CA2512243A1 - N-aryl heteroaromatic products, compositions containing same and use thereof - Google Patents

Abstract

N-aryl-heteroaromatic products, compositions containing them and use. The present invention relates to new chemical compounds, particularly new N-aryl-heteroaromatic products, compositions containing them, and their use as medicaments, in particular in oncology.

Description

WO 2004/07873

2 PCT / FR2004 / 000168 N-ARYL-HETEROAROMATIC PRODUCTS, COMPOSITIONS
CONTAINER AND USE
The present invention relates to new chemical compounds, particularly new N-aryl-heteroaromatic products, compositions containing them, and their use as medicaments.
More particularly, the invention relates to new N-aryl- products.
heteroaromatics with anticancer activity, and in particular tubulin polymerization inhibitory activity.
The N-aryl-heteroaromatic products discussed here meet the following general formulas (la), (Ib) or (Ic) X / ~ ~ N ~ R1 X ~ ~ I R1 X ~ ~ R1 N ~ \
'N ~~~ N ~' N ~~~ N ~ 'N ~ L ~
R2 R6 R ~ R6 RAI R6 General formula (la) General formula (Ib) General formula (Ic) Van Wijngaarden et al. (US 4772604, US 4874770, EP 0241053) claim piperazine derivatives with anti-aging properties psychotic. These patents have also been mentioned in Chem. Ans., Vol.
108 (1988), p.576, 221717q, where they were cited by two none of which is disclosed in the aforementioned patents. It's about N ~
NOT
--- NOT
O
HO
and of THIS

As can be seen from reading Van Wijngaarden's patents et al., the products described and claimed are either 2,5- pyrroles disubstituted, either 1,3- or 3,5-disubstituted pyrazoles. So the two products described above which are 1,5-disubstituted pyrazoles cannot be neither found nor deduced from the content of these documents.
Patent application WO 01/19798 claims compounds heterocyclics useful as Factor Xa inhibitors for treatment, for example, thrombosis, and to inhibit coagulation of samples organic. The products described are not included in the definition of products according to the invention, with the exception of the following compound ~ N
N / ~ N
Y ~ N
O '/
\) Ermondi et al., In Farr ~ ac ~, 53, 519 (1998), discloses analogues of the prazosin, which are potential inhibitors of adrenoceptor-a1. One prazosin analog is a 5- (4-heteroaryl-piperazinocarbonyl) -1 phenyl-pyrazole H2N OMe N '~ 1 OMe ~ N
~ N
N ~
N ~
NOT
O

3 Baxter et al. (WO 015782) claim piperidine compounds from formula below; for the treatment of diseases in which the modulation of chemokine receptors may be beneficial, such as pulmonary obstructions or rheumatoid arthritis.
R1 N / YU ~ O ~ (R3) n x ~ A ~ /

In any case, Q cannot represent a simple bond, so the products described in WO 015782 cannot be included in the present invention.
Surprisingly, it has been found that products meeting the general formula (I) below have an inhibitory activity on significant tubulin polymerization R3 R4 R5 R3 R4 R5 R3 R ~ R5 R9 ~ N ~ R1 x / ~ ~ R1 X ~ ~ R1 (I) ~ N ~~~ N ~ ~ N ~~~ N ~ ~ N ~~~ N ~
R2 R6 ~ R6 R ~ R6 General formula (la) General formula (Ib) General formula (Ic) in which 1) R1, R2 are independently selected from the group made up by aryl, heteroaryl, substituted aryl, substituted heteroaryl; R2 can also be selected from the group C5-C7 cycloalkyl;
2) L is selected from the group consisting of C (R7) (R8), C = O, C = S, C = N (R7);
3) R3 is selected from the group consisting of H, halogen, CF3, alkyl, substituted alkyl, alkylene, substituted alkylene, alkynyl, alkynyl substituted, cycloalkyl, cycloalkylene, heterocyclyl, heterocyclyl substituted, CO-R7, C (R7) = NO (R8), COOH, CONH-aryl, CONH-heteroaryl, 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-S02-R7, NH-S02-aryl, NH-S02-heteroaryl,

4 NH-CH2-C02 (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), NN = C (R7) (R8), CN, O-R7, O-CH2-aryl, O-CH2-heteroaryl, S-R7, SO-R7, S02-R7, aryl, heteroaryl, cycloalkyl substituted, substituted aryl, substituted heteroaryl;
4) R4 is selected from the group consisting of constituted by H, (C1-C3alkyle), cyclopropyle, (C2-C3) alkylene, (C2-C3) alkynyle, O (C1-C3) alkyl, S- (C1-C3) alkyl, F, CI, Br;

5) XestNouCH;

6) R5 and R6 are independently selected from the group formed by H, (C1-C3) alkyl, oxo, halgene;

7) R7, R8, R12 are independently selected from the group consisting of H, (C1-C3) alkyl, (C1-C3) substituted alkyl;

8) R9 is (C1-C3) alkyl;
in racemic form, enriched in an enantiomer, enriched in a diastereoisomer, its tautomers, its prodrugs and its salts pharmaceutically acceptable, provided that the product of formula (I) is not one of the following ~ N
Nl ~ N
\ N Ö
~~ S
\
you Me NOT/
NOT
O

Products of general formula (la) or (Ib) are preferred.
Products for which X is N are preferred.
A preferred substituent R1 may be chosen from phenyl; phenyl substituted by at least one radical chosen from halogen, (C1-C3) -alkyle, 5 CON (R10) (R11), O-R10, S-R10, N (R10) (R11), in which R10, R11 are independently selected from H, (C1-C3) -alkyl, (C1-C3) -alkylated halogen;
pyridyle; pyridyl substituted with at least one radical chosen from halogen, (C1-C3) -alkyl, CON (R10) (R11), O-R10, S-R10, N (R10) (R11), in which R10, R11 are independently chosen from H, (C1-C3) -alkyl, (C1-C3) halogenated alkyl.
More preferably, R1 will be phenyl substituted by halogen or (C1-C3) -alkyl, or (C1-C3) -alkoxy, or carboxamide; 2- or 3-pyridyle .; 2- or 3-pyridyl substituted by halogen or (C1-C3) -alkyl.
Very preferably, R1 is phenyl substituted by a chloro radical, one or two methoxy radicals or a carboxamide radical.
When R1 is substituted phenyl, preferred combinations of substitution can be chosen from phenyl-2,3-disubstituted, phenyl-2,5 disubstituted, phenyl-3-substituted, phenyl-3,5-disubstituted, phenyl-3,4 disubstituted, more preferably from phenyl-3-substituted, phenyl-3,5 disubstituted, phenyl-3,4-disubstituted.
When R1 is substituted 2-pyridyl, preferred substitutions are chosen from 2-pyridyl-4- or 6-substituted or 2-pyridyl-4,6-disubstituted.
When R1 is substituted 3-pyridyl, preferred substitutions are 3-pyridyl-2- or 5-substituted.
A preferred R2 substituent may be chosen from phenyl, 3-pyridyl, phenyl substituted by at least one radical chosen from halogen, alkyl, O-R10, S-R10, N (R10) (R11), in which R10, R11 are independently chosen from H, (C1-C3) alkyl, (C1-C3) halogenated alkyl.
A preferred R2 substituent is chosen from unsubstituted phenyl and 3-pyridyl. Unsubstituted phenyl is more preferred.

Preferably R3 is H or (C1-C3) alkyl, CF3, hydroxymethyl, amino, azétidino, pyrrolidino.
More preferably R3 is H or a methyl, hydroxymethyl, CF3 radical or amino.
Preferably R4 is H
In general, products of general formula (la), (Ib) or (Ic) according to the invention in which L is C (O) can be prepared by coupling of a 1-aryl (heteroaryl) -pyrrole-2-carboxylic acid, or an acid 2-aryl (heteroaryl) -pyrazole-3-carboxylic, of general formula (II), in which R2 R3 and R4 are defined as above, with, respectively, a piperazine derivative of general formula (Illa) or a derived from 1,2,3,6-tetrahydropyridine (Illb), in which R1 is defined as than previously, or a piperidine derivative of general formula (IIIc), in which R1 and R9 are defined as previously according to diagram 1 O
R3 + R1-N NH - ~ R1-N NR ~ la ~ N ~
() R2 X (II) 6 (Illa) R6 R ~~ N ~ X R3 O
.N ~ R3 + R1 ~ NH ~ R1 ~ N R4 R2 X (Illb) .-- (Ib) (II) R6 R6 R2 ~ N ~~ R3 H02C R4 Rg R5 Rg R5 O
¿~ R1 NH ~ R1 N R4 ~ N ~ R3 (Ic) R2 X (Illc) ""' (II) R6 R6 R2 ~ NX R3 Diagram 1 Pairing can be done using coupling methods known to those skilled in the art, in particular those consisting in the activation of the acid of general formula (II) in the form of chloride or anhydride or any of the coupling methods developed for synthesis peptide.

In general, products of general formula (la), (Ib) or (Ic) according to the invention in which L is C (O) can be prepared by coupling of a methyl or ethyl ester of 1-aryl (heteroaryl) acid -pyrrole-2-carboxylic acid, or 2-aryl (heteroaryl) -pyrazole-3-carboxylic acid, of general formula (II), in which R2 R3 and R4 are defined such that previously, with, respectively, a piperazine derivative of the formula general (Illa) or a 1,2,3,6-tetrahydropyridine derivative (Illb), in which R1 is defined as above, or a piperidine derivative of formula general (Illc), in which R1 and R9 are defined as above according to diagram 1 (bis) Me (And) WO ~ R4 R5 O
~ N ~ + R1-N NH - ~ R1- N R4 R2 X (R ~ 6 (Illa) ~ (la) , N, R3 Me (And) - ~ 02 O
~ R ~ + R1 ~ NH ~ R1 ~ N R4 R2 ~ N ~ X (Illb) - (Ib) (II) R6 R6 R2 ~ N, ~ R3 Me (And) W02 R4 R9 R5 R9 R5 O
+ R1 NH ~ R1 N R4 .N ~ R3 (Ic) R ~ X (II) (Illc) R6 R ~~ N '~ R3 Diagram 1a Pairing can be done using coupling methods known to those skilled in the art, in particular by activation of the amine (Illa) (Illb) or (Illc) with trimethylaluminum under the conditions described in Organic Synthesis. 59, 49-53 (1980).
Acids or esters, methyl or ethyl, of acids 1-aryl (heteroaryl) -pyrrole-2-carboxylic or 2-aryl (heteroaryl) -pyrazole-3-carboxylic compounds of general formula (II) can be obtained according to the methods known to those skilled in the art, in particular ortho-carboxylation a pyrrole or pyrazole derivative followed by N-alkylation or N-arylation of pyrrole or or or pyrazole according to scheme 2, in the case pyrazoles we generally obtain an easily separable mixture of substituted N-1 and N-2 products.
1-BuLi or other base, Rq. ODG cleavage R4 2_C02 or H (CI) C02R 'RO ~ C R'02C R4 , N ~ R3 i .N, R3 oDG HN ~ R3 CEO XXX
arylation oDG = orthodirector group such as Boc, Ac, COCF3 R '= H, Me or Et R'OZC R4 ~ N ~ R3 Diagram 2 When X represents a nitrogen atom, the arylation, advantageously performed by Suzulei type coupling, can be performed by operating in the conditions described in Tetrahedron, 55, 12757 (1999).
When X represents a nitrogen atom, the arylation can be very advantageously carried out by operating under the conditions described by Buchvvald in J. Amer. Chem. Soc., 123, 7727 (2001), with a halide of aryl R2-Hal, by catalysis with cuprous iodide in the presence of cesium and 1,2-diaminocyclohexane carbonate.
In the case where R2 represents a phenyl radical, X a CH group and R4 a hydrogen atom, it is possible to directly perform the otho-carboxylation 1-phenyl-pyrrole-2-carboxylic acid by operating according to Tetrahedron, 49, 10278 (1993).
R3 and / or R4 groups, different from the hydrogen atom, acids 1-aryl (heteroaryl) -pyrrole-2-carboxylic or 2-aryl (heteroaryl) -pyrazole-3-carboxylates of general formula (II) can also be introduced on 1-aryl (heteroaryl) -pyrrole-2-carboxylic or 2-aryl (heteroaryl) acids -pyrazole-3-carboxylates of general formula (II), in which R3 and / or R4 represent a hydrogen atom, by any of the methods classics known to those skilled in the art.

9 These methods include regioselective acid halogenation 1-aryl (heteroaryl) -pyrrole-2-carboxylic or 2-aryl (heteroaryl) -pyrazole-3-carboxylic followed by substitution.
In the context of the invention, when X represents a nitrogen atom, the substitution of a halogen in position 3 of an ester of 1-aryl-1 H- acid pyrazole-5-carboxylic proves to be a particularly advantageous method for a preparation of 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, aryl substituted, heteroaryl, substituted heteroaryl, NH2, NH-aryl, NH (R7), N (R7) (R8), NH-CO-R7, NH-CO-aryl, NH-S02-aryl, NH-CH2-C02R7, NH-CH2-aryl, N (R7) -N (R7) (R8), NN = C (R7) (R8), CN, OR7, SR7ï SO-R7, S02-R7, according to diagram 2bis.
1) NBS (NIS) 2) base GOLD' R'O C
R ~~ NN Ö R OZC substitution I% ~ ~ -OH ~~ gr (i) R2'N'N R3 (II) (II) R '= Me or Et Diagram 2bis In the context of the invention, the substitution of ester ethyl 3-bromo-1-phenyl-1 H-pyrazole-3-carboxylic acid, which can be prepared according to Tetrahedron Lett., 40, 2605 (1999).
In the context of the invention, the substitutions of the bromine atom will be advantageously carried out by heating a few minutes at 120-150 ° C in a microwave reactor, more particularly carbon-carbon couplings Suzuki and Heck type or Buchwald type aminations.
In the context of the invention, when X represents a nitrogen atom or a CH radical, the substitution of the bromine atom for a bromomethyl radical in position 3 of a 1-aryl-1H-pyrazole (pyrrole) -5-carboxylic acid ester is a particularly advantageous method for preparing a derivative of general formula (la) daris which X represents a nitrogen atom or a CH radical, R4 represents a hydrogen atom and R3 represents a alkyl radical, according to scheme 2ter.
R'OZC N ~ AIBN R'OZC - substitution R'02C -% ~ IX'-R'3 R2 'N' ~ R2 ~ N.
R2 'N'X Br X
(II) R'O ~ CX '= O, S, NH, N (R7;
R '= Me or Et I- \ Br R'3 = R8 ~~ N 'X ~
Br CaC03 microwave ROC amination ROC
reducing ~ 2 N- R 3 R2'N'X \ R2'N ' O
5 Diagram 2ter In the context of the invention, the substitutions of the bromine atom will be advantageously carried out by heating for a few minutes at 120-150 ° C
in a microwave reactor.
In the case where X represents a nitrogen atom, R3 a hydrogen atom or

10 a C1-C3 alkyl radical and R4 a hydrogen atom, it is advantageous use the method of synthesis of 2-aryl (heteroaryl) pyrazole-3- acids carboxylic described in J. Het. Chem., 30, 307 (1993), from aryl (heteroaryl) hydrazines, operating according to scheme 3 H .O ~ 1) AcOH HOZC
R2 ~ N ~ NH + ON reflux R4 ~ - ~ ~ N ~ R4 C02And 2) NaOH R2 N
Diagram 3 From aryl (heteroaryl) hydrazines, it is also advantageously possible prepare 2-aryl (heteroaryl) pyrazole-3-carboxylic esters, by operating according to J. Het. Chem., 36, 217 (1999), which will then be saponified into acids correspondents.

11 Another method of synthesis of 2-aryl (heteroaryl) pyrazole-3- esters carboxylic, particularly advantageous in the context of the invention, puts cycloaddition reactions, followed by oxidation of the adduct intermediate obtained by chloranil, aryl (heteroaryl) hydrazones with a propiolate by operating according to Tetrahedron, 36, 887 (1980).
Another method of synthesizing 1-aryl (heteroaryl) pyrrole-5- acid esters carboxylic, particularly advantageous in the context of the invention, puts implementing the reaction of an aryl (heteroaryl) amine with 2,5-dimethoxy-tetrahydrofuran by operating according to Heterocycles, 53, 2160 (2000).
The piperazine derivatives of general formula (Illa), in which R1, R5 and R6 are defined as above, are either commercial or prepared according to conventional methods known to those skilled in the art.
Among these methods, N1-aryl (heteroaryl) ation, according to scheme 4, of piperazines carrying a protective group on nitrogen 4, is particularly advantageous in the context of the invention arylation ~ GP cleavage HN N-GP ~ R1-N N-GP ~ R1-N NH

(IIIa) GP = Boc, Ac, Cbz, Bn ...
Diagram 4 The aryl (heteroaryl) reaction of piperazines, generally of the type Hartwig / Büchwald, can be performed by operating under the conditions described in ~ iorg. Med. Chem. Lett., 11, 1375 (2001) or in Biorg. Med.
Chem., 10, 3817 (2002).
Another method of synthesis of aryl (heteroaryl) piperazines, particularly advantageous in the context of the invention, when R5 and R6 represent hydrogen atoms, consists of the reaction of a aryl (heteroaryl) amine with a bis (2-hydroxy- or 2-halo-ethyl) amine, to temperature above 100-120 ° C according to diagram 5 OH (Hal) R1-NH +
H - ~ R1-N NH (Illa) U
OH (Hal)

12 Diagram 5 It is particularly advantageous to operate in the presence of microwaves in the conditions described in Synth. Comm. , 28, 1175 (1998) or in Tetrahedron Lett, 38, 6875 (1997).
1,2,3,6-tetrahydropyridine derivatives (Illb), in which R1, R5 and R6 are defined as above, are either commercial or prepared according to conventional methods known to those skilled in the art.
Among these methods, the action, according to diagram 6, of a derivative aryl organometallic (heteroaryl), such as an organomagnesium, a organolithian to organoceric, on a derivative of piperidin-4-one of which the nitrogen atom is substituted by a protective group, is particularly advantageous.
/ ~ R1-M R1 ~ R1 NH
O ~ N-GP-- ~ \ ~~ N-GP - ~ R1 ~ N-GP
H ~
(IIIb) GP = Boc, Ac, Cbz, Bn ....
M = MgCI (Br), CeCl2 ...
Diagram 6 One can in particular operate under the conditions described in J. Med.
Chem., 38, 1998 (1995) or in EP 306754. or in J. fi ~ ed. Chem., 28, 311 (1985 When R5 and R6 represent hydrogen atoms, the type coupling Suzuki N-Boc 1,2,3,6-tetrahydropyridyl-4 pinacolic ester boronic with a halide, preferably a bromide or an iodide, aryl or heteroaryl, under the conditions described in Tetrahedron Lett, 41, 3705 (2000), according to Figure 7, is particularly advantageous in the scope of the invention: It is understood that the protective group Boc can be replaced by any other protective group compatible with reaction conditions and that the pinacol boronic ester can also be replaced by any other boronic derivative, acid or ester, compatible with said conditions.

13 R1-Hal + ~ B ~ N-boc - ~. R1 ~ N-boc ~ R1 ~ NH
(IIIb) Diagram 7 Piperidine derivatives, in which R1, R6, R7 and R9 are defined as before are prepared according to conventional methods known to those skilled in the art.
Among these methods, the action, according to diagram 8, of a derivative alkyl organometallic, such as organomagnesium, organolithium or organoceric, on a derivative of piperidin-4-one whose nitrogen atom is substituted by a protective group, followed by the action of an aryl derivative or heteroaryl in the presence of an acid catalyst, of Lewis acid type or superacid according to Olah, is particularly advantageous in the context of the invention.
/ ~ Rg-M Rg Rg-H R9 R9 O ~ N-GP - ~ ~ N-GR ~ ~~ N-GP - ~ ~~~ NH
HO cat. acid R1 R1 GP = Boc, Ac, Cbz, Bn .... (Illc) M = MgCI (Br), CeCl2 ...
Diagram 8 One can in particular operate under the conditions described in J. ~ ed.
Chem., 41, 5320 (1998) or in Tetrahedron Lett., 41, 8853 (2000).
In general, products of general formula (la), (Ib) or (Ic) according to the invention in which L is CH2 can be prepared by reduction of a compound of general formula respectively (la), (Ib) or (Ic), where L is C (O), by any of the reduction methods known to those skilled in the art, such as for example the methods of Clemmensen or Wolff-Kishner, operating according to diagram 9

14 O
R1- ~ R4 (la) - ,. R1-N N R4 -- (the) R6 R2 ~ N ~ X R3 R6 ~ N ~ R3 R1. N R4 (Ib) R1 ~ ~ N R4 (Ib) R6, N. ~ R3 ~
R2 X R6 ~ N ~ R3 R1 N R4 (Ic) - ~ R1 N R4 (Ic) R6 ~~ N ~ X R3 R6 ~ N ~ R3 Diagram 9 In general, products of general formula (la), (Ib) or (Ic) according to the invention in which L is CNR can also be prepared from the esters of the products of general formula (II), in using the various methods known to those skilled in the art, according to the sequences of diagram 10 R3 ~ .N, R ~ (II) (la) (Illa) ~ N ~ R3 R2 'X
1- esterification 2- reduction (3- LG) R5 (Illb) R1 ~ N R't (Ib) R4 OH (LG) ~ R6 ~ N ~ R3 R3 ~ R2 X

(IIIc) LG = Hal, OTs, OMs .... R9 R5 R1 ~ N R4 (Ic) R6 ~ N ~ R3 Figure 10 In general, products of general formula (la), (Ib) or (Ic) in accordance with the invention in which L is CR7R8, with R7 and / or R8 different from the hydrogen atom, can also be prepared from products of general formula (II), or their esters, using the various methods known to those skilled in the art, according to the sequences of diagram 11 R4 OH (Oalk) ~ R ~ R8 the R3 XN ~ R2 (II) R1 ~ R4 () (Illa) Rg R2.NX R3 R5 R ~ R8 R4 R ~ R8 (Illb) R1 \ N. R4 (Ib) OH (LG) R3 ~ N. Rg R2 ~ N ~ X R3 X 'R2 (Illc) LG = Hal, OTs, OMs .... R9 R7 R8 (Ic) R6 R2 ~ N'X R3 5 Figure 11 In general, products of general formula (la), (Ib) or (Ic) according to the invention in which L is C (S) can be prepared by thionation of a compound of general formula respectively (la), (Ib) or (Ic), where L is C (O), by any of the reduction methods 10 known to those skilled in the art, operating according to diagram 12 S
R1- ~ R4 (la) -. ~ R1- ~ R4 (la) R6 R2.NX R3 ~ R2 ~ N ~ X R3 R1 ~. N R4 (Ib) ~ R1 \ NS R4 (Ib) R6, N, s R3 R2 X R6 R2.NX ~ R3 R1 N - R4 (Ic) R1 NS R4 (Ic) R6 R2 ~ NX R3 Rg R2 ~ N ~ X R3 Figure 12 It is particularly advantageous in the context of the invention to carry out the thionation using Lawesson's reagent, operating according to Bull. Soc. Chim.
Belg., 87, 293 (1978).
In general, products of general formula (la), (Ib) or (Ic) according to the invention in which L is C (NH) can be prepared for starting from the nitriles derived from the products of general formula (II), in using the various methods known to those skilled in the art, according to the sequences of diagram 13 R4 ~ HH

R3 XN ~ R2 (II) _ (la) (IIIa) R6 R2.NX R3 R4 / ~ (Illb) NH
R1 ~ ~ N R4 (Ib) R3 ~ .N.R2 R6 R ~~ N ~~ R3 (IIIc) R4 g % ~ (Ic) ~ R3. s X R2 R6 R2 ~ N ~ X R3 Figure 13 It is generally necessary to activate the nitrite, which is not very reactive, either with aluminum chloride, operating according to J. Chem. Soc. 1947, 1110; either with copper iodide, operating according to Tetrahedron Lett., 34, 6395 (1993);
either by transforming nitrite into iminoether prior to the reaction with the derivative of piperazine - or 1,2,3,6-terahydropyridine or piperidine, in operating according to Eur.J. Med. Chem., 24, 427 (1989).
In general, products of general formula (la) or (Ic) conform to the invention in which L is C (NR7), with R7 equal or different from the atom of hydrogen, can be prepared from the products of general formula respectively (la) or (Ic) in which L is C (O) and / or C (S), using the various methods known to those skilled in the art, according to the sequences of diagram 14 X ~ + y R4 / ~ N-R7 R1-N N R4 R1- ~ - R1-N N ~ R4 (la) 6, N ~ R3 R6 ~~ N, X R3 ~ ~, N ~ R3 R2 ~ X (la) ~ ~ X
(the) O R9 R5 y R9 R5 R1 N R4 R1 N ~ R4 N-R7 _ - ~ R1 N ~ R4 R6, N, ~ R3 R6, N, ~ R3 (Ic) R2 X ~ X R6 ~~ NX R3 (Ic) Figure 14 In the context of the invention when X is an oxygen atom, it is particularly advantageous to react the chloride successively of oxalyl, which leads to an intermediate in which Y is an atom of chlorine, then an amine R7-NH2, operating according to Pol. J. Chem., 58, 117 (1934) and in the case osa X is a sulfur atom to react first methyl iodide, which leads to an intermediate in which Y is a methylthio radical, then an amine R7-NH2, operating according to Eur. J. Med.
Chem, 12, 365 (1977).
More specifically and more particularly advantageously in the within the framework of the invention, products of general formula (la) in accordance with the invention in which L is C (~), X is N, R3 is methyl, R6 and R7 are H, R1 and R2 are as defined above, can be prepared by coupling between a 1-phenyl-pyrazole-3-carboxylic acid, and a derivative of piperazine according to reaction scheme 15 HON ~ O ~ 1) AcOH H02C 1) (COCI) 2, CHZCIZ ~ - ~ O
R1 ~ N ~ NH + ~ reflux ~ R1-N N
COzEt ~ .N. ~ U '-2) NaOH R2 N
2) R2- ~ NH RZ ~ N ~ N
THF, TEA
Figure 15 In this scheme, a phenylhydrazine, optionally in salified form, is condensed on an a-methyloxime of an a, y-diketoester in an acid medium to produce a mixture of 5-methyl-2-phenyl-2H-pyrazole-3- acids 1 ~
carboxylic and 5-methyl-1-phenyl-1 H-pyrazole-3-carboxylic. The acid 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid is isolated and then engaged in an amidation reaction between the carboxylic function beforehand activated pyrazole and an amine such as 4-aryl-piperazine in the middle basic to result in a product according to the invention.
5-alkyl-2-phenyl-2H-pyrazole-3-carboxylic and 5-alkyl-1-phenyl-1 H-pyrazole-3-carboxylic can be obtained and isolated in the conditions described by Ashton, in J. Het. Chem., 30, 307 (1993).
More specifically and more particularly advantageously in the within the framework of the invention, products in accordance with the invention can also hearths prepared on solid phase, according to reaction scheme 16 ~ \
OFFN '~ OH OFF R2 ~~ N \ / OH ~~ N \ / O N'N ---- ~ R1- NO R2 FF DMFP HFFO \ ~ DMF ~ ~ f ~ 1 8 p.m. 4 p.m. ~ N
Figure 16 More specifically and more particularly advantageously in the within the framework of the invention, products of general formula (la) in accordance with the invention in which L is C (~), X is N, R3 is different from H or methyl, R6 and R7 are H, R1 and R2 are as defined above, can be prepared from a product of general formula (la) in which R3 is a bromine atom or a bromomethyl radical or a radical formyl according to reaction schemes 17, 18 and 19:
not EtO2C \ - ~ / - '\ OO
R2'N '~ Br ~ R1-NV / -. ~ R1- V
LIKE3 \
R2 N'N Br R2 ~ N, N ~ R3 R3 = alkenyl, alkynyl, aryl, heteroaryl N (R7) (R8), ORB, SR8 ....
Figure 17 not EtO2C U ~ - ~ O ~ O
R1-N ~ ~ R1-N
R2'N ~~ AIMe,, Br 3 R2'N ~ N Br R2'N ~ NX _ 'R'3 X '= O, S, N (R7) R'3 = R8 Figure 18 - ~

Et02C ~ -J / - ~ O - / - ~ 0 R1-N N R1-N NX '= N (R7) .N. ~ ~ V - ~ V - R'3 = R8 R2 N \ O AIMe3, N, ~~, N, ~~
R2 N \ O R2 NX _ R'3 O
/ ~ ~ OO
R1- U - R1-N ~ R1 , "- ~ OH -R2'N'N N_ ~ ~ .NN ~ ~ .NN ~ X_R3 X '= O, N (R7) O
R'3 = R8 O

~ / - X'_R ~ 3 i R2'N ~ N
X '= O, N (R'T) R '3 = R 8 Figure 19 It is also advantageous, within the framework of the invention, to modify the stages) final (final) of the synthesis, the substitutes carried by the radicals R1 and / or R2, which represent substituted aryl or heteroaryl groups, by conventional methods known to those skilled in the art; like, as nonlimiting, reduction of a nitro radical to an amino radical, alkylation a phenol or thiophenol radical in ether or thioether of phenol, hydrolysis of a cyano radical into carboxy or carboxamide radical, acylation of a radical amino to amide, esterification or amidation of a carboxy radical.
The general methods of synthesis presented in diagrams 1 to 16 illustrate, without limitation, the possible preparations of the compounds of the invention. Many other synthetic routes can be used, especially 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 AN 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 AR
10 Jones et al (Academic Press);
Organic Chemistry in Monographs "Chemistry of Pyrroles, 15 (1974) by A. Gossauer (Springer Verlag).
The examples below illustrate, without limitation, the products of the invention.

15 General conditions 1. Reactions using onfi microwaves were carried out on a Personal Chemistry EmrysT "" Optimizer in EmrysTM
process vials of 0.5-2.0 ml or 2.0-5.0 ml.
2. Unless specific conditions explicitly described - as per 20 example for the products of the library example 3 - analyzes LC / MS are carried out under the conditions below - column X Terra RP ~ $ 2,1x50 mm 3,5 pm - oven 40 ° C, flow rate = 0.7 ml / min, injection volume V = 10 µl -eluent A: H20 + 0.1% HCOOH pH = 2 B: CH3CN
time (min) A% B%
0.0 95 5 5.0 5 95 6.5 5 95 7.0 95 5 9.0 95 5 - SM / ES detection positive and negative modes CV = 50V, m / z 50-DAD ~, = 200 to 400 nm ELSD T evaporation = 75 ° C, T nebulization = 80 ° C, flow rate = 1 I / min 3. Unless specific conditions explicitly described, the purifications by LC / MS preparations are carried out under the conditions below - column X Terra RP ~ $ 30x100 mm 5 pm -eluents:
i) pH = 5 A: 20 mM aqueous solution ammonium hydrogen carbonate + HCOOH (up to pH = 5) /
B: CH3CN, or ü) pH = 9 A: 20 mM aqueous solution ammonium hydrogen carbonate + ammonia (up to pH =
9) / B: CH3CN
- time (min) flow rate (ml / min) A% B%
0.0 10 70 30 3.0 30 50 50 4.0 30 40 60 11.0 30 0 100 12.5 30 0 100 12.9 20 0 100 - detection: SM / ES positive and negative modes CV = 20V, m / z 100-Example 1 [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone To a solution of 387 mg of 5-methyl-2-phenyl-2H-pyrazole-3 acid carboxylic acid, which can be obtained according to J. Het. Chem., 30, 307 (1993). in 4 mL of dichloromethane is added at 0 ° C, a solution of 250 pL
of oxalyl chloride in 1 mL of dichloromethane. To this reaction mixture a drop of dimethylformamide is added. After 3 hours of agitation at a temperature close to 20 ° C., the reaction mixture is concentrated to dry, taken up in 5 mL of tetrahydrofuran then added slowly to a 413 mg solution of 1- (3-chlorophenyl) -piperazine and 402 pL of triethylamine in 5 mL of tetrahydrofuran.
After 18 hours of stirring at room temperature, the reaction mixture is concentrated to dryness. The brown paste obtained is taken up in 20 ml of acetate ethyl, then washed 3 times with 10 ml of distilled water. The organic phase is dried over magnesium sulfate and then concentrated to dryness under pressure scaled down. After purification on silica (eluent cyclohexane / acetate ethyl) 402 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone are collected as a white powder with the following characteristics IR spectrum (KBr): 2835; 1634; 1593; 1500; 1445; 1236; 1003; 944;
762 and 692 cm ~
1 H NMR spectrum (300 MHz, (CD3) ZSO d6, b 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 1 H); 6.83 (dd, J = 8 and 1.5 Hz: 1 H); 6.86 (dd, J = 8 and 1.5 Hz: 1 H);
6.92 (t, J = 1.5 Hz: 1 H); 7.23 (t, J = 8 Hz: 1 H); 7.36 (tt, J = 7 and 2 Hz: 1 H) ; 7.40 at 7.55 (mt: 4H).
Example 2 [4- (3,4-dimethylphenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, but in replacing 1- (3-chlorophenyl) -piperazine with 400 mg of 1- (3,4-dimethylphenyl) -piperazine, 285 mg of [4- (3,4-dimethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone are obtained in the form a pale yellow solid with the following characteristics IR spectrum (CCI4): 2921; 2862; 2819; 1646; 1504; 1473; 1446; 1305;
1236; 1002 and 692 cm '~
1 H NMR spectrum (300 MHz, (CD3) 2S0 d6, â in ppm): 2.12 (s 3H); 2.17 (s: 3H); 2.30 (s: 3H); 2.71 (mt: 2H); 3.01 (mt: 2H); from 325 at 3.40 (mt: 2H); 3.68 (mt: 2H); 6.52 (s: 1H); 6.59 (dd, J = 8 and 2 Hz: 1 H);
6.70 (d, J = 2 Hz: 1 H); 6.97 (d, J = 8 Hz: 1 H); 7.36 (tt, J = 7 and 2 Hz : 1 H);
from 7.40 to 7.55 (mt: 4H).
Example 3 Example 3 below presents an application of the use of the general synthesis presented on diagram 16. In this case, N-phenyl piperazine and 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid can be substituted by radicals as defined above, to obtaining products according to the invention.
Library overview To a suspension of 50 mg of tetrafluorophenyl resin (IRORI, single sphere 200; 0.99 mmol / g substitution), in 0.6 mL of dimethylformamide are added 100 μL of a molar solution of N, N-düsopropylcarbodümide in the DMF, 100 NL of a decimolar solution of N-Dimethylaminopyridine in the DMF, then finally 200 pL of a 0.5 mol / L solution in DMF of acids corresponding pyrazoles. The reaction mixtures are allowed to stir at room temperature for 18 hours then filtered. The resins are then washed 3 times with 1 mL of DMF then alternately 4 times with 1 mL of CH2CI2 and 4 times with 1 ml of methanol then finally 2 times with 1 ml of CH2CI2.
The resins are dried in ambient air.
A solution containing 0.5 mol / L of substituted phenylpiperazine, and 0.75 mol / L of triethylamine, is added to a suspension of 50 mg of resin previously obtained in 0.9 mL of dimethylformamide. The middle reaction is kept under stirring for 18 hours then filtered. The residual resin is washed twice with 0.5 mL of dimethylformamide. The filtrate is concentrated to dryness and the oils obtained are purified by chromafiography high performance liquid coupled to a mass spectrometer (LC / MS).
Purification by LC / MS
Products were purified by LC / MS using a Waters system FractionsLynx composed of a Waters model 600 gradient pump, a Waters model 515 regeneration pump, Waters dilution pump Reagent üfianager, of a Waters model 2700 auto-injector, of two valves Rheodyne LabPro model of a Waters diode array detector model 996, a Waters mass spectrometer model ZMD and a Gilson fraction collector model 204. The system was controlled by the Waters FractionLynx software. Separation was carried out alternately on two Waters Symmetry columns (C ~ 8, 5 pM, 19x50 mm, reference catalog 186000210), a column being regenerated by a 95/5 (v / v) water / acetonitrile mixture containing 0.07% (v / v) of acid trifluoroacetic, while the other column was being separated.
Elution from columns was performed using a linear gradient of 5 at 95% acetonitrile containing 0.07% (v / v) trifluoroacetic acid in water containing 0.07% (v / v) trifluoroacetic acid, at a flow rate of 10 mL / min. To the leaving the separation column, one thousandth of the effluent is separated by a LC Packing Accurate, diluted with methyl alcohol at a flow rate of 0.5 mL / min and sent to the detectors, 75% to the bar detector diodes, and the remaining 25% to the mass spectrometer. The rest of the effluent (999/1000) is sent to the fraction collector where the flow East eliminated until the mass of the expected product is not detected by the software FractionLynx. Molecular formulas of expected products are provided FractionLynx software which triggers product collection when the signal mass detected corresponds to the ion [M + H] + and / or to [M + Na] +. In some case, depending on the results of analytical LC / MS, when an intense ion corresponding to [M + 2H] ++ was detected, the value corresponding to half of the calculated molecular mass (MW / 2) is also provided to the software FractionLynx. Under these conditions, the collection is also triggered when the signal of mass of the ion [M + 2H] ++ and / or [M + Na + H] ++ are detected. The products were collected in tared glass tubes. After collection, solvents have been evaporated in a Savant AES 2000 centrifugal evaporator or Genevac HT8 and the product masses were determined by weighing the tubes after evaporation of the solvents.
LC / MS analyzes were performed on a model Micromass device LCT connected to an HP 1100 device. The abundance of products was measured at using an HP G1315A diode array detector on a waveband from 200-600 nm and a Sedex 65 light scattering detector.
Mass spectra mass spectra were acquired on a range from 180 to 800. The data was analyzed using software Micromass MassLyna ~. Separation was performed on a Hypersil column BDS C18, 3 Nm (50 x 4.6 mm), eluting with a linear gradient from 5 to 90 acetonitrile containing 0.05% (v / v) trifluoroacetic acid (TFA) in the water containing 0.05% (v / v) TFA in 3.5 min at a flow rate of 1 mL / min: The total time analysis, including the column rebalancing period, is 7 min.
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-tetrahydro-pyrdin-1-yl) - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone To a solution of 300 mg of 5-methyl-2-phenyl-2H-pyrazole-3- acid carboxylic acid, which can be obtained according to J. Het. Chem., 30, 307 (1993) in 15 mL of dichloromethane, 316 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodümide (EDCI) and 20 mg hydrate 25, 1-hydroxybenzotriazole (HOBT). After 10 minutes of stirring at temperature ambient, 230 μL of triethylamine (TEA) and 323 mg of 4-phenyl-1,2,3,6-terahydropyridine hydrochloride then this mixture The reaction mixture is stirred for 36 hours at room temperature. After addition of 10 mL of water, the organic phase is decanted, then washed with water, dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a silica column (60; 35-70 pM), eluting with a mixture of cyclohexane and ethyl acetate (75/25 in volumes), 300 mg of (4-phenyl-1,2,3,6-tetrahydro-pyrdin-1-yl) - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, in the form of a meringue white with the following characteristics Melting point (Kofler) = 68 ° C
Mass spectrum (EI): m / z = 343 (M +) Example 5 [4- (3-chlorophenyl) -piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl) -methanone The procedure is similar to Example 1, but from 500 mg of acid 2-phenyl-2H-pyrazol-5yl-carboxylic acid, which can be prepared according to Heterocycles, 23, 943 (1985), 575 mg of 1- (3-chlorophenyl) -piperazine and 342 μL of oxalyl chloride in 20 ml of dichloromethane to obtain, after purification by flash chromatography on a silica column (60; 35-70 IaM), eluting with a mixture of dichloromethane and methanol (98/2 in volumes), 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 with the following characteristics Mass spectrum (EI): m / z = 366 (M +) Example 6 [4- (3-chlorophenyl) -piperazin-1-yl] - (1-phenyl-1 H-pyrrol-2-yl) -methanone The procedure is similar to Example 1, but from 187 mg of acid 1-phenyl-1 H-pyrrol-2yl-carboxylic acid, which can 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 dichloromethane to obtain, after purification by flash chromatography on a silica column (60; 35-70 pM), eluting with a mixture of dichloromethane and methanol (98/2 in volumes) then recrystallization from isopropyloxide, 200 mg of [4- (3-chlorophenyl) -piperazin-1-yl] - (1-phenyl-1 H-pyrrol-2-yl) -methanone, under form of white crystals with the following characteristics Mass spectrum (EI): m / z = 365 (M +) Melting point (Kofler) = 105 ° C
Example E2 [4- (3,5-dichloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example1), but replacing 1- (3-chlorophenyl) -piperazine with 486 mg of 1- (3,5-dichlorophenyl) -piperazine, we obtain 147 mg of [4- (3,5-dichlorophenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, as a white solid with the following characteristics IR spectrum (KBr): 2924; 2852; 1629; 1587; 1554; 1502; 1463; 1288;
1241; 982; 963; 794; 764; 691 and 672 cm ~
1 H NMR spectrum (400 MHz, (C ~ 3) ~ SO d6.5 in ppm): 2.31 (s 3H); 2.98 (mf: 2H); 3.25 (mf: 2H); 3.37 (mf: 2H); 3.67 (mf: 2H); 6.54 (s 1 H); 6.85 to 7.00 (mt: 3H); 7.37 (tt, J = 7.5 and 1.5 Hz: 1 H); 7.45 (d large, J = 7.5 Hz: 2H); 7.50 (wide t, J = 7.5 Hz: 2H).
Exemale E3 [4- (3 ~ iméthylamino-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone.
Step 1: To a solution of 1.2 g of N, N-dimethyl-benzene-1,3-diamine, which can be obtained according to J. Org. Chem., 57, 5254 (1992), in 15 mL of n-butanol, 1.6 g of bis- (2-chloroethyl) amine hydrochloride are added and 2.86 g of sodium carbonate. After 18 hours of heating at reflux, are added 50 mL of dichloromethane and 40 mL of water, the organic phase is decanted, then washed with 40 mL of water, dried over magnesium sulfate and concentrated under reduced pressure. 2.35 g of dimethyl- (3-piperazin-1-yl-phenyl) -amine in the form of a viscous brown oil used as is in the next step and whose characteristics are following Mass spectrum IC m / z = 206 MH + base peak Step 2: To a solution of 303 mg of 5-methyl-2-phenyl-2H-pyrazole-3- acid carboxylic acid, which can be obtained according to J. Het. Chem., 30, 307 (1993) in 15 mL of dichloromethane, 316 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodümide (EDCI), 20 mg hydrate 1-hydroxybenzotriazole (HOBT) and 0.48 g of dimethyl- (3-piperazin-1-yl-phenyl) -amine, this reaction mixture is stirred for 36 hours at ambient temperature. After adding 20 mL of water, the organic phase is decanted, then washed with water, dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash-chromatography on a silica column (60; 35-70 pM), eluting with a mixture of cyclohexane and ethyl acetate (60/40 by volume), one obtains 140 mg of [4- (3-dimethylamino-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone. in the form of a white meringue whose features are as follows 1 H NMR spectrum (400 MHz, (CD3) ~ SO d6, â in ppm): 2.31 (s 3H); 2.76 (mf: 2H); 2.87 (s: 6H); 3.08 (mf: 2H); 3.33 (mf: 2H); 3.70 (mf 2H); 6.18 (t, J = 2 Hz: 1 H); 6.22 (dd, J = 8.5 and 2 Hz: 1 H); 6.26 (dd, J = 8.5 and 2 Hz: 1 H); 6.54 (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).
Exemale E4 [4- (6-Chloro-pyridin-2-yl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 745 mg of 1- (6-chloro-2-pyridinyl) -piperazine, which can be obtained according to the patent US 4078063, 900 mg of [4- (6-chloro-pyridin-2-yl) -piperazin-1-yl] are obtained -(5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, in the form of a meringue white with the following characteristics NMR spectrum ~ H (300 MHz, (CD3) ZSO d6, b in ppm): 2.31 (s 3H); 3.22 (mf: 2H); 3.36 (mf: 2H); 3.51 (mf: 2H); 3.66 (mf: 2H); 6.54 (s 1 H); 6.71 (d, J = 7.5 Hz: 1 H); 6.76 (d, J = 8 Hz: 1 H); 7.36 (t wide, J = 7 Hz: 1 H); from 7.40 to 7.55 (mt: 4H); 7.58 (dd large, J = 8 and 7 Hz: 1 H).

