MXPA06013786A - Aminopyridine derivatives as selective dopamine d3 agonists. - Google Patents

Abstract

The present invention provides for compounds of formula (I) which are a class of dopamine agonists, more particularly a class of agonists that are selective for D3 over D2. These compounds are useful for the treatment and/or prevention of sexual dysfunction, for example female sexual dysfunction (FSD), in particular female sexual arousal disorder (FSAD), hypoactive sexual desire disorder (HSDD; lack of interest in sex), female orgasmic disorder (FOD; inability to achieve orgasm); and male sexual dysfunction, in particular male erectile dysfunction (MED). Male sexual dysfunction as referred to herein is meant to include ejaculatory disorders such as premature ejaculation, anorgasmia (inability to achieve orgasm) or desire disorders such as hypoactive sexual desire disorder (HSDD; lack of interest in sex). These compounds are also useful in treating neuropsychiatric disorders and neurodegenerative disorders.

Description

R3 is selected from: wherein: A represents O, S or CH2; n is 1 or 2; R 4 is selected from H and (C 1 -C 6) alkyl; wherein said (C1-C6) alkyl may be optionally substituted with 1 or 2 substituents each independently selected from alkyl (Ci-Ce), OR7, phenyl, substituted phenyl and heteroaryl; R5 is selected from H and (C1-C6) alkyl; wherein said (C1-C6) alkyl may be optionally substituted with 1 or 2 OR7 groups; R6 is selected from H and (C1-C6) alkyl; R7 is selected from H and (C1-C6) alkyl; wherein said alkyl (C1-C6) can be optionally substituted with a phenyl, or a substituted phenyl group; R8 is selected from H, methyl, ethyl, methoxy, and ethoxy; R9 represents (C1-C6) alkyl; and R10 is selected from H and alkyl (Ci-C6); wherein said alkyl (C1-C6) may be optionally substituted with 1 or 2 substituents each independently selected from OR7, phenyl or substituted phenyl; wherein heteroaryl means an aromatic ring of 5 to 7 members, containing from 1 to 4 heteroatoms, each of said heteroatoms independently selected from O, S and N; said heteroaryl may be optionally substituted with 1 or more substituents each independently selected from alkyl (Ci-C6), halo and OR7, each substituent may be the same or different; and wherein substituted phenyl means phenyl substituted with 1 or more substituents each independently selected from alkyl (C Ce), halo and OR7, each substituent may be the same or different; provided that: when R1 and R2 are H, R3 is the residue (II), A is O, R5 is H or alkyl (Ci-C6), and R6 is H or alkyl (Ci-Ce), then R4 is not it can be n-propyl; and its pharmaceutically acceptable salts, solvates, polymorphs and prodrugs. Unless otherwise indicated, the alkyl (Ci-Ce) may be straight or branched chain. Suitable heteroaryl groups include pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl. Unless otherwise indicated, the term halo means fluorine, chlorine, bromine or iodine. 'Unless otherwise indicated, the term substituted means substituted by one or more defined groups. In the case where the groups can be selected from several alternative groups, the selected groups can be the same or different.

The pharmaceutically acceptable salts of the compounds of the formula (I) include their acid addition salts and their base salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the salts of aceta-to, adipate, aspartate, benzoate, besilate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisilate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybienate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate. • Hemisal acids can also be formed, for example, hemisulfate. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties. Selection and Use by StahI and Wermuth (Wiley-VCH, 2002). The pharmaceutically acceptable salts of the compounds of formula I can be prepared by one or more of three methods: (I) by reacting the compound of formula I with the desired acid or base; (II) removing an acid or base labile protecting group from a suitable precursor of the compound of formula I or by ring opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (III) converting one salt of the compound of formula I to another by reaction with an acid or appropriate base or by means of a suitable ion exchange column. The three reactions are typically carried out in solution. The resulting salt can be precipitated and collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from completely ionized to almost non-ionized. The compounds of the invention can exist in a continuous series of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks order at a long distance at the molecular level and, depending on the temperature, it can exhibit the physical properties of a solid or a liquid. Typically such materials do not give characteristic X-ray diffraction patterns and, even exhibiting the properties of a solid, are more formally described as a liquid. After heating, a change of properties of solid to properties of liquid occurs which is characterized by a change of state, typically of second order ('vitreous transition'). The term 'crystalline' refers to a solid phase in which the material has a regular internal structure ordered at the molecular level and gives a characteristic X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically of first order ('melting point'). The compounds of the invention can also exist in solvated and unsolvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is used when said solvent is water. The pharmaceutically acceptable solvates of the compounds of the formula (I) include their hydrates. A currently accepted classification system for organic hydrates is one that defines hydrates of isolated site, channel, or coordinated with metal ion - see Polymorphsm in Pharmaceutical Sollds by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which water molecules are isolated from direct contact with each other by interposition of organic molecules. In channel hydrates, water molecules are located in channels of the crystal lattice in which they are adjacent to other water molecules. In hydrates coordinated with metal ion, the water molecules are bound to the metal ion. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of moisture. However, when the solvent or water is weakly bound, as in channel solvates and in hygroscopic compounds, the water / solvent content will be dependent on moisture and drying conditions. In such cases, non-stoichiometry will be the norm. Hereinafter all references to the compounds of formula I include references to their salts and solvates. The compounds of the invention include the compounds of formula I as defined hereinbefore, including all their polymorphs and crystalline growth forms, their prodrugs and isomers (including the optical, geometric and tautomeric isomers) as defined above. hereinafter and the compounds of formula I isotopically labeled. All stereoisomers, geometric isomers and tau-timer forms of the compounds of formula I are included within the scope of the present invention, including compounds that exhibit more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition salts or base salts in which the counter ion is optically active, for example, d-lactate or / -lysine, or racemic, eg, o-tartrate or a7-arg nina A compound of the formula (I) contains one or more asymmetric carbon atoms and therefore exists in two or more stereoisomeric forms. In addition, the skilled person will understand that the remainder (II) encompasses all stereoisomeric and diastereoisomeric forms, in particular: The separation of diastereoisomers can be achieved by conventional techniques, for example by fractional crystallization, chromatography or H.P.LC. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) can also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallization of the diastereomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate. The present invention includes all isotopically-labeled pharmaceutically acceptable compounds of formula I in which one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which It predominates in nature. Examples of suitable isotopes for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 1 C, 13C and 14C, chloro, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen, such as 13N and 15N, oxygen, such as 150, 170, and 180, phosphorus, such as 32P, and sulfur, such as 35S.

Certain isotopically-labeled compounds of formula I, for example, those incorporating a radioactive isotope, are useful in studies of the distribution in drug and / or substrate tissues. The radioactive isotopes tritium, ie 3H, and carbon-14, ie 14C, are particularly useful for this purpose in view of their ease of incorporation and their rapid detection means. Substitution with heavier isotopes such as deuterium, ie 2H, can provide some type of therapeutic advantages resulting from increased metabolic stability, for example, increased half-life in vivo or reduction of dosage requirements, and therefore It can be preferred in some circumstances. Substitution with positron-emitting isotopes, such as 1C, 8F, 150 and 13N, may be useful in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. The isotopically-labeled compounds of formula I can generally be prepared by conventional techniques known to those skilled in the art or by procedures analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the unlabeled reagent previously employed. The pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be isotopically substituted, for example D2O, acetone-d6, DMSO-d6. The following embodiments of the invention are particularly preferred - ¬ ¬ preferably: R1 is preferably selected from H, methyl and ethyl More preferably R1 is selected from H and methyl Most preferably R1 is H. Preferably R2 is selected from H, methyl and ethyl More preferably R2 is selected from H and methyl Most preferably R2 is H. When R3 is the rest (II): The residues (lia) and (llb) are preferred. Preferably A is O or CH 2 More preferably A is O Preferably R 4 is (C 1 -C 6) alkyl optionally substituted with a phenyl or a substituted phenyl group. More preferably R 4 is (C 1 -C 6) alkyl optionally substituted with phenyl. Even more preferably R 4 is selected from methyl, ethyl, n-propyl or n-butyl. Most preferably R 4 is selected from methyl, ethyl, and n-propyl. In a first preferred embodiment, R5 is selected from H and (C1-C4) alkyl; wherein said (C1-C4) alkyl may be optionally substituted with 1 or 2 groups OR7 More preferably R5 is selected from H, methyl and ethyl; wherein said methyl and said ethyl can be optionally substituted with an OR7 group. Most preferably R5 is selected from H, methyl and ethyl. In a second preferred embodiment, R5 is (C1-C4) alkyl optionally substituted with 1 or 2 groups OR7 More preferably R5 is selected from methyl and ethyl; wherein said methyl and said ethyl can be optionally substituted with an OR7 group. Most preferably R5 is selected from methyl and ethyl. Preferably R6 is selected from H, methyl and ethyl More preferably R6 is selected from H and methyl Most preferably R6 is H. Preferably R7 is selected from H and (C1-C4) alkyl; wherein said (C 1 -C 4) alkyl may be optionally substituted with 1 or 2 substituted phenyl or phenyl groups. More preferably R 7 is selected from H, methyl and ethyl; wherein said methyl and said ethyl are optionally substituted with a phenyl group Most preferably R7 is selected from H and (Ch ^ phenyl) When R3 is the moiety (III): Preferably n is 1 Preferably R4 represents (C1-C4) alkyl ), optionally substituted with 1 or 2 phenyl groups, substituted phenyl or heteroaryl.

More preferably R 4 represents ethyl, propyl or butyl, said groups being optionally substituted by a phenyl group. Most preferably R 4 represents ethyl or propyl, said groups being optionally substituted by a phenyl group. When R3 is the rest (IV): Preferably R8 is selected from H, methyl and methoxy. More preferably R8 is selected from H and methoxy. Most preferably R8 is H. Preferably R9 is selected from alkyl (Ci-C4). More preferably R9 is selected from methyl, ethyl and n-propyl. Most preferably R9 is n-propyl. Preferably R10 is selected from H and (C1-C3) alkyl; wherein said (C1-C3) alkyl may be optionally substituted with 1 or 2 groups OR7 or phenyl. More preferably R10 is selected from H and methyl. More preferably R10 is H. Preferably R3 is selected from residues (II) and (III) More preferably R3 is selected from residues (Ha), (llb), and (III) Most preferably R3 is selected from the residues ( lia) and (llb) Preferably the heteroaryl is a 5- or 6-membered aromatic ring, containing from 1 to 3 heteroatoms, said heteroatoms independently selected from O and N; More preferably the heteroaryl is a 5- or 6-membered aromatic ring, containing 1 to 2 nitrogen atoms. Particularly preferred are the compounds (and salts thereof) of the present invention which are exemplified herein; the most preferred are: 5- (Morpholin-2-yl) pyridin-2-amine (Example 2); 5- [4- (3-Phenylpropyl) morpholin-2-yl] pyridin-2-amine (Example 3); 5 - [(2R, 5S) -5-Methylmorpholin-2-yl] pyridin-2-amine (Example 7a); 5 - [(2S, 5S) -5-Methyl-4- (3-phenylpropyl) morpholin-2-yl] pyridin-2-amine (Example 9); 5 - [(2S, 5S) -4-Butyl-5-methylmorpholin-2-yl] pyridin-2-amine (Example 10); 5-. { (2R, 5S) -5 - [(Benzyloxy) methyl] -4-propylmorpholin-2-yl} pyridin-2-amine (Example 3); [6- (6-Aminopyridin-3-yl) -4-propylmorpholin-3-yl] methanol (Example 14); 4- Methyl-5- (4-Propylmorpholin-2-yl) pyridin-2-amine (Examples 18 and 19); 5- [(2S, 5S) -4,5-Diethylmorpholin-2-yl] pyridin-2-amine (Example 21); 5 - [(2R, 5S) -4,5-D-ethylmorpholin-2-yl] pyridin-2-amine (Example 22); 5- (2f?, 5S) - (4-ethyl-5-methylmorpholin-2-yl) -pyridin-2-ylamine (Example 25). In an alternative embodiment, the invention additionally comprises the compounds (+) - 5- (4-propylmorpholin-2-yl) -1,3-thiazol-2-amine and (-) - 5- (4-propylmorpholine- 2-yl) -1,3-thiazol-2-amine (Examples 26 and 27). The compounds of the invention can be prepared, in a known manner, in a variety of ways. The routes below illustrate the methods of synthesizing the compounds of formula (I); the expert will appreciate that other methods may be equally feasible. In all schemes the protected nitrogen of the 2-aminopyridine group is indicated as PGN, and Hal represents a halogen selected from Cl, Br, or I. The compounds of formula (I) wherein R1, R2, R4 and R6 are as are defined above, and R3, R5 and A are as described herein, can be prepared according to reaction scheme 1.

Scheme 1 Reaction Stage 1. Protection of aminopyridine The compounds of formula (V), in which, for example, NPG is the 2,5-dimethylpyrrole system [as described in J. Chem. Soc. Perkin Trans. 1, 1984, 2801-2807, and as illustrated by the compound of formula (Vía)], can be introduced through the reaction of an aminopyridine of formula (V) with 1-2 equivalents of 2,5-hexanedione in refluxing toluene with azeotropic removal of water and an acid catalyst, such as para-toluenesulfonic acid.

Reaction Stage 2. From halide to aldehyde The aromatic halide of formula (VI) can be converted to aldehydes of formula (VII), for example, by generating an organometallic reagent from a halogenated pyridine of formula (VI), followed by reaction with a formulating agent such as dimethylformamide or morphonyl-4-carbaldehyde. Suitable organometallic pyridine derivatives include Grignard (organomagnesium) or organolithium reagents, which can be prepared from bromide (or iodide) by halogen-metal exchange. Typical conditions comprise the addition of isopropylmagnesium chloride (or butyllithium) to bromide (VI) in an anhydrous ethereal solvent such as tetrahydrofuran at room temperature (heating may be required in certain cases when isopropylmagnesium chloride is used as the agent metalate) or below (for example -78 ° C when butyllithium is used) to carry out the halogen metal exchange reaction, followed by the addition of the formylating agent at 0 ° C or lower. Reaction Stage 3. Conversion of aldehyde to amino alcohol The compounds of formula (VIII) can be prepared by reacting an aldehyde of formula (VII) with a cyanide source, such as potassium cyanide or trimethylsilyl cyanide, or with nitromethane and a base, such as sodium hydroxide, to form an intermediate adduct that can be reduced by treatment with borane, lithium aluminum hydride or hydrogenation in an ethereal solvent. Typical conditions comprise reacting 1.0 equivalent of aldehyde in 1.5 equivalents of 3 M HCl with sodium sulfite (1.5 equivalents) followed by potassium cyanide (1.5 equivalents) at room temperature. The resulting cyanohydrin intermediate is then reduced by treatment with 1, 2 - 3.0 equivalents of borane in THF at reflux, followed by treatment with a strong acid to hydrolyze the boron complex initially formed from the product. The skilled person will know that other non-acid methods are available to break the boron complex for example the diethanolamine treatment. Reaction Stage 4. Reductive amination The compounds of formula (IX) can be prepared from compounds of formula (VIII) using standard conditions of amide bond formation followed by reduction of the intermediate amide with a reducing hydride agent such as borane or lithium aluminum hydride. For example, acid chlorides in the presence of a suitable base such as triethylamine or 4-methylmorpholine can be used for the amide formation step. Typical reaction conditions comprise 1.0 equivalents of amine (VIII), 1.2-2 equivalents of base (preferably triethylamine), 1.1-1.3 equivalents of acid chloride in dichloromethane at 25 ° C. C. Reductive agents such as borane or lithium aluminum hydride can be used for the amide reduction step. Typical conditions comprise 1.0 equivalent of amide, 1.2-3.0 of borane in THF at reflux, followed by treatment with a strong acid to hydrolyze the boron complex initially formed from the product. The skilled person will know that other non-acid methods are available to break the boron complex for example the diethanolamine treatment. The compounds of formula (IX) can also be made by reductive amination of the compounds of formula (VIII) with a suitable aldehyde (1 equivalent or more) in the presence of a reducing hydride agent such as sodium cyanoborohydride or sodium triacetoxyborohydride (1 equivalent or more) in an alcohol solvent such as ethanol at room temperature. Reaction Stage 5. Morpholinone formation The compounds of formula (X) can be prepared by reaction of the compounds of formula (IX) with chloroacetyl chloride or 2-chloroacyl chlorides substituted (such as 2-chloropropionyl chloride or 2-chlorobutyryl chloride) in the presence of a base such as triethylamine, sodium carbonate or potassium hydroxide. Typical conditions comprise 1.0 equivalents of amine (IX), 1.0-1.3 equivalents of acid chloride, 1.2-2.0 equivalents of triethylamine in dichloromethane at 25 ° C, then the reaction mixture crude is dissolved in IPA with 1, 2 - 3.0 equivalents of aqueous potassium hydroxide. Reaction Stage 6. Reduction of morpholinone The compounds of formula (XI) can be prepared by reaction of the compounds of formula (X) with reducing agents such as borane or lithium aluminum hydride. The typical conditions comprise 1, 0 equivalents of amide (X), 1, 2 - 3.0 equivalents of borane in THF at reflux, followed by treatment with a strong acid to hydrolyze the boron complex initially formed. The skilled person will know that other non-acid methods are available to break the boron complex for example the diethanolamine treatment. Reaction Step 7. Deprotection of aminopyridine The compounds of formula (I) can be prepared from the compounds of formula (XI) by deprotection. The nature of this reaction will depend on the protecting group selected for use. For example, when the 2,5-dimethylpyrrole system is used to protect the aminopyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions comprise 1.0 equivalent of compound (XI) and 5 equivalents of hydroxylamine hydrochloride in refluxing ethanol. Alternatively, the compounds of formula (IX), in which R1, R2, and R4 are as defined above, can be prepared according to reaction scheme 2.

Scheme 2 Reaction Step 8. From Halide to Chloroketone The chloroketones of formula (XII) can be formed from the halides of formula (VI) via generation of a reactive organometallic intermediate. Suitable pyridine organometallic derivatives include Grig-nard (organomagnesium) or organolithium reagents, which can be prepared from the bromide (or iodide) by halogen-metal exchange. Thus, treatment of (VI) with 1, 1 (or more) equivalents of butyllithium in an ethereal solvent such as tert-butylmethyl ether at low temperature (-78 ° C) provides an organometallic intermediate which can then be treated with 2-chloro-N-methoxy-N-methylacetamide to provide the chloroketones of formula (XII). Reaction Stage 9. Chloroketone to epoxide The chloroketones of formula (XII) can be converted to the epoxides of formula (XIII) via reduction to an intermediate chlorohydrin and formation of the epoxide promoted by base. Thus, the reaction of (XII) with sodium borohydride (0.3 equivalents or more) in dioxane with subsequent treatment with excess sodium hydroxide solution provides the epoxides of formula (XIII). The enantiomerically pure or enantiomerically enriched epoxides of formula (XIII) can be obtained by employing an asymmetric reducing agent. For example, the reaction of the chloroacetones of the general formula (XII) with (-) - B-chlorodiisopinocamfeylborane (1.5 or more equivalents) in tetrahydrofuran at low temperature (for example -30 ° C) and subsequent treatment of the intermediate chlorohydrin with sodium hydroxide provides enantiomerically enriched epoxides of formula (XIII).

Reaction Stage 10. Opening of the epoxide The epoxides of formula (XIII) when heated with suitable primary amines in an inert solvent such as DMSO at 90 ° C provide the compounds of formula (IX). The compounds of formula (I) in which R1, R2, R4, and R5 are as defined above, and R3, R6 and A are as described herein, can be prepared according to reaction scheme 3.

Scheme 3 Reaction Step 1 1. Amide formation The compounds of the formula (XV) can be prepared by reacting an amino acid ester of the formula (XIV) with acid chlorides (R = alkyl (?? -? Β)) in the presence of a suitable base such as triethylamine or 4-methylmorpholine (or other suitable amide bonding conditions). Typical reaction conditions comprise 1 equivalent of the amino acid ester (XIV), 1 equivalent of acid chloride and 3 equivalents of base in dichloromethane at 25 ° C. Examples of compounds of formula (XV) are also commercially available. Reaction Stage 12. Reduction of amide and ester following N-Boc formation The compounds of the formula (XVI) can be prepared by reacting the compounds of the formula (XV) with the borane-THF complex, followed by treatment with a strong acid (for example 5 M HCl) to hydrolyze the resulting boron complexes with the product. Other non-acidic methods are available to break the boron complex for example the diethanolamine treatment. This is followed by the protection with t-butyloxycarbonyl of the amine formed. Typical reaction conditions comprise 1 equivalent of the amide (XV) with 3 equivalents of BH3-THF in THF at reflux, cooling, careful addition of 6 M aqueous HCl, and heating at reflux for a further 6 h. Subsequent solvent evaporation, redissolution in a methanol mixture (8: 1), and addition of 5 equivalents of a base such as potassium hydroxide and 1.5 equivalents of di-tert-butyl di-tert-butyl dicarbonate, and stirring of the mixture for 72 hours. Reaction Stage 3. Deprotection of N-Boc The compounds of the formula (XVII) can be prepared by reacting the compounds of the formula (XVI) with an organic solution of HCl. Typical reaction conditions comprise 1 equivalent of the carbamate (XVI) and 1-10 equivalents of a 4 M solution of HCl in dioxane at 25 ° C. Examples of the compounds of formula (XVII) are also commercially available. Reaction Stage 14. Addition of chloroketone The compounds of the formula (XVIII) can be prepared by reacting the compounds of the formula (XVII) with an α-halo keto-na of the formula (XII), if necessary in the presence of a base such as triethylamine or 4-methylmorpholine. Typical conditions comprise 1 equivalent of the aminoalcohol (XVII) with 1-3 equivalents of triethylamine and 1 equivalent of a compound of the formula (XII) at 65 ° C. Reaction Stage 15. Reduction to Diol The morpholinol intermediates of formula (XVIII) can be reduced to diols of formula (XIX) by reaction with a reducing hydride agent such as sodium borohydride (1 equivalent or more) in an alcoholic solvent such as ethanol at room temperature. Reaction Stage 16. Closing of the morpholine ring The diol compounds of formula (XIX) can be closed in ring to the morpholine compounds of formula (XI) using various methods. For example, treating a solution of (XIX) in dichloromethane with excess concentrated sulfuric acid at room temperature will carry out the delation. Alternatively, ring closure can be effected using Mitsunobu-type conditions employing the use of 1.1 equivalents of a dialkyl azodicarboxylate reagent, such as diisopropyl azodicarboxylate (DIAD), and 1.1 equivalents of triphenylphosphine in an inert solvent such as tetrahydrofuran. A further alternative is to use a sulfonylating agent, such as p-toluenesulfonylimidazole (1 equivalent) in the presence of strong base such as sodium hydroxide in an inert solvent such as tetrahydrofuran, as described in Org. Lett. 2004, 6 (6), 1045-1047. Reaction Step 7. Deprotection of aminopyridine The compounds of formula (I) can be prepared from the compounds of formula (XI) by deprotection. The nature of this reaction will depend on the protecting group selected for use. For example, when the 2,5-dimethylpyrrole system is used to protect the aminopyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions comprise 1.0 equivalent of the compound (XI) and 5 equivalents of hydroxylamine hydrochloride in ethanol to reflux. Alternatively, in some cases it may be advantageous to deprotect the aminopyridine group (PGN) before ring closure to form the morpholine group. This is the most likely case when acidic conditions are used to effect delation. In this case, the compounds of formula (I) wherein R1, R2, R4, R5 and R6 are as defined above, and R3 and A are as defined herein, can be prepared from the compounds of formula (XIX) according to reaction scheme 4.

Scheme 4 Reaction Step 7. Deprotection of aminopyridine The compounds of formula (XX) can be prepared from the compounds of formula (XIX) by deprotection. For example, when the 2,5-dimethylpyrrole system is used to protect the aminopyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions comprise 1.0 equivalents of the compound (XIX) and 5 equivalents of hydroxylamine hydrochloride in refluxing ethanol. Reaction Stage 18. Closing of the Morpholine Ring Next the compounds of formula (I) can be prepared by cyclization of the compounds of formula (XX) by treatment with acid. Typical conditions employ concentrated sulfuric acid and dichloromethane as solvent at room temperature or higher. Other methods such as those described for Reaction Step 16 in Scheme 3 can also be used to form the morpholine ring.

Scheme 5 describes an alternative method for the conversion of the compounds of formula (XVIII) into compounds of formula (XI), wherein R1, R2, R4, R5 and R6 are as defined above.

Scheme 5 The compounds of formula (XI) can be formed from the compounds of the formula (XVIII) by the reaction step 19-reaction of a compound of formula (XVIII) with a hydride source such as triethylsilane and an acid reagent or Lewis acid such as trimethylsilyl triflate. Typical conditions comprise the addition of 5-10 equivalents of triethylsilane to 1 equivalent of morpholinol (XVIII) in dichloromethane at -78 ° C followed by the addition of 2 equivalents of trimethylsilyl triflate. Likewise, if the protecting group is absent from the compound of formula (XVIII), this step of the process provides an alternative route to the compounds of formula (I). An alternative procedure for the formation of the compounds of formula (XIX) is shown in Scheme 6, wherein R1, R2, R4, R5, and R6 are as defined above.

