NL1029139C2 - New aminopyridine derivatives and their use as pharmaceuticals. - Google Patents

Description

V

5 10

NEW AMINOPYRIDINE DERIVATIVES AND THEIR USE AS PHARMACEUTICS

The present invention relates to a class of dopamine amino 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 (hypoactive sexual desire) disorder (HSDD; no interest in sex), female orgasmic disorder (FPS; inability to achieve orgasm) and male sexual dysfunction, in particular male erectile dysfunction (male erec-tile dysfunction; MED). Male sexual dysfunction is understood herein to mean ejaculation disorders, such as premature ejaculation, anorgasmia (inability to achieve orgasm), or desire disorders, such as hypoactive sexual desire disorder (HSDD; no interest in sex). These compounds are also useful in the treatment of neuropsychiatric disorders and neurodegenerative disorders.

The present invention provides compounds of the formula (I): 1029139 2

5 h'nyV

R (O where: R 1 is selected from H and (C 1 -C 6) alkyl, R 2 is selected from H and (C 1 -C 6) alkyl, R 3 is selected from: f? VR 'T..

R <(II) R (III) <V) wherein: A represents O, S or CH 2, is η 1 or 2, R 4 is selected from H and (C 1 -C 6) alkyl, wherein the (C 1 -C 6) alkyl may be optionally substituted with 1 or 2 substituents each independently selected from (C 1 -C 6) alkyl, OR 7, phenyl, substituted phenyl and heteroaryl, R 5 is selected from H and (C 1 -C 6) alkyl, wherein the ( C 1-30 alkyl may be optionally substituted with 1 or 2 OR 7 groups, R 6 is selected from H and (C 1 -C 6) alkyl, R 7 is selected from H and (C 1 -C 6) alkyl, wherein the (C 1 -C 6) alkyl can be optionally substituted with a phenyl-35 or a substituted phenyl group, R8 is selected from H, methyl, ethyl, methoxy and ethoxy, 1 0 2 9 1 3 9 ..

3 R 9 represents (C 1 -C 6) alkyl and R 10 is selected from H and (C 1 -C 6) alkyl, wherein the (C 1 -C 6) alkyl may be optionally substituted with 1 or 2 substituents each independently selected from OR 7, phenyl or substituted phenyl, wherein heteroaryl means a five to seventy five aromatic ring containing 1 to 4 heteroatoms, each of which heteroatoms are independently selected from O, S and N, and the heteroaryl may be optionally substituted with one or more substituents each may be independently selected from (C 1 -C 6) alkyl, halogen, and OR 7, and each substituent may be the same or different and wherein substituted phenyl means phenyl substituted with one or more substituents each independently selected from ( C 1 -C 6 alkyl, halogen and OR 7, and any substituent can be the same or different, provided that: when R 1 and R 2 are H, R 3 is the radical (II), A is O, R 5 is H or (Οι-Οε ) is alkyl and R 6 is H or (C 1 -C 8) alkyl, R 4 is not a n- Can be propyl, and the pharmaceutically acceptable salts, solvates, polymorphs and prodrugs thereof.

Unless otherwise stated, (Οχ-Οδ) alkyl may have a straight or branched chain.

Suitable heteroaryl groups include pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl.

Unless otherwise stated, the term halogen means fluoro, chloro, bromo or iodo.

Unless otherwise indicated, the expression means that there is substituted with one or more defined groups. In the case where the groups can be selected from a number of alternative groups, the selected groups can be the same or different.

The pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and base salts thereof.

1 0 2 9 1 3 9, 4

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bi-carbonate / carbonate, bisulfate / sulfate, borate, cam-5 sylate, citrate, cyclamate, edisylate, and esylate -, formate, fumarate, glucepate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate -, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate , pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinophoate salts.

Hemi salts of acids can also be formed, for example hemisulphate.

For an overview of suitable salts, see: Handbook of Pharmaceutical Salts: Propertjes, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of compounds of the formula I can be prepared by one or more of these three methods: (i) by reacting the compound of the formula I with the desired acid or base, (ii) by removing a protecting group which is labile to acid or base from a suitable precursor of the compound of the formula I or by ring-opening a suitable cyclic precursor, for example a lactone or lactam, with the desired acid or base or (iii) by converting a salt of the compound of the formula I to another by reaction with a suitable acid or base, or by means of a column of a suitable ion exchanger.

35

The three reactions are all typically carried out in solution. The resulting salt can precipitate and be collected by filtration, or be obtained by evaporation of the solvent. The degree of ionization in the resulting salt can vary from fully ionized to substantially non-ionized.

The compounds of the present invention can exist in a series of solid states ranging from completely amorphous to fully crystalline. The term "amorphous" refers to a state in which the material at a molecular level over a longer distance lacks a certain arrangement and, depending on the temperature, can exhibit the physical properties of a solid or liquid. Such materials do not typically give characteristic X-ray diffraction patterns and, although exhibiting the properties of a solid, are nevertheless formally described as a liquid. Upon heating, a change in properties from solid to liquid occurs which is characterized by a change in state, typically a second order ("glass transition"). The term "crystalline" refers to a solid phase in which the material at the molecular level has a regularly ordered internal structure that gives characteristic X-ray diffraction patterns with defined peaks. Such materials, when heated sufficiently, also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase transition, in a typical case of the first order ("melting point").

The compounds of the present invention can exist in both unsolvated and solvated form. The term "solvate" is used herein to describe a molecular complex consisting of the compound of the present invention and one or more pharmaceutically acceptable solvent molecules, e.g., ethanol. The term "hydrate" is used when the solvent is water.

10 2 9 1 39 6

The pharmaceutically acceptable solvates of the compounds of formula (I) include the hydrates thereof.

A currently accepted classification system for organic hydrates is one that defines hydrates at a particular isolated site, channel hydrates, or hydrates coordinated with a metal ion - see Polymorphism in Pharmaceutical Solids by K.R. Morris (ed. H.G. Britain, Marcel Dekker, 1995). Hydrates in an isolated location are those in which the direct contact of the water molecules with each other is prevented by interposed organic molecules. In channel hydrates, the water molecules lie in lattice channels in which they lie alongside other water molecules. In hydrates coordinated with a metal ion, the water molecules are bound to the metal ion.

When the solvent or water is strongly bound, the complex will have a well-defined stoichiometry that is independent of the humidity. However, when the solvent or water is weakly bound, such as in channel solvents and hygroscopic compounds, the water / solvent content will depend on the humidity and the conditions under which drying is taking place. In such cases, non-stoichiometry will be the norm.

In the following, all references to compounds of the formula I include the references to the salts and solvates thereof.

The compounds of the present invention include the compounds of formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including the optical, geometric and tautomeric isomers) as defined below and isotope-labeled compounds of the formula I.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the formula I, including those which exhibit more than type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts in which the counter ion is optically active, e.g., d-lactate or 1-lysine, or is racemic, e.g., dl tartrate or dl arginine.

A compound of the formula (I) contains one or more asymmetric carbon atoms and therefore exists in two or more stereoisomeric forms. In addition, it will be apparent to those skilled in the art that radical (II) encompasses all stereoisomeric and diastereoisomeric forms, in particular: V / yR8 Va ^ r '15 S' "r5 X '" n5 R4 (Ha) R4 ( Nb)

The separation of diastereoisomers can be achieved by conventional techniques, e.g. by fractional crystallization, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of formula (I) can also be prepared with a corresponding optically pure intermediate, or by separation, such as by H.P.L.C. of the corresponding racemate with a suitable chiral carrier, or by fractional crystallization of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or a suitable optically active base, as applicable .

The present invention encompasses all pharmaceutically acceptable, isotope-labeled compounds of the formula (I) in which one or more atoms have been replaced by atoms with the same atomic number, but with an atomic mass or mass number that is resp. that differs from 1029139 8 the atomic mass or mass number that resp. that dominates in nature.

Examples of isotopes suitable for incorporation into the compounds of the present invention include isotopes of hydrogen, such as 2H and 3H, carbon such as nC, 13C and 14C, chlorine such as 36Cl, fluorine such as 18F, iodine such as 123I and 125 I, nitrogen such as 13 N and 15 N, oxygen such as 150, 170 and 180, phosphorus such as 32 P, and sulfur such as 35 S.

Certain isotope-labeled compounds of the formula I, for example those in which a radioactive isotope is incorporated, are useful in drug and / or substrate distribution studies in the tissues. The radioactive isotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of the ease with which they can be incorporated and the easy means of detection.

Substitution with heavier isotopes such as deuterium, i.e. 2H, can provide certain therapeutic benefits that result from greater metabolic stability, for example a longer in vivo half-life or lower dosage requirements, and may therefore be preferred in certain circumstances.

Substitution with isotopes that emit positrons, such as nC, 1SF, 150 and 13N, may be useful in Positron Emission Topography (PET) studies for the study of substrate receptor occupancy.

Compounds of the formula I which are provided with an isotope label can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying examples and preparations, wherein instead of a previously used non-labeled reagent now that an isotope-labeled reagent is used.

Pharmaceutically acceptable solvates in accordance with the present invention include those in which the crystallizing solvent can be isotopically substituted, e.g. D20, d6-acetone, d6-DMSO.

The following embodiments of the present invention are particularly preferred: Preferably, R 1 is selected from H, methyl and ethyl.

More preferably, R1 is selected from H and methyl.

Preferably R1 H.

Preferably, R2 is selected from H, methyl and ethyl.

More preferably, R2 is selected from H and methyl.

Preferably R2 is H.

When R 3 is the radical (II), the radicals (Ha) and (Ilb) are preferred, and A is preferably O or CH 2.

Rather is A 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 4) alkyl optionally substituted with phenyl.

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, R 5 is selected from H and (C 1 -C 4) alkyl, wherein the (C 1 -C 4) alkyl may be optionally substituted with 1 or 2 OR 7 groups.

More preferably, R 5 is selected from H, methyl and ethyl, where the methyl and the ethyl may be optionally substituted with an OR 7 group.

Most preferably, R 5 is selected from H, methyl and ethyl.

10 2 9 1 39.

In a second preferred embodiment, R 5 is (C 1 -C 4) alkyl optionally substituted with 1 or 2 OR 7 groups.

10

More preferably, R 5 is selected from methyl and ethyl, wherein the methyl and the ethyl may optionally be substituted with an OR 7 group.

Preferably R5 is selected from methyl and ethyl.

5

Preferably, R 6 is selected from H, methyl and ethyl. More preferably, R 6 is selected from H and methyl.

