MXPA99001507A

MXPA99001507A - Substituted pyrimidine derivatives and their pharmaceutical use

Info

Publication number: MXPA99001507A
Application number: MXPA/A/1999/001507A
Authority: MX
Inventors: Waterson David; Robert Brown George; John Newcombe Nicholas; Sophie Elizabeth Stokes Elaine
Original assignee: Robert Brown George; John Newcombe Nicholas; Sophie Elizabeth Stokes Elaine; Waterson David; Zeneca Limited
Priority date: 1996-08-14
Filing date: 1999-02-12
Publication date: 1999-06-01

Abstract

This invention concerns heterocyclic derivatives which are useful in inhibiting oxido-squalene cyclase, processes for their preparation and pharmaceutical compositions containing them. The present invention is also concerned with heterocyclic derivatives capable of inhibiting cholesterol biosynthesis and hence in lowering cholesterol levels in blood plasma. The present invention also relates to methods of using such heterocyclic derivatives in diseases and medical conditions such as hypercholesterolemia and atherosclerosis.

Description

DERIVATIVES OF SUBSTITUTE PYRIMIDINE AND ITS PHARMACEUTICAL USE DESCRIPTION OF THE INVENTION This invention relates to heterocyclic derivatives which are useful for inhibiting the schalene cyclase oxide, processes for its preparation and pharmaceutical compositions containing them. The present invention also relates to heterocyclic derivatives capable of inhibiting cholesterol biosynthesis and therefore decreasing cholesterol levels in blood plasma. The present invention also relates to methods for using such heterocyclic derivatives in diseases and medical conditions such as hypercholesterolemia and atherosclerosis. There is evidence that high levels of serum cholesterol are a major risk factor in coronary heart disease and associated diseases such as atherosclerosis and ischemic heart disease. As a result there is a lot of interest in finding ways to lower blood plasma cholesterol levels. Although it has been possible to obtain the same reduction by means of diet, only modest reductions have been obtained by controlling the dietary intake of cholesterol. Consequently, there is a need for therapeutic procedures to reduce cholesterol levels. Several different classes of compounds have been reported that have the ability to lower cholesterol levels in the blood plasma. For example, agents have been reported which inhibit the enzyme HMGCoA reductase, which is essential for the production of cholesterol, to reduce serum cholesterol levels. Illustrative of this class of compounds is the HMGCoA reductase inhibitor known as lovastatin which is described in U.S. Patent No. 4,231,938. Other agents which are reported to lower serum cholesterol include those which work by forming the bile acid complex in the intestinal system, called "bile acid sequestrants". It promotes the decrease of the levels of the acid of the bile that circulates in the enterohepatic system replacing the acids of the bile by synthesis in the liver from the cholesterol. This results in an upregulation of the liver LDL cholesterol receptor and as a consequence decreasing cholesterol levels in circulating blood. The biosynthesis of cholesterol is a complex process which will be considered in the present as three main stages, namely 1) the conversion of acetic acid to mevalonic acid 2) the conversion of mevalonic acid to esquelano and 3) the conversion of esqualeno to cholesterol . In the last stage, the esqualeno is first converted to 2, 3-oxido-squalene and then to lanosterol. The lanosterol is then converted to cholesterol through a number of enzymatic steps.

The conversion of 2,3-oxido-schalene to lanosterol is a key step in the biosynthesis of cholesterol. This conversion is catalyzed by the enzyme oxido-squalene cyclase. It follows that the inhibition of this enzyme decreases the amount of lanosterol available for conversion to cholesterol. Consequently, the inhibition of the schydane cyclase oxide must interrupt the biosynthesis of cholesterol and give rise to the decrease of cholesterol levels in the blood plasma. The present invention is based on the discovery that certain heterocyclic derivatives are inhibitors of the oxide skelenocylase and are therefore useful in the treatment of diseases and medical conditions in which the inhibition of the schydane cyclase oxide is desirable. According to the present invention there is provided a compound of the formula I (hereinafter indicated together with other formulas referred to herein in a separate sheet following the examples), or a pharmaceutically acceptable salt thereof , wherein: T1 is selected from N and CR, wherein R can be hydrogen, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl; R1 is hydrogen, amino, halogen, cyano, (1-6C) alkyl, (1-6C) alkylamino, dialkylamino (1-6C) or (1-6C) alkoxy; M is 1 or 2; T2 is selected from CH and N; T3 is selected from N and CR wherein R is as defined above; with the proviso that when T2 is CH then T3 is not CR and when T1 is CR then T3 is not CR; a and b are independently selected from 2 and 3; c and d are independently selected from 1 and 2; wherein the heterocyclic ring containing T1 and the heterocyclic ring containing T2 can be independently, optionally substituted by one or more substituents selected from (1-6C) alkyl, (1-6C) alkoxy, phenyl (1-4C) alkyl, halogen and alkoxycarbonyl (1-6C); X is selected from O, CO, S, SO, S02 and CH2; Q is selected from phenyl, naphthyl, phenyl alkenyl (2-6C) and a heteroaryl portion which comprises a 5- or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; and wherein Q may be unsubstituted or may carry one or more substituents selected from halogen, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C) ), (1-6C) alkoxy, (3-6C) cycloalkyl, (3-6C) cycloalkyl (1-4C), (1-4C) alkylenedioxy, (1-6C) alkylamino, di- [alkyl (1- 6C) lamino, N-alkylcarbamoyl (1-6C), di-N [(1-6C) alkyl] carbamoyl, alkanoylamino (1-6C), alkoxycarbonyl (1-6C), alkylthio (1-6C), alkylsulfinyl (1C) -6C), alkylsulfonyl (1-6C), halogen (1-6C) alkyl, (1-6C) alkanoyl, and tetrazolyl.

The compounds of the present invention are inhibitors of the schydane cyclase oxide and therefore possess the property of inhibiting cholesterol biosynthesis. Accordingly, a compound of the formula I, or a pharmaceutically acceptable salt thereof, is provided for use in medical therapy The use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, is also provided for the manufacture of a medicament for inhibiting the schalene cyclase oxide and in particular inhibiting cholesterol biosynthesis. In this way the compounds of the present invention will be useful in the treatment of diseases or medical conditions in which the inhibition of the schydane cyclase oxide is desirable, for example those in which the decrease in the level of cholesterol in the blood plasma is desirable. . In particular, the compounds of the present invention will be useful in the treatment of hypercholesterolemia and / or ischemic diseases associated with atheromatous vascular degeneration such as atherosclerosis. As inhibitors of cholesterol biosynthesis, the compounds of the present invention will also be useful in the treatment of fungal infections. Thus according to a further feature of the present invention there is provided a method for inhibiting the schydane cyclase oxide in a warm-blooded animal (such as man) that requires such treatment, the method comprising administering to the animal an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof. In particular, the present invention provides a method for inhibiting cholesterol biosynthesis, and more particularly to a method for treating hypercholesterolemia and atheromatous vascular degeneration (such as atherosclerosis). In this way the present invention also provides the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating diseases or medical conditions in which it is desirable to lower the cholesterol level in blood plasma (such as hypercholesterolemia and atherosclerosis). In particular, the compounds of the present invention are potentially useful in the inhibition of cholesterol biosynthesis in man and therefore in the treatment of medical conditions mentioned above in man. It will be understood that when the compounds of the formula I contain a chiral center, the compounds of the invention can exist in, and be isolated in, optically active or racemic form. The invention includes any optically active or racemic form of a compound of the formula I which possesses the beneficial pharmacological effect of inhibiting the schalene cyclase oxide. The synthesis of the optically active forms can be performed by standard techniques of organic chemistry well known in the art, for example by, resolution of a racemic form, by synthesis from optically active starting materials or by asymmetric synthesis. It will be appreciated that certain compounds of the formula I can exist as geometric isomers. The invention includes any geometric isomer of a compound of the formula I which possesses the beneficial pharmacological effect of inhibiting the schalene cyclase oxide. It will also be understood that certain compounds of the present invention can exist in solvated form, for example hydrated, as well as in unsolvated forms. It is understood that the present invention encompasses such solvated forms which possess the property of inhibiting the oxide schalene cyclase. It is also understood that generic terms such as "alkyl" include both the straight chain and branched chain groups such as butyl and tert-butyl. However, when a specific term such as "butyl" is used, this is specific for the straight chain or "normal" butyl group, branched chain isomers such as "t-butyl" are referred to specifically when proposed. Preferably R1 is hydrogen, halogen, cyano, (1-6C) alkyl or (1-6C) alkoxy.Preferably T is selected from N and CH. Preferably T3 is selected from N and CH. Preferably X is S02. Particular values for optional substituents which may be present in Q include, for example, alkyl; (1-4C) alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; cyclopropyl, cyclobutyl or For cycloalkyl; cyclopentyl; For cycloalkylalkylCycloalkyl (3-6C) alkyl (1-2C) such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl or cyclopentylmethyl, • For alkenyl; Alkenyl (2-4C), such as allyl, prop-1-enyl, 2-methyl-2-propenyl or 2-butenyl: For alkynyl; Alkynyl (2-4C), such as prop-2-ynyl or but-2-ynyl; For alkoxy; (1-6C) alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy or 3-methylbutoxy; For alkylamino; Alkylamino (1-4C), such as methylamino, ethylamino, propylamino or butylamino; For dialkylamino; di- [(1-4C) alkyl] amino such as dimethylamino, diethylamino, methylpropylamino or dipropylamino; For alkylcarbamoyl; alkylcarbamoyl (1-4C) such as N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-butylcarbamoyl or N-tert-butylcarbamoyl or (N- (2-methylpropyl) carbamoyl; For dialkylcarbamoyl; di- [alkyl (1- 4C)] carbamoyl, N, N-dimethylcarbamoyl or N, N-diethylcarbamoyl; For alkoxycarbonyl; (1-4C) alkoxycarbamoyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbaonyl or tert-butoxycarbonyl; For alkylthio; alkylthio (1-4C) such as methylthio, ethylthio, propylthio, isopropylthio or butylthio; for alkylsulphinyl; alkylsulfinyl (1-4C) such as methylsulfinyl, ethylsulphinyl, propylsulfinyl, isopropylsulfinyl or butylsulfinyl; for alkylsulfonyl; alkylsulfonyl (1-4C) such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or butylsulfonyl; for halogen; fluorine, chlorine, bromine or iodine; for halogenalkyl; halogen (1-4C) alkyl such as halogenoalkyl containing one, two or three halo groups; fluorinated, chlorine, bromine and iodine and an alkyl group selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and sec-butyl, thus particular values will include trifluoromethyl, difluoromethyl and fluoromethyl; For alkanoylamino; alkanolamino (1-4C) such as a formamido, acetamido, propionamido, isopropionamido, butyramido and isobutyramido; For alkylenedioxy; methylenedioxy or ethylenedioxy; For alkanoyl; (1-4C) alkanoyl such as formyl, acetyl, propionyl or butyryl Particular values for Q when it is heteroaryl which comprises a five or 6 membered monocyclic heteroaryl ring containing up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur is, for example, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, furazanyl and thiadiazolyl which can be attached through any available position including through any available nitrogen atom. Particular values for optional substituents on the heterocyclic rings containing T1 and T2 include, for example, For alkyl; (1-4C) alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl; For alkoxy; Alkoxy (1-4C) such as methoxy, ethoxy, propoxy, isopropoxy or butoxy; For phenylalkyl; Phenyl alkyl (1-2C) such as benzyl, 2-phenylethyl or 1-phenylethyl For halogen; Fluorine, chlorine, bromine, or iodine For alkoxycarbonyl; Methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or butyloxycarbonyl; A particular value for Q when this is phenyl is phenyl and when this is substituted phenyl it is, for example 4-halophenyl such as 4-chlorophenyl or 4-bromo phenyl. A particular value for Q when this is naphthyl is 1-naphthyl or 2-naphthyl and when this is substituted naphthyl it is 6-chloro or bromo naphth-1-yl or is 6-chloro or is bromo-naphth-2-yl. A particular value for pair Q when this is phenylalkenyl is, for example, phenyl (2-4C) alkenyl such as styryl, cinnamyl or 3-phenylprop-2-enyl. In general, the heterocyclic rings containing T1 and T2 will be substituted or will bear one or two substituents selected from those defined hereinbefore. In general, Q will not be substituted or will carry one, two or three (preferably one or two) substituents selected from those defined hereinbefore. A preferred value for X is S02. Specific values for optional substituents on the heterocyclic ring containing T1 or the heterocyclic ring containing t2 / T3 include, for example, alkyl (1-6C) (such as methyl) and (1-6C) alkoxycarbonyl (such as methoxycarbonyl or ethoxycarbonyl). Specific values for optional substituents for Q include, for example, halogen (such as fluorine, chlorine, bromine or iodine), (1-6C) alkoxy (such as methoxy or ethoxy), (1-6C) alkyl (such as methyl, isopropyl or t-butyl), halo (1-6C) alkyl (such as trifluoromethyl), di- [(1-6C) alkyl] amino (such as dimethyl), nitro, cyano, (1-6C) alkyl (such as methyl, ethyl, propyl or butyl), (1-6C) alkanoylamino (such as acetylamino) and pyridyl. Specific values for a, b, c and d include, for example, a = 2, b = 2, c = 2, and d = 2; a = 2, b = 3, c = 2 and d = 2; a = 2, b = 2, C = 2, u d = l. Specific values for R1 include, for example, hydrogen, amino, (1-6C) alkyl (such as methyl) and halogen (such as chlorine). In a particular aspect the heterocyclic rings containing T1 and T2 are unsubstituted. In each of the abovementioned particular embodiments, the preferred and specific values include the appropriate values mentioned above, and wherein the heterocyclic ring containing T1 and the heterocyclic ring containing T2 can be, independently, optionally substituted by one or more substituents selected from (1-6C) alkyl, (1-6C) alkoxy, phenyl (1-4C) alkyl, halogen, and (1-6C) alkoxycarbonyl but preferably both are unsubstituted. In one embodiment of the present invention, a, b, c and d are each 2, T1 is CH, T2 is N, Q is phenyl which carries one or two substituents independently selected from halogen and (1-6C) alkyl, and X , T3, R1 and m are as defined above in the present. In a further embodiment of the present invention, a, b, c and d are each 2, T1 is CH, T2 is N, Q is phenyl which carries one or two substituents independently selected from halogen and (1-6C) alkyl, and X, T3, R1 and m are as defined above in the present.

In a further embodiment of the present invention, a, b, c and d are each 2, T1 is N, T2 is N, Q is phenyl which carries one or two substituents independently selected from halogen and (1-6C) alkyl, and X, R1 and m are as defined hereinabove. In a further embodiment of the present invention, a, b, c and d are each 2, R1 is alkyl (1-6C), m is 1, T1 is CH, T2 is N, Q is phenyl which carries one or two substituents independently selected from halogen and (1-6C) alkyl, and X, and T3, are as defined hereinbefore. In a further embodiment of the present invention, a, b, c and d are each 2, R1 is alkyl (1-6C), m is 1, T1 is N, T2 is N, Q is phenyl which carries one or two substituents independently selected from halogen and (1-6C) alkyl, and X, and T3 are as defined hereinbefore. In a further embodiment of the present invention, a, b, c and d are each 2, R1 is alkyl (1-6C), m is 1, T1 is N, T2 is N, Q is phenyl which carries one or two substituents independently selected from halogen and (1-6C) alkyl, and X, is as defined hereinbefore. In a further embodiment of the present invention, a, b, c and d are each 2, R1 is methyl, m is 1, T1 is CH, T2 is N, Q is phenyl which carries one or two substituents independently selected from halogen and alkyl (1-6C), and X, and T3, are as defined hereinabove.

In a further embodiment of the present invention, a, b, c and d are each 2, R 1 is methyl, m is 1, T 1 is CH, T 2 is N, T 3 is N, Q is phenyl which carries one or two selected substituents independently of halogen and (1-6C) alkyl, and X, is as defined hereinabove. In a further embodiment of the present invention, a, b, c and d are each 2, R1 is methyl, m is 1, T1 is N, T2 is N, T3 is N, Q is phenyl which carries one or two substituents independently selected from halogen and alkyl (1-6C), and X, is as defined above in the present. In a further embodiment of the present invention, a, c and d are each 2 and b is 3, T1 is CH, T2 is N, Q is phenyl which carries one or two substituents independently selected from halogen and (1-6C) alkyl, and T3, R1 and m are as defined hereinabove. In a further embodiment of the present invention, a, c and d are each 2 and b is 3, T1 is N, T2 is N, Q is phenyl which carries one or two substituents independently selected from halogen and (1-6C) alkyl, and T3, R1 and m are as defined hereinabove. In a further embodiment of the present invention, a, c and d are each 2 and b is 3, T1 is N, T2 is N, T3 is N, Q is phenyl which carries one or two substituents independently selected from halogen and alkyl (1). -6C), and R1 and m are as defined hereinabove. In a further embodiment of the present invention, a, c and d are each 2 and b is 3. R1 is (1-6C) alkyl, m is T1 is CH, T2 is N, Q is phenyl which carries one or two selected substituents independently of halogen and (1-6C) alkyl, and X, and T3, are as defined hereinabove. In a further embodiment of the present invention, a, c and d are each 2 and b is 3, R1 is (1-6C) alkyl, m is 1, T1 is N, T2 is N, Q is phenyl which carries one or two substituents independently selected from halogen and (1-6C) alkyl, and X, and T3, are as defined hereinbefore. In a further embodiment of the present invention, a, c and d are each 2 and b is 3, R1 is (1-6C) alkyl, m is 1, T1 is N, T2 is N, T3 is N, Q is phenyl which is carries one or two substituents independently selected from halogen and (1-6C) alkyl, and X, is as defined hereinbefore. In a further embodiment of the present invention, a, c and d are each 2 and b is 3, R1 is methyl, m is 1, T1 is CH, T2 is N, Q is phenyl which carries one or two substituents independently selected from halogen and (1-6C) alkyl, and X, and T3, are as defined hereinabove. In a further embodiment of the present invention, a, c and d are each 2 and b is 3, R1 is methyl, m is 1, T1 is N, T2 is N, Q is phenyl which carries one or two substituents independently selected from halogen and (1-6C) alkyl, and X, and T3, are as defined hereinabove. In a further embodiment of the present invention, a, c and d are each 2 and b is 3, R1 is methyl, m is 1, T1 is N, T2 is N, T3 is N, Q is phenyl which carries one or two substituents independently selected from halogen and (1-6C) alkyl, and X, is as defined hereinabove. In a further embodiment of the present invention, a, c and d are each 2 and b is 3, R1 is halogen, m is 1, T1 is CH, T2 is N, Q is phenyl which carries one or two substituents independently selected from halogen and (1-6C) alkyl, and X, and T3, are as defined hereinabove. In a further embodiment of the present invention, a, c and d are each 2 and b is 3, R1 is halogen, m is 1, T1 is N, T2 is N, Q is phenyl which carries one or two substituents independently selected from halogen and alkyl (1-6C), and X, and T3, is as defined hereinbefore. In a further embodiment of the present invention, a, c and d are each 2 and b is 3, R1 is halogen, m is 1, T1 is N, T2 is N, T3 is N, Q is phenyl which carries one or two substituents independently selected from halogen and (1-6C) alkyl, and X is as defined hereinabove. Additional modalities include those in which R1, m, a, b, c, d, X and Q are as defined in any of the preceding paragraphs and T1, T2 and T3 are: (a) T1 is N, T2 is N and T3 is N; (b) T1 is N, T2 is N and T3 is CH; (c) T1 is N, T2 is CH and T3 is N; or (d) T1 is CH, T2 is CH and T3 is N; Compounds of special interest include those described in the appended examples and their pharmaceutically acceptable salts and are therefore provided as a further feature of the present invention. The compounds of formula I and their pharmaceutically salts can be prepared by processes known to be applicable in the preparation of structurally related compounds. These procedures are illustrated by the following representative processes in which the various groups and radicals such as R1, m, G, T1, T2, T3, X and Q are as defined hereinabove (unless otherwise stated) ), and are provided as an additional feature of the present invention. In cases where the compounds contain a group such as an amino, hydroxy, or carboxy group, this group can be protected using a conventional protecting group which can be eliminated when desired by conventional means. (a) For the compounds of the formula I wherein T3 is N by reacting an acid of the formula II, or a reactive derivative thereof, with an amine of the formula III: A suitable reactive derivative of an acid of the formula II is , for example, an acyl halide such as an acyl chloride formed by the reaction of the acid with an inorganic acid chloride such as thionyl chloride. Additional suitable reactive derivatives include a mixed anhydride such as an anhydride formed by the reaction of the acid with a chloroformate such as isobutyl chloroformate; an active ester such as an ester formed by the reaction of the acid and a phenol such as pentafluorophenol, an ester such as pentafluorophenyl thifluoroacetate or an alcohol such as N-hydroxybenzotriazole or N-hydroxysuccinimide; an acylazide, for example an azide formed by the reaction of the acid and an azide such as diphenylphosphoryl azide; an acylcyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphorylcide; or the product of the reaction of the acid and a carbodiimide such as N, '-dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimine. The reaction is conveniently carried out in the presence of a suitable base such as, for example, an alkali metal or alkaline earth carbonate, alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide , sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an organometallic base such as an alkyl lithium, for example n-butyl lithium, or a dialkylamino lithium, for example lithium di-isopropylamide, or, example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo [5, 4, 0] undec-7-ene. The reaction is also preferably carried out in a suitable inert solvent or diluent, for example dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-. ona, dimethylsulfoxide or acetone, and at a temperature in the range, for example, -78 ° to 150 ° C, conveniently at or near room temperature. A suitable protecting group for the amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as an acetyl group, an alkoxycarbonyl, for example a methoxycarbonyl group, ethoxycarbonyl or tert-butoxycarbonyl, an arylmethoxycarbonyl, for example an benzyloxycarbonyl or an aroyl group, for example benzoyl. The conditions of deprotection for the above protection groups necessarily vary with the choice of the protection group. Thus, for example, an acyl group such as the alkanoyl or alkoxycarbonyl group or an aroyl group can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group can be removed, for example, by treatment with a suitable acid such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group can be removed, for example, by hydrogenation in a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris (trifluoroacetate). An alternative protecting group suitable for a primary amino group is, for example, a phthaloyl group which can be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protection groups will necessarily vary with the choice of the protecting group. In this way, for example, an acyl group such as an alkanoyl group or an aroyl can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in a catalyst such as palladium on carbon.