Scheme 6 The compounds of formula (XIX) can be derivatized by the reaction step of reacting an amine of formula (XVII) with an epoxide of formula (XIII). The reaction is generally carried out in an inert solvent such as toluene or DMSO and at elevated temperature. Typical reaction conditions: they involve the heating of (XIII) and (XVII) together in DMSO at 90 ° C. An alternative method for the synthesis of the compounds of formula (XVIII) is shown in Scheme 7, wherein R1, R2, R4, R5, and R6 are as defined above.

Scheme 7 The compounds of formula (XVIII) can be prepared by the reaction step 21-reaction of an organometallic reagent generated from a halogenated pyridine compound of formula (VI), with a morpholinone compound of formula (XXI) ) (see scheme 8). Suitable organometallic pyridine derivatives include Grignard (organomagnesium) or organolithium reagents, which can be prepared from the bromide (or iodide) by halogen-metal exchange. Typical conditions comprise the addition of isopropylmagnesium (or butyllithium) chloride to bromide (VI) in an anhydrous ethereal solvent such as tetrahydrofuran at room temperature (heating may be required in certain cases when isopropylmagnesium chloride is used as the metalating agent) or below (for example -78 ° C when butyllithium is used) to carry out the halogen metal exchange reaction, followed by the addition of the morpholinone (XXI) at 0 ° C or lower. The morpholinone compounds of formula (XXI), wherein R 4, R5 and R6 are as defined above, they can be prepared as shown in Scheme 8. (xxii) (xviiy (22) Scheme 8 The morpholinone compounds of formula (XXI) can be prepared by reaction step 22 - the reaction of an amino alcohol of formula (XVII) with an a-halo ester compound such as bromoacetate of methyl (XXII) in the presence of a base such as triethylamine or 4-methylmorpholine. Typical conditions comprise 1 equivalent of amine-noalcohol (XVII) with 1-3 equivalents of triethylamine and 1 equivalent of methyl bromoacetate using toluene as solvent at room temperature or above. In some cases heating is required with azeotropic removal of methanol to achieve a good conversion to the desired product (XXI). An alternative method for the synthesis of epoxides of formula (XIII), where R1 and R2 are as defined above, is shown in the Scheme 9 (2. 3) Scheme 9 The compounds of formula (XIII) can be prepared by the reaction step 23-reaction of an aldehyde of formula (VII) with a reactive sulfur ylide such as that generated from trimethylsulphonium iodide and a base adequate Typical reaction conditions involve: reaction of trimethylisulfonium iodide (1 equivalent) with sodium hydride (1 equivalent) in DMSO at 0 ° C followed by the addition of the aldehyde (VII) and allowing the reaction to stand at room temperature. A further alternative method for the synthesis of the epoxide compounds of formula (XIII), wherein R1 and R2 are as defined above, is shown in Scheme 10.

(XXIII) (24) Scheme 10 The compounds of formula (XIII) can be prepared by the reaction step 24-treatment of an alkene of formula (XXIII) with an oxidizing agent such as m-chloroperbenzoic acid, or dimethyldioxirane. Typical reaction conditions comprise: reaction of 1 equivalent of alkene (XXIII) with 1-2 equivalents of m-chloroperbenzoic acid in d, -chloromethane at room temperature. The alkenes of formula (XXIII), in which R1 and R2 are as defined above, can be prepared according to scheme 1.

(XXMI) Scheme 11 The alkene compounds of formula (XXIII) can be prepared from the aldehydes of formula (VII) by reaction step 25. a Wittig or similar olefination reaction. Typical reaction conditions involve treating 1 equivalent of aldehyde (VII) with 1-2 equivalents of the ylide generated from the reaction of equimolar amounts of methyl triphenylphosphonium iodide and butyllithium, in tetrahydrofuran and room temperature or lower. Alternatively, the alkenes of formula (XXIII), in which R1 and R2 are as defined above, can be prepared according to the scheme Scheme 12 The alkene compounds of formula (XXIII) can be prepared by reaction step 26 - a palladium catalyzed vinylation reaction using halide compounds of formula (VI). Typical vinyl sources that can be used for this process include vinyltributyl tannano, ethene gas (at high pressure), or a vinyl boronic acid. Many Pd (0) or Pd (ll) catalysts are suitable for this transformation, such as Pd (PPh3) 4- Typical reaction conditions comprise: reaction of a halogenated pyridine of formula (VI) (1 equivalent) with ethylene gas (at high pressure for example 8.27 bar (120 psi)) in an acetonitrile solution, in the presence of a palladium catalyst such as Pd (OAc) 2 (1.5% mol), a phosphine ligand such as tri -o-tolylphosphine (5 mol%) and amine base, such as triethyl-lamina (large excess) at elevated temperatures (for example 80 ° C). In the preparation of a compound of formula (I), it will be clear to those skilled in the art that the R4 group (as defined above) can be introduced into any of several intermediates in the synthetic sequence. This is more conveniently achieved by reaction step 27, a reductive amination process. Examples of suitable intermediates for use in such a transformation are shown in Scheme 13, wherein R1, R2, R5 and R6 are as defined above. Other intermediates useful in the preparation of compounds of formula I may also be feasible.

Scheme 13 A typical procedure comprises reacting 1 equivalent of secondary amine (such as (XIX), (XI), or (I)), with 1 equivalent of an aldehyde in an inert solvent such as tetrahydrofuran or dichloromethane at room temperature, then the addition of 1 equivalent (or more) of sodium triacetoxyborohydride or sodium cyanoborohydride. In some cases, for example in the preparation of the compounds of formula (I) in which R4 is H, R3 and A are as defined herein and in which R1, R2, R5 and R6 are as As defined above, it may be advantageous to use a PG 'protecting group before the formation of the morpholine ring. This is illustrated in Scheme 14. Any nitrogen protecting group can be used (as described in "Protecting Groups in Organic Synthesis" 3rd Edition T. W. Greene and P. G. Wuts, Wiley-lnterscience, 1999). A common nitrogen protecting group (PG ') suitable for use herein is tert-butoxycarbonyl, which is easily removed by treatment with an acid such as trifluoroacetic acid or hydrogen chloride in an organic solvent such as dichloromethane .

Scheme 14 Reaction Step 28. Protection of N A compound of formula (XXIV) can be prepared by reaction step 28-N protection. A compound of formula (XIX) (wherein R 4 = H) is reacted with a nitrogen protective agent, such as benzyl chloroformate to produce the protected compound. Typical reaction conditions involve: reaction of 1 equivalent of secondary amine (XIX) with (1 equivalent, or more) of benzyl chloroformate in an inert solvent such as dichloromethane, together with triethylamine (1 equivalent, or more) at room temperature. Reaction Stage 16. Ring closure The closure of the diol ring (XXIV) to morpholine (XXV) can be carried out using many of the methods previously described herein, see Reaction Step 16, scheme 3. Particularly suitable in this case is a ring closure reaction of the Mitsunobu type by the action of a dialkyl azodicarboxylate reagent (1.1 equivalents) plus triphenylphosphine (1.1 equivalents) in an inert solvent such as tetrahydrofuran at room temperature . Reaction Stage 29. Removal of the protecting group The compounds of formula (I) can be prepared by the 29-deprotection reaction step of the morpholine (XXV), under conditions dependent on the nature of the protecting group used. For example, if benzyloxycarbonyl is used as the protecting group then it can be removed by hydrogenolysis in an inert solvent such as ethanol with a palladium catalyst such as palladium on carbon, under hydrogen pressure of 1 atmosphere or greater. If the nitrogen of the morpholine is protected with a benzylic group, it can be deprotected by hydrogenation by transfer. Typical conditions involve treating an equivalent of the compound of formula (XXV) with ammonium formate (10 equivalents) in ethanol in the presence of 10% palladium on carbon as catalyst (10% by weight), at reflux for 3 hours. The compounds of formula (XVII), in which R4, R5 and R6 are as defined above, can be prepared according to scheme 15. f "Yt0H RR ° (xvii) .HCl Scheme 15 The compounds of formula (XVII) (in which R4 is not H) can be prepared by reaction step 30. a reducing amine-reducing process. reaction of 1 amino-alcohol equivalent of formula (XVI) with 1.1 equivalents of an aldehyde in dichloromethane and the presence of dry molecular sieves of 4A at room temperature After filtration and evaporation of the reaction mixture, the The residue is redissolved in methanol and reacted with sodium borohydride (2 equivalents or more) at room temperature.

Alternatively, the reductive amination can be carried out in two steps via formation and then reduction of an intermediate amide, in a manner similar to that described for Reaction Step 4 (Scheme 1) and Reaction Steps 1 1 and 12 ( Scheme 3). One skilled in the art will know that many amine-alcohol compounds of formulas (XVI) and (XVII) are commercially available. Alternatively, they can be prepared according to numerous methods known to those skilled in the art, such as those described in Tetrahedron 2000, 56, 2561-2576 and the references cited therein. The compounds of formula (I), wherein R 1, R 2, R 4, R 5 and R 6 are as defined above, and R 3, R 5 and A are as described herein, can be prepared from chloropyridines of formula (XXVI) according to the scheme 16.

It will be clear to those skilled in the art that the chloropyridine intermediates of formula (XXVI) are accessible by application of synthetic methods analogous to those previously described herein for the production of protected aminopyridine compounds of formula (XI). Reaction Stage 31. Metal catalyzed amination reaction The compounds of formula (XXVII) can be prepared by reaction step 31. reaction of a compound of formula (XXVI) with the imine of benzophenone, in the presence of a suitable base and a metal catalyst, for example a Pd complex. Typical reaction conditions involve: reacting chloropyridine (XXVI) (1 equivalent) with the imine of benzophenone (1.2 equivalents), sodium tert-butoxide (1.4 equivalents), tris (dibenzylideneacetone) dipalladium (0) (1 mol%) and 2,2'-bis (diphenylphosphino) -1, 1'-binaphthyl (BINAP) (3 mol%) in toluene at 80 to 120 ° C. Reaction Stage 32. Deprotection of benzophenone Compounds of formula (XXVII) can be converted to compounds of formula (I) by hydrogenolysis (using an inert solvent and heterogeneous catalysis such as Pd on carbon at or above 1 atm. hydrogen pressure), or alternatively by treatment with an aqueous acid for example 2 M HCl in the presence of water and miscible organic solvent such as tetrahydrofuran or dioxane. Transfer hydrogenation can also be used to carry out this transformation. Typical conditions involve treating an equivalent of the compound of formula (XXVII) with ammonium formate (10 equivalents) in ethanol and the presence of 10% palladium on carbon as a catalyst (0% by weight), at reflux for 3 hours.

The compounds of formula (I) wherein R1, R2, and R4 are as defined above and R3 is as defined herein, can be prepared according to scheme 17.

Scheme 17 Reaction Stage 33. Zinc Compound Compounds The compounds of formula (XXX) can be prepared by reacting the compounds of the formula (XXIX) with the Zn / Cu pair (or other activated Zn source) with sonication, followed by the addition of a suitable 2-chloro-4-iodopyridine and palladium catalyst and ligand, and heating at 70 ° C for 18 hours. Typical conditions comprise 1 equivalent of azetidine (XXIX) with the Zn / Cu pair 40% by weight in DMF with sonication at room temperature for 4 hours, followed by the addition of 1.05 equivalents of halogenated pyridine (VI), 0.05 equivalents of tris (dibenzylideneacetone) dipalladium (0) and 0.1 equivalents of tri-o-furylphosphine and heating at 70 ° C for 18 hours. Compounds of the formula (XXIX) can be prepared as described in Synlett, 4, 1998, 379. Reaction Step 34. Deprotection of Boc Compounds of formula (XXXI) can be prepared by reacting compounds of formula (XXX) with a suitable acid, such as HCI or TFA in a suitable solvent such as dichloromethane or diethyl ether at room temperature or higher, if necessary in the presence of a cation scavenger such as Et3SiH. Typical conditions comprise 1 equivalent of azetidine (XXX) with CH 2 Cl 2 saturated with HCl gas at 0 ° C leaving it to be then at room temperature overnight. Reaction Stage 27. Reductive amination The compounds of formula (XXXII) can be prepared by reacting compounds of formula (XXXI) with 1-5 equivalents of the required aldehyde in a suitable solvent at room temperature in the presence of 1-5 equivalents of an agent suitable reducing agent such as sodium triacetoxy-borohydride or sodium cyanoborohydride in a suitable solvent such as dichloromethane or tetrahydrofuran with the optional addition of acetic acid. Typical conditions comprise reacting 1 equivalent of azetidine (XXXI) with 3.1 equivalents of the aldehyde and 3.1 equivalents of sodium tria-tethoxyborohydride in dichloromethane at room temperature for 18 hours. Reaction Stage 31. Metal-catalyzed amination reaction The compounds of formula (XXXII) can be converted to compounds of formula (I) via the intermediates (XXXIII). The conversion of (XXXII) to (XXXIII) can be carried out using the benzophenone mine together with a suitable base and a metal catalyst, for example a Pd complex. Typical reaction conditions involve: reacting chloropyridine (XXXII) (1 equivalent) with the imine of benzophenone (1.2 equivalents), sodium tert -butoxide (1.4 equivalents), tris (dibenzylidene ketone) dipalladium (0) (1 mol%) and 2,2'-bis (diphenylphosphino) -1,1-biphenyl (BINAP) (3 mol%) in toluene at 80 to 120 ° C. Reaction Stage 32. Deprotection of benzophenone Compounds of formula (XXXIII) can be converted to compounds of formula (I) or by hydrogenolysis (using an inert solvent and heterogeneous catalysis such as Pd on carbon at or above 1 atmosphere of pressure of hydrogen), or by treatment with an aqueous acid for example 2 M HCl in the presence of an organic solvent miscible with water such as tetrahydrofuran or dioxane. Transfer hydrogenation can also be used to carry out this transformation. Typical conditions involve treating an equivalent of the compound of formula (XXXIII) with ammonium formate (10 equivalents) in ethanol and the presence of 10% palladium on carbon as a catalyst (10% by weight), at reflux for 3 hours. Alternatively, the compounds of formula (I), wherein R1, R2 and R4 are as defined above and R3 is as defined herein, can be prepared according to scheme 18.

(XXXV) (27) (I) · (XXXVI) Scheme 18 Reaction Stage 33. Cincate linkage The compounds of formula (XXXIV) can be prepared by reacting the compounds of the formula (XXIX) with the Zn / Cu pair (or other activated Zn source) with sonication, followed by the addition of the compounds of the formula (VI) and a suitable palladium and ligand catalyst, and heating at 70 ° C for 18 hours. Typical conditions comprise 1 equivalent of azetidine (XXIX) with the Zn / Cu pair 40% by weight in DMF with sonication at room temperature for 4 hours, followed by the addition of 1.05 equivalents of halogenated pyridine (VI), 0.05 equivalents of tris (dibenzylideneacetone) dipalladium (0) and 0.1 equivalents of tri-o-furylphosphine and heating at 70 ° C for 18 hours. The compounds of the formula (XXIX) can be prepared as described in Synlett, 4, 1998, 379.

Reaction Stage 34. Deprotection of N-Boc Compounds of formula (XXXV) can be prepared by reacting compounds of formula (XXXIV) with a suitable acid, such as HCI or TFA in a suitable solvent such as dichloromethane or diethyl ether at room temperature. environment or higher, if necessary in the presence of a cation scavenger such as Et3S¡H. Typical conditions comprise 1 equivalent of azetidine (XXXIV) with CH 2 Cl 2 saturated with HCl gas at 0 ° C leaving it to be then at room temperature overnight. Reaction Stage 27. Reductive amination The compounds of formula (XXXVI) can be prepared by reacting compounds of formula (XXXV) with 1-5 equivalents of the required aldehyde in a suitable solvent at room temperature in the presence of 1-5 equivalents of an agent suitable reducing agent such as sodium triace-toxiborohydride or sodium cyanoborohydride in a suitable solvent such as dichloromethane or tetrahydrofuran with the optional addition of acetic acid. Typical conditions comprise 1 equivalent of azetidine (XXXV) with 3.1 equivalents of the aldehyde and 3.1 equivalents of triacetoxybo-sodium hydrohydride in dichloromethane at room temperature for 18 hours. Reaction Stage 7. Deprotection of aminopyridine Compounds of formula (XXXVI) can be converted to compounds of formula (I) by deprotection. For ple, when the 2,5-dimethylpyrrole system is used to protect the aminopyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions comprise 1.0 equivalents of the compound (XXXVI) and 5 equivalents of hydroxylamine hydrochloride in refluxing ethanol. SCHEMES 19-29 The compounds of formula I in which R3 is residue IV and unless otherwise indicated R1, R2, R8, R9 and R10 are as defined above, can be prepared using methods described in the Schemes 19 -29.

Scheme 19 Reaction Step 35. Nitrile Formation The compounds of formula (VII) can be converted to nitrile compounds of formula (XXXVII) by reaction with tosylmethyl isocyanide (TosMic). Typical conditions involve: treating the aldehyde (VII) (1 equivalent) with TosMic (1 equivalent) and potassium urea-butoxide (2 equivalents) in ethylene glycol dimethyl ether at -45 ° C after a period of 30 minutes, methanol is added and the reaction mixture is allowed to reach room temperature. Reaction Step 36. Nitrile reduction Nitriles of formula (XXXVII) can be converted to amines of formula (XXXVIII) by reduction of the nitrile group. This reduction can be achieved by the action of a reducing hydride agent, such as lithium aluminum hydride, or sodium borohydride in the presence of a transition metal salt, such as N1CI2 or C0CI2. Alternatively, the nitrile group can be reduced by hydrogenation with a transition metal catalyst such as Raney Nickel or Pd on carbon. Typical conditions involve: reacting nitrile (XXXVII) (1 equivalent) with nickel chloride (1 equivalent) in methanol followed by careful addition of sodium borohydride (3 equivalents or more) at 0 ° C. Reaction stage 27. Reductive amination. The primary amines (XXXVIII) can be converted to compounds of formula (XXXIX) by a reductive amination process, by reaction with an aldehyde and a reducing hydride agent such as sodium triacetoxybohydride or sodium borohydride. Typical conditions involve: reacting the compounds of formula (XXXVIII) with a suitable aldehyde (1 equivalent or more) in the presence of a reducing hydride agent such as sodium cyanoborohydride or sodium triacetoxyborohydride (1 equivalent or more) in an alcoholic solvent such like ethanol. Reaction Stage 7. Deprotection of aminopyridine The compounds of formula (XXXIX) can be converted to compounds of formula I using a reaction to deprotect the nitrogen of the aminopyridine group (PGN) to liberate the NH 2 in the compounds (I). The nature of this reaction will depend on the protective group selected for use. For ple, when the 2,5-dimethylpyrrole system is used to protect the aminopyridine group, it can be deprotected by hydroxylamine treatment. Typical conditions comprise 1.0 equivalent of the compound (XXXIX) and 5 equivalents of hydroxylamine hydrochloride in refluxing ethanol. Alternatively, the nitrile compounds of formula (XXXVII) can be converted to compounds of formula (I) as shown in Scheme 20.

Scheme 20 Reaction Step 37. Reductive Acylation Intermediates of formula (XXXVII) can be reduced for example with sodium borohydride and nickel chloride in the presence of an acylating agent, such as a carboxylic acid anhydride to provide amide intermediates of formula (XL ). Typical conditions involve: reacting the nitrile (XXXVII) (1 equivalent) with nickel chloride (1 equivalent) and a carboxylic acid anhydride (1 equivalent or more) in methanol followed by the careful addition of sodium borohydride (3 equivalents or more) at 0 ° C. Reaction Stage 38. Amide Reduction Amides of general formula (XL) can be reduced to amines using borane or lithium aluminum hydride. Typical conditions comprise 1.0 equivalents of amide (XL), 1.2-2.0 equivalents of borane in THF at reflux followed by heating in strong aqueous acid, such as 5M HCl. The resulting amine intermediates are then may deprotect to give the aminopyridine compounds of formula (I), as previously described in Reaction Step 7. An alternative preparation of the nitrile compounds of formula (XXXVII) is shown in Scheme 21.

Scheme 21 The compounds of formula (XXXVII) can be prepared by the reaction step 39-reaction of the halogenated pyridine (VI) with tributyl (cyanomethyl) stannane and a palladium catalyst according to the procedure described in Chem. Lett 1884, 1511- 1512 Typical conditions involve treating 1 equivalent of (VI) with 1.5 equivalents of tributyl (cyanomethyl) stannane, bis (acetonitrile) dichloropalladium (ll) (2.5 mol%) and tri-o-tolylphosphine (5 mol%) ) in xylene at 120 ° C. An alternative procedure for the preparation of the compounds of formula (XXXVIII) is shown in scheme 22.

(VI) (XLI > <) > Scheme 22 Reaction Step 40. Suzuki coupling of β-alkyl The protected amides of formula (XLII) are available by Suzuki coupling of β-alkyl between a vinyl carbamate ( XLI) and a halogenated pyridine (VI), in a manner similar to that described in J. Org. Chem. 1999, 64, 8743-8744. In a typical procedure, benzylated vinyl carbamate [commercially available, or prepared as described in J. Org. Chem. 1999, 64, 8743-8744] was treated with 1 equivalent of 9BBN solution in tetrahydrofuran at -10 ° C. After completion of the hydro boration step, the resulting organoborane intermediate is treated with sodium hydroxide, the PdCbídppfyCH Cb complex is added together with a halogenated pyridine of formula (VI). Reaction Stage 29. Deprotection of the amine The compounds of formula (XLII) can be converted to compounds of formula (XXXVIII) by deprotection. The nature of this reaction will depend on the protecting group selected for use. For example, when benzyloxycarbonyl is used as the protecting group then it can be removed by hydrogenolysis in an inert solvent such as ethanol with a palladium catalyst such as palladium on carbon. Typical reaction conditions involve: reacting the compounds of formula (XLII) in an alcoholic solvent (such as ethanol) with hydrogen (at a pressure of 1 atmosphere or greater) in the presence of a transition metal catalyst such as Pd on carbon. An alternative method for the production of the compounds of formula (XXXIX) is shown in Scheme 23.

Scheme 23 The compounds of formula (XXXIX) can be prepared by the step of reacting 41-deoxygenation of a compound of formula (IX) by, for example, hydrogenation (in an inert solvent such as eta-nol, in the presence of a transition metal catalyst, such as Pd on carbon in a hydrogen atmosphere (1 atmosphere or greater)). Alternatively, a hydride source such as triethylsilane may be used together with a suitable acid (as described in Heterocycles 2003, 1203-1209). Typical reaction conditions involve: dissolving (IX) in a mixture of dichloromethane and trifiuoroacetic acid at room temperature and adding 1 (or more) equivalents of triethylsilane. An additional method for the production of the compounds of formula (XXXVII) is shown in scheme 24.

Scheme 24 Reaction Step 42. Conversion to benzylic electrophile An aldehyde of formula (VII) is reduced by treatment with a reducing hydride agent such as sodium borohydride in an alcoholic solvent, such as ethanol at room temperature. The resulting alcohol can be activated with respect to the nucleophilic displacement by conversion to an X group (generally a halide or sulfonate ester) to give intermediates of formula (XLIII). Typical conditions involve: reaction of one equivalent of methanesulfonyl chloride and one equivalent of an amine base such as triethylamine in an inert solvent such as dichloromethane at 0 ° C. Reaction Stage 43. Displacement with Cyanide The intermediates of formula (XLIII) can be converted to compounds of formula (XXXVII) by the action of a nucleophilic source of cyanide, such as KCN, in an inert solvent, such as dimethylformamide, ao. above room temperature, in a procedure analogous to that described in US59143 9. A further method for the production of the compounds of formula (XXXIX) is shown in Scheme 25.

