MXPA01000106A - Muscarinic antagonists - Google Patents

Abstract

Heterocyclic derivatives of di-N-substituted piperazine or 1,4 di-substituted piperidine compounds in accordance with formula (I) (including all isomers, salts and solvates), wherein one of Y and Z is -N- and the other is -N- or -CH-;X is -O-, -S-, -SO-, -SO2- or -CH2-;Q is (1), (2), (3);R is alkyl, cycloalkyl, optionally substituted aryl or heteroaryl;R1, R2 and R3 are H or alkyl;R4 is alkyl, cyclolalkyl or (4);R5 is H, alkyl, -C(O)alkyl, arylcarbonyl, -SO2alkyl, aryl-sulfonyl-C(O)Oalkyl, aryloxycarbonyl, -C(O)NH-alkyl or aryl-aminocarbonyl, wherein the aryl portion is optionally substituted;R6 is H or alkyl;and R7 is H, alkyl, hydroxyalkyl or alkoxyalkyl;are muscarinic antagonists useful for treating cognitive disorders such as Alzheimer's disease. Pharmaceutical compositions and methods of treatment are also disclosed.

Description

MUSCARINIC ANTAGONISTS BACKGROUND OF THE INVENTION The present invention relates to heteroaromatic derivatives of di-N-substituted piperazines and 1,4-di-substituted piperidines useful for the treatment of cognitive disorders, to pharmaceutical compositions containing the compounds, methods for the treatment using the compounds , and to the use of said compounds in combination with the acetylcholinesterase inhibitors. Alzheimer's disease and other cognitive disorders have received a lot of attention lately, even treatments for these diseases have not been very successful. According to Melchiorre et al. (J. Med. Chem (1993) 36, 3734-3737), compounds that selectively antagonize M2 muscarinic receptors, especially with respect to M1 muscarinic receptors, must possess activity against cognitive disorders. Baumgold et al. (Eur. J. of Pharmacol., 251, (1994) 315-317) describes 3-a-chloroimperialine as a highly selective M2 muscarinic antagonist. Logemann et al. (Brit. J. Pharmacol (1961), 17, 286-296) discloses certain di-N-substituted piperazines, but these are different from the novel compounds of the present invention. Moreover, it is not disclosed that the compounds of Logemann et al. have activity against cognitive disorders. WO 96/26196 describes benzylpiperidines and piperazines useful as muscarinic antagonists.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to the compounds according to structural formula I including all stereoisomers and their pharmaceutically acceptable salts and solvates, wherein one of Y and Z is -N- and the other is -N- or -CH-; X is -O-, -S-, -SO-, -S02- or -CH2; R is alkyl of (CrC2o), cycloalkyl (C3-C-? 2), aryl, R8-aryl or heteroaryl; R1, R2 and R3 are independently selected from the group consisting of H and alkyl (CrC2o); R4 is alkyl (C? -C2fJ), cycloalkyl (C3-C? 2) or R5 is H, alkyl (CrC20), -C (0) alkyl (C20), R9-arylcarbonyl, -SO2-alkyl (Cr20), R9-arylsulfonyl-C (O) O-alkyl (Cr20), R9-aryloxy-carbonyl , -C (O) NH-alkyl (C? -C20) or R9-arylaminocarbonyl; R6 is H or alkyl (C20); R7 is H, alkyl (CrC2o), hydroxyalkyl (CrC2o) or alkoxy (CrC2o) -alkyl (C C2o); R8 is 1-3 substituents independently selected from the group consisting of H, alkyl (CrC2o), halogen, hydroxy, alkoxy (CrC20) or hydroxy (C2C2) alkyl, or two adjacent R8 groups can be joined to form an alkylenedioxy group (C-) ? -C2), and R9 is 1-3 substituents independently selected from the group consisting of H, (C? -C2o) alkyl, halogen, amino or alkylamino (C -? - C2o). In a preferred group of compounds Z is N. In another preferred group of compounds R is R8 substituted phenyl, especially 3,4-methylenedioxyphenyl, 3-methylphenyl, 3-chlorophenyl or 4-methoxyphenyl. X is preferably -CH2- or -S02-. -flMMttflrJtiáji- ^ HjtMBaa | jM | MfeHH Q is preferably R1 and R2 are each preferably H; R3 is preferably H or CH3. In another group of preferred compounds, R4 has the formula where R7 is H or CH3; R6 is H; and R5 is R9-arylcarbonyl, preferably R9- (l-naphthyl) -C (O) -, especially when R9 is fluoro, or R9-pheni-C (0) -, especially when R9 is 2-methyl, 2-amino , 2-bromo or 2-chloro. Another aspect of the invention is a pharmaceutical composition comprising an effective amount of a compound having the structural formula I as defined above in combination with a pharmaceutically acceptable carrier. Another aspect of the invention is the use of a compound of the formula I for the preparation of a pharmaceutical composition useful for the treatment of cognitive disorders and neurodegenerative diseases such as, for example, Alzheimer's disease. Another aspect of this invention is a method for treating a cognitive or neurodegenerative disease comprising administering to a patient suffering from this disease, an effective amount of a compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION Except where otherwise determined, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether the term is used by itself or in combination with other terms. Therefore, the definition of "alkyl" is applied to "alkyl" as well as to the "alkyl" portions of "alkoxy", etc. Alkyl represents a straight or branched saturated hydrocarbon chain having between 1 and 20 carbon atoms, more preferably between 1 and 8 carbon atoms. Cycloalkyl represents a saturated carbocyclic ring having between 3 and 12 carbon atoms. Halogen represents fluoro, chloro, bromo or iodo. Aryl represents phenyl or naphthyl. "Heteroaryl" refers to simple or benzofused aromatic rings of between 5 and 10 members comprising between 1 and 4 heteroatoms independently selected from the group consisting of -O-, -S- and -N =, if the rings do not include the adjacent oxygen and / or sulfur atoms. Examples of single-ring heteroaryl groups are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, midazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl. Examples of benzofused heteroaryl groups are indolyl, quinolyl, benzothienyl (ie, thiamphenyl), benzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl. The N-oxides of the nitrogen-containing heteroaryl groups are also included. The isomers of positions 2-, 3-, 5-, and 6- are contemplated, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl and 6-pyridyl. When a variable appears more than once in the structural formula, for example, R8, the identity of each variable that appears more than once can be selected independently of the definition for that variable. The compounds of this invention can exist in at least two stereo configurations based on the asymmetric carbon to which R1 is attached, if R1 and R2 are not identical. Also within the formula I, there are numerous other possibilities for stereoisomerism. All possible stereoisomers of formula I are within the scope of the invention. The compound of formula I can exist in unsolvated as well as solvated forms, including hydrated forms. In general, solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to unsolvated forms for the purpose of this invention.

