MXPA00012180A - Neuropeptide y5 receptor antagonists - Google Patents

Abstract

Compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein a and b are 0-2, provided that the sum is 0-3;Q is (i) or (-N=);X is -O-, -S-, -SO-, -SO2-, -CH(OR8)-, -C(O)-, -C(R23)2-, optionally substituted alkenyl, alkynyl or (ii);R1 is optionally substituted aryl, heteroaryl, substituted amino, alkyl-OC(O)R8, aryloxyalkyl, (iii) wherein m is 1-4, or (iv) wherein d and e are 0-2;R2, R3, R4 and R5 are H, alkyl, optionally substituted cycloalkyl, halogen, -OR8, -N(R8)2, -CO2R8 or CF3;R6 and R7 are H, alkyl, alkenyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkyl or cycloalkylalkyl, or R6 and R7, form a 3-7-membered carbocyclic ring, or a 4-7-membered heterocyclic ring;R8 is H, alkyl, cycloalkyl, optionally substituted aryl or heteroaryl;R9 is alkyl, cycloalkyl, optionally substituted aryl or heteroaryl;R11 is H, alkyl or cycloalkyl;and R23 is R8 or halogen;are claimed, as well as additional novel compounds;also claimed are pharmaceutical compositions and methods of using said novel compounds in the treatment of eating disorders and diabetes.

Description

RECEPTOR ANTAGONISTS Y5 NEUROPEPTIDES BACKGROUND OF THE INVENTION The present invention relates to Y5 receptor antagonists of neuropeptides Y which are useful in the treatment of eating disorders and diabetes, pharmaceutical compositions containing the compounds and methods of treatment using the compounds. Neuropeptide Y is a peptide of 36 amino acids that is widely distributed in the central and peripheral nervous systems. This peptide is an intermediary in a variety of physiological effects through its various receptor subtypes. Studies in animals have shown that neuropeptide Y is a powerful stimulus for food ingestion, and it has been shown that activation of Y5 receptors of neuropeptides Y results in hyperphagia and decreased thermogenesis. Therefore, compounds that antagonize neuropeptide Y in the Y5 receptor subtype represent a solution in the treatment of eating disorders such as obesity and hyperphagia. Phenylamides and ureas are known as antiatherosclerotic agents, see for example U.S. Patent No. 4,623,662, and is described in benzoic acid amides as antidiabetic agents in U.S. Patent No. 5,378,728: The N, N-alkylene bis (benzamides) are known as endocrinological agents, see North American patent No. ^^^^^^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^ g ^^^^^^ 4,009,208. WO 98/35957, published on August 20, 1998 discloses amide derivatives as selective receptor antagonists of neuropeptide Y.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds represented by structural formula I or a pharmaceutically acceptable salt thereof, wherein a and b are independently 0, 1 or 2, with the proviso that the sum of a and b is 0 to 3; C- Q is N = R X is -O-, -S-, -SO-, -SO2-, -CH (ORa) -, -C (O) -, -C (R 2"3 \) 2-, C (R25) = C (R25) - C = C- or - C-; ^^ s ^^^^ R1 is R15-aryl, R24-heteroaryl, -NHR12, -N (R12) 2-, - (C Cg) alk-OC (O) R8, where m is 1-4, or of d and e are independently 0, 1 or 2; R2, R3, R4 and R5 are independently selected from the group consisting of H, straight or branched chain C5 alkyl, (C3-C12) cycloalkyl, R? - (C3-C? 2) cycloalkyl, halogen, -OR8, -N (R8) 2, -CO2 (R8) 2 and CF3; R6 and R7 are independently selected from the group consisting of H, (CrC9) alkyl (C? -C9) alkenyl, hydroxy- (CrC9) alkyl, amino- (C? -Cg) alkyl, (C? -Cg) alkoxy- (C? -C9) alkyl, (C3-C? 2) cycloalkyl and (C3-C? 2) cycloalkyl- (C? -C6) alkyl, or R6 and R7 together with the carbon to which they are attached, form a ring carbocyclic of 3, 4, 5, 6 or 7 members form a carbocyclic ring, or a heterocyclic ring of 4, 5, 6 or 7 members, where 1, 2 or 3 ring members are independently selected from the group consisting of O, S and N; R8 is independently selected from the group consisting of H, (C? -C6) (C3-C? 2) cycloalkyl, R15-aryl and R24-heteroaryl; R9 is (C? -C6) alkyl, (C3-C12) cycloalkyl, R15-aryl or R24-heteroaryl; R11 is independently selected from the group consisting of H, (CrC6) alkyl and (C3-C? 2) cycloalkyl; R12 is independently selected from the group consisting of (C C9) straight or branched chain alkyl, hydroxy (C2-Cg) alkyl, ^^ tAi ^ Aa. ^ ... < ^^ ^^ a ^ ^^^^^ 1 ^. "3L-- -" • A '. ^? .. t, ^ .. & & t (C? -C9) alkoxy- (C2-C9) alkyl, N (R11) (R19) - (C2-C9) -alkyl, HS ( C2-C9) -alkyl, (C1-C9) -alkylthio- (C2-Cg) -alkyl, (C3-C? 2) -cycloalkyl R14- (C3-C12) cycloalkyl, R15 -aryl, R24-heteroaryl (C ? - C6). alkyl, and k are independently 0, 1 or 2, where q is 1 or 2, and s is 0, 1 or 2, or two groups R12, together with the nitrogen to which they are attached form a ring of formula: wherein p is 0, 1 or 2; R10 is -NR18-, -O- or -S-; R13 represents 1 to 3 substituents independently selected from the group consisting of hydrogen, (C? -C6) alkyl, halogen, (C? -C6) alkoxy and CF3; R14 represents 1 to 3 substituents independently selected from the group consisting of (CrC6) alkyl, benzyl, R13-aryl and R13-heteroaryl; .. ^ z ^? * ¿im¿Sl M. + M ^, i ^. "^" "__, a & Jgísá d teb i ^ É ^^ i,! *, R15 represents 1 to 3 substituents independently selected from the group consisting of hydrogen, (d-CßJalkyl, halo, polyhalo (C C6) alkyl, R17O-, -N (R17 ) 2 -S (R17), R17 0- (C? -C6) alkyl, (R17) 2N- (CrC6) alkyl, formyl, -C (O) R17, -COOR17, -CON (R17) 2, -OC (O) N (R17) 2, - 5 N (R17) C (O) N (R17) 2, -NR17C (O) R17, -NR17C (O) OR14, R17SO-, R17SO2-, - R17SO2NR17- and tri (CrC6) alkylsilyl R16 consists of 1-3 substituents independently selected from the group consisting of H, (CrCßJalkyl, (C3-C ?2) cycloalkyl, (C3-Ci2) spirocycloalkyl, (C3-C4) spiro-alkylenedioxy, R15- Aryl, R24-heteroaryl, benzyl, N-piperidinyl, -COR8, -C (O) NR8R9, -NR8R9 and -NR8C (O) R9, or when two R16 groups are bonded to carbon atoms of an adjacent ring, together with said carbon atoms, they can form a (C5-C7) cycloalkyl ring R17 is independently selected from the group consisting of H, (C? -C6) alkyl and (C3-Ci2) cycloalkyl (C3-Ci2) cycl oalkyl (Cr C6) a1-alkyl; R 13 -aryl and R 13 -heteroaryl; R18 is independently selected from the group consisting of H, (Ci-CβJalkyl, (C3-Ci2) cycloalkyl, (C3-Ci2) cycloalkyl- (Cr C6) alkyl, R15-aryl, R24-heteroaryl, -CO2R9, C (O ) (R8) 2, -COR8 and -SO2R9; R19 is H, (C3-C12) cycloalkyl- (C? -C6) alkyl, R15 -aryl, R24-heteroaryl C02R9-C (O) N (R8) 2, -COR8 or -SO2R9; R20 is (C C6) C3-C2-C2alkyl, (C3-C2) cycloalkyl- (C6-C6) alkyl, hydroxy (Cr6) alkyl, oxo (CrC6) alkyl or polyhalo (CrC6) alkyl; ^^^^^^^^^^^^^^^^^^^^^^^^^^^ - ^^^^^^^^^^^^^^^^^^^^ g ^^^^ | ^^^^^ R21 and R22 are independently selected from the group consisting of H, (C? -C6) alkyl, (C3-Ci2) cycloalkyl- (C? -C6) alkyl, hydroxy (C? -C6) alkyl, R15-aryl, R24-heteroaryl, R15-aryl (C6-6) alkyl or R24-heteroaryl (C6-6) alkyl; R23 is independently selected from the group consisting of H, halogen, (C? -C6) alkyl, (C3-C? 2) cycloalkyl, R15 -aryl and R24-heteroaryl; R 24 represents 1 or 2 substituents independently selected from the group consisting of hydrogen, (C 1 -Chajal, halo, polyhalo, (CrC 6) alkyl R 17 O-, -N (R 17) 2 S- (R 17), R 17 0 - (CrC 6) alkyl, - (R17) 2N- (C? -C6) alkyl, formyl, -C (0) R17, COOR17, -CON (R17) 2, OC (0) N (R17) 2, - N (R17) C ( O) N (R17) 2, N (R17) C (O) (R17), -N (R17C (O) O (R14), R17SO2, (R17) SO2, NR17- and tri (C? -C6) alkylsilyl and R25 is independently selected from the group consisting of hydrogen, halogen, (C? -C6) alkyl, and polyhalo (Cr C6) alkyl? = C-? 4 In a preferred group of compounds of formula I, Q is R 4 is H. Also preferred are compounds in which R 3 is H and where R 2 and R 5 are independently H or halogen, R 6 and R 7 are preferably (C Cg) alkyl, especially methyl, or R 6 and R 7 together with the carbon atom to which they are attached form a C3-C6 carbocyclic ring.

In the compounds of formula I, X is preferably -S-; -C (O) -; or -C (R8) 2, especially where R8 is H. More preferably X is -C (R8) 2-, and compounds in which X is -CH2 are especially preferred. In the compounds of formula I, a is preferably 1 or 2 and b is preferably 0. In the compounds of formula I, R1 is preferably -NHR12 or -N (R12) 2, especially 10 Wherein R18 is (C? -C6) alkyl or -SO2Rg; R9 is (C? -C6) alkyl or aryl; and R22 is (C? -C6) alkyl or (C3-Ci2) cycloalkyl (CrC6) alkyl. Another aspect of the invention is a pharmaceutical composition for treating eating disorders or diabetes comprising an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier. Another aspect of this invention is a method of treating a disorder of feeding or diabetes comprising administering a ^ "¿¿A aA ^? ^^^^? effective amount of a compound of formula I to a patient in need of such treatment. Likewise, new compounds similar to those of the formula I are claimed in which b is O, X is -O- or -S- and the substituent corresponding to R1 is optionally substituted alkyl.