Scheme 25 Reaction Step 44. Formation of Methyl Ketone Halogenated pyridines of formula (VI) can be converted to methyl ketones of formula (XLIV) by treatment first with butyllithium (or another agent capable of facilitating a metal halogen exchange reaction) and treating the resulting organometallic intermediate with a suitable acetyl source, such as acetylmorpholine or Weinreb amide derived from acetic acid. Reaction Stage 45. Willgerodt-Kindler reaction The methyl ketones of formula (XLIV) can be converted to arylacetic acids of formula (XLV) by treatment with sulfur and morpholine. A typical procedure involves: reacting 1 equivalent of the methyl ketone (XLIV) with sulfur (2 equivalents) in an excess of morpholine at reflux (or pure or in an alcohol solvent such as ethanol), followed by hydrolysis at reflux or in 2 M hydrochloric acid or NaOH 2. Reaction Stage 46. Amide Formation The pyridyl acetic acids of formula (XLV) can be converted to amides of formula (XLVI) by reaction with an amine of formula (XLVII) and a suitable amide coupling reaction, such as reaction with an anhydride or acid chloride after addition of a suitable amine, or using a peptide coupling reagent such as dicyclohexylcarbo-diimide, or another carbodiimide reagent. For example, acid chlorides can be used in the presence of a suitable base such as triethylamine or 4-methylmorpholine for the amide formation step. Typical reaction conditions comprise the conversion of the acid (XLV) to the acid chloride by treatment with oxalyl chloride with a trace of dimethylformamide as a catalyst in an inert solvent such as dichloromethane. After evaporation of the solvents and excess oxalyl chloride, 1.0 equivalents of amine (XLVII), 1.2-2.0 base equivalents (preferably triethylamine) are reacted with 1.0 equivalents of the Acid in dichloromethane at 25 ° C. Reaction Step 38. Amide Reduction Amides of general formula (XLVI) can be converted to compounds of formula (XXXIX) by reduction with a reducing hydride agent, such as borane-tetrahydrofuran complex. Typical conditions comprise 1.0 amide equivalents (XLVI), 1.2-2.0 equivalents of borane in THF at reflux after treatment with a strong acid such as 5 M HCl at elevated temperature to hydrolyze the boron complexes. formed initially with the product. Other non-acidic methods are available to break the boron complex for example the diethanolamine treatment.

An alternative method for the production of the compounds of formula (XLV) is shown in Scheme 26.

Scheme 26 The compounds of formula (XLV) can be prepared according to reaction step 47. hydrolysis. A nitrile of general formula (XXXVII) is hydrolyzed by heating in a strongly acidic or basic aqueous solution. Typical conditions involve heating a compound of formula (XXXVII) in a solution of 5 M HCl under reflux.

Scheme 27 The compounds of formula (XLVIII), wherein R is OMe, can be formed from the compounds of formula (IX) by the step of 48-methylation reaction of the alcohol (IX) with a suitable methyl-electrophilic source , such as iodomethane. In general, a strong base, such as sodium hydride, is required. Typical conditions involve treating 1 equivalent of (IX) with 1, 1 (or more) of sodium hydride in an inert solvent such as tetrahydrofuran or dimethylformamide then adding 1 (or more) equivalents of iodomethane at room temperature. The compounds of general formula (XLVIII) can be further converted to compounds of formula (I) using the same methods described for the conversion of the compounds of formula (XXXIX), as shown in Scheme 19. Additional examples of compounds of formula (I), in which R8 is not hydrogen, according to scheme 28.

Scheme 28 Reaction Step 44. Ketone Formation The halogenated pyridine compounds of formula (VI) can be easily converted to ketones of formula (XLIX) using methods similar to the formation of the methyl ketone compounds of formula (XLIV) (scheme 25). Specifically, by first treating with butyllithium (or other agent capable of facilitating a metal halogen exchange reaction) and treating the resulting organometallic intermediate with a suitable acyl source, such as acylmorpholine or Weinreb amide (both of which are easily prepared using methods well known to the skilled person). Reaction Step 45. Nitrile Formation The ketone of formula (XLIX) can then be converted to nitrile (XXXVII) by reaction with tosylmethyl isocyanide (TosMic). Typical conditions involve: treating the ketone (XLIX) (1 equivalent) with TosMic (1 equivalent) and potassium ferc-butoxide (2 equivalents) in ethylene glycol dimethyl ether at -45 ° C. After a period of 30 minutes, methanol is added and the reaction mixture is allowed to reach room temperature. The nitrites of formula (XXXVII) can be subsequently converted to compounds of formula (I) using the procedures previously described in scheme 19. (fifty) Scheme 29 Compounds of formula (XXXIX) or (I) in which R10 = H, can be easily converted to additional compounds of formula (XXXIX) or (I) in which R10 is not hydrogen, by reaction step - a reductive amination process as shown in Scheme 29. A typical procedure involves reacting 1 equivalent of a secondary amine (such as (XXXIX) or (I)), with 1 equivalent of an aldehyde in an inert solvent such as tetrahydrofuran or dichloromethane at room temperature, then addition of 1 equivalent (or more) of sodium triacetoxyborohydride or sodium cyanoborohydride. Alternatively, the reductive amination can be carried out in two steps via an intermediate amide in a manner similar to that described for Reaction Step 4 in scheme 1. The compounds of formula (I) wherein R 1, R 2, R 4 and R5 are as defined above, and R3, R5 and A are as described herein, they can be prepared according to reaction scheme 30.

Reaction Stage 51. Thioether Formation The thioethers of the formula (Ll) can be formed by reaction of a compound of formula (XLIII), wherein X is generally a halide or a sulfonate ester, with a compound of the formula ( L) [commercially available or prepared as described in J. Chem. Soc Perkin I, 1987, 11 11-120] in the presence of a base in an alcoholic solvent.

Typical conditions comprise 1.0 equivalent of alkyl halide, 1.0 equivalent of thiol and 1.0-4.0 equivalent of a tertiary amine base such as triethylamine in an alcohol solvent such as ethanol. Reaction Step 52. Deprotection of N-Boc Compounds of formula (Lll) can be prepared by reacting the compounds of formula (Ll) with a suitable acid, such as HCl or TFA in a suitable solvent such as dichloromethane or diethyl ether at room temperature or higher, if necessary in the presence of a cation scavenger such as EtaSiH. Typical conditions comprise adding 1 equivalent of the protected amine (Ll) to CH 2 Cl 2 saturated with HCl gas at 0 ° C leaving it to be then at room temperature overnight. Reaction Stage 4. Reductive amination The compounds of formula (LUI) can be prepared from compounds of formula (Lll) using standard conditions of amide bond formation followed by reduction of the intermediate amide with a reducing hydride agent such as borane or lithium aluminum hydride. For example, acid chlorides in the presence of a suitable base such as triethylamine or 4-methylmorpholine can be used for the amide formation step. Typical reaction conditions comprise 1.0 equivalents of amine (Lll), 1.2-2 equivalents of base (preferably triethylamine), 1.1-1.3 equivalents of acid chloride in dichloromethane at 25 ° C. Reductive agents such as borane or lithium aluminum hydride can be used for the amide reduction step. Typical conditions comprise 1.0 equivalent of amide, 1.2-3.0 of borane in THF at reflux, followed by treatment with a strong acid to hydrolyze the boron complex initially formed from the product. Other non-acidic methods are available to break down the boron complex, for example the diethanolamine treatment. Reaction Stage 53. Carbamate Formation The compounds of formula (LIV), wherein R11 is benzyl or alkyl (CI-C6), can be formed by treatment of compounds of formula (LUI) with an alkyl chloro.formiate or benzyl in an inert solvent such as dichloromethane or diethyl ether in the presence of a base. Typical conditions comprise 1.0 equivalent of the amine (LUI), 1.0 equivalent of an alkyl chloroformate such as methyl chloroformate and 1.0-3.0 equivalents of a tertiary amine base such as triethylamine in diethyl ether at 25 ° C. Reaction Stage 54. Formation of the thiomorpholinone ring The compounds of the formula (LV) can be formed by treating the thioether (LIV) with a strong base such as the lithium diisopropylamide in an inert solvent such as diethyl ether or THF. Typical conditions comprise the addition of 3.0 equivalents of a strong base such as lithium diisopropylamide to 1.0 equivalent thioether (LIV) at a temperature below -50 ° C in an inert solvent such as THF and allowing it to warm at room temperature.

Reaction step 55. Reduction of the amide The compounds of formula (LVI) can be prepared by reacting the compounds of formula (LV) with reducing agents such as borane or lithium aluminum hydride. Typical conditions comprise 1.0 amide equivalents (LV), 1.2-2.0 of borane in THF at reflux, followed by treatment with a strong acid to hydrolyze the initially formed boron complex. Other non-acidic methods are available to break the boron complex for example with diethanolamine. Reaction Stage 7. Deprotection of aminopyridine The compounds of formula (LVI) can be converted to compounds of formula (I) by deprotection. The nature of this reaction will depend on the protecting group selected for use. For example, when the 2,5-dimethylpyrrole system is used to protect the aminopyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions comprise 1.0 equivalent of the compound (LVI) and 5 equivalents of hydroxylamine hydrochloride in refluxing ethanol. The compounds of formula (LIX) in which R1, R2 and R3 are as defined above, can be prepared according to reaction scheme 31.

Scheme 31 Reaction Step 56. Activation of the primary alcohol Compounds of the formula (LVII) can be formed from the compounds of the formula (XXIV), wherein PG 'is a carbamate protecting group such as re-tert-butyloxycarbonyl or benzyloxycarbonyl, by selective conversion of the primary hydroxyl group to a group X (generally a halide or a sulfonate ester). Typical conditions involve: reaction of one equivalent of toluenesulfonyl chloride and one equivalent of an amine base such as triethylamine in an inert solvent such as dichloromethane at 0 ° C. Reaction Stage 57. Thioacetate formation The compounds of the formula (LVIII) can be formed from the compounds of the formula (LVII), in which PG 'is a carbamate protecting group such as tert-butyloxycarbonyl or benzyloxycarbonyl, by reaction with a suitable nucleophile such as thioacetic acid in an inert solvent such as acetonitrile in the presence of a suitable base. Typical conditions involve: reaction of one equivalent of compounds of the formula (VLII) with 1.0 - 2.0 equivalents of thioacetic acid in the presence of 1.0 - 5.0 equivalents of a suitable base such as potassium carbonate in an inert solvent such as acetonitrile and the mixture is heated to reflux. Reaction Step 58. Ring closure The compounds of the formula (LVIII) can be activated with respect to the nucleophilic displacement in the benzylic center by conversion to a group X (usually halide or sulfonate ester). The ring closure in situ may then occur to provide the compounds of the formula (LIX). Typical conditions involve: reaction of one equivalent of toluenesulfonyl chloride and one equivalent of an amine base such as triethylamine in an inert solvent such as dichloromethane at 0 ° C. Evaporation of the solvent followed by redissolution in a higher boiling solvent such as acetonitrile with 0-5.0 equivalents of a suitable base such as potassium carbonate and refluxing the mixture may be necessary to carry out the closing of the ring. Compounds of the formula (LIV), wherein PG 'is a carbamate protecting group such as re-tert-butyloxycarbonyl or benzyloxycarbonyl, can be converted to compounds of the formula (I) using analogous procedures to those described in Scheme 18 for the conversion of compounds of formula (XXXIV) into compounds of formula (I). The compounds of formula (I) wherein R1, R2 and R4 are as defined above, and R3 is as described herein, can be prepared according to reaction scheme 32.

Scheme 32 Reaction Step 59. Cycloaddition The compounds of the formula (LX) can be formed from an alkene of formula (XXIII) by reaction with N-benzyl-N- (methoxymethyl) -trimethylsilylmethylamine and a catalytic amount of an acid such as trifluoroacetic acid in an inert solvent such as dichloromethane, acetonitrile, tetrahydrofuran or toluene of -10 ° C at the reflux temperature of the reaction mixture. Alternative catalysts include anhydrous cesium or potassium fluoride, tetra-n-butylammonium fluoride, trifluoromethanesulfonic acid, trimethylsilyl tri-fluoromethanesulfonate and iodotrimethylsilane. Typical conditions involve: reaction of 1 equivalent of alkene (XXIII) with 1.5 equivalents of N-benzyl-N- (methoxymethyl) -trimethylsilylmethylamine and 0.1 equivalents of trifluoroacetic acid in dichloromethane. Reaction Stage 60. Debhenylation of pyrrolidine The compounds of the formula (LX) can be deprotected to secondary amines of the formula (LXI) by hydrogenolysis in an inert solvent such as ethanol with a palladium catalyst such as palladium on carbon. , under hydrogen pressure of 1 atmosphere or higher. Alternatively, it can be deprotected by hydrogenation by transfer. Typical conditions involve treating one equivalent of the compound of formula (LX) with ammonium formate (10 equivalents) in ethanol and the presence of 10% shovel-on-carbon as a catalyst (10% by weight), at reflux for 3 hours.

Reaction stage 27. Reductive amination The compounds of formula (LXII) can be prepared by reacting compounds of formula (LXI) with 1-5 equivalents of the required aldehyde in a suitable solvent at room temperature in the presence of 1-5 equivalents of an agent suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as dichloromethane or tetrahydrofuran with the optional addition of acetic acid. Typical conditions comprise reacting 1 equivalent of pyrrolidine (LX) with 3.1 equivalents of the aldehyde and 3.1 equivalents of triacetoxybo-sodium hydrohydride in dichloromethane at room temperature for 18 hours. Reaction Stage 7. Deprotection of aminopyridine The compounds of formula (LXI) can be converted to compounds of formula (I) by deprotection. The nature of this reaction will depend on the protecting group selected for use. For example, when the 2,5-dimethylpyrrole system is used to protect the aminopyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions comprise 1.0 equivalents of the compound (LXI) and 5 equivalents of hydroxylamine hydrochloride in refluxing ethanol. The compounds of formula (I) in which R1, R2, R4, R5 and R6 are as defined above and R3 and A are as described herein, can be prepared according to reaction scheme 33.

Scheme 33 Reaction Step 61. Reaction with 3-pyridyl borane The compounds of formula (LXIII) can be prepared from compounds of formula (VI) by reaction with 3-pyridyl borane (or similar botanical acid) in the presence of a base adequate and a suitable palladium catalyst. Typical conditions comprise the addition of 3-pyridyl borane to a compound of formula (VI) in toluene / ethanol as solvent, in the presence of tetrakis (triphenylphosphine) palladium (0) and sodium carbonate, followed by refluxing. Examples of 3-pyridyl boranes (or similar boronic acids) are commercially available. Reaction Step 62. Alkylation The compounds of formula (LXIV) can be prepared from compounds of formula (LXIII) by the addition of an alkyl iodide. Typical conditions comprise the addition of the alkyl iodide to a compound of formula (LXIII), in a suitable solvent such as acetonitrile and then heating to reflux. Reaction Step 63. Hydrogenation The compounds of formula (LXV) can be prepared from compounds of formula (LXIV) by hydrogenation. Typical conditions comprise hydrogenation of a compound of formula (LXIV), under elevated pressure, in a suitable solvent such as ethanol, in the presence of a suitable catalyst such as PtC > 2. Reaction step 7. Deprotection of aminopyridine The compounds of formula (LXV) can be converted to compounds of formula (I) by deprotection. The nature of this reaction will depend on the protecting group selected for use. For example, when the 2,5-dimethylpyrrole system is used to protect the aminopyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions comprise 1.0 equivalent of the compound (LXV) and 5 equivalents of hydroxylamine hydrochloride in refluxing ethanol. Methods for the resolution of racemic compounds In cases where the above-mentioned methods lead to racemic products, many methods are available for the separation of the racemate into its constituent enantiomers. These include: (1) formation and selective crystallization of diastereomeric salts produced by salt formation between a racemic base and an enantiomerically pure chiral acid component (or vice versa). (2) HPLC using a chiral stationary phase - many of which are commercially available. (3) Formation of diastereomeric adducts by reaction of a racemic compound with an enantiomerically pure chiral compound or reagentSubsequent reaction of the constituent diastereomers by physical methods, including crystallization or chromatography, and the separated adducts rupture to release the desired compound in enantiomerically enriched form. This is often called a classical resolution. For example, a racemic alcohol can be reacted with an enantiomerically pure chiral acid to form diastereomeric esters using standard ester formation reactions. These esters can then be separated, for example, by selective crystallization. After the separated diastereomeric esters can be hydrolysed separately under-TANDAR is ester hydrolysis to liberate the chiral alcohols in enantiomerically enriched form. (4) Selective reaction of a chiral reagent (including enzymes) with an enantiomer of a racemic mixture - called a kinetic resolution. The compounds of the present invention have utility as selective D3 agonists in the treatment of pathological conditions. There are several compounds with activity as agonists D2 and D3; however the use of such compounds is associated with a large number of side effects including nausea, vomiting, syncope, hypotension and bradycardia, some of which are a cause for serious concern. It was previously held that the efficacy of the prior art compounds was the result of their ability to agonize D2; however, D2 agonism is implicated as a cause of the side effects detailed above. The present invention provides a class of selective D3 agonists. Coincidentally, these have been found to be effective, while reducing the side effects associated with the non-selective compounds of the prior art. Accordingly, a further aspect of the invention provides a compound of formula (I) for use as a medicament. The compounds of the present invention are particularly useful in treating sexual dysfunction, female sexual dysfunction, including hypoactive sexual desire disorder, female sexual arousal disorder, female orgasmic disorder and sexual pain disorder; male erectile dysfunction, hypertension, neurodegeneration, depression, and psychiatric disorders. Accordingly, the present invention provides, the use of a compound of formula (I) in the preparation of a medicament for the treatment or prevention of sexual dysfunction. The compounds of the present invention are useful in male sexual dysfunction, particularly male erectile dysfunction. Male erectile dysfunction (MED), also known as male erectile disorder, is defined as: "the inability to achieve and / or maintain a penile erection for satisfactory sexual practice" (NIH Consensus Development Panel on Impotence, 1993) It has been estimated that the prevalence of erectile dysfunction (ED) of all grades (minimal, moderate and complete impotence) is 52% in men between 40 and 70 years of age, with greater proportions in those older than 70 (Melman et al. al., 1999, J. Urology, 161, p5-11). The condition has a significant negative impact on the quality of life of the individual and their partner, often resulting in an increase in anxiety and tension that leads to depression and low self-esteem. Whereas two decades ago, MED was considered primarily as a psychological disorder (Benet et al 1994, Comp.Ther., 20: 669-673), it is now known that for most individuals there is an underlying organic cause. Therefore, much progress has been made in identifying the mechanism of normal penile erection and in the pathophysiology of MED. Penis erection is a hemodynamic event that is dependent on the equilibrium of contraction and relaxation of the smooth muscle of the corpus cavernosum and the vasculature of the penis (Lerner et al 1993, J. Urology, 149, 1256-1255). The smooth muscle of the corpus cavernosum is also referred to herein as corporeal smooth muscle or in the plural sense corpora cavernosa. Relaxation of the smooth muscle of the corpus cavernosum leads to an increase in blood flow in the trabecular spaces of the corpora cavernosa, causing them to expand against the surrounding tunica and compress the drainage veins. This produces a huge elevation in blood pressure that results in an erection (Naylor, 1998, Br. J. Urology, 81, 424-431). The changes that occur during the erectile process are complex and require a high degree of coordinated control involving the central and peripheral nervous systems, and the endocrine system (Naylor, 1998, Br. J. Urology, 81, 424-431). The contraction of the corporal smooth muscle is modulated by the noradrenergic sympathetic innervation via activation of postsynaptic ai-adrenergic receptors. MED may be associated with an increase in the endogenous tone of the smooth muscle of the corpus cavernosum. However, the relaxation process of the corporal smooth muscle is partially mediated by non-adrenergic non-cholinergic neurotransmission (NANC). There are several other NANC neurotransmitters that are found in the penis, apart from NO, such as the peptide related to the calcitonin gene (CGRP) and the vasoactive intestinal peptide (VIP). The main relaxing factor responsible for mediating this relaxation is nitric oxide (NO), which is synthesized from L-arginine by nitric oxide synthetase (NOS) (Taub et al 993 Urology, 42, 698-704). It is thought that reducing the tone of the corporal smooth muscle can help the NO to induce the relaxation of the cavernous body. During sexual arousal in man, NO is released from neurons and the endothelium and binds to and activates soluble guanylate cyclase (cGC) located in smooth muscle cells and in the endothelium, which leads to an elevation in levels intracellular guanosine 3 ', 5'-monophosphate (cGMP). The increase in cGMP leads to a relaxation of the cavernous body due to a reduction in the intracellular concentration of calcium ([Ca2 +]), via unknown mechanisms that are thought to involve the activation of protein kinase G (possibly due to activation of the Ca2 + pumps and the K + channels activated with Ca2 +). Multiple potential sites within the central nervous system have been identified for the modulation of sexual behavior. The key neurotransmitters are thought to be serotonin, norepinephrine, oxytocin, nitric oxide, and dopamine. By mimicking the actions of one of these key neurotransmitters, sexual function can be adjusted. Dopamine D3 receptors are expressed almost exclusively in the limbic area of the brain, the regions involved in the reward, emotional and cognitive processes. Without being bound by any theory, it seems that "due to its role in the control of locomotor activity, the integrity of the dopaminergic nigroestriatal pathway is also essential for the manifestation of copulatory behavior. sexual function, it is likely that dopamine can trigger the erection of the penis by acting on the oxytocinergic neurons located in the paraventricular nucleus of the hypo thalamus, and perhaps on the parasympathetic sac-pro-erectile nucleus in the spinal cord. " Now it appears that the significant site is D3 and not as previously thought, D2. In essence, D3 is an initiator of sexual behavior. Accordingly, the present invention provides, the use of a compound of formula (I) in the preparation of a medicament for the treatment or prevention of erectile dysfunction. Patients with mild to moderate MED should benefit from treatment with the compounds according to the present invention, and patients with severe MED may also respond. However, early research suggests that the rate of patients responding to patients with mild, moderate and severe MED may be higher with a combination of selective D3 agonist / PDE5 inhibitor. The mild, moderate and severe MED will be terms known to the person skilled in the art, but guidance can be found in The Journal of Urology, vol. 151, 54-61 (January 1994). Early research suggests that the groups of patients mentioned below should benefit from treatment with a selective D3 agonist and a PDE5i (or other combination proposed hereinafter). These groups of patients, which are described in more detail in Clinical Andrology vol. 23, No. 4, p773-782 and chapter 3 of the book by I. Eardley and K. Sethia "Erectile Dysfunction-Current Investigation and Ma- nagement", published by Mosby-Wolfe, are as follows: psychogenic, organic sexual dysfunction , vascular, endocrinological, neurogenic, arteriogenic, drug induced (lactogenic) and sexual dysfunction related to cavernous factors, particularly venogenic causes.