A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which can be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which can be removed, for example, by treatment with an acid, for example an organic acid such as a trifluoroacetic acid, or for example a benzyl group which can be removed, for example, by hydrogenation in a catalyst such as palladium on carbon. (b) For compounds of the formula I in which T2 is N, reacting an amine of formula IV, with a compound of the formula Z-X-Q in which Z is a displaceable group. The reaction will be carried out, in general, conveniently in the presence of a suitable base. Suitable bases are those mentioned in (a) above. A suitable value for the displaceable group Z is, for example, a halogen or a sulfonyloxy group, for example a fluorine, chlorine, bromine, or mesyloxy or 4-tolylsulfonyloxy group. The reaction is conveniently carried out in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 0 or 150 ° C, conveniently at or near room temperature. (c) For compounds of the formula I in which T1 is N, reacting an amine of the formula V with an acid of the formula VIII, or a reactive derivative thereof. The reaction will be performed, in general, in the presence of a suitable base as mentioned in (a) above). Suitable reactive derivatives are also mentioned in (a) above. The reaction is conveniently carried out in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example 0 to 150 ° C, conveniently at or near room temperature. (d) Reacted a compound of the formula VI in which Z is a group displaceable with an amine of the formula VII. The reaction will be performed, in general, in the presence of a suitable base as mentioned in (a) above. The reaction is conveniently carried out in a suitable inert solvent as mentioned in (a) above and at a temperature in the range, for example 0 ° C to 150 ° C, conveniently in the range of 15 ° C to 100 ° C. As mentioned above, it will be appreciated that in some of the reactions mentioned herein it may be necessary / desirable to protect any of the sensitive groin the compounds. Cases where necessary or desirable and suitable methods for protection are known to those skilled in the art. Thus, if the reactants include grosuch as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. The appropriate protection groare mentioned in (a) above). The protecting grocan be eliminated at any convenient stage in the synthesis using conventional techniques well known in the chemical art. It will also be appreciated that certain of the various optional substituents in the compounds of the present invention can be introduced by standard aromatic substitution reactions or generated by modifications of conventional functional groeither before or immediately after the processes mentioned above, and as such they include in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. Reactants and reaction conditions for such processes are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acylhalide and Lewis acid (such as aluminum trichloride) under Friedel Crafts conditions.; the introduction of an alkyl group using an alkylhalide and Lewis acid (such as aluminum trichloride) under the Friedel Crafts conditions; and the introduction of a halogen group. Particular examples of modifications include the reduction of a nitro group to an amino group by, for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl. When a pharmaceutically acceptable salt of a compound of formula I is required, this can be obtained, for example, by reaction of the compound with the appropriate acid (which produces a physiologically acceptable anion), or with the appropriate base (which produces a physiologically acceptable cation), or by any conventional salt formation process. When an optically active form of a compound of formula I is required, it can be obtained, for example, by performing one of the above procedures using an optically active starting material or by resolution of a racemic form using a conventional procedure. The compounds of the formula II can be prepared by reacting a compound of the formula IX, wherein Y is a suitable ethoxycarbonyl ester, with a compound of the formula VI in an analogous process as described in (d) above, and subsequent conversion of the ester to the acid by reduction with an alkali metal hydroxide, such as LiOH in a suitable solvent such as tetrahydrofuran, suitably at room temperature. The compounds of formula IX are commercially available. The compounds of the formula III, wherein T2 is N, can be prepared by reacting a compound of the formula ZXQ with an excess of the compound of the formula X, where T2 is N, X is hydrogen and P is hydrogen, in an analogous method as it is described in (b). The compounds of the formula IV, where T3 is N, can be prepared by reacting a compound of the formula II with a compound of the formula X, where T3 is N and X is hydrogen and if T2 is N then P is a protecting group or if T2 is CH then P is hydrogen, in an analogous method as described in (a) above. The compounds of formula X are commercially available. The compounds of the formula IV, wherein T3 is CH, can be prepared by reacting a compound of the formula V with a compound of the formula X, where T3 is CH and X is C02H and if T2 is N then P is a protecting group or if T2 is CH then P is hydrogen, in an analogous manner as described in method (c) above. The compounds of the formula V can be prepared by reacting a compound of the formula VI with a compound of the formula IX, where if T1 is CH then Y is hydrogen and if T1 is N then Y is a protection group, in an analogous form as described in method (d) above. The compounds of the formula VI are commercially available. The compounds of the formula VI can be prepared by conversion of the corresponding 4-hydroxypyrimidine analog, for example by reacting with trichlorophosphate. The 4-hydroxypyrimidine analogs are commercially available. As mentioned previously, the compounds of the formula I (and their pharmaceutically acceptable salts) are inhibitors of the enzyme oxalkane cyclase. In this way, the compounds of the present invention are capable of inhibiting cholesterol biosynthesis and therefore decreasing cholesterol levels in blood plasma. The beneficial pharmacological properties of the compounds of the present invention can be demonstrated using one or more of the following techniques. (a) In vitro test to measure the inhibition of the schylane cyclase oxide. This test measures the inhibition of microsomal esqualene cyclase oxide in vitro by compounds at fixed concentrations in the incubation medium. Rat liver microsomes are prepared according to methods known in the art, for example, the method described in published European Patent Application No. 324,421 and stored in liquid nitrogen before testing. The test vials are maintained at 37 ° C throughout the incubation. Microsomes typically contain 15-20 mg of protein per ml of microsomes. For the assay, 1 ml of microsomes are diluted by the addition of 722 μl of 50 mM phosphate buffer pH 7.4. Tween ® 80 (polyoxyethylene sorbitan monolaurate) is prepared by adding 0.1 g of Tween 80 to 100 ml of the 50 mM phosphate buffer. A stock solution of squalene oxide is made as a solution in ethanol (0.65 mg ml "1), 18 μl of radiolabelled squalene oxide (1 μCi.Ml" 1) is evaporated to dryness under a stream of nitrogen and redissolved in 1 ml of ethanol and 1 ml of the stock solution of squalene oxide is added. The test compound is dissolved in dimethylsulfoxide to give a stock solution 10"4 M. The dilutions are made from the stock solution to give 10" 5 M, 10"6 etc. The Tween ® 80 is quenched with phosphate ( 28 μl) in 5 ml disposable plastic vials and add 4 μl of the test compound solution and mix well.An aliquot of the squalene oxide mixture (15 μl) is added and the vials are preincubated for 10 minutes at 37 ° C. A portion of the microsomes (14.6 μl) are then added and incubated for an additional hour.The reaction is stopped by the addition of 315 μl of a mixture of 16% KOH in 20% ethanol.

The samples are then placed in a water bath at 80 ° C for 2 hours to saponify. At the end of this process water (630 μl) is added followed by hexane (5 ml). The samples are mixed by agitation for 5 minutes and then centrifuged. The hexane phase is removed and evaporated under nitrogen. The samples are then reconstituted in 300 μl of an 80:20 mixture of an acetonitrile-isopropyl alcohol. The samples are then chromatographed using a Hichrom 30DsSl column with an isocratic elution using a 95: 5 mixture of acetonitrile: isopropyl alcohol and a velocity flow of 1 ml min "1. The UV detector output is connected to a radio detector to measure radiolabeled sterols The reaction rate is measured as soon as the conversion of squalene oxide to lanosterql is expressed, and the effects of test compounds as an inhibition of this process For example, the compound described in Example 10c below gives an IC50 of 81 nM. (b) In vivo test to measure the inhibition of the schylane cyclase oxide The test involves the administration of the compound to the rats in a reverse illumination regime. -55 g) under conditions of reverse lighting (red light of 0200 h -1400 h) for a period of approximately 2 weeks before the test. access to food and drinking water throughout this period. In the test, the animals must weigh 100 - 140Lg. the rats are dosed orally with the compound (typically 10-50 mg / kg) formulated in a mixture of polyethylene glycol / hydroxypropylmethylcellulose. After 1 hour the rat was mevalonate sodium crushed (15 μCi / kg) intraperitoneally. Two hours after administration of the compound the rats are sacrificed and a piece of the liver is removed and weighed. The tissue is saponified at 80 ° C for 2 hours in an ethanolic / potassium hydroxide solution (aqueous KOH 80% w / v diluted 1:10 with ethanol). Water (2 ml) is added and the mixture is extracted with isohexane (2 x 5 ml). Combine the organic extracts, evaporate to dryness under a stream of nitrogen and dissolve the residue in a mixture of acetonitrile / isopropanol (300 μl). An aliquot (200 μl) of this solution is loaded onto an HPLC column to separate the sterols. The content of the radio-label of each fraction is evaluated using a chemical radio flux detector. Skeletal cyclase oxide inhibitors are classified as those compounds which cause a substrate formation and a concomitant disappearance of cholesterol and its precursors. The ED50 values are generated in the usual way. For example, the compound described in Example 10c below gives 72% inhibition of cholesterol biosynthesis when dosed at 5 mg / kg.