Preferably R6 is H.

Preferably, R 7 is selected from H and (C 1 -C 4) alkyl, wherein the C 1 -C 4 alkyl is optionally substituted with 1 or 2 phenyl or substituted phenyl groups.

More preferably, R 7 is selected from H, methyl and ethyl, wherein the methyl and the ethyl are optionally substituted with a phenyl group.

Most preferably, R 7 is selected from H and (CH 2) phenyl.

When R 3 is a radical (III), n is preferably 1, R 4 preferably represents (C 1 -C 4) alkyl optionally substituted with 1 or 2 phenyl, substituted phenyl or heteroaryl groups, R 4 more preferably represents ethyl, propyl or butyl, wherein the groups are optionally substituted with a phenyl group, R 4 most preferably represents ethyl or propyl, wherein the groups are optionally substituted with a phenyl group.

When R3 is the radical (IV), R8 is preferably selected from H, methyl and methoxy, R8 is more preferably selected from H and methoxy, R8 is most preferably H.

Preferably, R 9 is selected from (C 1 -C 4) alkyl.

More preferably, R9 is selected from methyl, ethyl and n-propyl. Most preferably, R9 is n-propyl.

1029139.

11

Preferably, R 10 is selected from H and (C 1 -C 3) alkyl, wherein the (C 1 -C 3) alkyl may be optionally substituted with 1 or 2 OR 7 or phenyl groups.

More preferably, R10 is selected from H and methyl.

5 Preferably R10 H.

Preferably, R 3 is selected from the radicals (II) and (III).

More preferably, R 3 is selected from the radicals (Ha), (Ilb) and 10 (III).

Preferably R3 is selected from the residues (Ha) and (Ilb).

Preferably, heteroaryl is a five- or six-membered aromatic ring containing 1 to 3 heteroatoms, the heteroatom being independently selected from O and N.

More preferably, heteroaryl is a five- or six-membered aromatic ring containing 1 or 2 nitrogen atoms.

Particularly preferred are compounds (and salts thereof) of the present invention, examples of which are given herein; most preferred; 5- (Morpholin-2-yl) pyridine-2-amine (example 2), 5- [4- (3-Phenylpropyl) morpholin-2-yl] pyridine-2-amine (example 3), 5- [( 2R, 5S) -5-Methylmorpholin-2-yl] pyridine-2-amine (example 7a), 5 - [(2S, 5S) -5-Methyl-4- (3-phenylpropyl) morpholin-2-yl] pyri -dine-2-amine (example 9), 5 - [(2S, 5S) -4-Butyl-5-methylmorpholin-2-yl] pyridine-2-amine (example 10), 5 - {(2R, 5S) ) -5 - [(Benzyloxy) methyl] -4-propyl-morpholin-2-yl] pyridine-2-amine (Example 13), [6- (6-Aminopyridin-3-yl) -4-propyl-morpholin-3-yl] methanol (example 14), 4-Methyl-5- (4-Propyl-morpholin-2-yl) -pyridine-2-amine (examples 18 & 19), >ί> ζ y139 -12 5- [(2S, 5S) -4, 5-Diethylmorpholin-2-yl] pyridine-2-amine (Example 21), 5- [(2R, 5S) -4,5-methyl-morpholin-2-yl] pyridine-2-amine (Example 22), 5- 5- [(2R, 5S) - (4-Ethyl-5-methyl-morpholin-2-yl] pyridine-2-ylamine (Example 25),

In an alternative embodiment, the present invention furthermore comprises the compounds (+) -5- (4-propylmorpholine-2-yl) -1,3-thiazole-2-amine and (-) - 5- (4-propylmorpholine-2) -yl) -1,3-thiazole-2-amine (examples 26 and 27).

The compounds of the present invention can be prepared in various known ways. The following routes illustrate methods for synthesizing the compounds of formula (I); those skilled in the art will recognize that other methods can be practiced equally.

Throughout the schemes, the protected nitrogen of the 2-aminopyridine group is referred to as PGN, and Hal represents a halogen selected from Cl, Br or I.

The compounds of formula (I), wherein R 1, R 2, R 4 and R 6 have the meaning given above, and R 3, R 5 and A as described herein can be prepared according to reaction scheme 1. IX.

".Jqc_T m_ o *" "xXC j -« "(VI.) Jn

OH H OH

_ irV ^ 'R' _____ Ν '^ γΛ ^ ΝΗ> PGN- ^ n ^^ Ri (4) PGN ^ Y ^ R1 tB) R' (IX) R '(Vin) - h' ^ Y ^ Nr * - pgn'St'h 'W pgk ^ Vv m R «X> k' (XI)

a

H.M'VV

. R "schedule 1 (i | 1029139 13

Reaction step 1. Protection of the aminopyridine

The compounds of formula (V) wherein NPG is, for example, the 2,5-dimethylpyrrole system [as described in J. Chem. Soc. Perkin Trans., 1, 1984, 2801-52807, and of which the compound of the formula (VIa) illustrates], can be obtained by reacting an aminopyridine of the formula (V) with 1-2 equivalents 2.5 hexanedione in refueling toluene, whereby the water is removed azeotropically, and an acid catalyst is used, such as para-toluene-sulfonic acid.

Reaction step 2. From halide to aldehyde

The aromatic halide of the formula (VI) can be converted to the aldehydes of the formula (VII) by, for example, the formation of an organometallic reagent from a halogenated pyridine of the formula (VI), which is followed by reaction with a formylating agent such as dimethylformamide or morpholine 4-carbaldehyde. Suitable organometallic derivatives of pyridine include Grignard (organomagnesium) or organolithium reagents, which can be prepared from the bromide (or iodide) by the exchange of halogen metal. Typical conditions include the addition of isopropyl magnesium chloride (or butyl lithium) to the bromide (VI) in an anhydrous ether as a solvent, such as tetrahydrofuran, at room temperature (in certain cases, heating may be required when isopropyl magnesium chloride is used as a metallizing agent), or lower (e.g. -78 ° C when butyllithium is used), wherein the halogen-metal exchange reaction is carried out; this is followed by the addition of the formylating agent at 0 ° C or lower.

Reaction step 3. Conversion of aldehyde to amino alcohol The compounds of the formula (VIII) can be prepared by reacting an aldehyde of the formula (VII) with a cyanide source, such as potassium cyanide or trimethylsilyl cyanide, or with nitromethane and a base , such as sodium hydroxide, in which an adduct is formed as an intermediate which can be reduced by treatment with borane, lithium aluminum hydride or hydrogenation in an ether as solvent. Typical conditions include reacting 1.0 equivalent of aldehyde in 1.5 equivalents of 3M 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 under reflux, which is followed by treatment with a strong acid to hydrolyze the initially formed drilling complex of the product. The skilled person will be aware that other non-acidic methods are available for breaking down the drilling complex, e.g. treatment with diethanolamine.

Reaction step 4. Reductive amination

The compounds of the formula (IX) can be prepared from the compounds of the formula (VIII) using standard conditions for forming an amide bond, which is followed by reduction of the amide intermediate with a hydride as reducing agent, such as borane or lithium aluminum hydride. For the amide formation, for example, acid chlorides can be used in the presence of a suitable base such as triethylamine or 4-methylmorpholine. Typical reaction conditions include 1.0 equivalent of the amine (VIII), 1.2-2.0 equivalents of base (preferably triethylamine), 1.1-1.3 equivalents of acid chloride in dichloromethane at 25 ° C. For reducing the amide, reducing agents such as borane or lithium aluminum hydride can be used. Typical conditions include 1.0 equivalent of amide, 1.2-3.0 equivalents of borane in refluxing THF, which is followed by treatment with a strong acid to hydrolyze the initially formed drilling complex of the product. The skilled person will be aware that 1029139 other non-acidic methods are available for breaking down the drilling complex, e.g. treatment with diethanolamine.

The compounds of the formula (IX) can also be made by the reductive amination of the compounds of the formula (VIII) with a suitable aldehyde (1 equivalent or more) in the presence of a hydride as reducing agent, such as sodium cyanoborohydride or sodium triace -toxyborohydride (1 equivalent or more) in an alcoholic solvent such as ethanol, at room temperature.

Reaction step 5. Formation of the morpholinone

The compounds of the formula (X) can be prepared by reacting the compounds of the formula (IX) with chloroacetyl chloride or α-chloroacyl chlorides substituted in the 2-position (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 include 1.0 equivalent of the amine (IX), 1.0-3.3 equivalents of acid chloride, 1.2-2.0 equivalents of triethylamine in dichloromethane at 25 ° C, and then the crude reaction mixture is dissolved in IPA with 1.2-3.0 equivalents of potassium hydroxide in water.

Reaction step 6. Reduction of the morpholinone

The compounds of the formula (XI) can be prepared by reacting the compounds of the formula (X) with reducing agents such as borane or lithium aluminum hydride. Typical conditions include 1.0 equivalent of amide (X), 1.2-3.0 equivalents of borane in THF under reflux, which is followed by treatment with a strong acid to hydrolyze the initially formed boron complex. The person skilled in the art will be aware that other non-acidic methods are available for breaking down the drilling complex, e.g. treatment with diethanolamine.

1029139 16

Reaction step 7. Protection of the amino pyridine

The compounds of the formula (I) can be prepared from the compounds of the 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 amino pyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions include 1.0 equivalent of the compound 10 (XI) and 5 equivalents of hydroxylamine hydrochloride in ethanol under reflux.

Alternatively, the compounds of formula (IX), wherein R 1, R 2 and R 4 have the meaning given above, can be prepared according to reaction scheme 2.

15 R 11 Hal-PGN-VV (8) (9) PGN-V ^ R 2 R (VI) r 1 <* "> R 1 (X ,, I> (10) OH"

PGNs RV

25 r1) schedule 2 30

Reaction step 8. From halide to chloro ketone

The chloro ketones of the formula (XII) can be formed from the halogeniders of the formula (VI) via formation of a reactive organometallic intermediate. Suitable organometallic derivatives of pyridine include Grignard (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 ether solvent as tert-butyl methyl ether at a low temperature (-78 ° C) yields an organometallic intermediate product that can be treated with 2-chlorine -N-methoxy-N-methylacetamide, which gives the chloro ketones of the formula (XII).

10 Reaction step 9. From chloro ketone to epoxide

The chloro ketones of the formula (XII) can be converted to epoxides of the formula (XIII) via reduction to a chlorohydrin intermediate and epoxide formation promoted by base. Thus, reaction of (XII) with sodium borohydride (0.3 equivalents or more) in dioxane and subsequent treatment with excess sodium hydroxide solution yields epoxides of formula (XIII).