Example E5 [4- (3-vitro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 683.8 mg of 1- (3 nitro-phenyl) -piperazine, which can be obtained according to J. Med. Chem., 32, 7052 (1989), 500 mg of [4- (3-vitro-phenyl) -piperazin-1-yl] - (5-methyl-2) are obtained.
phenyl-2H-pyrazol-3-yl) -methanone, in the form of a yellow solid, the features are as follows Melting point (Kofler): 142 ° C
1 H NMR spectrum (300 MHz, (CD3) ZSO d6, â in ppm): 2.31 (s large: 3H); 3.00 (mf: 2H); 3.28 (mf: 2H); 3.42 (mf: 2H); 3.73 (mf:
2H);
6.56 (s: 1H); from 7.30 to 7.65 (mt: 9H).
Example E6 [4- (3-Sromo-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 1.25 g of 1- (3-bromo-phenyl) -piperazine, which can be obtained according to Chem. Pharm. full.
50, 453 (2002), 1.65 g of [4- (3-bromo-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, in the form of a white solid with the following characteristics Melting point (Kofler): 138 ° C
1 H NMR spectrum (300 MHz, (CD3) ~ SO d6.8 in ppm): 2.30 (s 3H); 2.87 (mf: 2H); 3.17 (mf: 2H); 3.38 (mf: 2H); 3.69 (mf: 2H); 6.54 (s 1 H); 6.89 (dd, J = 8.5 and 2 Hz: 1 H); 6.97 (dd large, J = 8.5 and 1.5 Hz:
1 H);
7.06 (broad s: 1 H); 7.17 (t, J = 8.5 Hz: 1H); 7.37 (tt, J = 7.5 and 1.5 Hz: 1 H);
from 7.40 to 7.55 (mt: 4H).
Exemale E7 [4- (3-Chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -méthanethione.
To a solution of 0.2 g of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, obtained in Example 1, in 10 ml of toluene, 212 mg of Lawesson reagent are added. After 1 hour 30 minutes of reflux and addition of 10 mL of ethyl acetate, the organic phase is decanted and then washed with 30 mL of saturated bicarbonate solution sodium and dried over magnesium sulfate, then concentrated under pressure scaled down. After purification by flash chromatography on a silica column (60; 35-70 pM), eluting with a mixture of cyclohexane and acetate ethyl (80-20 by volume), 130 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanethione under shape of a white meringue with the following characteristics Melting point: (Kofler) = 95-98 ° C
1 H NMR spectrum (300 MHz, (CD3) ZSO d6 with addition of a few drops of CD3COOD d4, 8 in ppm): 2.29 (broad s: 3H); from 2.80 to 3.70 (mf spread: 6H); from 4.00 to 4.50 (spread mf: 2H); 6.42 (broad s: 1 H); of 6.70 to 6.90 (mt: 3H); 7.21 (wide t, J = 8 Hz: 1 H); 7.33 (large t, J = 7 Hz: 1 H); of 7.40 to 7.55 (mt: 4H).
Example E8 [4- (6-Methoxy-pyridin-2-yl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone To a 300 mg solution of [4- (6-Chloro-pyridin-2-yl) -piperazin-1-yl] - (5 methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, described in Example E4, in 10 ml of methanol are added 169 mg of sodium methylate. After 48 reflux hours and concentration under reduced pressure, the crude mixture is purified by flash chromatography on a silica column (60; 35-70 pM), eluting with a mixture of cyclohexane and ethyl acetate (70-30 in volumes), 9 mg of [4- (6-methoxy-pyridin-2-yl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone as a white solid with the following characteristics 1 H NMR spectrum (300 MHz, (CD3) ZSO d6, â in ppm): 2.30 (s large: 3H); 3.20 (mf: 2H); 3.33 (mf: 2H); 3.49 (mf: 2H); 3.66 (mf:
2H);
3.77 (s: 3H); 6.08 (d, J = 7.5 Hz: 1 H); 6.30 (d, J = 8 Hz: 1 H); 6.54 (s 1 H); 7.37 (wide t, J = 7.5 Hz: 1 H); from 7.40 to 7.55 (mt: 5H).
Example E9 [4- (3-Amino-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone.

To a solution of 350 mg of [4- (3-nitro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone described in Example E5, in 10 mL
absolute ethanol, 9.5 mg of 10% palladium on carbon and hydrogen is supplied at a pressure of approximately 1 bar and at a temperature 5 near 20 ° C. After 20 hours of reaction, the catalyst is filtered and the filtrate is concentrated under reduced pressure. The residue is purified by flash-chromatography on a silica column (60; 35-70 pM), eluting with a mixture of cyclohexane and ethyl acetate (30/70 by volume), one obtains thus 265 mg of [4- (3-amino-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-10 pyrazol-3-yl) -methanone in the form of a white solid, the features are as follows Melting point (Kofler): 158 ° C
Mass spectrum (EI): m / z = 361 (M +) 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6, s in ppm): 2.30 (s 15 wide: 3H); 2.69 (mf: 2H); 2.98 (mf: 2H); 3.33 (mf: 2H); 3.67 (mf:
2H);
4.90 (broad s: 2H); from 6.00 to 6.10 (mt: 3H); 6.52 (s: 1H); 6.85 (t large, J =
8 Hz: 1 H); 7.37 (tt, J = 7 and 1.5 Hz: 1 H); from 7.30 to 7.55 (mt: 4H).
Example E10 [4- (3-Cyano-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -20 methanone To a solution of 0.5 g of [4- (3-bromo-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone described in Example E6, in 20 mL of toluene, 69 mg of sodium cyanide, 285 mg of palladium are added tetrakis-triphenylphosphine and 140 mg of aluminum oxide. After 8 p.m.
25 reflux and addition of 50 mL of ethyl acetate, the organic phase is decanted then washed with 2 times 50 mL of water and dried over sulphate magnesium. After purification by flash chromatography on a column of silica (60; 35-70 pM), eluting with a mixture of cyclohexane and acetate ethyl (60/40 by volume), 125 mg of [4- (3-cyano-phenyl) - are thus obtained 30 piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone as a white solid with the following characteristics Melting point (Kofler): 136 ° C
Mass spectrum (EI): m / z = 371 (M +) 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6, â in ppm): 2.31 (s 3H); 2.96 (mf: 2H); 3.24 (mf: 2H); 3.37 (mf: 2H); 3.70 (mf: 2H); 6.54 (s 1 H); from 7.15 to 7.55 (mt: 9H).
Exemale E11 [4- (3-trifluoromethyloxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 462 mg of 1- (3-trifluoromethyloxy-phenyl) -piperazine, which can be obtained according to J. Med.
Chem., 22, 554 (1979), 425 mg of [4- (3-trifluoromethyloxy-phenyl) - are obtained.
piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, as a white solid with the following characteristics Melting point (Kofler): 107 ° C
Mass spectrum (EI): m / z = 430 (M +) Exemale E12 [4- (1,3-benzodioxol-5-yl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 505 mg of 1- (1,3 benzodioxol-5-y) I-piperazine, which can be obtained according to Tetrahedron Lett., 39, 617 (1998), 920 mg of [4- (1,3-benzodioxol-5-yl) -piperazin-1 are obtained.
yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, as a solid white with the following characteristics Melting point (Kofler): 128 ° C
Mass spectrum (EI): m / z = 390 (M +) Example E13 [4- (3-Hydroxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chlorophenyl) -piperazine with 171 mg of 1- (3-hydroxy-phenyl) -piperazine, we obtain 258 mg of [4- (3-hydroxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, as of a solid with the following characteristics 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6, b in ppm): 2.30 (s 3H); 2.73 (mf: 2H); 3.03 (mf: 2H); from 3.25 to 3.40 (mf: 2H); 3.67 (mf:
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: 1 H); 7.36 (tt, J = 7 and 1.5 Hz: 1 H); from 7.40 to 7.55 (mt : 4H);
9.17 (s: 1 H).
Example E14 [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methane Step 1: To a solution of 404 mg of 5-methyl-2-phenyl-2H-pyrazole-3- acid carboxylic acid, 360 mg of 1- (3-dimethylaminopropyl) -3-ethyl- hydrochloride carbodümide and 270 mg of 1-hydroxybenzotriazole in 10 mL of dichloromethane, 195 mg of O, N-dimethyl hydrochloride are added hydroxylamine and 300 μL of triethylamine. After 96 hours of agitation at one temperature close to 20 ° C, the medium is diluted with 20 mL of dichloromethane, decanted, washed with 20 mL of 1 N acid solution hydrochloric then three times with 15 mL of distilled water. After drying on magnesium sulfate, concentration under reduced pressure and purification by flash chromatography on a silica column (60; 35-70 pM), eluting with a mixture of dichloromethane and methanol (gradient from 100 to 90 ° / ~ of dichloromethane by volume), 360 mg of N-methoxy-N-methyl-5-methyl-2-phenyl-2H-pyrazole-3-carboxamide are obtained, and used directly for the next step.
Etaae 2: To a suspension of 69 mg of mixed lithium hydride and of aluminum in 3.2 mL of ethyl ether is added at a temperature close to - 60 ° C, 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. After that the temperature has risen to 5 ° C, a solution of 315 mg sodium hydrogen sulfate in 1.1 ml of distilled water is added.
After dilution with 20 mL of ethyl ether, the organic phase is decanted, then washed twice with a 1 N solution of hydrochloric acid, at a temperature close to 0 ° C, twice with a saturated solution sodium hydrogencarbonate, once with saturated chloride solution sodium, dried over magnesium sulfate and concentrated under pressure scaled down. The concentrate is dissolved in 5 mL of dichloromethane and 200 mg of manganese dioxide are added. After 18 hours of agitation at a temperature close to 20 ° C., the medium is concentrated under pressure reduced, taken up in 20 ml of ethyl acetate, filtered in the presence of celite, then concentrated under reduced pressure to obtain 266 mg of 5-methyl-2-phenyl-2H-pyrazole-3-carboxaldehyde in the form of a meringue, used as it is in the next step after control by LC / MS analysis.
Etaae 33: To a solution of 39 mg of 1- (3-chlorophenyl) -piperazine in mL of acetonitrile, are added 55.8 mg of 5-methyl-2-phenyl-2H-10 pyrazole-3-carboxaldehyde, 17 pL acetic acid and 380 mg of sieve 3 A molecules in powder. After 2 hours of stirring at a temperature near 20 ° C, 18.9 mg of sodium cyanoborohydride are added.
After 48 hours of stirring at a temperature close to 20 ° C, 200 pL of water distilled are added. After filtration, concentration under pressure scaled down, then purification by LC / MS, 13 mg of trifluoroacetate of [4- (3-Chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methane, 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 H NMR spectrum (400 MHz, (CD3) 2S0 d6, at a temperature of 373 K, â in ppm): 2.27 (s: 3H); 2.69 (mf: 4H); 3.10 to 3.35 (mf: 4H);
3.75 (broad s: 2H); 5.33 (s: 1H); 6.80 (broad d, J = 8 Hz: 1 H); 6.88 (dd, J =
8 and 2 Hz: 1 H); 6.92 (mt: 1H); 7.22 (t, J = 8 Hz: 1 H); 7.42 (t wide, J = 7.5 and 1.5 Hz: 1H); 7.52 (wide t, J = 7.5 Hz: 2H); 7.62 (d wide, J = 7.5 Hz 2H).
Example E15 [4- (Isoquinolin-1-yl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-) hydrochloride pyrazol-3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 100 mg of 1- (piperazin-1-yl) isoquinoline, which can be obtained according to the patent WO 2002002568, 93 mg of [4- (isoquinolin-1-y) I hydrochloride are isolated piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone; form a white solid with the following characteristics Melting point (Kofler): 128 ° C
Mass spectrum (EI): m / z = 433 (M +) Example E16 [4- (4-Chloro-3-methyl-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol 3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 99.8 mg of 1- (4-chloro-3-methyl-phenyl) -piperazine, which can be obtained from (4-chloro-3-methyl-phenyl) amine by operating as described in step 1 of example E3, 70 mg of [4- (4-chloro-3-methyl-phenyl) -piperazin-1- are obtained yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, as a solid white with the following characteristics Melting point (Kofler): 110 ° C
Mass spectrum (EI): m / z = 394 (M +) Example E17 (5-Methyl-2-p hényl-2 H-pyrazo I-3-yl) - (4-qui no I i n-4-yl-p i pe razi n-1-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 100 mg of 4- (piperazin-1-yl) -quinoline, which can be obtained according to J. Het. Chem., 33, 475 (1996), 100 mg of (5-methyl-2-phenyl-2H-pyrazol-3-yl) - [4-(quinolin-4-yl) -piperazin-1-yl] -methanone, in the form of a white meringue with the following characteristics Mass spectrum (EI): m / z = 397 (M +) Example E18 N- {3- [4- (5-methyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -phenyl} -acetamide By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 800 mg of N- (3-piperazin-1-yl-phenyl) -acetamide, which can be obtained according to Tetrahedron Lett., 35, 7337 (7994), 1 g of N- ~ 3- [4- (5-methyl-2-phenyl-2H-) is obtained.

pyrazole-3-carbonyl) -piperazin-1-yl] -phenyl) -acetamide, in the form of a beige amorphous solid with the following characteristics:
Mass spectrum (EI): m / z = 403 (M +) 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6, â in ppm): 2.03 (s 5 3H); 2.31 (s: 3H); 2.76 (mf: 2H); 3.05 (mf: 2H); 3.33 (mf: 2H);
3.71 (mf 2H); 6.53 (s: 1H); 6.58 (broad dd, J = 8 and 2 Hz: 1 H); 7.03 (d wide, J
= 8 Hz: 1 H); 7.13 (t, J = 8 Hz: 1 H); 7.18 (br s: 1H); from 7.40 to 7.55 (mt 4H); 7.36 (tt, J = 7 and 1.5 Hz: 1 H); 9.79 (broad s: 1 H).
Exemale E19 10 (5-Methyl-2-phenyl-2H-pyrazol-3-yl) - (2,3,5,6-tetrahydro- [1,2 '] bipyrazinyl-4-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but by replacing 1- (3-chloro-phenyl) -piperazine by 51 mg of 2,3,5,6-Tetrahydro- [1,2 '] bipyrazine, which can be obtained according to J. Med. Chem., 21, 536 (9978), 70 mg of (5-methyl-2-phenyl-2H-pyrazol-3-yl) - (2,3,5,6- are obtained.
tetrahydro- [1,2 '] bipyrazinyl-4-yl) -methanone, as a white solid with the following characteristics Mass spectrum (EI): m / z = 348 (M +) 20 Melting point (Kofler): 129 ° C
E ~~ emale E2 ~
[4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -Piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chlorophenyl) -piperazine with 467 mg of 1- (3,5-dimethoxy-phenyl) -piperazine, 727 mg of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, under form of a solid with the following characteristics 30 - 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6.8 in ppm): 2.31 (s 3H); 2.80 (mf: 2H); 3.10 (mf: 2H); from 3.25 to 3.40 (mf: 2H); 3.68 (mf: 2H); 3.71 (s: 6H); from 5.95 to 6.05 (mt: 3H); 6.53 (s: 1H); 7.38 (t large, J = 7 Hz: 1 H); from 7.40 to 7.55 (mt: 4H).

Example E21 (5-Methyl-2-pyridin-2-yl-2H-pyrazol-3-yl) - (4-phenyl-piperazin-1-yl) -methanone Etaae 11: To a solution of 818 mg of 5-methyl-1-H-pyrazole-3- acid 2.26 ml of carboxylic acid in 10 ml of DMF, of isopropylethylamine, 2.96 g of HATU and 1.19 ml of 1-phenylpiperazine.
After 2 hours of stirring at room temperature, the reaction mixture is poured onto 100 mL of a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The organic phase is dried over sulphate magnesium and concentrated under reduced pressure. After purification by flash-chromatography on a silica column (40-63 pM), eluting with a mixture dichloromethane, methanol and ammonia (95/5 / 0.5 by volume), obtains 3.30 g of an orange oil. The product is taken up in 210 ml of dichloromethane in the presence of 22 g of Dowex ~ 50WX8 50-100 resin mesh, the suspension stirred for 1 hour at room temperature, filtered, rinsed with dichloromethane and wrung out. The resin is then taken up by 200 mL of a mixture of methanol and ammonia 9/1 and left in contact overnight then filtered and rinsed. The concentration of the filtrate gives 1.39 g of (5-methyl-1 H-pyrazol-3-yl) - (4-phenyl-piperazin-1-yl) -methanone, in the form a pale yellow solid with the following characteristics Mass spectrum (ES): m / z = 343 (MH +) Eta ~ e 2: In a microwave reactor, 100 mg of product of step 1 14 mg of copper 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, 20 mg of 1-ethyl-3-methylimidazolium chloride then on subjects to the microwave for 15 minutes at 140 ° C. We add 60 mg of copper iodide and 40 mg of 2-bromopyridine and are subjected to again in the microwave for 15 minutes at 140 ° C. The mixture reaction is poured onto 50 ml of water and extracted with ethyl acetate. The phase organic is dried over magnesium sulfate and concentrated under pressure scaled down. After purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of toluene, ethyl acetate and triethylamine (80/20 / 0.1 by volume), 52 mg of (5-methyl-2-pyridin-2-yl-2H-pyrazol-3-yl) - (4-phenyl-piperazin-1-yl) -methanone, as a pale yellow solid with the following characteristics Mass spectrum (EI): m / z = 347 (M +) 1 H NMR spectrum (400 MHz, (CD3) ~ 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, 1 H); 6.81 ppm (tl, J = 8 Hz, 1 H); 6.97 ppm (dl, J = 8 Hz, 2H); 7.23 ppm (tl, J = 8 Hz, 2H); 7.44 ppm (ddd, J = 1.5- 7.5- 8.5 Hz, 1 H); 7.85 ppm (dl, J = 8.5 Hz, 1 H); 8.03 ppm (ddd, J = 2- 7.5- 8.5 Hz, 1 H); 8.54 ppm (dm, J = 5 Hz).
Example E22 [4- (3-Chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-pyridin-2-yl-2H-pyrazol-3-yl) -methanone Step 1: To a solution of 4.325 g of 1- (3-chlorophenyl) piperazine in 60 ml of toluene are added, at 25 ° C., 14.7 ml of 2M solution of trimethylaluminium in toluene then, after 10 minutes, 2.26 g of ester 5-methyl-1-H-pyrazole-3-carboxylic acid ethyl. The middle reaction mixture is stirred for 6 hours at 60 ° C. then poured into 100 ml a 1 M aqueous solution of double sodium and potassium tartrate and extract with ethyl acetate. The organic phase is dried over sulphate magnesium efi concentrated under reduced pressure. After purification by flash-chromatography on a silica column (40-63 pM), eluting with a mixture of ethyl acetate and triethylamine (98/2 by volume), 3.22 g of (4- (3-Chloro-phenyl) -piperazin-1-yl] - (5-methyl-2H-pyrazol-3-yl) -methanone, in the form of a pale yellow solid whose characteristics are following Mass spectrum (EI): m / z = 304 (M +) Step 2: We proceed in a similar way to step 2 of example E21 starting from 100 mg of product from step 1 of the present example to obtain, after purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of toluene, ethyl acetate and triethylamine (80/20 / 0.1 by volume), 24 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-pyridin-2-yl-2H-pyrazol-3-yl) -methanone, in the form of an oil yellow with the following characteristics LC / MS analysis: tr = 4.12; m / z = 382 (MH +) 1 H NMR spectrum (400 MHz, CDCl3, 8 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, 1 H); 6.71 ppm (dd, J = 2.5-8.5 Hz, 1 H); 6.84 ppm (m, 2H); 7.15 ppm (m, 2H); 7.78 ppm (td, J = 8-1.5 Hz, 1 H); 7.88 ppm (dl, J = 8 Hz, 1 H); 8.26 ppm (dl, J = SHz, 1 H).

Example E23 3- [4- (5-Methyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzamide By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 11.13 g of 3- (piperazin-1-yl) -benzamide, which can be obtained according to the patent WO 9800400, 11.5 g of 3- [4- (5-methyl-2-phenyl-2H-pyrazole-3-) are obtained carbonyl) -piperazin-1-yl] -benzamide, in the form of an off-white solid of which the features are as follows Mass spectrum (EI): m / z = 389 (M +) Melting point (Kofler): 186 ° C
1 H NMR spectrum (300 MHz, (CD3) 2S0 d6.8 in ppm): 2.31 (s 3H); 2.89 (mf: 2H); 3.17 (mf: 2H); 3.38 (mf: 2H); 3.72 (mf: 2H); 6.54 (s 1 H); 7.04 (broad d, J = 8 Hz: 1 H); 7.20 to 7.55 (mt: 9H); 7.89 (mf:
1 H).
Example E24 [4- (Biphenyl-3-yl) -piperazin-1-yl) - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone We proceed in a similar way to the synthesis of [4- (3-chloro-phenyl) piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 250.9 mg of 1- (biphenyl-3-yl) -piperazine which can be prepared according to the patent WO 01/021604. 93 mg of [4- (biphenyl-3-yl-piperazin-1-yl) - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, in the form of a lacquer white with the following characteristics Mass spectrum (EI): m / z = 422 (M +) Example E25 [4- (3-phenylmethyloxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol 3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine by 149 mg of 1- (3 benzyloxy-phenyl) -piperazine, which can be obtained from (3-phenylmethyloxy-phenyl) amine by operating as described in step 1 of example E3, 121 mg of [4- (3-phenylmethyloxy-phenyl) -piperazine are obtained 1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, as a solid white with the following characteristics Mass spectrum (EI): m / z = 452 (M +) 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6.8 in ppm): 2.31 (s 3H); 2.81 (mf: 2H); 3.11 (mf: 2H); 3.33 (mf: 2H); 3.68 (mf: 2H); 5.07 (s 2H); 6.40 to 6.55 (mt: 3H); 6.53 (s: 1H); 7.13 (t, J = 8 Hz: 1 H);
from 7.25 at 7.55 (mt: 10H).
Exemale E26 [4- (3-Methanesulfonyl-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol 3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine by 150.2 mg of 1- (3-methanesulfonyl-phenyl) -piperazine, which can be obtained according to the patent WO 01/046145, 18 mg of [4- (3-methanesulfonyl-phenyl) -piperazin- are obtained 1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, as a solid white with the following characteristics Mass spectrum (EI): m / z = 424 (M +) Examples E27 and E28 Tert-butyl esters and ethyl ester of 3- [4- (5-methyl-2-phenyl-2H-) acid pyrazole-3-carbonyl) -piperazin-1-yl] -benzoic acid By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine by 1.5 g of a mixture (20/80) tert-butyl and ethyl esters of 3- (piperazin-1-yl) acid -benzoic, which can be obtained according to patent WO 98/02432, one obtains 0.3 g of 3- [4- (5-methyl-2-phenyl-2H-pyrazole-3-) tert-butyl ester carbonyl) -piperazin-1-yl] -benzoic, in the form of an off-white solid of which the features are as follows Mass spectrum (EI): m / z = 446 (M +) Melting point (Kofler): 144 ° C
1 H NMR spectrum (300 MHz, (CD3) 2S0 d6, â in ppm): 1.54 (s 9H); 2.30 (s: 3H); 2.84 (mf: 2H); 3.15 (mf: 2H); 3.38 (mf: 2H); 3.71 (mf 2H); 6.54 (s: 1H); 7.14 (mt: 1H); from 7.35 to 7.55 (mt: 8H).

and 1 g of ethyl ester of 3- [4- (5-methyl-2-phenyl-2H-pyrazole-3- acid) carbonyl) -piperazin-1-yl] -benzoic, in the form of a white solid whose features are as follows Mass spectrum (EI): m / z = 418 (M +) 5 Melting point (Kofler): 134 ° C
Example E29 [4- (1,3-benzodioxol-4-yl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -Piperazine-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 0.5 g of 1- (1,3-benzodioxol-4-yl) -piperazine, which can be obtained according to J. Med. Chem., 45, 4728 (2002), 0.59 g of [4- (1,3-benzodioxol-4-yl) -piperazin-1-yl]) is obtained -(5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, in the form of a white solid 15 the characteristics of which are as follows Mass spectrum (EI): m / z = 390 (M +) Melting point (Kofler): 131 ° C
Example E30 [4- (1, 3-B enzod ioxo I-4-yl) -pi pe razi n-1-yl] - (5-m ethyl-2-m-to lyl-2 H-pyrazo I-3-yl) -20 methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 0.5 g of 1- (1,3-benzodioxol-4-yl) -piperazine, which can be obtained according to J. Med. Chem., 45, 25 4728 (2002), and replacing 5-methyl-2-phenyl-2H-pyrazole-3- acid carboxylic acid with 5-methyl-2-m-tolyl-2H-pyrazole-3-carboxylic acid, which can be obtained according to J. Het. Chem., 30, 307 (1993), 0.73 g of [4- (1, 3-benzod ioxo I-4-yl) -pi pe razi n-1-yl] - (5-m ethyl-2-m-to lyl-2 H-pyrazo I-3-yl) -methanone, in the form of a white solid whose characteristics are Next 30 Mass spectrum (EI): m / z = 404 (M +) Melting point (Kofler): 132 ° C