No open toxicity is detected when compounds of the formula I are administered in several multiples of their dose or minimum inhibitory concentration. When used in the treatment of diseases and medical conditions such as those mentioned above it is envisaged that a compound of the formula I (or a pharmaceutically acceptable salt thereof) will be administered orally, intravenously or by some medically acceptable route in such a way that receives a dose in the general range of, for example, 0.01 to 10 mg per kg of body weight. However, it will be understood that the precise dose administered will necessarily vary according to the nature and severity of the disease, the age and sex of the patient being treated and the route of administration. In general, the compounds of the formula I (or a pharmaceutically acceptable salt thereof) will usually be administered in the form of a pharmaceutical composition, ie together with a pharmaceutically acceptable diluent or carrier, and such a composition is provided as an additional feature of the present invention. A pharmaceutical composition of the present invention can be in a variety of dosage forms. For example, this may be in the form of tablets, capsules, solutions or suspensions for oral administration, in the form of a suppository for rectal administration.; in the form of a sterile solution or suspension for parental administration such as by intravenous or intramuscular injection. A composition can be obtained by conventional procedures using pharmaceutically acceptable diluents and carriers well known in the art. Tablets and capsules for oral administration may conveniently be formed with a coating, such as an enteric coating (such as one based on cellulose acetate phthalate) to minimize the dissolution of the active ingredient of the formula I (or an acceptable farmacéuticmanete salt of it) in the stomach or to mask unpleasant taste. The compounds of the present invention may, if desired, be administered together with (or sequentially) one or more other pharmacological agents known to be useful in the treatment of cardiovascular disease, for example, together with agents such as HMG inhibitors. -CoA reductase, bile acid sequestrants, other hypocholesterolemic agents such as fibrates, for example gemfibrozil, and drugs for the treatment of coronary heart disease. As inhibitors of the schydane cyclase oxide, the compounds of the present invention can also find utility as antifungal agents, and therefore the present invention also provides a method for inhibiting cholesterol biosynthesis in fungi. In particular the present invention provides a method for treating fungal infections which comprises administration to a warm-blooded animal, such as a man, in need of such treatment an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt of the same. When used in this manner, the compounds of the present invention can be adapted, in addition to the formulations mentioned above, for topical administration and such composition is provided as a further feature of the present invention. Such a composition can be in a variety of forms, for example creams or lotions. Compounds of the general formula I and intermediates are described for their preparation in the published International Patent Application No. WO96 / 10022. The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise: (i) the evaporations are carried out by rotary evaporation in vacuo, (ii) the operations are carried out at room temperature, ie in the range of 18-26 ° C; (iii) rapid column chromatography or medium pressure liquid chromatography (MPLC) is performed on silica gel (Merck Kieselgel Art. 9385, obtained from E. Merck, Darmstadt, Germany); (iv) returns are given for illustration only and are not necessarily the maximum obtainable by diligent process development; (V) NMR spectra proton at 200 MHz using tetramethylsilane (TMS) as an internal standard are determined, and expressed as chemical shifts (delta values) obtained in DMSO-d6 (unless otherwise stated) in parts per million in relation to TMS using conventional abbreviations for designation of main peaks: s, singlet, m, multiplet; t, triplet; br, broad; d, doublet; (vi) all final products are characterized by microanalysis, NMR and / or mass spectroscopy; and (vii) conventional abbreviations are used for individual radicals and recrystallization solvents, for example, Me = methyl, Et = ethyl, Pr = propyl, Pr1 isopropyl, Bu = butyl, Bu1 = isobutyl, Fen = phenyl; EtOAc = ethyl acetate, Et0 = ether, MeCN = acetonitrile, MeOH = methanol, EtOH = ethanol, Pr1OH = 2 -propanol, H20 = water. Example 1 4-chloro-2-methylpyrimidine (135 mg) was added to a solution of 1- (4-bromophenylsulphonyl) -4- (4-piperidylcarbonyl) piperazine (415 mg) in THF (15 ml) containing triethylamine (0.2 ml). The mixture is heated under reflux for 16 hours. After cooling, THF evaporates. The residue is treated with H20 (20 ml) and the aqueous extract with ethyl acetate (3 x 20 ml). The combined organic phases are washed with combined brine (1 x 20 ml), dried and evaporated to give an oil which is purified by chromatography on silica gel. Elution with dichloromethane / methanol / 0.88 NH (96: 3: 1) gives an oil. Trituration with diethyl ether (10 mL), gives a colorless solid, 1- (4-bromo-phenylsulfonyl) -4- [1- (2-methylpyrimidyl) -4-piperidylcarbonyl] piperazine (152 mg), m.p. 200-202 ° C; NMR: 1.39-1.48 (m, 2H), 1.55-1.69 (m, 2H), 2.30 (s, 3H), 2.80-3.00 (m, 7H), 3.45-3.67 (m, 4H), 4.32 (m, 2H) ), 6.57 (d, ÍH), 7.65 (d, 2H), 7.83 (d, 2H), 8.03 (d, ÍH); EI-MS m / z 508 (M + H). The starting 4-chloro-2-methylpyrimidine is prepared by the method described in Ger. Offen DE 3905364 (Chem. Abs., 114, 81871). EXAMPLE 2 4-Chloro-2-methylpyrimidine hydrochloride (3.5 g) is added to a stirred solution of l-benzyl-4- [4-piperidylcarbonyl] piperazine (6.6 g), triethylamine (12.8 ml) and ethanol (120 g). ml). The mixture is heated under reflux for four hours and evaporated in vacuo to yield a substance similar to molasses. The residue is partitioned between ethyl acetate and wa The organic phase is washed with brine, dried (Na 2 SO 4) and evaporated. The residue is taken up in alumina and purified using dry flash chromatography eluting with increasingly polar mixtures of dichloromethane and methanol (1: 0 to 998: 2). The maal obtained is triturated with diethyl ether to give 1- (benzyl) -4- [1- (4-pyrimidinyl) -4-piperidylcarbonyl] piperazine (3.8 g, 45% yield, mp 107-108.5 ° C; NMR: 1.80 (m, 4H), 2.45 (m, 4H), 2.80 (m, ÍH), 3.00 (m, 2H), 3.60 (m, 6H), 4.40 (m, 2H), 6.50 (d, ÍH), 7.35 ( m, 5H), 8.15 (d, ÍH), 8.55 (s, ÍH), microanalysis, found C 68.7, H 7.4, N 19.0%, C2? H27N50 requires: C 69.0, H 7.45, N 19.2%, Example 3 add a solution of 4-cyanophenylsulfonyl chloride (363 mg) in dichloromethane (10 ml) to a stirred mixture of 1- [1- (4-pyrimidinyl) -4-piperidylcarbonyl] piperazine (412.5 mg) and triethylamine (0.28 ml) in dichloromethane (15 ml) and the resulting mixture is stirred at room temperature for 2 hours.The mixture is partitioned between dichloromethane and wa and the organic phase is washed with wa dried (Na2SO4) and evaporated. by column chromatography using 0.5% methanol in dichloromethane.Recrystallization from acetat or ethyl / hexane da, 1- (4-cyanophenylsulfonyl) -4- [1- (4-pyrimidinyl) -4-piperidylcarbonyl] iperazine (280 mg), m.p. 180-181 ° C; NMR (CDC13): • 1.7-1.8 (m, 4H), 2.7 (m, HI), 2.9-3.0 (m, 2H), 3.0-3.1 (m, 4H), 3.6-3.8 (m, 4H), 4.4 (d, 2H), 6.5 (d, 1H), 7.9 (s, 4H), 8.2 (dd, ÍH) and 8 (s, ÍH). The starting maal is prepared as follows: N-benzylpiperazine (40.0 ml) is added in one portion to a solution of succinimido-l-t-butoxycarbonylpiperidine-4-carboxylate (75.0 g) in dry dichloromethane (1600 ml). The solution is stirred at room temperature under an argon atmosphere for 17 hours. The solution is washed with wa(500 ml) and saturated brine (250 ml). The organic layer is dried (Na 2 SO) and evaporated. The residual oil is purified by chromatography on alumina, eluting with dichloromethane to give l-benzyl-4- [1- (t-butoxycarbonyl) -4-piperidylcarbonyl] piperidine as an oil; NMR (CDC13): 1.4-1.5 (9H, s), 1.6-1.85 (4H, m) t 2.4-2.5 (4H, t), 2.5-2.65 (1H, m), 2.67-2.83 (2H, m), 3.45-3.7 (6H, m), 4.05-4.2 (2H, m), and 7.2-7.35 (5H, m); m / z 388 (M + H) +. A solution of l-benzyl-4- [1- (t-butoxycarbonyl) -4-piperidylcarbonyl] piperazine (115.7 g) in dry dichloromethane (222 ml) is added in 45 minutes to trifluoroacetic acid (575 ml), maintaining the temperature below 25 ° C under an argon atmosphere. The solution is stirred at 23-25 ° C for one hour. The solution is evaporated using a bath temperature of 30 ° C. The residual oil is emptied, in portions, in saturated aqueous sodium carbonate solution (770 ml) while maintaining the temperature below 30 ° C. The aqueous mixture is extracted with dichloromethane (3 x 575 ml). Combine the dichloromethane extracts, dry (Na2SO4) and evaporate to give l-benzyl-4- (4-piperidylcarbonyl) piperazine (56.2 g, 65% yield) as a colorless solid; NMR (CDC13 + DMSOds): 1.84-2.1 (4H, m), 2.33-2.5 (4H,), 2.78-2.93 (ÍH, m), 2.93-3.12 (2H, m), 3.32-3.45 (2H, m) , 3.45-3.65 (6H, m) and 7.2-7.37 (5H,): m / z 288 (M + H). Ammonium formate (1.88 g) is added to a mixture of l-benzyl-4- [1- (4-pyrimidinyl) -4-piperidylcarbonyl] piperazine (2.73 g) and 10% palladium on carbon catalyst (0.55 g) in methanol (70 ml) under an argon atmosphere. The mixture is stirred under reflux for 1 hour. The cold mixture is filtered through diatomaceous earth and the filtrate slurry is washed well with methanol. The filtrate and the washes are combined and evaporated. The residual oil is suspended in saturated aqueous sodium carbonate solution (30 ml) and the mixture is extracted with dichloromethane (4 x 100 ml). Combine the dichloromethane extracts, dry (Na2SO4) and evaporate to give 1- [1- (4-pyrimidinyl) -4-piperidylcarbonyl] piperazine (1.94 g, 94%), as a bone-colored solid; Example 4 Using an analogous procedure to that described in Example 7, 1- [1- (4-pyrimidinyl) -4-piperidylcarbonyl] piperazine is reacted with the appropriate sulfonyl chloride to give the compounds listed below in the following table Compound R p.f. NMR (CDCl 3) No. (° C) 4-cyanophenyl 180-181 1.7-1.8 (m, 4H), 2.7 (m, ÍH), 2.9-3.0 (m, 2H), 3.0-3.1 (m, 4H), 3.6-3.8 (m, 4H), 4.4 (d, 2H), 6.5 (d, ÍH), 7.9 (s, 4H), 8.2 (dd, ÍH), and 8.6 (s, ÍH). 2-chloro-4-137-138 1.7-1.8 (m, 4H), 2.7 (m, cyanophenyl), 2.9-3.0 (m, 2H), 3.2-3.5 (m, 4H), 3.6-3.8 (m, 4H), 4.4 (d, 2H), 6.5 (d, ÍH), 7.7 (dd, ÍH), 7.9 (s, ÍH), 8.2 (dd, ÍH), 8.2 (d, ÍH) and 8.6 (s, ÍH) ). 3,4-dichlorophenyl 189-190 1.7-1.8 (m, 4H), 2.7 (m, ÍH), 2.9-3.0 (m, 2H), 3.0-3.1 (m, 4H), 3.6-3.8 (m, 4H) , 4.4 (d, 2H), 6.5 (d, 1H), 7.5-7.7 (m, 2H), 7. 9 (s, ÍH), 8. 2 (8 .2 (dd, ÍH), and 8 .6 (s, ÍH). 4 - . 4 - . 4-methoxyphenyl 205-206 1.7-1.8 (m, 4H), 2.7 (m, ÍH), 2.9-3.0 (m, 2H), 3.0-3.1 (m, 4H), 3.6-3.8 (m, 4H), 3.9 (s, 3H), 4.4 (d, 2H), 6.5 (d, lH), 7.0 (d, 2H), 7.7 (d, 2H), 8.2 (dd, ÍH), and 8.6 (s, ÍH). 4-chlorophenyl 196-197 1.7-1.8 (m, 4H), 2.7 (m, 1H), 2.9-3.0 (m, 6H), 3.6-3.8 (m, 4H), 4.4 (d, 2H), 6.5 (d) , ÍH), 7.5 (d, 2H), 7.7 (d, ÍH), and 8.6 (s, 1H). 2-cyanophenyl Sublima 1.7-1.8 (m, 4H), 2.75 (m, at 100 μH), 3.0 (m, 2H), 3.1-3.5 (m, 4H), 3.6-3.8 (m, 4H), 4.4 (d) , 2H), 6.5 (d, ÍH), 7.75 (m, 2H), 7.9 (dd, ÍH), 8.15 (dd, ÍH), 8.2 (d, ÍH) and 8.55 (s, ÍH). 2.4- Decomp 1.7-1.8 (m, 4H), 2.75 (m, difluorophenyl at 170-> H), 3.0 (m, 2H), 3.25 175 (m, 4H), 3.6-3.8 (m, 4H), 4.45 (m, 2H), 6.45-6.5 (dd, ÍH), 7.35-7.45 (d, 2H), 7.6-7.7 (d, 2H), 8.15-8.2 (d, ÍH), 8.55 - 8.6 (s, ÍH) . 3, 5-dimethyl-4-180-181 1.7-1.8 (m, 4H), 2.3 (s, fluorophenyl 6H), 2.7 (m, ÍH), 2.9-3.1 (m, 6H), 3.6-3.8 (m, 4H), 4.4 (m, 2H), 6.5 (dd, ÍH), 7.4 (d, 2H), 8.2 (d, ÍH), and 8.6 (s, ÍH). 2, 5 -dibromo 3,6- 148-149 1.7-1.8 (m, 4H), 2.7 (m, difluorophenyl 1H), 3.0 (m, 2H), 3.3-3.5 (m, 4H), 3.6-3.8 (m , 4H), 4.4 (d, 2H), 6.5 (d, ÍH), 7.6 (m, ÍH), 8.2 (d, 1H), and 8.6 (s, ÍH). 4-iodophenyl 194-195 1.7-1.8 (m, 4H), 2.7 (m, HH), 2.9-3.1 (m, 6H), 3.6-3.8 (m, 4H), 4.4 (d, 2H), 6.5 (d) , HH), 7.4 (d, 2H), 7.9 (d, 2H), 8.2 (d, HH), and 8.6 (s, HH) 273-175 1.7-1.8 (m, 4H), 2.2 (s, acetylaminophenyl 3H ), 2.7 (m, 1H), 2.9-3.1 (m, 6H), 3.6-3.8 (m, 4H), 4.4 (d, 2H), 6.5 (d, ÍH), 7.5 (s, ÍH), 7.7 ( s, 4H), 8.2 (d, ÍH), and 8.6 (s, ÍH). Phenyl 159-160 1.7-1.8 (m, 4H), 2.7 (m, ÍH), 2.9-3.1 (m, 6H), 3.6-3.8 (m, 4H), 4.4 (d, 2H), 6.5 (d, 1H) ), 7.6 (m, 3H), 7.8 (dd, 2H), 8.2 (d, ÍH), and 8.6 (s, ÍH). 4-ethylphenyl 171-174 1.2-1.35 (t, 3H), 1.65- 1.9 (m, 4H), 2.6-2.8 (m, 3H), 2.85-3.1 (m, 6H), 3.5-3.8 (m, 4H) , 4.3-4.45 (m, 2H), 6.45-6.5 (d, ÍH), 7.3-7.4 (d, 2H), 7.6-7.7 (d, 2H), 8.15-8.2 (d, ÍH) and 8.55-8.6 ( Yes H) . 4- (n- 138-140 0.87-1.03 (t, 3H), 1.6-propyl) phenyl 1.9 (m,, 6H) m 2.55-2.8 (m, 3H), 2.85-3.15 (m, 6H), 3.55-3.8 (m, 4H), 4.3-4.5 (m, 2H), 6.45- (d, ÍH) and 8.6 (s, ÍH). 3.5-227-228 1.7-1.8 (m, 4H), 2.7 (m, bistrifluoromethyl 1H), 3.0 (m, 2H), 3.2 (m, phenyl 4H), 3.6-3.8 (m, 4H), 4.4 ( d, 2H), 6.5 (d, 1H), 8.15 (d, ÍH), 8.2 (m, 3H), and 8.6 (s, ÍH). 4-nitrophenyl 219-220 1.7-1.8 (m, 4H), 2.7 (m, 1H), 2.9-3.0 (m, 2H), 3.1-3.2 (m, 4H), 3.6-3.8 (m, 4H), 4.4 (d, 2H), 6.5 (d, ÍH), 8.0 (d, 2H), 8.2 (d, ÍH), 8.4 (d, 2H), and 8.6 (s, ÍH). 4-chloro-3- 246-248 1.7-1.8 (m, 4H), 2.7 (m, nitrophenyl), 2.9-3.0 (m, 2H), 3.1-3.2 (m, 4H), 3.6-3.8 (m, 4H), 4.4 (d, 2H), 6.5 (d, ÍH), 7.8 (d, ÍH), 7.9 (d, ÍH), 8.15 (d, ÍH), 8.2 (d, ÍH), and 8.6 (s, ÍH). 133-134 1.7-1.8 (m, 4H), 2.75 (m, methoxycarbonylphenH), 3.0 (m, 2H), 3.2-3.3 ilo (m, 4H), 3.6-3.8 (m, 4H), Example 5 Dissolves 4- [1- (4-pyrimidinyl) piperazin-4-ylcarbonyl] piperidine (412 mg) in dichloromethane (16 ml), cooled in an ice bath, stirred and treated in drops with a mixture of sodium chloride and sodium chloride. -chlorophenylsulphonyl (338 nrg) and triethylamine (0.3 ml) in dichloromethane (16 ml). The reaction mixture is allowed to reach room temperature and is stirred for 18 hours before being treated with saturated NaHCO 3 solution. This mixture is extracted twice with dichloromethane. The combined organic extracts are washed twice with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure to a yellow solid. The solid obtained in this way is chromatographed through a pre-packed column with 10 g of silica "bond elut", eluting with 1% methanol, 1% ammonium hydroxide and 98% dichloromethane to obtain 1- (4 - chlorophenylsulfonyl) -4- [1- (4-pyrimidinyl) piperazin-4-ylcarbonyl] piperidine (178 mg, 26% yield based on the amine), as a white solid, mp 125-128 ° C.

Example 6 4- [1- (4-Pyrimidinyl) piperazin-4-ylcarbonyl] piperidine (385 mg) in dichloromethane (20 ml) is stirred at room temperature as a solid suspension and treated in drops with 4-bromophenylsulfonyl chloride (385 mg) and triethylamine (0.4 ml) in dichloromethane (15 ml). The resulting clear yellow solution is stirred at the same temperature for an additional 20 hours and treated with saturated NcHCO 3 solution (40 ml). The mixture is extracted twice with dichloromethane and the combined organic extracts are washed twice each with water and the brine is dried in anhydrous MgSO 4, filtered and evaporated under reduced pressure to a yellow solid. The solid is chromatographed through a pre-packed column with 10 g of silica elute bond, eluting with 1% methanol, 1% ammonium hydroxide and 98% dichloromethane to give 1- (4-bromophenylsulfonyl) -4- [1- (4-pyrimidinyl) piperazin-4-ylcarbonyl] piperidine (209 mg, 30% yield based on the amine), as a colorless solid, e.g. F. 171-174 ° C; NMR (CDC13): 1.74-188 (m, 2H), 1.86-2.03 (m, 2H), 2.45-2.58 (m, 3H), 3.49-3.82 (m, 10H), 6.49 (dd, ÍH), 7.60- 7.71 (m, 4H), 8.25 (d, ÍH), 8.62 (d, ÍH). The starting material is prepared as follows: 1- (t-Butoxycarbonyl) -4- [1- (4-pyrimidinyl) piperazin-4-ylcarbonyl] piperidine (5.23 g) in dichloromethane (50 ml) is dissolved and treated room temperature with trifluoroacetic acid (30 ml). The resulting pale yellow solution is stirred at the same temperature for 18 hours. After this period the reaction mixture is evaporated under reduced pressure to a brown oil which subsequently is formed in azeotropic mixture with toluene. The resulting oil is brought to basic pH with 40% w / v NaOH solution, taken to dichloromethane and filtered through celite. Wash the filtrate twice with brine, dry in anhydrous MgSO 4, filter and evaporate under reduced pressure to obtain the amine, a brown foam, 1545 g (40% yield based on the boc derivative), - NMR (CDC13 ): 1.67-1.80 (m, 4H), 2.64-2.79 (m, 3H), 3.15-3.25 (m, 2H), 3.55-3.79 (m, 8H), 6.51 (dd, ÍH), 8.26 (d, 1H) ), 8.63 (d, ÍH). An additional sample of the amine is obtained by washing the celite again with 10% methanol, 1% ammonium hydroxide and 89% dichloromethane. The dichloromethane solution is washed with brine (3 times), dried over anhydrous MgSO 4, filtered and evaporated to give a complex white foam. The foam is chromatographed through 60 vm silica gel, eluting with 10% methanol, 1% ammonium hydroxide and 89% dichloromethane to obtain an additional 676 mg (18% based on the boc derivative) of the amine. . The 4-pyrimidinylpiperazine (2.473 g) is dissolved; 15 mmol) in DMF (35 ml) and treated at room temperature with 1- [1- (t-butyloxycarbonyl) piperidin-4-ylcarbonyloxy] 2,5-dioxopyrrolidine (4.9 g, 15 mmol). The resulting clear solution is stirred at the same temperature for 65 hours to give a pale yellow solid suspension. The reaction mixture is poured into water (350 ml) and extracted four times with dichloromethane. The combined organic extracts are washed twice with water and brine, dried in anhydrous MgSO 4, filtered and evaporated under reduced pressure to obtain an unpurified oil. The oil is dried in a high vacuum pump to produce a colorless solid which is recrystallized with ethyl acetate / i-hexane to produce 1- (t-butoxycarbonyl) -4- [1- (4-pyrimidinyl) piperazine-4 -carbylcarbonyl] piperidine as colorless crystals (5.05 g, 90% yield based on 4-pyrimidylpiperazine), mp 159-163 ° C; NMR (CDC13): 1.44 (s, 9H), 1.54-1.85 (m, 4H), 2.59- 2.70 (m, 1H), 2.74-2.86 (m, 2H), 3.56-3.82 (m, 8H), 4.11- 4.22 (m, 2H), 6.52 (dd, ÍH), 8.25 (d, ÍH), 8.63 (d, ÍH). The 1- (benzyl) -4- (4-chloropyrimidin-6-yl) piperazine (58.0 g) is dissolved, with some heating, in methanol (700 ml), treated with Pd in 10% activated carbon (11.6%). g) and stirred and hydrogenated at atmospheric pressure for 8 hours. The catalyst is filtered off through celite. The filtrate obtained in this way is then evaporated under reduced pressure to a yellow brown viscous gum which is chromatographed through 60 vm silica gel, eluting with 5% methanol, 1% ammonium hydroxide and 94% dichloromethane. % to obtain 4- (4-pyrimidinyl) piperazine, as a white solid, 25 g (76% yield based on the substrate before hydrogenation); NMR (t, 4H), 3.50 (t, 4H), 6.75 (dd, ÍH), 8.14 (d, ÍH), 8.45 (d, ÍH). A mixture of 4,6-dichloropyrimidine (29.5 g), N-benzylpiperazine (44.0 g) and DIPEA (44 ml) is suspended in p-xylene (400 ml) and heated at 138 ° C under reflux. After 18 hours, allow the reaction mixture to cool to room temperature and filter. The filtrate is evaporated using the high vacuum pump apparatus to obtain 1- (benzyl) -4- (4-chloropyrimidin-6-yl) piperazine a brown solid, 60.5 g (105% based on 4,6-dichloropyrimidine) ); NMR (CDC13): 2.51 (t, 4H), 3.56 (s, 2H), 3.65 (t, 4H), 6.47 (s, 1H), 7.27-7.37 (m, 5H), 8.36 (s, ÍH). Example 7 1- (4-Bromophenylsulfonyl) -4- [1- (t-butoxycarbonyl) 4-piperidylcarbonyl] homopiperazine (290 mg) is dissolved in dichloromethane (15 ml). Trifluoroacetic acid (3 ml) is added and the reaction is stirred at room temperature for 1 hour. The solvent is removed in vacuo to give the unpurified trifluoroacetic acid salt of the deprotected piperidine. The unpurified salt is dissolved in ethanol (15 ml). Triethylamine (1 ml) and 4-chloropyrimidine hydrochloride (90 mg) are added.