DETAILED DESCRIPTION OF THE INVENTION Except where otherwise stated, the following 10 definitions will apply throughout the present description and claims. These definitions apply regardless of whether a term is used by itself or in other terms. Therefore the definition "alkyl" is applied to "alkyl" as well as to the "alkyl" portions of "alkoxy", etc. Alkyl represents branched saturated hydrocarbon chains having the designated carbon atom amount. If the amount of carbon atoms is not specific, for example if the term lower alkyl is used, chain lengths of 1 to 6 carbons are indicated. When X is -CR25) = C (R25) -, both 20 configurations are considered, the cis and the trans configuration. Cycloalkyl represents a saturated carboxylic ring having from 3 to 12 carbon atoms. The C3-C6-cycloalkyl rings are preferred.

In the definition of R16, the term (C3-C? 2) spirocycloalkyl refers to a (C2-Cn) alkylene chain attached at both ends to the same ring carbon, i.e. similarly, the term (C3-C4) spiroalkylenedioxy refers to the (C2-C3) alkylenedioxy group attached at both ends to the same ring carbon atom, i.e. in the definition of R6 and R7, the term "heterocyclic ring" refers to 4- to 7- membered saturated rings comprising 1 to 3 heteroatoms independently selected from the group consisting of -O-, -S- and -NH- , the remaining carbon ring members. When a ring Heterocyclic comprises more than one heteroatom rings are not formed when there are adjacent oxygen atoms, adjacent sulfur atoms, or three consecutive heteroatoms. Examples of heterocyclic rings are tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. 20 When two R12 groups form a ring of the formula those skilled in the art will recognize that the substituents -NR8R9 and -NR8C (O) R9 can not be attached to the carbon adjacent to the pipericinyl nitrogen. Halogen represents fluorine, chlorine, bromine or iodine. 5 Polihalo (C -? - C6) alkyl refers to a straight or branched alkyl chain substituted with 1 to 5 halogen atoms, which may be attached to the same or different carbon atoms, for example -CH2F, -CHF2, CF3, F3CCH2- and -CF2CF3. Hydroxy (CrC6) alkyl refers to an alkyl chain substituted on any substitutable carbon with a hydroxy group. Similarly, oxo (d -C-kajalyl refers to an alkyl chain substituted with a = O portion) Aryl represents phenyl or naphthyl Heteroaryl refers to simple or benzofused aromatic rings of from 5 to 10 members comprising 1 to 3 heteroatoms independently selected of the group consisting of -O-, -S- and N =, with the proviso that the rings do not include adjacent oxygen and / or sulfur atoms.Examples of heteroaryl groups of a ring are pyridyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, thiadiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazolyl Examples of benzofused heteroaryl groups are quinolinyl, isoquinolinyl, quinazolinyl, tianaphtenyl (ie benzothienyl), indolyl, benzimidazolyl, benzofuranyl and benzofurazanyl. Also included are the -N-oxides of nitrogen-containing heteroaryl groups All positional isomers ^ ^^ S ^^^^^^^^ Jj ^ ^ ^^^^^^^^^^^ ^^^ g ^^^^^^^ j ^ ^^^^^^^^^^^ ^^^^^^^^^^^^^^^ g are contemplated: for example, 2-pyridyl, 3-pyridyl and 4-pyridyl. Preferred heteroaryl groups are pyridyl, isoxazolyl, thienyl, thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl and quinazolinyl. 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 independently selected from the definition for this variable. For the compounds of the invention having at least one asymmetric carbon atom, all isomers, including diastereomers, enantiomers and rotational isomers are contemplated as forming part of the invention. The invention includes d and I isomers in both the pure and mixed forms, including racemic mixtures. The isomers can be prepared using conventional techniques, either by reaction of pure or optically enriched starting materials or by separation of the isomers of a compound of formula I. The compounds of formula I can exist in unsolvated as well as solvated form , including hydrated forms. In general, solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the forms are solvated for the purposes of this invention. A compound of formula I can form pharmaceutically acceptable salts with inorganic or organic acids. Examples of acids suitable for the formation of salts such as hydrochloric, sulfuric, phosphoric, acetic, citric, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids which are well known to the experts in the technique. 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 dilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodium bicarbonate. The free base forms differ somewhat in their respective salt forms in regard to certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for the purposes of the invention. The compounds of formula I can be produced by methods known to those skilled in the art as shown in the following examples. Typically, the claimed compounds in which X is -S- or -O- can be prepared as shown in the following reaction scheme: IA wherein an amine of formula II is reacted with an acid chloride or carbamoyl chloride in the presence of a base, or with a carboxylic acid in the presence of conventional amide coupling agents such as EDC and DMAP. The starting materials of formula II can be prepared using known methods. The compounds of formula I exhibit neuropeptide Y5 antagonist activity, which has been correlated with pharmacological activity to treat eating disorders such as obesity and hyperphagia. The compounds of formula I exhibit pharmacological activity in assay procedures designed to indicate antagonist activity of the Y5 neutropeptide receptor. The compounds are non-toxic in pharmaceutically therapeutic doses.

CAMP assay Cho cells expressing the various NPY receptor subtypes were maintained in Ham's F-12 medium (Gibco-BRL) supplemented with 10% FCS (ICN), 1% penicillin-streptomycin, 1% non-essential amino acids and 200 μg / ml of Geneticin ® (Gibco-BRL # 11811-031) under a 5% humidified CO2 atmosphere. Similarly, HEK-293 cells expressing the various NPY receptor subtypes were maintained in Dulbecco's modified Eagle medium (Gibco-BRL) supplemented with 10% FCS (ICN), 1% penicillin-streptomycin and 200 μg / ml of Geneticin ® (Gibco-BRL # 11811-031) under humidified CO2 atmosphere at 5%. Two days before the assay, cells from tissue culture flasks T-175 were released using a dissociating solution (1 X: non-enzymatic [Sigma # C 5914] and seeded in 96-well flat bottom tissue culture plates. at a density of 15,000 to 20,000 cells per receptacle.After approximately 48 hours the cell monolayers were rinsed with Hank's balanced salt solution (HBSS) and then preincubated with approximately 150 μl / supplemented test buffer receptacle (HBSS) with 4 Mm of MgCl2, 10 mM of HEPES, 0.2% of BSA [HH] that contained 1 mM of 3-isobutyl-1-methylxanthine ([IBMX] Sigma # 1-5879) with or without the antagonist compound of interest at 37 ° C. After 20 minutes 1 mM of the assay buffer IBMX-HH (antagonist +) was removed and replaced with a test buffer containing μM (CHO cells) or 5 μM (HEK-293 cells) forskolin (Sigma # F- 6886) and various concentrations of NPY in the presence or absence of a concentration of the antagonist compound of interest. After 10 minutes the medium was removed and the cell monolayers were treated with 75 μl of ethanol. The tissue culture plates were shaken on a platform shaker for 15 minutes, after which the plates were transferred to a hot water bath in order to Evaporate the ethanol. After bringing all the wells to dryness, the cell residues were re-solubilized with 250 μl of the Flash Pitate ® test buffer. The amount of cAMP from each receptacle was quantified using the equipment [125] -CAMP Flash Píate ® (NEN # SMP-001) according to the protocol provided by the manufacturer. The data were expressed as mol cAMP / ml or as control percentage. All data points were determined in triplicate and the EC50 (nM) was calculated using a non-linear (sigmoidal) regression equation (GraphPad Prism ™). The KB of the antagonist compound was estimated using the following formula: KB = [B] / (1- { [A '] / [A].}.) Where [A] is the EC50 of the agonist (NPY) in the absence of antagonist, [A '] is the EC50 of the agonist (NPY) in the presence of an antagonist, and [B] is the concentration of the antagonist.

NPY adhesion receptor assay Human NPY receptors were expressed in CHO cells. Adhesion assays were carried out in 50 mM HEPES, pH, 7.2, 2.5 mM, CaCl2, 1 mM MgCl2 and 0.1% BSA containing 5-10 μg membrane protein and 0.1 nM 125 I-peptide YY (for NPY1, NPY2 and NPY5 receptors) or 0.1 nM of 125l-pancreatic polypeptide (NPY4 receptor) in a total volume of 200 μl. The non-specific adhesion was determined in the presence of 1 uM of NPY. The reaction mixtures were incubated for 90 minutes at 30 ° C (NPY1 receptor) or at room temperature (NPY2, NPY4 and NPY5 receptors), and then filtered through Millipore MAFC glass filter plates that had been pre-soaked in 0.5%. of polyethyleneimine. The filters were washed with phosphate buffered saline, and the radioactivity was measured in a Packard TopCount scintillation counter. ^ ^^^^^^^^^^^^^^^^^^^ g | g ^ ¡g || ^^ g ^^^ gSg > ^^^ g ^^^^^^^ gg ^^ For the compounds of this invention a range of adhesion activity to the neuropeptide receptor Y5 of from about 0.1 to about 1000 nM was observed. The compounds of this invention preferably have an adhesion activity in the range of from about 0.1 to 250 nM, more preferably about 0.1 to 100 nM, and more preferably about 0.1 to 10 nM. To prepare pharmaceutical compositions from the compounds of formula I, inert pharmaceutically acceptable carriers were mixed with the active compounds. The pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, seals and suppositories. A solid carrier can be one or more substances which can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; They can also be an encapsulating material. Liquid form preparations include solutions, suspensions and emulsions. As an example, water or water-propylene glycol solutions for parenteral injection may be mentioned. Also included are solid form preparations which are intended to be converted shortly before use into liquid form preparation for oral or parenteral administration. Said liquid forms include solutions, suspensions and emulsions. These particular preparations in solid form are conveniently provided in unit dosage form and as such are used to provide a single liquid dosage unit. The invention also contemplates alternative administration systems that include but are not necessarily limited to transdermal administration. The transdermal compositions may take the form of creams, lotions and / or emulsions and may be in a transdermal dressing of the matrix or deposit type as conventionally used in the art for this purpose. Preferably the pharmaceutical preparation is in a unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate amounts of the active compound. The unit dosage form can be a packaged preparation, a package containing discrete quantities of preparation such as tablets capsules and powders packed in vials or ampoules. The unit dosage form may also consist of a capsule, seal or the same tablet, or may consist of the appropriate amount of any of these in packaged form. The amount of active compound in a preparation in unit dosage form can be varied or adjusted to from about 0.5 mg to 500 mg, preferably about 0.5 to 100 mg, according to the particular application and potency of the active ingredient and the proposed treatment. The composition may also contain, if desired, other therapeutic agents. ^^^^ tó ^^^^ The daily dose is from about 0.01 to about 20 mg / kg. The dosage may vary depending on the requirements of the patient, the severity of the condition being treated and the particular compound used. The determination of the appropriate dosage for a particular situation is within the experience of experts in the field of medicine. For reasons of convenience, the total daily dosage can be divided and administered in portions throughout the day or by the provision of a continuous supply. The invention described here is exemplified by the following examples that should not be considered limiting of the scope of the description. Alternative mechanistic pathways and analogous structures may be apparent to those skilled in the art. In the examples, the following abbreviations are used: phenyl (Ph), acetyl (Ac), ether (Et 2 O), ethyl acetate (EtOAc), dimethylformamide (DMF) and ethanol (EtOH). Ambient temperature is RT: PREPARATION 1 To a stirred mixture of 4-aminothiophenol (12.52 g, 0.100 mol) and 2-methyl-1-pentene (25.30 g, 0.300 mol) in anhydrous Et2O (100 ml) was added concentrated H2SO4 (15.3 ml, 0.300 mol) carefully . The clear solution is stirred for 45 min., then poured into cold saturated NaHCO3 (200 ml). the resulting white solid was collected, washed with cold water several times and dried under vacuum to provide 1 (100%). 1 H NMR (400 MHz CDCl 3) d 7.33 (d, 2 H, J = 8.7 Hz, Ar H). 6.68 (d, 2H, J = 8.6 Hz, ArH). 1.47 (m, 4H, CH2CH2CHa). 1.24 (s, 9H, (CH3) 3C), 0.97 (t, 3H, J = 7.0, Hz, (Ch) 3).