A compound of the formula I can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methane sulfonic and other mineral and carboxylic acids as well as those known to those skilled in the art. The salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in a conventional manner. The free base forms can be regenerated by treating the salt with a suitable dilute aqueous base solution such as, for example, dilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodium bicarbonate. The free base forms differ from their respective salt forms in some way with respect to certain physical properties, such as, for example, the solubility in polar solvents, but the salts are equivalent to their respective free base forms for the purpose of invention. The compounds of the formula I can be produced by means of the processes known to those skilled in the art as illustrated by the following reaction schemes: SCHEME 1 The compounds of formula IA where Y is N, Z is N, Q is tielidene, X is S02, R4 is substituted piperidinyl and R1 and R2 are each H, can be prepared by reacting the thiophenecarboxaldehyde with a 4-N-BOC-piperazine in the presence of sodium triacetoxy borohydride and acetic acid, followed by the reaction with n-butyllithium and R-sulfonyl-fluoride. The BOC group is removed with acid and the resulting piperazine is reacted with sodium piperidone and triacetoxy borohydride and acetic acid to obtain a compound of the formula IA.

SCHEME 2 The compounds of the formula IB; where Y is N, Q is pyridazinylidene, X is S02, R4 is substituted piperidinyl and R1 and R2 are each H, can be prepared by reacting an alkyl 6-chloropyridazine-3-carboxylate with a compound of the formula RS02Na, reducing the resulting carboxylate to the aldehyde, and attaching a substituted piperidine N-BOC-piperidyl or piperazine compound to the aldehyde. The group The suction of BOC is removed by means of the acid treatment, and the resulting piperidinyl compound is reacted with a compound of the formula R5COCI to obtain the desired compound of the formula IB.

SCHEME 3 The compounds of the formula IC, wherein Y is CH, Q is pyridazinylidene, X is S02, R4 is substituted piperidinyl and R1 and R2 are each H, can be prepared by reacting 3,6-diiodopyridazine with a compound of the formula RSH the presence of a strong base such as, for example, diazabicyclo-undecane (DBU), followed by oxidation of the thiol to the sulfonyl by means of treatment with a reagent such as, for example, m-chloroperbenzoic acid. 4 [(4-methylene) -piperidin-1-yl] -piperidine was treated with a reagent such as 9-borabicyclo [3.3.1] nonane (9-BBN) and then the resulting trialkylborane was reacted with pyridazine and a palladium (0) catalyst. The BOC protecting group is removed by the acid treatment, and the resulting piperidinyl compound was reacted with a compound of the formula R5COCI to obtain the desired compound of the formula IC. To prepare the compounds of the formula ID; where Y is CH, Q is pyridazinylidene, X is S; R4 is substituted piperidinyl and R1 and R2 are each H, RS-iodopyridazine is reacted with 4-methylenepiperidine in the presence of a palladium (0) catalyst as described above, followed by reaction with an N-BOC-4 -piperidone. The BOC protecting group is removed and the R5 substituent is attached in the manner described above to prepare the compounds of the formula IC.

SCHEME 4 The compounds of the formula IE, wherein Y is N, Q is pyridylidene, X is S02, R4 is substituted piperidinyl and R1 and R2 are each H, can be prepared by reacting a halo-substituted nicotinic acid with a compound of the formula RSH , then reducing the acid to the corresponding alcohol and oxidizing the thiol in the corresponding sulfonyl. The resulting compound is then linked with an N-BOC-piperidyl-substituted piperidine as described for scheme 2, and the R5 substituent is attached in the manner described for scheme 3.

SCHEME 5 The compounds of the formula IF; where Y is N, Q is pyridylidene, X is S02, R4 is substituted piperidinyl and R1 and R2 are each H, can be prepared by reacting 2,5-dibromopyridine with a compound of the formula RS02Na and n-butyllithium, followed by the binding with a substituted piperidine or piperazine N-BOC-piperidyl, removing the BOC protecting group as described in scheme 2 and reacting with R5COCI as described in scheme 3 to obtain the desired compound.

SCHEME 6 The compounds of the formula IG; where Y is CH, Q is pyridylidene, X is S02, R4 is substituted piperidinyl and R1 and R2 are each H, can be prepared by reacting 2,5-dibrompyridine with a compound of the formula RS02Na, then treating the resulting compound in a manner similar to that described in scheme 3 for preparing the compounds of formula IC.