The reaction is heated under reflux for 2 hours, and the solvent is removed in vacuo. The residue is partitioned between dichloromethane (50 ml) and aqueous sodium bicarbonate solution (50 ml). The product is extracted with dichloromethane (2 x 50 ml), dried (MgSO 4) and the solvent is removed in vacuo. Purify the product on a bond elut column (10 g) eluting with dichloromethane and [1% methanol, 1% ammonia, 98% dichloromethane] to give 1- (4-bromophenylsulfonyl) -4-] [1- ( 4-pyrimidinyl) -4-piperidylcarbonyl] homopiperazine as a foam (152 mg); NMR (1250 MHz): 1.40-1.95 (m, 6H), 2.85-3.1 (m, 3H), 3.25-3.80 (, 8H), 4.35-4.55 (m, 2H), 6.90 (d, ÍH), 7.78 ( d, ÍH), 7.82 (d, ÍH), 7.85-7.95 (m, 2H), 8.20 (d, ÍH), 8.53 (s, ÍH). The starting material is prepared as follows: 1- [1- (t-Butoxycarbonyl) -4-piperidylcarbonyloxy] 2,5-dioxopyrrolidine (450 mg) and 1- (4-bromophenylsulfonyl) 1, 4- are refluxed. diazepine (440 mg) in dichloromethane (25 ml) for 3 hours. The reaction is allowed to stand at room temperature for 60 hours. The solvent is removed in vacuo. The residue is partitioned between ethyl acetate (50 ml) and dilute citric acid (50 ml). The organic layer is washed with brine, dried (MgSO 4) and the solvent removed in vacuo. Purify the product on a silica elute bond column (10 g) eluting with ethyl acetate / hexane (40/60) gradually increasing the polarity to (60:40). 1- (4-Bromophenylsulfonyl) -4- [1- (t-butoxycarbonyl) -4-piperidylcarbonyl] homopiperazine is obtained as a foam (620 mg); NMR (250 MHz): 1.30-1.85 (m, 6H), 1.40 (3, 9H), 2.63-2.87 (m, 3H), 3.20-3.68 (m, 8H), 3.85-3.98 (m, 2H), 7.67 -7.7 (m, 2H), 7.77-7.87 (m, 2H). Slowly add 4-bromophenylsulfonyl chloride (1.50 g) in dichloromethane (50 ml) to a solution of homopiperazine (3.0 g) in dichloromethane (100 ml). The reaction is stirred at room temperature for 18 hours. The reaction mixture is washed with water (40 ml) and brine (50 ml), dried (MggSO4) and the solvent is removed in vacuo. The product is recrystallized from dichloromethane / hexane to give 1- (4-bromophenylsulfonyl) 1,4-diazepine a white solid (650 mg), m.p. 95-97 ° C; NMR (250 MHz): 1.57-1.75 (m, 2H), 2.67-2.79 (m, 4H), 3.15-3.30 (m, 4H), 7.73 (d, 2H), 7.82 (d, 2H). EXAMPLE 8 The lithium salt of 1-l-acid is heated under reflux. (4-pyrimidinyl) piperidine-4-carboxylic acid (426 mg), thionyl chloride (15 ml) and DMF (5 drops) for 1.5 hours. The thionyl chloride is removed in vacuo. Toluene (20 ml) is added and removed in vacuo to give the acid chloride without purification. A solution of the 1- (4-bromophenylsulfonyl) piperazine (610 mg) and triethylamine (2 ml) in dichloromethane (10 ml) is added to a solution of the unpurified acid chloride in dichloromethane (5 ml), cooled in a bath of ice. After the addition of the reagents, the ice bath is removed and the reaction is stirred at room temperature for 1 hour. Water (30 ml) is added. The mixture is washed with water (2x30 ml), it is dried (MgSO4) and the solvent is removed. The reaction mixture was purified on a silica elute bond column (10 g), eluting initially with dichloromethane and increasing the polarity to 3% methanol, 1% ammonia, 96% dichloromethane. This gives 1- (4-bromophenylsulfonyl) -4- [1- (5-chloropyrimidin-4-yl) -4-piperidylcarbonyl] piperazine (280 mg) and the monochloro derivative (110 mg) as a foam, m.p. 165-167 ° C; MR (250 MHz): 1.45-1.73 (m, 4H), 2.83-3.10 (m, 7H), 3.45-3.70 (m, 4H), 4.22-4.35 (m, 2H), 7.67 (d, 2H), 7.97 (d, 2H), 8.34 (s, ÍH), 8.50 (s, ÍH). Prepare the starting material as follows: Heat a solution of 1- (4-pyrimidinyl) -4- (ethoxycarbonyl) piperidine (.152 g) and lithium hydroxide monohydrate (300 mg) in ethanol (20 ml) under reflux. ) and water (20 ml for 1.5 hours) The solvents are removed in vacuo to give the lithium salt of 1- (4-pyrimidinyl) piperadine-4-carboxylic acid (.146 g) without purification which is used without purification. A solution of 4,6-dichloropyripty] idine (5.22 g), ethyl isopenicotate (5.50 g) and triethylamine (7 ml) in ethanol (60 ml) is stirred at room temperature for 2 hours, and the solvent in vacuo The mixture is fractionated without purification between ethyl acetate (100 ml) and water (50 ml), washed with brine, dried (MgSO 4) and the solvent removed to give the 1- (6-chloropyrimidine) 4-yl) -4- (ethoxycarbonyl) piperidine Ammonium formate (10 g) and 30% palladium on carbon (600 mg) are added to a solution of the monochloro pyrimidylpiperazine without purification in ethanol. anol (70 ml). The reaction is stirred at room temperature for 18 hours and filtered through a celite and the solvent is removed in vacuo. The crude product is partitioned between dichloromethane / sodium bicarbonate solution and exted with dichloromethane (3 x 50 ml). Dry the combined exts (MgSO4) and remove the solvent. The product is purified by flash column chromatography (methanol / 3% ethyl acetate) to give 1- (4-pyrimidinyl) -4- (ethoxycarbonyl) iperidine an oil (5.44 g); NMR (250 MHz); 1.2 (t, 3H), 1.40-1.60 (m, 2H), 2.10- 2.25 (m, ÍH), 3.0-3.13 (m, 2H), 4.07 (q, 2H), 4.20-4.35 (m, 2H), 6.82 (d, 1H), 8.13 (d, 1H), 8.45 (s, ÍH). EXAMPLE 9 The reaction mixture is refluxed with 4- (l- (4-bromophenylsulphonyl) piperazin-4-ylcarbonyl) piperidine (170 mg) and 4-chloropyrimidine.2HC1 in absolute alcohol (10 ml) and triethylamine (0.5 ml) in two. hours. The solution is evaporated in vacuo and water (50 ml) is added and organic material is exted into ethyl acetate (2 x 50 ml), washed with water, brine and dried (MgSO4). The solution is evaporated in vacuo to give an oil which is dissolved in ethyl acetate and purified by flash chromatography on alumina (ICN Alumina N 32-63) using an increasing concenion of methanol in ethyl acetate (0-10 %) as eluent. This gives a solid which is recrystallized once from a mixture of ethyl acetate / teydrofuran / isohexane and then from acetonitrile 1- (4-pyrimidinyl) -4- [1- (4-bromophenylsulfonyl) piperazine-4 -carbonyl] piperidine (155 mg), as a solid, mp 197-198 ° C; NMR;: 1.7-1.9 (m, 4H), 2.6-2.8 (m, ÍH), 2.9-3.2 (m, 6H), 3.5-3.8 (bs, 4H), 4.3-4.5 (dt, 2H), 6.45-6.55 (dd, ÍH), 7.6-7.7 (d, 2H), 7.7-7.8 (d, 2H), 8.15- 8.25 (d, ÍH), 8.6 (s, 1H); micronalysis, found: C, 48.2; H, 4.9; N, 13.9%; C2oH24BrN5? 3S requires: C, 48.6; H, 4.9; N, 14.2%; MS m / z 494 (MH) +. The starting material is prepared as follows: 1- [1- (t-Butoxycarbonyl) -4-piperidylcarbonyloxy] -2,5-dioxopyrrolidine (2.45 g) and 1- (4-bromophenylsulfonyl) piperazine (2.31 g) is stirred. together with dichloromethane (100 ml) overnight. The solution is then stirred with water (100 ml) for 30 minutes, washed with additional water, brine and dried (MgSO). The solution is evaporated in vacuo to give an oil which crystallizes on standing to give 1- [1- (t-butoxycarbonyl) -4- (1- (4-bromophenylsulfonyl) piperazine (3.64 g) mp 209-210 ° C.; NMR: 1.45 (s, 9H), 1.49-1.81 (m, 4H), 2.51 (m, ÍH), 2.72 (dt, 2H), 3.03 (t, 4H), 3.64 (bs, 4H), 4.11 (d , 2H), 7.59 (d, 2H), 7.69 (d, 2H), MS m / z 515 (MH) +, 1- [1- (t-Butoxycarbonyl) -4-piperidylcarbonyl] -4- ( 4-bromophenylsulfonyl) piperazine (3.3 g) in trifluoroacetic acid (20 ml) for one hour The solvent is evaporated in vacuo and the residual oil is treated with ice and the solution is brought to basic pH by the addition of solid potassium carbonate. Extract the organic material in ethyl acetate and wash with water and brine, dry (MgSO 4) and evaporate in vacuo to give 1- (4-bromophenylsulfonyl) -1- (4-piperidylcarbonyl) piperazine as an oil (2.1 g); NMR: 1.52-1.79 (m, 4H), 2.43-2.71 (m, 3H), 3.01 (t, 4H), 3.13 (dt, 2H), 3.64 (s, 4H), 7.61 (d, 2H) 7.70 (d , 2H); MS m / z 415 (MH) +. Example 10 The following compounds are prepared using a procedure analogous to that described in Example 14; Example 11 A solution of 4-cyanobenzoyl chloride (298 mg) in dichloromethane (10 ml) is added to a stirred mixture of 1- [1- (4-pyrimidinyl) piperidin-4-ylcarbonyl] piperazine (412.5 mg) and triethylamine (0.28 ml) in dichloromethane (15 ml) and the resulting mixture is stirred at room temperature for 2 hours. The mixture is partitioned between dichloromethane and water. The organic phase is washed with water, dried (Na 2 SO 4) and evaporated. The residue is purified by column chromatography using 0.5% methanol in dichloromethane. Recrystallization from ethyl acetate / hexane gives, as a solid, 1- [- (4-cyanobenzoyl) -4- [1- (4-pyrimidinyl) -4-piperidylcarbonyl] piperazine (280 mg), m.p. 192-193 ° C; NMR (CDC13): 1.8-1.9 (m, 4H), 2.8 (m, 1H), 2.9-3.0 (m, 2H), 3.4-3.9 (m, 8H), 4.4 (d, 2H), 6.5 (d, ÍH), 7.5 (d, 2H), 7.8 (d, 2H), 8.2 (dd, ÍH), 8.6 (s, ÍH). Example 12 The following compounds are prepared; using a procedure analogous to that described in Example 30.

Example 13 4-Bromophenylsulfonyl chloride (129 mg) is added at room temperature to a stirred solution of 1- [1- (4-pyrimidinyl) pyrrolidin-3-ylcarbonyl] iperazine (130 mg) in THF (8 ml) containing triethylamine (0.14 ml). The mixture is stirred for 2 hours then evaporated. The waste is treated with water (16 ml) and dichloromethane (30 ml) is added. The aqueous phase is separated and extracted again with dichloromethane (20 ml). The combined organic phases are washed with saturated brine (2 x 10 ml), dried and evaporated. The residue is purified by chromatography on neutral alumina eluting with dichloromethane / methanol (99/1 v / v) to give, as a colorless solid, 1- (4-bromophenylsulfonyl) -4- [1- (4-pyrimidinyl) pyrrolidin- 3-ylcarbonyl] piperazine (134 mg), m.p. 94-6 ° C; NMR (CDCl3) 2.05-2.42 (m, 2H), 2.90-3.17 (m, 4H), 3. 20-3.40 (m, ÍH), 3.35-3.55 (m, ÍH), 3.55-3.90 (, 7H), 6.26 (dd, ÍH), 7.61 (d, 2H), 7.70 (d, 2H), 8.17 (d , ÍH), 8.56 (s, ÍH); El-MS m / z 480 (M + H). The starting piperazine derivative used as the starting material is prepared as follows: The benzylchloroformate (2.86 ml) is added to a stirred suspension of N-benzyl-3-n-butoxycarbonylpyrrolidine (1.75 g) and sodium bicarbonate (2.52 g) in dichloromethane (30 ml). The reaction is stirred for 0.5 hours, filtered and the filtrate is evaporated to give an oil. The residual oil is purified by chromatography on silica gel; elution with ethyl acetate / hexane (1/9 v / v) gives, as a pale yellow oil, the N-Cnz-3-n-butoxycarbonylpyrrolidine (1.40 g); NMR (CDCl 3) 0.93 (t, 3H), 1.27-1.47 (m, 2H), 1.52-1.67 (m, 2H), 2.06-2.22 (m, 2H), 2.95-3.10 (m, ÍH), 3.33-3.75 (m, 4H), 4.07 (t, 2H), 5.12 (s, 2H), 7.25-7.40 (m, 5H), El-MS m / z 480 (M + H). Aqueous 1 M NaOH (6 mL) is added to a stirred solution of the above ester (1.37 g) in methanol (6 mL). After one hour, the methanol is evaporated. Water (20 ml) is added to the residue and 1 M HCl (6 ml) is added to the stirred mixture. This aqueous phase is extracted with ethyl acetate (3 x 25 ml). The combined organic phases are washed with saturated brine (1 x 20 ml), dried and evaporated to give, as a colorless oil, N-Cbz-3-carboxypyrrolidine (780 mg); NMR (CDC13) 2.1-2.25 (m, 2H), 3.00-3.15 (m, ÍH), 3.32-3.74 (m, 4H), 5.10 (s, 2H), 7.17-7.38 (m, 5H), El- MS m / z 248 (MH). N-t-Butoxycarbonylpiperazine (543 mg) is added to a solution of the above acid (727 mg) N-hydroxybenzotriazole (590 mg) in DMF (12 ml). L- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (612 mg) is added and the mixture is stirred for 16 hours. The DMF is evaporated, water (50 ml) is added and the aqueous phase is extracted with ethyl acetate (3 x 25 ml). The combined organic phases are washed with saturated sodium bicarbonate solution (2 x 20 ml). The organic phase is dried and evaporated to give, as a creamy solid, l-t-butoxycarbonyl-4- (1-Cbz-pyrrolidin-3-ylcarbonyl) piperazine (1.15 g); p.f. 70-74 ° C; NMR (CDCl 3) 1.45 (s, 9H), 1.96-2.30 (m, 2H), 3.08- 3.25 (m, ÍH), 3.35-3.50 (m, 8H), 3.52-3.77 (m, 4H), 5.12 (s) , 2H), 7.22-7.35 (m, 5H); El-MS m / z 418 (m + H). 10% palladium on carbon (75 mg) is added to a stirred solution of the above Cbz-pyrrolidinyl derivative (1.11G9 in ethanol (40 ml) and the mixture is hydrogenated at 1 atm H2 pressure at 25 ° C for 16 hours. The catalyst is removed by filtration through celite, the filtrate is evaporated to dryness to give a solid which is triturated with diethyl ether (10 ml) .The filtration gives, as a colorless solid, lt-butoxycarbonyl 4- (1 (H ) pyrrolidin-3-ylcarbonyl) piperazine (470 mg), mp 94-95 ° C; NMR (CDC13) 1.48 (s, 9H), 1.88-2.08 (m, 2H), 2.78-3.25 (m, 5H), 3.46 -3.62 (m, 2H); El-MS m / z 284 (M + H). 4-chloropyrimidine hydrochloride (210 mg) is added to a solution of the Boc-piperazino derivative (380 mg) in ethanol (10 ml). containing triethylamine (0.6 ml) The mixture is stirred at reflux temperature for 16 hours After cooling, the ethanol is evaporated The residue is treated with saturated sodium bicarbonate solution (20 ml) and the aqueous phase is extracted with acetate ethyl (3 x 20 ml). The combined organic phases are washed with saturated brine (2 x 20 ml), dried and evaporated. The residue is crystallized from ethyl acetate to give, as a pale gray solid, l-t-butoxycarbonyl-4- [1- (4-pyrimidinyl) pyrrolidin-3-ylcarbonyl] piperazine (301 mg); p.f. 156-7 ° C; NMR 1.42 (s, 9H), 1.95-2.25 (m, 2H), 3.25-3.70 (m, 13H), 6.48 (dd, 1H), 8.12 (d, ÍH), 8.12 (d, 1H), 8.43 (s) , ÍH); El-MS m / z 362 (M + H). Trifluoroacetic acid (ATF) (0.7 ml) is added to a stirred solution of the above pyrimidinylpyrrolidinecarbonylpiperazine derivative (216 mg) in dichloromethane (5 ml) at 25 ° C. After one hour, ATF (0.3 ml) is added. The dichloromethane / ATF mixture is evaporated after an additional hour. The residue is treated with saturated brine solution (2 ml) and 5M sodium hydroxide (2 ml). The aqueous phase is extracted with dichloromethane (5 x 15 ml). The combined organic phases are washed with saturated brine (2 x 25 ml), dried and evaporated to give, as a colorless solid, 4- [1- (4-pyrimidyl) pyrrolidin-3-ylcarbonyl] piperazine (143 mg) : pf 129-131 ° C; NMR (DMSOd6 / CD3COOD) 1.95-2.25 (m, 4H), 2.97-3.20 (m, 4H), 3.30-3.85 (m, 9H), 6.45 (d, 1H), 8.09 (d, 1H), 8.45 (s) , ÍH); El-MS m / z 262 (M + H). Example 14 2-Methyl-4-chloro-pyrimidine (0.34 g) is added to a suspension of 1- (4-bromophenylsulfonyl) -4- (1-piperazinylcarbonyl) piperidine (1.0 g) in ethanol (10 ml) and triethylamine ( 0.5 ml). The reaction is heated under reflux for 2 hours, it is cooled and the solvent is removed by evaporation. Purify the reaction mixture by filtration column chromatography (silica, gradient elution of dichloromethane to 10% methanol in dichloromethane) to give 1- (4-bromophenylsulfonyl) -4- [1- (2-methylpyrimidin-4- il) piperazin-4-ylcarbonyl] piperidine as a solid (0.82 g) tpf 239-240 ° C; NMR (CDC13) 1.75-2.0 (m, 5H), 2.5 (m, 2H), 3.45-3.8 (m, 10H), 6.3 (m, ÍH), 7.65 (m, 4H), 8.2 (m, ÍH). The starting material is prepared as follows. A solution of 4-bromophenylsulfonyl chloride (7.68 g) in dichloromethane (100 ml) over a period of 30 minutes is added dropwise to a solution of 4- (ethoxycarbonyl) iperidine (4.71). g) in dichloromethane (50 l) a 0 ° C and under argon. The mixture is stirred overnight during which time it is allowed to warm to room temperature. The organic phase is washed with water, brine, dried and evaporated to give a solid. This solid is crushed in petroleum ether (e.g., 40-60 ° C) to give 1- (4-bromophenylsulfonyl) -4- (ethoxycarbonyl) piperidine (10.05), m.p. 137-133 ° C. A solution of 40% (v / v) aqueous sodium hydroxide (10 ml) is added to a stirred mixture of l- (4-bromophenylsulfonyl) -4- (ethoxycarbonyl) piperidine (8.0 g) and ethanol (100 ml) at 25 ° C. A precipitate forms. Water is added (100 ml) and the mixture is stirred for an additional two hours.

The mixture is evaporated to dryness and the residue is dissolved in hot water (95 ° C, 470 ml). The solution is allowed to cool overnight. The solid is collected by filtration and suspended in water (125 ml). Acetic acid is slowly added (1.4 ml) to give pH 6 and the solid is collected by filtration.

The 1- (4-bromophenylsulfonyl) -4-carboxypiperidine (5.66 g), m.p. 224-7 ° C. N-Hydroxybenzotriazole (2.02 g) is added to a stirred solution of 1- (4-bromophenylsulfonyl) -4-carboxypiperidine (3.48 g) in DMF (40 ml) at 20 ° C under argon.