Enantiomerically pure, or enantiomerically enriched, epoxides of the formula (XIII) can be obtained by using an asymmetric reducing agent. Reaction of chloro ketones of the general formula (XIII) with (-) - B-chlorodiisopino-camphylborane (1.5 or more equivalents) in tetrahydrofuran at a low temperature (e.g. -30 ° C) and subsequent treatment of the chlorohydrin intermediate with sodium hydroxide yields the enantiomerically enriched epoxides of the formula (XIII).

Reaction step 10. Opening of the epoxide

The epoxides of the formula (XIII), when heated to 90 ° C with suitable primary amines in an inert solvent such as DMSO, yield the compounds of the formula (IX).

The compounds of formula (I) wherein R1, R2, R4 and R5 have the meaning given above, and R3, R6 and A are as described herein, can be prepared according to reaction scheme 3.

1029139 18 R * R *:

HsN 1 / O '- HN-4 Y0 "- 1 X 1 OH

O.HO, (11) Λ "0 2)" V <> 5 (XIV) (XV) R (XVI) (13)

"VS OH

R ’- hnJ ^ oh + (XII) (15) R N4 rS <14> R4 (XVII)

(XVIII) R, HCl

PGN ^ N. PGN ^ N.

R, ^ SVHrOH -r'-Vy0 ', - = - r'-Vy0 ^. R ’Vv (« I R ’l'NAR! R’ Vv 15 (XIX) · R4 (XI) R4 (!) R4 scheme 3 20 Reaction step 11. Formation of the amide

The compounds of the formula (XV) can be prepared by reacting an amino acid ester of the formula (XIV) with acid chlorides (R = (C 1 -C 6) alkyl) in the presence of a suitable base such as triethylamine and 4-25 methyl morpholine (or other suitable conditions for forming an amide bond). Typical reaction conditions include 1 equivalent of amino acid ester (XIV), 1 equivalent of acid chloride and 3 equivalents of base in dichloromethane at 25 ° C. Examples of compounds of the formula (XV) are also commercially available.

Reaction step 12. Reduction of amide and ester and then formation of the N-Boc group

The compounds of formula (XVI) can be prepared by reacting compounds of formula (XV) with borane-THF complex, which is followed by treatment with a strong acid (e.g., 5M HCl) for

10 2 9 1 IS

19 hydrolysing the resulting drilling complexes with the product. Other non-acidic processes for breaking down the drilling complex are also available, e.g. treatment with diethanolamine. This is followed by protection with a t-butyloxycarbonyl group of the amine formed. Typical reaction conditions include 1 equivalent of the amide (XV) with 3 equivalents of BH3-THF in THF under reflux, cooling, careful addition of 6M HCl in water and heating under reflux for an additional 6 hours. The solvent is then evaporated, redissolved in a methanol: water (8: 1) mixture and 5 equivalents of a base such as potassium hydroxide and 1.5 equivalents of di-tert-butyl carbonate are added and the mixture is then added for 72 hours. is stirred.

15

Reaction step 13. Deprotection of the N-Boc group

The compounds of the formula (XVII) can be prepared by reacting compounds of the formula (XVI) with an organic solution of HCl. Typical reaction conditions include 1 equivalent of the carbamate (XVI) and 1-10 equivalents of a 4M solution of HCl in dioxane at 25 ° C. Examples of compounds of the formula (XVII) are also commercially available.

Reaction step 14. Addition of chloro ketone

The compounds of the formula (XVIII) can be prepared by reacting the compounds of the formula (XVII) with an alpha-halo ketone of the formula (XII), if necessary in the presence of a base such as triethylamine or 4 methyl morpholine. Typical conditions include 1 equivalent of the amino alcohol (XVII) with 1-3 equivalents of triethylamine and 1 equivalent of a compound of the formula (XII) at 65 ° C.

35 Reaction step 15. Reduction to the diol

The morpholinol intermediates of the formula (XVIII) can be reduced to diols of the formula (XIX) 1029139 by reaction with a hydride as reducing agent such as sodium borohydride (1 equivalent or more) in a alcoholic solvent such as ethanol at room temperature.

5 Reaction step 16. Closure of the morpholine

The diol compounds of the formula (XIX) can be cyclized by a number of methods to form morpholine compounds of the formula (XI). Treatment of a solution of (XIX) in dichloromethane with an excess of concentrated sulfuric acid at room temperature will cause ring closure. Alternatively, ring closure can be achieved using conditions of the Mitsunobu type, using 1.1 equivalents of a dialkyl-zodicarboxylate reagent, such as diisopropylazodicarboxylate (DIAD), and 1.1 equivalents of triphenylphosphine in an inert solvent such as tetrahydrofuran .

Another alternative is the use of a sulfonating agent, such as p-toluene sulfonyl imidazole (1 equivalent) in the presence of a strong base such as sodium hydride in an inert solvent such as tetrahydrofuran, as described in Org. Lett., 2004, 6 (6), 1045-1047.

Reaction step 7. Deprotection of the aminopyridine

The compounds of the formula (I) can be prepared from the compounds of the 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 amino pyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions include 1.0 equivalent of the compound (XI) and 5 equivalents of hydroxylamine hydrochloride in ethanol under reflux.

Alternatively, it may prove beneficial in some cases to protect the aminopyridine group (PGN) before ring closing, thereby forming the morpholine group. This will most likely be the case when acidic conditions are used to effect the ring closure. In this case, compounds of formula (I), wherein R1, R2, R4, R5 and R6 have the meaning given above, and R3 and A are as described herein, can be prepared from compounds of formula (XIX) according to reaction scheme 4.

10 Tl ou? H H * NYNv, OH

r1 u [TrS__ Ri Jys. «((XIX) R4 A4 (XX) (18) 15 f f>, 'Vr ° rR1 R2 LnAr« R4 scheme 4 20

Reaction step 7. Protection of the aminopyridine The compounds of the formula (XX) can be prepared from the compounds of the formula (XIX) by deprotection. For example, when the 2,5-dimethylpyrrole system is used to protect the amino pyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions include 1.0 equivalent of the compound (XIX) and 5 equivalents of hydroxylamine hydrochloride in ethanol under reflux.

Reaction step 18. Closure of the morpholine compound The compounds of the formula (I) can then be prepared by ring closure of compounds of the formula (XX) by treatment with acid. Typical conditions utilize concentrated sulfuric acid and dichloromethane as a solvent at room temperature or above.

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 compounds of the formula (XVIII) into compounds of the formula (XI), wherein R1, R2, R4, R5 and R6 have the meaning given above.

10 PGI Vl? H rJyL <Y »· R * 25 R4 (XVIII) (19)

PGN ^ KL

20 R

(XI) Scheme 5 The compounds of the formula (XI) can be formed from compounds of the formula (XVIII) by a reaction such as reaction step 19 of a compound of the formula (XVIII) with a hydride source such as triethylsilane , or an acid or a Lewis acid such as trimethylsilyl triflate. Typical conditions include the addition of 5-10 equivalents of triethylsilane to 1 equivalent of the morpholinol (XVIII) in dichloromethane at -78 ° C, followed by the addition of 2 equivalents of trimethylsilyl triflate.

If the protecting group is missing in the compound of the formula (XVIII), this step of the method also provides an alternative route to compound of the formula (I).

An alternative procedure for the formation of compounds of the formula (XIX) is shown in Scheme 6, wherein R1, R2, R4, R5 and R6 have the meaning given above.

a

10 jfl, HN-V ™ PGN ^ fpR1 R4 R * (XVII)

(xiii) R-HCl

J (20) pgVh ° h.

15 φΥ R; R * R4 (XIX) scheme 6 20

The compounds of the formula (XIX) can be derivatized by means of a reaction such as reaction step 20 of an amine of the formula (XVII) with an epoxide of the formula (XIII). The reaction is generally carried out in an inert solvent such as toluene or DMSO, and at an elevated temperature. Typical reaction conditions involve heating together to 90 ° C of (XIII) and (XVII) in DMSO.

An alternative method for the synthesis of compounds of the formula (XVIII) is shown in scheme 7, wherein R1, R2, R4, R5 and R6 have the meaning given above.

35 1029139 24 N '^ VHal ° ^ 0 R "" * Vv "Vv R r4 5 Jei), X"> "Yi r

* 'ytY

W

R

(XVIII) schedule 7

The compounds of the formula (XVIII) can be prepared by a reaction such as reaction step 21 of an organometallic reagent generated from a halogenated pyridine compound of the formula (VI) and a morpholinone compound of the formula (XXI) (see scheme j 8). Suitable organometallic derivatives of pyridine include Grignard (organomagnesium) or organolithium reagents, which can be prepared from the bromide (or iodide) by the exchange of halogen metal. Typical conditions include the addition of isopropyl magnesium chloride (or butyl lithium) to the bromide (VI) in an anhydrous ether as a solvent, such as tetrahydrofuran, at room temperature (in certain cases, heating may be required when isopropyl magnesium chloride is used as a metallizing agent), or lower (e.g. -78 ° C when butyllithium is used), wherein the halogen-metal exchange reaction is performed; this is followed by the addition of the morpholinone (XXI) at 0 ° C or lower.

The morpholinone compounds of the formula (XXI), wherein R 4, R 5 and R 6 have the meaning given above, can be prepared as shown in scheme 8.

10 2 9 1 31.

25 HO ^ R * ° Y ° s X 5

7 * "V4 R

there R

5 (xx)) (xvii) (22)

OyOyR *, Ar5, R4, 10, xx, 8

The morpholinone compounds of the formula (XXI) can be prepared by a reaction such as reaction step 22 of an amino alcohol of the formula (XVII) with an alpha-halogen ester compound such as methyl bromoacetate (XXII) in the presence of a base such as triethylamine or 4 methyl morpholine. Typical conditions include an equivalent of the amino alcohol (XVII) with 1-3 equivalents of triethylamine and 1 equivalent of methyl bromoacetate, with toluene as a solvent, at room temperature or above. In some cases, heating with azeotropic removal of methanol is necessary to obtain a good conversion to the desired product (XXI).

An alternative method for the synthesis of epoxides of the formula (XIII), wherein R1 and R2 have the meaning given above, is shown in scheme 9.