SCHEME 7 The compounds of formula IH, wherein Y is N, Q is pyridylidene, X is S02, R4 is substituted piperidinyl, R1 is methyl and R5 is H, were prepared by converting 6-chloronicotinic acid to the corresponding chloro-ketone by means of Weinreb amide Chloro-cetaone is reacted with RS02Na in hot DMF, followed by an enantioselective reduction using the catalyst (S) -2-methyl oxaborolidine and boranomethyl sulfide to provide the chiral alcohol that is enriched in the R-enantiomer. The mesylate derived from alcohol is reacted with a piperazine piperidine refluxing acetonitrile, and the removal of the BOC protecting group followed by the binding with several aromatic acids (R5C02H) under the standard conditions provides the objective compounds IH. The above reactions can be followed if necessary or convenient by one or more of the following steps: (a) removing any of the protective groups of the compound produced in this way; (b) converting the compound of the product in this way to a pharmaceutically acceptable salt, ester and / or solvate; (c) converting a compound according to formula I thus produced into another compound according to formula I, and (d) isolating a compound of formula I, including separating the stereoisomers of formula I. Based on In the above reaction sequence, those skilled in the art will be able to select the starting materials necessary to produce any compound according to formula I. The compounds of formula I exhibit muscarinic antagonist activity m2 and / or m4, which has been correlated with the pharmaceutical activity for the treatment with cognitive disorders such as, for example, Alzheimer's disease and senile dementia. The compounds of the formula I show a pharmacological activity in the test procedures designed to indicate the muscarinic antagonist activity m1 and m2. The compounds are non-toxic at pharmaceutically therapeutic doses. The descriptions of the test procedures are given below.Muscarinic binding activity The compound of interest was tested for its ability to inhibit binding to human cloned subtypes of the muscarinic receptor m1, m2, m3 and m4. The sources of receptors in these studies were the membranes of the stably transfected CHO cell lines expressing each of the receptor subtypes. After development, the cells were pelletized and subsequently homogenized using a Polytron in 10 mM of a 50 volume cold Na / K phosphate buffer, pH 7.4 (Regulator B). The homogenates were centrifuged at 40,000 x g for 20 minutes at 4 ° C. The resulting supernatants were discarded and the pellets were re-suspended in a regulator B at a final concentration of 20 mg wet tissue / ml. These membranes were stored at -80 ° C until used in the binding assays described below. The binding to the cloned human muscarinic receptors was performed using 3H-quinuclidinyl benzylate (QNB) (Watson et al., 1986). Briefly, the membranes (approximately 8, 20 and 14 μg of the protein assay for the membranes containing m1, m2 and m4, respectively) were incubated with 3H-QNB (final concentration of 100-200 pM) and increasing concentrations of the drug not labeled in a final volume of 2 - ^ - ^? &? R ml at 25 ° C for 90 minutes. Non-specific bonds were tested in the presence of 1 μM of atropine. Incubations were terminated by vacuum filtration on GF / B glass fiber filters using a Skatron filtering apparatus and the filters were washed with 10 mM of a cold Na / K phosphate buffer, pH 7.4. A scintillation cocktail was added to the filters and the containers were incubated overnight. The bound radioligand was quantified in a liquid scintillation counter (50% efficiency). The resulting data were analyzed at their IC50 values (ie, the concentration of the compound required to inhibit the binding by 50%) using the EBDA computer program (McPherson, 1985). The affinity values (Ki) were then determined using the following formula (Cheng and Prusoff, 1973); K, ¡- - - 1 - ^ radioligand concentration ~ | The affinity (KD) of radioligand J therefore, a lower value of Ki indicates a higher binding affinity. To determine the degree of selectivity of a compound to bind the m2 receptor, the Ki value for the m1 receptors was divided by the Ki value for the m2 receptors. A higher ratio indicates a greater selectivity to bind to the m2 muscarinic receptor. For the compounds of this invention, the following range of muscarinic antagonist binding activity was observed (not all compounds were tested for m3 and m4 linkage activity): m1: 96 nM to 1860 nM ^ "^^^ j ^ * ^ m2: 1.5 nM to about 1400 nM, preferably 1.5 nM to about 600 nM m3: 59 nM to 2794 nM m4: 28 nM 638 nM A preferred compound of this invention, the compound of Example 39, has an average m.1 antagonist binding activity of 917 and an average m2 antagonist binding activity of 1.5 To prepare the pharmaceutical compositions with the compounds of the formula I, the pharmaceutically acceptable inert carriers were mixed with the active compounds The pharmaceutically acceptable carriers can be either solid or liquid Preparations for solid forms include powders, tablets, dispersible granules, capsules, cachets, and suppositories A solid carrier can be one or more substances that can also act as diluents , flavoring agents, solubilizers, lubricants, suspending agents, binders and disintegrating agents for tablets, can also be any material encapsulant Liquid preparations include solutions, suspensions and emulsions. As an example, water or propylene glycol water solutions can be mentioned for parenteral injection. Also included are preparations in solid form that are intended to be converted, briefly before use, into liquid form preparations for oral or parenteral administration. These liquid forms - ^? , M '- "A - include solutions, suspensions and emulsions.These particular solid form preparations are more conveniently provided in the form of unit doses and as such, are used to provide a single liquid dose unit. it also includes alternative distribution systems including, but not necessarily limited to, the transdermal distribution Transdermal compositions can take the form of creams, lotions and / or emulsions and can be included in a transdermal patch of the matrix or reservoir type as conventional compositions In the art for this purpose, the pharmaceutical preparation is preferably in the form of a unit dose In this form, the preparation is subdivided into unit doses containing suitable quantities of the active component The unit dosage form can be a packaged preparation, the container contains discrete quantities of the preparation as for example, tablets, capsules and powders packed in containers or ampoules. The unit dosage form can also be the same capsule, cachets or tablets, or it can have the appropriate amount of any of these in packaged form. The amount of the active compound in a unit dose preparation can be varied or adjusted from 1 mg to 100 mg according to the particular application, the potency of the active ingredient and the intended treatment. This would correspond to a dose between about 0.001 and about 20 mg / kg that can be divided into 1 to 3 administrations per day. In addition, the composition may, if desired, contain other therapeutic agents. The doses may be varied depending on the requirement of the patient, the severity of the condition to be treated and the particular compound to be used. The determination of the appropriate dose for a particular situation is within the capacity of those familiar with medical science. For convenience, the total daily dose can be divided and administered in portions throughout the day or providing continuous administration. The invention described herein is exemplified by the following examples which should not be taken as limiting the scope of the description. The mechanical ways and alternative analogous structures may be obvious to the person skilled in the art. As used herein, tetrahydrofuran is THF, dimethylformamide is DMF, ethyl acetate is EtOAc, trifluoroacetic acid is TFA, dimethisulfoxide is DMSO, m-chloroperbenzoic acid is MCPBA, triethyl amine is Et3N, diisopropyl ethylamine is Pr2EtN, 9- borabicyclo [3.3.1] -nonano is 9-BBN, 1,1'-bis (diphenyl-phosphino) -ferrocene palladium (II) chloride is Pd (dppf) CI2. In the examples, Ar in the structures is 3-methyiphenyl; Ar1 is 4-methoxyphenyl.

EXAMPLE 1 Reaction scheme: Step 1A: To a cooled (0 ° C) mixture of DMF (25 ml) and NaH (1.00 g of a suspension in 60% oil) slowly m-toluene thiol (3.10 g) was added dropwise. After the addition was complete, the cooling bath was removed, the resulting mixture was stirred for 1 hour at room temperature (RT), 6-bromo-nicotinic acid (5.00 g) was added at once and the resulting mixture was heated until refluxing for 6 hours. After cooling to room temperature, the mixture was poured into cold water (250 ml) and the resulting solid was collected, washed with water and dried to give the desired product 1 (4.91 g) in an 80% yield . BH3DMS (0.61 ml) was added, in the form of drops, to a solution of sulfide 1 (0.50 g) and THF (2 ml). The resulting solution was stirred for 1 hour at room temperature, diluted with EtOAc and ice and stirred for 5 minutes. The pH was adjusted to 11 with 2 N NaOH and the resulting mixture was extracted with EtOAc (3 x 10 mL). The EtOAc extracts were dried over brine, then over MgSO, filtered and evaporated to give a slightly colored foam 2 (0.44 g) which was used without further purification.

Step 1 B MCPBA (671 g technical grade) was added in three portions for 10 minutes, to a cooled solution (0 ° C) of 2 and CH2CI2. After warming to room temperature and stirring for 12 hours, the resulting mixture was diluted with CH2Cl2 (5 ml) and MCPBA (300 mg) was added. After 4 hours at room temperature, the resulting mixture was diluted with CH2Cl2 and washed successively with cold 1N NaOH, water and brine and dried over MgSO4. After filtration and evaporation, the crude oil was purified by means of plate chromatography (2000 μM plate; silica adsorbent; 2: 1 Ml ^^^ jiM. ^. ^^. eluent EtOAc: hexane) to give product 3 as a white solid (0.22 9) - Step 2: To a cooled (0 ° C) solution of sulfone 3 (0.20 g), CH2Cl2 (7.5 ml) and Et3N (0.13 ml) was added CH3S02CI (0.061 ml). The resulting solution was stirred for 5 minutes at 0 ° C and for 30 minutes at room temperature and then washed successively with water, 1 N NaOH and brine and dried over MgSO4. After filtration and evaporation, the resulting oil was dissolved in CH3CN (0.68 ml) and iPR2EtN (0.14 ml) and piperazine (0.29 g) was added. The resulting solution was stirred for 12 hours, during which time CH3CN (0.5 ml) was added and stirred for 2 days continuously. The CH3CN was removed in vacuo and the resulting crude mixture partitioned between CH2Cl2 and water. The pH was adjusted to 11 with 2 N NaOH, the CH2Cl2 layer was removed and the aqueous layer was extracted with CH2Cl2 (3 x 3 mL). The combined organic extracts were dried with brine and over MgSO 4, filtered and evaporated to give a crude gum which was purified by means of plate chromatography (2 x 2,000 μM plate, silica adsorbent, eluent EtOAc: Et 3 N 95: 5) to give the product 4a as a foam (0.29 g) in a yield of 82%. HRMS: calculated: M.H +: C28H4? N404S: 529.2849; measured: 529.2840.