After 10 minutes, N- (t-butoxycarbonyl) piperazine is added (1.86 g) followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (2.09 g). The mixture is stirred overnight under argon. The DMF is removed by evaporation. Water is added (150 ml) to the residue to give a solid which is collected by filtration and washed with water. This gives 1- (4-bromophenylsulfonyl) -4- [1- (t-butoxycarbonyl) piperazin-4-ylcarbonyl] iperidine which is recrystallized from propan-2-ol to give a solid (3.53 g ), pf 201-4 ° C. 1- (4-Bromophenylsulfonyl) -4- [1- (t-butoxycarbonyl) -4-piperidylcarbonyl] piperidine (3.42 g) is added to trifluoroacetic acid (22 ml) at 0 ° C under argon. The mixture is stirred for 1 hour at a temperature between 0 and 10 ° C. Excess trifluoroacetic acid is removed by evaporation. Ice (50 g) is added to the residue, followed by a saturated aqueous potassium carbonate solution (10 ml). The mixture is extracted with dichloromethane (3 x 100 ml). The extracts are combined, washed with brine, dried (NaS0) and evaporated to give 1- (4-bromophenylsulfonyl) -4- (1-piperazinylcarbonyl) piperidine as a solid (2.64 g), m.p. 158-9 ° C; NMR (CDC13): 1.55-1.97. (M, 4H), 2.35-2.62 (m, 3H), 2.70-2.85 (t, 4H), 3.27-3.62 (bd, 4H), 3.68-3.80 (dt, 2H) 7.52-7.70 (m, 4H). Example 15 Thionyl chloride (5 ml) is added to the lithium salt of 4-carboxylic acid 1- (4-pyrimidinyl) piperidine (320 mg), DMF (2 drops) and the reaction is stirred at room temperature for 1 hour . The reaction mixture is evaporated in vacuo. Toluene (10 ml) is added and then it is removed by evaporation to give the acid chloride without purification. The residue is dissolved in dichloromethane (15 ml), to which is added triethylamine (1.5 ml) and 1- (4-chlorophenylsulfonyl) homopiperazine (412 mg). The reaction is stirred at room temperature for 1 hour. The reaction is washed with water, dried (MgSO 4) and the solvent is removed by evaporation. Purification by chromatography (bond elution, silica, gradient elution, dichloromethane to 1% methanol, 1% ammonia in dichloromethane) gives 1- (4-chlorophenylsulfonyl) -4- [1- (4-pyrimidinyl) -4- piperidylcarbonyl] homopiperazine as a foam (326 mg); NMR (DMS0d6): 1.45-2.0 (m, 6H), 2.90-3.15 (m, 3H), 3.3-3.8 (m, 8H), 4.40-4.05 (m, 2H), 6.95 (dd, ÍH), 7.80 ( m, 2H), 7.90 (m, 2H), 8.25 (d, ÍH), 8.58 (s, ÍH). 1- (4-Chlorophenylsulfonyl) omopiperazine is prepared as follows. Slowly add 4-chlorophenylsulfonyl chloride (3.74 g) in dichloromethane (100 ml) to a solution of homopiperazine (6.73 g) in dichloromethane (100 ml). The reaction is allowed to stand at room temperature overnight. The reaction is washed with water, dried (MgSO 4) and the solvent removed in vacuo. The residue is triturated with 20% ether in hexane to give 1- (4-chlorophenylsulfonyl) homopiperazine (3.71 g); NMR (DMSOdg): 1.65 (m, 2H), 2.73 (m, 4H), 3.2-3.65 (m, 4H), 7.7 (m, 2H), 7.8 (m, 2H). Example 16 1- (4-trifluoroamethylphenylsulfonyl) homopiperazine (1.85 g) is treated in 20 ml of dichloromethane and 4 ml of triethylamine with a solution of 1- (2-methylpyrimidin-4-yl) -4- (acylchloride) iperidine ( prepared from 2 g of acid and thionyl chloride) in 20 ml of dichloromethane. After stirring overnight the reaction mixture is washed with water, followed by saturated sodium bicarbonate solution and brine. Dry in magnesium sulfate, evaporate and chromatograph (Bondelut 10 g, dichloromethane followed by 1% methanol / dichloromethane / 1% ammonia) to give 1- (4-trifluoromethylphenylsulfonyl) -1- [1- ( 2-methylpyrimidin-4-yl) -4-piperidylcarbonyl) homopiperazine (2.0 g) as a colorless foam; NMR (CDC13: 1.65-1.95 (4H, m), 1.95-2.1 (2H, m), 2.5 (3H, S), 2.66-2.77 (HI, m), 2.88-3.0 (2H, m), 3.28-3.4 (3H, m), 3.4-3.5 (HH, m), 3.63-3.78 (4H, m), 4.45 (2H, d), 6.32 (HH, d), 7.78-7.84 (2H, m), 7.9-7.97 (2H, m), 8.1 (1H, d) Prepare 1- (4-trifluoromethylphenylsulfonyl) homopiperazine as follows: 4-trifluoromethylphenylsulfonyl chloride (1.5 g) in 20 ml of dichloromethane is added dropwise to 5 g of homopiperazine and 1.8 ml of triethylamine in 55 ml of dichloromethane and allowed to stir overnight, washed with water and brine, dried (MgSO 4), and evaporated to give l- (4-trifluoromethylphenylsulfonyl) homopiperazine (1.80 g) as a colorless solid: NMR (CDC13): 1-75 (H, br), 1.78-1.9 (2H, m), 2.9-3.0 (4H, m), 2.3-3.44 (4H, m), 7.78 (2H, d), 7.93 (2H, d) Example 17 Using the method described in Example 7 but using 4-chloro-2,6-dimethylpyrimidine, the l- (4-bromophenylsulfonyl) -4- [1- (2, 6-dimethylpyrimidin-4-yl) -4-piperidylcarbon il] homopiperazine as a foam; NMR (CDCI3): 1.7-1.9 (m, 4H), 1.9-2.03 (m, 2H), 2.32 (s, 3H), 2.48 (s, 3H), 2.6-2.75 (m, ÍH), 2.84-2.98 ( m, 2H), 3.22-3.37 (m, 3H), 3.4-3.46 (m, ÍH), 3.6-3.75 (m, 4H), 4.4-4.5 (m, 2H), 6.2 (s, ÍH), 7.6- 7.7 (m, 4H). Example 18 Using the method described in Example 7 but with 4-chloro-6-methylpyrimidine, 1- (4-bromophenylsulfonyl) -4- [1- (6-methylpyrimidin-4-yl) -4-piperidylcarbonyl] homopiperazine is obtained as a foam: NMR (CDC13): d 1.7-1.9 (m, 4H), 1.92-2.05 (m, 2H), 2.36 (s, 3H), 2.64-2.78 (m, ÍH), 2.88-3.01 (m, 2H ), 3.22-3.37 (m, 3H), 3.4-3.46 (m, ÍH), 3.62-3.76 (m, 4H), 4.4-4.5 (, 2H), 6.38 (s, 1H), 7.6-7.7 (m, 4H), 8.5 (s, 1H). Example 19 Using a procedure analogous to that described in Example 16 with 1- (4-pyrimidinyl) -4-methyl-4- (ethoxycarbonyl) piperidine, lithium hydroxide, thionyl chloride and 1- (4-bromophenylsulfonyl) piperidine, this gives 1- (4-bromophenylsulfonyl) -4- [1- (4-pyrimidinyl) -4-methylpiperidin-4-ylcarbonyl] piperazine as a solid, mp 217-218 ° C; NMR (CDC13): 1.3 (s, 3H), 1.5-1.6 (m, 2H), 2.15-2.28 (m, 2H), 3.90-3.08 (m, 4H), 3.32-3.42 (m, 2H), 3.7-3.92 (m, 6H), 6.44 (d, ÍH), 7.68 (dd, 4H), 8.17 (d , ÍH), 8.57 (s, 3.-3). The starting material is prepared as follows. The 1- (4-pyrimidinyl) -4- (ethoxycarbonyl) piperidine (400 mg) is cooled in 4 ml of tetrahydrofuran at -70 ° C and treated with a solution of lithium diisopropylamide (1.0 ml in THF), under a argon atmosphere. After stirring for 1.5 hours, 1.2 ml of a solution of 1 ml of iodomethane in 10 ml of THF is added and the reaction mixture is allowed to reach room temperature overnight. Water is added and extracted twice with ethyl acetate. The organic extracts are washed with brine and dried over magnesium sulfate, filtered and evaporated to give l- (4-pyrimidinyl) -4-methyl-4- (ethoxycarbonyl) piperidine (370 mg) as an oil; NMR (CDCI3): 1.24 (s, 3H), 1.28 (t, 3H), 1.38-1.51 (m, 2H), 2.14-2.26 (m, 2H), 3.12-3.26 (m, 2H), 4.03-4.14 ( m, 2H), 4.2 (q, 2H), 6.5 (dd, ÍH), 8.17 (d, ÍH), 8.57 (s, ÍH). Example 20 Using an analogous procedure to that described in Example 4, and the appropriate sulfonyl chloride, the following compounds are thus obtained. (2 xlOO ml). The remaining unpurified solid is treated with thionyl chloride (100 ml) and stirred at room temperature overnight. The thionyl chloride is removed in vacuo and the unpurified acid chloride is formed azeotropically with toluene (2 x 50 ml). The crude acid chloride is suspended in dichloromethane (100 ml), to which 1- (tert-butoxycarbonyl) piperazine (7.1 g) in dichloromethane (100 ml) is added in 10 minutes. The solvent is removed in vacuo and the product by flash chromatography (silica; 10% methanol in dichloromethane) to give 1- (tert-butoxycarbonyl) -4- [1- (2,6-dimethylpyrimidin-4-yl) -4-piperidylcarbonyl] piperazine an oil (14.1 g); NMR (CDC13): 1.51 (s, 9H), 1.75-1.85 (m, 4H), 2.3 (s, 3H), 2.5 (s, 3H), 2.75-2.80 (m, ÍH), 2.85-3.00 (m, 2H), 3.35-3.65 (m, 8H), 4.43 (d, 2H), 6.21 (s, 1H). The 2,6-dimethyl-4-chloro-pyrimidine (1.0 g) in ethanol (10 ml) is slowly added to a solution of ethyl isopenicotate (1.1 g) and triethylamine (2.0 ml) in ethanol (20 ml). The reaction is stirred at room temperature overnight. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate and water, washed with water (2 x 50 ml), dried and evaporated to give l- (2,6-dimethylpyrimidin-4-yl) - 4- (ethoxycarbonyl) piperidine as an oil (1.71 g); NMR (CDC13): 1-25 (t, 3H), 1.65-1.80 (m.4H), 1.95-2.00 (m, 2H), 2.25 (s, 3H), 2.45 (s, 3H), 2.50-2.60 ( m, 1H), 3.00 (dt, 2H), 4.15 (q, 2H), 4.35 (d, 2H), 6.2 (s, ÍH). 2, 4-Dimethyl-6-hydroxypyrimidine (20 g) is added to phosphorous oxychloride (120 ml) and the mixture is refluxed for 2 hours. The excess phosphorous oxychloride is removed in vacuo, water is added and the product is extracted into dichloromethane (2 x 200 ml), dried (Na 2 SO 4) and the solvent is removed to give 2,6-dimethyl-4-chloropyrimidine as a oil (21 g) which crystallizes slowly at rest; NMR (CDC13): 2.52 (s, 3H), 2.71 (s, 3H), 7.05 (s, ÍH). Example 21 Using a procedure analogous to that described in Example 27 but with 2,6-dimethyl-4-chloropyrimidine as a starting material, 1- (4-chlorophenylsulfonyl) 4- (1- (2,6-dimethylpyrimidin-4) is obtained. -yl) -4-piperidylcarbonyl] homopiperazine as a foam, NMR (DMSSOd: 1.15-1.70 (m, 6H), 2.03 (s, 3H), 2.13 (s, 3H), 2.60-2.82 (m, 3H), 3.05 -3.55 (m, 8H), 4.10-4.30 (m, 2H), 6.32 (s, 1H), 7.45-7.55 (m, 2H), 7.60-7.68 (m, 2H) Example 22 Using a procedure analogous to that described in Example 7 and with chlorine benzene starting materials in place of the bromine benzene starting material and using 2-methyl-4-chloropyrimidine instead of 4-chloropyrimidine is obtained l- (4-chlorophenylsulfonyl) -4- [1 - (2-methylpyrimidin-4-yl) -4-piperidylcarbonyl] homopiperazine as a foam; NMR (DMSOds): 1.35-1.90 (m, 6H), 2.35 (s, 3H), 2.80-3.05 (m, 3H), 3.20-3.75 (m, 8H), 4.30-4.40 (m, 2H), 6.60 (dd, ÍH), 7.65-7.75 (m, 2H), 7.75-7.85 (m, 2H), 8.05 (d, ÍH). It is The intermediate is 1- (4-chlorophenylsulfonyl) -4- (l-tert-butoxycarbonylpiperidin-4-ylcarbonyl) homopiperazine as a foam; NMR (DMS0d6): 1.25-1.85 (m, 6H), 1.40 (s, 9H), 2.65-2.85 (m, 3H), 3.20-3.65 (m, 8H), 3.85-4.9 (m, 2H), 7.60- 7.70 (m, 2H), 7.75-7.85 (m, 2H). Example 23 Using a procedure similar to that described in Example 7 but using 2-methyl-4-chloropyrimidine in place of 4-chloropyrimidine, 1- (4-bromophenylsulfonyl) -4- [1- (2-methylpyrimidin-4- is obtained. il) -4-piperidylcarbonyl] homopiperazine as a foam; NMR (DMSOd6): 1.35-1.85 (m, 6H), 2.35 (s, 3H), 2.75-3.0 (m, 3H), 3.2-3.70 (m, 8H), 4.30-4.45 (m, 2H), 6.60 ( d, 1H), 7.65-7.85 (m, 4H), 8.05 (d, ÍH). Example 24 Using the procedure described in Example 16 with phenylsulfonyl chloride, 1- (phenylsulfonyl) -4- [1- (4-pyrimidinyl) -4-piperidylcarbonyl] homopiperazine is obtained as a gum; NMR (DMSOdg): 1.3-1.8 (m, 6H), 2.75-3.0 (m, 3H), 3.15-3.55 (m, 8H), 4.25-4.40 (m, 2H), 6.75 (dd, ÍH), 7.50- 7.65 (m, 3H), 7.65-7.75 (m, 2H), 8.08 (d, ÍH), 8.40 (s, ÍH). The intermediate 1- (phenylsulfonyl) homopiperazine is isolated as an oil; NMR (DMSOd6): 1.40-1.55 (m, 2H), 2.45-2.60 (m, 4H), 2.85-3.20 (m, 4H), 7.35-7.55 (m, 5H). Example 25 Ethyl acetate saturated with gaseous HCl is added to a solution of 1- (4-chlorophenylsulfonyl) -4- [1- (t-butoxycarbonyl) piperazine-4-ylcarbonyl] piperidine (1.10 g) in ethyl acetate (25 g). ml). The reaction is stirred at room temperature for 2 hours. The solvent is removed by evaporation to give 1- (4-chlorophenylsulfonyl) -4- (4-piperazinylcarbonyl) piperidine hydrochloride. They are heated by refluxing 1- (4-chlorophenylsulfonyl) -4- (piperazin-4-ylcarbonyl) piperidine hydrochloride, 2-methyl-4-chloro-pyrimidine hydrochloride (299 mg) and triethylamine (1.47 ml) in ethanol (12 ml) for 5 hours. The solvent is removed by evaporation. Purification by filtration column chromatography (silica) eluting with 2% methanol / dichloromethane increasing to 10% methanol / dichloromethane gives 1- (4-chlorophenylsulfonyl) -4- [1- (2-methylpyrimidin-4-yl. ) piperazin-4-ylcarbonyl] piperidine as a solid (0.87 g); NMR (CDC13): 1.7-2.0 (m, 5H), 2.5 (m, 5H), 3.5-3.8 (m, 10H), 6.3 (m, HI), 7.5 (m, 2H), 7.7 (m, 2H) , 8.2 (m, ÍH). The 1- (4-chlorophenylsulfonyl) -4- (1- (t-butoxycarbonyl) piperazin-4-ylcarrbonyl) iperidine used as a starting material is prepared as follows.

The 4-chlorophenylsulfonyl chloride (18 g) is added slowly to an ice-bath solution of isonipecotic acid (10 g) and triethylamine (22.65 ml) in dichloromethane (500 ml). After the addition is complete, the reaction is allowed to warm to room temperature and is stirred overnight. The reaction mixture is washed with water (2 x 200 ml), and reduced in vacuo to give the unpurified acid as a red oil. Thionyl chloride (5 ml) is added to the above crude acid and the reaction is refluxed for 2 hours. The reaction is evaporated in vacuo to give the acid chloride without purification. 1- (Tert-butoxycarbonyl) -piperazine (1.44 g) is added to a solution of the crude acid chloride in dichloromethane (25 ml). The reaction is allowed to stand at room temperature overnight. The reaction is then reduced in vacuo. The product is purified by filtration column chromatography (silica) eluting initially with dichloromethane with increased concentrations of ethyl acetate (up to 20%). Trituration with ether and hexane gives a solid (1.15 g); NMR (CDC13): 1.45 (s, 9H), 1.75 (m, 2H), 1.9 (m, 2H), 3.35-3.6 (m, 8H), 2.45 (m, 2H), 3.75 (m, 2H), 7.5 (m, 2H), 7.7 (m, 2H). Example 26 Using a procedure similar to that described in Example 27, 1- (4-bromophenylsulfonyl) -4- [1- (2-methylpyrimidin-4-yl) piperazin-4-ylcarbonyl] piperazine is prepared as a solid t.p.f. 219-220 ° C; NMR (CDC13): 2.5 (s, 3H), 3.05 (m, 4H), 3.3 (m, 4H), 3.4 (m, 4H), 3.65 (m, 4H), 6.3 (m, ÍH), 7.6 (m , 2H), 7.7 (m, 2H), 8.15 (m, 1H). The following intermediates are isolated: 1- (4-bromophenylsulfonyl) -4- [1- (tert-butoxycarbonyl) piperazin-4-ylcarbonyl] piperazine; NMR (CDCl 3): 1.45 (s, 9H), 3.0 (m, 4H), 3.15 (m, 4H), 3. 4 (m, 8H), 7.6 (m, 2H), 7.7 (m, 2H). 1- (4-bromophenylsulfonyl) -4- (4-nitrophenyloxycarbonyl) piperazine; NMR (CDC13): 3.1 (m, 4H), 3.6-3.8 (m, 4H), 7.25 (m, 2H), 7.65 (m, 2H), 7.7 (m, 2H), 8.25 (m, 2H). Example 27 Ethyl acetate saturated with gaseous HCl is added to a suspension of 1- (4-bromophenylsulfonyl) -4- [1- (tert-butoxycarbonyl) piperazin-4-ylcarbonyl] homopiperazine (1.2 g) in ethyl acetate (20 g). ml). After stirring overnight the reaction is evaporated in vacuo to give the amino hydrochloride as a white solid (1.31 g). This material is used directly without purification. Triethylamine (1.88 ml) is added to a suspension of the crude purine amine hydrochloride (1.3 g) in ethanol (20 ml). 4-Chloro-2-methyl-pyrimidine (318 mg) is added and the reaction is refluxed for 3 hours. The reaction is evaporated in vacuo. Purification by suction chromatography (silica, -elution gradient, dichloromethane to 7.8% methanol in dichloromethane) gives 1- (4-bromophenylsulfonyl) -4- [1- (2-methylpyrimidin-4-yl) piperazine-4- ilcarbonyl] homopiperazine as a gum (1.31 g); NMR (CDC13); 2.0 (m, 2H), 2.55 (s, 3H), 3.30 (m, 6H), 3.35-3.55 (m, 6H), 3.7 (m, 4H), 6.4 (s, 1H), 7.65 (s, 4H) , 8.15 (S, ÍH). The starting material is prepared as follows: Triethylamine (11.5 ml) is added to a suspension of 1- (4-bromophenylsulfonyl) -4- (4-nitrophenyloxycarbonyl) homopiperazine (4.0 g) in DMF (50 ml). 1- (Tert-butoxycarbonyl) piperazine (1.54 g) is added and the reaction is heated at 110 ° C for 70 hours. The reaction mixture is evaporated in vacuo. Purification by suction chromatography (silica, elution gradient, hexane to ethyl acetate) gives l- (4-bromophenylsulfonyl) -4- [1- (t-butoxycarbonyl) piperazin-4-ylcarbonyl] homopiperazine (1.28 g) NMR (CDCl 3): 0.45 (s, 9H), 2.0 (m, 2H), 3.1 (m, 4H), 3.3 (m, 2H), 3.45 (m, 10H), 7.65 (s, 2H). 4-Nitrophenylchloroformate (3.31 g) is added to an ice-cooled solution of the amine (5.0 g) and triethylamine (2.4 ml) in dichloromethane (200 ml). After stirring for 10 minutes, the reaction is allowed to warm to room temperature and is stirred for an additional hour. The reaction mixture is evaporated in vacuo. Purification by suction chromatography (silica; gradient of elution hexane to ethyl acetate and finally with methanol: ethyl acetate: dichloromethane [1: 4: 5] gives l- (4-bromophenylsulfonyl) -4- (4-nitrophenyloxycarbonyl) homopiperazine; as a yellow solid (4.29 g), - NMR (CDC13): 2.05 (m, 2H), 3.3-3.5 (m, 4H), 3.6-3.8 (m, 4H), 7.25 (m, 2H), 7.65 (s) , 4H), 8.25 (m, 2H). Example 28 Using a procedure similar to that described in Example 3, the following compounds are prepared.