Jfl H

30 R "MO

j (23)

O

R1 35 (X, "> scheme 9 1029139 26

The compounds of the formula (XIII) can be prepared by a reaction such as reaction step 23 of an aldehyde of the formula (VII) or a sulfur lylide agent, such as is generated from trimethylsulfonium iodide and a suitable base. Typical reaction conditions involve reaction of trimethylsulfonium iodide (1 equivalent) with sodium hydride (1 equivalent) in DMSO at 0 ° C, followed by addition of the aldehyde (VII) and allowing the reaction mixture to stand at room temperature.

Another alternative method for the synthesis of epoxide compounds of the formula (XIII), wherein R 1 and R 2 have the meaning given above, is shown in Scheme 10.

15 JO * (XXIII) (24)

20 A

PGN '^ S ^ R * R1 (XIII) scheme 10

The compounds of the formula (XIII) can be prepared by treatment as in reaction step 24 of an olefin of the formula (XXIII) with an oxidizing agent such as τη-chloroperbenzoic acid or dimethyldioxirane. Typical reaction conditions include reaction of 1 equivalent of alkene (XXIII) with 1-2 equivalents of m-chloroperbenzoic acid in dichloromethane at room temperature.

The olefins of the formula (XXIII), in which R1 and R2 have the meaning given above, can be prepared according to scheme 11.

102 9 1 39.

27 | Vh <25> Ν-γ1

PG1T ^ R * PGN'VV

5 R fv ») R" (XXIII) scheme 11

The olefin compounds of the formula (XXIII) can be prepared from aldehydes of the formula (VII) by reaction step 25, a Wittig or a similar olefin reaction. Typical reaction conditions involve the treatment of 1 equivalent of aldehyde (VII) with 1-2 equivalents of the ylide generated from the reaction of equimolar amounts of methyl triphenylphosphonium iodide and butyl lithium, in tetrahydrofuran, and at room temperature or below.

Alternatively, olefins of the formula (XXI-II), wherein R1 and R2 have the meaning given above, can be prepared according to scheme 12.

j? c - Jpi 25 <* ». The olefin compounds of the formula (XXIII) can be prepared by reaction step 26 - a palladium catalyzed vinylation reaction for which halide compounds of the formula (VI) are used. Typical vinyl sources that can be used for this process vinyl tributylstannane, ethylene gas (at high pressure) or a vinyl boronic acid, many Pd (0 (or Pd (II)) catalysts are suitable for this conversion, such as Pd (PPh3) 4. conditions include reaction of a halogenated pyridine of the formula (VI) (1 equivalent) with ethylene gas (at high pressure, e.g. 120 psi) as a solution in acetonitrile, in the presence of Pd-5 catalysts such as Pd (OAc) 2 (1 / 5 mol%), a phosphine ligand such as tri-o-tolyl phosphine (5 mol%) and an amine base such as triethylamine (large excess) at elevated temperatures (e.g. 80 ° C).

In the preparation of a compound of formula (I), it will be apparent to those skilled in the art that the R4 group (as defined above) can be introduced into any of the various intermediates in the synthetic sequence. This is most easily achieved by means of reaction step 27, a procedure for reducing amination. Examples of suitable intermediates for use in such conversion are shown in Scheme 13, wherein R1, R2, R5 and R6 have the meaning given above. Other intermediates useful in the preparation of compounds of formula (I) can be practiced equally.

PGNs ^ k OH PGN ^ N. OH

-¾¾ ^ H R "(XIX) <XIX> B *. oKR 'fV -E-pgn'jr1 b ’r’ (XI) (XI)? ”VR * i R»

hin '^ tvri Ï1 ^ N'rA

R "Η, Ν- ^ Y ^ r1 (I, R" (1) scheme 13 1uZ 9139.

29

A typical procedure involves reacting 1 equivalent of a 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, and then adding 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) wherein R 4 is H, R 3 and A have the meaning given herein, and R 1, R 2, R 5 and R 6 have the meaning given above, it may be beneficial to use a protecting group PG 'before morpholining occurs. This is explained in scheme 14.

Any suitable protecting group for nitrogen can be used (as described in "Protecting Groups in Organic Synthesis", T. W. Greene and P. G. Wuts, Wiley-Interscience, 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.

reVS oh Pony. 0H HjH N

«Vv -. r> ^ hv__ Λν

R (28) R2 (16) R * TNX_S

(XIX) H POOV) PG "g. R (χχν) (29) H2Nyv RiAr * Y0 yR * r2 η (I) schena 14 1029139 30

Reaction step 28. N-protection

A compound of the formula (XXIV) can be prepared by reaction step 28 - N-protection. A compound of the formula (XIX) (wherein R 4 = H) is reacted with a nitrogen protecting agent, such as benzyl chloroformate, which produces the protected compound. Typical reaction conditions involve reaction of 1 equivalent of a secondary amine (XIX) with (1 equivalent or more) benzyl chloroformate in an inert solvent such as dichloromethane, together with triethylamine (1 equivalent or more) at room temperature.

Reaction step 16. Ring closure

The ring closure from the diol (XXIV) to the morpholine (XXV) can be realized by many of the previously described methods, see reaction step 16, scheme 3. Particularly suitable in this case is a Mitsunobu type ring closure reaction which proceeds 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 step 29. Removal of the protecting group

The compounds of the formula (I) can be prepared by reaction step 29 - deprotection of the morpholine (XXV) under conditions which depend on the nature of the protecting group used. For example, if benzyloxycarbonyl is used as the protecting group, it can then be removed by hydrogenolysis in an inert solvent such as ethanol with a palladium catalyst such as palladium-on-carbon, under a hydrogen pressure of 1 atmosphere or higher. If the morpholine nitrogen is protected with a benzyl group, it can be deprotected by transfer hydrogenation. Typical conditions relate to the treatment of 1 equivalent of a compound of the formula (XXV) with ammonium formate (10 equivalents), in methanol and the presence of 10% palladium-on-carbon as a catalyst (10% by weight), for 3 hour under reflux.

The compounds of the formula (XVII), wherein R 4, R 5 and R 6 have the meaning given above, can be prepared according to scheme 15.

-V

(XVI).

10 (30)

Rs »Λ °« R4 Re (XVII)

.HCl

^ schedule 15

The compounds of formula (XVII) (wherein R 4 is not 20 H) can be prepared by reaction step 30, a procedure for a reductive amination. Typical conditions involve reaction of 1 equivalent of an amino alcohol of the formula (XVI) with 1.1 equivalents of an aldehyde in dichloromethane in the presence of dried 4A molecular sieves at room temperature. After filtration and evaporation of the reaction mixture, the residue is redissolved in methanol and reacted with sodium borohydride (2 equivalents or more) at room temperature.

Alternatively, the reductive amination can be achieved in two steps via the formation and then the reduction of an amide intermediate, in a manner similar to that described in reaction step 4 (scheme 1) and in the reaction steps 11 and 12 (scheme 3).

A person skilled in the art will be aware that many amino alcohol compounds of the formulas (XVI) and (XVII) are commercially available. Alternatively, these 1029139 32 can be prepared by 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 the formula (I), wherein R1, R2, R4, R5 and R6 have the meaning given above, and R3, R5 and A as described herein can be prepared from chloropyridines of the formula (XXVI) according to scheme 16.

10

Ph c, ys> = nvs JL II o R * (31) Ph _ o *

ηττΥ ——— r'Vvy R R> VV

R (XXVI) R4 (XXVII) (32)

Η, Ν N

r1 ifr ° TR6 20 R * R4 (I) scheme 16 25

It will be apparent to those skilled in the art that chloropyridine intermediates of formula (XVI) are accessible by using synthetic methods analogous to those previously described herein for the production of protected aminopyridine compounds of formula (XI).

Reaction step 31. Metal-catalyzed amine reaction 35 The compounds of the formula (XXVII) can be prepared by reaction step 31, the reaction of a compound of the formula (XXVI) with benzophenonimine, in the presence of a suitable base and a metal catalyst, e.g., a Pd complex. Typical reaction conditions involve reacting the chloropyridine (XXVI) (1 equivalent) with benzophenonimine (1.2 equivalents), sodium tert-butoxide (1.4 equivalents), tris (dibenzylidene acetone) dipalladium (0 ) (1 mol%) and 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP) (3 mol%) in toluene at 80 to 120 ° C.

10 Reaction step 32. Deprotection of the benzophenone

The compounds of the formula (XXVII) can be converted to the compounds of the formula (I) by hydrogenolysis (using an inert solvent and heterogeneous catalysis, such as Pd-on-carbon at or above a pressure of 1 atmosphere hydrogen), or alternatively by treatment with an acid in water, e.g. 2M HCl in the presence of water and an organic solvent mixable with it such as tetrahydrofuran or dioxane. Transfer hydrogenation can also be used to effect this conversion. Typical conditions relate to the treatment of 1 equivalent of the compound of the formula (XXVII) with ammonium formate (10 equivalents) in ethanol in the presence of 10% palladium-on-carbon as a catalyst (10% by weight), under reflux for 3 hours.

The compounds of the formula (I), wherein R 1, R 2 and R 4 have the meaning given above and R 3 has the meaning given herein, can be prepared according to scheme 17.

30 35 1029139 34 bOC μ / Lr * Γ <ί> _ <!> N> sf r1 + Y (33) LrRi <34) rVRi 5 Cl 1 nLr1 n ^ Lr, (xxvni) (xxix) egg (XXX) egg (XXX ») (27)

5f X

10 Φ Y. a

IR, AJI, 31, Y

nCCr, · Ά ’CC

I R Ph ^ N Nvf ^ R * NH * (,) X, (XXXIII) Cl (XXXII) 'scheme 17 15

Reaction step 33. Zinc gap coupling

The compounds of the formula (XXX) can be prepared by reacting compounds of the formula (XXIX) with Zn / Cu (or another activated Zn source) by treatment with an sonication, which is followed by the addition of a 2-chloro-4-iodo pyridine and a suitable palladium catalyst and a suitable ligand, and heating to 70 ° C for 18 hours. Typical conditions include 1 equivalent of the azetidine (XXIX) with 40 wt% of Zn / Cu in DMF, with an ultrasonic device treating at room temperature for 4 hours. This is followed by the addition of 1.05 equivalents of the halogenated pyridine (VI), 0.05 equivalent of tris (dibenzylideneacetone) dipalladium (0) and 0.1 equivalent of tri-o-furyl phosphine, and heating to 70 for 18 hours ° C. The compounds of the formula (XXIX) can be prepared as described in Syn-35 et al., 4, 1998, 379.