PREPARATION 2 A mixture of 3,4-difluomitrobenzene (1.0 ml, 9.03 mmol) and Na2S * 9H2O (3.25 g, 13.5 mmol) in DMF (10 ml) was stirred at RT for 20 h, then poured into cold water. The whole was extracted with CH2Cl2 (3x100 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated. To the residue was added 2-methyl-1-pentene (2.2 ml, 18.1 mmol) and Et, 2? (5.0 ml). To the vigorously stirred mixture was slowly added concentrated H2SO4 (1.0 ml). After 1 h, the reaction mixture was poured into cold water. The whole was extracted with CH2Cl2 (3x100 ml) and the combined organic layers were dried (Na2SO4), filtered and evaporated. Purification of the residue by column evaporative chromatography (1: 20 EtOAc / hexanes) provided 2 (100%).

^ Y - ^^^, .., ... ¿, < ^ X ** X »1J .s ^^^^^^ ^. . ^. ., _ ^. -ißaÉ6Éfc_ ii ^ 1H NMR (CDCI3 400 MHz) d 8.07 (m, 2H, ArH), 7.34 (t, 1 H, ArH), 1.59_ (m, 4H, CH3CH2CH2), 1.37 (s, CH, C) (CH3) 2S), 1.01 (m, 3H, CH3CH2CH2).

PREPARATION 3 A 4-toluene sulfonate mixture of S- (1, 1-dimethylbutyl) thiouronium (prepared as described: Evans, MB, et al., J. Chem. Soc, (1962), p.5045) (5.00 g, 15.0 g, 15.0 mmol) KOH (2.10 g, 37.5 mmol) and concentrated NH3 (1 drop) in EtOH (20 mL) was refluxed for 1 hour. 3-Chloro-4-fluornitrobenzene in EtOH (10 ml) was added to the reaction mixture. The mixture was refluxed for 0.5 h, allowed to cool and poured into cold water. The whole was extracted with CH2Cl2 (3x100). The combined organic layers were dried (Na 2 SO 4), filtered and concentrated to provide 3 (84%) which was used without further purification. 1 H NMR (CDCl 3 400 MHz) d 8.35 (d, 1 H J = 2.4 Hz, Ar H). 8.09 (dd, 1 H, J = 2.4, 8.5 Hz, ArH), 7.78 (d, 1 H, J = 8.5 Hz, ArH), 1.62) (m, 4H, CH3CH2CH2), 1.40 (s, 6H, C ( CH3) 2S), 0.98 (m, 3H, CH.3CH2CH2CH2).

PREPARATION 4 A mixture of 4-itrithiophenol (500 mg, 3.22 mmol), 1-iodo-2,2-dimethylpropane (0.43 ml, 4.8 mmol) and NaH (80%, 97 mg, 3.2 mmol) in DMF (10 ml) was stirred for 3 days. The reaction mixture was poured into H2O and the whole was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was subjected to evaporative chromatography (1: 50 EtOAc / hexanes) to provide 4 (190 mg, 26%) as a solid. 1 H NMR (CDCl 3 400 MHz) d 8.07 (m, 2 H, Ar H), 7.31 (m, 2 H, Ar H), 2.93 (s, 2 H, CH 2 S), 1.05 (s, 9 H, (CH 3) 3). j ^^ - * ^ & «w¡ ^ ¡» ^^^^ g2g? PREPARATION 5 Stage 1 : To an ice cooled solution of 2-methyl-2-pentanol (1.5 mL, 15 mmol) in DMF (20 mL) was added NaH (60% dispersion in mineral oil, 600 mg, 15 mmol) under an N2 The cold bath was removed and the suspension was stirred for 4 hours. The mixture was cooled in an ice bath, 4-fluornitrobenzene (1.1 ml, 10 mmol) was added in a single portion, and the The reaction mixture is stirred RT. After 18 h, the reaction mixture was poured into a suspension of ice water (300 ml) and extracted with Et2O (3x200 ml). The combined Et2O extracts were washed with H2O (6x200 ml) and saturated NaCl, dried (MgSO4), filtered and evaporated to give an oil (2.4 g). Evaporative chromatography (3: 1 Hexane / CH 2 Cl) of the crude product gave 6 (1.50 g, 67%) as an oil. 1 H NMR (CDCl 3 400 MHz) d 8.22 (2 H, m, Ar H). 1 -77 (2H, m, -OC (CH3) 2CH-), 1.52 (2H, m, - (CH2CH3), 1.47 (6H, s, -OC (CH3) 2-), 1.03 (3H, t, J = 7.3 Hz, -CH2CH3) .MS (Cl) m / e 224 (M + H) +.

Fig. 2: A mixture of 6 (1.40 g, 6.3 mmol) and 10% Pd / C (0.14 g) in CH3OH (40 ml) was stirred under a balloon of H2. After 16 h, the catalyst was removed by filtration through celite, and the filter pad was washed with CH 3 OH. The combined filtrate and washings were evaporated to give 5 as an oil (1.21 g, 100%). 1 H NMR (CDCl 3 400 MHz) d 6.83 (2H, m ArH). 6.66 (2H, m ArH), 2.61-1.50 (4H, m, -CH2CH2-), 1.25 (6H, s, -OC (CH3)? CHr). 1.25 (6H, s, -OC (CH3) 2-), 0.98 (3H, t, J = 7.1 Hz, -CH2CH3). 10 PREPARATION 6 Stage 1: To a solution of 2-chloro-5-nitropyridine (1.00 g, 6.3 mmol) in EtOH (10 ml) was added a solution of potassium 2-methyl-2-propanethiolate prepared from 2-methyl-2-propanethiol (0.71 ml, 6.3 mmol) and KOH (0.56 g, 10 mmol) in EtOH ( 10 ml). The reaction mixture was refluxed for 0.25 iiMiÉÉ MiiÉi Ifii j ^^ g ^ ^ aüa0 ¡mátáí-É? * i JfcMth¿to * fc ^ "'- i'? £ * -Át« M * ?? tg &S. h, then cooled in ice, the solid was extracted by filtration through celite, and the filtrate was evaporated to a syrup, which was dissolved in CH2Cl2 (100 ml) and washed with saturated NH4CI. Purification of the residue by evaporative chromatography (1: 4 CH2Cl2 / hexanes) gave 8 (0.80 g, 60%) as a waxy solid. 1 H NMR (CDCl 3 400 MHz) d 9.31 (1 H, d, J = 2.8 Hz ArH), 8.23 (1 H, dd, J = 8.9, 2.8 Hz, Ar H), 7.28 (1 H, d, J = 8.9 Hz ArH ) 1.70 (9H, s, -S (CH3) 3).

Step 2: To a solution of 8 (414 mg, 1.95 mmol) and NiCl2 * 6H2O (950 mg, 4.0 mmol) in CH3OH (20 mL) was added NaBH4 (301 mg, 8.0 mmol) in small portions. After 20 min, the reaction mixture was concentrated and the residue was purified by evaporative chromatography (3:97 CH3OH / CH2Cl2) to give 7 (120 mg, 34%). 1 H NMR (CDCl 3 400 MHz) d 8.35 (1 H, d, J = 2.4 Hz ArH), 7.43 (1 H, d, J = 8.3, Hz, Ar H), 7.30 (1 H, dd, J = 8.3, 2.4 Hz , ArH), 6.9 (2H, bs, NH2), 1.43 (9H, s, S (CH3) 3).

PREPARATION 7 Step 1: A mixture of 3,3-dimethylpentanoic acid (11.00 g, 84.0 mmol); Svnthesis (1985) 493) and SOCI2 (80.0 g, 678 mmol) were refluxed for 2 hours. The reaction mixture was concentrated in vacuo to provide the chloride acid in the form of a colorless oil (10.0 g, 80%). 1 H NMR (CDCl 3 400 MHz) d 2.83 (2H, s, CHzCO). 1.39 (2H, q, J = 7.3 Hz, (CH3) CH2) .1 1.02 (6H, s, C (CH3) 2, 0.86 (3H, t, J = 7.3 Hz, (CH3.) .2).

Stage 2: To an ice-cooled solution of the product from step 1 (6.00 g, 41.0 mmol) in dry Et2O (40 mL) was added 1.0 M slowly. fluorophenyl magnesium bromide in THF (37 ml, 37 mmol). The reaction mixture was stirred at 0 ° C for 3 h, then poured into a 1 N HCl solution (100 ml). The whole was extracted with EtOAc (3 x 100 ml) and the combined organic layers were dried (NaSO 4), filtered and evaporated. The purification of the residue by evaporative chromatography (hexane) gave the product (7.00 g, 82%) as a colorless oil. 1 H NMR (CDCl 3, 400 MHz) d 7.90 (2 H, m, Ar H), 2.80 (2 H, s, CH 2 CO), 1.4 (2 H, q, J = 8.0 Hz, CH s CHs), 0.87 (6 H, s (CHak C). 0.85 (3H, t, J = 7.6 Hz, CH3CH2). MS (ES) m / e 209 (M + H) +.

Step 3 To a solution of the product from step 2 (2.00 g, 9.60 mmoies) in DMSO (20.0 ml) in a sealed tube was added NaN3 (6.24 g, 96.0 mmoles). The vigorously stirred reaction mixture was heated at 140 ° C for 5 days, and then allowed to cool to RT and poured into 1 N NaOH (100 ml). The whole extract was extracted with EtOAC (3 x 100 ML). The combined organic layers were dried (Na2SO4), filtered and concentrated. Evaporative chromatography of the residue (1: 4 EtOAc / hexane) provided preparation 7 (0.66 g, 33%) as a light brown oil. 1 H NMR (CDCl 3, 400 MHz) d 7.80 (2H, d, J = 8.8 Hz, ArH). 6.70 (2H, d, J = 8.8 Hz ArH), 2.74 (2H, s, CHzCO, 1.40 (2H, q, J = 7.6 Hz, CH? CH3), 0.98 (6H, s, (CH3)? C), 0.86 (3H, t, J = 7.6 Hz, CH3CH2) .MS (FAB) m / e 206 (M + H) +.

PREPARATION 8 Using 2,2-dimethopentanoic acid as a starting material and the three-step procedure described for preparation 7, the title compound was prepared: 1 H NMR (CDCl 3, 400 MHz) d 7.76 (2H, m), 4.05 ( 2H, bs), 1.76 (2H, m), 1.30 (6H, s), 1.20 (4H, m), 0.83 (3H, t, J = 7.8 Hz). EM. M / e 206 (M + H) +.