-. «^«. «^. Step 3: To a cooled (0 ° C) solution of 4a (0.27 g) and CH2Cl2 (2.1 ml) was added TFA (0.42 ml) and water (9 μL). The resulting solution was stirred at room temperature for 2 hours; the volatile materials were removed in vacuo; CH2Cl2 (20 mL) was added; the pH was adjusted to 11 with 10% NaOH and the organic layer was removed. After drying (with brine and MgSO4) and evaporating, product 4 was collected as a white foam (0.16 g) in a yield of 71%.

Step 4: The product of step 3, 4 (29 mg) was mixed with CH3CN (0.4 mL), Pr2EtN (0.15 mL) and N-methyl isatoic anhydride (48 mg). After stirring for 2 days at room temperature, the resulting mixture was diluted with EtOAc (15 mL) and washed with cold water, brine and dried over MgSO, then filtered and evaporated to give a crude solid which was then purified by means of plate chromatography (500 μM plate, silica adsorbent; eluent EtOAc: Et 3 N 95: 5) to give the product as a foam (28 mg) in 75% yield. HRMS (as HCl): calculated: M H +: C3? H40N5O3S: 562.2852; measured: 562.2850; P.F: (HCL); 144-148 ° C (with decomposition). ^ jtó - ^ '* ají ^^^ = íjp EXAMPLE 2 Intermediate 4 (29 mg) was dissolved from the exemplol in CH2Cl2 (1.0 mL) and 2.0 M Na2CO3 (0.2 mL) was added. The resulting mixture was cooled to 0 ° C and CH3 (CH2) 2S02CI (7.62 μL) was added. The mixture was stirred for 5 minutes at 0 ° C and 15 minutes at room temperature, then MgSO4 was added. The CH2CI2 layer was removed and the solids were extracted with CH2Cl2 (3 x 3 mL), the CH2Cl2 extracts were combined, dried with MgSO4, filtered and evaporated to give a crude foam which was purified by means of chromatography by plates (500 μM plate, silica adsorbent, eluent EtOAc: Et 3 N 95: 5) to give the product as a foam (33 mg) in 90% yield. HRMS (as HCl): calculated: M * H +: C26H38N404S2: 535.2413; measured: 535.2405; P.F. (HCl): 146-150 ° C (with decomposition).

^ ¡^^^^^^^^^^^^^^^ EXAMPLE 3 Reaction scheme Step 1 To a cooled (-90 ° C) solution of 2,5-dibromopyridia (10 g) and THF (264 mL) was added dropwise, nBuLi (16.9 mL of 2.5 M solution in hexanes) and the solution The resultant was stirred for 5 minutes. The DMF (3.27 ml) was added as drops and the resulting solution was warmed to -50 ° C and stirred for 15 minutes at that temperature. The reaction solution was poured onto ice and extracted with EtOAc (3 X 75 mL). The combined EtOAc extracts were dried over MgSO, filtered and evaporated to give 7.8 g of the crude material which was purified by chromatography with silica gel (hexane: EtOAc 4: 1 as eluent). After combining the desired fractions and evaporating the solvents, the desired aldehyde 5 was isolated as a solid (0.89 g) with a yield of 11%.

Step 2 A mixture of 5 (0.20 g), DMSO (1.0 ml) and sulfinate of 3,4-methylene dioxy benzene, sodium salt (0.19 g) was heated to 40 ° C for 21 hours, then cooled and poured into water (10 ml). The resulting solution was made basic (pH = 11) with 2 N NaOH and extracted with EtOAc (3 X 5 mL). The combined extracts were dried with brine and MgSO 4, filtered and evaporated to give a crude oil which was purified by means of silica gel chromatography (eluent 2: 1 hexane: EtOAc). The desired fractions were combined and evaporated to give product 6 (0.10 g) with a yield of 33%.

Step 3 To a solution of 6 (0.10 g), piperazine 7 (0.23 g) and CH 2 Cl 2 (2.5 ml) was added NaB (OAc) 3 H (0.11 g) and the resulting solution was stirred for 1.5 hours. The reaction was diluted with CH2Cl2 and made basic with 2 N NaOH. The CH2Cl2 layer was removed and the aqueous layer and the aqueous layer was extracted with CH2Cl2 (2 x 5 mL). The organic extracts were combined, washed with water, brine and dried over MgSO 4, then filtered and evaporated to give a crude oil which was purified by means of plate chromatography (2000 μM plate, silica adsorbent; 1 eluent CH 2 Cl 2: acetone) to give the product as a foam (95 mg) with a yield of 47%. P.F. (HCl): decomposition above 225 ° C.

EXAMPLE 4 Reaction scheme Step 1 Carbinol intermediate 8 was prepared by the method outlined for step 1A of example 1, but m-toluene thiol was replaced with iso-propyl thiol. é ¡••. •. •. • > • > • _ ^ ^ ^ t? MJt ^ V * ». * Step 2 The carbinol intermediate 8 (50 mg) was dissolved in CHCl3 (1.0 ml) and Mn02 (165 mg) was added. The resulting mixture was heated to reflux for 2 days and the solid reaction mixture was then cooled, taken up in CHCl3 (10 mL), and filtered through celite. The solids were washed with CHCl3 (3 x 10 mL), the organic extracts were combined, dried over MgSO4; it was filtered and evaporated to give the desired aldehyde 9 (42 mg) in an 86% yield.

Step 3 The 9 was subjected to the same reaction conditions delineated in example 3, step 3, using the piperazine intermediate 7, to give the title compound (0.12 g) in a 50% yield. P.F.:(HCI): decomposition above 197 ° C.

EXAMPLE 5 Reaction scheme 2. Pd (dppf) CI2 fifteen - . 15 - * Ex. 5 N-methyl isatoic acid Step 1 A mixture of 2,5-dibromopyridine (3.7 g), parametoxy benzene sulfinate, sodium salt (3.0 g) and DMF (8.0 ml) was heated to reflux for 48 hours, cooled and partitioned between water and EtOAc. The aqueous layer was checked for basic (pH> 8) and extracted with EtOAc (2 X 75 ml). The organic extracts were combined, washed with water and brine and dried over MgSO4. After filtration and evaporation, the crude solid (3.5 g) was chromatographed on silica gel (gradient: 8: 1 hexanes: EtOAc; 4: 1 hexanes: EtOAc; 1: 1 hexanes: EtOAc) to give, after evaporation of the appropriate fractions, 10 (0.27 g) with a yield of 5.3%. P.F .: 104-107 ° C.