Reaction step 34. Protection of the Boc group 1029139 35

The compounds of the formula (XXXI) can be prepared by reacting the compounds of the formula (XXX) with a suitable acid, such as HCl or TFA, in a suitable solvent such as dichloromethane or diethyl ether at room temperature or above, if necessary in the presence of a cation trap such as EtoSiH. Typical conditions include 1 equivalent of the azetidine (XXX) with CH 2 Cl 2 saturated with HCl gas at 0 ° C, and then allowed to stand overnight at room temperature.

Reaction step 27. Reductive amination

The compounds of the formula (XXXII) can be prepared by reacting the compounds of the 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 a 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 include reacting 1 equivalent of the azetidine (XXI) with 3.1 equivalents of the aldehyde and 3.1 equivalents of sodium triacetoxyborohydride in dichloromethane for 18 hours at room temperature.

Reaction step 31. Metal-catalyzed amination reaction

The compounds of the formula (XXXII) can be converted to compounds of the formula (I) via the intermediates (XXXIII). The conversion of (XXXII) to (XXXIII) can be achieved with benzophenonimine and a suitable base and metal catalyst, e.g. a Pd (0) complex. Typical reaction conditions relate to reacting the chloropyridine (XXXII) (1 equivalent) with benzophenonimine (1.2 equivalents), sodium tert-butoxide (1.4 equivalents), tris (dibenzylidene acetone) dipalladium 1029139 36 (0) (1 mol%) and 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP) (3 mol%) in toluene at 80 to 120 ° C.

Reaction step 32. Deprotection of the benzophenone The compounds of the formula (XXXIII) can be converted to compounds of the formula (I) by both hydrogenolysis (with an inert solvent and heterogeneous catalysis such as Pd-on-carbon at or above 1 atmospheric pressure, as by treatment with acid in water in the presence of a water-miscible organic solvent such as tetrahydrofuran or dioxane. Transfer hydrogenation can also be used to effect this conversion. Typical conditions relate to the treatment of 1 equivalent of the compound of the formula (XXVII) with ammionium formate (10 equivalents) in ethanol and the presence of 10% palladium-on-carbon as a catalyst (10% by weight), for 3 hours under reflux.

Alternatively, the compounds of formula (1), wherein R 1, R 2 and R 4 have the meaning given above and R 3 has the meaning given herein, can be prepared according to scheme 18.

boo

Val boc N .N

AA i !, (33) <w> (34) O

iX. * ϋ-- 1 * -—- x * · X «Iw IX £ X, NP6 (XXXIV) NpG (XXXV) (27) R4 R <11 N> Nv AA - AA.

I T & J 1 * nvAri (I) NPG (XXXVI) scheme 18 1029139 37

Reaction step 33. Zinc gap coupling

The compounds of the formula (XXXIV) can be prepared by reacting compounds of the formula (XXIX) with Zn / Cu (or another activated Zn-5 source) by treatment with an sonication, which is followed by the addition of compounds of the formula (VI) and a suitable palladium catalyst and a suitable ligand, and heating to 70 ° C for 18 hours. Typical conditions include 1 equivalent of the azetidine 10 (XXIX) with 40% by weight of Zn / Cu in DMF, with an ultrasonic device treating at room temperature for 4 hours. This is followed by the addition of 1.05 equivalents of the halogenated pyridine (VI), 0.05 equivalents of tris (dibenzylideneacetone) dipaladium (0) and 0.1 equivalents of tri-o-furyl phosphine, and heating for 18 hours up to 7 0 ° C. The compounds of the formula (XXIX) can be prepared as described in Syn-lett., 4, 1998, 379.

Reaction step 34. Protection of the N-Boc group

The compounds of the formula (XXXV) can be prepared by reacting compounds of the formula (XXXIV) with a suitable acid, such as HCl or TFA, in a suitable solvent such as dichloromethane or diethyl ether at room temperature or above, if necessary in presence of a cation trap such as Et 3 SiH. Typical conditions include 1 equivalent of the azetidine (XXXIV) with CH 2 Cl 2 saturated with HCl gas at 0 ° C, then allowed to stand overnight at room temperature.

Reaction step 27. Reductive amine reaction

The compounds of the formula (XXXVI) can be prepared by reacting the compounds of the 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 a 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 include 1 equivalent of the azetidine (XXXV) with 3.1 'equivalents of the aldehyde and 3.1 equivalents of sodium triacetoxyborohydride in dichloromethane for 18 hours at room temperature.

10 Reaction step 7. Protection of the amino pyridine

The compounds of the formula (XXVI) can be converted by deprotection into the compounds of the formula (I). 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 amino pyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions include 1.0 equivalent of the compound (XXXVI) and 5 equivalents of hydroxylamine hydrochloride in ethanol under reflux.

SCHEDULES 19-29

The compounds of the formula (I) wherein R 3 is the radical (IV), and, unless otherwise indicated, R 1, R 2, R 8, R 9 and R 10 have the meaning given above, can be prepared by the methods which are described in schemes 19-29.

η ^ Λη OS) nV \ n (36), «• Y * M PG iS · P®rTV cmwo R (Vil) R (XXXVII) (27) H.

(7) * w PGN'y ^ 'R1 2 J. (1) R' (XXXIX) scheme 19 102 9 1 39 - 39

Reaction step 35. Formation of the nitrile

The compounds of the formula (VII) can be converted to nitrile compounds of the formula (XXXVII) by reaction with tosyl methyl isocyanide (TosMic). Typical conditions relate to treatment of aldehyde (VII) - (1 equivalent) with TosMic (1 equivalent) and potassium tert-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.

10

Reaction step 36. Reduction of the nitrile

The nitriles of the formula (XXXVII) can be converted to amines of the formula (XXXVIII) by reduction of the nitrile group. This reduction can be achieved by the action of a hydride as reducing agent, such as lithium aluminum hydride or sodium borohydride, in the presence of a transition metal salt, such as NiCl 2 or COCl 2. Alternatively, the nitrile group can be reduced by hydrogenation with a transition metal catalyst such as Ra-20 ney-nickel or Pd-on-carbon.

Typical conditions involve reacting the nitrile (XXXVII) (1 equivalent) with nickel chloride (1 equivalent) in methanol, followed by the careful addition of sodium borohydride (3 equivalents or more) at 0 ° C.

Reaction step 27. Reductive amination

The primary amines (XXXVIII) can be converted to compounds of the formula (XXXIX) by a reductive amination procedure, namely by reaction with an aldehyde and a hydride as reducing agent, such as sodium triacetoxyborohydride or sodium borohydride.

Typical conditions involve reacting compounds of the formula (XXXVIII) with a suitable aldehyde hyd (1 equivalent or more) in the presence of a hydride as reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride (1 equivalent or more) in an alcoholic solvent such as ethanol.

Reaction step 7. Deprotection of the aminopyridine The compounds of the formula (XXXIX) can be converted into compounds of the formula (I) by means of a reaction for deprotecting the nitrogen of the aminopyridine group (PGN), wherein the NH2-group is released in the compounds (I). 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 amino pyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions include 1.0 equivalent of the compound (XXXIX) and 5 equivalents of hydroxylamine hydrochloride in ethanol under reflux.

Alternatively, the nitrile compounds of the formula (XXXVII) can be converted to the compounds of the formula (I) as shown in scheme 20.

20 -V * '- PON · V * ° “Λ 25 R <xxxve> P' (XL) r” (i) scheme 20 30 Reaction step 37. Reductive acylation

The intermediates of the formula (XXXVII) can, for example, be reduced with sodium borohydride and nickel chloride in the presence of an acylating agent such as a carboxylic acid anhydride to provide amide intermediates of the formula (XL). Typical conditions include reacting the nitrile (XXXVII) (1 equivalent) with nickel chloride (1 equivalent) and a carboxylic anhydride 1029139 41 (1 equivalent or more) in methanol, followed by the careful addition of sodium borohydride (3 equivalents or more) ) at 0 ° C.

Reaction step 38. Reduction of the amide

The amides of the general formula (XL) can be reduced to amines using borane or lithium aluminum hydride. Typical conditions include 1.0 equivalent of the amide (XL), 1.2-3.0 equivalents of borane in 10 refluxing THF, which is followed by heating in strong acid in water, such as 5M HCl. The resulting amine intermediates can then be deprotected to give the amino pyridine compounds of formula (I) previously described in reaction step 7.

An alternative preparation of nitrile compounds of the formula (XXXVII) is shown in scheme 21.

N ^ VHal (39)

2 0 1 1, - I N

pgn '^ S * PGrr ^ V

R (V!) R1 (XXXVI!) Scheme 21 25

The compounds of the formula (XXXVII) can be prepared by reaction step 39 - the reaction of the halogenated pyridine (VI) with tributyl (cyanomethyl) stannane and a palladium catalyst according to the procedure described in Chem. Lett., 1984, 1511-1512. Typical conditions include the treatment of 1 equivalent (VI) with 1.5 equivalents of tributyl (cyanomethyl) stannane, bis (acetonitrile) dichloro palladium (II) (2.5 mol%) and tri-o-tolyl-35 phosphine (5) mql%) in xylene at 120 ° C.

1029139 42

An alternative procedure for the preparation of the compounds of the formula (XXXVIII) is shown in scheme 22.

5, pgn'V ^ 1 4 ^ n'pg '

R1 is H

(VI) <XLI} (40)

H

fV ^ Se-

1 pgn'JVsJV

R1 (XLII) J (29) PGNγ ^ R * R1 (XXXVIII) scheme 22 Reaction step 40. B-alkyl-Suzuki coupling

The protected amides of the formula (XLII) are available by B-alkyl-Suzuki coupling 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, benzyl vinyl carbamate [commercially available, or prepared as described in J. Org. Chem., 1999, 64, 8743-8744] treated with 1 equivalent of a solution of 9-BBN in tetrahydrofuran at -10 ° C. After the completion of the hydroboration step, the resulting organoborane intermediate is treated with sodium hydroxide, and the PdCl 2 (dppf) becomes. CH 2 Cl 2 complex added with a halogenated pyridine of the formula (VI).

1 ° 29139 35 Reaction step 29. Amine deprotection

The compounds of the formula (XLII) can be converted by deprotection to the compounds of the formula (XXXVIII). The nature of this reaction will depend on the protecting group selected for use. For example, when benzyloxy is used as the protecting group, it can be removed by hydrogenolysis in an inert solvent such as ethanol, and with a palladium catalyst such as palladium-on-carbon. Typical reaction conditions involve reacting compounds of the formula (XLII) in an alcohol solvent (such as ethanol) with hydrogen (at a pressure of 10 1 atmosphere or higher) in the presence of a transition metal catalyst such as Pd-on-carbon .