PREPARATION 9 Stage 1 To an ice-cooled solution of cyclopropyl acetonitrile (4.7 g, 58 mmol) in anhydrous Et2O (30 ml) was added 2M of 4-fluorophenyl magnesium bromide in Et2O (25 ml, 50 mmol) and the reaction mixture was added. stirred at 0 ° C for 2 hours. The reaction mixture was allowed to warm to RT and was stirred for an additional 2 hours. The pH was adjusted to 3 by the addition of 1 N HCl and the whole was extracted with Et 2 O (4 x 50 ml). The combined layers of Et20 were washed with saturated Na2CO3 and NaCl, dried (MgSO4), filtered and concentrated. Evaporative chromatography (2:98 EtOAc / hexane) of the residue afforded the product (5.02 g, 56%). 1 H NMR (CDCl 3, 400 MHz) d 7.98 (2 H, m), 7.13 (2 H, t), 2.85 (2 H, d), 1.15 (1 H, m), 0.61 (2 H, m), 0.19 (2 H, m ). 10 EM. m / e 179 (M + H) +.

Stage 2 To an ice-cooled solution of the product from step 1 (5.0 g, 28 mmol) in anhydrous THF (100 ml) under N2, KH (16.0 g, 35% in mineral oil, 140 mmol) was added, and the mixture of reaction was stirred for 0.5 hours. Then CH3I (26 ml, 280 mmol) was added dropwise to the reaction cooled with ice. After stirring at RT for 4 hours the reaction mixture was cooled in an ice bath and saturated NH 4 Cl was carefully added. The whole was extracted with EtOAc (3 x 100 mL), washed with H2O and with saturated NaCl dried (MgSO4), filtered and concentrated. Chromatography evaporation (hexanes, then 1: 9 EtOAc / hexanes) provided the product (3.96 g, 68%). 1 H NMR (CDCl 3, 400 MHz) d 7.84 (2H, m), 1.14 (6H, s), 1.23 (1 H, m), 0.51 (2H, m), 0.42 (2H, m).

Step 3 Using the procedure of preparation 7, step 3, reaction of the product of step 2 with NaN3, the preparation 9.%) was obtained. 1 H NMR (CDCl 3, 400 MHz) d 7.86 (2H, m), 6.67 (2H, m), 4.42. (2H, bs), 1.16 (1 H, m), 1.15 (6H, s), 0.49 (2H, m), 0.42 (2H, m).

PREPARATION 10 Stage 1 A mixture of 4-fluor nitrobenzene (10.0 g, 70.9 mmol), 4-methoxybenzyl mercaptan (14.8 ml., 106 mmol), and K2CO3 (19.6 g, 142 mmoles) in acetone (150 ml) was refluxed for 4 hours. The cold reaction mixture is poured into H2O and extracted with CH2Cl2 (3 x 100 ml). The combined organic extracts were dried (Na2SO), filtered and concentrated to give an oil (17.1 g, 87%) which was used without further purification. 1 H NMR (400 MHz CDCl 3) d 8.18 (m, 2 H, Ar H), 6.94 (m, 2 H, Ar H), 4.28 (s, 2 H, -CH 2 -), 3.87 (s, 3 H, CH 30-).

Step 2: The reduction of the product from step 1 (17 g, 62 mmol) with NiCl 2, 6 H 20 / NaBH 4 according to the procedure of preparation 6, step 2, gave the product aniline (6.67 g, 44%). 1 H NMR (CDCl 3, 400 MHz) d 7.18 (m, 4 H, Ar H), 6.82 (m, 2 H, Ar H), 6.61 (m, 2 H, Ar H), 3.95 (s, 2 H, -CH 2 -), 3.85 (s) , 3H, CH3O-).

Stage 3 A mixture of the product from step 2 (6.67 g, 27.2 mmol), trimethylacetyl chloride (5.0 ml, 40 mmol), and DMAP (6.64 g, 54.4 mmol) in CH2Cl2 (100 ml) was stirred for 0.3 h. Then CH2Cl2 was added ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ (200ml) and the mixture was washed with 1 M HCl The organic layer was dried (Na 2 SO 4) filtered and evaporated. Recrystallization of the residue from Et2O / hexane / CH2Cl2 gave the product (4.6 g, 51%) as a white solid. MS (Cl) m / e 330 MS. (M + H) +.

Step 4 To a stirred, ice-cooled solution of the product from step 3 (500 mg, 1.46 mmol) in CH2Cl2 (25 mL), was added CF3COOH (6 mL) and Hg (OAc) 2 (465 mg, 1.46 mmol). ). After 1.3 hours the reaction mixture was poured into H2O, aqueous Na2S was added and the mixture was extracted with 1: 2 EtOAc / hexanes. The organic layer was dried (Na2SO) filtered, and evaporated. The residue was subjected to evaporative chromatography (1: 2 EtOAc / hexanes) to give the product (305 mg, 100%). 1 H NMR (CDCl 3, 400 MHz) d 7.51 (m, 2 H, Ar H), 7.33 (m, 2 H, ArH), 1.49 (s, 3H, CH3) 3.

EXAMPLE 1 To a mixture of Preparation 1 (10.00 g, 47 7 mmol) and pyridine (7.70 mL), 95.5 mmol) in CH2Cl2 (100 mL) was added tmethyl acetyl chloride (8.80 mL)., 71.6 mmoles). The reaction mixture was stirred at RT for 0.5 h, then poured into 2 M HCl (100 mL). The mixture was extracted with CH2Cl2 (3 x 100 mL), dried (Na2SO4), filtered and concentrated. The residue was subjected to evaporative column chromatography (1: 10 EtOAc / hexanes) to provide the title compound (76%). 1 H NMR (CDCl 3, 400 MHz) d 7.50-7.39 (m, 4H, ArH), 7.32 (S, 1 H, NH), 1.50-1.35 (m, 4H, CHUCHA 1.29 (s, 9H, ÍCJH3) 2C), 0.88 (t, 3H, CH3CH2). MS (Cl) m / e 294 (M + H) +. Using the appropriate starting materials and essentially the same procedure, the following compounds can be prepared (Table 1).

TABLE 1 15 20 EXAMPLE 2 A mixture of Preparation 1 (1.03 g, 4.92 mmol), Et3N (3.40 mL, 24.6 mmol) and triphosphene (0.585 g, 1.97 mmol) in toluene (60 mL) was refluxed for 2 h, then allowed to cool to RT. (CH 3) 2 NH (2.0 M in THF) (4.90 mL, 9.84 mmol) was added. The reaction mixture was allowed to cool to RT for 1.5 h, then poured into cold water. The whole was extracted with CH2Cl2 (3x100 ml), dried (Na2SO4), filtered and concentrated. Purification of the residue by evaporative chromatography (1: 1 EtOAc / hexanes) afforded the title compound (1.03 g, 74%) as a white solid. 1 H NMR (CDCl 3, 400 MHz) d 7.43 (m, 4 H, Ar H), 6.39 (s, 1 H, NHCO), 3.97 (s, 6 H, N (CH 3) 3), 1.45 (m, 4 H, CHzCH 2 Cme? S ). 1.23 (s, 6H, (CH3) 2CS), 0.93 (t, 3H, J = 6.88 Hz, CH3CH2). MS (Cl) m / e 281 (M + H) +. Using the appropriate starting materials and essentially the same procedure, the following compounds can be prepared (Table 2).

TABLE 2 jS ^ »* ^ - ^ J3R g.a¿ ." to" : EXAMPLE 3 To an ice-cooled mixture of Preparation 2 (2392 g, 9.03 mmol) and NiCl2-6H2o (4.83 g, 20.3 mmol) in CH3OH (100 mL) was added NaBH (1.53 g, 40.6 mmol) in portions. After 1.5 h, the reaction mixture was poured into water and the whole was extracted with CH2CI (3 x 100 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give 3-fluoro-4- (1 ', 1'-dimethyl-butylthio) aniline (56%). A mixture of the aniline (60 mg, 0.264 mmol), pyridine (0.11 ml, 1.32 mmol), and (CH3) 3CCOCI (0.065 ml, 0.528 mmol) in CH2Cl2 (1.0 ml), was stirred overnight, then subjected to on foot (1: 6 EtOAc / hexanes) to give the title compound (41%). 1 H NMR (CDCl 3l 400 MHz) d 7.65 (m, 1 H, Ar H), 7.45 (m, 2 H, Ar H &NH), 7.29 (m, 2 H, Ar H), 1.52 (m, 4 H, CH 3 CH 2 CH 2), 1.37 (s) , 9H, C (CH3) 3), 1.27 (s, 6H, C (CH3) 2S), 0.96 (t, 3H, J = 6.8 Hz, CH3CH2CH2). MS (CI) m / e 312 (M + H) +. In a similar manner, the compounds of the formula were prepared: Using the compound of Preparation 3 and the appropriate acid chloride or carbamyl chloride, the procedure of Example 3 provided the following compounds: bg ^^^^^^^^^^ feg ^^^^^^^^^^^^^^^ l ^^^^^^^^^^^^ Step 1 A mixture of 2,4-difluoromethylbenzene (2.6 ml, 23.3 mmol), p-methoxybenzyl mercaptan (2.00 g, 11.7 mmol), K2CO3 (6.47 g, 46.8 mmol) in acetone (50 m) was refluxed for 20 h. The reaction mixture was poured into cold water. The whole was extracted with CH2Cl2 (3 x 100 mL), and the combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by evaporative chromatography (1: 30 → 1: 20 EtOAc / hexanes) to give 2-fluoro-4- (4'-methoxybenzylmercapto) nitrobenzene containing a small amount of 4-flour-2- (4 ' -methoxybenzyl mercapto) 15 nitrobenzene. MS (Cl) m / e 294 (M + H) +.

Step 2 To a cooled mixture with vigorously stirred ice of 2- 20 fluor-4- (4'-methoxy-benzylmercapto) nitrobenzene and NiCl "6H2O (6.08 g, 25.6 mmol) in CH3OH was added NaBH4 (1.93 g, 51.1 mmol). ) in portions. The reaction mixture was stirred for 1 h at 0 ° C, then poured into cold water. The whole was extracted with CH2Cl2 (3 x 100 ml) and the organic layers The combined extracts were dried (Na2SO4), filtered and evaporated to give 2-fluoro- 4- (4'-methoxybenzylmercapto) aniline. MS (LC) m / e 264 (M + H) +.

Step 3 A mixture of the product from step 2, pyridine (3.1 ml, 38.4 mmol) and (CH3) 3CCOCI (3.2 ml, 25.6 mmol) in CH2Cl2 (100 ml) was stirred for 2 h, then poured into cold water . The whole was extracted with CH2CI2 (3 x 100 ml) and the combined organic layers were dried (Na2SO4), filtered and concentrated to provide 2-fluoro-4- (4'-methoxybenzylmercapto) phenyl-2,2-dimethylpropanamide. . MS (LC) m / e 348 (M + H) +.