Step 2 To a degassed, cooled (0 ° C) sample of 11 (1.7 g) was added 9-BBN (17.5 ml of 0.5 M in THF). The cooling bath was removed and the solution was stirred for 1.5 h at room temperature. The resulting solution was added, at room temperature, to a mixture of sulfone 10 (0.27 g), Pd (dppf) CI2 (20 mg), triphenyl arsine (25 mg), DMF (2.0 ml), water (0.18 ml) and Cs2C03 (0.33 g). The resulting mixture was heated to 60 ° C for 3 hours 45 minutes. After cooling to room temperature and pouring a water, the pH was adjusted to 11 with 10% NaOH and the mixture was extracted with EtOAc (3 x 25 ml). The combined organic extracts were dried with brine and MgSO 4, filtered and evaporated to give a crude which was then purified by means of plate chromatography (2000 μM plate, silica adsorbent, eluent 1: 1 EtOAc: hexanes) to give the product 12 as a white foam (0.28 g) with a yield of 77%.

Step 3 The 12 was treated as described in Example 1, step 3. The product 13 was isolated as a foam (0.11 g) with a yield of 82%.

Step 4 The product 13 was treated as described in example 3, step 3, except that one equivalent of acetic acid was added and N-BOC-piperidone was used as the carbonyl component. After working, the crude was purified by means of plate chromatography (2000 μM plate, silica adsorbent, 95: 5 eluent EtOAc: Et 3 N) to give 14 as an oil (0.21 g).

Step 5 The product 14 was treated as described in example 1, step 3, to give 15 as a white foam (53 mg) at 41% in two steps. HRMS: calculated: M H +: C23H22N303S: 430.2164; measured 430.2160.

Step 6 The product 15 was treated as described in example 1, step 4 and purified by means of plate chromatography (500 μM plate; silica adsorbent; eluent 95: 5 EtOAc: Et3N) to give the title compound as an oil (33 mg) in 96% yield. P.F. (HCl): 108-110 ° C (with decomposition).

EXAMPLE 6 Intermediate 15 of Example 5, step 6 was treated as described in Example 2, except that the sulfonyl chloride was replaced with 4-fluoro-naphthoyl chloride and the crude was purified by plate chromatography (500 μM plate; silica adsorbent; 95: 5 eluent EtOAc: Et 3 N) to give the title compound as an oil (33 mg) in 96% yield. P.F .; (HCl): decomposition above 184 ° C.

EXAMPLE 7 Reaction scheme $ g ^ * S &¡g8É? «? U ^ Step 1 To CH2Cl2 (50 mL), 4-N-BOC-2- (R) -methylpiperazine (1 g, 4.9 mmol), thiophene-2-carboxaldehyde (0.46 mL), NaBH (OAc) 3 was added (1.5 g, 7.5 mmol) and acetic acid (0.25 ml), and stirred overnight at room temperature. Add CH2Cl2 (100 mL) and wash with saturated NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated on a rotary evaporator. The crude product 16 was purified on a silica column and eluted with EtOAc.

Step 2 16 was dissolved in THF (15 ml), then cooled in a dry ice / acetone bath when n-BuLi (0.64 ml, 2.5 M) was added in the form of drops. After 15 minutes, the temperature was raised to 0 ° C, stirred for 30 minutes, then re-cooled to -78 ° C when 4-methoxybenzenesulfonyl fluoride (0.3 g, 1.6 mmol) was added. After 10 minutes, the temperature was raised to 0 ° C for 15 minutes, then at room temperature for 15 minutes. After quenching with saturated NaHCO3, EtOAc was added and the organic phase was washed with brine and dried over Na2SO4. The crude product 17 was purified on a silica column using 2: 1 hexane: EtOAc.

Step 3: Product 17 (0.22 g) was dissolved in EtOAc (4 ml) and 6 N HCl (0.8 ml) was added with vigorous stirring. After 2 hours the reaction was neutralized with a saturated NaHCO 3 solution. CH2Cl2 (50 ml) was added and the organic phase was separated and dried over NaHCO3. After concentration on a rotary evaporator, the crude product 18 was used without purification.

Step 4 N-BOC-piperidone (0.09 g, 0.43 mmol), 18 (0.16 g, 0. 43 mmol), NaBH (OAc) 3 (0.14 g, 0.65 mmol) and acetic acid (0.025 ml) to CH2Cl2 (5 ml), and the mixture was stirred overnight at room temperature. CH2Cl2 (10 mL) was added and washed with saturated NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated on a rotary evaporator. The crude product 19 was purified on a silica column using EtOAc as eluent.

Step 5 The product 19 (0.2 g) was dissolved in EtOAc (3 ml) and 6 N HCl (0.5 ml) was added with vigorous stirring. After 2 hours, the reaction was neutralized with a saturated NaHCO 3 solution. CH2Cl2 (15 ml) was added and the organic phase was separated and dried over NaHCO3. After concentration on a rotary evaporator, the crude product was used without further purification.

Step 6 The product 20 (0.03 g) was dissolved in CH2Cl2 (1 ml) followed by the addition of Et3N (0.011 ml), and o-toluoyl chloride (0.007 ml). After 1 hour at room temperature, the solution was transferred directly to a TLC plate and eluted with EtOAc. The main UV band (Rf = 0.1) was collected and extracted with 10% CH3OH / EtOAc. Filtration and evaporation gave the purified material. The HCl salt was prepared by dissolving the product in a minimum amount of EtOAc followed by the addition of HCI / dry ether. The precipitate was collected by centrifugation, washed with ether and dried under vacuum to obtain the title compound. P.F: 190-192 ° C (decomposition).

EXAMPLE 8 Reaction scheme Step 1 Heat a mixture of ethyl 6-chloropyridazine-3-carboxylate 21 (1.8 g), sodium (3,4-methylenedioxy) -benzenesulfonate (2 g) and DMSO (20 ml) a Mf ^ ___ ^ _ ^^ • ilÉalaÉliíuiÉlta 120-125 ° C for 8 hours. Cool and add water (100 ml), stir 10 minutes, wash well with water and dry at room temperature under high vacuum to give compound 22 as a white solid (2.0 g). P.F. 153-155 ° C.

Step 2 An ice-cooled solution of compound 22 (0.6 g) in dry THF (40 ml) add 1 M diisobutylaluminium hydride in toluene (3.6 ml), stir for 5 minutes, add CH2Cl2 (100 ml) and then ice water in excess. Stir and add 2 N HCl (20 ml) to dissolve the solids. Extract with CH2CI2? Dry over MgSO4 and filter on a small silica gel cloth, washing with 20% EtOAc in CH2Cl2. Evaporate to obtain aldehyde 23 (0.42 g) as a yellow foam, suitable for the next step.