Example E31 (5-Methyl-2-phenyl-2H-pyrazol-3-yl) - [4- (4-methyl-pyridin-2-yl) -piperazin-1-yl] -methanone By proceeding in a similar manner to the synthesis of (4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 287 mg of 1- (4-methyl-pyridin-2-yl) -piperazine, we obtain 154 mg of (5-methyl-2-phenyl-2H-pyrazol-3-yl) - [4- (4-methyl-pyridin-2-yl) -piperazin-1-yl] -methanone, as a yellow gum with the following characteristics Mass spectrum (EI): m / z = 361 (M +) Exemale E32 [4- (3-phenylmethylamino-phenyl) -piperazin-1-yl] - (5-methyl-2- hydrochloride phenyl-2H-pyrazol-3-yl) -methanone.
Step 1: To a solution of 1.6 g of 3- (4-phenylmethyl-piperazin-1-yl) -phenylamine, which can be obtained according to patent WO 02/090327, in 50 mL of dichloromethane are added, near 0 ° C, 0.93 mL of triethylamine and 0.78 mL benzoyl chloride. After 72 hours at around room temperature and addition of 50 mL of water, the phase organic is decanted, washed with 2 times 50 mL of water, with 50 mL of saturated sodium chloride solution and dried over magnesium sulfate then concentrated under reduced pressure. After purification by flash-chromatography on a silica column (60; 35-70 pM), eluting with a mixture of cyclohexane and ethyl acetate (70-30 by volume), one obtains 1.2 g of N- (3- (piperazin-1-yl) -phenyl] -benzamide in the form of a brown solid amorphous with the following characteristics Mass spectrum IE m / z = 281 M + ' m / z = 239 (M - C2H4N) + 'base peak m / z = 105 C7H50 +
m / z = 77 C6H5 +
Step 2: To a solution of 0.5 g of N- [3- (piperazin-1-yl) -phenyl] -benzamide in 20 mL of tetrahydrofuran are added 106 mg of lithium hydride and of aluminum and the mixture is brought to the vicinity of reflux for 20 hours. There is thus obtained, after adding 1 ml of ethyl acetate, of 1 ml water, 1 mL of 1N sodium hydroxide and 1 mL of water; the insoluble is removed by filtration and after decantation, washing with 25 mL of solution aqueous saturated with sodium chloride and drying over sulfate. of magnesium, 0.5 g of phenylmethyl- [3- (piperazin-1-yl-) phenyl] -amine under form of an orange oil with the following characteristics Mass spectrum IC m / z = 282 M ~ H +
m / z = 268 MH +
m / z = 178 C ~ oH ~ 6N3 + base peak Step 3: By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 0.5 g of phenylmethyl- [3- (piperazin-1-yl) -phenyl] -amine, 200 mg of the [4- (3-phenylmethylamino-phenyl) -piperazin-1-yl] - (5-methyl-2- hydrochloride phenyl-2H-pyrazol-3-yl) -methanone, in the form of an amorphous white solid with the following characteristics Mass spectrum (EI): m / z = 451 (M +) Exemale E33 [4- (5-chloro-3-pirydinyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone Step 1: A suspension of 0.74 g of 3,5-dichloropyridine, 2.98 g of 1-terbutoxycarbonyl-piperazine, 7.33 g of cesium carbonate, 0.687 g of tris (dibenzylideneacetone) dipalladium (0), 1.96 g of 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl in 450 mL of 1,2-dimethoxyethane, esfi brought to 90 ° C for 100 hours. The medium is concentrated under pressure reduced, then taken up in 50 ml of dichloromethane and filtered in the presence of Celite. After concentration under reduced pressure and purification by flash-chromatography on a silica column (60; 35-70 NM), eluting with a mixture of cyclohexane and ethyl acetate (gradient from 100 to 50% of cyclohexane by volume), 715 mg of 1-terbutoxycarbonyl-4- (5-chloro-3-pirydinyl) -piperazine are obtained in the form of an oil whose features are as follows 1H NMR spectrum (300 MHz, (CD3) ~ SO d6.8 in ppm): 1.43 (s 9H); 3.26 (wide t, J = 5 Hz: 4H); 3.47 (broad t, J = 5 Hz: 4H); 7.45 (mt 1 H); 8.01 (d, J = 2 Hz: 1 H); 8.29 (d, J = 2.5 Hz: 1 H).
Step 2: A suspension of 680 mg of 1-terbutoxycarbonyl-4- (5-chloro-3-pirydinyl) -piperazine in 1.8 mL of 5N hydrochloric acid solution is heated at 60 ° C for 3 hours. The medium is concentrated under pressure reduced, then diluted with 20 mL of dichloromethane. After adding 5 mL of normal soda solution, the organic phase is decanted, then washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain 450 mg of 1- (5-chloro-3-pirydinyl) -piperazine, used as what in the next step.
Step 3: By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example1), but replacing 1- (3-chlorophenyl) -piperazine with 429 mg of 1- (5-chloro-3-pirydinyl) -piperazine, we obtain 286 mg of [4- (5-chloro-3-pirydinyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, in the form of a solid with the following characteristics IR spectrum (KBr): 2921; 2853; 1641 1574; 1502; 1445; 1363; 1234;
1002; 996; 946; 763 and 693 cm ~
1 H NMR spectrum (300 MHz, (CD3) 2S0 d6.8 in ppm): 2.31 (s 3H); 3.01 (mf: 2H); 3.28 (mf: 2H); 3.40 (mf: 2H); 3.70 (mf: 2H); 6.54 (s 1 H); from 7.35 to 7.55 (mt: 4H); 7.37 (tt, J = 7.5 and 1.5 Hz: 1 H); 7.41 (mt 1 H); 8.02 (d, J = 2 Hz: 1 H); 8.23 (d, J = 2.5 Hz: 1 H).
Example E34 [4- (3-Methylamino-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone Etaae 11: To a solution of 1.6 g of 3- (4-phenylmethyl-piperazin-1-yl) -phenylamine, which can be obtained according to patent WO 02/090327, in 50 mL of dichloromethane are added near 0 ° C 0.93 mL of triethylamine and 0.54 mL of methyl chloroformate. After 72 hours at around room temperature and addition of 50 mL of water, the phase organic is decanted, washed with 2 times 50 mL of water and with 50 mL of saturated sodium chloride solution, then dried over sodium sulfate magnesium and concentrated under reduced pressure. After purification by flash-chromatography on a silica column (60; 35-70 pM), eluting with a mixture of cyclohexane and ethyl acetate (70-30 by volume), one obtains 0.6 g of methyl ester of [3- (4-phenylmethyl-piperazin-1-yl) -phenyl] acid -carbamic, in the form of an orange oil whose characteristics are the following Mass spectrum (EI): m / z = 325 (M +) Etaae 22: By proceeding similarly to step 2 of example E34, but replacing the N- [3- (piperazin-1-yl) -phenyl] -benzamide with 1.5 g of ester [3- (4-Phenylmethyl-piperazin-1-yl) -phenyl] -carbamic acid methyl obtains 1.3 g of [3- (4-phenylmethyl-piperazin-1-yl) -phenyl] -methylamine, in the form of an orange oil with the following characteristics Mass spectrum IE m / z = 281 M + 'base peak m / z = 266 (M - CH3) +.
m / z = 190 (M - C ~ H ~) +
m / z = 135 CgH ~ ~ N2 +
m / z = 91 C ~ H ~ +
Etaae 33: To a solution of 1.3 g of [3- (4-phenylmethyl-piperazin-1-yl) -phenyl] -methylamine in 65 mL of methanol under an inert atmosphere, are 1.16 g of ammonium formate and 53 mg of palladium on carbon are added to %. After heating near reflux for 4 hours, the catalyst 15 is filtered through velite and the filtrate is concentrated under reduced pressure. 20 ml of water and 1 mL of 1N sodium hydroxide are added and then extracted 3 times mL of 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 silica column (60; 35-70 20 ~ rM), eluting with a mixture of dichloromethane and methanol (90-10 in volumes), 0.8 g of methyl- [3- (piperazin-1-yl) -phenyl] -amine is obtained, under form of an orange oil with the following characteristics Mass spectrum IE m / z = 191 M + ' m / z = 149 (M - C2H4N) + 'base peak Step 44: By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, but replacing 1- (3-chloro-phenyl) -piperazine with 0.5 g of methyl- [3-(piperazin-1-yl) -phenyl]) - amine, 0.31 g of [4- (3-methylamino-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, under shape of a beige meringue with the following characteristics Mass spectrum (EI): m / z = 375 (M +) Example E35 3-Hydroxy-2- {3- [4- (5-methyl-2-phenyl-2H-) methyl ester pyrazole-3-carbonyl) -piperazin-1-yl] -benzoylamino} -propionic acid Step 1: To a solution of 4.4 g of ethyl ester of 3- [4- (5-methyl-2- acid) phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzoic acid, described in Example E28, in 75 ml of distilled water and 150 ml of methanol, are added 763 mg of potassium hydroxide in pellets. After 8 p.m.
5 room temperature, the reaction mixture is concentrated under pressure reduced 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-methyl 2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzoic acid, in the form of pale yellow solid with the following characteristics 10 Melting point (Kofler): 206 ° C
1 H NMR spectrum (300 MHz, (CD3) 2S0 d6.8 in ppm): 2.30 (s 3H); 2.86 (mf: 2H); 3.15 (mf: 2H); 3.38 (mf: 2H); 3.71 (mf: 2H); 6.54 (s 1 H); 7.14 (broad d, J = 8.5 Hz: 1H); from 7.25 to 7.55 (mt: 8H); from 12.60 at 13.20 (mf very spread: 1 H).
Step 2: To a solution of 586 mg of 3- [4- (5-methyl-2-phenyl-2H-) acid pyrazole-3-carbonyl) -piperazin-1-yl] -benzoic acid, in 25 mL of dichloromethane, 316 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodümide (EDCI) and 223 mg hydrate 1-hydroxybenzotriazole (HOBT). After 10 minutes of stirring at temperature 20 ambient, are added 211 ~ pL of triethylamine (TEA) and 233 mg of 2-amino-3-hydroxypropionic acid methyl ester hydrochloride (D, L) then this reaction mixture is stirred for 20 hours at temperature room. After adding 50 mL of dichloromethane and 50 mL of water, the organic phase is decanted, then washed with water, dried over sulphate 25 magnesium and concentrated under reduced pressure. After flash flash chromatography on a silica column (60; 35-70 pM), eluting with pure ethyl acetate, 520 mg of acid methyl ester are obtained 3-hyd roxy-2- {3- [4- (5-methyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl]
benzoylamino} -propionic, in the form of a beige meringue whose 30 features are as follows Mass spectrum (EI): m / z = 491 (M +) 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6.8 in ppm): 2.31 (s 3H); 2.90 (mf: 2H); 3.19 (mf: 2H); 3.40 (mf: 2H); 3.67 (s: 3H); 3.73 (mf 2H); 3.80 (broad t, J = 5.5 Hz: 2H); 4.55 (mt: 1H); 5.06 (very wide, J = 5.5 35 Hz: 1 H); 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-Chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-pyrazin-2-yl-2H-pyrazol-3-yl) -methanone We proceed in a similar way to step 2 of example ~ E22 starting from 150 mg of product from step 1 of Example E22 and 85 mg then 39 mg of 2-chloropyrazine to obtain, after purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of dichloromethane, methanol and ammonia (98/2 / 0.1 by volume), 4 mg of [4- (3-chloro-phenyl) -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 following LC / MS analysis: tr = 3.90; m / z = 383 (MH +) 1 H NMR spectrum (400 MHz, CDCI3, b in ppm): 2.40 ppm (s, 3H);
3.11 ppm (m, 2H); 3.21 ppm (m, 2H); 3.50 ppm (m, 2H); 3.97 ppm (m, 2H);
6.32 ppm (s, 1 H); 6.80 ppm (dl, J = 8.5 Hz, 1 H); 6.89 ppm (m, 2H); 7.19 ppm (t, J = 8.5Hz, 1H); 8.23 ppm (sl, 1 H); 8.44 ppm (d, J = 2.5 Hz, 1 H); 9.24 ppm (sl, 1 H) Example E37 [4- (3-Ch lo ro-p hényl) -pi pe razi n-1-yl] - (5-methyl-2-th iazo I-2-yl-2 H-pyrazo I-3-yl) -methanone We proceed in a similar way to step 2 of example E22 starting from 150 mg of product from step 1 of Example E22 and 121 mg then 56 mg of 2-bromothiazole to obtain, after purification by flash chromatography on a silica column (30-60 NM), eluting with a mixture of toluene, ethyl acetate and triethylamine (80/20 / 0.1 by volume), 5 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-thiazol-2-yl-2H-pyrazol-3-yl) -methanone, in the form of a yellow oil with the following characteristics LC / MS analysis: tr = 4.16; m / z = 388 (MH +) 1 H NMR spectrum (400 MHz, CDCI3, 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, 1 H); 6.78 ppm (dl, J = 8.5 Hz, 1 H); 6.87 ppm (m, 2H); 7.06 ppm (d, J = 3.5 Hz, 1 H); 7.18 ppm (t, J = 8.5 Hz, 1 H); 7.45 ppm (d, J = 3.5 Hz, 1 H) Example E38 2- f 5- [4- (3-Chloro-phenyl) -piperazine-1-carbonyl] -3-methyl-pyrazol-1-yl) -nicotinonitrile We proceed in a similar way to step 2 of example E22 starting from 150 mg of product from step 1 of Example E22 and 68 mg then 32 mg of 2-chloro-3-cyanopyridine to obtain, after purification by flash-chromatography on a silica column (30-60 pM), eluting with a mixture toluene, ethyl acetate and triethylamine (80/20 / 0.1 by volume), 7 mg of 2- {5- [4- (3-chloro-phenyl) -piperazine-1-carbonyl] -3-methyl-pyrazol-1-yl) -nicotinonitrile, in the form of a white solid whose characteristics are the following LC / MS analysis: tr = 4.03; m / z = 408 (MH +) 1 H NMR spectrum (400 MHz, CDCI3, 8 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, 1 H); 6.82 ppm (dl, J = 8.5Hz, 1 H); 6.89 ppm (m, 2H); 7.21 ppm (t, J =
8.5 Hz, 1 H); 7.31 ppm (dd, J = 5-7.5 Hz, 1 H); 8.13 ppm (dd, J = 2-7.5 Hz, 1 H); 8.52 ppm (dd, J = 2-5 Hz, 1 H).
Example E39 {4- [3- (1-Hydroxy-ethyl) -phenyl] -piperazin-1-yl) - (5-methyl-2- hydrochloride phenyl-2H-pyrazol-3-yl) -methanone Step 1: To a solution of 2.78 g of N-phenylmethylpiperazine in 100 mL
toluene, 2.99 g of 3-bromo-acetophenone, 317 mg of (R) - (+) - 2,2'-bis (diphenylphosphino) -1,1'-binaphtyl, 114 mg acetate palladium and 1.59 g of sodium tert-butoxide. After 20 hours of heating at 80 ° C, the insoluble material is filtered, 25 mL of ethyl acetate and 25 mL of water are added and the organic phase is decanted, then washed with water, dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a silica column (60; 35-70 pM), eluting with a mixture of cyclohexane and ethyl acetate (20-70 by volume), obtains 0.4 g of 1- [3- (4-phenylmethyl-piperazin-1-yl) -phenyl] -ethanone, under form of an orange oil with the following characteristics Mass spectrum (EI): m / z = 294 (M +) Step 2: Proceeding similarly to step 3 of Example 34, but replacing [3- (4-phenylmethyl-piperazin-1-yl) -phenyl] -methylamine with 0.7 g of 1- [3- (4-phenylmethyl-piperazin-1-yl) -phenyl] -ethanone, we obtain 0.3 g of 1- [3- (piperazin-1-yl) -phenyl] -ethanol, in the form of an orange oil with the following characteristics Mass spectrum (EI): m / z = 294 (M +) 4 ~
Step 3: By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but by replacing 1- (3-chloro-phenyl) -piperazine with 0.3 g of 1- (3- (piperazin-1-yl) -phenyl] -ethanol, 0.15 g of hydrochloride is isolated {4- [3- (1-hydroxy-ethyl) -phenyl] -piperazin-1-yl) - (5-methyl-2-phenyl-2H-pyrazol 3-yl) -methanone, in the form of an amorphous off-white solid, the features are as follows Mass spectrum (EI): m / z = 390 (M +) Example E40 N- (2-hydroxy-ethyl) -3- [4- (5-methyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzamide By proceeding in a similar manner to the synthesis of the methyl ester of 3-hydroxy-2- {3- [4- (5-methyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzoylamino) -propionic from step 2 of example E35, but in replacing 2-amino-3-hydroxypropionic acid (D, L) with 62 pL
ethanolamine, 0.36 g of N- (2-hydroxy-ethyl) -3- [4- (5-methyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzamide, in the form of a beige meringue with the following characteristics Mass spectrum (EI): m / z = 433 (M +) 1 H NMR spectrum (300 MHz, (CD3) ZSO d6, 8 in ppm): 2.31 (s 3H); 2.87 (mf: 2H); 3.17 (mf: 2H); 3.33 (mt: 2H); 3.39 (mf: 2H); 3.52 (mt 2H); 3.73 (mf: 2H); 4.73 (t, J = 5.5 Hz: 1 H); 6.54 (s: 1H); 7.04 (mt : 1 H);
7.20 to 7.55 (mt: 8H); 8.37 (wide t, J = 5.5 Hz: 1 H).
Example E41 [4- (isoquinolin-4-yl) -piperazin-1-yl)] (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 213.3 mg of 4-piperazin-1-yl-isoquinoline, which can be obtained according to the patent DE 19900544, we obtain 320 mg of [4- (isoquinolin-4-yl) -piperazin-1-y]) - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, in the form of a white solid with the following characteristics Melting point (Kofler): 166 ° C
Mass spectrum (EI): m / z = 397 (M +) Example E42 [4- (3-Chloro-phenyl) -piperazin-1-yl] - [2- (2,4-difluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] -methanone And, aae 1: To a solution of 5.28 g of ethyl 2,4-dioxovalerate in 35 mL
of DMF and 35 ml of ethanol are added 3.35 g of hydrochloride methylhydroxylamine then 9.99 g of sodium acetate trihydrate. After 2 hours of stirring at 60 ° C, the reaction mixture is filtered and the filtrate concentrated. The oil obtained is taken up in isopropyl ether and the phase organic washed with saturated aqueous dihydrogen phosphate solution sodium, dried over magnesium sulfate and concentrated under pressure scaled down. After purification by flash chromatography on a silica column (40-63 pM), eluting with a mixture of heptane and ethyl acetate (60/40 in volumes), 2.13 g of ethyl 2,4-dioximino-valerate A are obtained, in the form a colorless liquid with the following characteristics Mass spectrum (EI): m / z = 216 (M +) Eta ~ e: To a solution of 1.65 g of 1- (3-chlorophenyl) piperazine in 45 mL of toluene are added, at 25 ° C, 5.6 mL of 2M solution of trimethylaluminium in toluene then, at 60 ° C, a solution of 1.21 g of dioxime A (step 1 of the present example) in 10 mL of toluene. The middle reaction mixture is stirred for 1 hour at 75 ° C. then poured over 100 ml a 1 M aqueous solution of double sodium and potassium tartrate and extract with ethyl acetate. The organic phase is dried over sulphate magnesium and concentrated under reduced pressure. After purification by flash-chromatography on a silica column (40-63 pM), eluting with a mixture heptane and ethyl acetate (80/20 by volume), 1.15 g of N- [4-(3-chlorophenyl) piperazin-yl] -2,4-dioximino-valeramide B, in the form of a yellow oil with the following characteristics Mass spectrum (ES): m / z = 367 (MH +) Et_ aae 3: To a solution of 110 mg of amide B in 0.6 ml of acetic acid and 0.3 mL of methylglycol is added, at 25 ° C, 108 mg of hydrochloride 2,4-difluorophénylhydrazine. The reaction medium is stirred for 3.5 hours at 100 ° C then concentrated. After purification by flash-chromatography on a silica column (40-63 pM), eluting with a mixture of heptane and ethyl acetate (70/30 by volume), 101 mg of [4- (3-Chloro-phenyl) -piperazin-1-yl] - [2- (2,4-difluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] -methanone, in the form of a pale yellow solid whose characteristics are the following:
LC / MS analysis: tr = 4.34; m / z = 417 (MH +) 1 H NMR spectrum (400 MHz, (CD3) 2S0 d6.8 in ppm): 2.29 ppm (s, 5 3H); 3.18 ppm (m, 4H); 3.66 ppm (m, 4H); 6.60 ppm (s, 1 H); 6.82 (dd, J
=
2- 8.5 Hz, 1 H); 6.91 ppm (dd, J = 2- 8.5 Hz, 1 H); 6.97 ppm (t, J = 2 Hz, 1 H);
7.22 ppm (m, 2H); 7.45 ppm (ddd, J = 2.5-9-11 Hz, 1 H); 7.61 ppm (dt, 6 9Hz, 1H).
Example E43 10 [4- (3-Chloro-phenyl) -piperazin-1-yl] - [5-methyl-2- (2,3,5,6-tetrafluoro-phenyl) -2H-pyrazol-3-yl] -methanone The procedure is similar to Example E42 from 75 mg of amide B, obtained in step 2 of Example E42, and 109 mg of 2,3,5,6-tetrafluorophenylhydrazine in the presence of 76 mg paratoluene acid-15 sulfonic monohydrate, for 9 hours at 100 ° C., to obtain, after purification by flash chromatography on a silica column (40-63 pM), eluting with a mixture of heptane and ethyl acetate (80/20 by volume), 14 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - [5-methyl-2- (2,3,5,6-tetrafluoro phenyl) -2H-pyrazol-3-yl] -methanone, in the form of a yellow solid, the 20 features are as follows LC / MS analysis: tr = 4.51; mlz = 453 (MH +) 1 H NMR spectrum (400 MHz, (CD3) ~ SO d6, b 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, 1 H); 6.83 ppm (dd, 2.5 -8.5 Hz, 1 H); 6.92 ppm (dd, J = 2.5- 8.5 Hz, 1 H);
6.98 25 ppm (t, J = 2.5 Hz, 1 H); 7.24 ppm (t, J = 8.5 Hz, 1 H); 8.10 ppm (m, 1 H) Example E44 [4- (3-Chloro-phenyl) -piperazin-1-yl] - [2- (2,5-dichloro-phenyl) -5-methyl-2H-pyrazol-3-yl] -methanone To a solution of 190 mg of amide B, obtained in step 2 of Example E42, 30 in 1.5 ml of acetic acid, at 25 ° C., 184 mg of 2.5-dichloro phenylhydrazine and 197 mg paratoluenesulfonic acid monohydrate. The reaction medium is stirred for 1.5 hours at 100 ° C and then concentrated.
After purification by flash chromatography on a silica column (60; 40-63 pM), eluting with a mixture of heptane and ethyl acetate (80/20 in 35 volumes), 84 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - [2- (2,5-dichlorophenyl) -5-methyl-2H-pyrazol-3-yl] -methanone, in the form of a yellow solid with the following characteristics LC / MS analysis: tr = 4.62; m / z = 449 (MH +) 1 H NMR spectrum (400 MHz, (CD3) 2S0 d6, â in ppm): 2.29 ppm (s, 3H); 3.20 ppm (m, 4H); 3.65 ppm (m, 2H); 3.76 ppm (m, 2H); 6.64 ppm (s, 1 H); 6.82 ppm (dd, J = 2.5- 8.5 Hz, 1 H); 6.91 ppm (dd, J = 2.5- 8.5 Hz, 1 H) ;
6.97 ppm (t, J = 2.5 Hz, 1 H); 7.23 ppm (t, J = 8.5 Hz, 1 H); 7.56 ppm (dd, 2.5 8.5 Hz, 1 H); 7.62 ppm (d, J = 2.5 Hz, 1 H); 7.63 ppm (d, J = 8.5 Hz).
Example E45 [4- (3-Chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-o-tolyl-2H-pyrazol-3-yl) -methanone To a solution of 106 mg of amide B, obtained in step 2 of Example E42 in 1.0 ml of acetic acid, 55 mg of hydrochloride are added at 25 ° C.
of orthotolylhydrazine. The reaction medium is stirred for 2 hours at 100 ° C then concentrated. After purification by flash chromatography on silica column (30-60 pM), eluting with a mixture of heptane and acetate ethyl (80/20 by volume), 22 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-o-tolyl-2H-pyrazol-3-yl) -methanone, as a white solid with the following characteristics LC / MS analysis: tr = 4.31; m / z = 495 (MH +) Example E4 ~
(1-Phenyl-1 H-pyrrol-2-yl) hydrochloride - [4- (pyridin-3-yl) -piperazin-1-yl] -methanone We proceed in a similar way to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 65.4 mg of 1- (pyridin-3-yl) -piperazine, which can be obtained according to Chem. Pharm. Bull., 49, 1314 (2001), and replacing 5-methyl-2-phenyl-2H-pyrazole-3- acid carboxylic acid per 75 mg of 1-phenyl-1 H-pyrrole-2-carboxylic acid, which can be obtained according to Synth. Commun., 28, 443 (1998). We thus isolate 77 mg of (1-phenyl-1 H-pyrrol-2-yl) hydrochloride - [(4- (pyridin-3-yl) -piperazin-1-yl] -methanone, in the form of a yellow solid whose characteristics are following Melting point (Kofler): 180 ° C
Mass spectrum (EI): m / z = 332 (M +) Exemale E47 [4- (3-Chloro-phenyl) -piperazin-1-yl] - [2- (2,5-dimethylphenyl) -5-methyl-2H-pyrazol-3-yl] -methanone The procedure is similar to Example E45 from 106 mg of amide B, obtained in step 2 of Example E42, and 60 mg of hydrochloride 2,5-dimethylphenylhydrazine to obtain, after purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture heptane and ethyl acetate (80/20 by volume), 46 mg of [4- (3-chloro phenyl) -piperazin-1-yl] - [2- (2,5-dimethyl-phenyl) -5-methyl-2H-pyrazol-3-yl]
methanone, in the form of a white solid whose characteristics are following LC / MS analysis: tr = 4.48; m / z = 409 (MH +) Exemale E48 [4- (3-Chloro-phenyl) -piperazin-1-yl] - (2-cyclohexyl-5-methyl-2H-pyrazol-3-yl) -methanone The procedure was similar to Example E45 from 106 mg of amide B, obtained in step 2 of Example E42, and 74 mg of hydrochloride cyclohexylhydrazine, for 6 hours at 100 ° C, to obtain, after purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of heptane and ethyl acetate (80/20 by volume), 70 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - (2-cyclohexyl-5-methyl-2H-pyrazol-3-yl) -methanone, in the form of a white solid, the features are as follows LC / MS analysis: tr = 4.51; m / z = 387 (MH +) Exemale E49 [4- (3-Chloro-phenyl) -piperazin-1-yl] - [5-methyl-2- (4-nitro-phenyl) -2H-pyrazol-3-yl] -methanone The procedure is similar to Example E45 from 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 paratoluenesulfonic acid monohydrate, for 4 hours at 100 ° C; to obtain, after purification by flash-chromatography on a silica column (40-63 pM), eluting with a mixture of heptane and ethyl acetate (80,120 by volume), 148 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - [5-methyl-2- (4-nitro-phenyl) -2H-pyrazol-3-yl] -methanone, under form of a yellow solid with the following characteristics LC / MS analysis: tr = 4.36; m / z = 426 (MH +) 1 H NMR spectrum (400 MHz, (CD3) 2S0 d6.8 in ppm): 2.31 ppm (s, 3H); 3.11 ppm (m, 2H); 3.28 ppm (masked, 2Hz); 3.53 ppm (m, 2H); 3.74 ppm (m, 2H); 6.66 ppm (s, 1 H); 6.81 ppm (dd, J = 2.5- 8.5 Hz, 1 H); 6.88 ppm (dd, J = 2.5- 8.5 Hz, 1 H); 6.94 ppm (t, J = 2.5 Hz, 1 H); 7.22 ppm (t, J
=
8.5 Hz, 1 H); 7.70 and 8.33 ppm (AA'BB 'system, 4H).
Example E50 [4- (3-Chloro-phenyl) -piperazin-1-yl] - [5-methyl-2- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -methanone The procedure is similar to Example E45 from 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 acid paratoluenesulfonic monohydrate, for 5 hours at 100 ° C, for get, after purification by flash chromatography on a silica column (40-63 pM), eluting with a mixture of heptane and ethyl acetate (80/20 by volume), 98 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - [5-methyl-2- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -methanone, in the form of a white solid, the features are as follows LC / MS analysis: tr = 4.61; m / z = 449 (MH +) 1 H NMR spectrum (400 MHz, (CD3) 2SO d6, â 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, 1 H); 6.82 ppm (dd, J = 2.5- 8.5 Hz, 1 H); 6.87 ppm (dd, J =
2.5- 8.5 Hz, 1 H); 6.93 ppm (t, J = 2.5 Hz, 1 H); 7.22 ppm (t, J = 8.5 Hz, 1 H);
7.66 and 7.85 ppm (AA'BB 'system, 4H).
Example E51 [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - (1-phenyl-1 H-pyrrol-) hydrochloride 2-yl) -methanone.
By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 89 mg of 1- (3,5-dimethoxy-phenyl) -piperazine and replacing 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid per 75 mg of 1-phenyl-1 H-pyrrole-2-carboxylic acid, which can be obtained according to Synth. Comm., 28, 443 (7998), on isolates 30 mg of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] hydrochloride - (1-1-phenyl H-pyrrol-2-yl) -methanone, in the form of an amorphous white solid with the following characteristics Mass spectrum (EI): m / z = 391 (M +) Exemale E52 [4- (3-Chloro-phenyl) -piperazin-1-yl] - [5-methyl-2- (pyridin-3-yl) -2H-pyrazol-3-yl] -methanone By proceeding in a similar manner to the synthesis of (4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but by replacing 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid with 203 mg of 5-methyl-2- (pyridin-3-yl) -2H-pyrazole-3-carboxylic acid, which can be obtained according to J. Het. Chem., 36, 217 (1999), 290 mg of [4- (3-ch lo ro-p hé nyl) -pi pérazi n-1-yl] - [5-m ethyl-2- (pyri di n-3-yl) -2 H-pyrazo l-3-yl] -methanone, in the form of a beige solid whose characteristics are following Melting point (Kofler): 124 ° C
Mass spectrum (EI): m / z = 381 (M +) Exemale E53 [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [5-methyl-2- (pyridin-3-yl) -2H
pyrazol-3-yl] -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - [5-methyl-2- (pyridin-3-yl) -2H-pyrazol-3-yl] -methanone (example 1), but by replacing 1- (3-chloro-phenyl) -piperazine by 602 mg of 1- (3,5-dimethoxy-phenyl) -piperazine, and 5-methyl-2-phenyl- acid 2H-pyrazole-3-carboxylic acid per 600 mg of 5-methyl-2-pyridin-3-yl-2H-pyrazole-3-carboxylic acid, which can be obtained according to J. Het. Chem., 36, 217 (1999), 800 mg of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - [5-methyl-2- (pyridin-3-y) I-2H-pyrazol-3-yl] -methanone, as a solid white with the following characteristics Melting point (Kofler): 60 ° C
Mass spectrum (EI): m / z = 407 (M +) Example E54 [4- (4-Fluoro-3-pirydinyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone By proceeding, in 3 steps, in a similar way to the synthesis of [4- (5-chloro-3-pirydinyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 33), but replacing in step 1 of the summary the 3,5-dichloropyridine per 3.52 g of 5-bromo-2-fluoropyridine, 5 step 3 of the synthesis 433 mg of [4- (4-fluoro-3-pirydinyl) -piperazin-1-yl] -(5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, in the form of a solid, the features are as follows 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6, â in ppm): 2.31 (s 3H); 2.85 (mf: 2H); 3.13 (mf: 2H); 3.39 (mf: 2H); 3.72 (mf: 2H); 6.54 (s 10 1 H); 7.05 (dd, J = 9 and 3 Hz: 1 H); 7.37 (tt, J = 7 and 1.5 Hz: 1 H);
from 7.35 to 7.60 (mt: 5H); 7.79 (dd, J = 3 and 1.5 Hz: 1 H).
Exemale E55 3- 5- [4- (3-Chloro-phenyl) -piperazine-1-carbonyl] -3-trifluoromethyl-pyrazol-1-yl} -benzonitrile 15 Proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (exemplel), but by replacing 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid with 100 mg of 2- (3-cyano-phenyl) -5-trifluoromethyl-2H-pyrazole-3- acid carboxylic acid, which can be obtained according to patent WO 02/000647, 20 72 mg of 3- ~ 5- [4- (3-chloro-phenyl) -piperazine-1-carbonyl] -3-trifluoromethyl-pyrazol-1-yl) -benzonitrile, in the form of a white meringue, the features are as follows Mass spectrum (EI): m / z = 459 (M +) Exemale E56 25 3- ~ 5- [4- (3,5-dimethoxy-phenyl) -piperazine-1-carbonyl] -3-trifluoromethyl-pyrazol-1-yl} -benzonitrile By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine by 79 mg of 1- (3,5-30 dimethoxy-phenyl) -piperazine and replacing 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid per 100 mg of 2- (3-cyano-phenyl) -5- acid trifluoromethyl-2H-pyrazole-3-carboxylic acid, which can be obtained according to WO 02/000647, we obtain 118 mg of 3- ~ 5- [4- (3,5-dimethoxy-phenyl) -piperazine-1-carbonyl] -3-trifluoromethyl-pyrazol-1-yl} -benzonitrile, under form a white meringue with the following characteristics Mass spectrum (EI): m / z = 485 (M +) Example E57 3- [4- (1-Phenyl-1 H-pyrrole-2-carbonyl) -piperazin-1-yl] -benzamide By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example1), but replacing 1- (3-chloro-phenyl) -piperazine with 113.2 mg of 3-piperazin-1-yl-benzamide, which can be obtained according to the patent WO 98/00400 and replacing 5-methyl-2-phenyl-2H-pyrazole-3- acid carboxylic acid per 75 mg of 1-phenyl-1 H-pyrrole-2-carboxylic acid, which can be obtained according to Synth. Comm., 28, 443 (1998), 65 mg of 3- [4- (1-1-phenyl H-pyrrole-2-carbonyl) -piperazin-1-yl] -benzamide, in the form of a solid amorphous beige with the following characteristics Mass spectrum (EI): m / z = 374 (M +) Example E58 [2- (3-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-pyridin-3-yl-piperazin-1-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, but in replacing 1- (3-chloro-phenyl) -piperazine with 214 mg of 1-pyridin-3-yl-piperazine which can be obtained according to Chemieal and Pharmaceufical bulletin, 49, 1314 (2001) and replacing 5-methyl-2-phenyl-2H-pyrazole-3- acid carboxylic by 288.7 mg of 2- (3-fluoro-phenyl) -5-methyl-2H-pyrazole- acid 3-carboxylic which can be obtained according to J. Het. Chem., 30, 304 (1993), 280 mg of [2- (3-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-pyridin-3-yl-piperazin-1-yl) -methanone are obtained in the form of a white powder with the following characteristics Melting point (Kofler): 132 ° C
Mass spectrum (EI): m / z = 365 (M +) Example E59 [4- (4-Bromo-3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol 3-yl) -methanone To a solution of 300 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1) in 6 ml of tetrachloride of carbon are added 140 mg of N-bromosuccinimide and 6.5 mg of 2,2'-azobis (2-methyl-propionitrile). The reaction mixture is brought to reflux under irradiation of a 250 W lamp (white light) for 3 hours then filtered and concentrated under reduced pressure. After purification by flash-s chromatography on a silica column (40-63 pM), eluting with a mixture of toluene and ethyl acetate (80/20 by volume), 350 mg of [4- (4-bromo-3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, in the form of a pale yellow oil whose characteristics are the following LC / MS analysis: tr = 4.49; m / z = 458 (MH +) 1 H NMR spectrum (400 MHz, (CD3) 2S0 d6.8 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, 2H); 6.51 ppm (s, 1 H); 6.80 ppm (dl J = 8.5 Hz, 1 H); 7.09 ppm (bs, 1 H);
7.35 ppm (tl, J = BHz, 1 H); from 7.41 to 7.52 ppm (m, 5H).
Exemale E60 (5-hydroxymethyl-2-phenyl-2H-pyrazol-3-yl) - [4- (3-Chloro-phenyl) -piperazin-1-yl] -methanone We proceed in a similar way to step 3 of example E73, from 0.3 g of 3-benzoyloxymethyl-1-phenyl-1-H-pyrazole-5 ethyl ester carboxylic obtained in step 2 of Example 73 and 537 mg of 1- (3 chlorophenyl) piperazine to obtain, after purification by flash-chromatography on a silica column (40-63 pM), eluting with a mixture dichloromethane and ethyl acetate (80/20 by volume), 253 mg of (5-hydroxymethyl-2-phenyl-2H-pyrazol-3-yl) - [4- (3-Chloro-phenyl) -piperazin-1-yl] -methanone in the form of a white solid the characteristics of which are following Mass spectrum (ES): m / z = 422 (MH +) Example E61 (5-Benzyloxy-2-pyridin-2-yl-2H-pyrazol-3-yl) - [4- (3-Chloro-phenyl) -piperazin-1-yl] -methanone Et_ ape 1: To a solution of 3.12 g of ethyl ester of 5-hydroxy-1H acid pyrazole-3-carboxylic acid, which can be prepared according to Chem. Pharm. Bull.
31 (4) 1228 (1983) using toluene instead of benzene, in 40 mL
dichloromethane and 3.1 mL of triethylamine, cooled to 0 ° C, add a solution of 4.58 g of N-terbutoxycarbonyl anhydride (Boc20) in 40 mL
dichloromethane. The reaction medium is stirred for 3 hours at room temperature, then washed with a saturated aqueous solution of sodium dihydrogen phosphate. The organic phase is dried over sulfate magnesium and concentrated under reduced pressure. After purification by flash chromatography on a silica column (40-63 pM), eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume), one obtains 3.26 g of 1-tert-butyl 3-ethyl diester of 5-hydroxy-pyrazole diacid 1,3-dicarboxylic, in the form of a white solid whose characteristics are the following Mass spectrum (ES): m / z = 257 (MH +) Step 2: A 796 mg of product from step 1 of the present example and 1.11 g of cesium carbonate in 15 mL of DMF at -5 ° C, a solution of 0.37 mL of benzyl bromide in 3 mL of DMF. The reaction medium is stirred for 3 hours at 0 ° C, then poured onto an aqueous solution saturated sodium dihydrogen phosphate and extracted with ethyl acetate. The sentence organic is dried over magnesium sulfate and concentrated under pressure scaled down. After purification by flash chromatography on a silica column (40-63 NM), eluting with a mixture of heptane and ethyl acetate (90/10 in volumes), 117 mg of 1-tert-butyl 3-ethyl diester of the diacid are obtained.
5-benzyloxy-pyrazole-1,3-dicarboxylic, in the form of a white solid of which the features are as follows Mass spectrum (ES): m / z = 347 (MH +) Step 3: At 1.50 g of product from step 2 of the example present in 12 mL
of dichloromethane at room temperature, 3 ml of acid are added trifluoroacetic. The reaction medium is stirred for 1 hour at room temperature, concentrated under reduced pressure, then purified by flash-chromatography on a silica column (40-63 pM), eluting with a mixture dichloromethane and ethyl acetate (97/3 by volume), to obtain 340 mg of 5-benzyloxy-2H-pyrazole-3-carboxylic acid ethyl ester in the form of a white solid with the following characteristics Mass spectrum (ES): m / z = 247 (MH +) Step 4: We proceed in a similar way to step 2 of example E42 starting from 320 mg of product from step 3 of the present example and 537 mg of 1- (3-chlorophenyl) piperazine to obtain, after purification by flash-chromatography on a silica column (40-63 pM), eluting with a mixture dichloromethane and ethyl acetate (80/20 by volume), 173 mg of (5-benzyloxy-1 H-pyrazol-3-yl) - [4- (3-chloro-phenyl) -piperazin-1-yl] -methanone in the form of a white solid with the following characteristics Mass spectrum (ES): m / z = 397 (MH +) Etaae 55: 100 mg of product is placed in a microwave reactor step 4 of the present example, 10 mg of copper iodide, 2.0 ml of 1,4-dioxane, 30 µL trans-1,2-diaminocyclohexane, 115 mg carbonate cesium, 37 pL of 2-bromopyridine, 30 ~ L of 1-hexyl-3-methylimidazolium pentafluorophosphate, then subjected to the microwave field for minutes at 140 ° C. Filter, rinse with 0.5 mL of 1,4-dioxane, add 10 mg of copper iodide, 30 NL of trans-1,2-diaminocyclohexane, 115 mg of cesium carbonate, 37 NI 2-bromopyridine, 30 µl 1-hexyl-3-methylimidazolium pentafluorophosphate, then resubmitted to 15 microwave field for 15 minutes at 140 ° C. The reaction mixture East 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 silica column (40-63 pM), eluting with a mixture of dichloromethane and ethyl acetate (80/20 in volumes), 62 mg of (5-benzyloxy-2-pyridin-2-yl-2H-pyrazol-3-yl) are obtained - [4-(3-chloro-phenyl) -piperazin-1-yl] -methanone in the form of an orange gum with the following characteristics LC / MS analysis: tr = 4.77; m / z = 474 (MH +) 1 H NMR spectrum (400 MHz, (CD3) 2S0 d6.8 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 (s, 1 H); 6.81 ppm (dd, J = 2.5- 8.5 Hz, 1 H); 6.88 ppm (dd, J = 2.5- 8.5 Hz, 1 H); 6.94 ppm (t, J = 2.5 Hz, 1 H); 7.21 ppm (t, J = 8.5 Hz, 1 H); 7.26 ppm (ddd, J = 1- 5- 7.5 Hz, 1 H); 7.36 ppm (tl, J = 8.5 Hz, 1 H); 7.41 ppm (tl, J =
8.5 Hz, 2H); 7.51 ppm (dl, J = 8.5 Hz, 2H); 7.76 ppm (td, J = 1- 8.5 Hz, 1 H);
7.96 ppm (ddd, J = 2- 7.5- 8.5 Hz, 1 H); 8.30 ppm (ddd, J = 1- 2- 5 Hz, 1 H).
Example E62 (5-methyl-2-phenyl-2H-pyrazol-3-yl) - [4- (2-nitro-phenyl) -piperazin-1-yl] -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 414.5 mg of 1- (2-nitro-phenyl) -piperazine, we obtain 490 mg of (5-methyl-2-phenyl-2H-pyrazol-3-yl) - [4- (2-nitro-phenyl) -piperazin-1-yl] -methanone, as yellow solid with the following characteristics 5 Melting point (Kofler): 127 ° C
Mass spectrum (EI): m / z = 391 (M +) Example E63 [4- (3,5-Dimethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone 10 By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 380.6 mg of 1- (3,5-dimethyl-phenyl) -piperazine, 450 mg of [4- (3,5-dimethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, as 15 of a white solid with the following characteristics Melting point (Kofler): 109 ° C
Mass spectrum (EI): m / z = 374 (M +) Examples E64 and E65 [5-Bromo-2- (4-bromo-phenyl) -2H-pyrazol-3-ylJ- [4- (3-chloro-phenyl) -piperazin 20 1-yl] -methanone (example E64) and (5-Sromo-2-phenyl-2H-pyrazol-3-yl) - [4- (3-chloro-phenyl) -piperazin-'i -yl] -methanone (example E65) Step 11: Synthesis of the ethyl ester of 5-bromo-2-phenyl-2H- acid pyrazole-3-carboxylic, according to Tetrahedron Lett., 40, 2605 (1999), from 25 1.64 g of (phenyl-hydrazono) acetic acid and 3.56 g of N-bromosuccinimide in 40 mL of DMF then addition of 5.1 mL of ethyl propiolate and 1.4 mL
of triethylamine gives after 2 successive purifications by flash-chromatography on a silica column (40-63 pM), eluting respectively with a mixture of heptane and ethyl acetate (90/10 by volume) and for 30 fractions still impure with another mixture of cyclohexane and acetone (95/5 by volume) 57 mg 5-bromo-2- (4-bromo-phenyl) -2H- ethyl ester pyrazole-3-carboxylic acid, in the form of an orange solid, the features are as follows Mass spectrum (ES): m / z = 374 (MH +) 1 H NMR spectrum (400 MHz, (CD3) 2S0 d6, â in ppm): 1.16 ppm (t, J = 7 Hz, 3H); 4.18 ppm (q, J = 7 Hz, 2H); 7.24 ppm (s, 1 H); 7.47 and 7.70 ppm (AA'BB 'system, 4H).
and ' 520 mg of 5-bromo-2-phenyl-2H-pyrazole-3- ethyl ester carboxylic, in the form of an orange solid whose characteristics are in agree with those of literature.
Step 2: We proceed in a similar way to step 2 of example E42 starting from 192 mg of 5-bromo-2-phenyl-2H-pyrazole-3- ethyl ester carboxylic acid, containing 10 to 20% of ethyl ester of 5-bromo-2- acid (4-bromo-phenyl) -2H-pyrazole-3-carboxylic acid, and 256 mg of 1- (3-chlorophenyl) piperazine to obtain, after purification by flash-chromatography on a silica column (40-63 pM), eluting with a mixture cyclohexane and ethyl acetate (80/20 by volume) 8 mg of [5-bromo-2- (4-bromo-phenyl) -2H-pyrazol-3-yl] - [4- (3-chloro-phenyl) -piperazin-1-yl] -methanone (example E64), in the form of a solid pale yellow with the following characteristics LC / MS analysis: tr = 4.78; m / z = 523 (MH +) 1 H NMR spectrum (400 MHz, CDCI3, 8 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, 1 H);
6.72 ppm (dd, J = 2.5-8.5 Hz, 1 H); 8.82 ppm (t, J = 2.5 Hz, 1 H); 5.90 ppm (Dd, J = 2.5-8.5 Hz, 1 H); 7.18 ppm (t, J = 8.5 Hz, 1 H); 7.42 and 7.59 ppm (system AA'BB ', 4H).
and 108 mg of (5-bromo-2-phenyl-2H-pyrazol-3-yl) - [4- (3-chloro-phenyl) -piperazin-1-yl] -methanone (example E65), in the form of a white solid of which the features are as follows LC / MS analysis: tr = 4.51; m / z = 445 (MH +) Exemale E66 [4- (3-Chloro-phenyl) -piperazin-1-yl] - (2,5-diphenyl-2H-pyrazol-3-yl) -methanone In a microwave reactor, at 90 mg of the product of example E65, mg phenylboronic acid and 42 mg sodium carbonate in 2 mL
of DMF are added 22 mg of tetrakis (triphenylphosphine) palladium (0) and 35 0.5 mL of water. The reaction mixture is subjected to the microwave field for 5 minutes at 140 ° C, then poured onto 10 mL of aqueous solution saturated with sodium dihydrogen phosphate 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 cyclohexane and acetone (80/20 by volume), 50 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] is obtained -(2,5-diphenyl-2H-pyrazol-3-yl) -methanone, in the form of a yellow resin with the following characteristics LC / MS analysis: tr = 4.77; m / z = 443 (MH +) Example E67 [4- (3-Chloro-phenyl) -piperazin-1-yl] - [2-phenyl-5- (pyridin-3-yl) -2H-pyrazol-3-yl] -methanone The procedure is similar to Example E66 from 74 mg of the product of example E65 and 29 mg of pyridyl-3-boronic acid to obtain, after purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of dichloromethane and ethyl acetate (80/20 in volumes), 35 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - [2-phenyl-5- (pyridin-3-yl) -2H-pyrazol-3-yl] -methanone, in the form of a white solid, the features are as follows LC / MS analysis: tr = 4.08; m / z = 444 (MH +) Example E5 ~
[4- (3-Chloro-phenyl) -piperazin-1-yl] - [2-phenyl-5- (thiophen-3-yl) -2H-pyrazol-3-yl] -methanone The procedure is similar to Example E66 from 74 mg of the product of Example E65 and 30 mg of thienyl-3-boronic acid to obtain, after successive purifications by flash chromatography on a silica column (30 60 pM), eluting with a mixture of heptane and ethyl acetate (90/10 in volumes), then by preparative HPLC / MS (H20 pH = 5 / CH3CN), 20.5 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - [2-phenyl-5- (thiophen-3-yl) -2H-pyrazol-3 yl]) - methanone, in the form of a white powder whose characteristics are the following LC / MS analysis: tr = 5.04; m / z = 449 (MH +) Exemale E69 [4- (3-Chloro-phenyl) -piperazin-1-yl] - [2-phenyl-5- (thiophen-2-yl) -2H-pyrazol-3-yl] -methanone The procedure is similar to Example E66 from 67 mg of the product of example E65 and 27 mg of 2-thienyl-boronic acid to obtain, after successive purifications by flash chromatography on a silica column (30 60 pM), eluting with a mixture of heptane and ethyl acetate (90/10 in volumes), then by preparative HPLC / MS (H20 pH = 5 / CH3CN), 27 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - [2-phenyl-5- (thiophen-2-yl) -2H-pyrazol-3 yl] -methanone, in the form of a white powder, the characteristics of which are the following LC / MS analysis: tr = 5.07; m / z = 449 (MH +) Exemale E70 5- [4- (3-Chloro-phenyl) -piperazine-1-carbonyl] -1-phenyl-1 H-pyrazole-3-carboxaldehyde Eta ~ e 1: A 9.63 g of ethyl ester of 5-dibromomethyl-2-phenyl-2-H-pyrazole-3-carboxylic, obtained in step 1 of example E73, in 260 mL
2.50 g of calcium carbonate is added at room temperature. The reaction mixture is stirred at reflux for 7 hours, cooled, acidified up to pH = 1 by controlled addition of concentrated hydrochloric acid and extract with ethyl acetate. The organic phase is dried over sulphate magnesium and concentrated under reduced pressure. After purification by flash-chromatography on a silica column (40-63 pM), eluting with a mixture of dichloromethane and heptane (70/30 by volume), 5.06 g of ester are obtained 5-formyl-2-phenyl-2-H-pyrazole-3-carboxylic acid ethylene, under form of a white powder with the following characteristics Mass spectrum (ES): m / z = 245 (MH +) Etaae 22: We proceed in a similar way to step 1 of example E22 starting from 63 mg of 5-formyl-2-phenyl-2-H-pyrazole-3- ethyl ester carboxylic acid and 101 mg of 1- (3-chlorophenyl) piperazine to obtain after purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of heptane and ethyl acetate (70/30 by volume), 60 mg of 5- [4- (3-chloro-phenyl) -piperazine-1-carbonyl] -1-phenyl-1 H
pyrazole-3-carboxaldehyde, in the form of a colorless oil, the features are as follows LC / MS analysis: tr = 4.47; m / z = 395 (MH +) Example E71 [4- (3,5-dméthoxy-phenyl) -piperazin-1-yl] - (5-isopropyl-2-phenyl-2H-pyrazol-3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 193.2 mg of 1- (3,5-dimethoxy-phenyl) -piperazine and replacing 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid per 200 mg of 5-Isopropyl-2-phenyl-2H-pyrazole-3-carboxylic, we obtain 300 mg of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - (5-isopropyl-2-phenyl-2H-pyrazol-3-yl) -methanone, as a white powder with the following characteristics Melting point (Kofler): 116 ° C
Mass spectrum (EI): m / z = 434 (M +) Example Ei2 [4- (3-chloro-4-fluoro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone By proceeding, in 3 steps, in a similar way to the synthesis of [4- (3-chloro-3-pirydinyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 33), but replacing in step 1 of the summary the 3,5-dichloropyridine per 40 ~. mg of 3-chloro-4-fluoro-bromobenzene, we obtains, in stage 3 of the synthesis, 213 mg of [4- (3-chloro-4-fluoro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, as of a solid with the following characteristics IR spectrum: 2924; 2839; 1647; 1501; 1221; 1003; 996; 771; 730 and 693 cm ~
1 H NMR spectrum (300 MHz, (CD3) ZSO d6, 8 in ppm): 2.31 (s 3H); 2.82 (mf: 2H); 3.118 (mf: 2H); from 3.25 to 3.40 (mf: 2H); 3.69 (mf 2H); 6.53 (s: 1H); 6.89 (dt, J = 9 and 3.5 Hz: 1 H); 7.05 (dd, J = 6 and 3 Hz 1 H); 7.26 (t, J = 9 Hz: 1 H); 7.36 (wide t, J = 7.5 Hz: 1 H); from 7.40 to 7.55 (mt: 4H).
Example E 73 [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - (3-hydroxymethyl-1-phenyl-1 H-pyrazol-5-yl) -methanone Step 1: In a 2L photochemical reactor, 13 g of ester are dissolved 3-methyl-1-phenyl-1-H-pyrazole-5-carboxylic acid ethyl which can be obtained according to J. Het Chem 1999, 36 (1), 217-220, in 250 mL of carbon tetrachloride, then 12.45 g of 5 N-bromo-succinimide and 0.65 g of 2,2'-azobis (2-methyl-propionitrile). We irradiate for 4 hours with a Hanovia lamp, then add 2.67 g of N-bromo-succinimide and irradiated again for 2 hours. After cooling to room temperature, filtering the insoluble material formed, wash 2 times with 50 mL of carbon tetrachloride, and the filtrates are concentrated 10 seals under reduced pressure. The orange oil obtained is purified by flash =
chromatography on a silica column (60; 35-70 pM), eluting with toluene, by collecting the fractions eluted between 600 and 1200 mL, 8 g 3-bromomethyl-1-phenyl-1-H-pyrazole-5 ethyl ester carboxylic, in the form of a yellow powder used as it is in the step 15 next.
And ~: In a knit of 500 mL under an argon atmosphere, we dissolve 14.22 g of ethyl ester of 3-bromomethyl-1-phenyl-1-H-pyrazole-5-carboxylic acid, obtained as in the previous step, in 170 mL of dimethylformamide, then 7.95 g of sodium benzoate are added and 20 heats at 50 ° C for 3 hours. After cooling and concentration under reduced pressure, the residue is poured into 200 ml of water and then extracted with 3 times 100 mL of ethyl acetate. The joined organic phases are washed with saturated aqueous ammonium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. We obtain 25.5 g of 3-benzoyloxymethyl-1-phenyl-1-H- ethyl ester pyrazole-5-carboxylic, in the form of a beige powder used as it is the next step.
Step 3: Dissolve in a 500 mL knit under an argon atmosphere 2.1 g of (3,5-dimethoxy-phenyl) piperazine in 8 mL of dry toluene to 30 ° C, 30 then 4.5 mL of a 2M toluene solution are added dropwise trimethylaluminum and stirred for 30 minutes. After cooling to 20 ° C., 1.06 g of ethyl ester is added acid 3-benzoyloxymethyl-1-phenyl-1-H-pyrazole-5-carboxylic obtained in step above in solution in 20 mL of toluene. After 7 hours of heating 35 at 60 ° C, the reaction medium is poured into 70 ml of a solution aqueous 1 M