An alternative method for the production of compounds of the formula (XXXIX) is shown in scheme 23.

15

H H H

(41)

PGN; JVV "PGN-SffV

r1 (ix) R (xxxix) Scheme 23 The compounds of the formula (XXXIX) can be prepared by reaction step 41 - the deoxygenation of a compound of the formula (IX) by, for example, hydrogenation (in an inert solvent such as ethanol , in the presence of a transition metal catalyst, such as Pd-30 on carbon in a hydrogen atmosphere (1 atmosphere or higher). Alternatively, a hydride source, such as triethylsilane, can 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 trifluoroacetic acid at room temperature and adding 1 (or more) equivalents of triethylsilane.

1029139 44

Another method for the production of compounds of the formula (XXXVII) is shown in scheme 24.

5 9 x H (* 2> (43) PGN "Sr R * pgn ^ T ^ R * pgn'YY'r" R1 (VII) R1 (XLIII) R (XXXVII) scheme 24 10

Reaction step 42. Conversion into a benzyl electrophile

An aldehyde of the formula (VII) is reduced by treatment with a hydride as reducing agent, such as sodium borohydride, in an alcoholic solvent, such as ethanol, at room temperature. The resulting alcohol can be activated for nucleophilic displacement by conversion to a group X (generally a halide or sulfonate ester), which gives intermediates of the formula (XLIII). Typical conditions involve reaction of an equivalent methanesulfonyl chloride and an equivalent of an amine base such as triethylamine in an inert solvent, such as dichloromethane at 0 ° C.

25

Reaction step 42. Displacement by cyanide 1

Intermediates of the formula (XLIII) can be converted to compounds of the formula (XXXVII) by the action of a nucleophilic source of cyanide, such as KCN, in an inert solvent, such as dimethylformamide, at or above room temperature, in a procedure analogous is to that described in US5914319.

Another method for the production of compounds of the formula (XXXIX) is shown in scheme 25.

35 1029139 45

Lj9! OH

c ifV (44) (45): R, c \, r »

PGN '^' f'R1 PGN * ^ f ^ R * PGN '^ f ^ R * ° + H

R1 (VI) R1 (XUV) R "(XLV) <XLVI) (46) R, e *?" * Io rr ^ 1 _22-yccC * PGN'V ^ 'R3 PGN iTΚ (XUV.1)

r1 (xxxix) R

scheme 25: Reaction step 44. Formation of the methyl ketone

Halogenated pyridines of the formula (VI) can be converted to methyl ketones of the formula (XLIV) by firstly treatment with butyl lithium (or another agent facilitating the exchange reaction between a halogen and a metal) and treatment of the resulting organometallic intermediate with a suitable acetyl source, such as acetyl morpholine, or the Weinrebamide derived from acetic acid.

25

Reaction step 45. Willgerodt-Kindler reaction

Methyl ketones of the formula (XLIV) can be converted to arylacetic acids of the formula (XLV) by treatment with sulfur and morpholine. A typical procedure involves reacting 1 equivalent of methyl ketone (XLIV) with sulfur (2 equivalents) and an excess of reflux morpholine (either undiluted or in an alcoholic solvent such as ethanol), followed by hydrolysis in 2M hydrochloric acid or 2M NaOH boiling under reflux.

1029139 46

Reaction step 46, Formation of the amide

Pyridylacetic acids of the formula (XLV) can be converted to amides of the formula (XLVI) by reaction with an amine of the formula (XLVII) and a suitable amide coupling reaction, such as by reaction with an acid chloride or anhydride and then addition of a suitable amine, or with a coupling reagent for peptides such as dicyclohexyl carbodiimide, 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 step in which the amide is formed. Typical reaction conditions include 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 the excess oxalyl chloride, 1.0 equivalent of amine (XL-VII), 1.2-2.0 equivalents of base (preferably triethylamine) are reacted with 1.0 equivalent of the acid chloride in dichloromethane of 25 ° C.

Reaction step 38. Reduction of the amide

Amides of the general formula (XLVI) can be converted to compounds of the formula (XXXIX) by reduction with a hydride as reducing agent, such as a borane-tetrahydrofuran complex. Typical conditions include 1.0 equivalent of the amide (XLVI), 1.2-3.0 equivalents of boar in THF under reflux, and then treatment with a strong acid, such as 5M HCl at elevated temperature, with the initial Boron complexes formed with the product are hydrolyzed. Other non-acidic methods for degrading the drilling complex are available, e.g. treatment with diethanolamine.

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

1029139 47 5 (47), ΝΎγ0Η: ΡβΝ iT ^ R2 PGN '^ f ^ R * ° R (XXXVII) r ’(Xlv, scheme 26 10

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

20? h Ίί ^ Γ ^ R (48) R <IX) R "(X L VIII) scheme 27 25

The compounds of the formula (XLVIII), wherein R8 is OMe, can be formed from compounds of the formula 30 (IX) by reaction step 48 - methylation of alcohol (IX) with a suitable electrophilic methyl source, such as iodomethane. In general, a strong base such as sodium hydride is also required. Typical conditions involve heating 1 equivalent of (IX) with 1.1 (or more) equivalent sodium hydride in an inert solvent such as tetrahydrofuran or dimethylformamide, and then adding 1 (or more) equivalents of iodomethane at room temperature.

The compounds of the general formula (XLVIII) can then be converted to compounds of the formula (I) by the same methods1 as described for the conversion of compounds of the formula (XXXIX), as shown in scheme 19 .

Other examples of compounds of formula (I) wherein R8 is not hydrogen can be prepared according to scheme 28.

*

O CN

(44) (49) | PG * ν 15 PGhTY ^ R2 PGN '^ V ^ R2 PGN ^ V ^ R * R1 (V1) R1 (XLIX) r ’(XXXVII) scheme 28 20

Reaction step 44. Formation of the ketone

Halogenated pyridine compounds of the formula (VI) can easily be converted to ketones of the formula (XLIX) by methods similar to the formation of methyl ketone compounds of the formula (XLIV) (Scheme 25), namely by first treatment with butyllithium (or another agent that can facilitate an exchange reaction of halogen and metal) and treating the resulting organometallic intermediate product with a suitable acyl source such as acyl morpholine or

Weinrebamide (both of which are easily prepared by methods known to those skilled in the art).

Reaction step 45. Formation of the nitrile 35 The ketone of the formula (XLIX) can then be converted to the nitrile (XXXVII) by reaction with tosyl methyl isocyanide (TosMic). Typical conditions concern the treatment of the ketone (XLIX) (1 equivalent) with TosMic (1 equivalent) and potassium tert-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 nitriles of the formula (XXXVII) can then be converted to compounds of the formula (I) using the procedures previously described in Scheme 19.

10

? H 5 H

PGN '^' p'R1 R '(XXXIX) R1 (I) (50) (50) 15 R * R' ° R '·? ”NV ^"' r 'rr ^ N'Rt r1 (XXXIX) RV) schedule 29 20

The compounds of the formula (XXXIX) or (I), in which R10 = H, can easily be converted to other compounds of the formula (XXXIX) or (I), in which R10 is not H, by reaction step 50 a procedure for a reductive amination as shown in scheme 29. A typical procedure involves reacting 1 equivalent of a secondary amine (such as (XXXIX) or (I)) 30 with 1 equivalent of an aldhyd in an inert solvent such as tetrahydrofuran or dichloromethane at room temperature, and then the addition of 1 equivalent (or more) of sodium triacetoxyborohydride or sodium cyanoborohydride.

Alternatively, the reductive amination via an amide intermediate can be carried out in two steps at 1029139 50 in a manner similar to that described for reaction step 4 in scheme 1.

The compounds of formula (I), wherein R1, R2, R4 and R5 have the meaning given above, and R3, R5 and A5 are as described herein, can be prepared according to reaction scheme 30.

I Ή "I

^ "Ti", γ ^ Υ PGN ^ ff ^ R2 (51) PGN'Y'R2 R ° R (XI-III) R iy) (53> N ^ Y ^ S ^ Y ^ 'R4 ΐ "Ύ ^ δΎ * ΝΗ2 PGN ^ fV R PGN j; r2 (U1)

r ’(Owl) R

O ^ O.-II 5 __ D *

T sYR s ^ R

ΪΎ (54) NVyN'R4 (») PGN ^ S '^ PGnV ^ R20 PGnV ^^ R (L, V) R1 (LV) R1 (LVI) (7) s ^ fRs H-NYr R1 (I) schedule 30 1029119 51

Reaction step 51. Formation of the thioether

The thioethers of the formula (LI) can be formed by reacting a compound of the formula (XLI-II), 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, 111-120] in the presence of a base in an alcoholic solvent.

Typical conditions include 1.0 equivalent of alkyl halide, 1.0 equivalent of thiol and 1.0-4.0 equivalents of a tertiary amine base such as triethylamine in an alcoholic solvent such as ethanol.

Reaction step 52. Deprotection of the N-Boc group. The compounds of the formula (Lil) can be prepared by reacting compounds of the formula (LI) with a suitable acid, such as HCl or TFA, in a suitable solvent such as dichloromethane or diethyl ether, at room temperature or above, if necessary in the presence of a cation trap such as EtaSiH. Typical conditions include the addition of 1 equivalent of the protected amine (L1) to CH 2 Cl 2 saturated with HCl gas at 0 ° C, and then allowed to stand overnight at room temperature.

25

Reaction step 4. Reductive aminq

The compounds of the formula (LUI) can be prepared from compounds of the formula (Lil) by using standard conditions for forming an amide bond, which is followed by reduction of the intermediate amide with a hydride as reducing agent, such as borane or lithium aluminum hydride.

For example, acid chlorides may be used in the presence of a suitable base such as triethylamine or 4-methylmorpholine prior to the step in which the amide is formed. Typical reaction conditions include 1.0 equivalent of the amine (Lil), 1.2-2.0 equivalents of a base t0 2 9 139 52 (preferably triethylamine), 1.1-1.3 equivalents of acid chloride in dichloromethane at 25 ° C. Reducing agents such as borane or lithium aluminum hydride can be used for the step in which the amide is reduced.

Typical conditions include 1.0 equivalent of amide, 1.2-3.0 equivalents of borane in refluxing THF, which is followed by treatment with a strong acid to hydrolyze the initially formed drilling complex of the product. Other non-acidic processes for breaking down the drilling complex are available, e.g. treatment with diethanolamine.