Step 4: A solution of the product from step 3 in CF3C02H (20 ml) was heated at 80 ° C for 28 hours, and then concentrated. The residue (963 mg) was dissolved in Et2? (2 ml). 2-Methyl-1-pentene (2.0 ml) and concentrated H2SO4 (0.5 ml) were added with stirring. After 20 min, the reaction mixture was poured into CH2Cl2 (200 mL), and washed with water and saturated NaCl. Lacquer Organic was dried (Na2S? 4), filtered and concentrated. The residue was purified by foot (1 x 10 EtOAc / hexanes) to proportionally the title compound with a 16% scavenging from 2,4-difluor-nitrobenzene. 1 H NMR (CDC b, 400 MHz) d 8.37 (t, 2H, J = 8.5 Hz, ArH), 7.71 (s, 1 H, NH), 7.30 (m, 2H, ArH), 1.50 (m, 4H, CHsC bCHz ), 1.37 (s, 9H, -C (CH3) 3), 1.25 (s, 6H, C (CH3) 2S), 0.95 (t, 3H, J = 7.0 Hz, CH3CH2CH2). MS (CI) m / e 312 (M + H) +.

EXAMPLE 5 To a refluxing suspension of FeSO47H20 (3.95 g, 14.2 mmol) and Fe powder (397 mg, 7.1 mmol) in 1: 1 H2O / EtO (100 mL) was added a hot solution of Preparation 4 (319 mg, 1.42 mmol) in EtOH (10 mL). The suspension was refluxed for 6 h, allowed to cool, and filtered through celite. The filtrate was extracted with CH2Cl2 and the organic extract was dried (Na2SO4), filtered, and concentrated to provide the aniline (185 mg). A portion of the aniline (30 mg, 0.15 mmol), trimethylacetyl chloride (47 mg, 0.38 mmol), pyridine (62 mg, 0.77 mmol) and 4-dimethylamino pyridine (19 mg, 0.15 mmol) in CH2CI2 (2 ml) It stirred during the night. The reaction mixture was subjected to evaporative chromatography (1:10 EtOAc / hexanes) to provide the title compound (37 mg, 95%) as a white solid. MS (Cl) m / e 280 (M + H) +.

EXAMPLE 6 Using the procedure of Example 1, the reaction of Preparation 5 (97 mg, 0.5 mmol) and trimethylacetyl chloride (0.12 mL, 1.0 mmol) afforded the title compound (137 mg, 99%) as a white solid. 1 H NMR (CDCl 3, 400 MHz) d 7.43 (2H, m, Ar H). 6-97 (2H, m, ArH), 1.64-1.48 (4H, m, CH2CH2-), 1.34 (9H, s, -CCH3) 2-), 0.97 (3H, t, J = 7.1 Hz, -CH2CH3) , 0.95 (t, 3H, J = 7.0 Hz, CH2CH3). MS (Cl) m / e 278 (M + H) +. Using the appropriate starting materials and essentially the same procedure, the following compounds can be prepared. ? < - ^ aaS ^? iatfcrt ^ The following compounds can also be prepared using the appropriate starting materials and similar methods: H 1 EXAMPLE 7 Using the procedure of Example 1, the reaction of the product of preparation 6 (21 mg, 0.11 mmol) and trimethylacetyl chloride (25 μl, 0.20 mmol) afforded the title compound (20 mg, 65%), in the form of a solid white. 10 1 H NMR (CDCl 3, 400 MHz) d 8.59 (1 H, s, Ar H) 8.17 (1 H, d, J = 8.6 Hz, Ar H), 7.47 (1 H, d, J = 8.6 Hz, Ar H), 2.49 (9H, s, -CO (CH3) 3), 1.30 (9H, s, -S (CH3) 3). MS (Cl) m / e 267 (M + H) +. Using appropriate starting materials and essentially the In the same procedure, the following compounds can be prepared: twenty MS (CI) m / e 316 (M + H) + 7B) EXAMPLE 8 Stage 1 To a mixture of Preparation 1 (2.00 g, 9.55 mmol) and pyridine (1.50 mL, 19.1 mmol) in CH2Cl2 (100 mL) was added 2-bromo isobutyryl bromide (1.80 mL, 14.3 mmol). The reaction mixture was stirred at RT for 15 min, then poured into 1N HCl and extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was subjected to evaporative chromatography (1: 10 EtOAc hexanes) to provide 13 (99%) as a white solid. 1 H NMR (CDCl 3, 400 MHz) d 8.55 (s, 1 H; NHCO), 7.55 (m, 4 H, Ar H), 2.10 (s, 6 H, (CH 2 CBr), 1.51 (m, CH p CH 2), 1.26 ( s, 6H, (CH ^ CS), 0.96 (t, 3H, CH3CH2, MS (Cl) m / e 358 (M + H) +. jt? * á m? mJ¡ -? * -. t ^ s ^ É ^ tií & Step 2 To a stirred solution of Et2NH (58 μL, 0.558 mmol) in THF (2.0 mL) was added NaH (8.0 mg, 0.307 mmol) followed by 13 (100 mg, 0.279 mmol). The reaction mixture was stirred at RT for 30 min, and then directly subjected to standing (1: 15 EtOAc / hexanes) to provide the title compound (61%). 1 H NMR (CDCl 3, 400 MHz) d 9.63 (s, 1 H, NHCO), 7.52 (m, 4 H, Ar H), 2.62 (q, 4 H, J = 7.15 Hz, N (CH 2 (CH 3) 2), 1.48 ( m, 4H, CHzCHzCme2S), 1.36 (s, 6H, (CjH3) 2CN), 1.24 (s, 6H, CH3) 2CS) 1.17 (t, 6H, J = 7.09 Hz, N (CH2CJH3) 2) 0.94 (t, 3H, J = 6.88, CH3 (CH2) 2Cme2S) Hz. MS (Cl) m / e 351 (M + H) + Using the same procedure and the appropriate amine, the following compounds were also prepared: EXAMPLE 9 Stage 1 Using the product of Preparation 1 (210 mg, 1.0 mmol) and 2-bromo-propionyl bromide (0.10 mL, 1.0 mmol) as Starting procedure described for 13 (example 8, step 1) yielded 14 (218 mg, 64%). 1 H NMR (CDCl 3 400 MHz) d 8.13 (1 H, bs NH), 7.55 (4 H, m, Ar H), 4.61 (2 H, q, J = 7 Hz, -CHCH 3 1), 2.03 (3 H, d, J = 7 Hz, -CHCH3), ArH), 1.60-1.45 5 (4H, m, CH2CH2CH = 3), 31.26 (6H, s (CH3) 2C), 0.97 t, 3H, J = 7 Hz < , CH2CO3).

Step 2: A mixture of 14 (102 mg, 0.30 mmol), benzylamine (65 μL, 0.59 mmol), and K2CO3 (83 mg, 0.60 mmol) in DMSO (1 mL) was stirred. After 2 h. H 2 O (10 mL) was added and the whole was extracted with CH 2 Cl 2. The combined organic layers were washed with saturated NaCl, dried (MgSO4), filtered and evaporated. The residue was subjected to standing (1: 1 EtOAc / hexanes) to provide the title compound (70 mg, 62%) as crystals. 1 H NMR (400 MHz CDCl 3) d 9.60 (1 H, bs, NH), 7.62 (2H, m, 15 ArH), 7.52 (2H, m, ArH) 7.48-7.30 (5H, m, Arh), 3.90 (2H , s, CH2Ph), 3.51 (1 H, m, -CH3), 1.60-1.45 (7H, m-CHCH3), CH2CH2CH3), 1.26 (6H, s (CH3C), 0.97 (t, 3H, J = 7 Hz , CH2CH3) .MS (Cl) m / e 371 (M + H) + Using the appropriate amine and essentially the same procedure, the following compounds can also be prepared: EXAMPLE 10 To a solution of preparation 10 (50 mg, 0.24 mmol) and 3-cyclopentyl-2-methylprop-1-ene (59 mg, 0.48 mmol) in Et 2 O (0.5 mL) was added H 2 SO 4 (26 μL, 0.48 mmol). The reaction mixture was stirred for 18 h, then subjected to standing (1: 6 EtOAc / hexanes) to give the product (28 mg, 35%). 1 H NMR (CDCl 3 400 MHz) d 7.57 (m, 4 H, Ar H), 7.45 (s, 1 H, -NH) 2. 13 (m, 1 H, aliphatic H), 1.96 (m, 2H, aliphatic H), 1.62 (m, 4H, aliphatic H), 1.41 (s, 9H, (CH3) 3C-), 1.31 (s, 6H, (CH3) 2C), 1.19 (m, 4H aliphatic). MS (Cl) m / e 334 (M + H) +. Using the appropriate starting materials and essentially the same procedure, the following compounds were prepared. 10A) "10B) EXAMPLE 11 .

Stage 1 i To a mixture of Preparation 1 (2.00 g, 9.56 mmol) and Nt-butoxy-carbonylpiperidia-4-carboxylic acid (2.40 g, 10.5 mmol) in DMF (50 mL) was added DMAP (0.092 g, 0.67 mmol) and EDC (1.83 g, 11.6 mmol). The reaction mixture was stirred at RT for 16 h, then partitioned between H20 (300 mL) and EtOAc (300 mL). The organic layer was washed with H2O, dried (MgSO4), filtered and evaporated. The residue was subjected to evaporative chromatography (1.5 EtOAc / hexanes) to give the product (2.16 g, 54%) as a white solid. 1 H NMR (CDCl 3 400 MHz) d 7.50 (4 H, m, Ar H), 7.26 (1 H, s, -NH) 4.23 (2 H, s, -CH 2) 2.83 (2 H, m-CH 2), 2.42 (1 H, m, -CH2), 1.93 (2H, m -CH2), 1.78 (2H, m, -CH2), 1.50 (9H, s, -C (CH3) 3, 1.50-1.42 (4H, m- (CH2) 2-), 1.23 (6H, s, (CH3CH2C-), 0.94 (3H, t, J = 7.3 Hz, CH3).

Stage 2 The product of step 2 (2.16 g, 5.1 mmol) was added to 4M of HCl in 1.4 dioxane (70 ml) and the reaction mixture was stirred for 0.5 h. The mixture was concentrated under reduced pressure to provide a white solid (1.80 g) which was used without further purification. 1 H NMR (CDCl 3 + CD 3 OD, 400 MHz) d 7.45 (4 H, m, Ar H), 3.32 (2H, m, -H-CH2) 3.06 (2H, m -CH2), 2.71 (1 H, m, -CH), 2.02 (2H, m-CH2), 1.91 (2H, m, -CH2), 1.45 -1.32 (4H, m, - (CH2) 2-). 1.14 (6H, s, (CjH3) 2C-), 0.84 (3H, t, J = 7.3 Hz, CH3).