mixed sodium and potassium tartrate, then extracted 3 times 50 mL
ethyl acetate. The combined organic phases are washed with 50 mL of 1 M aqueous solution of mixed sodium and potassium tartrate, dried over magnesium sulfate and concentrated under reduced pressure. oil orange obtained is purified by flash chromatography on a silica column (60; 35-70 pM), eluting with a mixture of dichloromethane and methanol (99.5 / 0.5 by volume), 0.8 g of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - (5-hydroxymethyl-2-phenyl-2H-pyrazol-3-yl) -methanone, in the form of a light beige meringue, the characteristics of which are the following Mass spectrum (EI): m / z = 422 (M +) Example E74 [4- (3-difluoromethoxy-phenyl) -piperazin-1-yl] - (5-methyl-2- hydrochloride phenyl-2H-pyrazol-3-yl) -methanone.
And ~: In a 50 mL knit inerted with argon, a mixture of 500.1 mg of 1-boc piperazine and 598.8 mg of 3-difluoromethoxy-commercial bromobenzene in 20 mL of toluene, then 56.85 mg are added of (R) - (+) - 2,2'-bis (diphenylphosphino) -1,1'-binaphthyle and 20.4 mg of acetate palladium (II). The reaction mixture is stirred and brought to reflux for

16 hours. After returning to 20 ° C., the reaction mixture is diluted to the water (20 mL) then extracted with ethyl acetate (2 x 30 mL. Organic extracts are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The compound obtained is purified by gel chromatography silica (AIT cartridge, Ref. FC-25 Si-BP-SUP, 20-40 pm, eluent dichloromethane, flow rate of 20 mL / min). The fractions containing the compound expected are combined and then evaporated under reduced pressure. So we isolate 253 mg of tert-butyl ester of 4- (3-difluoromethoxy-phenyl) acid -piperazine-1-carboxylic acid, the characteristics of which are as follows LC / MS: RT = 4.18 min, M + H + 329.31 (Micromass device LCT model connected to an HP 1100 device, HP G1315A diode array detector (200-600 nm) Sedex 65 light scattering detector; data analyzed with Micromass MassLynx software;. separation on a column Hypersil BDS C18, 3 trm (50 x 4.6 mm), eluting with a linear gradient of 5 to 90% acetonitrile containing 0.05% (v / v) trifluoroacetic acid (TFA) in water containing 0.05% (v / v) TFA in 3.5 minutes at a rate of 1 mL / min).
Etaae 22: In a 10 ml flask, a solution of 253 mg of ester is placed 4- (3-difluoromethoxy-phenyl) -piperazine-1- acid tert-butyl acid carboxylic acid in a mixture of 1016 pL of dioxane and 963 pL of acid hydrochloric. The reaction mixture is stirred at 20 ° C for 48 hours.
The solid formed is filtered, washed with 10 mL of di-isopropyl ether and dried under reduced pressure. 189 mg of 1- (3) hydrochloride are thus isolated.
difluoromethoxy-phenyl) -piperazine, which is used without purification for the next step.
Step 33: In a 50 mL knitted fabric, inerted with argon, a solution of 144.4 mg of 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid, which can be obtained according to J. Het. Chem., 30, 307 (1993), in 11 mL of dichloromethane then 189 mg of hydrochloride are successively added 1- (3-difluoromethoxy-phenyl) -piperazine, 106.1 mg of 1-hydroxybenzo-triazole, 150.6 mg of 1- (3-dimethyl aminopropyl) -3- hydrochloride ethylcarbodümide then 331 μL of triethylamine (331 μl). The mixture reaction mixture is stirred at 20 ° C for 48 hours then diluted with dichloromethane (20 mL) and water (20 mL), decanted and extracted (30 mL of dichloromethane). The organic extracts are combined, dried over sulphate magnesium, 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 cyclohexane / ethyl acetate, 80/20 to 60/40 in 60 minutes, flow rate of 7 ml / min). The fractions containing the expected compound are combined and then evaporated under reduced pressure. Evaporation residue is taken up in a mixture of ethyl ether (12 mL) and acid hydrochloric / ethyl ether 2N (500 pL), then triturated until a solid which is filtered, washed (5 mL) and dried under reduced pressure. We isolate, thus 199 mg of [4- (3-difluoromethoxy-phenyl) -piperazin-1- hydrochloride yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, in the form of a powder white with the following characteristics Melting point (Kofler): 127 ° C
Example E75 [4- (3-Chloro-phenyl) -piperazin-1-yl] - [5- (2-methyl-imidazol-1-ylmethyl) -2-phenyl-2H-pyrazol-3-yl] -methanone 6 ~
Etaae 11: In a microwave reactor, at 100 mg of ethyl acid ester 5-bromomethyl-2-phenyl-2-H-pyrazole-3-carboxylic acid, obtained in step 1 of Example E73, in 1.5 ml of THF is added 133 mg of 2-methylimidazole.
The reaction mixture is subjected to the microwave field for 10 minutes at 120 ° C, poured onto 20 ml of saturated aqueous solution of sodium bicarbonate and extract with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a silica column (30-60 rpm), eluting with a mixture of ethyl acetate and triethylamine (90/10 by volume), 74 mg of ethyl ester of 5- (2-methyl-imidazol-1-ylmethyl) acid are obtained -2-phenyl-2H-pyrazole-3-carboxylic, in the form of a colorless oil of which the features are as follows Mass spectrum (ES): m / z = 311 (MH +) Step 2: We proceed in a similar way to step 1 of example E22 starting from 114 mg of the product from step 1 of the present example and 145 mg of 1- (3-chlorophenyl) piperazine; to obtain, after purification by flash-chromatography on a silica column (30-60 pM), eluting with a mixture ethyl acetate and triethylamine (90/10 by volume), 21 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - [5- (2-methyl-imidazol-1-ylmethyl) -2-phenyl-2H-pyrazol 3-yl] -methanone, in the form of a yellow oil, the characteristics of which are the following LC / fÜiS analysis: tr = 2.85; m / z = 461 (li / IH +) Exemale E76 [4- (3-Chloro-phenyl) -piperazin-1-yl] - (2-phenyl-5-phenylaminomethyl-2H
pyrazol-3-yl) -methanone Etaae 11: We proceed in a similar manner to step 1 of example E75, to go 100 mg of product from step 1 of Example E73 and 151 mg of aniline for obtain after purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of toluene, ethyl acetate and triethylamine (80/20 / G, 1 ~ by volume), 79 mg of ethyl acid ester 2-phenyl-5-phenylaminomethyl-2H-pyrazole-3-carboxylic acid, in the form of a pale pink oil with the following characteristics Mass spectrum (ES): m / z = 322 (MH +) Step 2: We proceed in a similar way to step 2 of Example E75, starting from 79 mg of the product from step 1 of the present example and 170 mg of 1- (3-chlorophenyl) piperazine, to obtain, after purification by flash-chromatography on a silica column (30-60 pM), eluting with a mixture toluene, ethyl acetate and triethylamine (70/30 / 0.1 by volume), 39 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - (2-phenyl-5-phenylaminomethyl-2H-pyrazol-3-yl) -methanone, in the form of a pale yellow oil, the features are as follows LC / MS analysis: tr = 4.51; m / z = 472 (MH +) Example E77 [4- (2-Bromo-5-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol 3-yl) -methanone The procedure is similar to Example E59 starting from 300 mg of [4- (3 Chloro-phenyl) -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 benzoyl peroxide and 65 mg potassium carbonate for obtain, after successive purifications by flash chromatography on silica column (40-63 pM), eluting with a mixture of toluene and acetate ethyl (8/2 by volume), then by preparative HPLC / MS (H2O pH = 9 /
CH3CN), 16 mg of [4- (2-bromo-5-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, in the form of a cream solid, the features are as follows LC / MS analysis: tr = 4.45; m / z = 459 (MH +) 1 H NMR spectrum (400 MHz, (CD3) 2S0 d6, â 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, 1 H); 7.40 ppm (tl, J = 8 Hz, 1 H); 7.44 ppm (dl, J = 8 Hz, 2H); 7.50 ppm (tl, J = 8 Hz, 2H); 7.62 ppm (d, J = 8.5 Hz, 1 H); 7.05 ppm (d, J = 2.5 Hz, 1 H); 7.09 ppm (dd, J = 2.5- 8.5 Hz, 1 H).
Example E 78 [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - (3-dibromomethyl-1-phenyl-1 H-pyrazol-5-yl) -methanone Step 1: By operating as in step 1 of Example 73, but collecting the fractions eluted between 150 and 550 ml, 9 g of ethyl ester are obtained.

3-dibromomethyl-1-phenyl-1-H-pyrazole-5-carboxylic acid, in the form an orange oil used as is in the next step.
Step 2: To a 195 mg solution of 1- (3,5-dimethoxyphenyl) piperazine in 2 mL of toluene are added, at 25 ° C, 0.52 mL of 2M solution of 5 trimethylaluminium in toluene then, at 60 ° C, a solution of 162 mg of product of step 1 of the example present in 4 ml of toluene. The middle reaction mixture is stirred for 2.5 hours at 65 ° C and then 1.5 hours at 80 ° C then poured onto 10 ml of a 1 M aqueous solution of double sodium tartrate and potassium and extracted with ethyl acetate. The organic phase is dried 10 on magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a silica column (40-63 pM), eluting with a mixture of dichloromethane and ethyl acetate (90/10 in volumes), 235 mg are obtained (5-dibromomethyl-2-phenyl-2H-pyrazol-3-yl) - [4-(3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone, in the form of a solid 15 pale yellow with the following characteristics LC / MS analysis: tr = 4.36; m / z = 563 (MH +) 1 H NMR spectrum (400 MHz, (CD3) 2S0 d6.5 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, 1 H); 6.02 ppm (sl, 2H); 6.99 ppm (s, 1 H);
7.42 20 ppm (s, 1 H); 7.46 ppm (m, 3H); 7.54 ppm (tl, J = 8Hz, 2H).
Example ~ 6th E7 ~
[4- (2,4-Dibromo-5-chloro-phenyl) -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 of which the features are as follows LC / MS analysis: tr = 4.74; m / z = 537 (MH +) 1 H NMR spectrum (400 MHz, (CD3) 2S0 d6, S 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 30 (m, 2H); 6.53 ppm (s, 1 H); 7.23 ppm (s, 1 H); 7.40 ppm (tl, J = 8, 1 H) ; 7.44 ppm (dl, J = 8 Hz, 2H); 7.51 ppm (tl, J = 8 Hz, 2H); 8.01 ppm (s, 1 H).
Example E80 (5-benzyloxymethyl-2-phenyl-2H-pyrazol-3-yl) - [4- (3-Chloro-phenyl) -piperazin 1-yl] -methanone Step 1: To a solution of 87 mg of benzyl alcohol in 0.5 ml of DMF, 35 mg of 50% sodium hydride in the oil is added. The mixture stirred for 30 minutes at room temperature, then add a solution of 200 mg of ethyl ester of 5-bromomethyl-2- acid phenyl-2-H-pyrazole-3-carboxylic, obtained in step 1 of example E73, in 1.5 mL of DMF. The reaction mixture is stirred for 4 hours at at room temperature, then poured onto 50 mL of saturated aqueous solution of sodium dihydrogen phosphate and extract with ethyl acetate. The sentence organic is dried over magnesium sulfate and concentrated under pressure scaled down. After purification by flash chromatography on a silica column (30-60 ~ M), eluting with a mixture of ethyl acetate and triethylamine (90/10 by volume), 52 mg of ethyl acid ester are obtained 5-benzyloxymethyl-2-phenyl-2H-pyrazole-3-carboxylic acid, in the form of a colorless oil with the following characteristics Mass spectrum (ES): m / z = 337 (MH +) And ~: We proceeded in a similar way to step 2 of example E75, starting 52 mg of the product from step 1 of the present example and 122 mg of 1- (3-chlorophenyl) piperazine, for 1.5 hours at 60 ° C, to obtain, after purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of dichloromethane and ethyl acetate (95/5 in volumes), 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 with the following characteristics LC / MS analysis: tr = 4.63; m / z = 487 (MH +) Examples E81 and E82 [5-Bromo-2- (4-bromo-phenyl) -2H-pyrazol-3-yl] - [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone (example E81) and (5-B ro mo-2-phenyl-2 H-pyrazo I-3-yl) - [4- (3, 5-di methoxy-p hen nyl) -pi pe razi n-1-yl] -methanone (example E82) We proceed in a similar way to step 2 of examples E64 and E65 from 1.18 g of 5-bromo-2-phenyl-2H-pyrazole-3- ethyl ester carboxylic acid, obtained in step 1 of examples E64 and E65 and containing 10 to 20% 5-bromo-2- (4-bromo-phenyl) -2H-pyrazole- ethyl ester 3-carboxylic acid, and 1.87 g of 1- (3,5-dimethoxyphenyl) piperazine to obtain, after purification by flash chromatography on a silica column (40-63 pM), eluting with a mixture of cyclohexane and ethyl acetate (70/30 in volume) 58 mg of [5-bromo-2- (4-bromo-phenyl) -2H-pyrazol-3-yl] - [4- (3,5 dimethoxy-phenyl) -piperazin-1-yl] -methanone (example E81), in the form a solid ocher with the following characteristics LC / MS analysis: tr = 4.47; m / z = 549 (MH +) 1 H NMR spectrum (300 MHz, (CD3) 2SO d6.8 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, 1 H); 6.05 ppm (d, J = 2 Hz, 2 H); 6.98 ppm (S, 1 H); 7.42 and 7.77 ppm (AA'BB 'system, 4H).
and 1.80 g of (5-bromo-2-phenyl-2H-pyrazol-3-yl) - [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone (example E82), in the form of a resin orange with the following characteristics LC / MS analysis: tr = 4.17; m / z = 471 (MH +) Example E83 N- {3- [4- (5-methyl-2-phenyl-2H-pyrazole-3- acid methyl ester carbonyl) -piperazin-1-yl] -phenyl} -succinamic acid To a solution of 726 mg of [4- (3-amino-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, described in Example E9, in 35 mL of dichloromethane are added 424 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodümide (EDCI), 297 mg hydrate 1-hydroxybenzotriazole (HOBT) and 264 mg of methyl monoester succinic acid. The reaction mixture is stirred for 20 hours at ambient temperature. After adding 50 mL of dichloromethane and 50 mL of water, the organic phase is decanted, then washed with water, dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a silica column (60; 35-70 pM), eluting with pure ethyl acetate, 650 mg of acid methyl ester are obtained N- (3- [4- (5-methyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -phenyl} -succinamic, in the form of a white meringue whose characteristics are the following Mass spectrum (EI): m / z = 475 (M +) Example 84 Parallel synthesis of examples E84, E105, E108 and 109 E84 [4- (3-Isopropoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone E105 Hydrochloride of {3- [4- (5-methyl-2-phenyl-) acid methyl ester 2H-pyrazole-3-carbonyl) -piperazin-1-yl] -phenoxy} -acetic acid E108 [4- (3-Butoxy-phenyl) -piperazin-1-yl] - (5-methyl-2- hydrochloride phenyl-2H-pyrazol-3-yl) -methanone E109 [4- (3-ethoxy-phenyl) -piperazin-1-yl] - (5-methyl-2- hydrochloride phenyl-2H-pyrazol-3-yl) -methanone In 4 glass reactors (13 x 100 mm) identified from 1 to 4, equipped magnetic stirring and inerted with argon, a 100 mg solution is placed of [4- (3-hydroxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, prepared in Example 13, in 1000 μL of dimethylformamide (1000 μl) then 12.4 mg of sodium hydride are added to each reactor.
All the tubes are stirred at 20 ° C for 1.5 hours, then add them halogenated derivatives, respectively 38.87 pL of 2-bromopropane in the tube, 39.19 pL of methyl bromoacetate in tube 2, 44.67 pL of 1-bromobutane in tube 3 and 26.7 µL of uodoethane in tube 4. After one hour at 20 ° C, analysis by thin layer chromatography (cyclohexane / ethyl acetate 1/1) shows that reactions 2, 3 and 4 are completed while the reaction in tube 1 no longer progresses. We add then again, in reactor 1, 12.4 mg of sodium hydride. 38.87 pL
of 2-bromopropane After 30 minutes of additional reaction, the analysis by thin layer chromatography (cyclohexane / ethyl acetate 1/1) shows that reaction 1 is finished. The contents of reactors 1 to 4 are transferred into 4 glass tubes 36 x 100 each reactor tube being rinsed with ethyl acetate (15 mL) and water (15 mL) then transferred to the liquid liquid extraction platform. The following protocol is applied to the three reaction mixtures: decantation of the two phases, separation of heavy and light extracts, then extraction of the heavy phases with acetate ethyl (2 x 10 ml), reunification of organic extracts. After drying and evaporation, the compounds are isolated and purified by chromatography on silica gel (pre-filled cartridge, diameter 26 mm, height 135 mm, Si02 15-40 pm) eluting with mixtures of cyclohexane and ethyl acetate (E84: 90-10 in volumes at 10 mL / min; E105: 80-20 in volumes at 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, 5 - either the expected compound is isolated directly, and 80.3 mg are thus obtained [4- (3-isopropoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone E84, the characteristics of which are as follows 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6, chemical shift in ppm): 1.25 (d, J = 6.5 Hz: 6H); 2.30 (s: 3H); 2.80 (mf: 2H); 3.09 (mf 10 2H); 3.33 (mf: 2H); 3.68 (mf: 2H); 4.57 (mt: 1H); 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: 1 H) ; 7.36 (t wide, J = 7 Hz: 1 H); from 7.40 to 7.55 (mt: 4H).
- either the compound obtained is taken up in a mixture of ethyl ether (10 mL) and 2N hydrochloric acid / ethyl ether (150 pL), and triturated until a solid appears. After filtration, washing with ethyl ether (5 mL) and drying, the corresponding hydrochlorides are isolated, and we obtain so 81.4 mg hydrochloride of the methyl ester of acid {3- [4- (5-methyl-2 phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -phenoxy) -acetic E105, of which the features are as follows 1 H NMR spectrum (300 MHz, (CD3) ZSO d6, chemical shift in ppm): 2.30 (s: 3H); 2.82 (mf: 2H); 3.12 (mf: 2H); 3.35 (mf: 2H);
3.69 (mf: 2H); 3.71 (s: 3H); 4.75 (s: 2H); 6.37 (wide dd, J = 8.5 and 2 Hz:
1 H);
6.44 (broad t, J = 2 Hz: 1 H); 6.52 (broad dd, J = 8.5 and 2 Hz: 1 H); 6.53 (s 1 H); 7.12 (t, J = 8.5 Hz: 1H); 7.37 (broad t, J = 7 Hz: 1 H); from 7.40 to 7.55 (mt: 4H).
81.4 mg [4- (3-butoxy-phenyl) -piperazin-1-yl] - (5-methyl-2- hydrochloride phenyl-2H-pyrazol-3-yl) -methanone E108, the characteristics of which are following 1 H NMR spectrum (300 MHz, (CD3) 2S0 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 (mf: 2H); 3.10 (mf: 2H); 3.35 (mf: 2H); 3.69 (mf: 2H); 3.93 (T, J = 6.5 Hz: 2H); 6.35 to 6.45 (mt: 2H); 6.47 (d wide, J = 8.5 Hz: 1 H) ;