(CDC13): d (ppm) 1.82 (m, 2H), 1.94 (m, 2H), 2.50 (m, 3H), 3.51-3.79 (m, 10H), 6.50 (d, 1H), 7.24 (m, 2H) ), 7.79 (m, 2H), 8.25 (d, 1H), 8.62 (s, ÍH). H Phenyl 177-179 ^ N-NMR (200 / 250MHz) (CDC13): d (ppm) 1.75-2.20 (m, 4H), 2.49 (m, 3H), 3.49-3.78 (m, 10H), 6.50 (d , HH), 7.50-7.61 (m, 3H), 7.80 (m, 2H), 8.25 (d, HH), 8.60 (s, HH). 2,6-dimethyl 4-Br-f-enyl 173-174 1.75 (m, 4H), 2.3 (s, 3H), 2.50 (s, 3H), 2.7 (m, ÍH), 2.9 (m, 2H), 3.1 (m , 4H), 3.7 (m, 4H), 4.4 (m, 2H), 6.2 (s, ÍH), 7.6-7.8 (dd, 4H). H 4-CF 3 phenyl 201-202 1.75 (m, 4H), 2.7 (m, 1H), 2.9 (m, 2H), 3.1 (m, 4H), 3.7 (m, 4H), Example 29 Stir 1- (tert-butoxycarbonyl) -4- (1- (2-methylpyrimidin-4-yl) piperazin-4-ylcarbonyl) piperazine (700 mg) in dichloromethane (20 ml) and triethylamine (1.34 ml) and cooled in a water bath. ice. The 4-chlorobenzenesulfonyl chloride (0.56 g) is added and the reaction is allowed to warm to room temperature and then stirred overnight. The mixture is evaporated and the residue is purified by chromatography on silica gel using a gradient of dichloromethane to 8% methanol in dichloromethane as eluent to give a foam. This is triturated with diethyl ether to give 1- (4-chlorophenylsulfonyl) -4- [1- (2-methylpyrimidin-4-yl) piperazin-4-ylcarbonyl] piperazine as a colorless solid 1.05 g; p.f. 183-184 ° C; NMR (CDC13): 8.15 (m, ÍH), 7.7 (m, 2H), 7.55 (m, 2H), 6. 3 (m, ÍH), 3.65 (m, 4H), 3.45 (m, 4H), 3.35 (m, 4H), 3.05 (m, 4H), 2.5 (s, 3H). The starting material is prepared as follows: The dichloropyrimidine (24.79 g) and 1- (tert-butoxycarbonyl) piperazine (27.41 g) in ethanol (500 ml) and triethylamine (41 ml) are stirred overnight. The solvent is evaporated and the residue is dissolved in dichloromethane and washed with water. The organic phase is dried (Ns2S02), and evaporated to give 2-methyl-4-chloro-6- [1- (tert-butoxycarbonyl] piperazin-4-yl) pyrimidine as a solid (41.5 g); NMR (CDC1): 6.35 (s, ÍH), 3.65 (m, 4H), 3.65 (m, 4H), 3.5 (m, 4H), 2.5 (s, 3H), 1.45 (s, 9H). A mixture of 2-methyl-4-chloro-6- [1- (tert-butoxycarbonyl) piperazin-4-yl] pyrimidine (41.40 g), ethanol (500 ml) and 2 g of the catalyst (palladium on 30% carbon) is stirred. ) under hydrogen for 72 hours. The mixture is filtered through diatomaceous earth and the filtrate is evaporated to give 2-methyl-4- (tert-butoxycarbonyl) pyrimidine as a solid (36.13 g); NMR (CDCl 3): 8.2 (m, 1H), 6.85 (m, ÍH), 3.9 (bm, 4H), 3.6 (m, 4H), 2.75 (s, 3H), 1.5 (s, 9H). 2-Methyl-4- (1-tert-butoxycarbonyl) pyrimidine (36.16 g) is suspended in ethyl acetate (200 ml) and then saturated solution (200 ml) of acid chloride in ethyl acetate is added. The mixture is stirred overnight and then evaporated to give 2-methyl-4- (1-piperazinyl) pyrimidine hydrochloride as a white powder (44.80 g), - NMR (CDCl 3): 8.35 (d, 1H), 7.15 (d, ÍH), 2.55 (s, 3H), 3.8-4.4 (bm, 8H). The hydrochloride of 2-methyl-4- (1-piperazinyl) pyrimidine (18.80 g) and 1- (tert-butoxycarbonyl) -4- (4-nitrophenyloxycarbonyl) piperazine (25 g) in dry DMF (250 ml) is stirred. and triethylamine (40 ml) under argon. The reaction mixture is stirred at 110 ° C for 5 hours and then allowed to cool overnight. The solid is collected by filtration, washed with DMF and isohexane. Purify the solid by chromatography on silica gel using a gradient of dichloromethane to 5% methanol in dichloromethane as eluent to give 1- (tert-butoxycarbonyl) -4- (1- (2-methylpyrimidin-4-yl) piperazine- 4-ylcarbonyl) piperazine as a pale solid (19.92 g); NMR (CDC13): 8.15 (m, HH), 6.35 (m, HH), 3.7 (m, 4H), 3.45 (m, 4H), 3.35 (m, 4H), 3.3 (m, 4H), 2.5 (s) , 3H), 1.45 (s, 9H). The 1- (tert-butoxycarbonyl-4- (1- (2-methylpyrimidin-4-yl) piperazin-4-ylcarbonyl) piperazine (19.9 g) is suspended in ethyl acetate (2100 ml) and then a saturated solution is added. (100 ml) of acid chloride in ethyl acetate and stir the mixture overnight.The reaction mixture is evaporated to give a solid which is purified by chromatography using a gradient of dichloromethane to 10% methanol in dichloromethane to give a product which is partitioned between dichloromethane and water.The organic layer is separated, dried (Na2SO4) and evaporated to give 1- (tert-butoxycarbonyl) -4- (1- (2-methylpyrimidin-4-yl) iperazine. -4-alkylcarbonyl) piperazine; p.f. 212-213 ° C; NMR (CDCI3): 8.15 (m, HH), 6.3 (m, HH), 3.65 (m, 4H), 3.35 (m, 4H), 3.3 (m, 4H), 2.9 (m, 4H), 2.5 (s) , 3H). Example 30 The mixture of 4-nitrophenyl chloroformate (32.35 g), 1- (tert-butoxycarbonyl) iperazine (28.48 g) and triethylamine (23.4 ml) in dichloromethane (1000 ml) was stirred overnight. The solvent is removed by evaporation to give a yellow solid which is purified by filtration chromatography using hexane followed by ethyl acetate and then a gradient of 5% to 10% methanol in dichloromethane as eluent to give 1- (t-butoxycarbonyl ) -4- (4-nitrophenyloxycarbonyl) piperazine as a solid (56.6 g), - NMR (CDC13): 8.25 (, 2H), 7.3 (, 2H), 3.5-3.7 (m, 8H) and 1.5 (s, 9H ). A mixture of 1- (t-butoxycarbonyl) -4- (4-nitrophenyloxycarbonyl) piperazine (25 g) and 1- (4-bromophenylsulfonyl) piperazine (16.87 g) in dry DMF (300 ml) is stirred overnight under a argon atmosphere. The solvent is removed by evaporation. The residue is dissolved in dichloromethane, washed with water and aqueous sodium hydrogen carbonate solution. The organic phase is separated and evaporated to give a residue which is purified by chromatography using a gradient of hexane containing increased amounts of ethyl acetate as eluent to give 1- (4-bromophenylsulfonyl) -4- [1- (tert. -butoxycarbonyl) piperazin-4-ylcarbonyl] piperazine as a solid (18.02 g); NMR (CDC13): 7.7 (m, 2H), 7.6 (m, 2H), 3.4 (m, 8H), 3.2 (m, 4H), 3.05 (m, 4H), 1.45 (s, 9H).

A solution (200 ml) of ethyl acetate saturated with acid chloride is added to a mixture of 1- (4-bromophenylsulfonyl) -4- [1- (t-butoxycarbonyl) piperazin-4-ylcarbonyl] piperazine and ethyl acetate ( 200 ml). The mixture is stirred overnight. The solvent is removed by evaporation to give 1- (4-bromophenylsulfonyl) -4- (1-piperazinylcarbonyl) piperazine hydrochloride (16.30 g). 4-Methyl-6-chloropyrimidine (0.51 g) is added to a stirred mixture of 1- (4-bromo-phenylsulfonyl) -4- (1-piperazinylcarbonyl) piperazine hydrochloride (1.50 g) and ethanol (35 ml). Triethylamine (2.2 ml) is added and the mixture is heated to reflux for 6 hours. The solvent is removed by evaporation and the residue is purified by chromatography on silica gel using a gradient of 0% to 10% methanol in dichloromethane as eluent to give a foam. This is crystallized from methyl tert-butyl ether to give 1- (4-bromophenylsulfonyl) -4- [1- (-methylpyrimidin-6-yl) piperazin-4-ylcarbonyl] iperazine as a solid (0.77 g); p.f. 215-216 ° C; NMR (CDC13): 8.5 (s, ÍH), 7.7 (m, 2H), 7.6 (m, 2H), 6.35 (s, 1H), 3.6 (m, 4H), 3.4 (m, 4H), 3.3 (m , 4H), 3.05 (m, 4H), 2.33 (s, 3H). Example 31 Using a method similar to that described in Example 3, the following compounds are prepared: Example 32 Using a procedure analogous to that described in plo 3, the following compounds are prepared.