Reaction step 53. Formation of the carbamate

The compounds of the formula (LIV), wherein R 11 is benzyl or (C 1 -C 6) alkyl, can be formed by treating compounds of the formula (LIII) with an alkyl or benzyl chloroformate in an inert solvent such as dichloromethane or diethyl ether in the presence of a base.

Typical conditions include 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.

25

Reaction step 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 lithium diisopropylamide in an inert solvent such as diethyl ether or THF.

Typical conditions include the addition of 3.0 equivalents of a strong base such as lithium diisopropylamide to 1.0 equivalent of the thioether (LIV) at a temperature below -50 ° C in an inert solvent such as THF and allowed to warm to ambient temperature.

1029139 »53

Reaction step 55. Reduction of the amide

The compounds of the formula (LVI) can be prepared by reacting compounds of the formula (LV) with reducing agents such as borane or lithium aluminum hydride. Typical conditions include 1.0 equivalent of the amide (LV), 1.2-3.0 equivalents of borane in THF under reflux, which is followed by treatment with a strong acid to hydrolyze the initially formed boron complex. Other non-acidic methods for breaking down the drilling complex are available, e.g. treatment with diethanolamine.

Reaction step 7. Deprotection of the aminopyridine

The compounds of the formula (LVI) can be converted into compounds of the 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 amino pyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions include 1.0 equivalent of the compound (LVI) and 5 equivalents of hydroxylamine hydrochloride in ethanol under reflux.

The compounds of the formula (LIX), wherein R1, R2 and R5 have the meaning given above, can be prepared according to reaction scheme 31.

1029139 54 PGN ^ N. PGN ^ N ^ 'G' poov) * (LV ,,) PGN ^ N ^ PGN ^ .N. oh s R, XX.s w R «Vt Λ ΤΓ 10 R p» L Xs R * ^ N ^ R® ° R 2r · R CLVW)

PC '(LIX) PG

schedule 31 15 Reaction step 56. Activation of the primary alcohol

The compounds of the formula (LVII) can be formed from compounds of the formula (XXIV), wherein PG 'is a protective carbamate group, such as tert-butyl-oxycarbonyl or benzyloxycarbonyl, by selective conversion of the primary hydroxyl group into a group X (generally a halide or sulfonate ester). Typical conditions involve reaction of an equivalent of toluene sulfonyl chloride and an equivalent amine base such as triethylamine in an inert solvent such as dichloromethane at 0 ° C. 25

Reaction step 57. Formation of the thioacetate

The compounds of the formula (LVIII) can be formed from compounds of the formula (LVII), wherein PG 'is a protective carbamate group, such as tert-butyloxy-carbonyl or benzyloxycarbonyl, by treatment 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 an equivalent of the compounds of the formula (LVII) 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 a inert solvent such as acetonitrile, and heating the mixture under reflux.

Reaction step 58. Ring closure. The compounds of formula (LVIII) can be activated for nucleophilic displacement in the benzyl center by conversion to a group X (generally a halide or sulfonate ester). Subsequently, in situ closure can occur, which gives the compounds with the formula (LIX). Typical conditions involve reaction of an equivalent of toluene sulfonyl chloride and an equivalent of an amine base such as triethylamine in an inert solvent such as dichloromethane at 0 ° C. Evaporation of the solvent and then redissolution in a higher boiling solvent such as acetonitrile with 0-5.0 equivalents of a suitable base such as potassium carbonate and heating of the mixture under reflux may be necessary to effect the ring closure.

The compounds of the formula (LIX), wherein PG 'is a protective carbamate group, such as tert-butyloxycarbonyl or benzyloxycarbonyl, can be converted to compounds of the formula (I) by a procedure analogous to that which is described in scheme 18 for the conversion of compounds of the formula (XXXIV) to compounds of the formula (I).

The compounds of formula (I) wherein R1, R2 and R4 have the meaning given above, and R3 as described herein can be prepared according to reaction scheme 32.

1029139 56 II ΓΛι Γ> Η V (59, J7- 5 pgnV *! "« "V * ^" "Ύ" (LX ,, R1 (XXIII) R (LX) (27)

jTW

1 ° r-r4. -_ pGN '^ f; R2 R (UC ,,) R1 O) · scheme 32 15 Reaction step 59. Cycloaddition

The compounds of the formula (LX) can be formed from an olefin of the formula (XXIII) by reacting 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 between -10 ° C and the reflux temperature of the reaction mixture. Alternative catalysts include anhydrous potassium or cesium fluoride, tetra-n-butylammonium fluoride, trifluoromethanesulfonic acid, trimethylsilyl trifluoromethanesulfonate and iodotrimethylsilane. Typical conditions include reaction of 1 equivalent of the olefin (XXIII) with 1.5 equivalents of N-benzyl-N- (methoxymethyl) trimethylsilylmethylamine and 0.1 equivalent of trifluoroacetic acid in dichloromethane.

Reaction step 60. Debenzylation of the pyrrolidine

The compounds of the formula (LX) can be deprotected into secondary amines of the formula (XLI) by hydrogenolysis in an inert solvent such as ethanol with a palladium catalyst such as palladium-on-carbon, under a hydrogen pressure of 1 atmosphere or higher. Alternatively, it can be deprotected by transfer hydrogenation. Typical conditions relate to the treatment of 1 equivalent of the compound of the formula (LX) with ammonium formate (10 equivalents) in ethanol and the presence of 10% palladium-on-carbon as a catalyst (10% by weight), for 3 hours under reflux.

Reaction step 27. Reductive amine reaction

The compounds of the formula (LXII) can be prepared by reacting compounds of the 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 a 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 include reacting 1 equivalent of the pyrrolidine (LX) with 3.1 equivalents of the aldehyde and 3.1 equivalents of sodium triacetoxyborohydride in dichloromethane for 18 hours at room temperature.

Reaction step 7. Deprotection of the aminopyridine

The compounds of the formula (LXI) can be converted into compounds of the 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 amino pyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions include 1.0 equivalent of the compound (LXI) and 5 equivalents of hydroxylamine hydrochloride in ethanol under reflux.

The compounds of formula (I), wherein R1, R2, R4, R5 and R6 have the meaning given above, and R3 and A are as described herein, can be prepared according to reaction scheme 33.

1029138 ___ Μ— 58 R6 Re H-X '<61> "Y1 1 R1 (52) RYS fr, ^ υύ —- RN-Vr (V |) (LXII1) ^ n ^ nPG". ^ M ^ kipg 5 (LXIV ) (63) R6 f

Vs r2 rYS * 2 '

10 III I

(IJ N NPG i schedule 33! 15

Reaction step 61. Reaction with 3-pyridylborane

The compounds of the formula (LXIII) can be prepared from compounds of the formula (VI) by reaction with 3-pyridylboranes (or a similar boronic acid) in the presence of a suitable base and a suitable palladium catalyst. Typical conditions include the addition of the 3-pyridylborane to a compound of the formula (VI) in toluene / ethanol as solvent, in the presence of tetrakis (triphenylphosphine) palladium (0) and sodium carbonate, followed by refluxing . Examples of 3-pyridylboranes (or similar boronic acids) are commercially available.

Reaction step 62. Alkylation The compounds of the formula (LXIV) can be prepared from compounds of the formula (LXIII) by adding an alkyl iodide. Typical conditions include the addition of the alkyl iodide to a compound of the formula (LXIII) in a suitable solvent such as ace-35 tonitrile and then refluxing.

1029139 59

Reaction step 63. Hydrogenerq

The compounds of the formula (LXV) can be prepared by hydrogenation from compounds of the formula (LXIV). Typical conditions include the hydrogenation of a compound of the formula (LXIV), under elevated pressure, in a suitable solvent such as ethanol, in the presence of a suitable catalyst such as PtO 2

Reaction step 7. Deprotection of the aminopyridine 10 The compounds of the formula (LXV) can be converted into compounds of the 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 amino pyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions include 1.0 equivalent of the compound (LXV) and 5 equivalents of hydroxylamine hydrochloride in ethanol under reflux.

20

Methods for the separation of racemic compounds

In cases where the above 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 (e) chira (a) l (e) compound or reagent, then separation of the constituent diastereoisomers by physical methods, including crystallization or chromatography, and cleavage of the separated adducts, thereby releasing the desired compound in enantiomerically enriched form. This is often called a classical divorce. For example, a racemic alcohol can be reacted with an enantiomerically pure chiral acid, which forms diastereomeric esters with the aid of standard reactions for the formation of an ester. These esters can then be separated by, for example, selective crystallization. The separated diastereomeric esters can then be hydrolysed separately under standard conditions for the hydrolysis of an ester, thereby releasing the chiral alcohols in enantiomerically enriched form.

(4) Selective reaction of a chiral reagent (including enzymes) with an enantiomer from a racemic mixture - called a kinetic separation.

The compounds of the present invention have utility as selective D3 agonists in the treatment of disease states. There are a number of compounds with both agonistic activity on D2 and D3; however, the use of such compounds involves a large number of side effects, including nausea, emesis, syncope, hypotension, and bradycardia, some of which are cause for serious concern.

It was previously believed that the effectiveness of prior art compounds was due to their ability to agonize D2, but it is suspected that D2 agonism is a cause of the side effects mentioned above.

The present invention provides a class of selective D3 agonists. As a result of the researchers' expertise 30, it has been found that they are effective, while reducing the side effects that the non-selective compounds of the prior art are reducing.

Accordingly, another aspect of the present invention provides a compound of the formula (I) for use as a medicament.

1029139 61

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, hypertenia, neurodegeneration, depression and psychiatric disorders.

Accordingly, the present invention provides for 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, in particular male erectile dysfunction. Male erectile dysfunction (MED), otherwise known as male erectile disorder, is defined as: "the inability to obtain and / or maintain an erection of the penis for satisfactory sexual performance" (NIH Consensus Development) Panel on Impotence, 1993)

It is estimated that the occurrence of erectile dysfunction (ED) in all sizes (minimum, moderate and full impotence) in men between 40 and 70 years old is 52%, with the numbers for the elderly being over 70 (Melman et al., 1999, J. Urology, 161, pp. 5-11). The condition has significant negative consequences for the quality of life of the person and his partner, often resulting in increased anxiety and tension leading to depression and low self-esteem. Whereas, 20 years ago, MED was primarily regarded as a psychological disorder (Benet et al., 1994, Comp. Ther., 20: 669-673), today, on the other hand, 35 is known to have a fundamental organic cause for the majority of individuals. is. As a result, much progress has been made in identifying the mechanisms of normal penis erection and pathophysiologies of MED.