6.53 (s: 1H); 7.11 (t, J = 8.5 Hz: 1H); from 7.35 to 7.55 (mt: 4H); 7.37 (t large, J = 7 Hz: 1 H).
Melting point (Kofler) = 125 ° C
75.5 mg [4- (3-ethoxy-phenyl) -piperazin-1-yl] - (5-methyl-2- hydrochloride 5 phenyl-2H-pyrazol-3-yl) -methanone E109, the characteristics of which are following 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6, chemical shift in ppm): 1.32 (t, J = 7 Hz: 3H); 2.31 (s: 3H); 2.81 (mf: 2H); 3.10 (mf 2H); 3.25 to 3.45 (mt: 2H); 3.69 (mf: 2H); 3.99 (q, J = 7 Hz: 2H); of 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: 1 H); from 7.35 to 7.55 (mt: 4H); 7.37 (wide t, J = 7 Hz: 1 H).
Example E85 [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [2-phenyl-5- (thiophen-3-yl) -2H
pyrazol-3-yl] -methanone 15 The procedure is similar to Example E66 from 150 mg of the product.
of example E82 and 57.5 mg of thienyl-3-boronic acid, by reaction under microwave for 3 minutes at 140 ° C, to obtain, after purification through flash chromatography on a silica column (30-60 pM), eluting with a mixture of heptane and ethyl acetate (70/30 by volume), 126 mg of [4-3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [2-phenyl-5- (thiophen-3-yl) -2H-pyrazol-3-yl] -ethanone, in the form of an ocher solid, the characteristics of which are following LC / MS analysis: tr = 4.36; m / z = 475 (MH +) Example E86 25 [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [2-phenyl-5- (E-propen-2-yl) -2H-pyrazol-3-yl] -methanone The procedure is similar to Example E66 from 150 mg of the product of example E82 and 39 mg of trans-propenylboronic acid, per reaction under microwave for 3 minutes at 140 ° C, to obtain, after purification 30 by flash chromatography on a silica column (30-60 pM), eluting with a mixture of heptane and ethyl acetate (70/30 by volume), 85 mg of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - [2-phéyl-5- (E-propen-2-yl) -2H-pyrazol-3-yl] -methanone, in the form of a pale yellow solid whose characteristics are the following LC / MS analysis: tr = 4.15; m / z = 433 (MH +) 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6, â in ppm): 1.88 ppm (d, J = SHz, 3H); 2.79 ppm (m, 2H); 3.09 ppm (m, 2H); 3.33 (masked, 2H);
3.65 ppm (m, 2H); 3.68 ppm (s, 6H); 5.99 ppm (t, J = 2 Hz, 1 H); 6.01 ppm (d, J = 2Hz, 2H); 6.42 ppm (m, 2H); 6.86 ppm (s, 1 H); 7.37 ppm (m, 1 H);
of 7.42 to 7.53 ppm (m, 5H).
Exemale E87 [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - {5- [E-2- (4-fluoro-phenyl) -vinyl] -2-phenyl-2H-pyrazol-3-yl} -methanone The procedure is similar to Example E66 from 150 mg of the product of Example E82 and 75 mg of trans-2- (4-fluorophenyl) vinylboronic acid, by reaction under microwave for 3 minutes at 140 ° C., to obtain, after purification by flash chromatography on a silica column (30-60 ~ rM), eluting with a mixture of heptane and ethyl acetate (70/03 by volume), 118 g of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - {5- [E-2- (4-fluoro-phenyl) -vinyl] -2-phenyl-2H-pyrazol-3-yl} -methanone, as a yellow solid pale with the following characteristics LC / MS analysis: tr = 4.60; m / z = 513 (MH +) 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6.8 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, 1 H); 6.03 ppm (d, J = 2Hz, 2H);
7.05 ppm (s, 1 H); 7.23 ppm (t, J = 8.5 Hz, 2H); 7.20 ppm (d, J = 16.5 Hz, 1 H);
7.34 ppm (d, J = 16.5 Hz, 1 H); 7.40 ppm (m, 1 H); 7.50 ppm (m, 4H); 7.68 ppm (dd, J = 5- 8.5 Hz, 2H).
Example E88 [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [5- (4-fluoro-phenyl) -2-phenyl-2H-pyrazol-3-yl] -methanone The procedure is similar to Example E66 from 150 mg of the product of example E82 and 66 mg of 4-fluorophenylboronic acid, per reaction under microwave for 3 minutes at 140 ° C, to obtain, after purification by flash chromatography on a silica column (30-60 NM), eluting with a mixture of heptane and ethyl acetate (70/30 by volume), 133 mg of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - [5- (4-fluoro-phenyl) -2-phenyl-2H-pyrazol-3-yl] -methanone, in the form of a beige solid, the features are as follows LC / MS analysis: tr = 4.51; m / z = 487 (MH +) Exemale E89 [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [2-phenyl-5- (4-trifluoromethyl phenyl) -2H-pyrazol-3-yl] -methanone The procedure is similar to Example E66 from 150 mg of the product of Example E82 and 86 mg of 4- (trifluoromethyl) phenylboronic acid, by reaction in the microwave for 3 minutes at 140 ° C. to obtain, after purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of heptane and ethyl acetate (70/30 by volume), 147 mg of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - [2-phenyl-5- (4-trifluoro-methyl-phenyl) -2H-pyrazol-3-yl] -metetone, in the form of a yellow solid with the following characteristics LC / MS analysis: tr = 4.76; mlz = 537 (MH +) Exemale E90 [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [5- (furan-3-yl) -2-phenyl-2H-pyrazol 3-yl] -methanone The procedure is similar to Example E66 from 150 mg of the product of example E82 and 51 mg of furyl-3-boronic acid, by reaction under micro-waves for 3 minutes at 140 ° C, to obtain, after purification by flash-chromatography on a silica column (30-60 pM), eluting with a mixture heptane and ethyl acetate (70/30 by volume), 137 mg of [4- (3,5-d imethoxy-phenyl) -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 the following LC / MS analysis: tr = 4.17; m / z = 459 (MH +) Exemale E91 [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [2-phenyl-5- (1 H-pyrrol-2-yl) -2H-pyrazol-3-yl] -methanone The procedure is similar to Example E66 from 153 mg of the product from Example E82 and 105 mg of 1- (t-butoxycarbonyl) pyrrole-2-boronic acid, by reaction under microwave for 3 minutes at 140 ° C., to obtain, after purification by flash chromatography on a silica column (30-60 ~ M), eluting with a mixture of heptane and ethyl acetate (70/30 by volume), 68 mg of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - [2-phenyl-5- (1 H-pyrrol-2 yl) -2H-pyrazol-3-yl] -methanone, in the form of a pale yellow solid, the features are as follows LC / MS analysis: tr = 4.11; m / z = 458 (MH +) 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6, â in ppm): 2.80 ppm (m, 2H); 3.10 ppm (m, 2H); 3.36 ppm (masks, 2H); 3.67 ppm (m, 2H);
3.68 ppm (s, 6H); 5.99 ppm (t, J = 2 Hz, 1 H); 6.02 ppm (d, J = 2 Hz, 2 H);
6.12 ppm (m, 1 H); 6.51 ppm (m, 1 H); 6.83 ppm (m, 1 H); 6.92 ppm (s, 1 H) ;
7.39 ppm (m, 1 H); 7.52 ppm (m, 4H); 11.35 ppm (sl, 1 H).
Example E92 [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl) -methanone In a microwave reactor, at 50 mg of the product of Example E82, 10.5 mg tris (dibenzylideneacetone) dipalladium (0), 42 mg of 2-dicyclohexyl-phosphino-2 '- (N, N-dimethylamino) biphenyl in 0.30 mL THF, add 36 μL of pyrrolidine, 11 mg of sodium tert-butoxide and 0.20 ml of THF. The reaction mixture is subjected to the microwave field for 10 minutes at 80 ° C, then poured onto 10 mL of saturated aqueous solution of sodium dihydrogen phosphate and extract with ethyl acetate. The sentence organic is dried over magnesium sulfate and concentrated under pressure scaled down. After purification by preparative HPLC / MS (H ~ O pH = 9 / CH3CN), we obtains 6 mg of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl) -methanone, in the form of a pale yellow powder, the features are as follows LC / MS analysis: tr = 3.65; m / z = 393 (MH +) 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6.8 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, 1 H); 6.01 ppm (d, J = 2 Hz, 2H);
6.73 ppm (d, J = 2 Hz, 1 H); 7.40 ppm (m, 1 H); from 7.46 to 7.55 ppm (m, 4H); 7.81 ppm (d, J = 2 Hz, 1 H).
Example E93 [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [2-phenyl-5- (pyrrolidin-1-yl) -2H
pyrazol-3-yl] -methanone In a microwave reactor, at 50 mg of the product of Example E82, 10.5 mg tris (dibenzylideneacetone) dipalladium (0), 42 mg 2- (ditert butylphosphino) biphenyl in 0.30 mL of THF are added 36 μL of pyrrolidine, 11 mg sodium tert-butoxide and 0.20 mL THF. The mixture reaction is subjected to the microwave field for 10 minutes at 80 ° C., then poured onto 10 mL of saturated aqueous dihydrogen phosphate solution sodium and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by preparative HPLC / MS (H2O pH = 9 / CH3CN), 23 mg of [4- (3.5-dimethoxy-phenyl) -piperazin-1-yl] - [2-phenyl-5- (pyrrolidin-1-yl) -2H-pyrazol-3-yl] -methanone, in the form of a pale yellow powder whose characteristics are the following LC / MS analysis: tr = 4.13; m / z = 462 (MH +) Exemale E94 5- [4- (3,5-Dimethoxy-phenyl) -piperazine-1-carbonyl] -1-phenyl-1 H-pyrazole-3-carboxaldehyde oxime E
We proceed in a similar way to step 1 of example E95 starting from 440 mg of the product of example E100 and 80 mg of hydrochloride of hydroxylamine to obtain 401 mg of 5- [4- (3,5-dimethoxy-phenyl) piperazine-1-carbonyl] -1-phenyl-1 H-pyrazole-3-carboxaldehyde. oxime E, in the form of a white meringue whose characteristics are following LC / MS analysis: tr = 3.99; m / z = 436 (MH +) 1 H NMR spectrum (400 MHz, (CD3) ~ SO d6, S in ppm): 2.81 ppm (m, 2H); 3.12 ppm (m, 2H); 3.36 ppm (m, 2H); 3.68 ppm (m, 2H); 3.70 ppm (s, 6H); 5.98 ppm (t, J = 2 Hz, 1 H); 6.02 ppm (d, J = 2Hz, 2H); 6.92 ppm (s, 1 H); from 7.38 to 7.46 ppm (m, 5H); 8.15 ppm (s, 1 H); 11.46 ppm (sl, 1 H).
Example E95 5- [4- (3,5-Dimethoxy-phenyl) -piperazine-1-carbonyl] -1-phenyl-1 H-pyrazole-3-carboxaldehyde oxime Z
Et_ ape 1: At 300 mg of product from step 1 of Example E70 in 4 mL
ethanol and 120 μL of pyridine, 94 mg of hydrochloride hydroxylamine. The reaction mixture is stirred for 1 hour at room temperature, poured onto 10 ml of saturated aqueous solution of sodium dihydrogen phosphate and extract with ethyl acetate. The sentence organic is dried over magnesium sulfate and concentrated under pressure scaled down. After purification by flash chromatography on a silica column (40-63 pM), eluting with a mixture of dichloromethane and ethyl acetate (90/10 by volume), 115 mg of 5-Z- acid ethyl ester is obtained oximino-2-phenyl-pyrazole-3-carboxylic, in the form of a white solid of which the features are as follows 5 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6, â in ppm): 1.17 ppm (t, J = 7Hz, 3H); 4.19 (q, J = 7Hz, 2H); 7.63 ppm (s, 1 H); 7.50 ppm (m, 5Hz); 7.60 ppm (s, 1 H); 11.90 ppm (sl, 1 H).
Step 2: We proceed in a similar way to step 1 of example E22 starting from of 183 mg of the product from step 1 of the present example and 330 mg of 1- (3,5-10 dimethoxyphenyl) piperazine, for 5 hours at 80 ° C., to obtain, after purification by preparative HPLC / MS (H ~ O pH = 9 / CH3CN), 37 mg of 5- [4-(3,5-dimethoxy-phenyl) -piperazine-1-carbonyl] -1-phenyl-1 H-pyrazole-3-carboxaldehyde oxime Z, in the form of a white powder, the features are as follows LC / MS analysis: tr = 3.63; m / z = 436 (MH +) 1 H NMR NMR spectrum (400 MHz, (CD ~) ~ SO d6.5 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 (sl, 2H); from 7.42 to 7.57 ppm (m, 5H); 7.28 ppm (s, 1 H); 7.60 ppm (s, 1 H); 11.8 ppm (sl, 1 H).
20 Example E96 [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [5- (morpholin-4-yl) -2-phenyl-2H-pyrazol-3-yl] -methanone The procedure is similar to Example E93 from 100 mg of the product of example E82 and 116 μL of morpholine in 1,2-dimethoxyethane 25 (DME) by reaction under microwave for 10 minutes at 80 ° C., to obtain, after purification by preparative HPLC / MS (H2O pH = 9 / CH3CN), 91 mg of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - [5- (morpholin-4-yl) -2-phenyl-2H-pyrazol-3-yl] -methanone, in the form of a pale yellow solid of which the features are as follows LC / MS analysis: tr = 3.80; m / z = 478 (MH +) Example E97 3- [4- (5-Methyl-2-pyridin-3-yl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzamide By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 278 mg of 3- (piperazin-1-yl) -benzamide, which can be obtained according to the patent WO 98/00400 and 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid by 223.5 mg of 5-methyl-2-pyridin-3-yl-2H-pyrazole-3-carboxylic acid, which can be obtained according to J. Het. Chem., 36, 217 (1999), 300 mg of 3- [4- (5-methyl-2-pyridin-3-yl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzamide, in the form of a pale yellow meringue whose characteristics are the following Mass spectrum (EI): m / z = 390 (M +) Example E98 (5-Benzylamino-2-phenyl-2H-pyrazol-3-yl) - [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone The procedure is similar to Example E93, starting from 100 mg of the product from example E82, 21 mg of tris (dibenzylideneacetone) dipalladium (0), 64 mg of 2- (ditert-butylphosphino) biphenyl in 0.60 ml of DME, to which are ; added 116 μL 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 ° C, supplemented with 10 mg of tris (dibenzylidene-.
acetone) dipalladium (0) and again subjected to the microwave field for 3 minutes at 100 ° C. After treatment and purification by HPLC / MS
preparative (H2O pH = 9 / CH3CN), 38 mg of (5-benzylamino-2-phenyl-2H-pyrazol-3-yl) - [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone, in the form of a white powder, the characteristics of which are following LC / MS analysis: tr = 4.19; m / z = 498 (MH +) Example E99 (5-Amino-2-phenyl-2H-pyrazol-3-yl) - [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone Et_ ape 1: We proceed in a similar way to example E98 from 100 mg of the product of Example E82 and 142 μL of benzophenone imine. The mixture reaction is subjected to the microwave field for 12 minutes at 80 ° C., supplemented with 10 mg of tris (dibenzylideneacetone) dipalladium (0) and 100 pL

of DME and again subjected to the microwave field for 2 minutes at 90 ° C. After treatment and purification by flash chromatography on column silica (40-63 µM), 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-dimethoxy-phenyl) -piperazin-1-yl] -methanone, in the form of a yellow solid with the following characteristics Mass spectrum (EI): m / z = 571 (M +) Step 2: In a microwave reactor, at 66 mg of the product from step 1 of the example present in 2.5 ml of methanol, 131 mg of formate are added of ammonium and 60 mg of palladium on carbon at 10%. The mixture reaction is subjected to the microwave field for 3 minutes at 100 ° C., filtered, concentrated under reduced pressure, then purified by flash-chromatography on a silica column (30-60 pM), eluting with a mixture of dichloromethane and ethyl acetate (70/30 by volume), to give 29 mg of (5-amino-2-phenyl-2H-pyrazol-3-yl) - [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone, in the form of a pale yellow solid whose characteristics are the following LC / MS analysis: tr = 3.30; m / z = 408 (MH +) Example E100 5- [4- (3,5-Dimethoxy-phenyl) -piperazine-1-carbonyl] -1-phenyl-1H-pyrazole-3-carboxaldehyde In a microwave reactor, 150 mg of the product of Example E78 in 2 mL of 1,4-dioxane, 27 mg of calcium carbonate and 2 mL are added of water. The reaction mixture is subjected to the microwave field for 10 minutes at 120 ° C, acidified to pH = 5 by controlled addition of solution aqueous 1 M hydrochloric acid and extracted with ethyl acetate. The sentence organic is dried over magnesium sulfate and concentrated under pressure scaled down. After purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of dichloromethane and ethyl acetate (95/5 by volume), 98 mg of 5- [4- (3,5-dimethoxy-phenyl) - is obtained.
piperazine-1-carbonyl] -1-phenyl-1 H-pyrazole-3-carboxaldehyde, in the form a white solid with the following characteristics:
LC / MS analysis: tr = 3.73; m / z = 421 (MH +) Example E101 [4- (3-Chloro-phenyl) -piperazin-1-yl] - (5-phenoxymethyl-2-phenyl-2H-pyrazol-3-yl) -methanone Step 1: A solution of 68 mg of phenol in 1.5 mL of acetone is 0.58 mL of 1 M sodium hydroxide added. The reaction mixture is stirred for 45 minutes at room temperature, then treated with a 150 mg solution 5-bromomethyl-2-phenyl-2-H-pyrazole-3- ethyl ester carboxylic acid, obtained in step 1 of Example E73, in 1.5 ml of acetone. The reaction mixture is stirred for 5 hours at room temperature, then poured onto 20 mL of saturated aqueous dihydrogen phosphate solution sodium and extract with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of dichloromethane and heptane (70/30 by volume) then a mixture dichloromethane, ethyl acetate and acetic acid (70/30/1 by volume), 73 mg of 5-phenoxymethyl-2-phenyl-2H- ethyl ester are obtained pyrazole-3-carboxylic acid, in the form of a colorless oil, the features are:
Mass spectrum (ES): m / z = 323 (MH +) Step 2: We proceed in a similar way to step 2 of Example E75 from 73 mg of the product from step 1 of the present example and 179 mg of 1- (3-chlorophenyl) piperazine, for 3 hours at 60 ° C, to obtain, after purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of dichloromethane and ethyl acetate (95/5 in volumes), 78 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-phenoxymethyl-2-phenyl-2H-pyrazol-3-yl) -methanone, in the form of a white solid, the features are:
LC / MS analysis: tr = 4.59; m / z = 473 (MH +) Example E102 [4- (3-Chloro-phenyl) -piperazin-1-yl] - (2-phenyl-5-phénylsulfanylméthyl-2H-pyrazol-3-yl) -methanone Step 1: To a solution of 66 μL of thiophenol in 2 ml of THF, cooled at 5 ° C., a solution of 73 mg of potassium tert-butoxide is added in 1 mL of THF. The reaction mixture is stirred for 10 minutes at 10 ° C, then treated with a solution of 200 mg of ethyl acid ester 3-bromomethyl-1-phenyl-1-H-pyrazole-5-carboxylic acid, obtained in step 1 of Example E73, in 2 mL of THF. The reaction mixture is stirred for 16 hours at room temperature, then poured onto 50 mL of aqueous solution saturated with sodium dihydrogen phosphate 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 toluene and ethyl acetate (97/3 by volume), 235 mg of 2-phenyl-5- acid ethyl ester are obtained.
phenylsulfanylmethyl-2H-pyrazole-3-carboxylic, in the form of an oil pale yellow with the following characteristics Mass spectrum (ES): m / z = 339 (MH +) Etaae 22: We proceed in a similar way to step 2 of Example E75, to go 100 mg of the product from step 1 of the present example and 232 mg of 1- (3-chlorophenyl) piperazine for 2 hours at 60 ° C, to obtain, after purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of dichloromethane and ethyl acetate (98/2 in volumes), 114 mg of [4- (3-chloro-phenyl) -piperazin-1-yl] - (2-phenyl-5-phenylsulfanylmethyl-2H-pyrazol-3-yl) -methanone, in the form of a solid pale yellow with the following characteristics:
LC / MS analysis: tr = 4.65; m / z = 489 (MH +) Example E103 {4- [3- (2-Hydroxy-ethylamino) -phenyl] -piperazin-1-yl} - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone From 361 mg of [4- (3-amino-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, described in Example 9, in 2 mL of toluene 211 μL of triethylamine and 158 μL of 2-iodoethanol are added. After 20 hours of heating near reflux, 25mL of ethyl acetate and 25 mL of water are added, the organic phase is decanted, then washed with 2 times 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 acetate ethyl (80-20 by volume), 0.2 g of {4- [3- (2-hydroxy-ethylamino) -phenyl] -piperazin-1-yl} - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, under shape of an orange meringue with the following characteristics Mass spectrum (EI): m / z = 405 (M +) 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6.8 in ppm): 2.31 (s: 3H); 2.71 (mf: 2H); 3.02 (mf: 2H); 3.06 (q, J = 6 Hz: 2H); 3.32 (mf 2H); 3.54 (wide q, J = 6 Hz: 2H); 3.68 (mf: 2H); 4.65 (wide t, J = 6 Hz 5 1 H); 5.28 (t, J = 6 Hz: 1 H); from 6.05 to 6.15 (mt: 3H); 6.52 (s: 1 H) ; 6.91 (t wide, J = 8 Hz: 1 H); 7.38 (broad t, J = 7.5 Hz: 1 H); from 7.40 to 7.55 (mt : 4H).
Example E104 (5-Methyl-2-phenyl-2H-pyrazol-3-yl) - [4- (thiophen-3-yl) -piperazin-1-yl] -methanone 10 Et-J ~ e 1: To a solution of 4.6 g of tert-butyl ester of the acid piperazine 1-carboxylic acid in 100 mL of dichloromethane, 5.2 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodümide hydrochloride (EDCI), 3.3 g 1-hydroxybenzotriazole hydrate (HOBT) and 5 g of 5-methyl-2- acid phenyl-2H-pyrazole-3-carboxylic acid. The reaction mixture is stirred for 15 20 hours at room temperature. After adding 50 mL of dichloromethane and 50 mL of aqueous sodium bicarbonate solution saturated, the organic phase is decanted, then dried over sulphate magnesium and concentrated under reduced pressure. This gives 8.1 g of 4- (5-methyl-2-phenyl-2H-pyrazole-3-carbonyl) ter-butyl ester -20 piperazine-1-carboxylic acid, in the form of a white solid characteristics are the following Melting point (Kofler): 150 ° C
1H NMR spectrum (300 MHz, (CD3) 2S0 d6, â in ppm): 1.40 (s 9H); 2.29 (s: 3H); 3.03 (mf: 2H); 3.23 (mf: 2H); 3.32 (mf: 2H); 3.54 (mf 25 2H); 6.50 (s: 1 H); from 7.30 to 7.55 (mt: 5H).
Step 2: To a solution of 8 g of 4- (5-methyl-) tert-butyl ester phenyl-2H-pyrazole-3-carbonyl) -piperazine-1-carboxylic in 50 mL of dichloromethane, are added dropwise 27 mL of an acid solution 4N hydrochloric acid in dioxane. After 20 hours of reaction and 30 concentration under reduced pressure, the residue is taken up in a solution sodium hydroxide N up to pH 10, extracted with 50 ml of ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. We obtain thus 2.96 g of (5-methyl-2-phenyl-2H-pyrazol-3-yl) - (piperazin-1-yl) methanone in the form of a white solid whose characteristics are Next 35 Melting point (Kofler): 138 ° C
1 H NMR spectrum (300 MHz, (CD3) 2S0 d6, â in ppm): from 2.20 to 2.35 (mt: 2H); 2.29 (s: 3H); 2.60 (wide t, J = 4.5 Hz: 2H); 3.06 (t large, 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: To a solution of 200 mg of (5-methyl-2-phenyl-2H-pyrazol-3-yl) -(piperazin-1-yl) -methanone in 6 mL of toluene, 121 mg of 3-bromothiophene, 46 mg of (R) - (+) - 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, 17 mg of palladium acetate and 71 mg of sodium tert-butoxide.
After 20 hours of heating at 90 ° C, the insoluble material is filtered, 50 mL
acetate ethyl and the organic phase is decanted, then washed with 3 times 10 mL
of water, dried over magnesium sulfate and concentrated under reduced pressure.
After purification by flash chromatography on a silica column (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 as a yellow solid amorphous with the following characteristics 1 H NMR spectrum (300 MHz, (CD3) ~ SO d6, â in ppm): 2.31 (s 3H); 2.74 (mf: 2H); 3.01 (mf: 2H); 3.34 (mf: 2H); 3.69 (mf: 2H); 6.33 (Dd, J = 3 and 1.5 Hz: 1 H); 6.52 (s: 1H); 6.93 (dd, J = 5.5 and 1.5 Hz: 1 H);
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 1 H).
Exemale E105 This example is described with example E84 Exemale E106 [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [5- (3-hydroxy-pyrrolidin-1-yl) -2-phenyl-2H-pyrazol-3-yl] -methanone The procedure is similar to Example E98 from 100 mg of the product of example E82 and 90 NL of 3-pyrrolidinol, by reaction under microwave for 5 minutes at 90 ° C., to obtain after purification by HPLC / MS
preparative (H2O pH = 9 / CH3CN), 48 mg of [4- (3,5-dimethoxy-phenyl) -pi pe razi n-1-yl] - [5- (3-h yd roxy-pyrro I id i n-1-yl) -2-p hé nyl-2 H-pyrazo I-3-yl] -methanone, in the form of a white powder, the characteristics of which are the following 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 By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 82 mg of 1- [3-(piperazin-1-yl) -phenyl] ethanone, which can be obtained according to the patent WO 02/088107, 21.8 mg of 1- {3- [4- (5-methyl-2-phenyl-2H-) are obtained pyrazole-3-carbonyl) -piperazin-1-yl] -phenyl} -ethanone, as a solid white with the following characteristics:
Melting point (Kofler): 134 ° C
Mass spectrum (EI): m / z = 388 (M +) Example E108 This example is described with example E84 Example E109 This example is described with example E84 Exemale E110 N- (2-Methylamino-ethyl) -3- [4- (5-methyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzamide Step 1: To a solution of 4.4 g of ethyl ester of 3- [4- (5-methyl-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzoic acid, described in the example E28, in 75 mL of distilled water and 150 mL of methanol, 763 mg are added potassium hydroxide pellets. After 20 hours at temperature , ambient, the reaction mixture is concentrated under reduced pressure and the residue is acidified with 5N hydrochloric acid to pH 5. We obtain thus, after filtration of the solid formed, 3.9 g of 3- [4- (5-methyl-2-phenyl-) acid 2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzoic acid, in solid form pale yellow with the following characteristics Melting point (Kofler): 206 ° C
Mass spectrum (EI): m / z = 390 (M *) Et_ ape 2: To a solution of 390.5 mg of 3- [4- (5-methyl-2-phenyl-2H-) acid pyrazole-3-carbonyl) -piperazin-1-yl] -benzoic acid in 17 mL of dichloro-methane, are added 211 mg of 1- (3-dimethylaminopropyl) hydrochloride -3-ethylcarbodümide (EDCI), 148 mg of 1-hydroxybenzotriazole hydrate (HOBT) and 175 mg of (2-amino-ethyl) -methyl- tert-butyl ester carbamic. The reaction mixture is stirred for 72 hours at ambient temperature. After addition of 25 mL of dichloromethane and 25 mL of water, the organic phase is decanted, then washed with 25 mL of a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate magnesium and concentrated under reduced pressure. After purification by flash-chromatography on a silica column (60; 35-70 pM), eluting with a mixture of cyclohexane and ethyl acetate (70-30 by volume), one obtains 500 mg of methyl- (2- {3- [4- (5-methyl-2-phenyl-) tert-butyl ester 2H-pyrazole-3-carbonyl) -piperazin-1-yl] benzoylamino) -ethyl) -carbamic acid benzyl ester, in the form of a beige meringue whose characteristics are following Mass spectrum (EI): m / z = 546 (M +) And ~: To a solution of 440 mg of fart-butyl ester of methyl- (2-{3- [4- (5-methyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzoylamino ~ -ethyl) -carbamic in 1 mL of dioxane, are added drop by drop 1 mL of a 4N hydrochloric acid solution in the dioxane. This gives after 20 hours of reaction and concentration under reduced pressure, 440 mg of N- (2-methylamino-ethyl) -3- [4- (5-methyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzamide, in the form of a amorphous yellow solid with the following characteristics Mass spectrum (EI): m / z = 446 (M +) 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6.8 in ppm): 2.32 (s 3H); 2.60 (t, J = 5 Hz: 3H); 2.93 (mf: 2H); 3.09 (mt: 2H); 3.20 (mf 2H); 3.40 (mt: 2H); 3.58 (mf: 2H); 3.73 (mf: 2H); 6.55 (s: 1H); 7.08 (d wide, J = 8 Hz: 1 H); from 7.25 to 7.55 (mt: 8H); 8.77 (large t, J = 5 Hz 1 H); 8.89 (mf: 2H).
Example E111 (5-Methyl-2-phenyl-2H-pyrazol-3-yl) - [4- (3,4,5-trifluoro-phenyl) -piperazin-1-yl] -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 200 mg of 1- (3,4,5 trifluoro-phenyl) -piperazine, which can be obtained from 3,4,5-trifluoro-bromo-benzene by operating in a similar fashion to the synthesis of 1- [3- (4-benzyl-piperazin-1-yl) -phenyl] -ethanone from step 1 of Example E39 - and the characteristics are as follows: 1 H NMR spectrum (300 MHz, (CD3) 2SO d6, â in ppm): 3.19 (mf: 4H); 3.43 (broad t, J = 5, S Hz: 4H);
6.96 (dd, J = 12 and 6.5 Hz: 2H); 9.23 (mf: 2H). 115 mg of (5-methyl-phenyl-2H-pyrazol-3-yl) - [4- (3,4,5-trifluoro-phenyl) -piperazin-1-yl] -methanone, in the form of a white solid with the following characteristics Melting point (Kofler): 204 ° C
Mass spectrum (EI): m / z = 400 (M +) Example E112 E-3-f5- [4- (3,5-dimethoxy-phenyl) -piperazine-1- ethyl ethyl ester carbonyl] -1-phenyl-1 H-pyrazol-3-yl} -acrylic To a solution of 196 mg of product of 5- [4- (3,5-dimethoxy-phenyl) piperazine-1-carbonyl] -1-phenyl-1 H-pyrazole-3-carboxaldehyde, obtained at Example E100, in 3 mL of THF, is added at room temperature, 195 mg of (carbethoxymethylene) triphenylphosphorane. After 12 hours stirring at 50 ° C., the reaction mixture is concentrated under pressure reduced and purified by flash chromatography on a silica column (40-63 pM), eluting with a mixture of dichloromethane and ethyl acetate (95/5 in volumes), to obtain 130 mg of ethyl ester of E-3- ~ 5- [4- (3,5-dimethoxy-phenyl) -piperazine-1-carbonyl] -1-phenyl-1 H-pyrazol-3-yl} -acrylic, in the form of a white solid, the characteristics of which are following LC / MS analysis: tr = 4.16; m / z = 491 (MH +) Example E113 3- [4- (5-methoxymethoxymethyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin 1-yl] -benzamide Et_ ape 1: To a solution of 1.4 g of ethyl ester of 5-hydroxy acid methyl-2-phenyl-2H-pyrazole-3-carboxylic acid, which is obtained as a product secondary in the synthesis of Example 71, in 35 mL of tetrahydrofuran, are added in the vicinity of 0 ° C 455 mg of hydride 60% sodium in petrolatum oil and 1.15 g of chloro-methoxy-methane.
After 20 hours of reaction at room temperature, 50 mL of water and 50 mL

ethyl acetate are added and the organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated under reduced pressure.
After purification by flash chromatography on a silica column (60; 35-70 pM), eluting with pure dichloromethane, 1.1 g of the ester are obtained 5 ethyl 5-methoxymethoxymethyl-2-phenyl-2H-pyrazole-3-carboxylic, in the form of an orange oil, the characteristics of which are the following Mass spectrum (EI): m / z = 290 (M +) Step 2: To a solution of 1.1 g of the ethyl ester of 5-methoxy- acid 10 methoxymethyl-2-phenyl-2H-pyrazole-3-carboxylic acid in 12 ml of ethanol, 6 ml of water and 250 mg of potassium hydroxide are added. After 20 hours at room temperature, the mixture is concentrated under pressure reduced, taken up with an aqueous solution of hydrochloric acid N until pH1, extracted with 3 times 25 mL of dichloromethane. The organic phase is Decanted, washed with 25 mL of water, dried over magnesium sulfate and concentrated under reduced pressure. 500 mg of acid are thus obtained 5-methoxymethoxymethyl-2-phenyl-2H-pyrazole-3-carboxylic in the form an orange oil with the following characteristics Mass spectrum (EI): m / z = 262 (M +) Etaae 3: By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, but replacing 1- (3-chloro-phenyl) -piperazine with 556 mg of 3-piperazin-1-yl-benzamide, which can be obtained according to patent WO 98/00400, and replacing 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid with 525 mg 25-5-methoxymethoxymethyl-2-phenyl-2H-pyrazole-3-carboxylic acid, obtains 900 mg of 3- [4- (5-methoxymethoxymethyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzamide, in the form of an amorphous beige solid with the following characteristics:
Mass spectrum (EI): m / z = 449 (M +) 30 Example E114 3- (5- [4- (3,5-Dimethoxy-phenyl) -piperazine-1-carbonyl] -1-phenyl-1 H-pyrazol-3-yl} -thiophene-2-carboxaldehyde The procedure is similar to Example E66 from 86 mg of the product from Example E82 and 40 mg of 2-formyl-3-thiopheneboronic. After reaction 35 in the microwave for 3 minutes at 140 ° C., 6 mg of tétraleis (triphenylphosphine) palladium (0) and 0.2 mL DMF, and again in the microwave for 1 minute at 140 ° C, to obtain after treatment and successive purifications by flash chromatography on silica column (30-60 pM), eluting with a mixture of heptane and acetate ethyl (6/4 by volume), then by preparative HPLC / MS (H2O pH = 9 /
CH3CN), 33 mg of 3- {5- [4- (3,5-dimethoxy-phenyl) -piperazine-1-carbonyl] -1-1-phenyl H-pyrazol-3-yl) -thiophene-2-carboxaldehyde, in the form of a pale yellow powder with the following characteristics LC / MS: tr = 4.63; m / z = 503 (MH +) Example E116 N-Methyl-3- [4- (5-methyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzamide Step 1: To a solution of 3.1 g of tert-butyl ester of 4- (3-carboxy-phenyl) -piperazine-1-carboxylic acid, which can be obtained according to GB 2327609, in 15 mL of dioxane, is added at 0 ° C, a solution of 0.86 mL of oxalyl chloride. At this reaction mixture is added a drop of dimethylformamide. After 2 hours of agitation at one temperature close to 20 ° C, the reaction mixture is added drop to drop on 50 mL of a 40% aqueous methylamine solution. After 1 hour of stirring at room temperature, the reaction mixture is taken up in 200 mL of dichloromethane, then washed twice with 50 mL of distilled water.
The organic phase is dried over magnesium sulfate and then concentrated dry under reduced pressure. 1.5 g of tert-butyl ester are thus obtained.
4- (3-methylcarbamoyl-phenyl) -piperazine-1-carboxylic acid, in the form an orange whose characteristics are as follows 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6, â in ppm): 1.45 (s 9H); 2.78 (d, J = 4.5 Hz: 3H); 3.16 (broad t, J = 5.5 Hz: 4H); 3.49 (t large, J = 5.5 Hz: 4H); 7.11 (broad dt, J = 7.5 and 2 Hz: 1 H); from 7.20 to 7.35 (mt 2H); 7.39 (br s: 1 H); 8.32 (wide q, J = 4.5 Hz: 1 H).
Step 2: To a solution of 1.5 g of tert-butyl ester of 4- (3-methylcarbamoyl-phenyl) -piperazine-1-carboxylic in 5.8 mL of dioxane, are added dropwise 5.9 mL of an acid solution 4N hydrochloric acid in dioxane. We thus obtain, after 6 hours of reaction at room temperature and concentration under reduced pressure, 950 mg of N-methyl-3- (piperazin-1-yl) -benzamide hydrochloride, under form of an amorphous brown solid with the following characteristics 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6.8 in ppm): 2.79 (d, J = 4.5 Hz: 3H); 3.15 (mf: 4H); 3.44 (broad t, J = 5.5 Hz: 4H); 7.15 (mt 1 H); from 7.25 to 7.40 (mt: 2H); 7.44 (br s: 1H); 8.42 (q large, J =
4.5 Hz 1 H); 9.17 (mf: 2H).
Step 33: By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but by replacing 1- (3-chloro-phenyl) -piperazine by 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, in the form of a beige solid, the characteristics of which are following Melting point (Kofler): 180 ° C
Mass spectrum (EI): m / z = 403 (M +) Example E11i [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - (2-phenyl-5-trifluoromethyl-2H-pyrazol-3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but by replacing ~ ant 1- (3-chloro-phenyl) -piperazine with 244.5 mg of 1- (3,5-dimethoxy-phenyl) -piperazine and replacing 5-methyl-2 acid phenyl-2H-pyrazole-3-carboxylic acid per 256 mg of 2-phenyl-5 acid trifluoromethyl-2H-pyrazole-3-carboxylic acid, which can be obtained according to WO 03/024222, 340 mg of [4- (3,5-dimethoxy-phenyl) - are obtained.
piperazin-1-yl] - (2-phenyl-5-trifluoromethyl-2H-pyrazol-3-yl) -methanone, under form of a white solid with the following characteristics Melting point (Kofler): 84 ° C
Mass spectrum (EI): m / z = 460 (M +) Example E118 [4- (3-Chloro-phenyl) -piperazin-1-yl] - (2-phenyl-5-trifluoromethyl-2H-pyrazol-3-yl) -methanone By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but by replacing 5-methyl-2-phenyl-2H-pyrazole-3-carboxylic acid with 256 mg of 2-phenyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid, which can be obtained according to patent WO 03/024222, 240 mg of [4- (3-Chloro-phenyl) -piperazin-1-yl] - (2-phenyl-5-trifluoromethyl-2H-pyrazol-3-yl) -methanone, in the form of a white solid, the characteristics of which are following Melting point (Kofler): 160 ° C
Mass spectrum (EI): m / z = 434 (M +) Example E119 3- [4- (2-Phenyl-5-trifluoromethyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzamide By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 306 mg of 3- (piperazin-1-yl) -benzamide, which can be obtained according to the patent WO 93/00400, and replacing 5-methyl-2-phenyl-2H-pyrazole-3- acid carboxylic acid per 256 mg of 2-phenyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid, which can 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, in the form of a white solid, the features are as follows Melting point (Kofler): 160 ° C
Mass spectrum (EI): m / z = 443 (M +) Example E120 (5-Aminomethyl-2-phenyl-2H-pyrazol-3-yl) - [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone Etaae 11: To a solution of 150 mg of ethyl acid ester 5-bromomethyl-2-phenyl-2-H-pyrazole-3-carboxylic acid, obtained in step 1 of Example E73, in 2 mL of DMSO at room temperature, the following is added 32 mg sodium azide. The reaction mixture is stirred for 2 hours at room temperature, then 1 hour at 50 ° C and finally poured over 50 mL of water and extract with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure to give 135 mg 5-azidomethyl-2-phenyl-2H-pyrazole-3- ethyl ester carboxylic, in the form of a pale yellow oil whose characteristics are the following TLC analysis: heptane / AcOEt, 7/3 Rf = 0.35 Mass spectrum (ES): m / z = 272 (MH +) Step 2: We proceed in a similar way to step 2 of example E94, starting from 135 mg of the product from step 1 of the present example and 221 mg of 1- (3,5-dimethoxyphenyl) piperazine for 6 hours at 60 ° C, to obtain, after purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of dichloromethane and ethyl acetate (95/5 in volumes), 129 mg of (5-azidomethyl-2-phenyl-2H-pyrazol-3-yl) - [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone, in the form of a white solid with the following characteristics Mass spectrum (ES): m / z = 448 (MH +) Step 3: To a solution of 129 mg of the product from step 2 of the example present in 3 mL of THF at room temperature, 90 mg of triphenylphosphine. The reaction mixture is stirred for 6 hours at room temperature, then added with 0.6 mL of water, stirred for 40 hours at room temperature, concentrated to dryness under reduced pressure and taken up in dichloromethane. The organic phase is washed with a 1 M aqueous hydrochloric acid solution then a saturated aqueous solution sodium bicarbonate, 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-dimethoxy-phenyl) -piperazin-1-yl] -methanone, under form of a white solid with the following characteristics LC / MS analysis: tr = 2.63; m / z = 422 (MH +) Exemale E121 {5- [4- (3,5-Dimethoxy-phenyl) -piperazine-1-carbonyl] allylic acid ester -1-phenyl-1 H-pyrazol-3-ylmethyl} -carbamic To a 100 mg solution of (5-aminomethyl-2-phenyl-2H-pyrazol-3-yl) - [4 (3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone, obtained in Example 120, in 1 mL of dichloromethane and 33 µL of triethylamine, at 5 ° C, added 23 μL of allyl isocyanate. The reaction mixture is stirred for 1.5 hours at 5 ° C then 18 hours at 20 ° C, then poured over 50 mL of solution saturated aqueous sodium dihydrogen phosphate and acetate extract ethyl. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash-chromatography on a silica column (30-60 pM), eluting with a mixture of dichloromethane and ethyl acetate (60/40 by volume), 48 mg is obtained of allylic ester of ~ 5- [4- (3,5-dimethoxy-phenyl) -piperazine-1- acid 5 carbonyl] -1-phenyl-1 H-pyrazol-3-ylmethyl} -carbamic, in the form of a white solid with the following characteristics LC / MS analysis: tr = 4.71; m / z = 506 (MH +) Example E122 {5- [4- (3,5-Dimethoxy-phenyl) -piperazine-1-carbonyl] ethyl ester of -10 1-phenyl-1 H-pyrazol-3-ylmethyl) -carbamic The procedure is similar to Example E121 from 100 mg (5-Aminomethyl-2-phenyl-2H-pyrazol-3-yl) - [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone, obtained in Example 120 and 21 μL of isocyanate ethyl to obtain, after purification by flash chromatography on 15 silica column (30-60 pM) ï eluting with a mixture of dichloromethane and ethyl acetate (60/40 by volume), 74 mg of ethyl ester of {5-[4-(3,5-dimethoxy-phenyl) -piperazine-1-carbonyl] -1-phenyl-1 H-pyrazol-3-ylmethyl) -carbamic, in the form of a white solid whose characteristics are the following LC / MS analysis: tr = 4.62; m / z = 494 (MH +) E ~~ c ~ m ~ Be E12 ~
[4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [5- (2-fluoro-ethoxymethyl) -2-phenyl 2H-pyrazol-3-yl] -methanone Step 1: We proceed in a similar way to step 1 of example E80, starting from 25 of 34 pL of 2-fluoroethanol and 150 mg of ethyl acid ester 5-bromomethyl-2-phenyl-2-H-pyrazole-3-carboxylic acid, obtained in step 1 of Example E73, to obtain, after purification by flash chromatography on silica column (30-60 pM), eluting with a mixture of heptane and acetate ethyl (80/20 by volume), 66 mg of ethyl ester of 5- (2-fluoro- acid) Ethoxymethyl) -2-phenyl-2H-pyrazole-3-carboxylic, in the form of an oil pale yellow with the following characteristics Mass spectrum (ES): m / z = 293 (MH ~) Step 2: We proceed in a similar way to step 2 of example E80, starting from 66 mg of the product from step 1 of the present example and 151 mg of 1- (3,5-dimethoxyphenyl) piperazine for 4 hours at 60 ° C, to obtain, after purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of dichloromethane and ethyl acetate (60/40 in volumes), 86 mg of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - [5- (2-fluoro-ethoxymethyl) -2-phenyl-2H-pyrazol-3-yl] -methanone, in the form of an oil pale yellow with the following characteristics LC / MS analysis: tr = 3.70; m / z = 469 (MH +) Exemale E124 [5- (Cyclo pe ntyl-hyd roxy-m ethyl) -2-phenyl-2 H-pyrazo I-3-yl] - [4- (3, 5-d im ethoxy-phenyl) -piperazin-1-yl] -methanone 0.24 mL of 1 N solution of cyclopentylmagnesium bromide in THF
is added, at room temperature, a solution of 100 mg of 5- [4- (3,5-dimethoxy-phenyl) -piperazine-1-carbonyl] -1-phenyl-1 H-pyrazole-3-carboxaldehyde, obtained in Example E100, in 1.5 mL of THF. After 2 hours of stirring at room temperature, the reaction mixture is poured onto 5 mL of saturated aqueous ammonium chloride solution and ether extract. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash-chromatography on a silica column (30-60 pM), eluting with a mixture of dichloromethane and ethyl acetate (60/40 by volume), 18.5 mg of [5- (cyclopentyl-hydroxy-methyl) -2-phenyl-2H-pyrazol-3-yl] - [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone, in the form of a resin colorless with the following characteristics:
LC / MS analysis: tr = 3.27; m / z = 423 (MH +) Example E125 [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [5- (1-hydroxy-propyl) -2-phenyl-2H-pyrazol-3-yl] -methanone The procedure is similar to Example E124, starting from 0.595 ml of 1 N solution of ethyl magnesium bromide in THF and 100 mg of 5- [4 (3,5-dimethoxy-phenyl) -piperazine-1-carbonyl] -1-phenyl-1 H-pyrazole-3 carboxaldehyde, obtained in Example E100, in 1.5 mL of THF, to obtain, after purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of dichloromethane and ethyl acetate (60/40 in volumes), 36 mg of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - [5- (1-hydroxy-propyl) -2-phenyl-2H-pyrazol-3-yl] -methanone, in the form of a resin colorless with the following characteristics LC / MS analysis: tr = 3.53; m / z = 451 (MH +) Example E126 E-3-f5- [4- (3,5-dimethoxy-phenyl) -piperazine-1- methyl ester carbonyl] -1-phenyl-1 H-pyrazol-3-yl) -acrylic To a solution of, 100 mg of 5- [4- (3,5-dimethoxy-phenyl) -piperazine-1-carbonyl] -1-phenyl-1 H-pyrazole-3-carboxaldehyde, obtained in Example E100, in 1 mL of THF and 1 mL of methanol is added, at room temperature, 0.205 mL of 1 N solution of lithium aluminum hydride in THF.
After 6 hours of stirring at room temperature, the reaction mixture is poured onto 50 ml of saturated aqueous dihydrogen phosphate solution sodium 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 silica column (30-60 pM), eluting with a mixture of dichloromethane and ethyl acetate (95/5 by volume), obtains 49 mg of methyl ester of E-3- ~ 5- [4- (3,5-dimethoxy-phenyl) acid -piperazine-1-carbonyl] -1-phenyl-1 H-pyrazol-3-yl ~ -acrylic, in the form of a white solid with the following characteristics LC / MS analysis: tr = 3.95; m / z = 477 (MH +) 1 H NMR spectrum (300 MHz, (CD3) ~ S ~ d6, â in ppm): 2.81 ppm (m, 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, 1 H); 6.02 ppm (sl, 2H);
6.70 ppm (d, J = 16 Hz, 1 H); 7.28 ppm (s, 1 H); from 7.40 to 7.58 ppm (m! 6H).
This product can also be obtained in a similar way to example E112 with (carbomethoxymethylene) triphenylphosphorane.
Example E127 [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [5- (1-hydroxy-ethyl) -2-phenyl-2H-pyrazol-3-yl] -methanone To 87 μL of 1.5 M solution of methyllithium in THF, are added to room temperature 0.5 mL THF and a 50 mg solution of 5- [4- (3,5-dimethoxy-phenyl) -piperazine-1-carbonyl] -1-phenyl-1 H-pyrazole-3-carboxaldehyde, obtained in Example E100, in 1 ml of THF. After 20 hours of stirring at room temperature, the reaction mixture is poured onto 5 ml of saturated aqueous ammonium chloride solution and ether extract. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash-chromatography on a silica column (30-60 NM), eluting with a mixture of dichloromethane and ethyl acetate (60/40 by volume), 6 mg is obtained of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - [5- (1-hydroxy-ethyl) -2-phenyl-2H-pyrazol-3-yl] -methanone, in the form of a pale yellow solid, the features are as follows LC / MS analysis: tr = 3.38; m / z = 437 (MH ~) Exemale E128 3-Hydroxy-N- {3- [4- (5-methyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -phenyl} -propionamide 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 20mL of dichloromethane, are added at 0 ° C 1 mL of 1 M chloride solution diethylaluminum in hexane and 72 mg of oxetan-2-one. After 20 minutes at 0 ° C, and 3 hours at room temperature, the mixture is again cooled at around 0 ° C. and 1 ml of a hydrochloric acid solution N is added. The the reaction mixture is then neutralized with a saturated solution of sodium bicarbonate, extracted with three times 50 mL of dichloromethane, washed with 50 mL of water. After drying over magnesium sulfate and concentration under reduced pressure, then purification by flash chromatography on a column 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, in the form of an amorphous beige solid, the features are as follows Mass spectrum (EI): mlz = 433 (M +) 1 H NMR spectrum (300 MHz, (CD3) 2S0 d6, b in ppm): 2.32 (s 3H); 2.45 (t, J = 6.5 Hz: 2H); 2.76 (mf: 2H); 3.06 (mf: 2H); 3.36 (mf:
2H);
3.70 (mt: 4H); 4.65 (mf: 1H); 6.53 (s: 1H); 6.58 (d wide, J = 8 Hz:
1 H);
7.04 (broad d, J = 8 Hz: 1 H); 7.12 (t, J = 8 Hz: 1 H); 7.24 (wide s: 1 H); 7.36 (large t, J = 7.5 Hz: 1 H); from 7.40 to 7.55 (mt: 4H); 9.75 (broad s: 1 H).