Step 3: To a mixture of the product from step 2 (0.10 g, 0.28 mmol) and Et3N (0.06 ml, 0.43 mmol) in CH2Cl2 (1.5 ml), benzene sulfonyl chloride (63 mg, 0.36 mmol) was added. The reaction mixture was stirred for 3 days, then diluted with CH2Cl2. The mixture was washed with 10% NH OH, 1 M HCl, and saturated NaCl, then dried (MgSO4) filtered and evaporated. The residue was subjected to standing (1: 99 CH3OH / CH2Cl2) to give the product (90 mg, 70%) as a white solid. Anal cale., For C2 H32N2H3S2: C, 62.58; H, 7.00; N, 6.08; S, 13.92 Found: C, 62.20; H 7.05; N, 6.07; S, 13.72%. MS (1 ~ AB) m / e 461 (M + H) +.

Using the appropriate sulphonyl chloride starting material and from step 3, the following compounds were prepared EXAMPLE 12 H jorn Stage 1 To a mixture of Nt-butoxycarbonyl-4-piperidone (10.0 g, 0.050 mol) and aqueous CH3NH2 (40% w / w, 10 ml) in 1,2-dichloroethane (125 ml) was added BaBH (OAc) 3 ( 16.0 g, 0.075 mol). The reaction mixture was stirred overnight, then 1 M NaOH (250 mL) was added and the whole was extracted with Et2O (700 mL). The organic layer was washed with saturated NaCl, dried (MgSO 4), filtered, and concentrated to give the product (10.5 g, 97%) as an oil that was used directly in step 2. 1 H NMR (CDCl 3 , 400 MHz) d 4.09 (2H, m), 2.86 (2H, m) 2.55 (1 H, m), 2.50 (3H, s), 1.90 (2H, m), 1.51 (9H, s), 1.30 (2H , m).

Stage 2 Using the procedure of example 1, the product of step 1, triphosgene, and the product of preparation 1 were reacted to obtain the product. 1 H NMR (CDCl 3, 400 MHz) d 7.32 (4 H, m, Ar H) 6.32 (1 H, s, NH), 4.35 (1 H, m, CH), 4.15 (2 H, m, CH 2), 2.81 (3 H, s, NCH3), 2.73 (2H m, CH2), 1.65-1.32 (8H, m, CH2x4), 1.90 (2H, m), 1.40 (9H, s, C (CH3) 3), 1.13 (6H, s, (CH3) 2), 0.83 (3H, t, J = 6.9 Hz, (CH3).

Stage 3 Using the procedure of example 11, step 2, the product of step 2 was reacted with 4M of HCl in 1,4-dioxane to obtain the product. 1 H NMR (CD 3 OD, 400 MHz) d 7.38 (1 H, m, CH), 3.50 (2 H, m, CH 2), 3.12 (2 H, m, CH 2), 2.96 (3 H, s, NCH 3), 2.03 (2 H m, CH2) 1.93 (2H, m, CH2), 1.55-1.38 (4H, m, CH2 x 2), 1.18 (6H, s, (CH3) 2), 0.91 (3H, t, J = 7.2 HZ, (CH3) .

Y '/ K J.q - -. - < ¿¿^ ^ -a I ^? ^^ i'íwímm ^ tWÉMát? I? ^ SíMu ^ íi ^^^? ^ rJ. "» -j. &. Í > ?! - ~ Jk: »ja?, S.

Step 4 To a suspension of the product from step 3 (200 mg, 0.52 mmol) and NaBH (OAc) 3 (155 mg, 0.73 mmol) in 1,2-dichloroethane (2.5 ml) was added cyclopropane carboxaldehyde (0.12 ml, 1.6 mmol). After stirring 5 for 16 h, the reaction mixture was added to 1 M NaOH (10 mL) and extracted with CH2Cl2 (20 mL). The organic layer was dried (MgSO), filtered and evaporated. The residue was subjected to standing (1: 9 CH 3 OH / CH 2 Cl 2 was saturated with conc. NH 4 OH), to give the product (166 mg, 79%) as a white solid. Anal cale., For C23H37N3 OS: C, 68.44; H, 9.24; N, 10.41; S 10 7.44. Found: C, 68.09; H 9.18; N, 10.36; S, 7.56%. MS (Cl) m / e 404 (M + H) +. Treatment of the product with 1 M excess HCl in Et 2 O followed by evaporation of the Et 2 O under reduced pressure afforded the HCl salt. Anal cale., For C23H38N3 OSC 0.5H2O: C, 61.38; H, 8.96; N, 9.34; S 7.12. Found: C, 61.72; H 8.65; N, 9.30; S, 6.81%. Using the appropriate ketone or aldehyde starting materials and the procedure of step 4, the following compounds were prepared: ^ ¡Rj £ áy ^^ ^^ ^ j &3e ^^ EXAMPLE 13 Using the procedure of example 11, step 3, the reaction of the product of example 12 step 3, with 1-naphthalenesulfonyl chloride BiaAd-Sfca-Hm -A «- 'gteiB ^ S di.l» to- provided the product. Anal cale., For C23H3N3 OS »0.25H2O: C, 64, 0.3; N, 770; S, 11.88. Found: C, 63.75; H, 6.77; N, 7.70; S, 12.05%. MS (Cl) m / e 540 (M + H) +. Using the appropriate sulfonyl chloride starting material, the following were prepared: H I X 'Y "5 *] MS (Cl) m / e 490 (M + H) * C) EXAMPLE 14 Stage 1 : To a stirred mixture of 1,4-cyclohexanedione monoethylene ketal (4.68 g, 30 mmol) and 40% w / w aqueous CH3NH2 (6.0 mL) in 1,2-dichloroethane (75 mL), Na (OAc) 3BH (9.6 g, 45 mmol) was added in portions. The reaction mixture was stirred vigorously for 16 h, then 1N NaOH (75 ml) was added. The organic layer was washed with saturated NaCl, dried (MgSO), filtered and evaporated to give an oil (4.60 g, 90%) which was used without further purification. 1 H NMR (CDCl 3) d 3.97 (4H, s), 2.47 (1 H, m) 2.46 (3H, s), 1.91 (2H, m), 1.80 (2H, m), 1.59 (2H, m), 1.45 ( 2H, m).

Stage 2 Using the procedure of example 2, the reaction of the product from step 1 with the isocyanate derived from preparation 1 gave the product MS m / e 407 (M + H) +.

Stage 3 10 A mixture of the product from step 2 (1.13 g, 2.8 mmol) and 3M HCl (10 ml) in THF (20 ml) was stirred at RT for 1 h. The mixture of The reaction was neutralized with 1 M NaOH and extracted with CH2Cl2 (2 x 50 mL). The combined organic layers were dried (MgSO4), filtered and evaporated. Chromatography (1: 99 CH3OH / CH2Cl2) of the residue gave the product (0.90 g, 88%, MS m / e 363 (M + H) +.

Step 4 To a stirred mixture of the product from step 3 (100 g, 0.28 mmol) and 40% w / w (CH 3) 2 NH (0.09 ml, 0.9 mmol) in CH 2 Cl 2 (1 ml) was added Na (OAc) 3) BH (88 mg, 0.42 mmol). After 16 h, it was added 1 M NaOH (5 ml) and the whole was extracted with CH2Cl2 (2 x 10 ml). The combined organic layers were dried (MgSO4), filtered and concentrated. Purification of the residue by preparative tic (1: 7: 92 conc NH4OH / CH3OH / CH2 CI2) gave the less polar cis isomer, 14 A (48 mg, 45%) and the more polar trans isomer, 14B (31 mg, 29%). 14A, cis isomer 1 H NMR (CDCl 3 + CD 3 OD, 400 MHz) d 7.22 (4 H, m), 4.08 (1 H, m) 2.79 (3 H, s), 2.13 (6 H, s), 2.08 (1 H, m) , 1.83 (2H, m), 2.60 (2H, m), 1.40-1.23 (8H, m), 1.03 (6H, s), 0.74 (3H, t = 7.3 Hz) MS m / e 392 (M + H) +. 14B, trans isomer 1 H NMR (CDCl 3 + CD 3 OD, 400 MHz) d 7.22 (4 H, m), 3.92 (1 H, m) 2.72 (3 H, s), 2.13 (6 H, s), 1.96 (1 H, m) , 1.93 (2H, m), 1.63 (2H, m), 1.45-1.22 (8H, m), 1.04 (6H, s), 0.74 (3H, t = 7.2 Hz) MS m / e 392 (M + H) +. Using the appropriate amine and essentially the same procedure outlined in example 14, step 4, the following compounds were prepared. s ~ t * ^! í £ * 10 15 20 fifteen Using the procedure of Example 2, Preparation 7, Pr2Net, triphosgene, and 4- (2-methylamino) ethylpyridine were reacted to obtain the product. 1 H NMR (CDCl 3, 400 MHz) d 8.50 (2H, s, Ar H). 7.85 (2 H, m, Ar H), 7.41 (2 H, m, Ar H) 7.19 (2 H, m, Ar H) 6.60 (1 H, s, NH) 3.60 (2 H, 17, J = 6.8 Hz, CH 2 N), 2.97 ( 3H, s, CH3N), 2.95 (2H, 7, J = 7.2 Hz, NCH2CH2) 2.77 (2H, s, (CH2CO), 1.40 (2H, q, J = 7.6 Hz, CH3CH2); 1.03 (6h, S, CH.C), 0.85 (3H, t, J = 7.6 Hz, CH3CH2) .MS (ES) m / e 368 (M + H) + .The reaction of preparation 7, 8 or 9, triphosgene, and the amine suitable by essentially the same procedure provided the following compounds: where a, R 36, D R7, I R-.20 and R) 12 are as defined in the table M & »and» ytlsCjma EXAMPLE 16 Step 1: Using the procedure described in Example 11, Step 2, the compound of Example 15H was treated with HCl to obtain the hydrochloride. MS m / e 346 (M-CI) +. Step 2- Using the procedure described in Example 12, Step 4, cyclopropane carboxaldehyde was reacted with the product of Step 1 to obtain the title compound. MS m / e 400 (M + H) +. Using the appropriate starting materials and essentially the same procedure, the following compounds were prepared: 'Mafe ».; -»: foj »' *» - > . suate &afet? rt? i va? ab EXAMPLE 17 Step 1: To a mixture of t-butyl diphenyl chlorosilane (9.3 g, 34 mmol) and Et3N (5.12 g, 51 mmol) in CH3CN (50 mL) was slowly added N-methy-ethylenediamine (5.0 g, 67 mmol) The reaction mixture was stirred for 2 h After the CH3CN removal, the residue was dissolved in CH2Cl2 and washed with saturated NaHCO3 and H2O. The organic layer was dried (MgSO) filtered and evaporated to give a colorless oil (10.2 g) which was used directly in Step 2.

Stage 2 Using the procedure of Example 2, the reaction of preparation 8, triphosgene and the product of Step 2 gave the product MS m / e 306.1 (M + H) +.