Step 3: Shake a mixture of compound 23 (0.42 g), 1- (1-tert-butoxy-carbonyl-piperidin-4-yl) -piperazine (0.42 g) and NaBH (Oac) 3 (0.42 g) in CH2Cl2 (30 ml) at room temperature for 6 hours. Wash with 1 N of an aqueous NaOH solution, dry over MgSO 4 and evaporate. Isolate the product by means of silica gel chromatography with a gradient of EtOAc in CH 2 Cl 2, evaporate the pure fractions to obtain compound 24 as a white foam (0.58 g).

Step 4 Shake the product from step 3 in EtOAc (20 ml) and concentrated HCl (5 ml) for 2 hours at room temperature. Basify with 2N Excess NaOH with ice cooling, extract with several portions of CH 2 Cl 2, dry over K 2 CO 3 and evaporate to obtain the amine 25 as a light yellow foam (0.35 g).

Step 5 Stir for 20 hours at room temperature a mixture of compound 25 (0.04 g), o-toluoyl chloride (0.04 g), CH2Cl2 (10 ml) and 1 N aqueous NaOH (10 ml). Separate the organic phase, dry and evaporate. Dissolve the residue in CH2Cl2 (1 mL) and add to the ether (15 mL) containing HCI-dioxane (4M, 0.25 mL). Centrifuge and wash by centrifugation of 3x suspension with ether, then dry under nitrogen flow, and finally at high vacuum / room temperature to give the hydrochloride of the title compound as a cream powder (0.035 g). P.F. 195-198 ° C with decomposition.

EXAMPLE 9 Use the procedure of Example 8, replacing the toluoyl chloride with 1-naphthoyl chloride (0.05 g) to obtain the final hydrochloride (0.042 g) of the title compound as a white powder. P.F 175-180 ° C with decomposition.

EXAMPLE 10 Stir for 20 hours at room temperature, a mixture of compound 25 of example 8 (0.058 g), DMF (2 ml), Pr2EtN (0.1 ml), hydroxybenzotriazole (HOBT) (0.038 g), 3-methylpicolinic acid hydrochloride ( 0.036 g) and N-ethyl-N '- (dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (0.055 g). Extract in NaHCO 3 aqueous EtOAc, wash with several portions of 5% aqueous NaCl, dry over MgSO 4, evaporate and pump under vacuum to remove any residual DMF. Precipitate the HCl salt as described in example 8 to obtain the title compound (0.035 g) as a hygroscopic powder with a wide melting range.

EXAMPLE 11 Use the procedure of Example 8, but replacing the toluoyl chloride with 2-bromobenzolyl chloride (0.05 g) to obtain the hydrochloride of the title compound (0.040 g) as a white powder, m.p. 198-203 ° C, with decomposition.

EXAMPLE 12 Reaction Scheme 29 ^^^ éég jtt ^ j ^^^ Step 1 Agitate diiodopyridazine (3.4 g) and p-methoxybenzenethiol (1.4 g) in CH2CI2 (40 ml) and add diazabicycloundecane (DBU, 2 ml) as drops. Stir for 1.5 hours, dilute with hexanes (50 mL) and chromatograph on silica gel, eluting with a gradient of CH2Cl2 in hexanes. Evaporate the product fractions and recrystallize from ether-hexanes to give pure product 26 (1.65 g), P.F .: 113-114 ° C.

Step 2: Shake 1- (t-butoxycarbonyl) -4-methylenepiperidine (0.86 g) in 0.5 M of 9-BBN / THF (9 ml) at room temperature for 1 hour, under N2. Add the product 26 (1.33 g), DMF (9 ml), water (1 ml), triphenylarsine (0.10 g), the Pd complex (dppf) CI2 (0.10 g) and Cs2C03 (2.0 g) and heat up to 90 ° C for 2.5 hours. Extract in water-CH2CI2, dry over MgSO4 and evaporate, then pump to remove the DMF. Chromatograph on silica gel, eluting with an ether gradient in CH2Cl2. Combine and evaporate the fractions of the crude product to give 27 (1.13 g), P.F: 90-92 ° C.

Step 3: Shake compound 27 (0.5 g) in TFA (4 ml), water (0.25 ml) and CH2Cl2 (2 ml) at room temperature, for 1 hour, evaporate, add 1 N NaOH and extract with several portions of CH2Cl2. Dry over MgSO4, evaporate and add to the residue CH2Cl2 (6 mL), 1-Boc-4-piperidinone (0.33 g), NaBH (OAc) 3 (0.4 g). Stir for 24 hours, wash with 1 N NaOH, dry, evaporate and chromatograph on silica gel with a gradient of CH3OH in CH2Cl2. Evaporate the pure fractions to give 28 as a foam (0.44 g).

Step 4: Shake the product 28 in TFA (4 ml) for 2 hours, evaporate and work in 1N NaOH with extractions of CH2Cl2. Dry and evaporate to obtain product 29 as a pale yellow solid (0.33 g). HRMS found: 399.2220; theory for MH + = 399.2219.

Step 5: Shake the product 29 (0.04 g) in CH2Cl2 (3 ml) with 1 NaOH (3 ml) and 6-chloronaphthoyl chloride (0.05 g) for 0.5 hour. Separate the organic phase, add CH3OH (20 ml) and evaporate. Isolate the product by t.l.c, eluting with EtOAc, and convert to the HCl salt as described in Example 8. The title compound (0.025 g) was obtained as a pale yellow powder, P.F: 180-190 ° C with decomposition. -t ^ -aje EXAMPLE 13 Reaction scheme Step 1 Shake the sulfur 26 (0.24 g) in CH2Cl2 (5 ml) and add mCPBA (85%, 0.4 g). Stir at room temperature for 3 hours, dilute with CH 2 Cl 2 and wash with aqueous solutions of Na 2 CO 3 and then with NaH 3. Dry, evaporate and recrystallize from CH2Cl2-hexanes to give the product as white crystals (0.23 g), P.F: 193-196 ° C.

Step 2 Heat a solution of 1- (tert-butoxycarbonyl) -4 - [(4-methylene) -piperidin-1-yl] -piperidine (0.20 g) in 0.5 M 9-BBN-THF (1.6 ml) under nitrogen at 60-70 ° C for 2 hours, then dilute with DMF (2 ml) and water (0.4 ml). Add the product 30 (0.20 g), triphenylarsine (0.03 g), the Pd complex (dppf) CI2 (0.022 g) and Cs2C03 (0.36 g), wash with DMF (1 ml) and heat at 60-70 ° C for 1 hour. Work in water with CH2CI2 extractions, wash with water, dry, evaporate and pump under vacuum and at room temperature for 4 hours. Isolate by t.l.c. on silica eluting with 1: 1 hexanes-acetone to obtain product 31 as a foam (0.16 g). HRMS found: 531.2655; MH + requires 531.2641.