Exemale E129 [5- (Azetid i n-1-yl) -2-ph enyl-2 H-pyrazo I-3-yl] - [4- (3, 5-di methoxy-p h é
nyl) -piperazin-1-YLJ-methanone The procedure is similar to Example E98 from 100 mg of the product of example E82 and 72 μL of azetidine, by reaction under microwave for 5 minutes at 90 ° C., to obtain, after purification by HPLC / MS
preparative (H2O pH = 9 / CH3CN), 23.5 mg of [5- (azetidin-1-yl) -2-phenyl-2H
pyrazol-3-yl] - (4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone, under form of a white powder with the following characteristics LC / MS analysis: tr = 4.05; m / z = 448 (MH +) Exemale E130 (5-allylamino-2-phenyl-2H-pyrazol-3-yl) - [4- (3,5-dimethoxy-phenyl) -piperazin 1-yl] -methanone The procedure is similar to Example E98 from 100 mg of the product of example E82 and 80 μL of allylamine, by reaction under microwave for 3 minutes at 100 ° C. We add 10 mg of tris (dibenzylideneacetone) dipalladium (0), 80 NL of allylamine, 0.20 mL of DME, then subject to again in the microwave for 3 minutes at 100 ° C., to obtain, after purification by preparative HPLC / MS (H20 pH = 9 / CH3CN), 33 mg 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 features are as follows LC / MS analysis: tr = 4.22; m / z = 448 (MH +) Exemale E131 [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [5- (hydroxy-phenyl-methyl) -2-phenyl-2H-pyrazol-3-yl] -methanone The procedure is similar to Example E124, starting from 0.36 ml of 1 N solution of phenylmagnesium bromide in THF and 100 mg of 5- [4-(3,5-dimethoxy-phenyl) -piperazine-1-carbonyl] -1-phenyl-1 H-pyrazole-3-carboxaldehyde, obtained in Example E100, in 1.5 mL of THF, to obtain, after purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of dichloromethane and ethyl acetate (60/40 in volumes), 81 mg of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - [5- (hydroxy-phenyl-methyl) -2-phenyl-2H-pyrazol-3-yl] -methanone, as a solid white with the following characteristics LC / MS analysis: tr = 3.86; m / z = 499 (MH +) Example E132 [4- (3-Hydroxymethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone Step 11: To an 850 mg solution of the tert-butyl ester of acid 4-(3-hydroxymethyl-phenyl) -piperazine-1-carboxylic acid, which can be obtained according to WO 00/015609, in 4 mL of dioxane, are added dropwise drop 3.6 mL of a 4N hydrochloric acid solution in dioxane.
After 20 hours of reaction, the precipitate formed is filtered and then washed with 20 ml petroleum ether. This gives 770 mg of [3- (piperazin-) hydrochloride.
1-yl) -phenyl] -methanol, in the form of an amorphous brown solid, the features are as follows Mass spectrum (EI): m / z = 192 (M +) Etaae 2: By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, but replacing 1- (3-chloro-phenyl) -piperazine with 265 mg hydrochloride of [3- (piperazin-1-yl) -phenyl] -methanol, 250 mg of [4- (3-hydroxymethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone, in the form of a beige meringue whose characteristics are the following Mass spectrum (EI): m / z = 376 (M +) Example E133 3- [4- (2-Phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzamide By proceeding in a similar manner to the synthesis of [4- (3-chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (example 1), but replacing 1- (3-chloro-phenyl) -piperazine with 556 mg of 3- (piperazin-1-yl) -benzamide, which can be obtained according to the patent WO 98/00400 and replacing 5-methyl-2-phenyl-2H-pyrazole-3- acid carboxylic acid per 376.4 mg of 2-phenyl-2H-pyrazole-3-carboxylic acid, obtains 530 mg of 3- [4- (2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzamide, in the form of an amorphous white solid whose characteristics are the following Mass spectrum (EI): m / z = 375 (M +) Example E134 3- [4- (5-Hydroxymethyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzamide To a solution of 840 mg of 3- [4- (5-methoxymethoxymethyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzamide, obtained in Example E113, 1.17 ml of an acid solution are added to 30 ml of absolute ethanol 4N hydrochloric acid in dioxane. After 20 hours of reaction to room temperature and concentration under reduced pressure, the residue is taken up in 20 mL of water and in a 10% aqueous solution of bicarbonate sodium up to pH 8. The solid formed is filtered, washed with 2 times 25 mL of water then with 2 mL of absolute ethanol. 555 mg of 3- [4- (5-hydroxymethyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -benzamide in the form of an off-white solid whose characteristics are following Melting point (Kofler): 216 ° C
Mass spectrum (EI): m / z = 405 (M +) Example E135 (5-Cyanomethyl-2-phenyl-2H-pyrazol-3-yl) - [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone Step 1: To a solution of 150 mg of ethyl acid ester 5-bromomethyl-2-phenyl-2-H-pyrazole-3-carboxylic, obtained in step 1 of Example E73, in 2 mL of DMSO at room temperature, the following is added 32 mg potassium cyanide. The reaction mixture is stirred for 4 hours at 20 ° C, then poured onto 50 mL of saturated aqueous solution of sodium dihydrogen phosphate and extract with ethyl acetate. The sentence organic is dried over magnesium sulfate and concentrated under pressure scaled down. After purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of heptane and ethyl acetate (70/30 in volumes), 102 mg of 5-cyanomethyl-2- acid ethyl ester are obtained.
phenyl-2H-pyrazole-3-carboxylic acid, in the form of a colorless oil, the features are as follows Mass spectrum (ES): m / z = 256 (MH +) Step 22: We proceed similarly to step 2 of Example E80, to go 100 mg of the product from step 1 of the present example and 174 mg of 1- (3,5-dimethoxyphenyl) piperazine for 4 hours at 60 ° C, to obtain, after purification by flash chromatography on a silica column (30-60 pM), eluting with a mixture of dichloromethane and ethyl acetate (80/20 in volumes), 106 mg of (5-cyanomethyl-2-phenyl-2H-pyrazol-3-yl) - [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone, in the form of an oil colorless with the following characteristics LC / MS analysis: tr = 3.64; m / z = 432 (MH +) Example E136 [4- (3-difluoromethoxy-phenyl) -piperazin-1-yl] - (5-methyl-2- hydrochloride phenyl-2H-pyrazol-3-yl) -methanone Step 1: 4- (3-Difluoromethoxy-phenyl) -piperazine-1- acid tert-butylate carboxylic In a 50m1 knit inerted with argon, we place a mixture of 1-boc commercial piperazine (500.1 mg, 2,685 mmol) and 3-difluoromethoxy-commercial bromobenzene (598.8 mg, 2,685 mmol) in toluene (20 ml) 15. then add the ligand (R) - (+) - 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (56.850 mg, 91.2 pmol) and Palladium acetate (ü) (20.4 mg, 91.2 pmol). The reaction mixture is stirred and brought to reflux for 16 hours. After back to 20 ° C., the reaction mixture is diluted with water (20 ml) then extract to ethyl acetate (2x30 ml). The organic extracts are combined, dried on magnesium sulfate, filtered and evaporated under reduced pressure. The compound obtained is purified by chromatography on silica gel (Carkouche AIT, Ref.
FC-25 Si-BP-SUP, 20-40 pm, eluent dichloromethane, flow rate of 20 ml / min).
The fractions containing the expected compound are combined and then evaporated under reduced pressure. Is isolated, the acid tertiobutylate 4- (3-Difluoromethoxy-phenyl) -piperazine-1-carboxylic expected (253 mg) of which the characteristics are as follows.
LC / MS analysis: tr = 4.18 min, M + H + 329.31 Step 2: 1- (3-Difluoromethoxy-phenyl) -piperazine hydrochloride In a 10 ml flask, place a solution of the acid tert-butylate 4- (3-Difluoromethoxy-phenyl) -piperazine-1-carboxylic, (253 mg, 3.8 mmol) in a mixture of dioxane (1016 μl) and hydrochloric acid (963 μl). The reaction mixture is stirred at 20 ° C for 48 hours. The solid formed East filtered, washed (di-isopropyl ether, 10 ml) and dried under reduced pressure.
We isolates, identifies and characterizes 1- (3-Difluoromethoxy-) hydrochloride phenyl) -piperazine, (189 mg) used as in the next step.
Step 3: [4- (3-Difluoromethoxy-phenyl) -piperazin-1-yl] hydrochloride - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone.
In a 50 ml knit, inerted with argon, we place a solution of the acid 5-Methyl-2-phenyl-2H-pyrazole-3-carboxylic acid, which can be obtained according to J. Het. Chem., 30, 307 (1993), (144.4 mg, 714 pmol) in dichloromethane (11 ml) then successively add 1- (3-Difluoromethoxy-phenyl) -piperazine, (189 mg, 714 pmol), 1-hydroxy-benzotriazole (106.1 mg, 785 pmol), 1- (3-dimethyl hydrochloride aminopropyl) -3-ethylcarbodümide (150.6 mg, 785 pmol) then triethylamine (331 pl). The reaction mixture is stirred at 20 ° C for 48 hours then diluted with dichloromethane (20 ml) and water (20 ml), decanted and extracted (30 ml of dichloromethane). The organic extracts are combined, dried on magnesium sulfate, filtered and evaporated under reduced pressure. The compound obtained is purified by chromatography on silica gel (AIT cartridge, Ref.
I = C 25-Si-HP, 15-35tam, eluent cyclohe ~ donkey / ethyl acetate, 80/20 to 50/40 in 60 minutes, flow rate of 7 ml / min). The fractions containing the compound expected are combined and then evaporated under reduced pressure. The residue evaporation is taken up in a mixture of ethyl ether (12 ml) and acid hydrochloric / ethyl ether 2N (500 μl), then triturated until a solid which is filtered, washed (5 ml) and dried under reduced pressure. We isolate, the [4- (3-Difluoromethoxy-phenyl) -piperazin-1-yl] - (5-methyl-2) hydrochloride phenyl-2H-pyrazol-3-yl) -methanone, (199 mg) whose characteristics are the following Melting point 127 ° C (Koffler).
Example E137 N - {tert (butyl ester) (3 - ([4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] -carbonyl) -2-phenyl-2H-pyrazin-5-yl} glycine The procedure is similar to Example E98 from 100 mg of the product of example E82 and 145 μL of glycine terbutyl ester, by reaction under microwave for 5 minutes at 100 ° C. We add 21 mg of tris (dibenzylideneacetone) -dipalladium (0), 145 μL of terbutyl ester of glycine, 0.20 mL of DME, then subjected again to the microwave field for 5 minutes at 120 ° C then 5 minutes at 140 ° C, to obtain, after purification by preparative HPLC / MS (H2O pH = 9 / CH3CN), 2.2 mg of ester N - {{3- ~ [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] -carbonyl-2 teryl butyl phenyl-2H-pyrazin-5-yl} glycine, in the form of a white powder, the features are as follows LC / MS analysis: tr = 4.23; m / z = 476 (MH +) Example E138 [4- (3,5-d imethoxy-phenyl) -piperazin-1-yl] - [5- (piperidin-1-yl) -2-phenyl-2H-pyrazol-3-yl) -methanone The procedure is similar to Example E98 from 100 mg of the product of example E82 and 105 μL of piperidine, by reaction under microwave for 5 minutes at 90 ° C., to obtain, after purification by HPLC / MS
preparative (H ~ O pH = 9 / CH3CN), 12 mg of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - [5- (piperidin-1-yl) -2-phenyl-2H-pyrazol-3-yl) -methanone, under form of a white powder with the following characteristics LC / MS analysis: tr = 4.57; m / z = 522 (MH +) Example E139 [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - (4,5-difluoro-2-phenyl-2H-pyrazol-3-yl) -methanone To a solution of 100 mg of (5-bromo-2-phenyl-2H-pyrazol-3-yl) ester - [4-(3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone (example E82) in 2 mL
of THF, cooled to -78 ° C, 0.30 mL of a 1.7N solution of terbutyllithium in THF. The reaction medium is stirred for minutes at -78 ° C then treated with a solution of 87 mg of 30 N-fluorobenzenesulfonimide in 1 mL of THF. The reaction medium is stirred for 1.5 hours at -78 ° C then 16 hours at room temperature, poured over 50 mL of saturated aqueous solution of dihydrogen phosphate sodium and extract with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a silica column (30-60 NM), eluting with a mixture of toluene and ethyl acetate (90/10 by volume), 15 mg is obtained of [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] - (4,5-difluoro-2-phenyl-2H-pyrazol-3-yl) -methanone in the form of a yellow oil, the features are as follows LC / MS analysis: tr = 4.26; m / z = 429 (MH +) Example E140 [4- (5-hydroxy-pyridin-3-yl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone Step 1: 3-Benzyloxy-5-bromo-pyridine In a 50 ml knit, inerted with argon, a solution of 5-bromo-pyridine-3-ol (1g, 5.74 mmol) in dimethylformamide (15 ml) then, at 20 ° C, potassium carbonate (794.3 mg, 5.74 mmol) and bromide are added benzyl (687 µl, 5.74 mmol). The reaction mixture is stirred at 20 ° C
for 16 hours then diluted with ethyl acetate (150 ml) and water (150 ml);
After decantation, extraction is carried out with 2 portions of ethyl acetate (50 ml). 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 (Cartridge FC-50-Si-BP-Sup, 20-40 pm, eluent dichloromethane, flow rate of 20 ml / min). The fractions containing the expected compound are combined and then evaporated under reduced pressure, providing 3-benzyloxy-5-bromo-pyridine, 350 mg, the features are as follows Mass spectrum: (IE) m / z = 263 M + '; m / z = 91 C ~ H7 + base peak Etaae 2: 4- (5-benzyloxy-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester In a 50 ml knit inerted with argon, place a mixture of 1-boc piperazine (246.8 mg, 1,325 mmol) and 3-Benzyloxy-5-bromo-pyridine (350 mg, 1,325 mmol) in toluene (10 ml) then the ligand (R) - (+) - is added 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (28.05 mg, 45.05 pmol) and Palladium acetate (ü) (10.10 mg, 45.05 pmol). The reaction mixture is stirred and brought to reflux for 16 hours. After returning to 20 ° C, the mixed reaction mixture is diluted with water (30 ml) then extracted with ethyl acetate (2x30 ml).
The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crystallized compound obtained is taken up in ethyl ether (20 ml) then triturated, filtered and dried under pressure scaled down.

The terbutyl ester of 4- (5-Benzyloxy-pyridin-3-yl) acid is isolated -piperazine 1-carboxylic, 280.1 mg, the characteristics of which are as follows LC / MS analysis: tr = 3.04 min. ; m / z = 370.34, (M + H +) Step 3: 1- (5-benzyloxy-pyridin-3-yl) -piperazine hydrochloride In a 50 ml flask, a solution of the terbutyl ester of 4- (5-benzyloxy-pyridin-3-yl) -piperazine-1-carboxylic acid (280.1 mg, 0.758 pmol) in dioxane (1 ml) then stirred at 22 ° C while adding hydrochloric acid (948 µl). The reaction mixture is stirred at 22 ° C
for 16 hours. The yellow solid formed is filtered, rinsed with ether di-isopropyl (15 ml) then dried under reduced pressure. We isolate the 1- (5-Benzyloxy-pyridin-3-yl) -piperazine hydrochloride, 280 mg, 98%) than it is used as in the next step.
Etaae 44: [4- (5-Benzyloxy-pyridin-3-yl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone In a 50 ml knit, inerted with argon, we place a solution of the acid 5-Methyl-2-phenyl-2H-pyrazole-3-carboxylic acid, which can be obtained according to J. Het CMem., 30, 307 (1993), (150 mg, 742 pmol) in dichloromethane (11 ml) then the hydrochloride of 1- (5-Benzyloxy-pyridin-3-yl) -piperazine (226.9 mg, 742 pmol), 1-hydroxybenzotriazole (110.3 mg, 816 pmol), 1- (3-dimethyl aminopropyl) -3- hydrochloride ethylcarbodümide (156.5 mg, 742 pmol) then triethylamine (344 µl). The reaction mixture is stirred at 20 ° C for 16 hours then diluted with of dichloromethane (20 ml) and water (10 ml), decanted and extracted (30 ml of dichloromethane). The organic extracts are combined, dried over sulphate magnesium, filtered and evaporated under reduced pressure. The compound obtained is purified by chromatography on silica gel (AIT cartridge, Ref. FC 25-Si-HP, 15-35pm, eluent 100% dichloromethane to dichloromethane / methanol 90/10 in 60 minutes, flow rate of 7 ml / min). The fractions containing the compound expected are combined and then evaporated under reduced pressure, the [4- (5-benzyloxy-pyridin-3-yl) -piperazin-1-yl] - (5-methyl-2-phenyl-2h-pyrazol-3-yl) -methanone (268 mg) with the following characteristics LC / MS analysis: tr = 2.90 min; m / z = 454.24 (M + H +
Etaae 4: [4- (5-Hydroxy-pyridin-3-yl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone In a 50 ml flask, place a solution of [4- (5-Benzyloxy-pyridin-3-yl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (268 mg; 591 pmol) in ethanol (22.5 ml) then the formate is added ammonium (231.1 mg, 3.664 mmol) and palladium on carbon (94.3 mg, 88.6 pmol) and the reaction mixture is brought to 80 ° C for 3.5 hours.
After returning to 20 ° C., the catalyst is removed by filtration on celite then we evaporates the filtrate under reduced pressure. The compound obtained is purified by chromatography on silica gel (Cartridge 26 mm diameter, 135 mm height, 20 g of silica 15-40 pm, eluent of 100% dichloromethane at dichloromethane / methanol 80/20 in 60 minutes, flow rate of 10 ml / min). The fractions containing the expected compound are combined and then evaporated under reduced pressure, providing a compound which is again purified by chromatography on silica gel (Cartridge 26 mm diameter, 135 mm height, 20 g of silica 15-40pm, eluent from 100% ethyl acetate to acetate 80/20 ethyl / methanol in 60 minutes, flow rate of 10 ml / min). Fractions containing the expected compound are combined and then evaporated under pressure reduced, providing [4- (5-Hydroxy-pyridin-3-yl) -piperazin-1-yl] - (5-methyl-phenyl-2H-pyrazol-3-yl) -methanone (154 mg) the characteristics of which are the following Melting point: 128 ° C (Koffler).
Among the products obtained, particularly preferred products are - [4- (3-Chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example 1) - [4- (3,4-Dimethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example 2) - [4- (3,5-Dichloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E2) - [4- (Quinoline-4-yl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E17) - [4- (3-Chloro-phenyl) -piperazin-1-yl] - (5-hydroxymethyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E60) - [4- (3,4-Methylenedioxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E30) - [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E20) - [4- (3,5-Dimethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E63) - [4- (3-Difluoromethoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E74) - [4- (3-Chloro-phenyl) -piperazin-1-yl] - [5- (2-methyl-imidazol-1-yl-methyl) -2-phenyl-2H-pyrazol-3-yl] -methanone (Example E75) - [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [5- (1 H-pyrrol-2-yl) -methyl-2-phenyl-2H-pyrazol-3-yl] -methanone (Example E91) - [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [5- (pyrrolidin-1-yl) -methyl-2-phenyl-2H-pyrazol-3-yl] -methanone (Example E93) - [4- (3-Carboxamido-phenyl) -piperazin-1-yl] - (5-trifluoromethyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E119) - [5- (Azetidin-1-yl) -2-phenyl-2H-pyrazol-3-yl] - [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone (Example E129) - [4- (3-Carboxamido-phenyl) -piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl) -methanone (Example E133) - [4- (3-Carboxamido-phenyl) -piperazin-1-yl] - (5-hydroxymethyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E134) - [4- (3-Carboxamido-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E23) - [4- (3,5-Dimethoxy-phenyl) -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-dimethoxy-phenyl) -piperazin-1-yl] -methanone (Example E99).
Among the particularly preferred products, the following are:
preferred:
- [4- (3-Carboxamido-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E23) - [4- (3,5-Dimethoxy-phenyl) -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-dimethoxy-phenyl) -piperazin-1-yl] -methanone (Example E99).
A product according to the invention can be used for the manufacture of a drug useful for treating a medical condition, in particular cancer.

The present invention also relates to therapeutic compositions contains a compound according to the invention, in combination with an excipient pharmaceutically acceptable according to the mode of administration chosen. The pharmaceutical composition can be in solid, liquid or liposomes.
Among the solid compositions, mention may be made of powders, capsules, tablets. Among the oral forms one can also include the solid forms protected against the acidic environment of the stomach. The supports used for solid forms consist in particular of mineral supports such as phosphates, carbonates or organic supports such as lactose, celluloses, starch or polymers. Liquid forms are consisting of solutions of suspensions or dispersions. They contain as a dispersive support either water or an organic solvent (ethanol, NMP
or others) or mixtures of surfactants and solvents or agents complexing agents and solvents.
The liquid forms will preferably be injectable and, therefore, will have a formulation acceptable for such use.
Acceptable routes of injection include intravenous, intraperitoneal, intramuscular, and subcutaneous, the intravenous being preferred.
The administered dose of the compounds of the invention will be adjusted by the practitioner depending on the route of administration of the patient and the state of this latest.
The compounds of the present invention can be administered alone or in combination mixed with other anticancer drugs. Among the possible associations are can quote ~ alkylating agents and in particular cyclophosphamide, melphalan, ifosfamide, chlorambucil, busulfan, thiotepa, prednimustine, carmustine, lomustine, semustine, steptozotocin, decarbazine, temozolomide, procarbazine and hexamethylmelamine ~ platinum derivatives such as cisplatin, carboplatin or oxaliplatin ~ antibiotic agents such as bleomycin, mitomycin, dactinomycin ~ antimicrotubule agents such as vinblastine in particular, vincristine, vindésine, vinorelbine, taxoides (paclitaxel and docetaxel) ~ anthracyclines such as doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone, losoxantrone ~ group I and II topoisomerases such as etoposide, teniposide, famsacrine, irinotecan, topotecan and tomudex ~ fluoropyrimidines such as 5-fluorouracil, UFT, floxuridine ~ Cytidine analogs such as 5-azacytidine, cytarabine, gemcitabine, 6-mercaptomurine, 6 thioguanine ~ adenosine analogs such as pentostatin, cytarabine or fludarabine phosphate ~ methotrexate and folinic acid ~ various enzymes and compounds such as L-asparaginase, hydroxyurea, trans-retinoic acid, suramin, dexrazoxane, amifostine, herceptin as well as the hormones estrogenic, androgenic ~ anti-vascular agents such as derivatives of combretastatin or colchicine and their prodrugs.
It is also possible to combine with the compounds of the present invention radiation treatment. These treatments can be administered simultaneously, separately, sequentially. The treatment will be adapted by the practitioner depending on the patient to be treated.
A product according to the invention may be useful for inhibiting the tubulin polymerization in vitro.

Evaluation of the inhibition of tubulin polymerization Tubulin is purified from pig brains using methods published (Shelanski et al., 1973, Proc. Natl. Acad. Sci.USA, 70, 765-768.
Weingarten et al., 1975, Proc. Natl. Acad. Sci. USA, 72, 1858-1862).
Briefly, the brains are ground and centrifuged in a buffer extraction. The tubulin, contained in the supernatant of the extract undergoes two successive cycles of polymerization at 37 ° C and depolymerization at 4 ° C, before to be separated from MAPs (Microtubule Associated Proteins) by P11 phosphocellulose column chromatography (Whatman). The tubulin, thus isolated is more than 95% pure. It is kept in a buffer named RB / 2 30% gljrcerol, the composition of which is MES-NaOH
[2- (N-morpholino) -ethanesulfonic acid] 50 mM, pH 6.8; 0.25 mM MgCl2;
0.5 mM EGTA; glycerol 30% (v / v), GTP (guanosine-5'-tri-phosphate) 0.2 mM.
Tubulin polymerization in microtubules is monitored by turbidimetry as follows: tubulin is adjusted to a concentration of 10 pM (1 mg / ml) in RB / 2 30% glycerol buffer to which 1 mM GTP and 6 mM are added MgCl. The polymerization is triggered by an increase in the temperature from 6 ° C to 37 ° C in a tank with a 1 cm path optical, placed in a UVIKON 931 spectrophotometer (Kontron) equipped with a cell holder thermostatically controlled. The increase in the turbidity of the solution is followed at 350 nm.
The products are dissolved in 10 mM in DMSO and added to variable concentrations (0.5 to 10 NM) to the tubulin solution before polymerization. Cl5o is defined as the concentration of product which inhibits the rate of polymerization by 50%. We consider to be very active a product whose Cl5o is less than or equal to 25 pM.
A product according to the invention may be useful for inhibiting the proliferation tumor cells in vitro.
Test to determine the inhibition of proliferation of the line human colon tumor HCT116 The proliferation of HCT116 cells is evaluated by measuring the incorporation of [~ 4C] -thymidine as follows. HCT116 cells (from ATCC) are cultivated in a DMEM medium (Gibco) which contains 10% of serum fetal calf and antibiotics (penicillin 1%, streptomycin 1%). For efPerform the proliferation test, the cells are seeded in 96-well cytostar microplates (Amersham), at a rate of 5000 cells per well. Then added [~ 4C] -thymidine (0.1 NCi / well) and the products to assess. Variable product concentrations up to 10 pM are used;
the DMSO (solvent used to dissolve products) must not exceed 0.5 in the middle. 48 hours after incubation at 37 ° C., the radioactivity incorporated into cells by counting the plate in a counter TRI-LUX (Wallac). Cl ~ o is defined as the concentration of product which reduces radioactivity by 50% compared to an untreated control. We considers a product with a CISO of less than 3 pM to be cytotoxic Test to determine the inhibition of vascularization An endothelial cell detachment test was established in order to select products based on their ccin activity vitro ".
This endothelial cell detachment test is characterized in that the endothelial cells, seeded in plates whose bottom is covered with a binding agent preferably chosen from gelatin, fibronectin or vitronectin, after culture, are added with a medium containing the compound to be tested, then the cells are labeled with a fluorescent substance, the cells which become detached are washed away and the fluorescence of the remaining cells is counted at fluorometer.
This test consists of measuring the detachment of endothelial cells cultivated on substrates based on a binding agent preferably chosen from fibronectin, vitronectin or gelatin. Preferably one day after seeding of the cells in plates containing for example 96 wells, the culture medium is replaced by a medium containing the compound to be tested in absence of serum. We prepare the same preparation three times three times different concentrations (0.1, 0.3 and 0.6 pM) and six times the control without addition of anti-vascular product. After two hours of treatment with the test substance, cells are labeled with calcein-AM
(1.6 pg / ml) in culture medium supplemented with 0.1% BSA. The detached cells are removed by washing with culture containing 0.1% bovine serum albumin; we add 100 pl of medium at each well. The fluorescence of the remaining cells is counted at fluorometer. The data obtained are expressed relative to the control (untreated cells).
The evaluation of detachment of endothelial cells in vitro is determined as follows. HDMEC cells (Human Dermal Microvascular Endothelial Cells, Promocell, c-122102) are grown in a ECGM-MV medium which contains 5% fetal calf serum, growth (EGF 10 ng / ml, hydrocortisone 1 pg / ml, 0.4% supplement growth with heparin) and antibiotics (amphotericin 50 ng / ml, gentamicin 50 pg / ml). For the detachment test, the HDMECs are seeded to 5,000 cells in 96-well brightfield plates (Costar) pre-coated with fibronectin (10 pglml) or vitronectin (1 pg / ml) or gelatin. Twenty four hours later, the culture medium is replaced by ECGM-MV 0.1% BSA medium containing the products indicated. The concentrations tested are 0.1-0.3 and 1 pM 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. The detached cells are then removed by washing with ECGM-MV 0.1% BSA medium; 100 μl of medium is added to each well. The fluorescence of the cells which remain attached to the substratum of the well is counted using a fluorimeter, Spectrafluor Plus ('fecan, 485 nm excitation, and 535 nm emission). Data is the average of six different samples and are expressed as a percentage of the control (cells not processed).
A cell detachment effect greater than or equal to 15% is considered as significant.

