-2-p-tolyl-2H-pyrazole-3-carbonyl)piperazin-1-yl]-phenyl} methanesulfonamide - (5-Methyl-2-m-tolyl-2H-pyrazol-3-yl)(4-phenylpiperazin-1l-yl)methanone 30 [4-(2-Methoxyphenyl)piperazin-1 -yl](5-methyl-2-m-tolyl-2H-pyrazol-3-yl)meth anone - (5-Methyl-2-m-tolyl-2H-pyrazol-3-yl)[4-(3-trifluoromethylphenyl)piperazin-1 yl]methanone - [4-(4-Fluorophenyl)piperazin-1-yl](5-methyl-2-m-tolyl-2H-pyrazol-3-yl)meth 35 anone 180 - 1-{4-[4-(5-Methyl-2-m-tolyl-2H-pyrazole-3-carbonyl)piperazin-1-yl]-phenyl} ethanone - [4-(2,4-Dimethylphenyl)piperazin-1-yl](5-methyl-2-m-tolyl-2H-pyrazol-3-yl) methanone 5 - [4-(3,4-Dichlorophenyl)piperazin-1-yl](5-methyl-2-m-tolyl-2H-pyrazol-3-yl) methanone - [4-(3,4-Dimethylphenyl)piperazin-1-yl](5-methyl-2-m-tolyl-2H-pyrazol-3-yl) methanone - (5-Methyl-2-m-tolyl-2H-pyrazol-3-yl)(4-o-tolylpiperazin-1-yl)methanone 10 - [4-(2,3-Dimethylphenyl)piperazin-1-yl](5-methyl-2-m-tolyl-2H-pyrazol-3-yl) methanone - [4-(2-Ethylphenyl)piperazin-1-yl](5-methyl-2-m-tolyl-2H-pyrazol-3-yl)meth anone - [4-(3-Chlorophenyl)piperazin-1-yl](5-methyl-2-m-tolyl-2H-pyrazol-3-yl)meth 15 anone - [4-(3-Methoxyphenyl)piperazin-1-yl](5-methyl-2-m-tolyl-2H-pyrazol-3-yl) methanone - (5-Methyl-2-m-tolyl-2H-pyrazol-3-yl)(4-m-tolylpiperazin-1-yl)methanone - [4-(4-Methoxyphenyl)piperazin-1-yl](5-methyl-2-m-tolyl-2H-pyrazol-3-yl) 20 methanone - [4-(2,4-Dimethoxyphenyl)piperazin-1-yl](5-methyl-2-m-tolyl-2H-pyrazol-3-yl) methanone - [4-(2-Methylsulfanylphenyl)piperazin-1-yl](5-methyl-2-m-tolyl-2H-pyrazol-3 yl)methanone 25 - [4-(4-Chlorophenyl)piperazin-1-yl](5-methyl-2-m-tolyl-2H-pyrazol-3-yl)meth anone - (5-Methyl-2-m-tolyl-2H-pyrazol-3-yl)(4-naphthalen-1-ylpiperazin-1-yl)meth anone - [4-(5-Chloro-2-methylphenyl)piperazin-1-yl](5-methyl-2-m-tolyl-2H-pyrazol-3 30 yl)methanone - [4-(2-Ethoxyphenyl)piperazin-1-yl](5-methyl-2-m-tolyl-2H-pyrazol-3-yl)meth anone -[4-(2,3-Dichlorophenyl)piperazin-1-yl](5-methyl-2-m-tolyl-2H-pyrazol-3-yl) methanone 35 - (5-Methyl-2-m-tolyl-2H-pyrazol-3-yl)[4-(4-trifluoromethylphenyl)piperazin-1 yl]methanone 181 - [4-(5-Chloro-2-methoxyphenyl)piperazin-1-yl](5-methyl-2-m-tolyl-2H-pyrazol 3-yl)methanene - [4-(4-Benzyloxyphenyl)piperazin-1-yl](5-methyl-2-m-tolyl-2H-pyrazol-3-yl) methanone 5 - (5-Methyl-2-m-tolyl-2H-pyrazol-3-yl)[4-(2-trifluoromethylphenyl)piperazin- 1 yl]methanone - [4-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl](5-methyl-2-m-tolyl-2H pyrazol-3-yl)methanone - N-{4-[4-(5-Methyl-2-m-tolyl-2H-pyrazole-3-carbonyl)piperazin-1-yl]-phenyl} 10 methanesulfonamide - (2H-Indazol-3-yl)(4-phenylpiperazin-1-yl)methanone - (2H-Indazol-3-yl)[4-(2-methoxyphenyl)piperazin-1 -yl]methanone - (2H-Indazol-3-yl)[4-(3-trifluoromethylphenyl)piperazin-1-yl]methanone - [4-(4-Fluorophenyl)piperazin-1 -yl](2H-indazol-3-yl)methanone 15 - 1-{4-[4-(2H-Indazole-3-carbonyl)piperazin-1-yl]-phenyl}ethanone - [4-(2,4-Dimethylphenyl)piperazin-1-yl](2H-indazol-3-yl)methanone - [4-(3,4-Dichlorophenyl)piperazin-1-yl](2H-indazol-3-yl)methanone - [4-(3,4-Dimethylphenyl)piperazin-1-yl](2H-indazol-3-yl)methanone - (2H-Indazol-3-yl)(4-o-tolylpiperazin-1 -yl)methanone 20 - [4-(2,3-Dimethylphenyl)piperazin-1-yl](2H-indazol-3-yl)methanone - [4-(2-Ethylphenyl)piperazin-1-yl](2H-indazol-3-yl)methanone - [4-(3-Chlorophenyl)piperazin-1-yl](2H-indazol-3-yl)methanone - (2H-Indazol-3-yl)[4-(3-methoxyphenyl)piperazin-1-yl]methanone - (2H-Indazol-3-yl)(4-m-tolylpiperazin-1 -yl)methanone 25 - (2H-Indazol-3-yl)[4-(4-methoxyphenyl)piperazin- 1-yl]methanone - [4-(2,4-Dimethoxyphenyl)piperazin-1-yl](2H-indazol-3-yl)methanone - (2H-Indazol-3-yl)[4-(2-methylsulfanylphenyl)piperazin-1-yl]methanone - [4-(4-Chlorophenyl)piperazin-1-yl](2H-indazol-3-yl)methanone - (2H-Indazol-3-yl)(4-naphthalen-1-ylpiperazin-1-yl)methanone 30 - [4-(5-Chloro-2-methylphenyl)piperazin-1-yl](2H-indazol-3-yl)methanone - [4-(2-Ethoxyphenyl)piperazin-1-yl](2H-indazol-3-yl)methanone - [4-(2,3-Dichlorophenyl)piperazin-1 -yl](2H-indazol-3-yl)methanone - (2H-Indazol-3-yl)[4-(4-trifluoromethylphenyl)piperazin-1-yl]methanone - [4-(5-Chloro-2-methoxyphenyl)piperazin-1 -yl](2H-indazol-3-yl)methanone 35 - [4-(4-Benzyloxyphenyl)piperazin-1-yl](2H-indazol-3-yl)methanone - (2H-I ndazol-3-yl)[4-(2-trifluoromethylphenyl)piperazin-1 -yl]methanone 182 - [4-(2,3-Dihydrobenzo[1 ,4]dioxin-6-yI)piperazin-1 -yt](2H-indazol-3-yI)meth anone - N-{4-[4-(2H-Indazole-3-carbonyl)piperazin-1 -yl]-phenyllmethanesulfonamide - (2-Methyl-i -quinolin-2-yI-1 H-pyrrol-3-yl)(4-phenylpiperazin-1 -yl)methanone 5 - [4-(3,4-Dichlorophenyl)piperazin-1 -yI](2-methyl-1 -quinolin-2-yl-1 H-pyrrol-3 yI)methanone - [4-(2-Methoxyphenyl)piperazin- 1-yI](2-methyl-l1-qu inol in-2-yl-1 H-pyrrol-3-y ) methanone - [4-(3,4-Dimethylphenyl )piperazin- 1-yl](2-methyl-1 -qu inol in-2-yI-1 H-pyrrol-3 10 yl)methanone - [4-(3-Chlorophenyl)piperazin-1 -yI] (2-methyl-i -qu inolin-2-yI-1 H-pyrrol-3-yl) methanone - [4-(3,4-Dimethylphenyl)piperazin-1 -yI](1 -isoqu inolin- I -yI-2-methyl-1 H-pyrrol 3-yl)methanone 15 - [4-(3-Chlorophenyl)piperazin-1 -yI](1 -isoquinolin-1 -yI-2-methyl-1 H-pyrrol-3 yI)methanone - (3, 5-Dimethyl-1 -phenyl-1 H-pyrazol-4-yI)[4-(3-methoxyphenyl)piperazin-1 -yI] methanone - N-{4-[4-(3 ,5-Dimethyl-1 -phenyl-1 H-pyrazole-4-carbonyl)piperazin-1 -yI] 20 phenyl~methanesulfonamide - [2-(4-Methoxyphenyl)-5-methyl-2 H-pyrazol-3-yI] [4-(3-methoxyphenyl)pi per azin-1 -yl]methanone - N-(4-{4-[2-(4-Methoxyphenyl)-5-methyl-2H-pyrazole-3-carbonyl]piperazin-1 yIlphenyl)methanesulfonamide 25 - [2-(3-Methoxyphenyl)-5-methyl-2H-pyrazol-3-yI] [4-(3-methoxyphenyl )pi per azin-1 -yljmethanone - N-(4-{4-[2-(3-Methoxyphenyl)-5-methyl-2H-pyrazole-3-carbonyllpiperazin-1 yI~phenyl)methanesulfonamide - (5-Methyl-2-phenyl-2H-pyrazol-3-yI)[4-(2-trifluoromethylphenyl)piperazin-1 30 yI]methanone - [4-(4-Benzyloxyphenyl)piperazin-1 -yI][2-(2-fluorophenyl)-5-methyl-2H pyrazol-3-yI] methanone - N-(4-{4-[2-(4-Fluorophenyl)-5-methyl-2H-pyrazole-3-carbonyllpiperazin-I -yI} phenyl)methanesulfonamide 35 - [2-(4-Methanesulfonylphenyl)-5-methyl-2H-pyrazol-3-yl][4-(2-methoxy phenyl)piperazin-I -yI] methanone 183 - [4-(4-Fluorophenyl)piperazin-1-yl][2-(4-methanesulfonylphenyl)-5-methyl-2H pyrazol-3-yI]methanone - [4-(3,4-Dichlorophenyl)piperazin-1 -yI][2-(4-methanesulfonyiphenyl)-5 methyl-2H-pyrazol-3-yIlmethanone 5 - [4-(3,4-Dimethylphenyl)piperazin-1 -yI][2-(4-methanesulfonylphenyl)-5 methyl-2H-pyrazol-3-yI]methanone - [4-(2 .3-Dimethyl phenyl )piperazin-1 -yI][2-(4-methanesulfonylphenyl )-5 methyl-2 H-pyrazol-3-yI]methanone - [2-(4-M eth anesulIfo nyl ph enyl)-5-m ethyl -2 H-pyrazo1-3-yl] [4-(4- methoxy 10 phenyl)piperazin-1 -yI]methanone - [2-(4-Methanesulfonylphenyl)-5-methyl-2H-pyrazol-3-yI](4-naphthalen-1 -yi piperazin-1 -yI)methanone - [4-(5-Chloro-2-methoxyphenyl)piperazin-1 -yI][2-(4-methanesulfonylphenyl) 5-methyl-2 H-pyrazol-3-yI] metha none 15 - N-(4-{4-[2-(4-Methanesulfonylphenyl )-5-methyl-2 H-pyrazole-3-carbonyl] piperazin-1 -yI~phenyl)methanesulfonamide - [2-(3-Chlorophenyl)-5-methyl-2H-pyrazol-3-yI][4-(4-fluorophenyl)piperazin- 1 yI]methanone - [2-(3-Chlorophenyl)-5-methyl-2H-pyrazol-3-y][4-(3,4-d ichlorophenyl)piper 20 azin- 1-yI] metha none - [2-(3-Chlorophenyl)-5-methyl-2H-pyrazol-3-yIJ[4-(2-ethyl phenyl)piperazin-1 yI] methanone - [2-(3-Chlorophenyl)-5-methyl-2H-pyrazol-3-yI][4-(3-chlorophenyl)piperazin-1 yI]methanone 25 - [2-(3-C hloroph enyl)-5-m ethyl-2 H-pyrazol-3-yI] [4-(4-meth oxyph enyl) p iper azin-1 -yI]methanone - [4-(5-Chloro-2-methylphenyl)piperazin-1 -yIJ[2-(3-chlorophenyl)-5-methyl-2H pyrazol-3-yI] meth anone - N-(4-{4-[2-(3-Chlorophenyl)-5-methyl-2H-pyrazole-3-carbonyl]piperazin-1 30 yI~phenyl)miethanesulfonamide - [2-(4-C hloro phe nyl)-5-methyl-2 H-pyrazol-3-yi] [4-(2 ,4-d i methyl ph enyl) pi per azin-1 -yI]methanone - [2-(4-Chlorophenyi)-5-methyl-2H-pyrazol-3-yI][4-(3-methoxyphenyl )piper azin-1 -yI]methanone 35 - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-yI][4-(2 ,4-dimethoxyphenyl)piper azin-1 -yI]methanone 184 - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-yl][4-(2-methylsulfanylphenyl) piperazin-1 -yl]methanone - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-yl][4-(2-ethoxyphenyl)piperazin 1-yl]methanone 5 - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-yl][4-(4-trifluoromethylphenyl) piperazin-1 -yl]methanone - [2-(4-Chlorophenyl)-5-methyl-2H-pyrazol-3-yl][4-(2-trifluoromethylphenyl) piperazin-1 -yl]methanone - N-(4-{4-[2-(4-Chlorophenyl)-5-methyl-2H-pyrazole-3-carbonyl]piperazin-1 10 yl}phenyl)methanesulfonamide - [4-(2-Methoxyphenyl)piperazin-1 -yl](5-methyl-2-p-tolyl-2H-pyrazol-3-yl)meth anone - [4-(4-Fluorophenyl)piperazin-1-yl](5-methyl-2-p-tolyl-2H-pyrazol-3-yl)meth anone 15 - [4-(2,4-Dimethylphenyl)piperazin-1-yl](5-methyl-2-p-tolyl-2H-pyrazol-3-yl) methanone - [4-(3,4-Dimethylphenyl)piperazin-1-yl](5-methyl-2-p-tolyl-2H-pyrazol-3-yl) methanone 14. The product as claimed in claim 1, characterized in that it is chosen 20 from: - [4-(3-Chlorophenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)meth anone (Example 1) - [4-(3,4-Dimethylphenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone (Example 2) 25 - [4-(3,5-Dichlorophenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone (Example E2) - [4-(Quinolin-4-yl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl)meth anone (Example E17) - [4-(3-Chlorophenyl)piperazin-1-yl](5-hydroxymethyl-2-phenyl-2H-pyrazol-3 30 yl)methanone (Example E60) - [4-(3,4-Methylenedioxyphenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol 3-yl)methanone (Example E30) - [4-(3,5-Dimethoxyphenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone (Example E20) 185 - [4-(3,5-Dimethylphenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone (Example E63) - [4-(3-Difluoromethoxyphenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol 3-yl)methanone (Example E74) 5 - [4-(3-Chlorophenyl)piperazin-1-yl][5-(2-methylimidazol-1-yl-methyl)-2 phenyl-2H-pyrazol-3-yl]methanone (Example E75) - [4-(3,5-Dimethoxyphenyl)piperazin-1 -yl][5-(1 H-pyrrol-2-yl)methyl-2-phenyl 2H-pyrazol-3-yl]methanone (Example E91) - [4-(3,5-Dimethoxyphenyl)piperazin-1-yl][5-(pyrrolidin-1-yl)methyl-2-phenyl 10 2H-pyrazol-3-yl]methanone (Example E93) - [4-(3-Carboxamidophenyl)piperazin-1-yl](5-trifluoromethyl-2-phenyl-2H pyrazol-3-yl)methanone (Example El19) - [5-(Azetidin-1-yl)-2-phenyl-2H-pyrazol-3-yl][4-(3,5-dimethoxyphenyl)piper azin-1-yl]methanone (Example E129) 15 - [4-(3-Carboxamidophenyl)piperazin-1-yl](2-phenyl-2H-pyrazol-3-yl)meth anone (Example E133) - [4-(3-Carboxamidophenyl)piperazin-1-yl](5-hydroxymethyl-2-phenyl-2H pyrazol-3-yl)methanone (Example E134) - [4-(3-Carboxamidophenyl)piperazin-1-yl](5-methyl-2-phenyl-2H-pyrazol-3 20 yl)methanone (Example E23) - [4-(3,5-Dimethoxyphenyl)piperazin-1-yl](5-hydroxymethyl-2-phenyl-2H pyrazol-3-yl)methanone (Example E73) - (5-Amino-2-phenyl-2H-pyrazol-3-yl)[4-(3,5-dimethoxyphenyl)piperazin-1l-yl] methanone (Example E99). 25 15. The product as claimed in claim 14, characterized in that it is chosen from: - [4-(3-Carboxamidophenyl)piperazin-l1-yl](5-methyl-2-phenyl-2H-pyrazol-3 yl)methanone (Example E23) - [4-(3,5-Dimethoxyphenyl)piperazin-1-yl](5-hydroxymethyl-2-phenyl-2H 30 pyrazol-3-yl)methanone (Example E73) - (5-Amino-2-phenyl-2H-pyrazol-3-yl)[4-(3,5-dimethoxyphenyl)piperazin-1-yl] methanone (Example E99). 16. A pharmaceutical composition comprising a product as claimed in any one of the preceding claims, in combination with a pharmaceutically 35 acceptable excipient. 186 17. The use of a product as claimed in any one of claims 1 to 15, as an agent for inhibiting tubulin polymerization. 18. The use of a product as claimed in any one of claims 1 to 15, as an agent for inhibiting the proliferation of tumoral cells. 5 19. The use of a product as claimed in any one of claims 1 to 15, for promoting the disintegration of lumps of cells originating from vascular tissue. 20. The use of a product as claimed in any one of claims 1 to 15, for the manufacture of a medicinal product that is useful for treating a pathological condition. 10 21. The use as claimed in claim 20, in which the pathological condition is cancer.
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