Step 3: To a solution of the product from Step 2 (95 mg, 0.31 mmol) and Et3N (63 mg, 0.62 mmol) in CH2Cl2 (2 mL) was added CH3SO2CI (72 mg, 0.63 mmol) per drop. After 5 min., The reaction mixture was subjected to preparative TLC (CH2Cl2 / CH3OH / conc.NH4OH 10: 1: 0.1) to provide the product (70 mg, 59%) 1 H NMR (CDCl3, 400 MHz) d 7.76 (2H, r, ArH), 7.47 (2H, m, ArH), 7.20 (1 H, s, NH) 5.90 (1 H, bs, NH), 3.50 (2H, m, CH2CH2), 3.30 (2H, m , CH2CH2), 2.98 (3H, s, CH3), 2.97 (s, 3H, CH3) 1.70 (m, 2H, CH2) 1.05-1.4 (8H, m, (CH3) 2, &CH2), 0.9 (t , 3H, J = 7.3 Hz, CH3). MS m / e 384.1 (M + H) +.

EXAMPLE 18 To a solution of Example 15 (330 mg, 0.90 mmol) in CH 3 OH (10 mL) at RT was added NaBH (68 mg, 18 mmol) in portions. The reaction was stirred at room temperature for 2 h, then poured into saturated NaHCO3. The whole was extracted with CH2Cl2 (3 x 50 mL), the combined organic layers were washed with H2O and brine, dried (NaSO4), filtered and concentrated. The crude product (230 mg, 69%) was used in the next step without further purification. 1 H NMR (CDCl 3, 400 MH «d 8.50 (2H, br ar), 7.10-7.30 (CH, m, ArH), 6.30 (1 H, s, NH), 4.75 (1 H, m, HOCH), 3.60 ( H, t, J = 7.2 Hz, CHZN), 2.93 (3H, s, CH3N), 2.88 (2H, t, J = 7.6 Hz, NCH2CH2), 2.22 (1 H, br, OH), 1.70 (1 H, m, HOCHClHaHb), 1.50 (1 H, m, HOCHCHaHb), 1.31 (m, 2H, C zQ g), 0.89 (6H, s, (CH3)? C), 0.80 (3H, t, J = 7.2 Hz, CH3CH2) Using the appropriate starting material and essentially the same procedure, the following compounds were obtained. where a, R, R, R > 20 and R > 12 are as defined in the table EXAMPLE 19 To a solution of Example 18 (230 mg, 0.62 mmol) in dry CH 2 Cl 2 (20 mL) was added Et 3 SiH (723 mg, 6.2 mmol) and CF 3 CO H (142 mg, 1.2 mmol). The reaction mixture was stirred at RT for 16 h, then concentrated The residue was subjected to preparative TLC (1:10 (2M NH 3 in CH 3 OH) / CH 2 Cl 2) to give the product (180 mg, 82%) as a colorless oil. 1 H NMR (CDCl 3, 400 MHz) d 8.50 (2H, m ArH), 7.0-7.25 (6H, m, ArH), 6.20 (1 H, s, NH), 3.60 (2H, t, J = 7.20 Hz, CjH2N ), 2.94 (3H, s, CH2N), 2.85 (2H, t, J = 7.20 Hz, CH? CH7N), 2.45 (2H, m, CHgCH2) CMe2), 1.40 (2H, m, CH2CH2) CMe2), 1.30 (2H, q, J = 7.2 Hz, CH3CH2), 0.88 (CH, s, C (C3)?), 0.80 (3m, t, J = 7.6 Hz, CJH3CH2). MS (ES) m / e 354 (M + H) +. Using the appropriate starting material and essentially the same procedure, the following compounds were prepared. where a, R6, R7, R20 and R12 are as defined in the table.

^^^^^ M ^^ j ^^^^^^^^^^^^ i ^^^^^^ EXAMPLE 20 Stage 1 The reaction of preparation 8 with the product of example 14, step 1 according to the procedure of example 2, provided the product. 1 H NMR (CDCl 3, 400 MHz) d 7.76 (2 H, m), 7.42 (2 H, m), 6.48 (1 H, s), 4.28 (1 H, m), 3.95 (4 H, s), 2.91 (3 H, s), 1.75 (10H, m), 1.30 (6H, s), 1.21 (2H, m), 0.83 (3H, t) MS m / e 403 (M + H) +.

Stage 2: Reaction of the product from step 1 with HCl by the procedure of example 14, step 3, provided the product. 1 H NMR (CDCl 3, 400 MHz) d 7.77 (2 H, m), 7.44 (2 H, m), 6.58 (1 H, s), 4.81 (1 H, m), 2.91 (3 H, s), 2.57 (2 H, m), 2.46 (2H, m), 2.03 (2H, m), 1.75 (2H, m), 1.30 (6H, s), 1.21 (2H, m), 0.83 (3H, t). MS m / e 359 (M + H) +.

Step 3: Reaction of the product of step 2 with cyclopropane methylamine by the procedure of example 14, step 4, gave the product as a mixture of cis and trans isomers which was separated by preparative tic (1: 9 (2M NH3 in CH 3 OH) / CH 2 Cl 2. 20A cis isomers less polar * v 1H NMR (CDCl 3, 400 MHz) d 7.75 (2H, m), 7.44 (2H, m), 6.58 (1 H, s), 4.14 (1 H, m), 2.94 (3 H, s), 2.93 (1 H, m), 2.46 (2 H, m), 1.85 (4 H, m), 1.74 (2 H, m) , 1.59 (2H, m), 1.59 (2H, m), 1.46 (2H, m), 1.29 (6H, s) 1.20 (2H, m) 0.98 (1 H, m) 0.82 (3H, t J = 7.2 Hz ), 0.51 (2H, m), 0.14 (2H, m) MS m / e 414 (M + Hf. 20B trans isomers more polar v: 1 H NMR (CDCl 3, 400 MHz) d 7.75 (2 H, m), 7.45 (2 H, m), 6.64 (1 H, s), 4.16 (1 H, m), 2.89 (3 H, s ), 2.50 (3H, m), 2.05 (2H, m), 1.74 (4H, m), 1.51 (2H, m), 1.38 (2H, m), 129 (6H, s), 123 (2H, m) , 0.98 (1 H, m), 0.82 (3H, t J = 7.3 Hz), 0.49 (2H, m), 0.15 (2H, m), MS m / e 414 (M + H) +. . rte - »* - In a similar way they were prepared from the product of the stage C 1 H NMR (CDCl 3, 400 MHz) d 7.77 (2 H, m), 7.42 (2 H, m), 6.50 (1 H, s), 4.14 (1 H, m), 2.93 (3 H, s), 2.72 (1 H, m), 2.39 (3H, s), 1.84 (4H, m), 1.76 (2H, m), 1.59 (2H, m), 1.46 (2H, m), 1.30 (6H, s), 1.21 (2H, m), 0.82 (3H, t J = 7.2 Hz), MS m / e 374 (M + H) +. 20 1 H NMR (CDCl 3, 400 MHz) d 7.76 (2H, m), 7.42 (2H, m), 6.48 (1 H, s), 4.17 (1 H, m), 2.89 (3 H, s), 2.44 ( 3H, s), 2.35 (1 H, m), 2.05 (2H, m), 1.75 (4H, m), 1.50 (2H, m), 1.46 (2H, m), 1.30 (6H, s), 1.21 ( 2H, m), 0.83 (3H, t J = 7.3 Hz), MS m / e 374 (M + H) +.

E 1 H NMR (CDCl 3, 400 MHz) d 7.75 (2 H, m), 7.43 (2 H, m), 6.51 (1 H, s), 4.14 (1 H, m), 3.70 (2 H, m), 2.93 ( 3H, s), 2.80 (2H, m), 2.52 (1H, m), 1.88 (4H, m), 1.75 (2H, m), 1.71 (2H, m), 1.51 (2H, m), 1.30 ( 6H, s), 1.21 (2H, m) 0.83 (3H, t J = 7.3 Hz). MS m / e 404 (M + H) +.

F 1 H NMR (CDCl 3, 400 MHz) d 7.75 (2 H, m), 7.43 (2 H, m), 6.54 (1 H, s), 4.14 (1 H, m), 3.70 (2 H, m), 2.88 ( 3H, s), 2.86 (2H, m), 2.51 (3H, m), 2.08 (2H, m), 2.51 (3H, m), 2.08 (2H, m), 1.75 (4H, m), 1.51 (2H , m), 1.30 (6H, s) 1.21 (2H, m), 0.83 (3H, t J = 7.3 Hz). MS m / e 404 (M + H) +.

EXAMPLE 21 Reduction of Example 20 A with NaBH 4 by the procedure of Example 18 afforded the title compound. 1 H NMR (CDCl 3, 400 MHz) d 7.34 (2 H, m), 7.20 (2 H, m), 6.32 (1 H, s), 4.40 (1 H, s), 4.16 (1 H, m), 2.93 (4 H , s), 2.46 (2H, m), 1.88 (4H, m), 1.60 (2H, m), 1.49 (2H, m), 1.49 (2H, m), 1.31 (4H, m), 0.99 (1H , m), 0.87 (6H, s) 0.79 (3H, m) 0.51 (2H, m) 0.15 (2H, m). MS m / e 416 (M + H) +. In a similar way, it was prepared: 21A 10 1 H NMR (CDCl 3, 400 MHz) d 7.34 (2H, m), 7.21 (2H, m), 6.31 (1 H, s), 4.41 (1 H, s), 4.18 (1 H, m), 2.93 (3 H, s), 2.78 (1 H, m), 2.43 (3 H, s), 1.87 (4 H, m ), 1.62 (2H, m), 1.49 (2H, m), 1.31 (4H, m), 0.87 (6H, s), 0.79 (3H, m). MS m / e 376 (M + H) +.

EXAMPLE 22 The reduction of Example 20 with Et3SiH / TFA by the procedure of Example 19 afforded the title compound. 1 H NMR (CDCl 3, 400 MHz) d 7.28 (2H, m), 7.10 (2H, m), 6.26 (1 H, s), 4.16 (1 H, s), 2.93 (3 H, s), 2.89 (1 H , m), 2.47 (2H, m), 2.43 (2H, s), 1.87 (4H, m), 1.60 (2H, m), ? ^ L & ^ Ss? &M ^! ¡^ S?., - * ^ v £ tS? Ll ^^ ß ^^ Me, 1.48 (2H, m), 1.31 (2H, m), 1.16 ( 2H, m), 0.99 (1 H, m) 0.88 (3H, t, J = 7.3 Hz), 0.81 (6H, s) 0.50 (2H, m), 0.15 (2H, m) MS m / e 400 (M + H) +. In a similar manner, the following compound was prepared: 22A 1 H NMR (CDCl 3, 400 MHz) d 7.27 (2H, m), 7.01 (2H, m), 6.26 (1 H, s), 4.18 (1 H, m), 2.92 (3 H, s), 2.77 (1 H, m), 2.43 (5H, s), 1.88 (4H, m), 1.66 (2H, m), 1.50 (2H, t), 1.30 (2H, m), 1.11 (2H, m), 0.88 (3H , s), 0.81 (6H, s) MS m / e 360 (M + H) +.