_ _ _ _ _, ~ ~ r. ~, Biological results Inhibition of Percent Inhibition Ex. Mass polymerization proliferation of de N ~ Molar structure of the HCT116 tubulin detachment CI 50 (pM) CI 50 (NM) from HDMEC to 1 uM
__ ~ N ~
NIN ~ N
3l1 ~ \ I ~ 376.457 20 O
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NN ~ N
3/2 ~ \ p I ~ 404, 511 0.312 O
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313 ~ \; I ~ 390.49 1.8 0.087 __ ~ N
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3/4 ~ \ p I / 424.93 1.8 0.389 O
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3/5 ~ \ Ö I ~ 440.93 3 0.238 O
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3/6 ~ 0 '- ~ 346.44 4.5 0.177 - -. . m. ~ ar s ~ 6 NOT' NOT
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3/7 ~ O ~ - ~ 376.46 5.6 0.040 FF
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3/8 ~ OV 414.43 6.5 0.841 N ~
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3/9 / \ p ~ - ~ 374.49 7 0.494 1 ~ _ O 380.87 0.6 0.002 22 O
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NN ~ N
3/10 '~ \ (~ 376.46 2 0.025 O \
O
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3/11 ~ ~ I ~ 360.46 3 0.036 O
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3/12 ~ ~ I ~ 392.53 3 0.145 S

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3/13 S \ I ~ 396, 5 6 0.466 _- ~ N ~
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3/14 ~ ~ I ~ O 404.47 15 0.352 OJ

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3115 F ~ \ I ~ 394.45 2 0.0040 O ~
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3116 F ~ ~ I ~ 378.45 6 0.224 O
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3/17 ~ \ FI ~ 392.48 3.5 0.159 O
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3/18 ~ \ FI ~ 398.87 2 0.028 THIS

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3/19 ~ \ FI ~ 378.45 1.8 0.017 O
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3/20 ~ \ F '~ 414.49 3 1.846 __ ~ N
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3/21 ~ \ FI ~ 412.9 1.8 0.469 O
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3/22 ~ ~ FI ~ 428, 9 1.5 0.046 O
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3/23 ~ ~ I i 432,419 3 0.434 FFFF
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3/24 N ~ ~ ~ N 398.87 5 0.239 F

- ~. _ .. _, r _. . ~ ~ w. mm THIS
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3/25 N ~ ~ O- 410,902 1.8 0.040 THIS
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3/26 N ~~ S ~ 426,969 1.5 0.090 O
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3/27 N w CI 384.903 4.5 0.217 O
~ N \ /
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N ~ 374,485 7 0.269 O
Ü \ /
Born 3/29 N ~ \ 388,512 5 0.452 O
NV \ /
NOT
3/30 N ~ ~ 388,512 2.9 0.729 '°' ~ ~ i ~ e .. 59 V 'i' e8 O
NOT
3/31 N ~ ~ CI 394,903 1.3 0.140 O
NOT
3/32 N ~ ~ ~ ~ 410, 518 3 0.556 N ~
NOT
N ~ ~
3/33 ~ O \ - ~ 394,903 3 0.170 THIS
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3/34 N ~ ~ CI 415,322 2.5 0.526 O
_ '~ N ~.
3135 NN ~ N
\ O ~ 410.902 5 0.284 THIS
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3136 ~ ~ CI I ~ 415,322 1.8 0.119 THIS

- _ _ _ ~ ~. ~ e O
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N_N ~ N \
3/37 F ~ \ I ~ 398,867 20 1,436 THIS
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N_N ~ N \
3/38 ~ \ (~ 398,867 6 0.338 F CI
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3/39 ~ \ I ~ 410, 902 25 0.734 ~ CI
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3/40 N ~ ~ 380.876 3 0.775 N ~
NOT
~ N ~ ~ F
3/41 ~ OR 364,421 6.5 0.2940 NOT' NOT
3/42 / \ p NUN 360,458 5 0.0850 O
NOT
3/43 e \ O ~ --7 390,484 9 0.2290 O
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3/44 N ~ ~ 360.458 2 0.0470 ' O
NOT
3/45 N ~ ~ O 390,484 3 0.0730 O -3146 N ~ ~ F 428.455 8 0.1970 FF
'O
\ / F
NOT
3/47 N ~ ~ 378.448 8 0.3120 O _ _ \ /
NOT
3/48 N ~ ~ 374,485 5 0.1180 O
NOT
3/49 N ~ ~ O- 390.484 1 0.0079 m ~. , ~.

O ~ - ~
N /
3/50 N ~ 374.485 1.5 0.0061 O _ Ü \ /
NOT
3151 N ~ ~ S ~ 406.551 2 0.0370 THIS
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3152 N ~ ~ 394.903 13 0.2560 THIS
O ~ _ 3153 ~ / N ~ N \ /
408.930 1.2 0.0520 C ~
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3/54 N ~ ~ O 424, 929 1 0.1170 O
ü \ /
NOT
3/55 N ~ ~ F 428,455 5.5 1.3500 FF

O
\ / ü \ / o N>
3/56 N ~ ~ O ~ 418,494 5 0.1390 O
__ ~ N ~
N ~ N ~ NW
3/57 ~ ~ I ~ 378,448 1.4 0.0150 F
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__ ~ N ~
NIN ~ N
3/58 ~ \ I ~ 410,514 4.5 3.9370 S
F
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NN ~ N
3/59 ~ \ I ~ 414,481 5.7 4.9750 -F
O
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NN ~ N ~ CI
3160 ~ \ I ~ 428.892 1.3 0.0086 O
F
F
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3161 N ~ FF F 432.419 25 _ _ F
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New O
3/62 422.457 6 0.0710 O
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N_N ~ N
3/63 ~ 394,447 0.9 0.0190 Ow THIS
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NV \ /
NOT
3/64 N ~ ~ 408.930 25 Cl O
\ ~ ~ \ / CI
NOT
3/65 N ~ ~ CI 449,767 1.3 0.0730 THIS
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\ / Ü \ /
NOT
3/66 N ~ ~ 408.930 2 0.0730 THIS
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\ l ~ N \ /
NOT
3167 N ~ ~ 394.903 2.7 0.1270 Q

THIS
O ~ -3/68 \ NN ~ .J \ /
408.930 1.5 0.0360 i ~ / \ / CI
NOT
3/69 N ~ ~ 415, 322 18 0.3470 THIS
THIS
i o \ l ü \ /
NOT
3/70 N ~~ 429,348 12.5 THIS
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3/71 N ~ ~ O 424,929 2.5 0.2200 THIS
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\ / V \ /
NOT
3/72 N ~ \ FFF 448, 874 7 0.1430 THIS
O
\ N ~ N \ /
3/73 N ~ \ O 410,902 2.5 0.1110 _ ~ __ _ _. . _ ~ ~, ~, THIS
'O -\ / ~ N \
N ~
3/74 N ~ 394.903 7.5 0.2980 CI CI
O
V \ /
NOT \
3175 N ~ ~ 445.347 17 0.4680 'O
V ~ / CI
NOT
3/76 N ~ CI 429.348 3 1.0810 O _ \ ~ ~ \ /
3177 N ~ 388.512 25 '~ O
N /
N ~
3/78 N ~ 374.485 25 O
\ / Ü \ /
NOT
3/79 N ~ 388, 512 25 . ~ E ~. ar '~ oa ° 9r é i ~ U i. ~ d O
\
NOT
3180 N ~ O 390.484 5 0.0780 O.
__ ~ N ~
~ N ~

~ O (~ CI 445.347 3.5 ~ 0.2950 THIS
O
O ~ _ NN
3182 N ~ ~ \ / 406,483 1.2 0.0083 y O-O
__ ~ N ~
NN ~ N ~ CI
3183 ~ ~ I ~ 410.902 1.5 0.0066 O
O
NN
NU ~ ~
Ny F
3l84 FF 414.428 5.5 0.1760 O
__ ~ N ~
NN ~ N
3l85 F ~ \ I ~ 394,447 3 0.1890 O

~ - - -. .

O
__ ~ N
N_N ~ N \
3/86 F ~ \ I ~ 392.475 12.5 0.385 O
__ ~ N ~
N, N ~ N
3187 F '~ \ I ~ 378.448 15 0.2380 O
__ ~ N
NN ~ N ~ CI
3188 F ~ \ I ~ 428.892 6 0.0605 O
O
__ ~ N
N_N ~ N
3/89 ° ~ \ FI ~ 364,421 2.2 0.0140 O
__ ~ N ~
N_N ~ N
3190 '~ \ FI ~ 394.447 3 0.0330 O
O
_- ~ N
N_N ~ N
3/91 ~ \ F ~ 432,419 1.5 0.0140 FFF
O
_ ~ N ~
N, N ~ N
382.412 12.5 0.1580 3/92 ~ \ FF

-m O
__ ~ N
NN ~ N ~
3/93 ~ ~ FI ~ CI 433,312 1.7 0.0320 THIS
O
__ ~ N ~
N_N ~ N
3/94 ~ \ FI ~ 392,475 0.8 0.0320 O
__ ~ N ~
N'N ~ N \
3/95 ~ ~ FI ~ 392,475 3 0.1640 O
_ ~ N ~
N, N ~ N \
3/96 ~ \ FI ~ 394,447 1.8 0.0036 O ~
O
__ ~ N ~
N'N ~ N \
3/97 ~ \ FI ~ 410,514 3 0.0830 S

_ ~ N ~
N, N ~ N \
3/98 ~ \ FI ~ 408,474 7 0.1570 O
J

- m ~ ~ e. ~ v -vr ax ~ s ~ ë 1 ~ / ~ i O
__ .. ~ N ~
NN ~ N ~
3/99 ~ \ FCI I ~ 433, 312 2 0.0410 THIS
O
-_ .. ~ N ~
N, N ~ N
3/100 ~ \ F ~ O 422,457 <25 oJ

~ N ~
NN ~ N ~
3/101 ~ ~ I ~ 364,421 5 0.5690 F

__ ~ N
NN ~ N ~
31102 ~ \ I ~ 394.447 13 0.1810 O
F

__ ~ N ~
N ~ .N ~ N
3/103 ~ \ I ~ 392,475 21 F
O
__ ~ N ~
NN ~ N
3! 104 ~ 392.475 5 0.2850 F

--O
O
\ / NOT \ /
NOT
N ~ \
3/105 406.483 4.5 0.1180 O
__ ~ N
N_N ~ N ~
3/106 ~ ~ CI I ~ 445,347 7 0.9850 O CI
O
_ ~ N ~
N ~ 'N \ / ~~ N \
I
3/107 ~ \ N ~ 347.419 12.5 O
__ ~ N ~
N_N ~ N
3! 108 ~ \ I ~ 374.485 3.5 NN
N ~ / \ /
3/109 N ~ 374.485 8 4.3300 THIS
O
NN CI
NV \ /
3/110 N ~ 415.322 0.2987 .

O
\ /
NOT
N ~ \
2,374,485 0.6 0.1600 16 F
_.- O
NOT
\ /
NOT \
3/111 N ~ 364.421 12.5 NOT
O
N ~ \ /
3/112 N ~ 380.876 15 1.5240 O
NOT
\ /
NOT \
Nw 4 343.427 3 0.0588 THIS
O
~ N \ / ~ I
NOT
3! 113 N ~ \ 429.348 1.2 0.0750 O
\ /
NOT
3/114 N ~ \ 388.512 0.8 _ ~ ~ uë s ~ ~ ~ d 'T l 18' ~ ~

O
O
NN
3/115 N \ U ~ / 404.511 20 N ~
CI CI
O
NN \ /
NOT
3/116 N ~ \ 429.348 3 0.1410 F CI
\
NOT \
3/117 N ~ 412,893 7 F
O
\ / NOT -O
3/118 N / ~ / 408.474 25 i Nw F CI CI
O
. NOT \ /
NOT
3/119 N ~ 433.312 3.1 0.5620 THIS
O
\
NOT
3/120 N '\ p 410.910 0.040 ~ ~ ~ _ o. _ d, ~. "

cl N ~ \ /
NOT
3/121 N ~ ~ F 448.874 3.3 0.0510 FF
THIS
O -NOT \ /
NOT
3/122 N ~ ~ 408,930 7.5 THIS
\ _ /
NOT
3/123 ~ ~ ~ 394.903 3.3 0.051 cl O
\ /
NOT
3/124 ~ ~ ~ \ / 430.936 12 cl cl cl o / \ - / \ /
NOT
3/125 N ~ ~ 449,767 12.5 0.1480 this O ~ - F
N ~ \ ~ FF
3/126 N ~ \ 448.874 25 8.7350 cl cl s NOT
3/127 N ~ ~ -0 445.347 1.8 cl o / - ~
3/128 N ~ ~ F 448.874 12 0.9010 FF
CI CI CI
p _ \ /
I \
3/129 N ~ 449,767 <25 2.5580 O
VN \ /
¿\ _ 3/130 N ~ 0 390,484 <25 I \ F
3/131 N ~ FF 428.455 3.1 0.1350 cl CI

vl ~
~ N \ /
i \
3/132 N ~ 429.348 20 3.0980 _ ~ _ _ _ _. _ o ' NOT
3/133 N F 444.454 6.2 0.2140 FF
O ' ' O
3! 134 ¿~ 390.484 4.3 N ~
0 ' O
NOT
31135 1 ~ 404..511 6 0.3210 N ~
O ' r O
NOT
3/136 I ~ 404.511 12.5 0.9320 Nw o ' 3/137 N \ ~ S 422.550 4.2 o ' 3/138 N / 426.517 <25 19.9550 - ° ~ ~ - .. ... o ar ~ ~ ~ 6 ~

o ' / o ~
\ /
3/139 N \ \ c ~ ci 445.347 <25 1.3490 o ' \ / N \ -% \ / o.
NOT
3/140 N ~ ~ ° ~ 434.500 <25 2.9680 O
FN \
N ~
3/141 392.475 7 0.0660 o VN \ /
F ~
N ~
31142 ~ 392.475 3.8 0.1100 o \ /
FN
3/143 \ / 414.481 2.5 0.1400 V ~ /
FN ~ \ -O
3/144 394.45 9.5 0.2550 \ /
F ~ F
N ~
3/145 FF 432.419 10 1.5060 ~~~~ "~. ~~~! ~ U ï ~~

F

THIS
NOT \
THIS
3/146 433.312 1.3 0.0430 F
0 / - \
VN \ /
I \
31147 N ~ 378.448 7 1.2920 F _ O
\ /

3! 148 N ~ 392.475 1.5 0.1980 o ~ - ~ -NN ~ /
31149 N 440 440 28 7.5 this l I \
N ~ 366.850 1.2 0.0041 this o ~ -~ N \ /
NOT
6 ~ 365.862 1.2 0.0382 O / --- ~ N.
\ /
I \
3/150 N ~ 361.446 1.1 0.0055 ~~ ~ - ~ ~ em v ° ï! ~ J

at \ / o ¿\
3/151 N ~ 394.903 1.7 0.0221 F
O
% ~ -~ N \ l i \
3/152 N ~ 364.421 0.8 0.0063 Y ~ N
N /
\.
N ~
3/153 347.419 2.2 0.0224 cl \ O / - \
~ / N \ /
i \ cl E2 N ~ 415.32 1.5 0.0001 NOT-~ N \ /
E3 ¿\ 399.50 25 N ~
THIS
--\ NOT_ \ ~ \ /
E4 N ~ 381.87 1.3 0.0047 ~~ ~ s ~ ~. ~ e eo - ~!

~ N =

\ O -NOT
NOT

E5 V 391.43 0.8 0.0030 i \
N ~

Br O

E6 N \ 425.33 0.9 0.0012 C ~

\ s ~

~ N

E7 N ~ 396.92 1.4 0.0110 o-\ O
-NOT

/
\
-VN

I
E8 N \ 377.45 2 NOT

\ o VN \

E9 N \ 361.45 3 0.0531 NOT
N \ ~

E10 N 371.44 0.9 0.0049 \ o ~ - \ -~ - N ~ F
E11 N \ O ~ F 430.43 1 0.0120 F

_ v o ' \ o l-¿\
E12 N \ 390.44 2.3 0.0031 \ o / - \
VN \ /
E13 362.43 1 0.0142 c ~
\ ~
\ /
I \
E14 N ~ 480.91 12 3.079 \ ~ / --- \ N-VN \ I
N ~~ \ /
E15 H ~ ci 434.94 14 0.2387 this \ o ~
r I \
E16 N ~ '394.90 1.5 0.0390 \ o ~ N
N ~~ \ /
E17 397.48 1.5 0.0085 o ~ --- ~ -yj \ /
NOT ' N ~ \ N
O
E18 403.48 1.2 0.0595 ~ ~ -Y ~ N
NN ~ l ~
i \
NOT \
E19 348.41 6 0.040 o-'~ VN \ /
¿\ O-E20 N \ 406.48 0.29 0.0015 ~~ o NOT
NOT \
E21 347.42 9.5 0.1982 NOT
~ / N \ /
THIS
E22 381.87 1.9 0.0064 o /
N ~ \ /
N \\ N
E23 0 389.46 0.32 0.010 \ o / - ~ -"'~, N \ /
NOT \
N ~ / \
E24 422.53 1.7 0.3119 o ~
'' ~ J '' \ / _ N ~
\ /
E25 438.53 6 0.5602 ~ - _ _ ~ ~. ~.

\ o / -N ~ N
NOT

E26 0 ~ ~ 424.52 6.4 0.1351 / \ o ~
\ /
O
O
E27 446.55 22.5 / ~ -N ~ \ /
Nw \ ô

E28 418.49 3.4 0.0606 \ o / - \
N ~ \ /
E29 390.44 0.46 0.0095 / \ o ~ - ~ -VN \ / o y OJ
E30 404.47 0.42 0.0021 \ o ~ N-~ N ~ /
¿\
N ~
E31 361.45 1.5 0.0208 o ~ - ~ - ~ \
NVN \
N ~ \ N
E32 451.47 3.1 0.5135 -_-. . _ r ~. v \ o ~ -N
~ N \ /
THIS
E33 381.87 0.9 0.0089 \ o ~ - \
N ~ N
NOT
\ NOT_ E34 375.47 0.8 0.0140 \ o ~ - \ - o V / o / ~ \ ~ N

E35 ~ 477.52 5.5 NOT
C, o ~ \
NOT- \
THIS
E36 382.85 20 0.9388 _ NOT
THIS
E37 387.89 2 0.0377 I \\ NO
N CI
E38 N 406.88 4 0.0196 \ O /
'VN \ /
O
E39 390.48 2.5 0.0719 ~.

\ o ~ - o ~% \ /
N
E40 ° 433.51 1.6 0.1185 \ O ~ -N
N ~~ ~ I
E41 397.48 4.5 0.0894 F
O
I
F ~
E42 N ~ ~~ 416.86 2.09 0.0502 F
FO
F ~ N ~ I
NOT
E43 FN ~ ~ C ~ 452.84 2.17 1.4635 C ~
' NOT
E44 ~~ N ~ ~ CI 449.77 1.68 0.2357 \ o ' C ~
E45 394.90 0.99 0.0105 \ o N VN ~ N
E46 \ 332.41 14.5 1.2360 \

o NOT
~

E47 CI 408.93 1.55 N ~

~ N \ /

NOT \
E48 CI 386.92 3.28 0.4895 p ~ N +

O

_ ~ \ /

E49 ~ ~ 425.87 20.2 cl FF

F
O

~ N
NOT

E50 N ~ ~ ci 448.87 25 O

~ N ~ /
NOT

O-E51 ~ 427.93 1.3 2.2980 ,THIS

H

O

VN ~ /

No CI

E52 381.87 1.41 0.0102 o-o _ VN
NOT
O-E53 N ~ 407.47 0.62 0.0111 o NN F
\ \-/ NOT
N ~
E54 365.41 14.2 1.0370 ~ \ o ~ - \ -N- '~ j \ l this E55 FF 459.86 3.6 1.3370 F
O-O ~ -O-E56 FF 485.46 1.1 0.1450 F
\ O
\ - / N \ ~
NOT \
NOT
E57 0 374.44 2.0 0.0898 \ o ~ \
F ~ NN
i \ V ~~ N
N ~
E58 365.41 1 0.0411 \ o ~
N ~ ~ ~ Br NOT
THIS
E59 459.77 2.1 0.1040 \ o . ~ N
THIS
E60 396.88 1.37 0.0117 \\ NO
VN
THIS
E61 / I 473.96 2.3 6.0900 \ o N ~
E62 N â 391.43. 13.5 \ o ~
¿
E63 N ~ 374.49 0.6 0.0022 Br \ 0 ¿
E64 N ~ ~ I 524.64 3.5 Br \ O
~ N
THIS
E65 445.75 1.7 0.0106 st N ~ N
THIS
E66 442.95 3.7 1.828 N ~ N \ /
NIC, E67 443.94 2.3 0.2370 I
NOT
THIS
E68 448.98 1.4 0.3390 w THIS
E69 448.98 1.7 6.1540 r O
~ N
THIS
E70 394.86 1.3 0.0108 O-O ~
N ~ O-E71 N ~ 434.54 3.74 0.2000 ° '~. ° vs ~ sav ~ C6 1 ~~ ~ d ' cl E72 398.87 1.55 0.0066 o-\ o / -o-E73 N ~ 422.48 0.99 0.0069 o ~
N ~ N ~ /

E74 HiCI F ~ 448.90 F
O
VN
THIS
E75 460.97 5.1 0.0612 \ o ~
N ~ ~ /
THIS
E76 471.99 1.9 0.1375 NOT
Br \ o ~ / N ~ /
cl E77 N ~ 466.76 0.7 0.0267 ~ ew ~ w .. esv ~ 6 '6! 8 ~

o-\ o ¿~ O-E78 N ~ 564.28 13.98 0.3180 Br ~ Br Br \ o ~ _ N ~ \ / Br THIS
E79 545.66 2.2 1.0380 \ o ~
No CI
E80 487.00 4.4 1.1260 Br ~ -\ O /
E81 550.25 17.1 Br O-\ O
O
E82 N ~ 471.34 0.94 0.0018 Br N ~ ~
N ~ 0 E83 ~ J 475.55 20 \ o ~ -NOT
NOT

\
N ~~, CI C
H

E84 426.94 0.65 0.0029 o-\ o ~

1 ~

o-E85 N ~ 474.58 1.39 0.1807 o-~ ~ o ~

~

o-E86 N ~ 432.52 0.87 0.0068 o-\ o a 1 \

o-E87 ~ ~ 512.58 1.26 1.2830 F

O-\ O /

N ~ ~ I

O-~

E88 486.54 4.53 1.2570 F

- .. a _ .. ~ ~ r .rer ~ r ~ AA 'W, y - o-\ o ~

~ N ~ N

E89 N ~ 536.55 3.42 1.0980 w FF
F

O-\ O /

~ N

O-E90 N ~ 458.53 1.73 0.0188 o-\ ~

~ N

457.53 1 0.0105 NOT

o-\ o ~

VN

O-NOT

E92 ~ 392.46 1.16 0.0010 o-\ p I

_ ~ N

O-NOT

E93 ~ 461.56 2.02 0.0063 .,, ~ -., e ~. _ o, ~ ~ ~, ao ,,, o-o ~ -.. N ~ \ /
N ~ O-E94 435.48 0.9 0.0020 ~ N
O
O-\ O
~ N \ /
l \ p-E95 N ~ 435.48 0.8 0.00017 NOT
O-\ O
~ N \ /
E96 N ~ 477.56 11.37 0.0733 ~ N ~
p NOT
\ O
N ~ N \ l NOT
NOT
E97 p 390.44 3.6 0.0811 o-\ o VN \ /
o-E98 N ~ ~ I 497.60 1.4 0.2230 NOT

~~ ~~~ es 4, ï ~ "~ i 'Ld dl éd ii o-\ o / ~ o-Egg N \ 407.47 1 0.0024 NOT
O-\ °
NOT
/ \ O-E100 N \ 420.47 0.5 0.0041 \ o ~ - \
N ~ N
N \ \ CI
E101 / ~ 472.97 25 \ o ~
V
/ this E102 489.04 18 s \ ° ~
~ I \ /
NOT
O
E103 405.50 1 0.0167 l \ o /
~ j ~ s i \
NOT\
E104 352.46 8 0.8389 \ o / - ~ -~ / N \ /
N \\ O
E105 404.51 3.6 1.6510 - ~ ° ~~ '- w V -ssv ~

o-/ \ o A ~ I
1 ~ o-E106 N ~ 477.56 10 0.1419 NOT
O
O / -~ N \ I
1 \
N ~
E107 0 388.47 1.4 0.0104 o ~
NV \ / °
i \ o \
N ~
E108 434.49 0.9 \ o ~
NN "\ /
O
N ~ \
E109 418.54 5.2 8.0450 \ o ~ -~ .- / N \ /
NOT
H ~ CI
O
E110 483.01 12 1.1661 F
/ \ o VN ~ IF
1 ~ F
E111 N ~ 400.40 2.33 o-\ o ~
N ~ N
NOT
I ~ o-E112 N ~ 490.56 3 w O
\ o N ~ N \ /
N ~~ N
E113 0 449.51 9.2 o-\ o ~
VN
I ~ o-E114 N ~ 502.59 12.9 ~ o S
N
N ~ N - <~ JI
S
N ~
E115 353.45 <25 3.2370 \ o ~ - ~ -E116 0 403.48 2.07 0.0113 o ~ vv ~ / 1 iJ ~

~ N
O-.
E117 N ~ 460.45 7.9 0.0284 FF 'F
. ~ ~ N \ /
\ THIS
E118 434.85 2.3 0.4030 F
\ /
\ NOT
E119 ~ 443.43 1.2 0.0103 FF
F

~ N \ /
i -E120 N \ 421.50 17.9 NOT
O-N ~ \ /
\ O-E121 N \ 505.57 0.9 WE

_ _ ~ -. ~ r _. . _ _ o-o ~
NVN \ /
O-E 122 N ~ 493.56 1.2 ON ~
O-O
~ N ~ ~ ' E123 N ~ 468.53 2.5 ~ F
O

O
~ N
~ -E124 N ~ 490.60 <25 o-~ / N \ /
o-E125 N ~ 450.54 4.1 o ~
o-~ N
O-E126 N ~ 476.53 0.8 ~ _ .., o-\ o /
'~ "' \ /
¿\ O-E127 N ~ 436.51 2.3 ~ \ o / - ~
O
E128 0 433.51 3.0 0.1196 o-\ ~
VN \ /
¿~ O-E129 N ~ 447.54 0.9 o-\ o /NOT
~ ~ ~ O
E130 N ~ 447.54 1.5 o-\ o / - ~ -~%

E131 498.58 <25 o \ o /
E132 N \ p 376.48 0.9 o ~
\ /
E133 0 375.43 1 \ o '- \
N \ -. IN \ /
E134 N 405.46 3.2 oh \ o ~ N \ /
E135 ~ \ 431.95 0.5 N \ O-NOT
-. ~ NV
E136 N \ \ oC 448.89 1.3 iCl F
O-\ O
N ~ N \ / ' E137 ~ \ 537.66 3.2 N \ O-O
o-\ o ~ - \
~% \ /
E138 N \ \ o- 475.59 22 NOT

m o-\

o ~

~ N ~ I

E139 ~ ~ 428.43 2.9 o-N ~ F

F

NOT
\ o ~ -NOT

p E140 363.41 16.5

Claims (19)

1. Product corresponding to the following formula (1):
in which R1 is chosen from - phenyl, - phenyl substituted with at least one radical chosen from halogen, (C1-C3) -alkyl, CON (R10) (R11), O-R10, S-R10, N (R10) (R11), pyridyl, - pyridyl substituted with at least one radical chosen from halogen, (C1-C3) -alkyl, CON (R10) (R19), O-R10, S-R10, N (R10) (R11), in which R10, R11 are independently chosen from H, (C1-C3) -alkyl, (C1-C3) -halogenated alkyl;
R2 is chosen from phenyl, 3-pyridyl, phenyl substituted by at least one radical chosen from halogen, alkyl, O-R10, S-R10, N (R10) (R11), in which R10, R11 are independently selected from H, (C1-C3) alkyl, (C1-C3) halogenated alkyl;
L is selected from the group consisting of C (R7) (R8), C = O, C = S, C = N (R7);
R3 is selected from the group consisting of H, halogen, CF3, alkyl, alkyl substituted, alkylene, substituted alkylene, alkynyl, substituted alkynyl, cycloalkyl, cycloalkylene, heterocyclyl, substituted heterocyclyl, CO-R7, C (R7) = NO (R8), COOH, CONH-aryl, CONH-heteroaryl, 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-C3) alkylene, NH-CH2- (C2-C3) alkynyl, N (R7) -N (R8) (R12), NN = C (R7) (R8), CN, O-R7, O-CH2-aryl, O-CH2-heteroaryl, S-R7, SO-R7, SO2-R7, aryl, heteroaryl, substituted cycloalkyl, substituted aryl, substituted heteroaryl;
R4 is selected from the group consisting of consisting of H, (C1-C3alkyle) , cyclopropyl, (C2-C3) alkylene, (C2-C3) alkynyl, O (C1-C3) alkyl, S- (C1-C3) alkyl, F, Cl, Br;
X is N or CH;

R7, R8, R12 are independently selected from the group consisting of H, (C1-C3) alkyl, (C1-C3) substituted alkyl, LG-R1 is selected from the group consisting of - L, R1 as defined above, - R5 and R6 are independently selected from the group consisting of H, (C1-C3) alkyl, oxo, halogen; and R9 = (C1-C3) alkyl:
in racemic form, enriched in an enantiomer, enriched in a diastereomer, its tautomers, prodrugs and pharmaceutically acceptable salts, under provided that the product of formula (1) is not one of the following compounds:
[4- (3-methoxy-phenyl) -piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl) methanone, [4- (6méthyl-pyridin-2-yl) -piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl) -methanone [4- (3-hydroxy-phenyl) -piperazin-1-yl] - (2-phenyl-2 H-pyrazol-3-yl -) - methanone, [9- (3,5-dimethoxyphenyl) piperazin-1-yl] - (1- (4-nitrophenyl-5-trifluoromethyl-1 H-pyrazol-4-yl) -methanone, 2. Product according to claim 1, characterized in that X is N. 3. Product according to claim 1 or 2, characterized in that LG-R1 is in which R5 and R6 are each H. 4. Product according to claim 3, characterized in that R1 is chosen among:
- halogen-substituted phenyl, (C1-C3) -alkyl, (C1-C3) -alkoxy, or carboxamide, 2-pyridyle or 3-pyridyle, - 2-pyridyle or 3-pyridyle substituted by halogen or (C1-C3) -alkyle. 5. Product according to claim 4, characterized in that R1 is phenyl substituted by:
a chloro radical, or - one or two methoxy radicals, or - a carboxamide radical. 6. Product according to any one of claims 4 to 5, characterized in that that R1 is chosen from phenyl-2,3-disubstituted, phenyl-2,5-disubstituted, phenyl-3-substituted, phenyl-3,5-disubstituted, phenyl-3,4-disubstituted. 7, Product according to claim 4, characterized in that R1 is chosen from 2-pyridyle-4-substituted, 2-pyridyle-6-substituted, 2-pyridyle-4,6-disubstituted, 3-pyridyl-2-substituted, and 3-pyridyl-5-substituted. 8, Product according to claim 1, characterized in that R3 is chosen from H
(C1-C3) alkyl, CF3, hydroxymethyl, amino, azétidino and pyrrolidino. 9. Product according to claim 8, characterized in that R3 is chosen from methyl, hydroxymethyl, CF3 and amino. 10. Product according to claim 1, characterized in that R4 is H. 11. Product according to claim 1, characterized in that it is chosen among:

(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl) - (4-phenyl-piperazin-1-yl) methanone - (3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl) - [4- (2-methoxy-phenyl) -piperazin-1-yl] -methanone - (3,5-Dimethyl-1, phenyl-1H-pyrazol-4-yl) - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone - (3,5-Dimethyl-1-phenyl-1H-pyrazol-4yl) - [4- (4-fluoro-phenyl) -piperazin-1-yl] -methanone -1- (4- [4- (3,5-Dimethyl-1-phenyl-1H-pyrazole-4-carbonyl) -piperazin-1-yl] -phenyl} -ethanone - [4- (2,4-Dimethyl-phenyl) -piperazin-1-yl] - (3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl) -methanone - [4- (3,4-Dichloro-phenyl) -piperazin-1-yl] - (3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl) -methanone - [4- (3,4-Dimethyl-phenyl) -piperazin-1-yl] - (3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl) -methanone - (3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl) - (4-o-tolyl-piperazin-1-yl) methanone - [4- (2,3-Dimethyl-phenyl) -piperazin-1-yl] - (3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl) -methanone (3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl) - [4- (2-ethyl-phenyl) -piperazin-1-yl] -methanone - [4- (3-Chloro-phenyl) -piperazin-1-yl] - (3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl) -methanone - (3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl) - (4-m-tolyl-piperazin-1-yl) methanone - (3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl) - [4- (4-methoxy-phenyl) -piperazin-1-yl] -methanone - [4- (2,4-Dimethoxy-phenyl) piperazin-1-yl] - (3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl) -methanone - (3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl) - [4- (2-methylsulfanyl-phenyl) -piperazin-1-yl] -methanone - [4- (4-Chloro-phenyl) -piperazin-1-yl] - (3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl) -methanone - (3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl) - (4-naphthalen-1-yl-piperazin-1-yl) -methanone - [4- (5-Chloro-2-methylphenyl) -piperazin-1-yl] - (3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl) methanone - (3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl) - [4- (2-ethoxy-phenyl) -piperazin-1-yl] -methanone - [4- (2,3-Diohloro-phenyl) -piperazin-1-yl] - (3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl) -methanone - (3,5-Dimethyl-1-phenyl-1H-pyrazol-4-y1) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone - [4- (5-Chloro-2-methoxy phenyl) -piperazin-1-yl] - (3,5-dimethyl-1-phenyl-1H-pyrazol 4-yl) methanone - [4- (4-Benzyloxy-phenyl) -piperazin-1-yl] - (3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl) -methanone - (3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl) - [4- (2-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone - [4- (2,3-Dihydro-benzo [1,4] dioxin-6-yl) -piperazin-1-yl] - (3,5-dimethyl-1-phenyl-pyrazol-4-yl) methanone - [2- (4-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-phenyl-piperazin-1-yl) -methanone - [2- (4-Methoxy-phenyl] -5-methyl-2H-pyrazol-3-yl] - [4- (2-methoxy-phenyl) -piperazin-1-yl] methanone - [2- (4-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [4- (4-Fluoro-phenyl) -piperazin-1-yl] - [2- (4-methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone -1- (4- {4- [2- (4-Methoxy-phenyl) -5-methyl-2H-pyrazole-3-carbonyl] -piperazin-1-yl} -phenyl) -ethanone - [4- (2,4-Dimethyl-phenyl) -piperazin-1-yl] - [2- (4-methoxy-phenyl) -5-methyl-2H-pyrazol 3-yl] methanone - [4- (3,4-Dichloro-phenyl) -piperazin-1-yl] - [2- (4-methoxy-phenyl) -5-methy1-2H-pyrazol 3-yl] methanone - [4- (3,4-Dimethyl-phenyl) -piperazin-1-yl] - [2- (4-methoxy-phenyl) -5-methyl-2H-pyrazol 3-yl] methanone - [2- (4-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-o-tolyl-piperazin-1-yl) -methanone - [4- (2,3-Dimethyl-phenyl) -piperazin-1-yl] - [2- (4-methoxy-phenyl) -5-methyl-2H-pyrazol 3-yl] methanone - [4- (2-Ethyl-phenyl) -piperazin-1-yl] - [2- (4-methoxy-phenyl) -5-methyl-2H-pyrazol 3-yl] -methanone - [4- (3-Chloro-phenyl) -piperazin-1-yl] - [2- (4-methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (4-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-m-tolyl-piperazin-1-yl) -methanone - [2- (4-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-methoxy-phenyl) -piperazin-1-yl] methanone - [4- (2,4-Dimethoxy-phenyl) -piperazin-1-yl] - [2- (4-methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (4-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-methylsulfanyl-phenyl) -piperazin-1-yl] methanone - [4- (4-Chloro-phenyl) -piperazin-1-yl] - [2- (4-methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (4-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-naphthalen-1-yl-piperazin-1-yl) -methanone - [4- (5-Chloro-2-methylphenyl) -piperazin-1-yl] - [2- (4-methoxy-phenyl) -5-methyl-pyrazol-3-yl] methanone - [4- (2-Ethoxy-phenyl) -piperazin-1-yl] - [2- (4-methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [4- (2,3-Dichloro-phenyl) piperazin-1-yl] - [2- (4-methoxy-phenyl) -5-methyl-2H-pyrazol 3-yl] methanone - [2- (4-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [4- (5-Chloro-2-methoxy-phenyl) -piperazin-1-yl] - [2- (4-methoxy-phenyl) -5-methyl-pyrazol-3-yl] methanone - [4- (4-Benzyloxy-phenyl) -piperazin-1-yl] - [2- (4-methoxy-phenyl) -5-methyl-2H-pyrazol 3-yl] methanone - [2- (4-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-tritfluoromethyl-phenyl) -piperazin-1-yl] methanone - [4- (2,3-Dihydro-benzo [1,4] dioxin-6-yl) -piperazin-1-yl] - [2- (4-methoxy-phenyl) -methyl-2H-pyrazol-3-yl] methanone - [2- (3-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-phenyl-piperazin-1-yl) -methanone - [2- (3-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-methoxy-phenyl) -piperazin-1-yl] methanone - [2- (3-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [4- (4-Fluoro-phenyl) piperazin-1-yl] - [2- (3-methoxy-phenyl) -5-methyl-2H-pyrazol yl] methanone -1- (4- {4- [2- (3-Methoxy-phenyl) -5-methyl-2H-pyrazole-3-carbonyl] -piperazin-1-yl} -phenyl) -ethanone - [4- (2,4-Dimethyl-phenyl) -piperazin-1-yl] - [2- (3-methoxy-phenyl) -5-methyl-2H-pyrazol 3-yl] methanone - [4- (3,4-Dichloro-phenyl) -piperazin-1-yl] - [2- (3-methoxy-phenyl) -5-methyl-2H-pyrazol 3-yl] methanone - [4- (3,4-Dimethyl-phenyl) -piperazin-1-yl] - [2- (3-methoxy-phenyl) -5-methyl-2H-pyrazol 3-yl] methanone - [2- (3-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-o-tolyl-piperazin-1-yl) -methanone - [4- (2,3-Dimethyl-phenyl) -piperazin-1-yl] - [2- (3-methoxy-phenyl) -5-methyl-2H-pyrazol 3-yl] methanone - [4- (2-Ethyl-phenyl) -piperazin-1-yl] - [2- (3-methoxy-phenyl) -5-methyl-2H-pyrazol 3-yl] -methanone - [4- (3-Chloro-phenyl) -piperazin-1-yl] - [2- (3-methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (3-Methoxy phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-m-tolyl-piperazin-1-yl) -methanone - [2- (3-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-methoxy-phenyl) -piperazin-1-yl] methanone - [4- (2,4-Dimethoxy-phenyl) -piperazin-1-yl] - [2- (3-methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (3-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-methylsulfanyl-phenyl) -piperazin-1-yl] methanone - [4- (4-Chloro-phenyl) -piperazin-1-yl] - [2- (3-methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (3-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-naphthalen-1-yl-piperazin-1-yl) -methanone - [4- (5-Chloro-2-methylphenyl) -piperazin-1-yl] - [2- (3-methoxy-phenyl) -5-methyl-pyrazol-3-yl] methanone - [4- (2-Ethoxy-phenyl) -piperazin-1-yl] - [2- (3-methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [4- (2,3-Dichloro-phenyl) -piperazin-1-yl] - [2- (3-methoxy-phenyl) -5-methyl-2H-pyrazol 3-yl] methanone - [2- (3-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [4- (5-Chloro-2-methoxy phenyl) -piperazin-1-yl] - [2- (3-methoxy-phenyl) -5-methyl-pyrazol-3-yl] methanone - [4- (4-Benzyloxy-phenyl) -piperazin-1-yl] - [2- (3-methoxy-phenyl) -5-methyl-2H-pyrazol 3-yl] methanone - [2- (3-Methoxy-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [4- (2,3-Dihydro-benzo [1,4] dioxin-6-yl) -piperazin-1-yl] - [2- (3-methoxy-phenyl) -methyl-2H-pyrazol-3-yl] methanone - (5-Methyl-2-phenyl-2H-pyrazol-3-yl) - (4-phenyl-piperazin-1-yl) methanone - [4- (2-Methoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone - (5-Methyl-2-phenyl-2H-pyrazol-3-yl) - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone - [4- (4-Fluoro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone -1- {4- [4- (5-Methyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -phenyl} -ethanone - [4- (2,4-Dimethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone - [4- (3,4-Dichloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone - (5-Methyl-2-phenyl-2H-pyrazol-3-yl) - (4-o-tolyl-piperazin-1-yl) -methanone - [4- (2,3-Dimethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone - [4- (2-Ethyl-phenyl) piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone - [4- (3-Chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone - [4- (3-Methoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone - (5-Methyl-2-phenyl-2H-pyrazol-3-yl) - (4-m-tolyl-piperazin-1-yl) -methanone - [4- (4-Methoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone - [4- (2,4-Dimethoxy phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone - (5-Methyl-2-phenyl-2H-pyrazol-3-yl) - [4- (2-methylsulfanyl-phenyl) -piperazin-1-yl] -methanone - [4- (4-Chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl] -methanone - (5-Methyl-2-phenyl-2H-pyrazol-3-yl) - (4-naphthalen-1-yl-piperazin-1-yl) -methanone - [4- (5-Chloro-2-methyl-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone - [4- (2-Ethoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone - [4- (2,3-Dichloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone - (5-Methyl-2-phenyl-2H-pyrazol-3-yl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone - [4- (5-Chloro-2-methoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone - [4- (4-Benzyloxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone - [4- (2,3-Dihydro-benzo [1,4] dioxin-6-yl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) methanone - N- {4- [4- (5-Methyl-2-phenyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -phenyl} -methanesulfonamide - [2- (2-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-phenyl-piperazin-1-yl) -methanone - [2- (2-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-methoxy-phenyl) -piperazin-1-yl] methanone - [2- (2-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-fluoro-phenyf) -piperazin-1-yl] -methanone -1- (4- {4- [2- (2-Fluoro-phenyl) -5-methyl-2H-pyrazole-3-carbonyl] -piperazin-1-yl} -phenyl) -ethanone - [4- (2,4-Dimethyl-phenyl) -piperazin-1-yl] - [2- (2-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [4- (3,4-Dichloro-phenyl) -piperazin-1-yl] - [2- (2-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (3,4-Dimethyl-phenyl) -piperazin-1-yl] - [2- (2-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (2-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-o-tolyl-piperazin-1-yl) -methanone - [4- (2,3-Dimethyl-phenyl) -piperazin-1-yl] - [2- (2-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [4- (2-Ethyl-phenyl) -piperazin-1-yl] - [2- (2-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] -methanone - [4- (3-Chloro-phenyl) -piperazin-1-yl] - [2- (2-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] -methanone - [2- (2-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3-methoxy-phenyl) -piperazin-1-yl] methanone - [2- (2-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-m-tolyl-piperazin-1-yl) -methanone - [2- (2-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-methoxy-phenyl) -piperazin-1-yl] methanone - [4- (2,4-Dimethoxy-phenyl) -piperazin-1-yl] - [2- (2-fluoro-phenyl) -5-methyl-2H-pyrazol 3-yl] methanone - [2- (2-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-methylsulfanyl-phenyl) -piperazin-1-yl] methanone - [4- (4-Chloro-phenyl) -piperazin-1-yl] - [2- (2-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] -methanone - [2- (2-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-naphthalen-1-yl-piperazin-1-yl) -methanone - [4- (5-Chloro-2-methyl-phenyl) -piperazin-1-yl] - [2- (2-fluoro-phenyl) -5-methyl-pyrazol-3-yl] methanone - [4- (2-Ethoxy-phenyl) -piperazin-1-yl] - [2- (2-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] -methanone - [4- (2,3-Dichloro-phenyl) -piperazin-1-yl] - [2- (2-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (2-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [4- (5-Chloro-2-methoxy-phenyl) -piperazin-1-yl] - [2- (2-fluoro-phenyl) -5-methyl-pyrazol-3-yl] methanone - [2- (2-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [4- (2,3-Dihydro-benzo [1,4] dioxin-6-yl) -piperazin-1-yl] - [2- (2-fluoro-phenyl) -5-methyl 2H-pyrazol-3-yl] methanone -N- (4- (4- [2- (2-Fluoro-phenyl) -5-methyl-2H-pyrazole-3-carbonyl] -piperazin-1-yl} -phenyl) -methanesulfonamide - [2- (3-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-phenyl-piperazin-1-yl) -methanone - [2- (3-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-methoxy-phenyl) -piperazin-1-yl] methanone - [2- (3-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [2- (3-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-fluoro-phenyl) -piperazin 1-yl] -methanone -1- (4- {4- [2- (3-Fluoro-phenyl) -5-methyl-2H-pyrazole-3-carbonyl] -piperazin-1-yl} -phenyl) -ethanone - [4- (2,4-Dimethyl-phenyl) -piperazin-1-yl] - [2- (3-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [4- (3,4-Dichloro-phenyl) -piperazin-1-yl] - [2- (3-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [4- (3,4-Dimethyl-phenyl) -piperazin-1-yl] - [2- (3-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (3-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-o-tolyl-piperazin-1-yl) -methanone - [4- (2,3-Dimethyl-phenyl) -piperazin-1-yl] - [2- (3-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [4- (2-Ethyl-phenyl) -piperazin-1-yl] - [2- (3-fluoro-phenyl) -5-methyl-2H-pyrazol 3-yl] -methanone - [4- (3-Chloro-phenyl) -piperazin-1-yl] - [2- (3-fluoro-phenyl) -5-methyl-2H-pyrazol 3-yl] -methanone - [2- (3-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3-methoxy-phenyl) -piperazin-1-yl] methanone - [2- (3-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-m-tolyl-piperazin-1-yl) -methanone [2- (3-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-methoxy-phenyl) -piperazin yl] methanone - [4- (2,4-Dimethoxy-phenyl) -piperazin-1-yl] - [2- (3-fluoro-phenyl) -5-methyl-2H-pyrazol 3-yl] methanone - [2- (3-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-methylsulfanyl-phenyl) -piperazin-1-yl] methanone - [4- (4-Chloro-phenyl) -piperazin-1-yl] - [2- (3-fluoro-phenyl) -5-methyl-2H-pyrazol 3-yl] -methanone - [2- (3-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-naphthalen-1-yl-piperazin-1-yl) -methanone - [4- (5-Chloro-2-methylphenyl) -piperazin-1-yl] - [2- (3-fluoro-phenyl) -5-methyl-pyrazol-3-yl] methanone - [4- (2-Ethoxy-phenyl) -piperazin-1-yl] - [2- (3-fluoro-phenyl) -5-methyl-2H-pyrazol 3-yl] -methanone - [4- (2,3-Dichloro-phenyl) -piperazin-1-yl] - [2- (3-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (3-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [4- (5-Chloro-2-methoxy-phenyl) -piperazin-1-yl] - [2- (3-fluoro-phenyl) -5-methyl-pyrazol-3-yl] methanone - [4- (4-Benzyloxy-phenyl) -piperazin-1-yl] - [2- (3-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (3-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [4- (2,3-Dihydro-benzo) [1,4] dioxin-6-yl) -piperazin-1-yl] - [2- (3-fluoro-phenyl) -5-methyl 2H-pyrazol-3-yl] methanone -N- (4- {4- [2- (3-Fluoro-phenyl) -5-methyl-2H-pyrazole-3-carbonyl] -piperazin-1-yl} -phenyl) -methanesulfonamide - [2- (4-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-phenyl-piperazin-1-yl) -methanone - [2- (4-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-methoxy-phenyl) -piperazin yl] methanone - [2- (4-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [2- (4-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-fluoro-phenyl) -piperazin 1-yl] -methanone -1- (4- {4- [2- (4-Fluoro-phenyl) -5-methyl-2H-pyrazole-3-carbonyl] -piperazin-1-yl} -phenyl) -ethanone - [4- (2,4-Dimethyl-phenyl) -piperazin-1-yl] - [2- (4-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [4- (3,4-Dichloro-phenyl) -piperazin-1-yl] - [2- (4-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [4- (3,4-Dimethyl-phenyl) -piperazin-1-yl] - [2- (4-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (4-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-o-tolyl-piperazin-1-yl) -methanone - [4- (2,3-Dimethyl-phenyl) -piperazin-1-yl] - [2- (4-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [4- (2-Ethyl-phenyl) -piperazin-1-yl] - [2- (4-fluoro-phenyl) -5-methyl-2H-pyrazol 3-yl] -methanone - [4- (3-Chloro-phenyl) -piperazin-1-yl] - [2- (4-fluoro-phenyl) -5-methyl-2H-pyrazol 3-yl] -methanone - [2- (4-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3-methoxy-phenyl) -piperazin-1-yl] methanone - [2- (4-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-m-tolyl-piperazin-1-yl) -methanone - [2- (4-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-methoxy-phenyl) -piperazin-1-yl] methanone - [4- (2,4-Dimethoxy-phenyl) -piperazin-1-yl] - [2- (4-fluoro-phenyl) -5-methyl-2H-pyrazol 3-yl] methanone - [2- (4-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-methylsulfanyl-phenyl) -piperazin-1-yl] methanone - [4- (4-Chloro-phenyl) -piperazin-1-yl] - [2- (4-fluoro-phenyl) -5-methyl-2H-pyrazol 3-yl] -methanone - [2- (4-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-naphthalen-1-yl-piperazin-1-yl) -methanone - [4- (5-Chloro-2-methylphenyl) -piperazin-1-yl] - [2- (4-fluoro-phenyl) -5-methyl-pyrazol-3-yl] methanone - [4- (2-Ethoxy-phenyl) -piperazin-1-yl] - [2- (4-fluoro-phenyl) -5-methyl-2H-pyrazol 3-yl] -methanone - [4- (2,3-Dichloro-phenyl) -piperazin-1-yl] - [2- (4-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (4-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [4- (5-Chloro-2-methoxy-phenyl) -piperazin-1-yl] - [2- (4-fluoro-phenyl) -5-methyl-pyrazol-3-yl] methanone - [4- (4-Benzyloxy-phenyl) -piperazin-1-yl] - [2- (4-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (4-Fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [4- (2,3-Dihydro-benzo [1,4] dioxin-6-yl) -piperazin-1-yl] - [2- (4-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (4-methanesulfonyl-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-phenyl-piperazin-1-yl) -methanone - [2- (4-methanesulfonyl-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3-trifluoromethyl phenyl) -piperazin-1-yl] methanone -1- (4- {4- [2- (4-methanesulfonyl-phenyl) -5-methyl-2H-pyrazole-3-carbonyl] -piperazin 1-yl} -phenyl) -ethanone - [4- (2,4-Dimethyl-phenyl) -piperazin-1-yl] - [2- (4-methanesulfonyl-phenyl) -5-methyl-2H
pyrazol-3-yl] methanone - [2- (4-methanesulfonyl-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-o-tolyl-piperazin-1-yl) -methanone - [4- (3-Chloro-phenyl) -piperazin-1-yl] - [2- (4-methanesulfonyl-phenyl) -5-methyl-pyrazol-3-yl] methanone - [2 - (- 4-methanesulfonyl-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3-methoxy-phenyl) -piperazin-1-yl] methanone - [2- (4-methanesulfonyl-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-m-tolyl-piperazin-1-yl) -methanone - [4- (2,4-Dimethoxy-phenyl) -piperazin-1-yl] - [2- (4-methanesulfonyl-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (4-methanesulfonyl-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-methylsulfanyl phenyl) -piperazin-1-yl] methanone - [4- (4-Chloro-phenyl) -piperazin-1-yl] - [2- (4-methanesulfonyl-phenyl) -5-methyl-pyrazol-3-yl] methanone - [4- (5-Chloro-2-methylphenyl) -piperazin-1-yl] - [2- (4-methanesulfonyl-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [4- (2-Ethoxy-phenyl) -piperazin-1-yl] - [2- (4-methanesulfonyl-phenyl) -5-methyl-pyrazol-3-yl] methanone - [4- (2,3-Dichloro-phenyl) -piperazin-1-yl] - [2- (4-methanesulfonyl-phenyl) -5-methyl-2H
pyrazol-3-yl] methanone - [2- (4-methanesulfonyl-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-trifluoromethyl phenyl) -piperazin-1-yl] methanone - [4- (4-Benzyloxy-phenyl) -piperazin-1-yl] - [2- (4-methanesulfonyl-phenyl) -5-methyl-2H
pyrazol-3-yl] methanone - [2- (4-methanesulfonyl-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [4- (2,3-Dihydro-benzo [1,4] dioxin-6-yl) -piperazin-1-yl] - [2- (4-methanesulfonyl phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-phenyl-piperazin-1-yl) -methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-methoxy-phenyl) -piperazin-1-yl] methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4 (3-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [2- (3-Chloro-phenyl) -5-methyl-2N-pyrazol-3-yl] - [4- (2,4-dimethyl-phenyl) -piperazin-1-yl] methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3,4-dimethyl-phenyl) -piperazin-1-yl] methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-o-tolyl-piperazin-1-yl) -methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2,3-dimethyl-phenyl) -piperazin-1-yl] methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3-methoxy-phenyl) piperazin-1-yl] methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-m-tolyl-piperazin-1-yl) -methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2,4-dimethoxy-phenyl) -piperazin 1-yl] methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-methylsulfanyl-phenyl) -piperazin-1-yl] methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-chloro-phenyl) -piperazin-1-yl] -methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-naphthalen-1-yl-piperazin-1-yl) -methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-ethoxy-phenyl) -piperazin-1-yl] -methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2,3-dichloro-phenyl) -piperazin-1-yl] methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [4- (5-Chloro-2-methoxy-phenyl) -piperazin-1-yl] - [2- (3-chloro-phenyl) -5-methyl-pyrazol-3-yl] methanone - [4- (4-Benzyloxy-phenyl) -piperazin-1-yl] - [2- (3-chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -piperazin-1-yl] methanone - [2- (4-Chloro-phenyl) 5-methyl-2H-pyrazol-3-yl] - (4-phenyl-piperazin-1, yl) -methanone - [2- (4-Chloro-phenyl) -6-methyl-2H-pyrazol-3-yl] - [4- (2-methoxy-phenyl) -piperazin-1-yl] methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-fluoro-phenyl) -piperazin-1-yl] -methanone -1- (4- [4- [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazole-3-carbonyl] -piperazin-1-yl] -phenyl) -ethanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3,4-dichloro-phenyl) -piperazin-1-yl] methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3,4-dimethyl-phenyl) -piperazin-1-yl] methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-o-tolyl-piperazin-1-yl) -methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2,3-dimethyl-phenyl) -piperazin-1-yl] methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-ethyl-phenyl) -piperazin 1-yl] -methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3-chloro-phenyl) -piperazin 1-yl] -methanone - [2- (4-Chloro-phenyl) 5-methyl-2H-pyrazol-3-yl- (4-m-tolyl-piperazin-1-yl) -methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-methoxy-phenyl) -piperazin-1-yl] methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-chloro-phenyl) -piperazin 1-yl] -methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-naphthalen-1-yl-piperazin-1-yl) -methanone - [4- (5-Chloro-2-methylphenyl) -piperazin-1-yl] - [2- (4-chloro-phenyl) -5-methyl-pyrazol-3-yl] methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2,3-dichloro-phenyl) -piperazin-1-yl] methanone - [4- (5-Chloro-2-methoxy-phenyl) -piperazin-1-yl] - [2- (4-chloro-phenyl) -5-methyl-pyrazol-3-yl] methanone - [4- (4-Benzyloxy-phenyl) -piperazin-1-yl] - [2- (4-chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -piperazin-1-yl] methanone - (5-Methyl-2-p-tolyl-2H-pyrazol-3-yl) - [4-phenyl-piperazin-1-yl) methanone - (5-Methyl-2-p-tolyl-2H-pyrazol-3-yl) - [4- (3-trifluoromethyl-phenyl) -piperazin 1-yl] -methanone -1- (4- [4- (5-Methyl-2-p-tolyl-2H-Pyrazole-3-carbonyl) -piperazin-1-yl] -phenyl} -ethanone - [4- (3,4-Dichloro-phenyl) -piperazin-1-yl] - (5-methyl-2- p-tolyl-2H-pyrazol-3-yl) -methanone - (5-Methyl-2-p-tolyl-2H-pyrazol-3-yl) - (4-o-tolyl-piperazin-1-yl) methanone - [4- (2,3-Dimethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-p-tolyl-2H-pyrazol-3-yl) -methanone - [4- (2-Ethyl-phenyl) -piperazin-1-yl] (5-methyl-2-p-tolyl-2H-pyrazol-3-yl) -methanone - [4- (3-Chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-p-tolyl-2H-pyrazol-3-yl) -methanone - [4- (3-Methoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-p-tolyl-2H-pyrazol-3-yl) -methanone - (5-Methyl-2-p-tolyl-2H-pyrazol-3-yl) - (4-m-tolyl-piperazin-1-yl) methanone - [4- (4-Methoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-p-tolyl-2H-pyrazol-3-yl) -methanone - [4- (2,4-Dimethoxy phenyl) -piperazin-1-yl] - (5-methyl-2-p-tolyl-2H-pyrazol-3-yl) -methanone - [4- (2-methylsulfanyl-phenyl) -piperazin-1-yl] - (5-methyl-2-p-tolyl-2H-pyrazol-3-yl) -methanone - [4- (4-Chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-p-tolyl-2H-pyrazol-3-yl) -methanone - (5-Methyl-2-p-tolyl-2H-pyrazol-3-yl) - (4-naphthalen-1-yl-piperazin-1-yl) -methanone - [4- (5-Chloro-2-methylphenyl) -piperazin-1-yl] - (5-methyl-2-p-tolyl-2H-pyrazol 3-yl) -methanone - [4- (2-Ethoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-p-tolyl-2H-pyrazol-3-yl) -methanone - [4- (2,3-Dichloro-phenyl) -piperazin-1-yl] - (5-methyl-2-p-tolyl-2H-pyrazol-3-yl) -methanone - (5-Methyl-2-p-tolyl-2H-pyrazol-3-yl) - [4- (4-trifluoromethyl-phenyl) -piperazin 1-yl] -methanone - [4- (5-Chloro-2-methoxy phenyl) -piperazin-1-yl] - (5-methyl-2-p-tolyl-2H-pyrazol-3-yl) -methanone - [4- (4-Benzyloxy-phenyl) -piperazin-1-yl] - (5-methyl-2-p-tolyl-2H-pyrazol-3-yl) -methanone - (5-Methyl-2-p-tolyl-2H-pyrazol-3-yl) - [4- (2-trifluoromethyl-phenyl) -piperazin 1-yl] -methanone - [4- (2,3-Dihydro-benzo [1,4] dioxin-6-y1) -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-phenyl-piperazin-1-yl) methanone [4- (2-Methoxy phenyl) -piperazin-1-yl] - (5-methyl-2-m-tolyl-2H-pyrazol-3-yl) -methanone - (5-Methyl-2-m-tolyl-2H-pyrazol-3-yl) - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone - [4- (4-Fluoro-phenyl) -piperazin-1-yl] - (5-methyl-2-m-tolyl-2H-pyrazol-3-yl) -methanone -1- {4- [4- (5-Methyl-2-m-tolyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -phenyl} -ethanone - [4- (2,4-Dimethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-m-tolyl-2H-pyrazol-3-yl) -methanone - [4- (3,4-Dichloro-phenyl) -piperazin-1-yl] - (5-methyl-2-m-tolyl-2H-pyrazol-3-yl) -methanone - [4- (3,4-Dimethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-m-tolyl-2H-pyrazol-3-yl) -methanone - (5-Methyl-2-m-tolyl-2H-pyrazol-3-yl) - (4-o-tolyl-piperazin-1-yl) -methanone - [4- (2,3-Dimethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-m-tolyl-2H-pyrazol-3-yl) -methanone - [4- (2-Ethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-m-tolyl-2H-pyrazol-3-yl) -methanone - [4- (3-Chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-m-tolyl-2H-pyrazol-3-yl) -methanone - [4- (3-Methoxy phenyl) piperazin-1-yl] - (5-methyl-2-m-tolyl-2H-pyrazol-3-yl) -methanone - (5-Methyl-2-m-tolyl-2H-pyrazol-3-yl) - (4 - m-tolyl-piperazin-1-yl) -methanone - [4- (4-Methoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-m-tolyl-2H-pyrazol-3-yl) -methanone - [4- (2,4-Dimethoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-m-tolyl-2H-pyrazol-3-yl) -methanone - [4- (2-Methylsulfanyl-phenyl) -piperazin-1-yl] - (5-methyl-2-m-tolyl-2H-pyrazol-3-yl) -methanone - [4- (4-Chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-m-tolyl-2H-pyrazol-3-yl) methanone - (5-Methyl-2-m-tolyl-2H-pyrazol-3-yl) - (4-naphthalen-1-yl-piperazin-1-yl) -methanone - [4- (5-Chloro-2-methyl-phenyl) -piperazin-1-yl] - (5-methyl-2-m-tolyl-2H-pyrazol-3-yl) -methanone - [4- (2-Ethoxy-phenyl) piperazin-1-yl] - (6-methyl-2-m-tolyl-2H-pyrazol-3-yl) -methanone - [4- (2,3-Dichloro-phenyl) -piperazin-1-yl] - (5-methyl-2-m-tolyl-2H-pyrazol-3-yl) -methanone - (5-Methyl-2-m-tolyl-2H-pyrazol-3-yl) - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone - [4- (5-Chloro-2-methoxy phenyl) piperazin-1-yl] - (5-methyl-2-m-tolyl-2H-pyrazol-3-yl) -methanone - (4- (4-Benzyloxy-phenyl) -piperazin-1-yl] - (5-methyl-2-m-tolyl-2H-pyrazol-3-yl) -methanone - (5-Methyl-2-m-tolyl-2H-pyrazol-3-yl) - [4- (2-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone - [4- (2,3-Dihydro-benzo [1,4] dioxin-6-yl) -piperazin-1-yl] - (5-methyl-2-m-tolyl-pyrazol-3-yl) methanone - N- {4- [4- (5-Methyl-2-m-tolyl-2H-pyrazole-3-carbonyl) -piperazin-1-yl] -phenyl} -methanesulfonamide - (2H-Indazol-3-yl) - (4-phenyl-piperazin-1-yl) -methanone - (2H-Indazol-3-yl) - (4- (2-methoxy-phenyl) -piperazin-1-yl] -methanone - (2H-Indazol-3-yl) - [4- {3-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone - [4- (4-Fluoro-phenyl) -piperazin-1-yl] - (2H-indazol-3-yl-methanone - 1- {4- [4- (2H-Indazole-3-carbonyl) -piperazin-1-yl] -phenyl) -methanone - [4- (2,4-Dimethyl-phenyl) -piperazin-1-yl] - (2H-indazol-3-yl) -methanone - [4- (3,4-Dichloro-phenyl) -piperazin-1-yl] - (2H-indazol-3-yl) -methanone - [4- (3,4-Dimethyl-phenyl) -piperazin-1-yl] - (2H-indazol-3-yl) -methanone - (2H-Indazol-3-yl) - (4-o-tolyl-piperazin-1-yl) -methanone - [4- (2,3-Dimethyl-phenyl) -piperazin-1-yl] - (2H-indazol-3-yl) -methanone - [4- (2-Ethyl-phenyl) -piperazin-1-yl] - (2H-indazol-3-yl) -methanone - [4- (3-Chloro-phenyl) -piperazin-1-yl] - (2H-indazol-3-yl) -methanone - (2H-Indazol-3-yl) - [4- (3-methoxy phenyl) piperazin-1-yl] -methanone - (2H-Indazol-3-yl) - (4-m-tolyl-piperazin-1-yl) -methanone - (2H-Indazol-3-yl) - [4- (4-methoxy-phenyl) -piperazin-1-yl] -methanone - [4- (2,4-Dimethoxy-phenyl) -piperazin-1-yl] - (2H-indazol-3-yl) -methanone - (2H-Indazol-3-yl) - [4- (2-methylsulfanyl-phenyl) -piperazin-1-yl] -methanone - [4- (4-Chloro-phenyl) -piperazin-1-yl] - (2H-indazol-3-yl) -methanone - (2H-Indazol-3-yl) - (4-naphthalen-1-yl-piperazin-1-yl) -methanone - [4- (5-Chloro-2-methyl-phenyl) -piperazin-1-yl] - (2H-indazol-3-yl) -methanone - [4- (2-Ethoxy-phenyl) piperazin-1-yl] - (2H-indazol-3-yl) -methanone - [4- (2,3-Dichloro-phenyl) -piperazin-1-yl] - (2H-indazol-3-yl) -methanone - (2H-Indazol-3-yl) - [4- (4-trifluorornethyl-phenyl) -piperazin-1-yl] -methanone - [4- (5-Chloro-2-methoxy-phenyl) -piperazin-1-yl] - (2H-indazol-3-yl) -methanone - [4- (4-Benzyloxy-phenyl) -piperazin-1-yl] - (2H-indazol-3-yl) -methanone - (2H-Indazol-3-yl) - [4- (2-trifluoromethyl-phenyl] -piperazin-1-yl] -methanone - [4- (2,3-Dihydro-benzol [1,4] dioxin-6-yl) -piperazin-1-yl] - (2H-indazol-3-yl) -methanone - N- {4- [4- (2H-Indazole-3-carbonyl) -piperazin-1-yl] -phenyl} -methanesulfonamide - (2-Methyl-1-quinolin-2-yl-1H-pyrrol-3-yl) - (4-phenyl-piperazin-1-yl) -methanone - [4- (3,4-Dichloro-phenyl) -piperazin-1-yl] - (2-methyl-1-quinolin-2-yl-1H-pyrrol-3-yl) -methanone - [4- (2-Methoxy-phenyl) -piperazin-1-yl] - (2-methyl-1-quinolin-2-yl-1H-pyrrol-3-yl) -methanone - [4- (3,4-Dimethyl-phenyl) -piperazin-9-yl] - (2-methyl-1-quinolin-2-yl-1H-pyrrol-3-yl) -methanone - [4- (3-Chloro-phenyl} -piperazin-1-yl] - {2-methyl-1-quinolin-1-yl-1H-pyrrol-3-yl) -methanone - [4 (3,4-Dimethyl-phenyl) -piperazin-9-yl] - {1-isoquinolin-1-yl-2-methyl-1H-pyrrol-3-yl) -methanone - [4- (3-Chloro-phenyl) -piperazin-1-yl] - (1-isoquinolin-1-yl-2-methyl-1H-pyrrol-3-yl) -methanone - (3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl) - [4- (3-methoxy-phenyl) -piperazin-1-yl] -methanone - N- (4- [4- (3,5-Dimethyl-1-phenyl-1-phenyl-pyrazole-4-carbonyl) -piperazin-1-yl] -phenyl} -methanesulfonamide - [2- (4-Methoxy-phenyl-5-methyl-2H-pyrazol-3-yl] - [4- (3-methoxy-phenyl) -piperazin-1-yl] methanone - N- (4- {4- [2- (4-Methoxy-phenyl) -5-methyl-2H-pyrazole-3-carbonyl] -piperazin-1-yl} -phenyl) -methanesulfonamide - [2- (3-Methoxy phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3-methoxy-phenyl) -piperazin-1-yl] methanone - N- (4- {4- [2- (3-Methoxy-phenyl) -5-methyl-2H-pyrazole-3-carbonyl] -piperazin-1-yl) -phenyl) -methanesulfonamide - (5-Methyl-2-phenyl-2H-pyrazol-3-yl) - [4- (2-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone - [4- (4-Benzyloxy-phenyl) -piperazin-9-yl] - [2- (2-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] methanone - N- (4- [4- [2- (4-Fluoro-phenyl) -5-methyl-2H-pyrazole-3-carbonyl] -piperazin-1-yl} -phenyl) -methanesulfonamide - [2- (4-Methanesulfonyl-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4- (2-methoxy-phenyl) -piperazin-1-yl] methanone - [4- (4-Fluoro-phenyl) -piperazin-1-yl] - [2- (4-methanesulfonyl-phenyl) -5-methyl-pyrazol-3-yl] methanone - [4- (3,4-Dichloro-phenyl) -piperazin-1-yl] - [2- (4-methanesulfonyl-phenyl) -5-methyl-2H
pyrazol-3-yl] methanone - [4- (3,4-Dimethyl-phenyl-piperazin-1-yl] - [2- (4-methanesulfonyl-phenyl) -5-methyl-2H
pyrazol-3-yl] methanone - [4- (2,3-Dimethyl-phenyl) -piperazin-1-yl] - [2- {4-methanesulfonyl-phenyl} -5-methyl-2H
pyrazol-3-yl] methanone - [2- (4-Methanesulfonyl-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-methoxy-phenyl) -piperazin-1-yl] methanone - [2- (4-Methanesulfonyl-phenyl) -5-methyl-2H-pyrazol-3-yl] - (4-naphthalen-1-yl-piperazin-1-yl) methanone - [4- (5-Chloro-2-methoxy-phenyl) -piperazin-1-yl] - [2- (4-methanesulfonyl-phenyl) -methyl-2H-pyrazol-3-yl] methanone -N- (4- (4- [2- (4-methanesulfonyl-phenyl) -5-methyl-2H-pyrazole-3-carbonyl] -piperazin 1-yl) -phenyl) -methanesulfonamide - [2- (3-Chloro-phenyl) 5-methyl-2H-pyrazol-3-yl] - [4- (4-fluoro-phenyl) -piperazin-1-yl] -methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3,4-dichloro-phenyl) -piperazin-1-yl] methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-ethyl-phenyl) -piperazin-1-yl] -methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3-chloro-phenyl) -piperazin-1-yl] -methanone - [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-methoxy-phenyl) -piperazin-1-yl] methanone - [4- (5-Chloro-2-methyl-phenyl) -piperazin-1-yl] - [2- (3-chloro-phenyl) -5-methyl-pyrazol-3-yl] methanone - N- (4- {4- [2- (3-Chloro-phenyl) -5-methyl-2H-pyrazole-3-carbonyl] -piperazin-1-yl} -phenyl) -methanesulfonamide - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2,4-dimethyl-phenyl} -piperazin-1-yl] methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (3-methoxy-phenyl) -piperazin-1-yl] methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2,4-dimethoxy-phenyl) -piperazin 1-yl] methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-methylsulfanyl-phenyl) -piperazin-1-yl] methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-ethoxy-phenyl) -piperazin-1-yl] -methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] - [4- (2-trifluoromethyl-phenyl) -piperazin-1-yl] methanone - N- (4- {4- [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazole-3-carbonyl] -piperazin-1-yl) -phenyl) -methanesulfonamide - [4- (2-Methoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-p-tolyl-2H-pyrazol-3-yl) -methanone - [4- (4-Fluoro-phenyl) piperazin-1-yl] - (5-methyl-2-p-tolyl-2H-pyrazol-3-yl) -methanone - [4- (2,4-Dimethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-p-tolyl-2H-pyrazol-3yl) -methanone - [4- (3,4-Dimethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-p-tolyl-2H-pyrazol-3-yl) -methanone 12. Product according to claim 1, characterized in that it is chosen from :
- [4- (3-Chloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example 1) - [4- (3,4-Dimethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example 2) - [4- (3,5-Dichloro-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E2) - [4- (Quinoline-4-yl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E17) - [4- (3-Chloro-phenyl) piperazin-1-yl] - (5-hydroxymethyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E60) - [4- (3,4-Methylenedioxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E30) - [4- (3,5-Dimethoxy phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E20) - [4- (3,5-Dimethyl-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E63) - [4- (3-Difluoromethoxy-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E74) - [4- (3-Chloro-phenyl) -piperazin-1-yl] - [5- (2-methyl-imidazol-1-yl-methyl) -2-phenyl-2H-pyrazol-3-yl] -methanone (Example E75) - [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [5- (1H-pyrrol-2-yl) -methyl-2-phenyl-2H-pyrazol-3-yl] -methanone (Example E91) - [4- (3,5-Dimethoxy-phenyl) -piperazin-1-yl] - [5- (pyrrolidin-1-yl) -methyl-2-phenyl-2H-pyrazol-3-yl] -methanone (Example E93) - [4- (3-Carboxamido-phenyl) -piperazin-1-yl] - (5-trifluoromethyl-2-phenyl-2H-pyrazol-3-yl) methanone (Example E119) - [5- (Azetidin-1-yl) -2-phenyl-2H-pyrazol-3-yl] - [4- (3,5-dimethoxy-phenyl) -piperazin-1-yl] -methanone (Example E129) - [4- (3-Carboxamido-phenyl) -piperazin-1-yl] - (2-phenyl-2H-pyrazol-3-yl) -methanone (Example E133) - [4- (3-Carboxamido-phenyl) -piperazin-1-yl] - (5-hydroxymethyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E134) - [4- (3-Carboxamido-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E23) - [3- (3,5-Dimethoxy-phenyl) -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-dimethoxy-phenyl) -piperazin-1-yl] -methanone (Example E99). 73. Product according to claim 12, characterized in that it is chosen among:
- [4- (3-Carboxamido-phenyl) -piperazin-1-yl] - (5-methyl-2-phenyl-2H-pyrazol-3-yl) -methanone (Example E23) - [4- (3,5-Dimethoxy-phenyl) -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-dimethoxy-phenyl) -piperazin-1-yl] -methanone (Example E99). 14. Pharmaceutical composition comprising a product according to any one of the preceding claims, in combination with an excipient pharmaceutically acceptable. 15. Use of a product according to any one of claims 1 to 13, as an agent inhibiting the polymerization of tubulin. 16. Use of a product according to any one of claims 1 to 13, as an agent inhibiting the proliferation of tumor cells. 17. Use of a product according to any one of claims 1 to 13, for promote the disintegration of clusters of cells from vascular tissue. 18. Use of a product according to any one of claims 1 to 13, for the manufacture of a medicament useful for treating a pathological condition. 19. Use according to claim 18, wherein the pathological condition is the Cancer.