Accordingly, the present invention provides the use of a compound of formula (I) in the preparation of a medicament in combination with a PDE5 inhibitor for the treatment of erectile sexual dysfunction. Suitable PDE5 inhibitors are described herein. The compounds of the present invention are useful in the treatment or prevention of female sexual dysfunction (FSD), in particular female sexual arousal disorder (FSAD), hypoactive sexual desire disorder (HSDD, lack of interest in sex). , FSAD with concomitant HSDD, and female orgasmic disorder (FOD, inability to reach orgasm). According to the invention, FSD can be defined as the difficulty or inability of a woman to find satisfaction in sexual expression. The FSD is a collective terminology for several diverse female sexual disorders (Leiblum, SR (1998) - Definition and classification of female sexual disorders, Int. J. Impotence Res. 10, S104 - S106; Berman, JR, Berman , L. &Goldstein, I. (1999) - Female sexual dysfunction: Incidence, pathophysiology, evaluations and treatment options, Urology, 54, 385-391). The woman may have a lack of desire, difficulty with excitement or orgasm, pain with intercourse or a combination of these problems. Various types of illnesses, medications, injuries or psychological problems can cause FSD. The treatments under development are aimed at treating specific subtypes of FSD, predominantly disorders of desire and arousal. The FSD categories are better defined by comparing them with the phases of the normal female sexual response: desire, excitement and orgasm (Leiblum, SR (1998) - Definition and classification of female sexual di-sorders, Int. J. Impotence Res. 10, S104-S106). Desire or libido is the access path for sexual expression. Their manifestations often include sexual thoughts when in the company of a partner of interest or when exposed to other erotic stimuli. Arousal is the vascular response to sexual stimulation, an important component of which is genital engorgement and includes increased vaginal lubrication, elongation of the vagina and increased genital sensation / sensation. Orgasm is the release of sexual tension that has culminated during the excitement. Therefore, FSD occurs when a woman has an inadequate or unsatisfactory response in any of these phases, usually desire, arousal or orgasm. The FSD categories include hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorders, and sexual pain disorders. Although the compounds of the invention will improve the genital response to sexual stimulation (as in female sexual arousal disorder), doing so may also improve the associated pain, anguish and discomfort associated with intercourse and thus treat other sexual disorders. feminine The hypoactive sexual desire disorder occurs if a woman has no desire or has little desire to be sexual, and has no sexual thoughts or fantasies or has few. This type of FSD may be caused by low testosterone levels, due to either natural menopause or surgical menopause. Other causes include illness, medications, fatigue, depression and anxiety. Female sexual arousal disorder (FSAD) is characterized by inadequate genital response to sexual stimulation. Genitalia does not experience the congestion that characterizes sexual arousal. The vaginal walls are poorly lubricated, so intercourse is painful. It can prevent orgasm. The arousal disorder can be caused by the reduction of estrogen at menopause or after delivery and during lactation, as well as by diseases, with vascular components such as diabetes and atherosclerosis. Other causes result from treatment with di-uretics, antihistamines, antidepressants for example selective inhibitors of serotonin re-uptake (SSRIs) or antihypertensive agents. Sexual pain disorders (including dyspareunia and vaginismus) are characterized by pain resulting from penetration and may be caused by medications that reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease, or urinary tract problems. As previously discussed, it is thought that D3 is an initiator of sexual behavior. The clitoris is considered to be a penis homologue (Levin, R. J: (1991), Exp. Clin. Endocrinol., 98, 61-69); The same mechanism that provides an erectile response in the male produces an increase in the genital flow of blood in women with an associated effect after FSD. In addition there are changes in proceptivity and receptivity. Thus, according to a preferred aspect of the invention, there is provided the use of a compound of formula (I) in the preparation of a medicament for the treatment or prophylaxis of female sexual dysfunction, more especially hypoactive sexual desire disorder, female sexual arousal disorder, female orgasmic disorder and sexual pain disorder. Preferably the compounds of formula (I) are useful in the treatment or prophylaxis of female sexual arousal disorder (FSAD), FSAD with concomitant hypoactive sexual desire disorder, orgasmic disorder, and hypoactive sexual desire disorder, and more preferably in the treatment and prophylaxis of female sexual arousal disorder. In a preferred embodiment the compounds of formula (I) are useful in the treatment of a patient with female sexual arousal disorder and concomitant hypoactive sexual desire disorder. The Diagnostic and Statistical Manual (DSM) IV of the American Association of Psychiatry defines the Disorder of Female Sexual Anxiety (FSAD) as being: "... a persistent or recurrent disability to achieve or maintain until the conclusion of Sexual activity The proper lubrication-swelling response of sexual arousal The disturbance should cause marked anxiety or interpersonal difficulty The excitement response consists of vasocongestion in the pelvis, vaginal lubrication and expansion and swelling of the external genitalia. marked anxiety and / or interpersonal difficulty FSAD is a widespread sexual disorder that affects pre-, peri- and post-menopausal women (± hormone replacement therapy (HRT)). It is associated with concomitant disorders such as depression, cardiovascular diseases, diabetes and urogenital disorders (UG) The main consequences of FSAD are lack of congestion / swelling, lubrication and lack of pleasurable genital sensation. The secondary consequences of FSAD are reduction of sexual desire, pain during intercourse and difficulty in reaching an orgasm. Recently, it has been hypothesized that there is a vascular basis for at least a proportion of patients with symptoms of FSAD (Goldstein et al., Int. J. Impot. Res., 10, S84-S90, 1998) with data from animals that support this opinion (Park et al., Int. J. Impot. Res., 9, 27-37, 1997). RJ Levin teaches us that because "... male and female genitalia develop embryologically from the common tissue primordium, it is argued that the male and female genital structures are homologous to each other." Thus the clitoris is the homologue of the penis. and the homologous lips of the scrotal sac ... "(Levin, RJ (1991), Exp. Clin. Endocrinol., 98, 61-69). The candidate drugs to treat FSAD, which are under investigation of efficacy, are mainly erectile dysfunction treatments that stimulate circulation to the male genitalia. The compounds of the present invention are advantageous in providing a means to restore a normal response of sexual arousal - namely by increasing the genital flow of blood leading to vaginal, clitoral and labial congestion. This will result in increased vaginal lubrication via plasma transudation, increased vaginal compliance and increased genital sensitivity. Therefore, the present invention provides a means to restore or enhance the normal response of sexual arousal. Thus, according to a preferred aspect of the invention, there is provided the use of a compound of formula (I) in the preparation of a medicament for the treatment or prophylaxis of female sexual arousal disorder and female sexual arousal disorder with concomitant hypoactive sexual desire disorder. By female genitalia we mean in this report: "The genital organs consist of an internal and external group, the internal organs are located inside the pelvis and consist of ovaries., uterine tubes, uterus and vagina. The external organs are superficial to the urogenital diaphragm and below the pelvic arch. They include pubic hair, the major and minor lips of the vagina, the clitoris, the vestibule, the vestibular bulb, and the larger vestibular glands "(Gray's Anatomy, CD Clemente, 13th American Edition). in patients with FSD that arises from: - i) Vasculogenic etiologies such as cardiovascular or atherosclerotic diseases, hypercholesterolemia, cigarette smoking, diabetes, hypertension, radiation and perineal trauma, traumatic injury to the vascular system, pudendal lyiohypogastric, ii) Neurogenic etiologies such as lesions of spinal cord or central nervous system diseases including multiple sclerosis, diabetes, Parkinson's disease, stroke, peripheral neuropathies, trauma or radical pelvic surgery iii) Hormonal / endocrine diseases such as hypothalamus / pituitary / gonadal axis dysfunction , or dysfunction of the ovaries, dysfunction of the pancreas s, medical or surgical castration, androgen deficiency, high circulating levels of prolactin such as hyperprolactinemia, natural menopause, premature ovarian failure, hyper and hypothyroidism. iv) Psychogenic etiologies such as depression, obsessive-compulsive disorder, anxiety disorder, postnatal depression / puerperal depression, emotional or relationship issues, consummatory anxiety, marital discord, dysfunctional attitudes, sexual phobias, religious inhibition or past traumatic experiences. v) Drug-induced sexual dysfunction resulting from treatment with selective serotonin reuptake inhibitors (SSRis) and other antidepressant treatments (tricyclics and major tranquillizers), antihypertensive treatments, sympatholytic drugs, chronic oral contraceptive pill treatment. The compounds of the present invention are also useful in the treatment of depression. D3 dopamine receptors are expressed almost exclusively in the limbic area of the brain, regions involved in the reward, emotional and cognitive processes. It is known that chronic treatment with several classes of antidepressants increases the expression of D3 in the limbic area, and the antidepressant effects of desipramine can be blocked by sulpride (D2 / D3 antagonist) when injected into the nucleus accumbens (D3 rich area). ) but not to the caudate putamen (area rich in dopamine D2 receptors). In addition, antidepressant effects were observed in preclinical models of depression and in patients treated with pramipexole, a D2 / D3 agonist with D3 preference. The available information suggests that D3 receptors mediate antidepressant activity and that selective D3 receptor agonists represent a new class of antidepressant drugs. Since antidepressants are known to be effective in other psychiatric disorders, D3 agonists would have the potential to treat psychiatric disorders. Suitable conditions include depression (for example, depression in cancer patients, depression in Parkinson's patients, post-myocardial infarction depression, symptomatic subsyndromal depression, depression in infertile women, major depression, depression induced by child maltreatment, postpartum depression, and bad-tempered old man), recurrent major or episodic major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, psychomotor retardation or wakefulness in the wee hours of the morning; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, seasonal affective disorder and pediatric depression; bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclo-thymic disorder; conduct disorder; disruptive behavior disorder; trico-tilomania, kleptomania, attention deficit hyperactivity disorder (ADHD); behavioral disturbances associated with mental retardation, autistic disorder, borderline personality disorder; evasive personality disorder; anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without a history of panic disorder, specific phobias, for example, specific animal phobias, social anxiety, social phobia, obsessive-compulsive disorder, stress disorders including stress disorder posttraumatic and acute stress disorder, and generalized anxiety disorders; emotional lability, pathological crying; schizophrenia and other psychotic disorders, for example schizophreniform disorders, schizoaffective disorders, delirious disorders, brief psychotic disorders, shared psychotic disorders, psychotic disorders with delusions or hallucinations, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania and depression associated with bipolar disorder; mood disorders associated with schizophrenia; eating disorders (for example anorexia nervosa and bulimia nervosa), obesity; movement disorders such as akinesias, dyskinesias, including paroxysmal familial dyskinesias, spasticities, Tourette's syndrome, Scott's syndrome, paralysis and rigid-akinetic syndrome; extrapyramidal movement disorders such as drug-induced movement disorders, eg, neuroleptic-induced Parkinsonism, neuroleptic malignant syndrome, acute neuroleptic-induced dystonia, acute neuroleptic-induced akathisia, neuroleptic-induced tardive dyskinesia and tremor postural induced by medication; addictions and chemical dependencies (for example dependencies of, or addictions to, alcohol, heroin, cocaine, benzodiapines, nicotine, or phenobarbitol) and conditional addictions such as pathological gambling; eye disorders such as glaucoma and ischemic retinopathy; sleep disorder (cataplexy) and concussion. In a further preferred embodiment, the present invention provides the use of a compound of formula (I) in the preparation of a medicament for the treatment of depression or psychiatric disorders. Depressive diseases and appropriate psychiatric disorders are described above. In a further preferred embodiment, the present invention provides the use of a compound of formula (I) in the preparation of a medicament for the treatment of obesity. The compounds of the present invention also have utility in the treatment of neurodegeneration; the sources of neurodegeneration include neurotoxin poisoning; loss of vision caused by neuro-degeneration of the visual path, such as a stroke in the visual path for example in the retina, optic nerve and / or occipital lobe; Epileptic crisis; and the deficient supply of glucose and / or oxygen to the brain. Diseases related to neurodegeneration include Restless Legs Syndrome, Huntington's disease, Multiple Sclerosis, mild cognitive impairment, Down syndrome, stroke, Hereditary Cerebral Hemorrhage with Dutch Type Amyloidosis, cerebral amyloid angiopathy, delirium, dementia, cognitive impairment related to age (ARCD), and amnestic and other cognitive or neurodegenerative disorders, such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, Alzheimer's type dementia, memory disorders, loss of executive function, vascular dementia, dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy , dementia associated with cortical basal degeneration, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or brain trauma, dementia associated with Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease , dementia related to AIDS or HIV, diffuse Lewy body type Alzheimer's disease, frontotemporal dementias with parkinsonism (FTDP), cranial trauma, spinal cord injury, demyelinating diseases of the nervous system, peripheral neuropathy, pain, amyloid angiopathy cerebral, amyotrophic lateral sclerosis, multiple sclerosis , dyskinesia associated with dopamine agonist treatment, mental retardation, learning disorders, including reading disorder, math disorder, or a written expression disorder; Cognitive impairment related to age, amnestic disorders, neuroleptic-induced parkinsonism, tardive dyskinesia, and acute and chronic neurodegenerative disorders. Accordingly, the present invention provides the use of a compound of formula (I) in the preparation of a medicament for the treatment of degeneration. Neurodegenerative diseases are described above. In addition to their role in the treatment of sexual dysfunction, depression, neurodegeneration and psychiatric disorders, the compounds of the present invention are likely to be effective in several additional indications. Accordingly, the present invention provides the use of a compound of formula (I), in the preparation of a medicament for the treatment of hypertension, premature ejaculation, obesity, histamine headache, migraine, pain, endocrine disorders (e.g. hyperprolactinemia), vascular spasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), premenstrual syndrome, fibromyalgia syndrome, stress incontinence, trichotillomania and chronic paroxysmal hemicrania, headache (associated with vascular disorders). It should be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment. DETERMINATION OF D3 / D2 AGONIST Activity in the dopamine D3 receptor can be determined using the methods described in WO 2004/05237. Using this analysis, all compounds of the present invention exhibit a functional potency at the D3 receptor expressed as an EC50, less than 1000 nM and a 10-fold selectivity for D3 on D2. The selectivity is calculated as the EC50 value of D2 divided by the EC50 value of D3. Where the value of the EC50 of D2 was > 10000, a figure of 10,000 was used in the calculation. The compound of Example 14 has a functional potency at the D3 receptor, expressed as an EC50, of 20 nM, with an Emax (maximum response value) of 98% (relative to the maximum effect of the standard agent pramipexole). In front of the D2 receptor this compound gave only a response of 22% (relative to the maximum effect of pramipexole) at 10000 nM. Auxiliary active agents suitable for use in the combinations of the present invention include: 1) synthetic or natural prostaglandins or their esters. Prostaglandins suitable for use herein include compounds such as alprostadil, prostaglandin Ei, prostaglandin Eo, 13,14-dihydroprostaglandin Ei, prostaglandin E2, eprostinol, synthetic and semi-synthetic natural prostaglandins and their derivatives including those described in WO-00033825 and / or US 6,037,346 published March 14, 200 all incorporated herein by reference, PGEo, PGE1, PGA1, PGB1, PGFia, 19-hydroxy-PGAi, 19-hydroxy-PGBi, PGE2, PGB2, 19-hydroxy-PGA2, 19-hydroxy-PGAB2, PGE3a, carboprost tromethamine dino-prost, tromethamine, dinoprostone, lipo prost, gemeprost, meteneprost, sulpros-tone, tiaprost and moxysilate; 2) Adrenergic receptor antagonist compounds also known as α-adrenoceptors or a-receptors or α-blockers. Compounds suitable for use herein include: α-adrenergic receptor blockers such as those described in PCT application WO99 / 30697 published June 14, 1998, descriptions of which relating to α-adrenergic receptors are incorporated herein as reference and include, selective blockers of a? -adrenoceptors or 02-adrenoceptors and non-selective adrenoceptor blockers, suitable a? -adrenoceptors blockers include: phentolamine, phenolamine mesylate, trazodone, alfuzosin, indoramin , naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxane, efaraxane, yohimbine, alkaloids of rauwolfia, Recordati 15/2739, SNAP 1069, SNAP 5089, RS17053, SL 89.0591, doxazo-sine, terazosin, abanoquilo and prazosin; A2 blockers of U.S. 6,037,346 [March 14, 2000] dibenarnine, tolazoline, trimazinesine and dibenarnine; a-adrenergic receptors such as those described in U.S. Patents: 4,188,390; 4,026,894; 3.51 1.836; 4,315,007; 3,527,761; 3,997,666; 2,503,059; 4,703,063; 3,381,009; 4,252,721 and 2,599,000 each of which is incorporated herein by reference; 02-adrenoceptor blockers include: clonidine, papaverine, papaverine hydrochloride, optionally in the presence of a carotonic agent such as pirxamine; 3) NO donor compounds. NO donor compounds suitable for use herein include organic nitrates, such as organic mono- or tri-nitrates or nitrate esters that include glyceryl trinitrate (also known as nitroglycerin), 5-sosorbide mononitrate. , isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside (SNP), 3-morpholinosidnonimine molsidomine, S-nitroso-N-acetyl penicillamine (SNAP) S-nitroso-N-glutathione (SNO-GLU), N- hydroxy-L-arginine, amyl nitrate, linsidomine, linsidomine hydrochloride, (SfN-1) S-nitroso-N-cysteine, diazenium diolate, (NONOatoses), 1,5-pentanodinitrate, L-arginine, ginsén, zizyphi fructus , molsidomine, Re-2047, nitrosylated moxysilyl derivatives such as NMI-678-1 and NMI-937 as described in published PCT application WO 0012075; 4) Modulators and openers of the potassium channel. The modulators / openers of the potassium channel for use herein include nicorandil, cromokalim, levcromakalim, lemakalim, pinacidil, cliazoxide, minoxidil, caribdotoxin, glyburide, 4-amino pyridine, BaC; 5) Vasodilating agents. Vasodilating agents suitable for use herein include nimodipine, pinacidil, cyclohexade, isoxsuprine, chloropromazine, Rec 15/2739, trazodone; 6) Thromboxane A2 agonists; 7) Active agents of CNS 8) Alkaloids of ergot. Suitable ergot alkaloids are described in U.S. Pat. No. 6,037,346 published March 14, 2000 and includes acetergamine, brazergoline, bromerguride, cianergo-lina, delorgotril, dysulergine, ergonovine maleate, ergotamine tartrate, etisulergine, lergotryl, lysergide, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propigested, protergurida, tergurida; 9) Compounds that modulate the action of natriuretic factors in particular atrial natriuretic factor (also known as atrial natriuretic peptide), type B and type C natriuretic factors such as inhibitors or neutral endopeptidase; 10) Compounds that inhibit the convergent angio-tensine enzyme such as enapril, and combined inhibitors of angiotensin converting enzyme and neutral endopeptidase such as omapatrilat; 1 1) Angiotensin receptor antagonists such as losar-tán; 12) Substrates for NO-synthetase, such as L-arginine; 13) Calcium channel blockers (calcium antagonists) such as amlodipine; 14) Endothelin receptor and endothelin receptor antagonists or endothelin converting enzyme; 15) Cholesterol level lowering agents such as statins (for example atorvastatin / Lipitor - commercial name) and fibrates; 16) Antiplatelet and antithrombotic agents, for example tPA, uPA, warfarin, hirudin and other thrombin inhibitors, hepari-na, inhibitors of thromboplastin activation factor; 17) Insulin sensitizing agents such as rezulin and hypoglycemic agents such as glipizide; 18) Acetylcholinesterase inhibitors such as donezepil; 19) Steroidal or non-steroidal anti-inflammatory agents; 20) Estrogen receptor modulators and / or estrogen agonists and / or estrogen antagonists, preferably raloxifene or laso-foxifen, (-) - cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl) -ethoxy) -phenyl] -5,6,7,8-tetrahydronaf-talen-2-ol and its pharmaceutically acceptable salts, the preparation of which is detailed in WO 96/21656; 21) A PDE inhibitor, more particularly an inhibitor of PDE 2, 3, 4, 5, 7, or 8, preferably inhibitor of PDE2 or PDE5 and more preferably a PDE5 inhibitor (see below in this memory), said inhibitors preferably having an IC 50 against the respective enzyme of less than 100 nM (provided that the PDE 3 and 4 inhibitors are only administered topically or by injection to the penis); 22) Vasoactive intestinal protein (VIP), VIP mimic, VIP analogue, more particularly mediated by one or more of the VIP receptor subtypes VPAC1, VPAC or PACAP (pituitary adenylate cyclase activating peptide), one or more of a VIP receptor agonist or a VIP analogue (eg Ro-125-1553) or a VIP fragment, one or more of an α-adrenergic receptor antagonist with VIP combination (eg, Invicorp, Aviptadil); 23) An agonist or modulator of the melanocortin receptor (particularly subtype MC3 or MC4) or a melanocortin enhancer, such as melanotan II, PT-14, PT-141 or compounds claimed in WO-09964002, WO- 00074679, WO-09955679, WO-00105401, WO-00058361, WO-001 14879, WO-001131 12, WO-09954358; 24) An agonist, antagonist or modulator of the sero-tonin receptor, more particularly agonists, antagonists or modulators for 5HT1A receptors (including VML 670), 5HT2A, 5HT2C, 5HT3 and / or 5HT6, including those described in WO-09902159 , WO-00002550 and / or WO-00028993; 25) A testosterone replacement agent (including de-hydroandrostenedione), testosterone (Tostrelle), dihydrotestosterone or a testosterone implant; 26) Estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) (ie as a combination), or estrogen and hormone replacement agent with methyl testosterone (eg HRT especially Premarin, Cenestin, Oestrofeminal, Equin, Estrace, Estrofem, Elleste Solo, Estring, Eastraderm TTS, Eastraderm Matrix, Dermestril, Premp-hase, Preempro, Prempak, Premique, Estratest, Estratest HS, Tibolona); 27) A modulator of the transporters for norepinephrine, dopamine and / or serotonin, such as bupropion, GW-320659; 28) An agonist and / or purinergic receptor modulator; 29) A neurokinin receptor (MK) antagonist, including those described in WO-09964008; 30) An opioid receptor agonist, antagonist or modulator, preferably agonists for the ORL-1 receptor; 31) An agonist, antagonist or modulator for oxytocin receptors, preferably a selective oxytocin agonist or modulator; 32) Modulators of cannabinoid receptors; 33) An SEP inhibitor (SEPi), for example an SEPi having an IC5o of less than 100 nanomolar, more preferably, less than 50 nanomolar; 34) Preferably, the SEP inhibitors according to the present invention have the selectivity for SEP greater than 30 times, more preferably greater than 50 'times over the neutral endopeptidase NEP EC 3.4.24.1 1 and the angiotensin converting enzyme (ACE) . Preferably SEPi also has a selectivity greater than 100 times over the endothelin converting enzyme (ECE). 35) An antagonist or modulator for the NPY receptor (particularly subtype Y1 and Y5). 36) An antagonist or modulator of Sex Hormone Binding Globulin that inhibits estrogens and / or androgens from being linked. 37) An arginase II inhibitor. 38) An agonist, antagonist or modulator for vasopressin receptors, preferably selective for the V1 a receptor. 39) A PDE5 inhibitor. Suitable PDE5 inhibitors include: 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one (sildenafil), particularly sildenafil citrate; (6R, 12aR) -2, 3,6,7,12, 12a-hexahydro-2-methyl-6- (3,4-methylenedioxypheni-pyrazino-1-yle.l-pyridoIS ^ -bJindol-l ^ -dione (IC-351 or tadalafil); 2- [2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-midazole [5,1 -f] [1, 2,4] triazin-4-one (vardenafil); 5- (5-Acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl) 3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one-5- (5-Acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- ( 1-isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; and 5- [2-ethoxy-5- (4-ethylpiperazine-1 - ilsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one - 4 - [(3-chloro -4-methoxybenzyl) amino] -2 - [(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -N- (pyrimidin-2-ylmethyl) pyrimidine-5-carboxamide (TA-1790); 1-methyl-7-oxo-3-propyl-6,7-dihydro-1 H-pyrazolo [4,3-d] pnmidin-5-yl) -N- [2- (1-methylpyrrolidin-2- il) ethyl] -4-propoxybenzenesulfonamide (DA 8159) and its pharmaceutically acceptable salts 40) A selective D receptor agonist 4 of dopamine such as 2 - [(4-pyridin-2-ylpiperazin-1-yl) methyl] -1 H -benzimidazole (ABT724). By reference herein to compounds contained in patents and patent applications that may be used in accordance with the invention, we refer to the therapeutically active compounds as defined in the claims (particularly claim 1) and the specific examples ( all of which are incorporated herein by reference). If a combination of active agents is administered, then they can be administered simultaneously, separately or sequentially. The biopharmaceutical properties of the compounds of formula I, such as solution solubility and stability (through pH), permeability, etc., should be evaluated to select the most appropriate dosage form and route of administration for the treatment of the proposed indication. The compounds of the invention intended for pharmaceutical use can be administered as crystalline or amorphous products. They can be obtained, for example, as solid masses, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying can be used for this purpose. They can be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any of their combinations). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used in the present specification to describe any ingredient other than the compound (s) of the invention. The choice of excipient will depend to a large extent on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions suitable for administering the compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Reminqton's Pharmaceutical Sciences. 19th Edition (Mack Publishing Company, 1995). Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (I), and a pharmaceutically acceptable carrier or diluent. The compounds of the invention can be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and / or buccal, lingual, or sublingual administration by which the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; hard or soft capsules containing multi- or nano-particles, liquids or powders; pills (including those filled with liquid); chewable; gels; pharmaceutical forms of rapid dispersion; films; ovules aerosol sprays; and buca-les / mucoadhesive patches. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be employed as fillers in hard or soft capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil. , and one or more emulsifying agents and / or suspending agents. Liquid formulations can also be prepared by reconstituting a solid, for example, from a sachet. The compounds of the invention can also be used in rapid disintegration and rapid dissolution pharmaceutical forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981-986, by Liang and Chen (2001). For dosage forms in tablets, depending on the dose, the drug can comprise from 1% by weight to 80% by weight of the dosage form, more typically from 5% by weight to 60% by weight of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose substituted with lower alkyl, starch, pregelatinized starch. and sodium alginate. Generally, the disintegrant will comprise from 1% by weight to 25% by weight, preferably from 5% by weight to 20% by weight of the pharmaceutical form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxyprop-cellulose and hydroxypropyl methylcellulose. The tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. The tablets may also optionally comprise surfactants, such as sodium lauryl sulfate and polysorbate 80, and antiadhesives such as silicon dioxide and talc. When present, the surfactants may comprise from 0.2 wt% to 5 wt% of the tablet, and the antiadhesives may comprise from 0.2 wt% to 1 wt% of the tablet. The tablets generally also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise from 0.25% by weight to 10% by weight, preferably from 0.5% by weight to 3% by weight of the tablet. Other possible ingredients include anti-oxidants, colorants, flavoring agents, preservatives and savoring masking agents. Exemplary tablets contain up to about 80% of drug, from about 10% by weight to about 90% by weight of binder, from about 0% by weight to about 85% by weight of diluent, from about 2% by weight to about -10% by weight of disintegrant, and from about 0.25% by weight to about 10% by weight of lubricant. The mixtures of the tablets can be compressed directly or by rollers to form the tablets. The mixtures of the tablets or portions of the mixtures can alternatively be granulated by wet, dry or molten route, coagulated by molten route, or extruded before compressing. The final formulation can comprise one or more layers and can be coated or uncoated; it can even be encapsulated. Tablet formulations are discussed in Pharmaceuti-cal Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980). Oral films of consumption for humans or veterinary use are typically forms thin-film flexible water-soluble or swollen pharmaceuticals in water that can be easily dissolved or mucoadhesive and typically comprise a compound of formula I, a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity modifying agent and a solvent. Some components of the formulation can perform more than one function. The compound of formula I can be soluble or insoluble in water. A water-soluble compound typically comprises from 1% by weight to 80% by weight, more typically from 20% by weight to 50% by weight, of the solutes. Less soluble compounds can comprise a greater proportion of the composition, typically up to 88% by weight of the solutes. Alternatively, the compound of formula I can be in the form of multiparticulate pellets. The film-forming polymer can be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range of 0.01 to 00% by weight, more typically in the range of 30 to 80% by weight. Other possible ingredients include anti-oxidants, colorants, flavors and flavor enhancers, preservatives, saliva stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and anti-oxidant agents. taste masking The films according to the invention are typically prepared by evaporative drying of thin aqueous films coated on a tear-off paper or backing. This can be done in a drying oven or tunnel, typically a combined drying dryer, or by lyophilization or vacuum aspiration. Solid formulations for oral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsating, controlled, targeted and programmed release. Modified release formulations suitable for the purposes of the invention are described in U.S. Pat. No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles should be found in Pharmaceutical Technology On-line. 25 (2), 1-14, by Verma et al (2001). The use of chewing gums to achieve controlled release is described in WO 00/35298. The compounds of the invention can also be administered directly into the blood stream, into the muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for parenteral administration include needle injectors (including microneedle), needleless injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of 3 to 9), but, for some applications, may be more adequately formulated as a non-sterile solution. aqueous or as a dry form to be used together with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, can be easily carried out using standard pharmaceutical techniques well known to those skilled in the art. The solubility of the compounds of formula I used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques, such as the incorporation of solubility enhancing agents. Formulations for parenteral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsating, controlled, targeted and programmed release. Thus the compounds of the invention can be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted reservoir that provides modified release of the active compound. Examples of such formulations include drug-coated stents and semisolids and suspensions comprising poly (d / -lactic-coglycolic acid) (PGLA) microspheres coated with drugs. The compounds of the invention can also be administered topically, (intra) dermally, or transdermally to the skin or mucosa.

Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusts, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical vehicles include alcohol, water, mineral oil, petroleum jelly, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated - see, for example, J. Pharm. ScL, 88 (10), 955-959, by Finnin and Morgan (October 1999). Other means of topical administration include administration by electroporation, iontophoresis, phonophoresis, sonophoresis, and miracle-needle or needle-free injection (e.g., Powderject ™, Bioject ™, etc.). Formulations for topical administration can be formulated to be immediate and / or modified release. Formulated release formulations include delayed, sustained, pulsating, controlled, targeted and programmed release. The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (or alone, as a mixture, for example, in a dry mixture with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, such as an aerosol spray from a pressurized container, pump, sprayer, atomizer (preferably an atomizer that uses electrohydrodynamics to produce a fine vaporization), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1, 1, 1, 2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurized container, pump, sprayer, atomizer or nebulizer contains a solution or suspension of the compound (s) of the invention comprising, for example, ethanol, aqueous ethanol, or an alternative agent suitable for dispersing, solubilizing, or extending the release of the active ingredient, a propellant (s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. Before being used in a dry powder or suspension formulation, the drug product is micronized to a size suitable for inhalation treatment (typically less than 5 microns). This can be achieved by any suitable spraying method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying. Capsules (made, for example, of gelatin or hydroxypropyl methylcellulose), blisters and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound of the invention, a powder base suitable as lactose. or starch and a performance modifier such as / -leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the monohydrate form, preferably this. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A suitable formulation of the solution for use in an atomizer that uses electrohydrodynamics to produce a fine vaporization can contain from 1 pg to 20 mg of the compound of the invention per actuation and the actuation volume can vary from 1 μ? at 100 μ ?. A typical formulation may comprise a compound of formula I, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol. Suitable essences, such as menthol and le-vomentol, or sweeteners, such as saccharin or sodium saccharin, can be added to the formulations of the invention intended for inhaled / intranasal administration. Formulations for inhaled / intranasal administration can be formulated to be immediate release and / or modified using, for example, PGLA. Modified release formulations include delayed, sustained, pulsating, controlled, targeted and programmed release. In the case of dry powder inhalers and aerosols, the dosing unit is determined by means of a valve that delivers a measured quantity. The units according to the invention are typically arranged to deliver a metered dose or "puff containing from ... to ... pg of the compound of formula I. The total daily dose will typically be in the range ... pg. a ... mg that can be administered in a single dose or, more usually, as divided doses throughout the day.

The compounds of the invention can be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but several alternatives can be used as appropriate. Formulations for rectal / vaginal administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsating, controlled, targeted and programmed release. The compounds of the invention can also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, sterile, pH adjusted saline. Other formulations suitable for ocular and otic administration include ointments, gels, biodegradable (e.g., absorbable gel sponge, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicle systems, such as niosomes. or liposomes. A polymer such as crosslinked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gellan gum, can be incorporated together with a preservative, such as chloride of benzalkonium. Such formulations can also be administered by iontophoresis. Formulations for ocular / otic administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsating, controlled, targeted and programmed release. The compounds of the invention can be combined with soluble macromolecular entities, such as cyclodextrin and its suitable derivatives or polyethylene glycol-containing polymers, to improve its solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the mentioned modes of administration. It is found that drug-cyclodextrin complexes, for example, are generally useful for most pharmaceutical forms and routes of administration. Inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, i.e. as a vehicle, diluent or solubilizer. The most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which can be found in international patent applications No. WO 91/1 1172, WO 94/02518 and WO 98 / 55148. Since it may be desired to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a Composed according to the invention, they can conveniently be combined in the form of a kit suitable for the co-administration of the compositions. Thus, the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula I according to the invention, and means for separately storing said compositions, such as a container, a bottle or a bottle. -dida, or envelope of divided aluminum foil. An example of such a kit is the known blister used for the packaging of tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for adjusting the dose of the separate compositions against each other. To promote therapeutic compliance, the kit typically comprises instructions for administration and can be provided with a so-called reminder. The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are used: optical rotation at 587 nm. Ac20 acetic anhydride APCI chemical ionization at atmospheric pressure Arbacel® broad filter agent Boc rerc-butoxycarbonyl Bu butyl CDCI3 chloroform-d1 CD3OD methanol-d4 d chemical displacement d doublet doubled double DCM dichloromethane DMF N, N-dimethylformamide DMSO dimethylsulfoxide eq equivalents (molar) ESI electrospray ionization Et ethyl AcOEt ethyl acetate H hours HCl hydrogen chloride HPLC high performance liquid chromatography HR M / S high resolution mass spectrum IPA isopropyl alcohol KOAc potassium acetate m multiplet Me methyl MeCN acetonitrile M / S mass spectrum Min minutes NMR nuclear magnetic resonance c quadruplet t.a. room temperature s singlet sat saturated t triplet td triplet of doublets Tf trifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran TIPS triisopropylsilyl TLC / t.l.c. thin layer chromatography The nuclear magnetic resonance (NMR) spectra of 1 H were in all cases consistent with the proposed structures. The characteristic chemical shifts (d) are given in parts-per-million 5H to smaller field from tetramethylsilane using the conventional abbreviations for the designation of the main peaks: for example s, singlet; d, doublet; t, triplet; c; quadruple m, multiplet; an, wide. The following abbreviations have been used for common solvents: CDC, deuteroclo-roformo; DMSO, dimethylsulfoxide. The abbreviation psi means pounds per square inch and LRSM means low resolution mass spectrometry. When thin layer chromatography (TLC) has been used, it is referred to as TLC on silica gel using silica gel plates 60 F254, Rf is the distance traveled by a compound divided by the distance traveled by the front of the solvent on the TLC plate. Example 1 5 - [(2?) - 4-benzylmorpholin-2-yl] pyridin-2-amine The morpholine from preparation 7 (2.05 g, 6 mmol) was dissolved in ethanol (75 ml), hydroxylamine hydrochloride (2.05 g, 30 mmol) was added and the mixture was heated at 80 ° C for the entire night (~ 16 h). After cooling to room temperature, the reaction mixture was evaporated to dryness to a yellow oily residue which was purified by flash chromatography on silica gel eluting with dichloromethane / metharyol / 0.880 98: 2: 0 NH 3 increasing the polarity at 95: 5: 0 then 95: 5: 0.5, then 90: 10: 1 to provide the title compound (645 mg, 40%) 1 H NMR (400 MHz, CDCl 3) d? 8.01 (1 H, s), 7.43 (1 H, d), 7.33 (5H, m), 6.46 (1 H, d), 4.45 (3 H m an), 3, 96 (1 H, d), 3.8 (1 H, t), 3.54 (2 H, s), 2.84 (1 H, d), 2.74 (1 H, d), 2.26 (1 H, m), 2.12 (1 H, t) MS (APCI +) 270 (MH +) Example 2 5 - [(2f?) - morpholin-2-yl] pyridin-2-amine The benzyl morphine from Example 1 (990 mg, 3.7 mmol) was dissolved in methanol (20 mL), ammonium formate (1.16 g, 18.5 mmol) was added followed by 10% Pd on carbon (495 mg) and the mixture was heated to reflux for 2 hours. The cooled reaction mixture was filtered through a bed of arbo-cel® and evaporated to give an orange solid (1.49 g). This material was purified by flash chromatography on silica gel (the compound was pre-adsorbed on silica) eluting with dichloromethane / methanol / 0.880 90: 10: 1 NH 3, to give the title compound as a white solid (467 mg, 70%). %). H NMR (400 MHz, CD3OD) d? 7.82 (1 H, s), 7.45 (1 H, d), 6.58 (1 H, d), 4.34 (1 H, d), 3.95 (1 H, d), 3.72 (1 H, t), 2.95-2.80 (3H, m) 2.7 (1 H, t) MS (APCI +) 180 (MH +) [cr] 25D -39.4 (c = 0.12, MeOH) Example 3 5 - [(2R) -4- (3-phenylpropyl) morpholin-2-yl] pyridin-2-amine The morpholine from Example 2 (80 mg, 0.45 mmol) was dissolved in tetrahydrofuran (15 mL) and 3-phenylpropionaldehyde (59 pL, 0.45 mmol) was added as a solution in tetrahydrofuran (15 mL) over a period of time. 15 minute interval. After the addition was complete, sodium triacetoxyborohydride (227 mg, 1 mmol) was added and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was then diluted with saturated sodium hydrogencarbonate solution (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic fractions were dried (MgSC), filtered and evaporated to give a yellow oil. Purification by flash chromatography on silica gel eluting with dichloromethane / methanol / NH 3, 880 98: 2: 0.2 increasing the polarity to 95: 5: 05 gave the title compound (51 mg, 38%). H NMR (400 MHz, CD3OD) d? 7.86 (1 H, d), 7.45 (1 H, dd), 7.27-7.10 (5H, m), 6.55 (1 H, d), 4.39 (1 H, d), 3.95 (1 H, d), 3.75 (1 H, t), 2.83 (2 H, m), 2.64 (2 H, t), 2.41 (2 H, t), 2.20 (1 H, m), 2.05 (1 H, t), 1.84 (2H, m) MS (APCf) 298 (MH +) [a] 25D +6.9 (c = 0.13 , MeOH) Example 4 5 - [(2f?) - 4-Butylmorpholin-2-yl] pyridin-2-amine The morpholine from Example 2 (80 mg, 0.45 mmol) was mixed with tetrahydrofuran (10 mL) (only partially soluble) and butyric aldehyde (40 μ ?, 0.45 mmol) was added, resulting in a homogeneous solution. . The mixture of. The reaction was stirred for a further 30 minutes before the addition of sodium triacetoxyborohydride (227 mg, 1 mmol). The reaction mixture was then stirred at room temperature overnight (~ 16 h) before being diluted with sodium hydrogencarbonate solution (100 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were separated, dried (MgSO 4), filtered and evaporated to give a yellow oil. Purification by flash chromatography on silica gel eluting with dichloromethane / methanol / 0.880 98: 2: 0.2 NH 3 increasing the polarity to 95: 5: 05 afforded the title compound (17 mg, 16%). 1 H NMR (400 MHz, CD 3 OD) d? 7.86 (1 H, s), 7.47 (1 H, d), 6.55 (1 H, d), 4.39 (1 H, d), 3.98 (1 H, d), 3.76 (1 H, t), 2.86 (2H, t), 2.41 (2H, t), 2.21 (1 H, t), 2.07 (H, t), 1.50. (2H, m), 1, 35 (2H, m), 0.95 (3H, t) MS (APCI +) 236 (MH +) Example 5 5 - [(2 /?) - 4-pentylmorpholin-2-yl] pyridin-2-amino The morpholine from example 2 (80 mg, 0.45 mmol) was mixed with tetrahydrofuran (15 mL) and pentanal (47 pL, 0.45 mmol) was added dropwise as a solution in tetrahydrofuran (15 mL) during an interval of 15 minutes. After the addition was complete, triacetoxybohydroxide sodium (227 mg, 1 mmol) was added and the reaction mixture was stirred at room temperature overnight (~ 16 h). The reaction mixture was then diluted with saturated sodium hydrogencarbonate solution (75 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were separated, dried (MgSC), filtered and evaporated to give a yellow oil. Purification by flash chromatography on silica gel eluting with dichloromethane / methanol / Nhb 0.880 98: 2: 0.2 increasing the polarity to 95: 5: 05 afforded the title compound (67 mg, 61%). 1 H NMR (400 MHz, CD 3 OD) d? 7.86 (1 H, s), 7.46 (1 H, d), 6.55 (1 H, d), 4.41 (1 H, d), 3.94 (1 H, d), 3.77 (1 H, t), 2.86 (2H, t), 2.39 (2H, t), 2.21 (1 H, t), 2.06 (H, t), 1, 54 (2H, m), 1, 34 (4H, m), 0.92 (3H, t) MS (APCI +) 250 (MH +) [or] 25D +4.42 (c = 0.13, MeOH) Example 6 5 - [(2R) -4- (2-phenylethyl) morpholin-2-yl] pyridn-2-amine The morpholine from Example 2 (80 mg, 0.45 mmol) was mixed with tetrahydrofuran (15 mL) and phenylacetaldehyde (52 pL, 0.45 mmol) was added dropwise as a solution in tetrahydrofuran (15 mL) over an interval 15 minutes. After the addition was complete, the re-action mixture was allowed to stir at room temperature for 1 hour before the addition of sodium triacetoxyborohydride (227 mg, 1 mmol). The reaction mixture was stirred at room temperature overnight (~ 16 h) and then diluted with saturated sodium hydrogencarbonate solution (100 ml_) and extracted with ethyl acetate (100 mL). The combined organic layers were separated, dried (MgSO 4), filtered and evaporated to give a yellow oil. Purification by flash chromatography on silica gel eluting with dichloromethane / methanol / Nh 0.880 98: 2: 0.2 afforded the title compound (31 mg, 24%). 1 H NMR (400 MHz, CD 3 OD) d? 7.87 (1 H, s), 7.47 (1 H, d), 7.20 (5H, m) 6.55 (1 H, d), 4.42 (1 H, d), 3, 97 (1 H, d), 3.78 (1 H, t), 2.93 (2H, t) 2.82 (2H, m), 2.66 (2H, t) 2.30 (2H, t ), 2.21 (1 H, t), 2.15 (1 H, t) MS (APCI +) 284 (MH +) Example 7a 5 - [(2 /? 5S) -5-methylmorpholin-2-yl] pyridin-2-amine The product of Preparation 10 (410 mg, 1.25 mmol) was dissolved in ethanol (10 mL), Pd 5% on charcoal (40 mg) was added and the mixture was hydrogenated at room temperature overnight at 1 atmosphere . The mixture was then filtered through a bed of arbocel®, washing the bed with ethanol and the combined filtrates and washes were evaporated to a light yellow solid. Purification by flash chromatography on silica gel eluting with dichloromethane / methanol / NI- 0, 880 93: 7: 0.5 gave the title compound as a white solid (110 mg, 45%). 1H NMR: d? (400 MHz, CD3OD) 7.85 (1 H, d), 7.45 (1 H, dd), 6.55 (1 H, d), 4.29 (1 H, m), 3.90 ( 1 H, m), 3.30 (1 H, m), 2.95-2.85 (2H, m), 2.75 (1 H, m), 1, 01 (3H, d) MS (ES + ) 194 (MH +) Alternatively the morpholine ring can be formed by the following conditions to provide a mixture of diastereoisomers: Example 7b 5 - [(2R) -5-Methylmorpholin-2-yl] pyridin-2-amine (mixed of diastereomers) The diol of preparation 11 (1.26 g, 5.96 mmol) was dissolved in di-chloromethane (20 mL) and treated with concentrated sulfuric acid (8 mL) at room temperature. The mixture was stirred for 2 hours before the reaction was stopped by careful addition of water, alkalization with NH3 to pH ~ 9 and extracted with dichloromethane (2 x 150 mL). The combined organic substances were dried over magnesium sulfate, filtered and evaporated to give the title compounds as a 3: 1 mixture of diastereomers (R, S) and (S, S) respectively. 1H NMR: d? (400 MHz, CD3OD) 7.85 (1 H, m), 7.52-7.45 (1 H, 2xdd), 6.60-6.52 (1 H, 2xd), 4.38-4.22 (1 H, 2xdd), 3.95-3.80 (1 H, 2xdd), 3.30 (1 H, m), 3.10-2.83 (2H, m), 2.75 (1 H, m), 1, 39-0.99 (3H, 2xd) Examples 8 and 9 A mixture of the compounds of The morpholine from Example 7b (240 mg, 1.2 mmol) was dissolved in tetrahydrofuran (45 mL) and to the stirred solution was added dropwise 3-phenylpropionaldehyde (165 pL, 1.2 mmol) as a solution in tetrahydrofuran (45 mL ). Once the addition was complete, sodium triacetoxyborohydride (270 mg, 1.2 mmol) was added and the reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated and then diluted with water (30 mL) and extracted with dichloromethane (2 x 100 mL). The combined organic fractions were dried (MgSO 4), filtered and evaporated to give a clear oil of a mixture of about 2: 1 trans: cis diastereoisomers. The diastereoisomers were separated by HPLC on a Chiralcel AD-H column with a mobile phase of methanol: ethanol 50:50 and a flow rate of 15 ml / min. Example 8 (diastereomer 1) 5 - [(2?, 5S) -5-methyl-4- (3-phenylpropyl) morpholin-2-yl] pyridin-2-amine Retention time 4.80 min. 1H NMR: d? (400 MHz, CD3OD) 7.83 (1 H, s), 7.44 (1 H, d), 7.29-7.08 (m, 5H) 6.52 (1 H, d), 4, 40 (1 H, d), 3.79 (1 H, d), 3.30 (1 H, nn), 2.91-2.78 (2H, m), 2.60-2.50 (2H , m), 2.40 (1 H, m), 2.29 (1 H, m), 2.19 (1 H, rn), 1, 88-1, 68 (2H, m), 0.95 (3H, d) MS (APCI +) 312 (MH +) Example 9 (diastereomer 2) 5 - [(2S, 5S) -5-methyl-4- (3-phenylpropyl) morpholin-2-yl] pyridin-2-amine Retention time 7.60 min. 1H NMR: d? (400 MHz, CD3OD) 7.89 (1 H, s), 7.49 (1 H, d), 7.29-7.09 (5H, m), 6.55 (1 H, d), 4 , 42 (1 H, m), 3.87 (1 H, m), 3.72 (1 H, d), 2.90 (1 H, m), 2.70-2.62 (2H, m ), 2.60-2.42 (4H, m), 1, 90-1, 75 (2H, m), 1, 09 (3H, d) MS (APCI +) 312 (MH +) Examples 10 and 1 1 Diol from preparation 31 (350 mg, 1.3 mmol) was dissolved in di-chloromethane (5 mL) and concentrated H2SO4 (2.5 mL) was added to the stirred solution. The reaction mixture was allowed to stir at room temperature for 2 h then the reaction was stopped by careful addition of water (10 mL) then basified by the addition of 0.880 NH 3 to pH 8 - 9. The mixture was then extracted with dichloromethane (2 x 50 mL) and the combined extracts were dried (MgSO 4), filtered and evaporated to give a brown oil of a mixture of cis and trans morpholine diastereomers (275 mg 85%).