EXAMPLE 23 Etap H Using the procedure of example 1, the reaction of preparation 8, trimethyl acetyl chloride and pyridine provided the product toßb & d tYes & tiu v & kae *. *? * !. , & -a > -f at 1 H NMR (CDCl 3, 400 MHz) d 7.76 (d, 2 H, J = 8.8 Hz, Arh), 7.57), (d, J = 8.4 Hz Arh). 7.41 (s, 1 H, NH) 1.75 (m, 2H, CH3CH2CH2), 1.32 (s, 9H, CH ^ C), 1.30 (s, 6H, CH ^ C, 1.26 (m 2H CH2CH3) 0.84 (t, 3H, J = 7.2 Hz, CH3CH2) MS m / e 290 (M + H) + Step 2: To a solution of the product from step 1 (100 mg, 0. 346 mmoles) in dry CH 2 Cl 2 (1.0 ml) was added (diethylamino) sulfur trifluoride (557 mg, 23.46 mmoles). The reaction mixture was heated at 80 ° C overnight, and then allowed to cool to RT. The crude mixture was subjected to standing (1: 6 EtOAc / hexanes) to give the product (25.0 mg, 23%) as a colorless oil. 1 H NMR (CDCl 3, 400 MHz) d 7.37 (m, 2 H, Ar H), 7.26 (m, 2 H, Ar H), 1.32 (m, 13 H, Cj H 3) 3 C d CH 3 CH 2 CH 2), 0.98 (s, 6 H, (CH 3) 2C, 0.87 (m, 3H, CH3CH2). MS m / e 312 (M + H) +.

Claims (13)

NOVELTY OF THE INVENTION CLAIMS Having thus specially described and claimed the nature of the present invention and the manner in which it is to be put into practice, it is claimed to claim as property and exclusive right:

1. - A compound that has the structural formula or a pharmaceutically acceptable salt thereof, wherein a and b are independently 0, 1 or 2, with the proviso that the sum of a and b is 0 to 15 3; X is -O-, -S-, -SO-, -SO2-, -CH (OR ÑOR8 20 C (R25) = C (R25) - C = C- or - C-; R1 is R15-aryl, R24-heteroaryl, -NHR12, -N (R12) 2, - (d-C9) alk-OC (O) R8, aryloxy (C? -9) alkyl, where m is 1-4, or where d and e are independently 0, 1 or 2; R 2, R 3, R 4 and R 5 are independently selected from the group consisting of H, straight chain C 1 -C 5 alkyl or > a8S »~. * -. - "-. ^". ^ Aaírt ». ' - ^ ¿? S IBßRa t *** ?? & s * .¿? «A. >," - ^ MBS ».¡,« .Aat - aaranj- .. branched (C3-C2) cycloalkyl, R14- (C3-C12) cycloalkyl, halogen, -OR8, -N (R8) 2, -C02R8 and CF3; R6 and R7 are independently selected from the group consisting of H, (CrC9) alkyl (CrC9) alkenyl, hydroxy- (C? -9) alkyl, amino- (CrC9) alkyl, (C1-C9) alkoxy- (C? C9) alkyl, (C3-C?) Cycloalkyl and (C3-Ci2) cycloalkyl- (C? -C6) alkyl, or R6 and R7 together with the carbon to which they are attached, form a carbocyclic ring of 3, 4, 5 , 6, or 7 members form a carbocyclic ring, or a 4, 5, 6 or 7 membered heterocyclic ring, wherein 1, 2 or 3 ring members are independently selected from the group consisting of O, S and N; R8 is independently selected from the group consisting of H, (C1-C6) (C3-C12) alkyl, cycloalkyl, R15-aryl and R24 heteroaryl; R9 is (C C6) alkyl, (C3-C12) cycloalkyl, R15-aryl or R24-heteroaryl; R11 is independently selected from the group consisting of H, (C? -C6) alkyl and (C3-Ci2) cycloalkyl; R12 is independently selected from the group consisting of (C? -Cg) straight or branched chain alkyl, hydroxy (C2-C9) alkyl, (C1-C9) alkoxy- (C2-C9) alkyl, N (R11) R19 ) - (C2-C9) alkyl, HS (C2-C9) alkyl, (d- C9) alkylthio- (C2-C9) -alkyl, (C3-C12) -cycloalkyl, R14- (C3-C? 2) cycloalkyl R15-aryl, R24-heteroaryl, R15-aryl (C? -C6) -alkyl, R24-heteroaryl (C? -C6) -alkyl, where j and k are independently 0, 1 or 2, where q is 1 or 2, and s is 0, 1 or 2, or two groups R12, together with the nitrogen to which they are attached form a ring of formula: 10 in which p is 0, 1 or 2; R 0 is -NR 18, -O- or -S-; R13 represents 1 to 3 substituents independently selected from the group consisting of hydrogen, (Ci-β-chalkyl, halogen, (C?-Cd) alkoxy and CF 3; R 14 represents 1 to 3 substituents independently selected from the group consisting of (C?-C6) alkyl, benzyl, R13-aryl and R13-heteroaryl, R15 represents 1 to 2 Substituent (s) independently selected from the group consisting of hydrogen, (C? -C6) alkyl, halo, polyhalo (C? -C6) alkyl, R170-. -NR17) 2-S (R17), R17 0- (C? -C6) alkyl, (R17) 2N- (C? -C6) alkyl, formyl, -C (O) R17, -COOR17, -CON (R17) ) 2) -OC (O) N (R17) 2, -N (R17) C (O) N (R17) 2, -NR17C (O) R17, -NR17C (O) OR14, R17SO-, R17SO2-, R17SO NR17- and trí (C1-C6) alkylsilyl: R16 20 consists of 1-3 substituents independently selected from the group consisting of H, (CrCßJalkyl, (C3-C2) cycloalkyl, (C3-C2) spirocycloalkyl, (C3-C4) spiro-alkylenedicxy, R15-aryl, R24-heteroaryl, benzyl, N-piperidinyl, -COR8, -C (O) NR8R9, -NR8R9 and -NR8C (O) R9, or when two R16 groups are attached to carbon atoms of an adjacent ring, together with said carbon atoms, they can form a (C5-C) cycloalkyl ring; R17 are independently selected from the group consisting of H, (CrCßJalkyl and (C3-Ci2) cycloalkyl (C3-C12) cycloalkyl (Cr5C6) alkyl; R13-aryl and R13-heteroaryl; R18 is independently selected from the group consisting of H, (d-CβJalkyl, (C3-C ?2) cycloalkyl, (C3-C12) cycloalkyl- (CrC6) alkyl; R15-aryl, R24-heteroaryl, -CO2R9, C (O) (R8) 2, -COR8 and -SO2R9; R19 is H, (C3-C2) cycloalkyl- (C6C6) alkylof R15-aryl, R24-heteroaryl CO2R9-C (O) N (R8) 2, -COR8 or -SO2R9; R20 is (d- 10 C6) (C3-C [alpha]) cycloalkyl, (OrC ^ cycloalkyl-id-d alkyl, hydroxy (d-C-alkylalkyl, oxo (CrC6) alkyl or polyhalo (d-C6) alkyl; R21 and R22 are independently selected the group consisting of H, (d-CdJalkyl, (C3-C? 2) cycloalkyl- (C? -C6) alkyl, hydroxy (d-C6) alkyl, R15-aryl, R24-heteroaryl, R15- aryl (C C6) alkyl or R24-heteroaryl (C? -C6) alkyl; R23 is Independently selected from the group consisting of H, halogen, (dC 6) alkyl, (C 3 -C 2) cycloalkyl, R 15aryl and R 24 heteroaryl; R24 represents 1 or 2 substituents which are independently selected from the group consisting of hydrogen, (dC6) alkyl, halo, polyhalo, (CrC6) alkyl, R17O-, - N (R17) 2S- (R17), R17O- ( CrC6) alkyl, - (R ^ N-id-CeJalkyl, formyl, -C (O) R17, 20 COOR17 '-CON (R17) 2, OC (O) N (R7) 2, -N (R17) C (O) N (R17) 2, N (R17) C (O) (R17), - N (R17) C (O) O (R14), R17S (O) -, R17SO2) (R17) SO

2, NR17- and tri (d- C-chalkyalkylsilyl; and R25 is independently selected from the group consisting of hydrogen, halogen, (C ? -C6) alkyl, and polyhalo (d-C6) alkyl. = C- 2.- A compound of claim 1 wherein Q is R4

3. A compound according to claim 1 wherein R3 and R4 are each H; and R2 and R5 are independently selected from the group consisting of hydrogen and halogen.

4. A compound according to claim 1 wherein X is -S-; CO)-; CH (OR8) - or -C (R23) 2.

5. A compound according to claim 4, wherein X is -C (R23) 2- and R23 is hydrogen.

6. A compound according to claim 1, wherein a is 1 or 2 and b is 0.

7. A compound according to claim 1, wherein R1 is -NHR12 or -N (R12) 2.

8. A compound according to claim 7, wherein R1 is twenty where R18 is (C1-C6) alkyl or -SO2R9; R9 is (C6) alkyl or aryl; R22 is (d-C6) alkyl or (C3-C12) cycloalkyl (d-C6) alkyl.

9. A compound according to claim 1 wherein R6 and R7 are each (C? -C6) alkyl, or R6 and R7, together with the carbon to which they are attached, form a C3-Cß carboxylic ring.

10. A compound according to claim 1, selected from the group consisting of those having the structural formula wherein R > 2/0 ?, D R6 °, R D7 ', a, X, R12 are as defined in the following table: «-ihtoSEtet .. m-? * f »*« -o- '¿t. -a? gu. - »

11. - A compound selected from the group consisting of those that have the structural formula wherein R20, R6, R7, a, X, R5, R2, R3, Q and R1 are as defined in the following table:

12. - A pharmaceutical composition comprising a compound as defined in claim 1, in combination with a pharmaceutically acceptable carrier.

13. The use of a compound of claim 1, for the 15 preparing a medication to treat an eating disorder or diabetes. SUMMARY OF THE INVENTION Compounds of the formula I are claimed or a pharmaceutically acceptable salt thereof, in which a and b are 0-2 with the condition that the sum is 0-3; Q is -N = R " X is -O-; -S-, -SO- -SO2-, -CH (OR, -C (O) -, -C (R > 2 ^ 3) 2-, optionally substituted alkenyl, alkynylOR8, or i_R1 is optionally substituted aryl , heteroaryl, substituted amino, alkyl-OC (0) R, aryloxyalkyl, where d and e are O-2; R2, R3, R4 and R5 are H, optionally substituted cycloalkyl alkyl, halogen-OR8, -N (R8) 2, -CO2R8 or CF3; R6 and R7 are H, alkyl, alkenyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkyl, or R6 and R7, form a 3-7 membered carbocyclic ring or a 4-7 membered heterocyclic ring; R8 is H, alkyl, cycloalkyl, aryl or optionally substituted heteroaryl; R9 is optionally substituted alkyl, cycloalkyl, aryl or heteroaryl; R11 is H, alkyl or cycloalkyl; and R23 is R8 or halogen; as well as also new additional compounds; likewise pharmaceutical compositions and methods are claimed - jJßía. -. - > . Y . -TO ^ i »a8¡fc, j3k -. &ii. Use of said new compounds in the treatment of eating disorders and diabetes. . v • SCHERING / all * P00 / 1725F