Example 33 4- [1- (2-Methylpyrimidin-4-yl) -piperazin-4-ylcarbonyl] iperazine (0.90 g, 3.10 mmol) is stirred in dichloromethane (25 ml). 4-Cyanobenzoyl chloride (570 mg, 3.41 mmol) is added followed by triethylamine (0.52 ml, 3.72 mmol). The reaction is stirred overnight at room temperature and then reduced in vacuo to yield an 1- (4-cyanobenzoyl) -4- [1- (2-methylpyrimidin-4-yl) -piperazin-4-ylcarbonyl] piperazine as a colorless solid, 1.23 g (95%) mp 201-202 ° C. ^ NMR (CDC13) 8.15 (d, ÍH), 7.75 (m, 2H), 7.50 (m, 2H), 6.3 (d, 2H), 3.2-3.9 (6M, 16H), 2.5 (s, 3H). EXAMPLE 34 1- (4-bromobenzyl) -4- [1- (2-methylpyrimidin-4-yl) -piperazin-4-ylcarbonyl] iperazine using 4-bromobenzyl bromide is produced in a method analogous to Example 33 rubber in 85% yield. ^? NMR (CDCI3) 8.15 (d, ÍH), 7.45 (m, 2H), 7.2 (m, 2H), 6.3 (d, 1H), 3.65 (m, 4H), 3.4 (s, 2H), 3.3 ( m, 8H), 2.5 (s, 3H), 2.45 (m, 4H). Example 35 Using a procedure to that described in Example 27, 1- (4-bromo-phenylsulfonyl) -4- [1- (6-methylpyrimidin-4-yl) piperazin-4-ylcarbonyl] piperazine is prepared as a pale yellow solid. The chloride salt of 1- (4-bromophenylsulfonyl) -4- (piperazin-4-ylcarbonyl) piperazine (1.50 g) in ethanol (35 ml) is suspended and 4-methyl-6-chloropyrimidine (0.51 g) is added. by triethylamine (2.2 ml). The reaction is then refluxed for 6 hours and reduced in vacuo. The residue (silica) DCM is transferred to 10% methanol / dichloromethane yielding the above compound 0.77 g, 57% yield, m.p. 215-216 ° C. XHNMR (CDC13) 8.5 (s, ÍH), 7.7 (m, 2H), 7.6 (m, 2H), 6.35 (s, ÍH), 3.6 (m, 4H), 3.4 (m, 4H), 3.3 (M, 4H), 3.05 (m, 4H), 2.35 (s, 3H). Example 36 In a similar process as that described in Example 39 using 1- (2-ethylpyrimidin-4-yl) -4-methylpiperidine-4-carboxylic acid and 1- (4-bromophenylsulfonyl) piperazine the following is produced 1- ( 4-bromophenylsulfonyl) -4- [1- (2-ethylpyrimidin-4-yl) -4-methylpiperidin-4-ylcarbonyl] piperazine. NMR: 1.28 (s, 3H), 1.3 (t, 3H), 1.5-1.6 (m, 2H), 2.18 (d, 2H), 2.74 (qt, 2H), 3.02 (br s, 4H), 3.38 (t , 2H), 3.73 (brs, 4H), 3.87 (d, 2H), 6.28 (d, ÍH), 7.68 (dd, 4H), 8.13 (d, ÍH). The starting materials are prepared as follows: 1- (2-Ethylpyrimidin-4-yl) -4-methyl-piperidine-4-carboxylic acid is prepared in 4-methyl-4-ethoxycarbonyl-piperidine (as a ATF) 3 mmoles in 7 ml of ethanol and 1 ml of Et3N treated with a solution of 0.531 g of 2-ethyl-4,6-dichloropyrimidine in 4 ml of ethanol. After 20 hours at room temperature. The ethanol is removed and the residue is fractionated between water and alcohol, wash with sodium hydrogen carbonate solution and brine. Evaporate to give a rubber (88.3%) NMR: 1.23 (s, 3H), 1.27 (dt, 6H), 1.37-1.5 (m, 2H), 2.19 (d, 2H), 2.73 (qt, 2H), 3.12 -3.23 (m, 2H), 4.06 (d, 2H), 4.2 (qt, 2H), 6.32 (s, ÍH). 4-Methyl-4-ethoxycarbonylpepperidine is prepared by alkylation of 1- (benzyloxycarbonyl) -4-ethoxycarbonyl-piperidine (H. Med. Chem 1994, 37 p. 368) 2.6 g (10 mmol) 1. In 25 ml of dry THF at -70 ° C under argon, treat with 7 ml of lithium diisopropylamide solution (2M). After stirring for 1.5 hours, a solution of 1.5 equivalents of alkyl halide in 5 ml of THF is added dropwise. The reaction is allowed to warm to room temperature for several hours, diluted with ethyl acetate and water. The aqueous layer is extracted twice with ethyl acetate, the organic solution is washed with brine and dried. It evaporates to give the liquid product. NMR: 0.82 (t, 3H), 1.27 (t, 3H), 1.45 (s, 9H), 1.56 (qt, 2H), 2.1 (d, 2H), 2.8-2.94 (m, 2H), 3.8-3.95 (d, 2H), 4.18 (qt, 2H). Example 37 1- (2-Methylpyrimidin-4-yl) -4-ethyl-piperidine-4-carboxylic acid 2.03 g (8.16 mmol) is treated with 70 ml of thionyl chloride, stirred for 1.5 hours at 25-35 ° C. The thionyl chloride is evaporated and the residue is suspended in 50 ml of dichloromethane and added to a solution of 2.49 g of 4-bromophenylsulfonylpiperazine in 80 ml of dichloromethane containing 10 ml of triethylamine and allowed to stir overnight. It is washed with water and brine, dried, evaporated to an oil. It is chromatographed (Bond elut, dichloromethane and then 1% methanol / dichloromethane / 1% ammonium hydroxide), the resulting gum is dissolved in ethyl acetate, ether is added to give 4- (bromophenylsulfonyl) -1- [ 1- (2-methylpyrimidin-4-yl) -4-ethyl-4-piperidylcarbonyl] piperazine as a colorless solid 0.975 g, m.p. 170.5 ° C. NMR: 0.8 (t, 3H), 1.43-1.57 (m, 2H), 1.65 (qt, 2H), 2.28 (d, 2H), 2.5 (s, 3H), 3.03 (t, 4H), 3.2-3.3 ( m, 2H), 3.76 (t, 4H), 3.94 (d, 2H), 6.28 (d, ÍH), 7.65 (dd, 4H), 8.08 (d, ÍH). EXAMPLE 38 The 1- (2-methylpyrimidin-4-yl) -4-propen-2-yl-piperidine-4-carboxylic acid (1.98 g) is stirred for 18 hours with 70 ml of thionyl chloride at room temperature to form an The residue is suspended in 50 ml of dichloromethane and added to a solution of 1.9 g of 4-bromo-phenylsulfonylpiperazine in 60 ml of dichloromethane containing 10 ml of triethylamine and stirred overnight. The dichloromethane is washed with water and brine, dried and evaporated to a gum which is chromatographed (Bondelut, dichloromethane then 1% methanol / dichloromethane / 1% ammonium hydroxide) and the product is recrystallized from ethyl acetate / ether to give 1- (4-bromophenylsulfonyl) -4- [1- (2-methylpyrimidin-4-yl) -4-propen-2-yl-piiperidin-4-ylcarbonyl] piperazine 1.12 g, white solid pf 217 ° C. NMR: 1.52-1.64 (m, 2H), 2.24 (d, 2H), 2.36 (d, 2H), 2.47 (s, 3H), 3.03 (t, 4H), 3.2-3.32 (m, 2H), 3.7 ( t, 4H), 3.92 (d, 2H), 4.98 (d, ÍH), 5.04 (d, ÍH), 5.52-5.66 (m, ÍH), 6.23 (d, ÍH), 7.65 (dd, 4H), 8.08 (d, ÍH). The starting materials are prepared in an analogous procedure as described in Example 47. 1- (2-Methylpyrimidin-4-yl) -4-propen-2-yl-piperidine-4-carboxylic acid is isolated. NMR: 1.27 (t, 3H), 1.3-1.4 (m, 2H), 1.45 (s, 9H), 2.08 (d, 2H), 2.27 (d, 2H), 2.9 (t, 2H), 3.8-3.95 ( d, 2H), 4.18 (qt, 2H), 5.0-5.1 (m, 2H), 5.6-5.76 (m, ÍH). Example 39 1- (4-Bromophenylsulfonyl) -4-methyl-piperidine-4-carboxylic acid (12.73 g) is added to 120 ml of thionyl chloride and stirred at 30-35 ° C for 3 hours. The thionyl chloride is removed and the residue is dissolved in 150 ml of dichloromethane and added dropwise over 30 minutes to a solution of 8.9 g of 1- (2-methylpyrimidin-4-yl) iperazine in 170 ml of dichloromethane which contains 20 ml of triethylamine. The mixture is stirred overnight, washed with water and brine, dried and evaporated to give 18.1 g of a beige solid. Recrystallization from ethyl acetate gives 1- (bromophenylsulfonyl) -4- [1- (2-methylpyrimidin-4-yl) piperazin-4-ylcarbonyl] -4-methyl-piperidine 12.6 g m.p. 213.6 ° C. NMR: 1.28 (s, 3H), 1.57-1.7 (m, 2H), 2.28 (d, 2H), 2.52 (s, 3H), 2.72 (t, 2H), 3.47 (d, 2H), 3.57-3.70 ( m, 8H), 6.3 (d, 1H), 7.63 (dd, 4H), 8.18 (d, ÍH). They are getting ready starting materials as follows: 1- (4-Bromophenylsulfonyl) -4-methyl-4-ethoxycarbonylpiperidine-1- (benzyloxycarbonyl) -4-methyl-4-ethoxycarbonyl-piperidine (12 g) in 80 ml dichloromethane with 80 ml of ATF. After 30 minutes the mixture is evaporated to dryness and dissolved in 250 ml of THF and 26.5 l of triethylamine. A solution of 11.3 g of 4-bromo-phenylsulfonyl chloride in 90 ml of THF is added dropwise and the mixture is stirred. The THF is evaporated and the residue is treated with sodium hydrogen carbonate solution and extracted with dichloromethane. Wash the mixture with brine, dry, to produce a product in quantitative yield. NMR: 1.15 (t, 3H), 1.16 (s, 3H), 1.47-1.6 (m, 2H), 2.17 (d, 2H), 2.45 (dt, 2H), 3.5 (d, 2H), 4.06 (qt, 2H), 7.63 (dd, 4H). 1- (4-Bromophenylsulfonyl) -4-methylperipidine-4-carboxylic acid 17.3 g of 1- (4-bromo-phenylsulfonyl) -4-methyl-4-ethoxycarbonylpiperidine in 200 ml of THF is refluxed for 2 hours with a solution of 11.3 g of lithium hydroxide in 70 ml of water / 70 ml of ethanol. The solvent is evaporated, water is added and the aqueous solution is extracted with ether. The aqueous phase is made acidic by adding concentrated HCl. The resulting solid is filtered, washed and dried to give 12.73 g of the product (79.3% yield). NMR: 1.21 (s, 3H), 1.5-1.63 (m, 2H), 2.16 (d, 2H), 2. 6 (t, 2H), 3.5 (d, 2H), 7.64 (dd, 4H). EXAMPLE 40 1- (4-Bromophenylsulfonyl) -4- (l-butyloxycarbonyl-4-methyl-4-piperidylcarbonyl) piperazine 0.616 g in 5 ml of dichloromethane is treated with 6 ml of trifluoroacetic acid for 1.5 hours and the mixture is evaporated to dryness. The residue is dissolved in 10 ml of ethanol and 3 ml of triethylamine and a solution of 2-methyl-4-chloropyrimidine, 180 mg (1.2 equivalents), is added in 3 ml of ethanol and heated to reflux for 2 hours. The residue is dissolved in ethyl acetate, washed with sodium bicarbonate solution followed by brine and then evaporated. The product is chromatographed on Bondelute (dichloromethane then 1% methanol / dichloromethane / 1 & amp; amine hydroxide) to give l- (4-bromophenylsulfonyl) -4- [1- (2-methyl-pyrimidin-4-) il) -4-methyl-4- piperidylcarbonyl] piperazine 360 mg solid. NMR: 1.28 (s, 3H), 1.48-1.6 (m, 2H), 2.19 (d, 2H), 2.47 (s, 3H), 3.03 (t, 4H), 3.3-3.42 (m, 2H), 3.75 ( t, 4H), 3.84 (d, 2H), 6.27 (d, ÍH), 7.66 (dd, 4H), 8.05 (d, ÍH). The starting materials are prepared as follows: The l-benzyloxycarbonyl-4-methyl-piperidine-4-carboxylic acid is treated in 6 ml of THF, under argon, with a solution of 0.82 g, 1-carbonyldiimidazole in 15 ml. of THF and stirred for one hour. 1.53 g of 4-bromo-phenylsulfonylpiperazine in 10 ml of THF / 5 ml of added dichloromethane and stir overnight. The solvent is removed and the residue is partitioned between ethyl acetate and water, washed with brine, dried and evaporated. Take chromatography (Bondelute, dichloromethane then 2% methanol / dichloromethane / 1% ammonium hydroxide) to give 0.626 g of solid. 1- (4-bromophenylsulfonyl) -4- (1-t-butyloxycarbonyl-4-methyl-4-piperidylcarbonyl) piperazine. NMR: 1.24 (s, 3H), 1.43 (s, 9H), 2.04 (d, 2H), 2.5 (t, 2H), 3.0 (t, 4H), 3.1-3.26 (m, 2H), 3.54 (d, 2H), 3.73 (t, 4H), 7.65 (dd, 4H). Example 41 A solution of 1- (4-trifluoromethylphenylsulfonyl) -4- [1- (6-chloropyrimidin-4-yl) -piperazin-4-ylcarbonyl] piperidine (20.0 g) in 33% methylamine in ethanol is heated (400 ml) at 110 ° C in a Carius tube for 8 hours. The mixture is evaporated to dryness and then dissolved in dichloromethane and washed with aqueous ammonium chloride solution, dried (Na 2 SO 4) and evaporated. Recrystallization from methanol / ethyl acetate gives, as a solid 1- (4-trifluoromethylphenylsulfonyl) -4- [1- (6-methylaminopyrimidin-4-yl) -piperazin-4-ylcarbonyl] piperidine (13.24 g), pf 237-238 ° C. Found C, 51.50; H, 5.10 and N, 16.40%. C22H27F3N6? 3S requires C, 51.55; H, 5.31 and N, 16.40%. NMR (CDC13): 1.80 (m, 2H), 1.95 (m, 2H), 2.55 (m, 3H), 2.90 (d, 3H), 3.50 (m, 4H), 3.65 (m, 4H), 3.80 (m , 2H), 5.40 (s, ÍH), 7.80 (d, 2H), 7.90 (d, 2H), and 8.15 (s, H); m / z 513 (M + l). The starting material is prepared as follows: A solution of 4,6-dichloropyrimidine (10.05 g), tert-butoxycarbonylpiperazine (11.94 g) and triethylamine (28.20 ml) in ethanol (150 ml) is heated to reflux for 18 hours . The solvent is evaporated and the residue is dissolved in ethyl acetate and washed with water, saturated aqueous ammonium chloride solution, dried (Na 2 SO 4) and evaporated. Recrystallization from ethyl acetate / hexane gives, as a solid, 1- (tert-butoxycarbonyl) -4- (6-chloro-pyrimidin-4-y-piperazine (16.80 g). NMR (CDCl 3): 1.40 (s, 9H), 3.50 (m, 4H), 3.60 (m, 4H), 6.50 (s, ÍH), and 8.40 (s, lH) m / z 298 (M + l). Ethyl acetate saturated with gaseous HCl is added to a solution of 1- (tert-butoxycarbonyl) -4- (6-chloro-pyrimidin-4-yl) piperazine (16.80 g) in ethyl acetate (50 ml) and stirred the resulting suspension at room temperature for 3 hours. The solvent is evaporated to give (6-chloro-pyrimidin-4-yl) piperazine hydrochloride (13.25 g) as a cream-colored solid. A solution of the carbonyldiimidazole (8.32 g) in tetrahydrofuran (70 ml) is added to a solution of N-tert-butoxycarbonyl isopenicotic acid (12.93 g) in tetrahydrofuran (250 ml) at 0 ° C. The resulting solution is stirred at room temperature for 2 hours. The solution is cooled to 0 ° C and a solution of (6-chloro-pyrimidin-4-yl) piperazine hydrochloride (13.25 g) and triethylamine (23.57 ml) in dichloromethane (200 ml) is added in drops over 20 minutes. . The suspension obtained is stirred at room temperature for 18 hours. The mixture is diluted with dichloromethane and washed with water, 2 M aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, dried (Na 2 SO 4) and evaporated to give 1- (tert-butoxycarbonyl) -4- [4 - (6-chloropyrimidin-4-yl) piperazin-1-ylcarbonyl] piperidine (17.45 g) as a cream colored solid. NMR (CDC13): 1.40 (s, 9H), 1.70 (m, 4H), 2.60 (m, ÍH), 2.80 (m, 2H), 3.65 (m, 8H), 4.15 (m, 2H), 6.50 (s, ÍH), and 8.40 (s, ÍH); m / z 410 (N + l). Ethyl acetate saturated with gaseous HCl is added to a solution of 1- (tert-butoxycarbonyl) -4- [4- (6-chloro-pyrimidin-4-yl) iperazin-1-ylcarbonyl] piperidine (17.45 g) in acetate of ethyl (75 ml) and the resulting suspension is stirred at room temperature for 3 hours. The solvent is evaporated to give 4- [4- (6-chloro-pyrimidin-4-yl) piperazin-1-ylcarbonyl] hydrochloride (14.72 g) as a cream colored solid. NMR (d6-DMS0): 1.70 (m, 4H), 2.90 (m, 3H), 3.20 (m, 2H), 3.40-3.70 (m, 8H, partially obscured by the HOD peak) 7.00 (s, ÍH), 8.40 (s, 1H); m / z 310 (M + l). A solution of 4-trifluoromethylbenzenesulfonyl chloride (10.64 g) in dichloromethane (20 ml) is added dropwise over 15 minutes to a mixture of 4- (4- (6-chloro-pyrimidin-4-yl) piperazin-1-ylcarbonyl. ] hydrochloride (14.72 g) and triethylamine (29.72 ml) in dichloromethane (200 ml) at 0 ° C. The solution is stirred at room temperature for 18 hours, the solution is diluted with dichloromethane and washed with water, dried (Na 2 SO 4). ) and evaporated The residue was purified by chromatography eluting with 3% methanol in dichloromethane to give 1- (4-trifluoromethylphenylsulfonyl) -4- [1- (6-chloro-4-pyrimidyl) -piperazin-4-ylcarbonyl] piperidine (20.05 g) as a solid, NMR (CDC13): 1-80 (m, 2H), 1.95 (m, 2H), 2.55 (m, 3H), 3.50-3.80 (m, 10H), 6.50 (s, ÍH), 7.80 (d, 2H), 7.90 (d, 2H), and 8.40 (s, ÍH); m / z 518 (M + 1). Example 42 A solution of phenylsulfonyl chloride (6.71 g) in dichloromethane (20 ml) is added dropwise over 15 minutes to a mixture of 1- (6-methyl-pyrimidin-4-yl) -4- (4-hydrochloride. -piperidylcarbonyl) piperazine (11.79 g) and triethylamine (25.20 ml) in dichloromethane (100 ml) at 0 ° C. The solution is stirred at room temperature for 18 hours. The solution is diluted with dichloromethane and washed with water, dried (Na 2 SO 4) and evaporated. The residue is purified by chromatography eluting with 4% methanol in dichloromethane. Recrystallization from ethyl acetate / hexane gives 1-phenylsulfonyl-4- [1- (6-methyl-pyrimidin-4-yl) -4-piperidylcarbonyl] piperazine (9.40 g) as a solid. Found C, 58.60; H, 6.40 and N, 16.10%. C 21 H 27 5 O 3 S requires C, 58.72; H, 6.34 and N, 16.30%. NMR (CDCl 3): 1.70 (m, 4H), 2.35 (s, 3H), 2.70 (m, ÍH), 3.00 (m, 6H), 3.65 (m, 4H), 4.40 (m, 2H), 6.35 (s) , ÍH), 7.60 (m, 3H), 7.80 (d, 2H) and 8.50 (s, ÍH); m / z 430 (M + l). The starting material is prepared as follows: To a solution of N-benzyloxycarbonyl isopenipecotic acid (123.64 g) in tetrahydrofuran (300 ml) at 0 ° C is added a solution of carbonyldiimidazole (68.80 g) in tetrahydrofuran (500 μl) and dichloromethane (300 ml). The resulting solution is stirred at room temperature for 2 hours. This solution is cooled to 0 ° C and a solution of 1- (tert-butoxycarbonyl) piperazine (87.02 g) in tetrahydrofuran (200 ml) is added dropwise over 20 minutes. The suspension obtained is stirred at room temperature for 48 hours. The solvent is evaporated. The residue is dissolved in diethyl ether / dichloromethane (1500 ml) and washed with water, 2M aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, dried (Na 2 SO 4) and evaporated to give 1- (tert-butoxycarbonyl) - 4- [1- (benzyloxycarbonyl) -4-piperidylcarbonyl] iperazine (180.00 g) as a solid. NMR (CDC13): 1.45 (s, 9H), 1.75 (m, 4H), 2.60 (m, ÍH), 2.85 (m, 2H), 3.40 (m, 6H), 3.60 (m, 2H), 4.20 (m , 2H), 5.10 (s, 2H), and 7.35 (m, 5H); m / z 432 (M + l). A solution of 1- (tert-butoxycarbonyl) -4- [l-benzyloxycarbonyl-4-piperidylcarbonyl] piperazine (41.31 g) in ethanol (1200 ml) is hydrogenated in palladium on 10% carbon for 18 hours. Filter the reaction mixture through celite and evaporate the solvent to give 1- (tert-butoxycarbonyl) -4- (4-piperidylcarbonyl) piperazine (18.95 g) as a solid. NMR (CDCl 3): 1.45 (s, 9H), 1.70 (m, 4H), 2.60 (m, 2H), 2.80 (m, ÍH), 3.50 (m, 10H); m / z 298. A solution of 6-methyl-2,4-dichloropyrimidine (10.26 g), 1- (tert-butoxycarbonyl) -4- (4-piperidylcarbonyl) (18.71 g) and triethylamine (26.30 ml) in ethanol (300 ml) refluxing for 8 hours. The solvent is evaporated and the residue is dissolved in ethyl acetate and washed with water, dried (Na 2 SO 4) and evaporated. The residue is purified by chromatography eluting ethyl acetate to give, as a solid 1- (tert-butoxycarbonyl) -4- [1,2-chloro-6-methylpyrimidin-4-yl) -4-piperidylcarbonyl] piperazine (15.37 g ). NMR (CDC13): 1-45 (s, 9H), 1.80 (m, 4H), 2.35 (s, 3H), 2.80 (m, ÍH), 3.50 (m, 10H), 4.40 (m, 2H) and 6.25 (s, ÍH) m / z 424 (M + l). A solution of 1- (tert-butoxycarbonyl) -4- [1- (2-chloro-6-methyl-pyrimidin-4-yl) -4-piperidylcarbonyl] piperazine (15.37 g) in ethanol (350 ml) is hydrogenated in palladium on carbon at 10% for 18 hours. Filter the reaction mixture through celite and evaporate the solvent to give, as a solid, 1- (tert-butoxycarbonyl) -4- [1- (6-methylpyrimidin-4-yl) -4-piperidylcarbonyl] piperazine (14.07 g). NMR (CDCI3): 1.45 (s, 9H), 1.90 (m, 4H), 2.60 (s, 3H), 2.95 (m, ÍH), 3.50 (m, 12H), 6.50 (s, ÍH) and 8.50 (s) , ÍH); m / z 390 (M + l). Ethyl acetate saturated with gaseous HCl is added to a solution of 1- (tert-butoxycarbonyl) -4- [1- (6-methylpyrimidin-4-yl) -4-piperidylcarbonyl] piperazine (14.07 g) in ethyl acetate ( 50 ml) and the resulting suspension is stirred at room temperature for 3 hours. The solvent is evaporated to give 4- [1- (6-methylpyrimidin-4-i-L) -4-piperidylcarbonyl] piperazine hydrochloride (11.79 g) as a solid. NMR (d6-DMSO): 1.50 (m, 2H), 1.80 (m, 2H), 2.40 (s, 3H), 3.05 (m, 8H), 3.30 (m, ÍH), 3.65 (m, 4H), 3.80 (m, 4H), 7.15 (s, ÍH) and 8.70 (s, ÍH) m / z 290 (M + l). Example 43 A solution of 1- (4-trifluoromethylphenylsulfonyl) -4- [1- (6-chloro-pyrimidin-4-yl) piperazin-4-ylcarbonyl] iperazine (26.0 g) in 33% methylamine in ethanol is heated ( 400 ml) at 110 ° C in a Carius tube for 8 hours. The mixture is evaporated to dryness and the residue is recrystallized from methane to give, as a solid 1- (4-trifluoromethylphenylsulfonyl) -4- [1- (6-methylamino-pyrimidin-4-yl) piperazin-4-ylcarbonyl ] piperazine (13.67 g), mp 230-231 ° C. Found C, 49.10; H, 4.90 and N, 19.00%. NMR (CDC13): 2.85 (d, 3H), 3.10 (m, 4H), 3.30 (m, 4H), 3.40 (m, 4H), 3.60 (m, 4H), 4.75 (m, 1H), 5.40 (s) , ÍH), 7.80 (d, 2H), 7.90 (d, 2H), and 8.15 (s, 1H); m / z 514 (M + l). The starting material is prepared as follows: To a solution of tert-butoxycarbonylpiperazine (37.20 g) and triethylamine (39.00 ml) in dichloromethane (750 ml) is added at 3 ° C a solution of 4-nitrophenylchloroformate (42.30 g) in dichloromethane (200 ml) in drops for 1 hour and the resulting yellow solution is stirred at room temperature for 3 hours. The solution is washed with aqueous citric acid solution, IM, water, dried (Na 2 SO 4) and evaporated. Recrystallization from ethyl acetate / hexane gives, as a colorless solid 1- (tert-butoxycarbonyl) -4- (4-nitrophenoxy) carbonylpiperazine (60.50 g). NMR (CDC13): 1.45 (s, 9H), 3.60 (m, 8H), 7.25 (d, 2H) and 8.20 (d, 2H). A solution of 1- (tert-butoxycarbonyl) -4- (4-nitrophenoxy) carbonylpiperazine (42.05 g), piperazine (61.82 g) in tetrahydrofuran (200 ml) is heated to reflux for 18 hours. The solvent is evaporated and dichloromethane is added to the residue. The mixture is filtered and the filtrate is washed with saturated aqueous sodium carbonate solution, water, dried (Na2SO4) and evaporated to give, as a pale yellow solid 1- [1- (tert-butoxycarbonyl) -piperazine-4 - ilcarbonyl] piperazine (33.75 g). NMR (CDCl 3): 1.45 (s, 9H), 2.85 (m, 4H), 3.20 (m, 8H), and 3.40 (m, 4H); m / z 299 (M + l). A solution of 4,6-dichloropyrimidine (8.60 g), 1- [1- (tert-butoxycarbonyl) -piperazin-4-ylcarbonyl] piperazine 15.64 g) and triethylamine (21.95 mJ-) in ethanol (300 ml) is stirred a room temperature for 30 minutes. The solvent is evaporated and the residue is dissolved in dichloromethane and washed with water, saturated aqueous sodium chloride solution, dried (NA2SO4) and evaporated to give, as a pale yellow solid 1- [1- (tert-butoxycarbonyl ) -piperazin-4-ylcarbonyl] -4- (6-chloro-pyrimidin-4-yl) iperazine (21.20 g). NMR (CDCI3): 1.45 (s, 9H), 3.25 (m, 4H), 3.40 (m, 4H), 3.45 (m, 4H), 3.70 (m, 4H), 6.50 (s, ÍH) and 8.40 (s) , ÍH); m / z 411 (M + l).