Step 3 Shake the product 31 (0.15 g) for 2 hours at room temperature in ETOAc (3 ml) and concentrated HCl (0.7 ml) then dilute with water, discard the EtOAc phase, basify the aqueous phase with excess 2N NaOH and extract with several portions of CH2Cl2. Dry over K2C03 and evaporate to obtain product 32 as a light brown foam, suitable for subsequent reactions.

Step 4 Stir at room temperature for 5 hours a mixture of compound 32 (0.035 g), 4-fluoro-naphthoic acid (0.02 g), DMF (1.25 ml), HOBT (0.02 g), diisopropyl-ethylamine ( 0.05 g) and EDCI (0.04 g). Dilute with aqueous NaHC03, extract with CH2Cl2, dry over MgSO4 and evaporate, then pump under vacuum to remove residual DMF. Isolate the main product by t.l.c. in acetone on silica, and converting the product to the HCl salt as described in the above preparations, to obtain the title compound as a white powder (0.032 g). Following the procedures of Examples 1 to 13, using the appropriate starting materials and modifications known to those of ordinary skill in the art, additional compounds of the following structure were prepared: where R, X, Q, Y, R3, and R5 are as defined in the table ^^^^ jH ^ ^ gi ^^^ ¿^ • ^ S ei ^ ^ jií The physical data for compounds 14-52 are illustrated in the next box: át ???? i ^^ l ^ EXAMPLE 54 Step 1 A suspension of 6-chloronicotinic acid (5.0 g, 31.85 mmol) in CH 2 Cl 2 (40 ml) containing DMF (0.2 ml) was treated with CICOCOCI (3.3 ml, 38. 22 mmol) and warmed up to 40 ° C for two hours. The resulting light red solution was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in toluene and concentrated once more to remove any unreacted CICOCOCI and traces of HCl. The resulting red gum was dissolved in CH2Cl2 (30 ml). N-hydrochloride was added to this solution, 0-dimethyl hydroxylamine (4.66 g, 47.7 mmol) and Pr2EtN (11 mL, 63.7 mmol). The reaction vessel was capped and stirred overnight at room temperature. After work of extraction and passage through a column of silica gel, Weinreb amide (5.7 g (yield: 89%)) was obtained as an amber syrup. TLC Rf = 0.5 in 25% EtOAc / CH2Cl2.

Step 2 CH3MgBr (10 ml of 3M solution) was added dropwise to a solution of the product from step 1 (5.7 g, 28 mmol) in 25 ml of dry THF at 0 ° C, generating a yellow precipitate. After stirring for 1 hour at room temperature, the reaction was quenched with a saturated NH CI solution and the product was isolated by extracting with CH2Cl2. The product was purified by flash chromatography on silica gel and 3.7 g (84%) was isolated as a white solid. TLC: Rf: 0.6 in 25% EtOAc / CH2Cl2.

Step 3 A solution of the product from step 2 (3.1 g, 20 mmol) and sodium salt of 3,4-methylenedioxyphenyl sulfinic acid (4 g, 20 mmol) in dry DMF was heated at reflux for 16 hours. The yellow solution ^ ^ It became cloudy brown and the starting material was completely consumed. The reaction mixture was cooled to room temperature and warmed with water. Extraction with EtOAc gave 5 g of a dark yellow solid. The product was purified by flash chromatography on silica gel and isolated as an off-white solid (3.1 g, yield: 50%). TLC Rf = 0.4 in 25% acetone-hexane.

Step 4 (S) -2-Methyl oxaborolidine (1M in toluene, 0.5 ml) was added to a solution of the product from step 3 (0.75 g, 2.46 mmole) in 6 ml of CH2Cl2 and 2 ml of THF at room temperature. It was introduced in the form of drops to a solution of (CH3) 2S »BH3 in THF (2M, 0.74 ml) for 4 minutes. After stirring at room temperature for 1 hour, the reaction was warmed with CH3OH and the volatiles were removed in vacuo. The residue was dissolved in 20 ml of CH2Cl2 and worked through an extraction work to obtain a yellow solid. The product was purified by flash chromatography on silica gel to obtain the pure chiral alcohol as a white foamy solid (0.66 g, 88%). TLC: Rf = 0.3 in 25% acetone-hexane.

Step 5: Et3N (4 mmol, 0.55 ml) and CH3S02CI (2.6 mmol, 0.2 ml) were added in sequence to a solution of the product from step 4 (0.6 g, 1.95 mmol) in 5 ml of CH2Cl2 at 0 ° C. After stirring and warming gradually to room temperature for 1.5 hours, the reaction mixture was diluted with 10 ml of CH2Cl2 and subjected to aqueous work to remove most of the byproducts. Concentration in vacuo gave 0.72 g (96%) of the mesylate as a dark yellow gum. This was re-diluted in dry CH3CN (8 ml) and treated with 1- (1-tert-butoxycarbonyl-piperidin-4-yl) -3 (R) -methyl-piperizine (0.566 g, 2 mmoles) and 2.2, 6,6-tetramethyl piperidine (0.33 ml) and refluxed for 8 hours. The reaction mixture was cooled to room temperature and quenched with water. Extraction work in CH2Cl2 gave 1 gram of crude product, which was purified by flash chromatography on silica gel using 25% acetone in CH2Cl2 to obtain an intermediate (S; R-dia stereomer) as a white foamy solid ( 0.7 g, yield = 70%) and its R, R-dia stereomer (0.1 g, yield = 10%). TLF: Rf = 0.55 for S, R-isomer and 0.4 for R, R-isomer in 25% acetone-CH2CI2.

Step 6 The product of step 6 (S, R) was converted to its free base form by treatment with TFA in CH 2 Cl 2 followed by a basic extraction work to obtain free piperazine piperidine as a white foamy solid. To a solution of piperazine-piperidine (0.048 g, 0.1 mmol) in CH2Cl2 (1 ml) were added in sequence: EDCI (0.029 g, 0.15 mmol), HOBT (0.020 g, 0.15 mmol), 2-amino-3- acid. methyl-benzoic (0.031 g; 0.2 mmol) and iPr2Et2N (0.0345 mL, 0.2 mmol). After stirring at room temperature for 10 to 16 hours, the reaction mixture was diluted with excessive CH2Cl2 and washed with water, 10% citric acid, 10% NaOH solution and brine. The resulting crude product was purified by flash chromatography to give the free base form of the title compound as a colorless film (0.055 g, yield = 91%). Treatment with 1 HCl in Et20 converted it into an HCl salt. P.F.:180-182°C. Using a similar procedure and the appropriate acid, the following compounds were prepared: in which R5 is as defined in the table * ^^^^^^ _ ^ * ^ --Afe, j "•" ^^ "- EXAMPLES 60 AND 60A Reaction scheme 34 A -? EJ EMPLO 60 EXAMPLE 60 -? - »EXAMPLE 60A Step 1 The procedure of example 5, step 2, was used for the preparation of product 33 using intermediate 11 (7.93 ml), 9-BBN (92 ml), 2,5-dibromopyridine (10 g), DMF (95 ml) ), H20 (9.1 ml), K2C03 (7.62 g) and Pd (dppf) Cl2 (1.03 g). After purification, the product 33 was asylated as a solid (14.3 g) with a yield of 96%, P.F: 66 ° C.