MS (ES +) 250 (MH +) The sample of mixed diastereomers was subjected to HPLC using a Chiralcel OD-H column, the mobile phase was IPA / hexane 30:70 with 0.1% diethylamine, at a flow rate of 20 mL / min. Example 10 (diastereomer 1) 5 - [(2S, 5S) -4-butyl-5-methylmorpholin-2-yl] pyridin-2-amine Retention time 4.90 min. 1H NMR: d? (400 MHz, CD3OD) 7.86 (1H, d), 7.49 (1H, dd), 6.56 (1H, d), 4.44 (1H, m), 3.86 (1H, m) , 3.39 (1H, m), 2.99 (1H, m), 2.88 (1H, m), 2.52 (1H, m an), 2.41-2.28 (2H, m) , 1.60-1.27 (4H, m), 1.07 (3H, d), 0.96 (3H, t) MS (APCI +) 250 (MH +) Example 11 (diastereomer 2) 5 - [(2R , 5S) -4-butyl-5-methylmorpholin-2-yl] pyridin-2-amine Retention time 7.20 min. 1 H NMR: 5H (400 MHz, CD3OD) 7.88 (1H, d), 7.48 (1H, dd), 6.55 (1H, d), 4.41 (1H, m), 3.83 ( 1H, m), 3.72 (1H, d), 2.90 (1H, m), 2.60-2.52 (2H, m), 2.48-2.40 (2H, m), 1 , 54-1, 44 (2H, m), 1, 40-1, 32 (2H, m), 1, 13 (3H, d), 0.94 (3H, t) MS (APCI +) 250 (MH +) Example 12 5 - [(2 /? 5S) -5 - [(benzyloxy) methyl] morpholin-2-yl] pyridin-2-amine The morpholine from preparation 14 (4.4 g, 9.21 mmol) was dissolved in ethanol (50 mL), hydroxylamine hydrochloride (3.2 g, 46 mmol) was added and the mixture was heated at 80 ° C for all night (-16 h). After cooling to room temperature the mixture was diluted with 10% aqueous K2CO3 solution (100 mL) and extracted with dichloromethane (2 x 100 mL). The combined organic fractions were dried over magnesium sulfate, filtered and evaporated to give a brown oil of crude deprotected intermediate of 2-amino-pyridine (3.6 g). This morpholine protected with boc (3.6 g, 9 mmol) was treated with 4 M HCl in dioxane (30 mL) and the mixture was stirred at room temperature for 4 h. The solvent was then evaporated and the residue was treated with 2 M sodium hydroxide (100 mL) and extracted with dichloromethane (4 x 100 mL). The combined organic fractions were dried over magnesium sulfate, filtered and evaporated to give a light brown solid which was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880 NH3 (93: 7: 0.5) to give the title compound as a light brown solid (1.43 g, 51%) H NMR: d? (400 MHz, CD3OD) 7.85 (1 H, d), 7.45 (1 H, dd), 7.36-7.25 (5H, m), 6.54 (1 H, d), 4 , 52 (2H, s), 4.28 (1 H, m), 3.97 (1 H, m), 3.49-3.38 (3H, m), 3.06 (1 H, m) , 2.96 (1 H, m), 2.76 (1 H, m) MS (ES +) 300 (MH +) Example 13 5 - [(2 /? 5S) -5 - [(benzyloxy) methyl] - 4-propylmorpholin-2-yl] pyridin-2- The morpholine of Example 1 1 (1.4 g, 4.8 mmol) was dissolved in THF (200 mL) and propanal (350 [mu] L, 4.8 mmol) in THF (150 mL) was added dropwise to the stirred mixture. After the addition was complete, NaBH (OAc) 3 (1.02 g, 4.8 mmol) was added in one portion and the reaction mixture was allowed to stir at room temperature overnight (~ 16 h) . The TLC analysis showed that there was still starting product, so additional NaBH (OAc) 3 (1 g) was added and the reaction mixture was stirred for a further 24 h. Saturated aqueous NH4CI (200 mL) was added and the organic layer was separated, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880 NH 3 (93: 7: 0.5) to give the title compound as a light brown solid (540 mg, 33%). 1H NMR: d? (400 MHz, CD3OD) 7.86 (1 H, d), 7.46 (1 H, dd), 7.36-7.26 (5H, m), 6.53 (1 H, d), 4 , 52 (2H, m), 4.38 (1 H, m), 4.00 (1 H, im), 3.60-3.53 (2H, m), 3.47-3.42 (1 H, m), 2.89 (1 H, m), 2.78-2.69 (1 H, m), 2.59 (1 H, m), 2.32-2.21 (2H m) , 1, 60-1, 37 (2H, m), 0.84 (3H, t) MS (ES +) 342 (MH +) Examples 14-17 [6- (6-aminopyridin-3-yl) -4-propylmorpholine -3il] metamol The diol of preparation 16 (1.4 g, 3.9 mmol, 1 eq) was dissolved in dichloromethane (15 ml_) and treated with concentrated sulfuric acid (10 ml_) at room temperature. The mixture was stirred at room temperature for 2 h before the reaction was stopped by the addition of ice, and then basified with 880 NH 3 to pH ~ 9. The mixture was extracted with dichloromethane (3 x 150 mL) and the combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880 NH 3 (95: 5: 0.5 increasing the polarity to 93: 7: 0.5) to provide 10 mg of a light brown oil of the composed of the title as a mixture of 4 diastereoisomers. The diastereoisomers were separated by HPLC on a Chiralpak AD column, IPA / Hexane mobile phase 20:80 with 0.1% DEA providing four stereoisomers. Example 14 Stereoisomer 1 (retention time: 9.50 min) enantiomer 1 trans. 1H NMR: d? (400 MHz, CD3OD) 7.86 (1H, d), 7.49 (1H, dd), 6.55 (1H, d), 4.40 (1H, m), 4.05 (1H, m) , 3.71 (1H, m), 3.55 (2H, m), 2.93 (1H, m), 2.82 (1H, m), 2.47 (1H, m), 2.34 ( 1H, m), 2.26 (2H, m), 2.27-1.42 (2H, m), 0.90 (3H, t) Example 15 Stereoisomer 2 (retention time:, 90 min) enantiomer 1 cis. H NMR (400 MHz, CD3OD) d? (ppm): 0.9 (t, 3H), 1.5-1.7 (m, 2H), 2.5-2.8 (m, 5H), 3.7-4.0 (m, 3H) ), 4.05-4.15 (m, 1H), 4.4-4.55 (m, 1H), 6.6 (d, 1H), 7.5 (d, 1H), 7.85 ( s, 1H) Example 16 Stereoisomer 3 (retention time: 16.60 min) enantiomer 2 cis. 1 H NMR (400 MHz, CD 3 OD) d? (ppm): 0.9 (t, 3H), 1.5-1.7 (m, 2H), 2.5-2.8 (m, 5H), 3.7-4.0 (m, 3H) ), 4.05-4.15 (m, 1H), 4.4-4.55 (m, 1H), 6.6 (d, 1H), 7.5 (d, 1H), 7.85 ( s, 1H) Example 7 Stereoisomer 4 (retention time: 19.70 min) enantiomer 2 trans. 1H NMR: d? (400 MHz, CD3OD) 7.86 (1 H, d), 7.49 (1 H dd), 6.55 (1 H, d), 4.40 (1 H, m), 4.05 (1 H, m), 3.71 (1 H, m), 3.55 (2 H, m), 2.93 (1 H, m), 2.82 (1 H m), 2.47 (1 H, m), 2.34 (1 H, m), 2.26 (2H, m), 2.27-1, 42 (2H, m), 0.90 (3H, t) Examples 18-19, 4-methyl -5- (4 ^ ropilmorpholin-2-yl) pyridin-2-amine The diol of preparation 21 (950 mg, 3.7 mmol) was dissolved in di-chloromethane (15 ml_) and treated with concentrated sulfuric acid (7 mL) at room temperature and the mixture was stirred for a further 2 h. The reaction was then stopped by the addition of ice, then basified by dropwise addition of 880 NH 3 to pH ~ 9. The mixture was then extracted with dichloromethane (4 x 50 mL) and the combined organic substances were dried with magnesium sulfate, filtered and evaporated to give the title compound as a light brown oil (700 mg, 79%). . 1H NMR: d? (400 MHz, CD3OD) 7.85 (1 H, d), 6.38 (1 H, d), 4.60 (1 H, m), 3.99 (1 H, m), 3.78 ( 1 H, m), 2.92-2.82 (2H, m), 2.38 (2H, m), 2.28-2.18 (4H, m), 2.12 (1 H, m) , 1, 62-1, 50 (2H, m) 0.93 (3H, t) MS (APCI +) 236 (MH +) The racemic morpholine was subjected to HPLC using a Chiralcel OD-H column eluting with acetonitrile. This provided the two enantiomers. Example 18 (enantiomer 1) Retention time: 5.1 min. 1H NMR: d? (400 MHz, CD3OD) 7.85 (1 H, d), 6.38 (1 H, d), 4.60 (1 H, m), 3.99 (1 H, m), 3.78 ( 1 H, m), 2.92-2.82 (2H, m), 2.38 (2H, m), 2.28-2.18 (4H, m), 2.12 (1 H, m) , 1, 62-1, 50 (2H, m) 0.93 (3H, t) MS (APCI +) 236 (MH +) Example 19 (enantiomer 2) Retention time: 6.5 min. 1H NMR: d? (400 MHz, CD3OD) 7.85 (1 H, d), 6.38 (1 H, d), 4.60 (1 H, m), 3.99 (1 H, m), 3.78 ( 1 H, m), 2.92-2.82 (2H, m), 2.38 (2H, m), 2.28-2.18 (4H, m), 2.12 (1H, m) , 1, 62-1, 50 (2H, m) 0.93 (3H, t) Example 20 3-methyl-5 - [(5S) -5-methyl-4-propylmorpholin-2-yl] pyridin-2 - amine The diol of preparation 29 (200 mg, 0.74 mmol) was dissolved in dichloromethane (4 mL) and treated with concentrated sulfuric acid (2 mL) at room temperature and the mixture was stirred for a further 2 h. The reaction was then stopped by careful addition of water, then alkalized by dropwise addition of 880 NH 3 to pH-9. The mixture was then extracted with dichloromethane (3 x 70 mL) and the combined organic substances were dried with magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel to afford the title compound as a clear oil as a mixture of diastereoisomers (35 mg, 19%). 1H NMR: d? (400 MHz, CD3OD) 7.77 (1 H, d), 7.38 (1 H, d), 4.41 (H, m), 3.88-3.70, 2.95-2.72 (3H, 2xm), 2.57 (1H, m), 2.50-2.35 (2H, m), 2.29-2.19 (1H, m), 2.1 1 (3H, 2xs), 1, 61-1, 39 (2H, m), 1, 18-1, 00 (3H, 2xd), 0.91 (3H, m) MS (ES +) 250 (MH +) Examples 21 v 22 The Diol from preparation 24 (990 mg, 3.9 mmol) was dissolved in dichloromethane (10 mL) and treated with concentrated sulfuric acid at room temperature. The mixture was allowed to stir for 2 h before the reaction was stopped by the addition of ice and then made alkaline by the addition of 880 NH 3 to pH ~ 9. The mixture was then extracted with dichloromethane (3 x 150 mL), the combined organic substances were dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / NI-880 (95: 5: 0.5) to give the title compound as a mixture of diastereoisomers (470 mg, 51%). MS (ES +) 236 (MH +) The diastereoisomers were separated using chiral HPLC on a Chiralcel OD-H column eluting with 30% IPA in hexane with 0.1% diethylamine. To provide: Example 21 (diastereomer 1) 5 - [(2S, 5S) -4,5-diethylmorpholin-2-yl] pyridin-2-amine Retention time: 4.1 min. 1H NMR: d? (400 MHz, CD3OD) 7.88 (1H, d), 7.48 (1H, dd), 6.57 (1H, d), 4.43 (1H, m), 3.98 (1H, d) , 3.77 (1H, m), 2.67-2.54 (1H, m), 1.60 (1H, m), 1.11 (3H, t), 0.96 (3H, t) MS (ES +) 236 (MH +) Example 22 (diastereomer 2) 5 - [(2R, 5S) -4,5-diethylmorpholin-2-yl] pyridin-2-amine Retention time: 7.3 min. 1H NMR: d? (400 MHz, CD3OD) 7.87 (1H, d), 7.47 (1H, dd), 6.56 (1H, d), 4.40 (1H, m), 3.98 (1H, m) , 3.43 (1H, m), 3.01-2.90 (2H, m), 2.44 (1H, m), 2.33 (1H, m), 2.25 (1H, m), 1.78 (1H, m), 1.32 (1H, m), 1.06 (3H, t), 0.93 (3H, t) MS (ES +) 236 (MH +) Example 23 5- (1 - propylazetidin-3-yl) pyridin-2-amine The aminopyridine imine from preparation 35 (95 mg, 0.267 mmol, 1.0 eq) was dissolved in EtOH (2 mL), 10% Pd / C (10 mg) and ammonium formate (168 mg, 2.67 mmol) were added. , 10 eq) and the mixture was heated to a gentle reflux for 3 h. Additional 10% Pd / C (10 mg) and ammonium formate (168 mg, 2.67 mmol, 10 eq) were added and the mixture was heated to reflux for 48 hours. The catalyst was filtered through arbocel, and washed with EtOH. The filtrate was evaporated in vacuo to give a colorless oil. This material was dissolved in THF (5 mL), 2 M HCl (aC) was added and stirred at r.t. for 3 h. The mixture was evaporated in vacuo and basified with K2CO3 (aqueous 10% w / v) and extracted with CH2Cl2 (3 x 20 mL), dried (MgSO4), filtered and evaporated to give a colorless oil. This oil was purified by flash chromatography on silica gel with an elution gradient from 100% CH 2 Cl 2 to CH 2 Cl 2: MeOH: NH 4 OH 90: 10: 1 to give the product as a colorless oil that solidifies leaving it to stand (21 mg, 41 %). TLC Rf = 0.24 (CH2Cl2: MeOH: NH4OH 90: 10: 1 UV visualization) MS (APCI +) 192 (MH +) 1H NMR: d? (400 MHz, CD3OD) 7.95 (1 H, s), 7.45 (1 H, d), 6.5 (1 H, d), 4.2-4.6 (2 H, s an), 3.5-3.8 (3H, m), 3.05 (2H, 1), 2.45 (2H, t), 1, 3-1, 5 (2H, m), 0.9 (3H, t) Examples 24 v 25 5- (2?, 5S) -4-ethyl-5-methylmorpholin-2-yl) -pyridin-2-ylamine and 5- (2S, 5S) -4-ethyl-5 -methylmorpholin-2-M) ^ iridin-2-ylamine The morpholine from Preparation 38 (1 g, 4.17 mmol) was dissolved in CH 2 Cl 2 (15 mL) and concentrated sulfuric acid (7.5 mL) was added. The mixture was stirred at t.a. for 2 h, it was basified by careful addition of 0.880 NH 3, and extracted with CH 2 Cl 2 (2 x 200 mL), the organics were combined, dried over magnesium sulfate, filtered and purified by flash chromatography on silica gel eluting with Ch ^ C ^ MeOI-LNh OH 97: 3: 1 to give the title compound as a light brown oil (560 mg, 61%). The diastereoisomers were separated on a Chiralcel OdH column (500 * 50 mm) with a mobile phase of 20% IPA, 80% hexane, 0.1% DEA at a flow rate of 80 ml / min to give: Diastereoisomer 1 - retention time 5.47 min (Example 24, diastereomer (2S.5S)) 1H NMR: d? (400 MHz, CD3OD) 7.88 (1 H, s), 7.46-7.52 (1 H, m), 6.58 (1 H, d), 4.40-4.46 (1 H , m), 3.84-3.92 (1 H, m), 3.75-3.79 (1 H, m), 2.91-2.98 (H, m), 2.47-2 , 60 (4H, m), 1, 08-1, 18 (m, 6H) MS (APCI +) 222 (MH +) Diastereoisomer 2 - retention time 7.96 min (Example 25, diastereomer (2R.5S)) 1H NMR: d? (400 MHz, CD3OD) 7.88 (1 H, s), 7.44-7.50 (1 H, m), 6.56 (1 H, d), 4.40-4.46 (m, 1 H), 3.80-3.88 (1 H, m), 3.28-3.41 (1, H, m), 2.88-3.00 (2H, m), 2.35-2.52 (2H, m), 2.16-2.24 (1H, m), 1, 00-1, 08 (m, 6H) MS (APCI +) 222 (MH +) Examples 26 v 27 (+) - 5- (4-propylmorpholin-2-yl) -1,3-thiazol-2-amine and (-) - 5- ( 4-propylmorpholin-2-yl) -1,3-thiazole-2-amino To 2- (2-bromo-1,3-thiazol-5-yl) -4-propylmorpholine (2.5 g, 8.56 mmol) in ethylene glycol (60 mL) at -78 ° C was added Cu20 (61 mg , 0.43 mmol, 0.05 eq) and NH3 (i) (20 mL) in a cylinder. The vessel was sealed, and heated at 80 ° C for 18 h. The vessel was allowed to cool, vented, and partitioned between AcOEt (2 x 200 mL) and water (100 mL), the organic layers were combined, dried over MgSO4 and the solvent was evaporated to give a brown oil. This material was chromatographed on an Is-co Companion Combiflash autochromatography system with an elution gradient from ChbCb / MeOH / NhUOH 99/1/0, 1 to CH2Cl2 / MeOH / NH4OH 95/5 / 0.5 to give the product as a brown oil (1.1 g). This material was separated by HPLC on a Chiralcel OJ column (250 + 21.5) with a mobile phase of Hexane: IPA 70:30 at a flow rate of 18 ml / min to give two enantiomers. Enantiomer 1, retention time 5.140 min. 1 H NMR (400 MHz, CD 3 OD) d (ppm): 6.99 (s, 1 H), 4.63 (d, 1 H), 3.87-3.93 (m, 1 H), 3.70 -3.77 (m, 1 H), 2.95 (d, 1 H), 2.78 (d, 1 H), 2.31-2.39 (m, 2H), 2.10-2, 23 (m, 2H), 1, 48-1, 60 (m, 2H), 0.92 (t, 3H) MS (APCI +) 228 (MH +) Optical rotation [a] D25 +48.45 (c = 1 , 45 mg / mL MeOH) Elemental Analysis +0.55 H20 PM Total = 237.24 Calculated C (50.63), H (7.69), N (17.71) Real C (50.90, 50, 79), H (7.48, 7.51), N (17.35, 17.38) Enantiomer 2, retention time 10.750 min. 1 H NMR (400 MHz, CD 3 OD) d (ppm): 6.99 (s, 1 H), 4.63 (d, 1 H), 3.87-3.93 (m, 1 H), 3.70-3.77 (m, 1 H), 2.95 (d, 1 H), 2.78 (d, 1 H), 2, 31-2.39 (m, 2H), 2.10-2.23 (m, 2H), 1, 48-1, 60 (m, 2H), 0.92 (t, 3H) MS (APCI +) 228 (MH +) Optical rotation [a] D25 -43.56 (c = 2.6 mg / mL MeOH) Elemental Analysis +1 H20 PM Total = 245.35 Calculated C (48.96), H (7.81), N (17.13) Real C (49.05, 49.07), H (7.83, 7.85), N (17.00, 16.99) The following preparations illustrate the synthesis of certain intermediate media used in the preparation of the preceding examples : Preparation 1 5-bromo-2- (2,5-dimethyl-pyrrol-1-yl) -pyridine 2,5-hexanedione (46.2 g, 0.41 mol) was added to a suspension of 2-amino-5-bromopyridine (50.0 g, 0.29 mol) and the reaction was heated to reflux for 24 hours under conditions of Dean and Stark. Para-toluenesulfonic acid (100 mg) was added and the reaction was refluxed for a further 18 hours. 8 mL of water was removed, so the reaction was cooled to room temperature, washed with water (100 mL) and passed through a pad of silica gel, eluting with toluene. The eluent was concentrated in vacuo and the residue was dissolved in pentane: dichloromethane (1: 1 by volume) and passed through a pad of silica gel, eluting with pentane: dichloromethane (1: 1 by volume). The eluent was concentrated in vacuo to give a red liquid, which solidified leaving it to stand still. The solid was recrystallized (isopropanol) to give the title compound as a light yellow solid (54.4 g). 1 H NMR (400 MHz, CDCl 3): d? 8.66 (1 H, s), 7.93-7.92 (1 H, d), 7.13-7.11 (1 H, d), 5.91 (2 H, s), 2.13 (6H, s). LRMS (thermospray): m / z [M + H] + 252.

Preparation 2 2-Chloro-1 - [6- (2,5-dimethyl-pyrrol-1-yl) -pyridin-3-yl] -ethanone A solution of 2.5 M n-butyl lithium in hexanes (35 mL, 87.6 mmol) was added to a solution of the bromide from Preparation 1 (20.0 g, 79.7 mmol) in fer-butyl methyl ether (300 mL) at -78 ° C under nitrogen for a 10 minute interval. The reaction was stirred for a further 10 minutes and 2-chloro-N-methoxy-A / -methylacetamide (12.1 g, 87.6 mmol) in tert-butyl methyl ether (40 mL) was slowly added. The reaction was stirred at -78 ° C for 20 minutes and then 1 M hydrochloric acid (200 mL) was added. The mixture was allowed to warm to room temperature, stirred 2 hours and the organic phase was separated. The aqueous phase was extracted with fer-butyl methyl ether and the combined organic extracts were washed with water (100 mL), saturated aqueous sodium chloride (100 mL) and 1 M sodium hydroxide (100 mL). The organic phase was dried (sodium sulfate), concentrated in vacuo and the residual oil was purified by flash column chromatography on silica gel eluting with penta-no: dichloromethane: methanol (75: 25: 0 changing to 0:99: 1, in volume). The resi-duo was recrystallized from pentane: dichloromethane to give the title compound as a yellow solid (14.37 g, 73%). 1 H NMR (400 MHz, CDCl 3): d? 9.1 1 (1 H, s), 8.34-8.33 (1 H, d), 7.32-7.30 (1 H, d), 5.91 (2 H, s), 4, 66 (2H, s), 2.17 (6H, s) LRMS (electrospray): m / z [M + Na] + 247. Preparation 3 2- (2,5-dimethyl-pyrrol-1-yl) -5 - [(2R) -oxiranyl] pyridine A solution of the chloride from preparation 2 (12.0 g, 48.1 mmol) in tetrahydrofuran (20 mL) was added slowly to a solution of (-) - S-chlorodiisopinocamfeylborane (20.1 g, 62.5 mmol) in fer-butyl methyl ether (15 mL) and tetrahydrofuran (30 mL) at -30 ° C under nitrogen. The reaction was stirred for 6 hours at -30 ° C and then sodium tetrabohydrate perborate (7.4 g, 48.1 mmol) was added followed by fer-butyl methyl ether (50 mL). The reaction was stirred at room temperature for 18 hours, treated with 2 M aqueous sodium hydroxide (190 ml) and stirred for a further 6 hours. The organic phase was separated and the aqueous phase was extracted with additional ferc-butylmethylether (50 mL). The combined organic extracts were washed with 1 M aqueous sodium hydroxide (50 mL), saturated aqueous sodium chloride (50 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with penta-no: dichloromethane (80:20 changing to 100: 0, in volume) to give the crude epoxide (65% by weight, 11.0 g), which were used without further purification. 1 H NMR (400 MHz, CDCl 3): d? 8.58 (1 H, s an), 7.68-7.66 (1 H, dd), 7.22-7.20 (1 H, d), 3.97-3.96 (1 H, m), 3.26-3.24 (1 H, m), 2.91-2.89 (1 H, (6H, s) LRMS (electrospray): m / z [M + H] + 215, [ M + Na] + 237. Preparation 4 (1 R) -2- (benzylamino) -1 - [6- (2,5-dimethyl-1 H -pyrrol-1-yl) pyridin-3-yl] ethanol The epoxide of Preparation 3 (2.66 g, 12 mmol) was dissolved in DMSA (30 mL), treated with benzylamine (1.62 mL, 15 mmol) and the mixture was heated at 90 ° C overnight (~ 16 h). After cooling to room temperature the reaction mixture was evaporated under high vacuum at 60C'C to remove most of the DMSO. The residue was diluted with ethyl acetate (150 mL) and washed with water (100 mL). The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate (100 mL). The combined organic fractions were dried (gSC ^), filtered and evaporated to give the title compound as a yellow oil (3.29 g, 84%). 1 H NMR (400 MHz, CDCl 3) 8.55 (1 H, s), 7.85 (1 H, d), 7.35-7.25 (5H, m), 7.2 (1 H, d) , 5.9 (2H, s), 4.8 (1 H, m), 3.89 (2H, s), 3.01 (1 H, dd), 2.78 (1 H, t), 2 , 1 (6H, s) MS (APCI +) 322 (MH +) Preparation 5 / V-benzyl-2-chloro- / V-. { (2R) -2- [6- (2,5-Dimethyl-1 H -pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl} acetamide The amino alcohol of Preparation 4 (3.22 g, 10 mmol) was dissolved in dichloromethane (100 mL), sodium hydroxide (2 g, 50 mmol) was added in an aqueous solution (35 mL) and the mixture was stirred vigorously. Chloroacetyl chloride (0.96 mL, 12 mmol) was added dropwise and then stirring was continued at room temperature overnight (-16 h). The reaction mixture was then diluted with dichloromethane (200 mL) and water (100 mL). The organic layer was separated, dried (MgSO 4), filtered and evaporated to give a brown oil (4.35 g). The H NMR spectrum indicated that a mixture of chloroamide and morpholinone (product of preparation 5) was formed, so the mixture was carried forward without further purification. MS (APCI +) 398 (MH +, chloro amide), 362 (MH +, cyclized morpholinone) Preparation 6 (6) -4-benzyl-6- [6- (2,5-dimethyl-1W-pyrrol-1-yl) p Ridin-3-yl] morpholin-3-one The crude mixture of preparation 5 was dissolved in propan-2-ol (100 mL), water (5 mL) was added followed by potassium hydroxide (673 mg). The mixture was stirred vigorously at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate (200 mL) and water (150 mL). The organic layer was separated and washed with brine (150 mL), dried (MgSO 4), filtered and evaporated to give a dark orange oil. Purification by flash chromatography on silica gel eluting with 99: 1 dichloromethane / methanol gave the title compound as a yellow oil (69%). 1 H NMR (400 MHz, CDCl 3) 8.52 (1 H, s), 7.79 (1 H, d), 7.30 (5 H, m), 7.20 (1 H, d), 5.89 (2H, s), 4.89 (1H, dd), 4.76 (1H, d), 4.63-4.42 (3H, m), 3.49 (1H, t), 3 , 38 (1 H, dd), 2.09 (6H, s) MS (APCI +) 362 (MH +) Preparation 7 (2R) -4-benzyl-2- [6- (2,5-dimethyl-1H-pyrrole -1-l) pyridin-3-yl-morpholine The morpholinone from Preparation 6 (2.47 g, 6.8 mmol) was dissolved in tetrahydrofuran (100 mL) and cooled (flask in an ice / water bath). Lithium aluminum hydride (1 M in tetrahydrofuran, 10.2 mL, 10.2 mmol) was added dropwise and after the addition the reaction mixture was allowed to stir at room temperature overnight (~ 16 h) . The reaction was stopped by careful addition of 1 M sodium hydroxide (10 mL) then diluted with water (150 mL) and stirred for 10 minutes. Ethyl acetate (200 mL) was added, the organic layer was separated, dried over MgSO4, and evaporated to give the title compound as a yellow oil (2.09 g, 89%). 1 H NMR (400 MHz, CDCl 3) 8.59 (1 H, s), 7.81 (1 H, d), 7.3 (5 H, m), 7.2 (1 H, d), 5.9 (2 H, s), 4.69 (1 H, d), 4.05 (1 H, d), 3.9 (1 H, t), 3.6 (2 H, s), 3.0 (1 H, d), 2.8 (1 H, d), 2.35 (1 H, t), 2.19 (1 H, t), 2.1 (6H, s) MS (APCI +) 348 (MH + ) Preparation 8 (2S) -2- ( { (2R) -2- [6- (2,5-dimethyl-1 H -pyrrol-1 -M) pyridin-3-yl] -2-hydroxyethyl} amino) propan-1 -ol The epoxide of preparation 3 (5.4 g, 20 mmol) was dissolved in DMSO (50 mL) together with (S) -2-aminopropan-1-ol (2.0 g, 20 mmol) and the mixture was heated at 90 ° C overnight (approximately 16 h). After cooling to room temperature, the mixture was evaporated at high vacuum and the residue was purified by flash chromatography on silica gel eluting with di-chloromethane / methanol (95: 5 increasing the polarity to 90:10) to provide the title as a light yellow oil (5.0 g, 75%).