Ethyl acetate saturated with gaseous HCl is added to a solution of 1- [1- (tert-butoxycarbonyl) -piperazin-4-ylcarbonyl] -4- (6-chloro-pyrimidin-4-yl) piperazine (21.20 g) in ethyl acetate (75 ml) and the resulting suspension is stirred at room temperature for 3 hours. The solvent is evaporated to give 4- [1- (6-chloro-pyrimidin-4-yl) piperazin-4-ylcarbonyl] piperazine hydrochloride (13.25 g) as a pale yellow solid. NMR (d6-DMS0): 3.00 (m, 4H), 3.25 (m, 4H), 3.40 (m, 4H), 3.60 (m, 4H), 7.00 (s, ÍH) and 8.40 (s, ÍH). A solution of 4-trifluoromethylphenylsulfonyl chloride (13.26 g) in dichloromethane (30 ml) is added dropwise over 15 minutes to a mixture of 4- [1- (6-chloro-pyrimidin-4-yl) piperazin-4-ylcarbonyl. ] iperazine (21.50 g) and triethylamine (43.13 ml) in dichloromethane (270 ml) at 0 ° C. The solution is stirred at room temperature for 18 hours. Dilute the solution with dichloromethane and wash with water, dry (Na 2 SO 4) and evaporate to give 1- (4-trifluoromethylphenylsulfonyl) -4- [1- (6-chloropyrimidin-4-yl) piperazin-4-ylcarbonyl] iperazine (26.0 g) as a solid. NMR (CDC13): 3.10 (m, 4H), 3.30 (m, 4H), 3.40 (m, 4H), 3.60 (m, 4H), 6.50 (s, 1H), 7.80 (d, 2H), 7.90 (d, 2H) and 8.40 (s, ÍH); m / z 519 (M + l). A solution of 1- (4-bromophenylsulfonyl) -4- [1- (6-chloropyrimidin-4-yl) -piperazin-4-ylcarbonyl] piperazine (1.20 g) in 33% methylamine in ethanol (35 ml) is heated at 110 ° C in a Carius tube for 16 hours. The mixture is evaporated to dryness and then dissolved in dichloromethane and washed with saturated aqueous ammonium chloride solution, dried (NA2SO4) and evaporated. The residue is recrystallized from methanol / ethyl acetate to give, as a solid 1- (4-bromophenylsulfonyl) -4- [1-6-methylaminopyrimidin-4-yl) -piperazine-4-ylcarbonyl] iperazine (0.65 g) ), pf 219-221 ° C. Found C, 45.80; H, 5.10 and N, 18.50%. C2oH26BrN703S C, 45.80 is required; H, 5.00 and N, 18.70%. NMR (CDC13): 2.85 (d, 3H), 3.00 (m, 4H), 3.30 (m, 4H), 3.40 (m, 4H), 3.60 (m, 4H), 4.75 (m, ÍH), 5.40 (s, ÍH), 7.60 (d, 2H), 7.70 (d, 2H) and 8.15 (s, 1H) ): m / z 524 (M + l). The starting material is prepared in an analogous manner as described in Example 53. The following intermediate is isolated. 1- (4-Bromobenzenesulfonyl) -4- [1- (6-chloropyrimidin-4-yl) -piperazin-4-ylcarbonyl] piperazine (36.69 g) as a solid. NMR (CDCl 3): 3.05 (m, 4H), 3.30 (m, 4H), 3.40 (m, 4H), 3.65 (m, 4H), 6.50 (s, ÍH), 7.10 (d, 2H), 7.20 (d , 2H) and 8.40 (s, ÍH); m / z 529 (M + l). Example 45 A solution of l- (4-bromophenylsulfonyl) -4- [1- (6-chloro-pyrimidin-4-yl) -iperidi-4-ylcarbonyl] piperazine (3.0 g) in 33% methylamine is heated. in ethanol (70 ml) at 110 ° C in a Carius tube for 16 hours. The mixture is evaporated to dryness and then dissolved in dichloromethane and washed with saturated aqueous ammonium chloride solution, dried (Na 2 SO) and evaporated. The residue is crystallized from methanol / ethyl acetate to give, as a solid 1- (4-bromophenylsulfonyl) -4- [1- (6-methylamino-pyrimidin-4-yl) -piperidin-4-ylcarbonyl ] piperazine (2.43 g), mp 214-215 ° C. Found C, 48.40; H, 5.20 and N, 16.10%. C2? H27BrN603S requires c, 48.19; H, 5.20 and N, 16.05%. NMR (CDC13): 1.70 (m, 4H), 2.35 (m, ÍH), 2.85 (d, 3H), 3.00 (m, 6H), 3.65 (m, 4H), 4.35 (m, 2H), 4.65 (m , ÍH), 5.40 (s, ÍH), 7.60 (d, 2H), 7.70 (d, 2H) and 8.15 (s, ÍH); m / z 523 (M + l). The starting material is prepared as follows: A solution of carbonyldiimidazole (68.80 g) in tetrahydrofuran (500 ml) and dichloromethane is added to a solution of N-benzyloxycarbonylisonipecotic acid (123.64 g) in tetrahydrofuran (300 ml) at 0 ° C. (300 ml). The resulting solution is stirred at room temperature for 2 hours. This solution is cooled to 0 ° C and a solution of 1- (tert-butoxycarbonyl) iperazine (87.02 g) in tetrahydrofuran (200 ml) is added in drops over 20 minutes. The suspension obtained is stirred at room temperature for 48 hours. The solvent is evaporated. The residue is dissolved in diethyl ether / dichloromethane (1500 ml) and washed with water, 2 M aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, dried (Na 2 SO 4) and dried. evaporate to give 1- (tert-butoxycarbonyl) -4- [1- (benzyloxycarbonyl) -4-piperidylcarbonyl] piperazine (180.00 g) as a solid. NMR (CDC13): 1.45 (s, 9H), 1.75 (m, 4H), 2.60 (m, ÍH), 2.85 (m, 2H), 3.40 (m, 6H), 3.60 (m, 2H), 4.20 (m , 2H), 5.10 (s, 2H), and 7.35 (m, 5H); m / z 432 (M + l). A solution of 1- (tert-butoxycarbonyl) -4- [1-benzyloxycarbonyl) -4-piperidylcarbonyl] piperazine (41.31 g) in ethanol (1200 ml) is hydrogenated in palladium on 10% carbon for 18 hours. The reaction mixture is filtered through celite and the solvent is evaporated to give 1- (tert-butoxycarbonyl) -4- (piperidin-4-ylcarbonyl) piperazine (18.95 g) as a solid. NMR (CDCl 3) .- 1.45 (s, 9H), 1.70 (m, 4H), 2.60 (m, 2H), 2.80 (m, ÍH), 3.50 (m, 10H); m / z 298. A solution of 4,6-dichloropyridine is heated (3.60 g), 1- (tert-butoxycarbonyl) -4- (-4-piperidylcarbonyl) piperazine (6.0 g) and sodium acid carbonate (4.20 g) in ethanol (100 ml) refluxing for 6 hours. The solvent is evaporated and the residue is dissolved in ethyl acetate and washed with water, dried (Na 2 SO 4) and evaporated. The residue is recrystallized from ethyl acetate to give, as a solid 1- (tert-butoxycarbonyl) -4- [1- (6-chloropyrimidin-4-yl) -piperidin-4-ylcarbonyl] iperazine (7.40 g) . NMR (CDCl 3): 1.45 (s, 9H), 1.80 (m, 4H), 2.80 (m, ÍH), 3.10 (m, 2H), 3.50 (m, 8H), 4.40 (m, 2H), 6.50 (s) , ÍH) and 8.40 (s, 1H); m / z (M + l). Ethyl acetate with gaseous HCl is added to a solution of 1- (tert-butoxycarbonyl) -4- [1- (6-chloropyrimidin-4-yl) -piperidin-4-ylcarbonyl] piperazine (7.40 g) in ethyl acetate (30 ml) and the resulting suspension is stirred at room temperature for 3 hours. The solvent is evaporated to give 1- [1- (6-chloropyrimidin-4-yl) -4-piperidylcarbonyl] hydrochloride (7..10 g) as a solid. NMR (d6-DMS0): 1.40 (m, 2H), 1.70 (m, 2H), 3.00 (m, 7H), 3.70 (m, 4H), 4.40 (m, 2H), 6.95 (s, ÍH) and 8.30 (Yes H) . 4-Bromophenylsulfonyl chloride (2.77 g) is added to a mixture of 1- [1- (6-chloro-pyrimidin-4-yl) -4-piperidylcarbonyl] hydrochloride (5.20 g) and triethylamine (10.10 ml) in dichloromethane. (200 ml) at 0 ° C. The solution is stirred at room temperature for 18 hours. The solution is diluted with dichloromethane and washed with water, dried (Na 2 SO 4) and evaporated. The residue is purified by chromatography eluting with 1.5% methanol in dichloromethane to give 1- (4-bromobenzenesulfonyl) -4- [1- (6-chloro-pyrimidin-4-yl) -4-piperidylcarbonyl] piperazine (2.00 g) as a solid. NMR (CDC13): 1.80 (m, 4H), 2.70 (m, HI), 3.00 (m, 6H), 3.65 (m, 4H), 4.35 (m, 2H), 6.50 (s, ÍH), 7.60 (d , 2H), 7.70 (d, 2H) and 8.40 (s, ÍH); m / z 528 (M + l). Example 46 A solution of 1- (4-trifluoromethylphenylsulfonyl) -4- [1- (6-chloropyrimidin-4-yl) -4-piperidylcarbonyl] piperazine (1.80 g) in 33% methylamine in ethanol (70 ml) is heated at 110 ° C in a Carius tube for 16 hours. The mixture is evaporated to dryness and then dissolved in dichloromethane and washed with saturated aqueous ammonium chloride solution, dried (Na 2 SO 4) and evaporated. The residue is recrystallized from methanol / ethyl acetate to give, as a solid 1- (4-trifluoromethylphenylsulfonyl) -4- [1- (6-methylamino-pyrimidin-4-yl) -4-piperidylcarbonyl] iperazine (1.26 g), pf 237-239 ° C. Found C, 51.70; H, 5.30 and N, 16.30%. C22H27F3Ne03S requires C, 51.55; H, 5.30 and N, 16.40%. NMR (CDC13): 1.70 (m, 4H), 2.60 (m, 1H), 2.85 (d, 3H), 2.90 (m, 2H), 3.10 (m, 4H), 3.65 (m, 4H), 4.35 (m , 2H), 4.65 (m, ÍH), 5.40 (s, 1H), 7.80 (d,, 2H), 7.90 (d, 2H) and 8.15 (S, ÍH); m / z 513 (M + l). The starting material is prepared as per the methods described in Example 55, and the following intermediates are isolated: 4-trifluoromethylphenylsulfonyl chloride is added (1.32 g) to a mixture of 1- [1- (6-chloropyrimidin-4-yl) -4-piperidylcarbonyl] piperazine hydrochloride (2.60 g) and triethylamine (5.00 ml) in dichloromethane (100 ml) at 0 ° C. The solution is stirred at room temperature for 18 hours. The solution is diluted with dichloromethane and washed with water, dried (Na 2 SO 4) and evaporated. The residue is purified by chromatography eluting with 1.5% methanol in dichloromethane to give 1- (4-trifluoromethylphenylsulfonyl) -4- [1- (6-chloropyrimidin-4-yl) -4-piperidylcarbonyl] piperazine (1.30 g) as a solid. NMR (CDCl 3): 1.80 (m, 4H), 2.70 (m, 1H), 3.00 (m, 6H), 3.70 (m, 4H), 4.35 (, 2H), 6.50 (s, 1H), 7.80 (d, 2H), 7.90 (d, 2H) and 8.40 (s, ÍH); m / z 518 (M + 1). Example 47 A white suspension of 1- (2-ethylpyrimidin-4-yl) piperazine dihydrochloride (3 g, 10,362 mmoles) in DMF is added. (70 ml) and triethylamine (4.194 g / 5.77 ml / l.449 mmol) at room temperature 1- (4-bromophenylsulfonyl) -4- (4-nitrophenyloxycarbonyl) piperazine (5.625 g, 10.363 mmol). This solution is allowed to stir for 16 hours at 100 ° C. It evaporates to DMF. Water (250 ml) and dichloromethane are added, the mixture is brought to basic pH with NaOH. The organic phase is washed repeatedly with water. The organic phase is dried and evaporated. The residue is purified by "flash" chromatography on silica gel using methanol: dichloromethane (0 to 100%) as eluent to give a light brown solid. Trituration with ether (100 ml) gives 1- (bromophenylsulfonyl) -4- [1- (2-ethylpyrimidin-4-yl) piperazin-4-ylcarbonyl] piperazine as a light brown solid (3.555 g): P.F. 155-156 ° C NMR (CDCl 3): 1.25 (t, 3H), 2.75 (q, 2H), 3.05 (t, 4H), 3.32 (t, 4H), 3.40 (t, 4H), 3.65 (t, 4H ), 6.30 (d, ÍH), 7.66 (d, 2H), 7.70 (d, 2H), 8.20 (d, ÍH); ESP- MS m / z 524 (M + H). Example 48 Illustrative pharmaceutical dosage forms suitable for presenting the compounds of the invention for therapeutic or prophylactic use include the following tablet and capsule formulations, which can be obtained by conventional procedures well known in the pharmacy art and are suitable for therapeutic use or prophylactic in humans. (a) Tablet I Ms / tablet Compound Z * 1.0 Lactose Ph. Eur. 93.25 Croscarmellose sodium 4.0 Corn starch paste (5% w / v 0.75 aqueous paste) Magnesium stearate 1.0 (b) Tablet II Mg / tablet Compound Z * 50 Lactose Ph. Eur. 223.75 Croscarmellose sodium 6.0 Corn starch 15.0 Polyvinylpyrrolidone (5% w / v aqueous paste) 2.25 Magnesium stearate 3.0 (c) Tablet III Mg / tablet Compound Z * 100 Lactose Ph. Eur. 182.75 Croscarmellose sodium 12.0 Corn starch paste (5% w / v aqueous paste) 2.25 Magnesium stearate 3.0 (d) Capsule Mg / capsule Compound Z * 10 Lactose Ph. Eur. 488.5 Magnesium stearate 1.5 Note * The active ingredient compound Z is a compound of formula I, or a salt thereof, for example a compound of the formula I described in any of the preceding Examples. The tablet compositions (a) - (c) may be enteric coated by conventional means, for example, with cellulose acetate phthalate.

FORMULAS

Claims

CLAIMS 1. A compound of the formula I, or a pharmaceutically acceptable salt;
T1 is selected from N and CH; R1 is hydrogen, amino, halogen, cyano, (1-6C) alkyl, or (1-6C) alkoxy; M is 1 or 2; T2 is selected from CH and N; T3 is selected from N and CH with the proviso that when T2 is CH then T3 is not CH and when T1 is CH then T3 is not CH; wherein the heterocyclic ring containing T1 and the heterocyclic ring containing T2 can be independently, optionally substituted by one or more substituents selected from (1-6C) alkyl, (1-6C) alkoxy, phenyl (1-4C) alkyl, halogen and alkoxycarbonyl (1-6C); X is selected from O, CO, S, SO, S02 and CH2; Q is phenyl and wherein Q is substituted by one or two substituents independently selected from halogen and (1-6C) alkyl. 2. A compound of formula I in accordance with claim 1 characterized in that T1, T2 and T3 are N.
3. A compound of formula I according to either claim 1 or 2, characterized in that R 1 is selected from hydrogen, amino, (1-6C) alkyl and halogen.
4. A compound of the formula I according to claim 3 characterized in that R1 is selected from hydrogen, amino, methyl and chloro.
5. A compound of formula I according to claim 4 characterized in that m is 1 and R1 is methyl.
6. A compound of formula I according to any preceding claim characterized in that T1 and T2 are not replaced.
7. 1- (4-Bromophenylsulfonyl) -4- [1- (6-methylpyrimidin-4-yl) piperazin-4-ylcarbonyl] piperazine.
8. A pharmaceutical composition characterized in that it comprises a compound of the formula I according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier therefor.
9. A compound of formula 1 according to any claim 1 to 7 or a pharmaceutically acceptable salt thereof for use in medical therapy.
10. The use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, T1 is selected from N and CH; R1 is hydrogen, amino, halogen, cyano, (1-6C) alkyl, or (1-6C) alkoxy, - M is 1 or 2; T2 is selected from CH and N; T3 is selected from N and CH with the proviso that when T2 is CH then T3 is not CH and when T1 is CH then T3 is not CH; A and b are independently selected from 2 and 3; C and d are independently selected from 1 and 2; wherein the heterocyclic ring containing T1 and the heterocyclic ring containing T2 can be independently, optionally substituted by one or more substituents selected from (1-6C) alkyl, (1-6C) alkoxy, phenyl (1-4C) alkyl, halogen and alkoxycarbonyl (1-6C); X is selected from O, CO, S, SO, S02 and CH2; Q is selected from phenyl, naphthyl, phenyl (2-6C) alkenyl and a heteroaryl portion which comprises a five or six phenyl monocyclic heteroaryl ring containing up to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; and wherein Q may be unsubstituted or may carry one or more substituents selected from halogen, hydroxy, amino, nitro, oiano, carboxy, carbamoyl, alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C) ), (1-6C) alkoxy, (3-6C) cycloalkyl, (3-6C) cycloalkyl (1-4C), (1-4C) alkylenedioxy, (1-6C) alkylamino, di- [alkyl (1- 6C)] amino, N-alkylcarbamoyl (1-6C), di-N [(1-6C) alkyl] carbamoyl, (1-6C) alkanoylamino, (1-6C) alkoxycarbonyl, (1-6C) alkylthio, (1-6C) alkylsulfinyl, alkylsulfonyl (1) -6C), halogen (1-6C) alkyl, alkanoyl (1-6C) and tetrazolyl, or as defined in any of claims 1 to 7, for the manufacture of a medicament for treating or preventing diseases or medical conditions in which it is desirable to decrease the level of blood cholesterol.
11. A method for inhibiting the squalene cyclase oxide in a warm-blooded animal that requires such treatment is the method that is characterized in that it comprises administering to the animal an effective amount of a compound of the formula I as defined in accordance with any of the claims. 1 to 7 or claim 10, or a pharmaceutically acceptable salt thereof.