Step 2: NaH (1.01 g of a 60% oil dispersion) was washed with hexane (6.0 ml), N, N-dimethylacetamide (8.4 ml) was added, the resulting mixture was cooled in an ice bath and added 3-chlorothiophenol (2.94 ml) in the form of drops. After stirring at room temperature for 15 minutes, the product 33 (3.00 g) and Cul (4.82 g) were added all at once and the resulting mixture was heated at 120 ° C for 12 hours and then at 140 ° C for 4 hours. hours. After cooling to room temperature, EtOAc (150 ml) was added, the mixture was filtered and rinsed with EtOAc. The combined EtOAc portions were washed with water and brine, dried over MgSO, filtered and evaporated to give a crude oil (4.77 g) which was then purified by column chromatography (silica adsorbent, 225 g, 1: 8 EtOAc hexanes, 1: 4 EtOAc: hexanes, 1: 2 EtOAc, hexanes as eluent). After evaporation of the appropriate fractions, the product 34 (1.87 g) was asylated as a waxy solid in a yield of 53%.

Step 3: The product 34 (1.00 g) was dissolved in CH2Cl2 (24 ml), the resulting solution was cooled to 0 ° C, and then mCPBA (1.21 g) was added for 10 minutes. The resulting mixture was stirred at room temperature for 24 hours. The two new components are characterized by TLC analysis (2: 1 hexanes: EtOAc). The reaction mixture was diluted with CH2Cl2, and made basic (pH = 11) with 2N NaOH and the CH2Cl2 layer was removed. The organic layer was washed with water and brine, dried over MgSO, filtered and evaporated to give an oil (700 mg) which was then purified by column chromatography (silica adsorbent, 1: 8 EtOAc: hexanes, 1: 4). EtOAc: hexanes; 1: 2 EtOAc: hexanes as eluent), 35 A (196 mg) was quenched as a foam with an 18% yield. The more polar component, 35 B (339 mg) was whitened as a white foam with a yield of 35%.

Step 4: Intermediate 35 A was treated as in example 5, steps 3 and 4 to obtain the compound of example 60.

Step 5: The compound of example 60 was treated as in example 5, step 5, followed by the procedure of example 13, step 4, using 2-amino-3-methylbenzoic acid in place of 4-fluoronaphthoic acid to obtain the compound of Example 60 A. After work and purification, product 60 A (15 mg) was isolated in its free base form as a foam with 54% yield.

¿F ^^ = ^ íg HRMS: calculated: M H +: C30H35N4O3SCI: 567.2197; measured 567. 2189 EXAMPLE 61 AND 61 A Reaction scheme Example 61 EXAMPLE 61 - »? EXAMPLE 61 A Intermediate 35B was treated in the same manner as 35A to give initially, the compound of Example 61 (48% in 2 steps from 35B), and then Example 61A (20% in 3 steps) in the hydrochloride form, as a white solid. P.F .: decomposition above 151 ° C.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has the structural formula: including all stereoisomers and their pharmaceutically acceptable salts and solvates, wherein one of Y and Z is -N- and the other is -N- or -CH-; X is -O-, -S-, -SO-, -S02- or -CH2;

R is (C1-C20) alkyl, (C3-C2) cycloalkyl, aryl, R8-aryl or heteroaryl; R1, R2, R3 are independently selected from the group consisting of H and alkyl (d-C20); R4 is cycloalkyl (C3-C-? 2) or

R5 is H, alkyl (CrC20), -C (0) alkyl (C20), R9-arylcarbonyl, -S02-(C1-C20) alkyl, R9-arylsulfonyl-C (O) O-alkyl (C20-20), R9-aryloxycarbonyl, -C (0) NH- ^^ ^ ^^^^^? ^? ^^^^^ ^ a ^ a ^ am alkyl (C? -C2o) or R9-arylaminocarbonyl; R6 is H, or alkyl (C -? - C2o); R7 is H, (C1-C20) alkyl, hydroxyalkyl (C? -C20) or (C? -C20) alkoxy-alkyl (CrC2o); R8 is 1-3 substituents independently selected from the group consisting of H, (C-pCo) alkyl, halogen, hydroxy, alkoxy (CrC20) oh ddroxy (C? -C20) alkyl, or two adjacent R8 groups can be attached to forming an alkylenedioxy group (C C2o); and R9 is 1-3 substituents independently selected from the group consisting of H, alkyl (CrC2o), halogen, amino or alkylamino (CrC20). 2. A compound of claim 1 wherein Z is N. 3. A compound of claim 1 wherein R is 3,4-methylenedioxyphenyl, 3-methylphenyl, 3-chlorophenyl or 4-methoxyphenyl.

4. A compound of claim 1 wherein X is -CH2- or -SO2-.

5. A compound of claim 1 wherein R1 and R2 are each H and R3 is H or CH3.

6. A compound of claim 1 wherein R4 is where R7 is H or CH3; R6 is H; and R5 is R9-arylcarbonyl.

7. A compound of claim 6 wherein R5 is R9- (1-naphthyl) -C (O) -, o-toluoyl-C (O) - or 2-aminophen-C1 (0) -.

8. A compound as defined in claim 1 selected from the group consisting of: fifteen

9. A pharmaceutical composition comprising an effective amount of a compound as defined in claim 1 in combination with a pharmaceutically acceptable carrier.

10. The use of a compound of claim 1 for the preparation of a medicament for treating a cognitive or neurodegenerative disease in a mammal in need of this treatment. SUMMARY OF THE INVENTION The heterocyclic derivatives of the di-N-substituted piperazine or 1,4-di-substituted piperidine compounds according to formula 1 (including all isomers, salts and solvates) where one of Y and Z is -N- and the other is -N- or -CH-; X is -O-, -S-, -SO-, -S02- or -CH2; Q is (2) or (3) (2) (3) R is optionally substituted alkyl, cycloalkyl, aryl or heteroaryl; R1, R2 and R3 are H or alkyl; R4 is alkyl, cycloalkyl or (4) (4) where R5 is H, alkyl, -C (0) alkyl, arylcarbonyl, -S02alkyl, aryl-sulfonyl-C (0) alkyl, aryloxycarbonyl, -C (0) NH-alkyl or aryl-aminocarbonyl, where the aryl is optionally substituted; R6 is H, or alkyl; R7 is H, alkyl, hydroxyalkyl or alkoxyalkyl; they are muscarinic antagonists useful for the treatment of cognitive disorders such as Alzheimer's disease; Pharmaceutical compositions and methods of treatment are also disclosed. > SCHERING / aom * eos * mvh * yac * pbg * jtc * isg * rcp * osu * cgm * P00 / 1831 F ? - _ ^ & ^^