Preparation 9 (2 /? 5S) -2- [6- (2,5-Dimethyl-1 H -pyrrol-1-yl) pyridin-3-yl] -5-methylmorpholine-4-carboxylic acid benzyl ester The diol of preparation 8 (5 g, 17.2 mmol) was dissolved in dichloromethane (60 mL) and treated with benzyl chloroformate (2.72 mL, 19 mmol) and triethylamine (2.65 mL, 19%). mmol). The mixture was stirred overnight (-16 h) before the reaction was stopped by the addition of 2 M sodium hydroxide (100 mL). The mixture was extracted with dichloromethane (2 x 100 mL) and the combined organic fractions were dried (MgSO 4), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with a gradient from 25% to 60% ethyl acetate in pentane to provide the CBz-protected intermediate as a light brown oil (2.56 g, 35%). . MS (ES +) 446 (MNa +) MS (ES ") 422 (M-H +) A sample of the diol protected with CBz above (2 g, 4.7 mmol) was dissolved in toluene (30 mL) together with triphenylphosphine ( 1.5 g, 5.6 mmol). Diisopropyl azodicarboxylate (1.12 mL, 5.6 mmol) was added dropwise and the reaction mixture was allowed to stir overnight (~ 16 h). The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL) The combined organic fractions were dried (MgSO.sub.4), filtered and evaporated The residue was purified by flash chromatography on silica gel. silica eluting with 20% ethyl acetate in penntane to give the title compound as a clear oil (1.68 g). 1 H NMR shows that the sample contains ~ 3 equivalents of hydra-cyan-1,2-dicarboxylate of diisopropyl together with the title compound, so that ~ 40% by weight of the material is the title compound, which corresponds to an approximate yield of 36%. NMR: d (400 MHz, CDCl 3) 8.62 (1 H, d), 7.80 (1 H, dd), 7.37-7.27 (5H, m), 7.11 (1 H, d). 5.88 (2H, s), 5.18 (1 H, d), 5.10 (1 H, d), 4.26 (1 H, m), 4.08 (1 H, m), 3 , 72 (2H, m), 3.46-3.40 (2H, m), 2.09 (6H, s), 1.37 (2H, d) MS (ES +) 406 (MH +) Preparation 10 Benzyl ester of 2- (6-amino-pyridin-3-yl) -5-methyl-morpholine-4-carboxylic acid The morpholine from preparation 9 (680 mg, 1 mmol) was dissolved in ethanol (12 mL) and treated with hydroxylamine hydrochloride (600 mg, 8.4 mmol) and the mixture was heated at 80 ° C overnight (-16 h). After cooling to room temperature the solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with dichloromethane in 0% methanol increasing the polarity to 2% to give the title compound as a purple oil (410 mg , 95%). 1 H NMR (400 MHz, CD 3 OD) d? 7.91 (1 H, d), 7.43 (1 H, dd), 7.37-7.28 (5H, m), 6.52 (1 H, d), 5.13 (2H, 2 xd), 4.79 (1 H, m), 4.12 (1 H, m), 4.04 (2H, m), 3.37 (2H, m), 1, 30 (3H, d) MS (ES +) 328 (MH +) Preparation 1 1 (2S) -2-. { [(2?) - 2- (6-aminopyridin-3-yl) -2-hydroxyethyl] amino} pro- The diol of preparation 8 (1 g, 3.35 mmol) was dissolved in ethanol and treated with hydroxylamine hydrochloride (1.2 g, 16.75 mmol) and the mixture was heated at 80 ° C overnight (~ 16 h). After cooling to ambient temperature the solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880 NH 3 (85: 15: 1 increasing the polarity to 82: 17: 1) to provide the title compound as a light brown oil (670 mg, 95%). 1 H NMR (400 MHz, CD 3 OD) d? 7.91 (1 H. s), 7.52 (1 H, d), 7.6 (1 H, d), 4.72 (1 H, d), 3.67 (1 H, d), 3.45 (1 H, m), 3.1-2.85 (3H, m), 1, 15 (3H, d) MS (ES +) 212 (MH +), 234 (MNa +) Preparation 12 (2) - 3- (benzyloxy) -2- ( { (2R) -2- [6- (2,5-dimethyl-1 H -pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl}. amino) propan-1 -ol The epoxide of preparation 3 (5.4 g, 25 mmol) was dissolved in DMSO (50 mL) together with (S) -2-amino-3-benzyloxypropan-1-ol (5.0 g, 27.6 mmol) and the mixture was heated at 90 ° C overnight (approximately 16 h ). After cooling to room temperature, the mixture was evaporated under high vacuum to provide a brown oil-12 g of the desired title compound containing some residual DMSO but of sufficient purity for use in the subsequent step without further purification. 1 H NMR (400 MHz, CD 3 OD) d? 8.54 (1 H, d), 7.99 (1 H, dd), 7.25-7.22 (6H, m), 5.81 (2H, s), 4.51 (2H, m) , 3.67-3.45 (5H, m), 3.01-2.81 (3H, m), 2.03 (6H, s) MS (ES +) 396 (MhT) Preparation 13 enzyloxy) -1- (hydroxymethyl) ethyl]. { (2f?) -2- [6- (2,5-Dimethyl-1 H -pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl} ferrous butyl carbamate The crude diol from preparation 12 (10 g, -25 mmol) was dissolved in dichloromethane (150 ml_) and treated with di-re-butyl dicarbonate (5.52 g, 25 mmol) and the mixture was stirred at room temperature. All night long (~ 16 h). The reaction mixture was diluted with 10% aqueous K2CO3 solution (200 mL), the organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 300 mL). The combined organic fractions were dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 35% ethyl acetate in pentane increasing the polarity of the eluent to 50% ethyl acetate in pentane to give the title compound as a pale yellow oil (6.2 g, 50% yield on the 2 steps of preparations 12 and 13). H NMR: d? (400 MHz, CD3OD) 8.55 (1 H, d), 8.04-7.95 (1 H, m), 7.38-7.23 (6H, m), 5.81 (2H, s) ), 5.05 (1 H, m an) 4.54 (2 H, m), 3.93 (1 H, m an), 3.83 (1 H, m an), 3.78-3.60 (5H, m), 3.44-3.32 (1 H, m), 2.05 (6H, s), 1.44 and 1.40 (9H, two singlets) MS (APCI +) 496 (MH +) Preparation 14 (2R, 5S) -5 - [(benzyloxy) methyl] -2- [6- (2,5-dimethyl-1 H-pyrrol-1-yl) pyridin-3-yl] morpholine-4 ferric butyl carboxylate The diol of preparation 13 (6.2 g, 12.5 mmol) was dissolved in toluene (100 mL) and treated with triphenylphosphine (4 g, 15 mmol) at room temperature. Diisopropyl azodicarboxylate (DIAD) (3 mL, 15 mmol) was added dropwise and the mixture was allowed to stir overnight (~ 16 h). The reaction mixture was then diluted with water (200 mL), the organic layer was separated and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate in pentane increasing the polarity to 15% ethyl acetate in pentane to give the title compound as a clear oil (4, 4 g, 74%) H NMR: d? (400 MHz, CDCl 3) 8.64 (1 H, d), 7.88 (1 H, dd), 7.36-7.27 (5H, m), 7.22 (H, d), 5, 89 (2H, s), 4.96 (1 H, m), 4.62 (1 H, m), 4.44 (1 H, d), 4.28 (1 H, m), 4.12 (1 H, m) 3.82-3.68 (4H, m), 3.60 (1 H, dd), 2.12 (6H, s), 1.44 (9H, s) MS (APCI +) 478 (MH +) Preparation 15 (2?) - 3- (benzyloxy) -2- [. { (2 /?) -2- [6- (2,5-d.methyl-1 H-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl} (propyl) amino] propan-1-ol The crude diol from preparation 12 (3 g, 7.6 mmol) was dissolved in dichloromethane and propanal (1.1 mL, 15.2 mmol) and NaBH (OAc) 3 (3.25 g, 15.2 g) were added. mmol). The reaction mixture was stirred at room temperature overnight (-16 h) and then the solvents were evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880 NH 3 (97: 3: 0.5) to give the title compound as a light brown oil which still contained ~ 3 equivalents of DMSO from the previous stage (4.5 g, corrected by DMSO ~ 2.95 g of product 89% yield). 1 H NMR: 5H (400 MHz, CDCl 3) 8.52 (1 H, d), 8.81 (1 H, dd), 7.38-7.22 (5H, m), 7.17 (1 H, d), 5.86 (2H, s), 4.72 (1H, m), 4.54 (2H, s), 3.48-3.68 (4H, m), 3.16 (1H , m), 2.88-2.95 (1 H, m) 2.82-2.55 (3H, m), 2.07 (6H, s), 1.50 (2H, m), 0, 87 (3H, t) MS (APCI +) 438 (MH +), 460 (MNa +) Preparation 16 (2S) -2-. { [(2R) -2- (6-aminopyridin-3-yl) -2-hydroxyethyl] (propyl) amine} -3- (benzyloxy) propan-1 -ol The diol of preparation 15 (2.95 g, 6.7 mmol) was dissolved in ethanol (50 mL) treated with hydroxylamine hydrochloride (2.34 g, 33.7 mmol) and the mixture was heated to 80 °. C all night (-16 h). After cooling to room temperature the solvents were evaporated and the residue was purified by flash chromatography on silica gel eluting with dichloromethane-methanol / Nh 880 (95: 5: 0.5 increasing the polarity to 91: 9: 0, 5) to provide the title compound as a light brown oil (1.4 g, 58%). 1H NMR: d? (400 MHz, CD3OD) 7.82 (1 H, d), 7.46 (1 H, dd), 7.38-7.22 (5H, m), 6.57 (1 H, d), 4 , 57-4.44 (3H, m), 3.63-3.46 (4H, m), 3.07 (1 H, m), 2.77 (2H, d), 2.71-2, 53 (2H, m), 1, 46 (2H, m), 0.97 (3H, t) MS (APCI +) 360 (MH +), 382 (MNa +) Preparation 17 5-bromo-2- (2,5- dimethyl-1H-pyrrol-1-yl) -4-methylpyridine 2-Amino-5-bromo-4-methylpyridine [commercially available] (6 g, 32 mmol) was dissolved in toluene (100 mL), hexane-2,5-dione (5.3 mL, 45 mmol) was added. ) and para-toluenesulfonic acid monohydrate (50 mg) and the mixture was heated to reflux with a coupled Dean-Stark apparatus. When the water collection stopped, the reaction mixture was cooled and diluted with water (50 mL) and 10% aqueous K2CO3 solution (50 mL), the organic layer was separated and the aqueous layer was extracted with ethyl acetate. (200 mL). The combined organic fractions were dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 5% ethyl acetate in pentane to give the title compound as a light yellow oil (8 g, 95%). 1H NMR: d? (400 MHz, CDCl 3) 8.62 (1 H, s), 7.1 1 (1 H, s), 5.90 (2 H, s), 2.45 (3 H, s), 2.15 (6 H , s) MS (ESI +) 267 (MH +) Preparation 18 4-propylmorpholin-2-one Methyl 2-bromoacetate (50 mL, 0.54 mol, 1 eq) was added slowly to / V-propylaminoethanol (62.4 mL, 0.54 mol, 1 eq) and Et3N (75 mL, 0.54 mol, 1 eq) in toluene at 0 ° C and allowed to stir at room temperature overnight. Water (1 L) was added, and the mixture was extracted with AcOEt (2 x 500 mL). The organic layers were combined, dried (MgSO4), filtered and the solvent removed in vacuo to give 62.7 g (81%) of the title compound as a clear oil. TLC AcOEt Rf = 0.5 M / S (APCI +) 144 (MH +) 1 H NMR (400 MHz, CD3OD) d? 0.9 (t, 3H), 1, 4-1, 6 (m, 2H), 2.3-2.4 (m, 2H), 2.6-2.7 (m, 2H), 3, 3 (s, 2H), 4.4 (m, 2H) Preparation 19 2- [6- (2,5-Dimethyl-1 H -pyrrol-1 -yl) -4-methylpyridin-3-yl] -4- propolmor-folin-2-ol The bromopyridine from Preparation 17 (5 g, 18.8 mmol) was dissolved in THF (80 mL) and cooled to -78 ° C. Rerc-butyllithium (22 mL, 37.7 mmol) was added dropwise to the stirred solution. Immediately after the reaction was finished, morpholinone (from preparation 18) (2.7 g, 18.8 mmol) was added as a solution in THF (20 mL) and the reaction mixture was allowed to stir at -78 ° C. for 1 hour. The reaction was then quenched by addition over saturated aqueous NH4Cl solution (100 mL), then extracted with ethyl acetate (100 mL). The organic fraction was dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 35% ethyl acetate in pentane increasing the polarity of the eluent to 40% ethyl acetate in pentane to give the title compound as a light yellow oil (1). , 95 g, 32%). H NMR: d? (400 MHz, CDCl 3) 8.78 (1 H, s), 7.00 (1 H, s |;). 5.86 (2H, s), 5.21 (1 H, s an), 4.23 (1 H, m), 3.85 (1 H, m), 3.03 (1 H, m), 2.82 (1 H, m), 2.62 (3H, s), 2.56-2.37 (4H, m), 2.08 (6H, s), 1.58 (2H, m), 0.97 (3H, t) MS (ESI +) 330 (MH +) Preparation 20 1 - [6- (2,5-Dimethyl-1 H -pyrrol-1 -yl) -4-methylpyridin-3-yl] -2 - [(2-hydroxyethyl) (propyl) amino] ethanol The morpholinol from Preparation 19 (1.95 g, 5.9 mmol) was dissolved in ethanol (25 mL_) and water (10 mL) and sodium borohydride (900 mg, 23.6 mmol) was added to the stirred mixture. room temperature. Stirring was maintained overnight (~ 16 h) before the reaction was stopped by the addition of saturated aqueous ammonium chloride (100 mL) and extracted with dichloromethane (2 x 100 mL). The combined organic fractions were dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane-methanol / 880 NH 3 (96: 4: 0.5) to give the title compound as a light yellow oil (1.4 g, 71%). . H NMR: d? (400 MHz, CDCl 3) 8.59 (1 H, s), 7.16 (1 H, s), 5.80 (2 H, s), 5.07 (1 H, m), 3.67-3 , 58 (2H, m), 2.82-2.54 (6H, m), 2.47 (3H, s), 2.02 (6H, s), 1.50 (2H, m), 0, 90 (3H, t) MS (ESI +) 332 (MH +) Preparation 21 1 - (6-amino-4-methylpyridin-3-yl) -2 - [(2-hydroxyethyl) (propyl) amine] ethanol The diol of preparation 20 (1.4 g, 4.22 mmol) was dissolved in ethanol (30 mL) and treated with hydroxylamine hydrochloride (1.12 g, 16.9 mmol), and the mixture was heated to 0.degree. reflux throughout the night (~ 16 h). After cooling to room temperature the mixture was diluted with 10% aqueous K2CO3 solution and extracted with dichloromethane (2 x 200 ml_). The combined organic fractions were dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880 NH 3 (93: 7: 1) to give the title compound as a light brown oil (950 mg, 89%). H NMR: d? (400 MHz, CD3OD) 7.90 (1 H, s), 6.39 (1 H, s), 4.81 (1 H, m), 3.66-3.57 (2H, m), 2 , 80-2.72 (1 H, m), 2.67-2.48 (5H, m), 2.24 (3H, s), 1, 58-1, 46 (2H, m), 0, 91 (3H, t) MS (ESI +) 254 (MH +) Preparation 22 (2S) -2- ( { (2R) -2- [6- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl) .amino) butan-1 -ol The epoxide of preparation 3 (10.6 g, 49.4 mmol) was dissolved in DMSO (100 ml_) together with (S) -2-aminobutan-1-ol (5.6 g, 59.4 mmol) [ commercially available] and the mixture was heated at 90 ° C overnight (approximately 16 h). After cooling to room temperature, the mixture was evaporated under high vacuum to provide a dark oil of the title compound (17.7 g) containing residual DMSO but of sufficient purity for use in the subsequent step. 1H NMR: d? (400 MHz, CDCl 3) 8.56 (1 H, d), 7.82 (1 H, dd), 7.18 (1 H, d), 5.83 (2 H, s), 4.77 (1 H, m), 3.63 (1 H, m), 3.39 (1 H, m), 3.04 (1 H, m), 2.96-2.78 (2 H, s an), 2 , 70 (1 H, m), 2.58 (1 H, m), 2.05 (6H, s), 1, 54-1, 38 (2H, m), 0.92 (3H, t) S (ESI +) 304 (MH +) Preparation 23 (2S) -2- ( { (2R) -2- [6- (2,5-Dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] - 2-hydroxyethyl} - (ethyl) amino) butan-1 -ol The diol of preparation 22 was dissolved in dichloromethane (50 ml_) and treated with ethanal (1.66 mL, 29.6 mmol) and NaBH (OAc) 3 (6.3 g, 29.6 mmol) and the mixture it was stirred at room temperature overnight (-16 h). The solvents were then evaporated and the residue purified by flash chromatography on silica gel eluting with dichloromethane-methanol / 880 NH3 (97: 3: 0.5) to give the title compound as a light brown oil (2.8 mg). The material was re-purified by flash chromatography on silica gel eluting with methanol in 1% ethyl acetate increasing the polarity to 2% to provide the title compound as a clear oil (1.42 g, 43%). H NMR: d? (400 MHz, CDCl 3) 8.58 (1 H, d), 7.95 (1 H, dd), 7.21 (1 H, d), 5.87 (2 H, s), 4.98 (3 H , m an), 3.72 (1 H, dd), 3.57 (1 H, m), 3.10 (1 H, dd), 2.95 (2H, m), 2.78 (2H, m), 2.10 (6H, s), 1.57 (1 H, m), 1, 43 (1 H, m), 1, 18 (3H, t), 0.97 (3H, t) MS (ESI +) 332 (MH +) Preparation 24 (2S) -2-. { [(2R) -2- (6-aminopyridin-3-yl) -2-hydroxyethyl] (tl) ami-no} butan-1 -ol The diol of preparation 23 (1.42 g, 4.3 mmol) was dissolved in ethanol (50 mL) and treated with hydroxylamine hydrochloride (1.5 g, 21.4 mmol) and the mixture was heated to 80 ° C throughout the night (-16 h). After cooling to room temperature, the solvents were evaporated and the residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880 NH3 (91: 9: 0.5) to give the title compound as a light brown oil (990 mg, 91%). 1H NMR: d? (400 MHz, CD3OD) 7.88 (1 H, d), 7.48 (1 H, dd), 6.58 (1 H, d), 4.50 (1 H, m), 3.42 (2 H, m), 2.80 (1 H, m), 2.68 (2 H, m), 1, 83 (2 H , m), 1, 48 (1 H, m), 1.38 (m, 1 H), 1, 04 (3H, 1), 0.92 (3H, t) MS (ESI +) 254 (MH +), 276 (MNa +) Preparation 25 5-bromo-2- (2,5-dimethyl-1H-pyrrol-1-yl) -3-methylpyridine 2-Amino-3-methyl-5-bromopyridine (5.86 g, 31.3 mmol) was dissolved in toluene (50 mL), hexane-2,5-dione (5.15 mL, 43.9 mmol) was added. ) and para-toluenesulfonic acid monohydrate (20 mg) and the mixture was heated to reflux with a coupled Dean-Stark apparatus. When the water collection stopped, the reaction mixture was evaporated and the residue was purified by flash chromatography on silica gel eluting with 5% ethyl acetate in pentane to give the title compound as a light yellow oil (5.1 g, 61%). 1H NMR: d? (400 MHz, CDCl 3) 8.51 (1 H, d), 7.81 (1 H, d), 5.90 (2 H, s), 2.01 (3 H, s), 1.97 (6H, s) TLC Rf = 0.5 (AcOEt 5%: Pentane) Preparation 26 (5S) -5-methyl-4-propylmorpholin-2-one The material of preparation 36 (4 g, 26 mmol) was dissolved in benzene (80 mL), followed by the addition of A / -ethyldiisopropylamine (9.07 mL, 52 mmol) and methyl bromoacetate (2.4 mL, 26 mmol). The mixture was heated to reflux with azeotropic removal of water overnight. After cooling to room temperature, the solvent was removed by evaporation, the crude material was dissolved in methanol, pre-absorbed on S1O2 and purified by flash chromatography on S1O2 eluting with 40% EtOAc in pentaton to provide the compound of the title as a clear oil (1.78 g). 1H NMR (CDCI3, 400MHz) d? 0.9 (t, 3H), 1, 1 (d, 3H), 1.5 (m, 2H), 2.25 (m, 1 H), 2.6 (m, 1 H), 2.8 (m, 1 H), 3.2 (d, 1 H), 3.6 (d, 1 H), 4.05 (dd, 1 H), 4.3 (dd, 1 H) TLC Rf = 0 , 18 (AcOEt 50% in pentane, UV visualization) Preparation 27 (5S) -2- [6- (2,5-dimethyl-1H ^ irrol-1-yl) -5-methylpyridin-3-yl] -5- methyl-4-propylmorpholin-2-ol The bromopyridine from preparation 25 (2.5 g, 9.4 mmol) was dissolved in THF (60 mL) and cooled to -78 ° C. Rerc-butyllithium (1.5 M in pentane, 12.6 mL, 18.8 mmol) was added dropwise to the stirred solution. Immediately after the reaction was finished, morpholinone (from Preparation 26) (1.5 g, 9.4 mmol) was added as a solution in THF (10 mL) and the reaction mixture was allowed to stir at -78 °. C for 1 hour. The reaction was then stopped by addition of saturated aqueous NH 4 Cl solution (100 mL), then extracted with ethyl acetate (80 mL). The organic fraction was dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate in pentane increasing the polarity of the eluent to 40% ethyl acetate and then 70% in pentane to give the title compound as a yellow oil clear (590 mg, 18%). H NMR: d? (400 MHz, CDCl 3) 8.70 (1 H, s), 7.92 (1 H, s), 5.88 (2 H, s), 3.77 (2 H, s an), 3.0-2 , 37 (5H, m), 2.02 (3H, s), 1, 90 (6H, s), 1, 65-1, 58 (2H, m), 1, 10 (3H, m), 0, 99-0.84 (3H, m) MS (ESI +) 344 (MH +) Preparation 28 (2S) -2- [. { 2- [6- (2,5-Dimethyl-1 H -pyrrol-1 -yl) -5-methylpyridin-3-yl] -2-hydroxyethyl} (propyl) amino] propan-1-ol The morpholinol from Preparation 27 (600 mg, 1.7 mmol) was dissolved in ethanol (6 mL) and water (3 mL) and sodium borohydride (270 mg, 7 mmol) was added to the stirred mixture at room temperature. Stirring was maintained overnight (~ 16 h) before the reaction was stopped by the addition of saturated aqueous ammonium chloride (100 mL) then basified (basified) to pH ~ 9 with 2M NaOH solution and extracted with dichloromethane (2 x 200 mL). The combined organic fractions were dried over magnesium sulfate, filtered and evaporated to give the title compound as a mixture of diastereomers as a yellow oil (450 mg, 75%) which was used directly without further purification.

MS (ESI +) 346 (MH +), 368 (MNa +) Preparation 29 (2S) -2 - [[2- (6-amino-4-methylpyridin-3-yl) -2-hydroxyethyl] (propyl) a-mino] propan-1-ol The diol from Preparation 28 (420 mg, 1.5 mmol) was dissolved in propanol (5 mL) and water (1.5 mL) was treated with hydroxylamine hydrochloride (2.2 g, 31.4 mmol) and triethylamine. (2.2 ml_, 15.7 mmol), and the mixture was refluxed for 12 h. After cooling to room temperature the mixture was evaporated, and the residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880 NH3 (90: 10: 1) increasing the polarity to (85: 15: 3) to give a white solid (1.3 g) which was triturated with dichloromethane (3 x 50 ml_), the residual solvent was removed under vacuum to give 700 mg of white solid which was further purified by flash chromatography on silica gel eluting with dichloromethane methanol / Nh 880 (92.5: 7.5: 0) to provide the title compound as a clear oil (200 mg, 50%). MS (ESI +) 254 (MH +) Preparation 30 (2S) -2- [. { (2R) -2- [6- (2, 5-dimethyM-pyrrol-1-yl) pyridine hydroxyethyl} (butyl) amino] propan-1-ol The diol from Preparation 8 (1 g, 3.35 mmol, 1 eq) was dissolved in dichloromethane (20 mL) and treated with butanal (910 pL, 10 mmol, 3 eq). ) and NaBH (OAc) 3 (201 g, 10 mmol, 3 eq) and the mixture was stirred at room temperature overnight (~ 16 h). The reaction was quenched with water (50 mL) and extracted with CH2Cl2 (2 x 100 mL), the combined organic layers were dried (MgSC), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane-methanol / 880 NH 3 (95: 5: 0.5) to give the title compound as a clear oil (900 mg, 86%). H NMR: d? (400 MHz, CDCl 3) 8.55 (1 H, d), 7.85 (1 H, dd), 7, 20 (1 H, d), 6.88 (2 H, s), 4.85 (1 H, m), 3.10-2.97 (1 H, m), 2.87-2.94 (1 H, m), 2.43-2.70 (3H, m), 2.10 ( 6H, s), 1, 22-1, 60 (6H, m), 0.87-1, 0 (6H, m) MS (ESI +) 346 (MH +), 368 (MNa +) Preparation 31 (2S) -2 - [[(2f?) - 2- (6-aminopyridin-3-yl) -2-hydroxyethyl] (butyl) ami-no] propan-1 -ol The diol of preparation 30 (900 mg, 2.6 mmol) was dissolved in ethanol (15 mL) and treated with hydroxylamine hydrochloride (905 mg, 13 mmol) and the mixture was heated at 80 ° C overnight (~ 16 h). After cooling to room temperature, the solvents were evaporated and the residue was pre-absorbed on silica gel and purified by flash chromatography on silica gel eluting with a gradient of dichloromethane / methanol / 880 NH 3 (95: 5: 0, 5 to 92: 8: 0.5) to afford the title compound as a light brown oil (330 mg) 1 H NMR: d? (400 MHz, CD3OD) 7.83 (1 H, d), 7.50 (1 H, dd), 6.59 (1 H, d), 4.50 (1 H, m), 3.25- 3.40 (2H, m), 2.86-2.98 (1H, m), 2.42-2.78 (4H, m), 1, 20-1, 42 (4H, m), 0 , 87-1, 0 (6H, m) MS (ESI +) 268 (MH +), 290 (MNa +) Preparation 32 3- (6-Chloropyridin-3-yl) -azetidin-1-carboxylic acid fer-t-butyl ester Zinc powder (127 mg, 1.94 mmol, 1.1 eq) was dried for 18 h at 100 ° C under vacuum, transferred to a round bottom flask and heated with a vacuum hot air gun. The flask was allowed to cool to room temperature and DMF (2 mL) and 1,2-dibromoethane (12 pL, 0.141 mmol, 0.08 eq) were added. The mixture was heated at 70 ° C for 10 min, allowed to cool to room temperature, and TMSCI (18 pL, 0.141 mmol, 0.08 eq) was added dropwise. The mixture was stirred at t.a. for 30 min before the dropwise addition of the 3-iodoazetidine-1-carboxylic acid fer-t-butyl ester (Ref. SynLett, 1998, 4, 379) (500 mg, 1.766 mmol, 1.0 eq) as a solution in DMF (2 ml_). The mixture was stirred at 40 ° C for 1 h. 2-Chloro-5-iodopyridine was dissolved in DMF (2 mL) and added, followed by Pd2dba3 (32 mg, 0.035 mmol, 0.02 eq) and tri-2-furylphosphine (17 mg, 0.071 mmol, 0.04). eq) and the mixture was heated at 70 ° C for 4 h. The mixture was allowed to cool, diluted with Et20 (40 mL) and NH4CI (40 mL, saturated aqueous), the layers were separated, the aqueous layer was re-extracted with Et20 (20 mL), the organic substances were combined, washed with brine (2 x 30 mL), dried (MgSO), filtered and evaporated to give a yellow solid. This solid was chromatographed by flash chromatography on silica gel with an elution gradient from 100% CH 2 Cl 2 to CH 2 Cl 2: MeOH 99: 1 to give 235 mg of the impure product. This material was further purified by flash chromatography on silica gel with an elution gradient from 100% toluene to toluene: AcOEt 95: 5 to give the title compound as a yellow solid (193 mg, 41%). TLC Rf = 0.13 (AcOEt 10% / Toluene UV visualization) MS (APCI +) 269 (MhT) 1H NMR: d? (400 MHz, CDCl 3) 8.3 (1 H, s), 7.7 (1 H, m), 7.35 (1 H, d), 4.35 (2 H, t), 3.9 (2 H , t), 3.65-3.8 (1 H, m), 1.45 (9H, s) Preparation 33 5-Azetidn-3-yl-2-chloropyridine dihydrochloride The 3- (6-chloropyridin-3-yl) -azetidine-1-carboxylic acid tert -butyl ester (190 mg, 0.707 mmol, 1.0 eq) was dissolved in CH2Cl2 (4 mL), cooled to 0 °. C and HCl (g) was bubbled through for 10 min to give a dark orange solution. This was stirred at t.a. for 72 h. The mixture was evaporated to give a light brown solid, triturated with EI20, the resulting solid was filtered and dried at 60 ° C under vacuum to give the title compound (141 mg, 83%). TLC Rf = 0.15 (CH2Cl2: MeOH: NH4OH 90:10: 1) MS (APCI +) 169 (MH +) MS (ESI +) 169 (MH +). 1H NMR: d? (400 MHz, CD3OD) 8.4 (1 H, s), 7.95-8.05 (1 H, m), 7.55 (1 H, d), 4.2-4.5 (5H, m) Preparation 34 2-chloro-5- (1 -propylazetidin-3-yl) -pyridine The dihydrochloride of 5-azetidin-3-yl-2-chloropyridine (131 mg, 0.542 mmol, 1.0 eq) was partitioned between CH2Cl2 (10 mL) and K2CO3 (10 mL, aqueous 10% w / v), the layers were separated, and the aqueous layer was re-extracted with CH2Cl2 (10 mL). The organic layers were combined, dried (MgSO4), filtered and evaporated to approximately 2 mL volume. Pro-pionaldehyde (79 pL, 1.084 mmol, 2.0 eq) and sodium triacetoxyborohydride (230 mg, 1.084 mmol, 2.0 eq) were added and the mixture was stirred at r.t. for 2.5 h. The mixture was stopped with H20 (0, 5 mL) and partitioned between CH2Cl2 (10 mL) and K2CO3 (10 mL, aqueous 10% w / v), the layers were separated, and the aqueous layer was re-extracted with CH2Cl2 (10 mL). The organic layers were combined, dried (MgSO-i), filtered and evaporated to give a dark brown oil. This oil was purified by flash chromatography on silica gel with an elution gradient from 100% CH 2 Cl 2 to CH 2 Cl 2: MeOH 99: 1 to give the title compound as a yellow oil (41 mg, 36%). TLC Rf = 0.39 (CH2Cl2: MeOH: NH4OH 90: 10: 1 UV visualization) MS (APCI +) 211 (MH +) 1 H NMR: d? (400 MHz, CDCl 3) 8.25 (1 H, s), 7.65-7.75 (1 H, m), 7.25 (1 H, d), 3.6-3.75 (3H, m), 3.1 (t, 2H), 2.4 (t, 2H), 1, 3-1, 5 (m, 2H), 0.9 (t, 3H) Preparation 35 Benzhydrylidene- [5- ( 1-propylazetidin-3-1 l) -pyridin-2-yl] amine 2-Chloro-5- (1-propylazetidin-3-yl) -pyridine (100 mg, 0.475 mmol, 1.0 eq), 1,1-diphenylmethanimine (95 pL, 0.570 mmol, 1.2 eq. ), palladium (II) acetate (4.4 mg, 0.00475 mmol, 0.01 eq), BINAP (8.7 mg, 0.014 mmol, 0.03 eq) and sodium tert-butoxide (49 mg, 0.665) mmol, 1.4 eq) in toluene (2 mL) and heated at 80 ° C for 16 h. Palladium (II) acetate (4.4 mg, 0.00475 mmol, 0.01 eq) and additional BINAP (8.7 mg, 0.014 mmol, 0.03 eq) were added and the mixture was heated to reflux for 4 hours. h. The mixture was allowed to cool to t.a. and partitioned between AcOEt (25 mL) and K2CO3 (20 mL, aqueous 10% w / v), the layers were separated, and the aqueous layer was re-extracted with AcOEt (2 x 25 mL). The organic layers were combined, dried (MgSO), filtered and evaporated to give an orange oil. This oil was purified by flash chromatography on silica gel with an elution gradient from 100% CH2Cl2 to CH2Cl2: MeOH: NH4OH 95: 5: 0.5 to give the title compound as a yellow oil (110 mg, 66%) . TLC Rf = 0.22 (CH2Cl2: MeOH: NH4OH 90: 10: 1 UV visualization) MS (APCI +) 356 (MH +) H NMR: d? (400 MHz, CDCl 3) 8.2 (1 H, s.;), 7.8 (2 H, m), 7.0-7.6 (9H, m), 6.55 (1 H, d), 3.65-3.8 (3H, m), 3.1 (2H, t), 2.45 (t, 2H), 1, 3-1, 5 (m, 2H), 0.96 (t, 3H) CHN +0.75 H2O Calculated C (78.12) H (7.24) N (1, 39) Observed C (77.85, 78.12) H (7.04, 7, 04) N ( 11, 18, 11, 28) Preparation 36 (2S) -2- (propylamino) propane hydrochloride A (2S) - (+) - 2-aminopropan-1-ol (19.6 g, 0.26 mol) dissolved in CH2Cl2 (500 mL) was added propionaldehyde (20.9 mL_, 0.28 mol) followed by 4Á molecular sieves pre-dried and pulverized (40 g) and the mixture was stirred at room temperature overnight. The mixture was filtered through a pad of celite® (filtering agent), the pad was washed with CH 2 Cl 2, and the solvent was evaporated from the filtrate to give a clear oil. This oil was dissolved in methanol (200 mL) and NaBH 4 was added little by little over a period of 15 minutes. The mixture was stirred at t.a. overnight, then the reaction was stopped by careful addition of 2 M aqueous HCl (200 mL), made basic by the addition of 2 M aqueous NaOH (200 mL) and the methanol removed by evaporation. Di-fer-butyl dicarbonate (115 g, 0.52 mol) was added to the residue followed by 1,4-dioxane (200 mL) and the mixture was stirred at r.t. All night long. The 1,4-dioxane was removed by evaporation and the residue was diluted with water (750 mL) and extracted with CH 2 Cl 2 (2 x 750 mL). The combined organic fractions were dried (MgSO 4), filtered and evaporated to give a clear oil. To this oil was added 4 M HCl in 1,4-dioxane (200 mL) and the mixture was stirred at r.t. all night. The solvent was removed by evaporation to give the title compound as a white solid (24 g). 1 H NMR (DMSO, 400 MHz) d: 0.95 (3 H, t), 1, 2 (3 H, d), 1, 6 (2 H, m), 2.8 (2 H, m), 3.15 ( 1 H, m), 3.5 (1 H, m an), 3.8 (1 H, m), 5.4 (1 H, b), 8.6-8.9 (2 H, d an) M / S (APCf) 1 18 (MH +) Preparation 37 (2S) -2- (. {2- 2- (2,5-dimethyl-1 H -pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl.} Amino) propan-1-ol The epoxide of preparation 40 (950 mg, 4.4 mmol) was dissolved in DMSO (10 mL) together with (2S) -2-aminopropan-1 -ol (380 μ? _, 4.9 mmol) and the mixture it was heated at 90 ° C overnight (approximately 16 h). After cooling to room temperature, the mixture was evaporated under high vacuum and the residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 0.880 NH 3 (98: 2: 0.5 increasing polarity to 90: 10: 1) to provide the title compound as a light yellow oil (780 mg, 67% over 2 steps from preparation 40). H NMR: d? (400 Hz, CDCl 3) 8.61 (1 H, d), 7.86 (1 H, dd), 7.21 (1 H, d), 5.90 (2 H, s), 4.90 (1 H, m), 3.68 (1 H, m), 3.46 (1 H, m), 3.26-2.72 (4H, m), 2.1 1 (6H, s), 1, 14 (3H, 2 xd) MS (APCI +) 290 (MH +) Preparation 38 (2S) -2- [. { 2- [6- (2,5-Dimethyl-1 H -pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl} (ethyl) amino] propan-1-ol (mixture of diastereomers) The diol of preparation 37 (1.5 g, 5.2 mmol) was dissolved in dichloromethane (25 mL) and treated with acetaldehyde (870 pL, 15.5 mmol) and sodium triace-toxiborohydride (3, 3 g, 15.5 mmol) and the reaction mixture was allowed to stir at room temperature overnight (-16 h). The reaction mixture was diluted with saturated ammonium chloride solution, then basified by addition of 10% aqueous K2CO3 solution, and then extracted with dichloromethane (2 x 150 mL). The combined organic substances were dried (MgSC), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane-methanol / 0.880 NH 3 (93: 7: 0.5) to afford the title compound as a mixture of diastereomers as a slightly impure light brown oil (2). , 5 g). This material was used directly without further purification. 1H NMR: d? (400 MHz, CDCl 3) 8.56 (1 H, m), 7.87 (1 H, m), 7.21 (1 H, d), 5.89 (2 H, s), 4.82 (1 H, m), 3.77-3.65 (1 H, m), 3.18-3.05 (1 H, m), 2.95-2.57 (5H, m), 2.10 ( 6H, s), 1, 18-1, 10 (2 x 3H, t), 1, 00-0.92 (2 x 3H, d) MS (ESI +) 318 (MH +) Preparation 39 (2S) -2- [[2- (6-aminopyridin-3-yl) -2-hydroxyethyl] (ethyl) amino] pro-pan-1 -ol (mixture of diastereomers) The diol of preparation 38 (2.5 g, 7.8 mmol) was dissolved in ethanol (80 ml_) and treated with hydroxylamine hydrochloride (2.7 g, 21.4 mmol) and the mixture was heated at 80 ° C overnight (-16 h). After cooling to room temperature, the solvents were evaporated and the residue was purified by flash chromatography on silica gel eluting with dichloromethane-methanol / 880 NH 3 (95: 5: 0.5 increasing the polarity to 90: 10: 1 ) to provide the title compound as a light brown oil (1.5 g, 80%) 1 H NMR: d? (400 MHz, CDCl 3) 7.86 (1 H, m), 7.50 (1 H, m), 6.58 (1 H, m), 4.62-4.49 (1 H, m), 3.66-3.29 (2H, m), 3.06-2.41 (7H, m), 1.13-0.86 (6H, m) MS (ESI +) 240 (MH +) Preparation 40 2- (2,5-dimethyl-pyrrol-1-yl) -5- [oxiranyl] pyridine Ethanolamine (0.24 ml) was added dropwise to a solution of borane tetrahydrofuran complex (1 M solution in tetrahydrofuran, 8 ml, 8 mmol) in tetrahydrofuran (5 ml) cooled to 0 ° C for 15 minutes. cough. The mixture was allowed to reach room temperature and then the chloride of Preparation 2 (1 g, 4 mmol) in tetrahydrofuran was added dropwise to the stirred solution. The reaction mixture was then stirred at room temperature for 30 minutes, then the reaction was stopped by adding 2 M sodium hydroxide (10 ml_) and the reaction mixture was stirred for a further 1 hour. The mixture was then extracted with ethyl acetate (2 x 50 ml_), dried (MgSO 4), filtered and evaporated to give the ra-cemie epoxide as a yellow oil (950 mg). The 1 H NMR was as for preparation 3. The material was carried forward without further purification. Preparation 41 4-propyl-2-thiazol-5-yl-morpholin-2-ol To 2-trimethylsilyl thiazole (9.5 g, 60.5 mmol, 1 eq) in Et: 20 (200 ml_) at -78 ° C was added dropwise n-butyllithium (36 mL, 2.5 M in hexane, 90.7 mmol, 1.5 eq) and the mixture was stirred at -78 ° C for 30 min. 4-Propylmorpholin-2-one (prepared according to the method described in WO 2004/052372- 8.65 g, 60.5 mmol, 1 eq) in Et20 (50 mL) was added over a 5 min interval ( temperature increased to -55 ° C during the addition). The mixture was re-cooled to -78 ° C and allowed to stir at -78 ° C for 2 h. The reaction was stopped by dropwise addition of water, allowed to warm to t.a. and extracted with AcOEt (2 x 500 mL) and dichloromethane (2 x 300 mL). The combined organic extracts were dried over MgSO-i and the solvent was evaporated to give a brown oil. The oil was purified through a S1O2 column in an Isco Companion Combiflash autochromatography system with an elution gradient from CH2Cl2: MeOH: NH3 98: 2: 0.5 to CH2Cl2: MeOH: NH3 95: 5: 0, 5 to give a light brown solid (8.5 g, 61%). 1 H NMR (400 MHz, CD 3 OD) 5 (ppm): 8.91 (s, 1 H), 7.91 (s, 1 H), 4.13-4.22 (m, 1 H), 3.68 -3.75 (m, 1 H), 2.97 (d, 1 H), 2.68-2.80 (m, 1 H), 2.26-2.40 (m, 4H), 1, 48-1, 60 (m, 2H), 0.93 (m, 3H) M / S (APCI +) 229 (MH +) TLC CH2Cl2: MeOH: NH3 95: 5: 0.5 Rf = 0.35 TLC AcOEt Rf = 0.3 Preparation 42 2 - [(2-hydroxyethyl) (propyl) amino] -1 - (1,3-thiazol-5-yl) e tanol To 4-propyl-2-thiazol-5-yl-morpholin-2-ol (8.5 g, 37.3 mmol) in EtOH (125 mL) and water (125 mL) was added NaBH4 and the mixture was stirred ta for 1 h. The mixture was diluted with water (200 mL) and extracted with dichloromethane (3 x 250 mL). The combined organic layers were dried over MgSO4 and the solvent was evaporated to give a clear oil (6.2 g). 1 H NMR (400 MHz, CD 3 OD) or (ppm): 8.92 (s, 1 H): 7.80 (s, 1 H), 5.05 (t, 1 H), 3.56-3.65 (m, 2H), 2.62-2.80 (m, 4H), 2.51-2.59 (m, 2H), 1, 43-1, 53 (m, 2H), 0.87 (t , 3H) M / S (APCI +) 231 (MH +) TLC CH2Cl2 / MeOH / NH3 90/10/1 Rf = 0.45 Preparation 43 4-propyl-2- (1,3-thiazol-5-yl) morpholine 2 - [(2-Hydroxyethyl) (propyl) amino] -1- (1,3-thiazole-5-yl) ethanol (5.7 g, 24.8 mmol) was treated. in dichloromethane (20 mL) with concentrated sulfuric acid (50 mL). After the addition, the dichloromethane was removed in vacuo and the resulting mixture was heated at 140 ° C for 1 h. The mixture was allowed to cool to t.a., poured onto ice and the reaction was carefully quenched by addition of 0.880 NH 3 with ice cooling keeping T < 20 ° C. The mixture was extracted with dichloromethane (2 x 250 mL), dried over MgSO4 and the solvent was evaporated to give a brown oil. This material was chromatographed on an Isco Companion Combiflash autochromatography system with an eluent of CH2Cl2: MeOH: NH3 98: 2: 0.5 to give the product as a light brown oil. 1 H NMR (400 MHz, CD 3 OD) 5 (ppm): 8.94 (s, 1 H), 7.84 (s, 1 H), 4.93 (dd, 1 H), 3.93-4.0 (m, 1 H), 3.76-3.84 (m, 1 H), 3.07 (d, 1 H), 2.81 (d, 1 H), 2.35-2.41 (m, 2H), 2.17-2.30 (m, 2H), 1.50-1.62 (m, 2H), 0.94 (t, 3H) M / S (APCI +) 213 (MH +) TLC CH2Cl2 / MeOH / NH3 95/5 / 0.5 Rf = 0.55 Preparation 44 2- (2-bromo-1,3-thiazole-5 -il) -4-propylmorpholine To 4-propyl-2- (1, 3-triazol-5-yl) morpholine (2.9 g, 13.7 mmol) in THF (50 ml_) at -78 ° C was added n-butyllithium (5.5 ml_, 2.5 M in hexane, 13.7 mmol) and allowed to stir at -78 ° C for 30 min. A solution of carbon tetrabro-wall (4.5 g, 13.7 mmol) in THF (20 mL) was added maintaining T < -70 ° C during the addition, and the mixture was allowed to stir at -70 ° C for 1 h. The reaction was stopped by careful addition of water and allowed to warm to t.a. during a period of 18 h. The mixture was extracted with AcOEt (3 x 150 mL), dried over MgSO4 and the solvent was evaporated to give a brown oil. This material was chromatographed on an Isco Com-panion Combiflash autochromatography system with an elution gradient from ChkCk / MeOH / NI-b 99: 1: 0.1 to CH2Cl2 / MeOH / NH3 95: 5: 0.5 to give the product as a brown oil (2.5 g, 63%). 1 H NMR (400 MHz, CD 3 OD) or (ppm): 7.54 (s, 1 H), 4.83-4.89 (m, 1 H), 3.90-3.96 (m, 1 H) , 3.70-3.79 (m, 1 H), 3.02 (d, 1 H), 2.75 (d, 1 H), 2.35-2.41 (m, 2H), 2, 17-2.30 (m, 2H), 1, 50-1, 62 (m, 2H), 0.94 (t, 3H) M / S (APCI +) 293 (MhT) TLC CH2CI2 / MeOH / NH3 95 / 5 / 0.5 Rf = 0.75

Claims (15)

1. CLAIMS 1.- The compounds of formula (I): wherein: R1 is selected from H and (C1-C6) alkyl; R2 is selected from H and (C1-C6) alkyl; R3 is selected from: wherein: A represents O, S or CH2; n is 1 or 2; R 4 is selected from H and (C 1 -C 6) alkyl; wherein said (C1-C6) alkyl may be optionally substituted with 1 or 2 substituents each independently selected from (C1-C6) alkyl, OR7, phenyl, substituted phenyl and heteroaryl; R5 is selected from H and (C1-C6) alkyl; wherein said (C1-C6) alkyl may be optionally substituted with 1 or 2 OR7 groups; R6 is selected from H and (C1-C6) alkyl; R7 is selected from H and (C1-C6) alkyl; wherein said (Ci-C6) alkyl may be optionally substituted with a phenyl, or a substituted phenyl group; R8 is selected from H, methyl, ethyl, methoxy, and ethoxy; R9 represents (C1-C6) alkyl; and R10 is selected from H and (C1-C6) alkyl; wherein said alkyl
2. (C1-C6) may be optionally substituted with 1 or 2 substituents each independently selected from OR7, phenyl or substituted phenyl; wherein heteroaryl means an aromatic ring of 5 to 7 members, containing from 1 to 4 heteroatoms, said heteroatom independently selected from O, S and N; said heteroaryl may be optionally substituted with 1 or more substituents each independently selected from (C1-C6) alkyl, halo and OR7, each substituent may be the same or dient; and wherein substituted phenyl means phenyl substituted with 1 or more substituents each independently selected from (C 1 -C 6) alkyl, halo and OR 7, each substituent may be the same or dient; provided that: when R and R2 are H, R3 is the residue (II), A is O, R5 is H or (C1-C6) alkyl, and R6 is H or (C1-C6) alkyl, then R4 is not it can be n-prop; and its pharmaceutically acceptable salts, solvates, polymorphs and prodrugs. 2. A compound according to claim 1, wherein R1 and R2 each independently are selected from H and methyl.
3. 3. - A compound according to claims 1 or 2, wherein R3 is the residue (II).
4. 4. A compound according to claim 3, wherein A is selected from O or CH2.
5. 5. A compound according to claim 4, wherein R4 is (C1-C4) alkyl optionally substituted with phenyl; R5 is selected from methyl and ethyl, wherein said methyl and said ethyl can be optionally substituted with an OR7 group; and R6 is selected from H and methyl.
6. 6. - A compound according to claims 1 or 2, wherein R3 is the residue (III).
7. 7. A compound according to claim 6, wherein n is 1 and R4 is selected from ethyl, propyl or butyl, said alkyl groups being optionally substituted by a phenyl group.
8. 8. A compound according to claim 1 or 2 wherein R3 is the moiety (IV), R8 is selected from H and methoxy; and R10 is selected from H and methyl.
9. 9. A compound according to claim 1 selected from: 5- (Morpholin-2-yl) pyridin-2-amine; 5- [4- (3-Phenylpropyl) morpholin-2-yl] pyridin-2-amine; 5 - [(2 /, 5S) -5-Methylmorpholin-2-yl] pyridin-2-amine; 5 - [(2S, 5S) -5-Methyl-4- (3-phenylpropyl) morpholin-2-yl] pyridin-2-amine; 5 - [(2S, 5S) -4-Butyl-5-methylmorpholin-2-yl] pyridin-2-amine; 5-. { (2R, 5S) -5 - [(Benzyloxy) methyl] -4-propylmorpholin-2-yl} pyridin-2-amine; [6- (6-Aminopyridin-3-yl) -4-propylmorpholin-3-yl] methanol; 4- Methyl-5- (4-Propylmorpholin-2-yl) pyridin-2-amine; 5- [(2S, 5S) -4,5-Diethylmorpholin-2-yl] pyridin-2-amine; 5 - [(2R, 5S) -4,5-Diethylmorpholin-2-yl] pyridin-2-amine; and 5- (2R, 5S) - (4-ethyl-5-methylmorpholin-2-yl) -pyridin-2-ylamine.
10. 10. A compound according to any of claims 1 to 9, for use as a medicament.
11. 11. The use of a compound according to any of claims 1 to 9, in the preparation of a medicament for the treatment of sexual dysfunction.
12. 12. The use according to claim 1, wherein the sexual dysfunction is male erectile sexual dysfunction or female sexual dysfunction.
13. 13. The use of a compound according to any of claims 1 to 9, in the preparation of a medicament for the treatment of depression or psychiatric disorders.
14. 14. The use of a compound according to any of claims 1 to 9, in the preparation of a medicament for the treatment of the 20 neurodegeneration.
15. 15. - A pharmaceutical composition comprising a compound according to any of claims 1 to 9, and a pharmaceutically acceptable diluent or carrier.