Erection of the penis is a hemodynamic event that depends on the balance between contraction and relaxation of the smooth muscles 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 corporal smooth muscle or, in the plural, corpus cavernosa. Relaxation of the smooth muscles of the corpus cavernosum leads to increased blood flow in the trabecular spaces of the corpus cavernosum, causing it to expand against the surrounding tunica and compressing the draining veins. This causes a sharp rise in blood pressure with an erection as a result (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 peripheral and central nervous systems, and the endocrine system. (Naylor, 1998, Br. J. Urology, 81, 424-431). Contraction of corporal smooth muscles is modulated by sympathetic noradrenergic innervation via activation of post-synaptic <Xi adrenoceptors. MED can be associated with an increased endogenous tension in the smooth muscles of the corpus cavernosum. The process of relaxation of corporal smooth muscles is promoted in part by non-adrenergic, non-cholinergic (NANC) neurotransmission. A number of other NANC neurotransmitters other than NO have been found in the penis, such as calcitonin gene related peptide (CGRP) and vasoactive intestinal peptide (VIP). The major relaxing factor responsible for promoting this relaxation is nitric oxide (NO), which is synthesized from L-arginine by nitric oxide synthase (NOS) (Taub et al., 1993, Urology, 42, 698-704) . It is believed that lowering the tension of corporal smooth muscles NO can be helpful in causing 1U2 913 $ - 63 of relaxation of the corpus cavernosum. During sexual arousal in men, NO is released from neurons and the endothelium, and this binds and activates soluble guanylate cyclase (sGC) present in smooth muscle cells and the endothelium. This leads to an increase in the intracellular levels of cyclic guanosine 3 ', 5' monophosphate (cGMP). This increase in cGMP leads to a relaxation of the corpus cavernosum as a result of a reduction in the intracellular calcium concentration ([Ca2 +]) via unknown mechanisms that, however, are believed to involve activation of protein kinase G (possibly due to activation of Ca2 + - pumps and the K + channels activated by Ca2 +).

Within the central nervous system, several potential sites have been identified for the modulation of sexual behavior. These vital neurotransmitters are believed to be serotonin, norepinephrine, oxytocin, nitric oxide and dopamine. Sexual function can be adjusted by simulating the workings of one of these vital neurotransmitters. Dopamine D3 receptors are almost only expressed in the limbic region of the brain, areas that are involved in reward, emotional and cognitive processes.

Without being bound by any theory, it appears that "due to its role in controlling locomotor activity, the integrity of the nigrostriatal dopaminergic pathway is also essential for exhibiting copulation behavior. Somehow, that more specifically for sexual function, it is likely that dopamine can induce erection of the penis by acting on oxytocinergic neurons located in the paraventricular nucleus of the hypothalamus, and perhaps on the pro-erectile sacral para-sympathetic nucleus within the spinal cord ". It now appears that the important place is D3, and not, as previously thought, D2.

In essence, D3 is an initiator of sexual behavior.

1 0 2 9 1 39 64

The present invention thus provides for 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 would benefit from treatment with the compounds of the present invention, and patients with severe MED could also respond. However, the first studies suggest that the response rate of patients with mild, moderate, or severe MED may be greater with a selective combination of a D3 agonist / PDE5 inhibitor. Mild, moderate and severe MED are expressions known to those skilled in the art, but guidelines can be found in The Journal of 15 Urology, vol. 151, 54-61 (January 1994).

The first studies suggest that the groups of MED patients listed below might benefit from treatment with a selective D3 agonist and a PDE5 inhibitor (or another combination explained below). These patient groups, described in more detail in Clinical Andrology, vol. 23, no. 4, pages 773-782, and chapter 3 of the book by I. Eard-ley and K. Sethia "Erectile Dysfunction-Current Investment and Management", published by Mosby-Wolfe, are as follows : psychogenic, organic, vascular, endocrinological, neurogenic, arteriogenic, drug-induced sexual dysfunction (lactogenic) and sexual dysfunction related to corpus cavernoma-related factors, in particular venogenic causes.

The present invention thus provides for 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 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; no interest in sex) , FSAD with concomitant HSDD, and female orgasmic disorder (FPS; inability to achieve orgasm).

In accordance with the present invention, FSD can be defined as the problems or inability of a woman to find satisfaction in sexual expression. FSD is a joint expression for various diverse female sexual disorders (Leiblum, 10 S.R. (1998) - Definition and classification of female sexual disorders. Int. J. Impotence Res., 10, S104-S106;

Berman, J. R., Berman, L. & Goldstein, I, (1999) - Female sexual dysfunction: Incidence, pathophysiology, evaluations and treatment options, Urology, 54, 385-391). The woman may experience lack of desire, problems with arousal or orgasm, pain with intercourse or a combination of these problems. Various types of illnesses, drugs, injuries or psychological problems can cause FSD. The treatments that are being developed are aimed at treating specific subtypes of FSD, mainly desire and arousal disorders.

The categories of FSD can best be defined by contrasting them with the phases of a normal female sexual response: desire, arousal and orgasm (Leiblum, SR (1998) - Definition and classi fication of female sexual disorders. Int J. Impotence Res., 10, S104-S106 Desire or libido is the impetus for sexual expression, the manifestations of which often include sexual thoughts, either when one is in the company of an interested partner or when one is at Excitement is the vascular response to sexual stimulation, an important component of which is a genital response and which includes moistening of the vagina, elongation of the vagina and increased genital sensation / sensitivity. 39 - 66 gasme is the release of sexual tension that reaches its peak during the excitement.

FSD thus occurs when a woman has an inadequate or unsatisfactory response in one of these stages, 5 usually desire, excitement, or orgasm. FSD categories include hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorders, and sexual pain disorders. Although the compounds of the present invention will improve the genital response to sexual stimulation (such as in female sexual arousal disorder), they will thereby also improve the associated pain, tension and discomfort in intercourse, and thus also other female treat sexual disorders.

15 Hypoactive sexual desire disorder occurs when a woman has little or no desire for sex and has few or no sexual thoughts or fantasies. This type of FSD can be caused by low testosterone levels, which may be due to the natural menopause or menopause due to surgery. Other causes include illness, medication, fatigue, depression and anxiety.

Female sexual arousal disorder (FSAD) is characterized by an inadequate genital response to sexual stimulation. The genitals do not undergo the reaction that characterizes normal sexual arousal. The walls of the vagina hardly get wet, if at all, so communion is painful. Orgasms can be difficult. The arousal disorder can be caused by a reduced amount of estrogens at the menopause or after the birth of children and during nursing, as well as in diseases, with vascular components such as diabetes and atherosclerosis. Other causes are the result of treatment with diuretics, antihistamines, antidepressants, e.g. selective inhibitors of the reuptake of serotonin (SSRIs) or antihypertensive agents.

1029139 67

Sexual pain disorders (these include dyspareunia and vaginism) are characterized by pain during penetration and can be caused by moisturizing drugs, endometriosis, inflammatory pelvic disease, inflammatory bowel disease, and urinary tract problems.

As discussed earlier, it is believed that D3 is an initiator of sexual behavior. The clitoris is considered a penis homologue (Levin, R. J. (1991), Exp. Clin. Endocrinol., 98, 61-69); the same mechanism that causes an erectile response in men triggers a stronger flow of blood from the genitals in women, and associated effects occur with FSD. In addition, there are changes in proceptivity and receptivity.

Thus, according to a preferred aspect of the present invention, use is made of a compound of formula (I) in the preparation of a medicament for the treatment or prophylaxis of female sexual dysfunction, more particularly 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 most preferably in the treatment or prophylaxis of female sexual regrowth 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.

35 In The Diagnostic and Statistical Manual (DSM) IV of

American Psychiatry Association, female sexual arousal disorder (FSAD) is defined as: 1029139 68 "... a persistent or persistent inability to attain or maintain until the completion of sexual activity an adequate response consisting of moist-swelling in sexual arousal. This 5 disorder will cause significant tensions or problems between people ... "

The excitement response consists of vasocongestion in the pelvis, moistening of the vagina and expansion and swelling of the external genitalia. The disorder causes considerable tension and / or problems between people.

FSAD is a common sexual disorder that affects women in pre, peri and post menopause (± hormone replacement therapy (HRT)). This is accompanied by accompanying disorders such as depression, cardiovascular disorders, diabetes and urogenital (UG) disorders.

The main consequences of FSAD are a lack of res-punching / swelling, not getting moist and a lack of pleasant sexual sensation. The secondary consequences of FSAD are less sexual desire, pain in intercourse and problems in achieving an orgasm.

Recently, the hypothesis has been established that there is a vasculary ground for at least a portion of patients with symptoms of FSAD (Goldstein et al., Int. J. Im-pot. Res., 10, S84-S90, 1998 ), with animal data supporting this insight (Park et al., Int. J. Impot. Res., 9, 27-37, 1997).

30 R.J. Levin states that "... male and female genitalia develop embryologically from a common tissue construction, and [that] male and female genital structures are said to be homologues of each other. The clitoris is thus homologous to the penis and the labia so homologues of the ball bag ... "(Levin, RJ

(1991), Exp. Clin. Endocrinol., 98, 61-69).

1 ü 2 9 1 3 ft - 69

Drug candidates for the treatment of FSAD that are being tested for efficacy are primarily erectile dysfunction therapies that promote circulation in the male genitalia.

The compounds of the present invention are advantageous in that they provide means for restoring a normal sexual arousal response - namely, increased blood flow of the genitals leading to a vaginal, clitoral, and labial response. This will result in a moistening of the vagina via transduction of plasma, an increased reaction of the vagina and a stronger genital sensitivity. The present invention thus provides means for restoring or potentiating the normal sexual arousal response.

Thus, according to a preferred aspect of the present 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 associated with hypoactive sexual pleasure disorder.

With female genitalia is meant: "The genital organs consist of an internal and external group. The internal organs are located within the pelvis and consist of the ovaries, the fallopian tubes, the uterus and the vagina. The external organs are above the urogenic diaphragm and under the pelvic arch. These consist of the mons pubis, the labia majora and minora pudendi, the clito-30 ris, the vestibulum, the bulbus of the vestibulum and the larger vestibular glands "(Gray's Anatomy, CD Clemente, 13th American Edition).

The compounds of the present invention find use in the following sub-populations of patients with FSD: young, elderly, pre-menopausal, peri-menopausal, post-menopausal women with or without hormone replacement therapy.

1029139 70

The compounds of the present invention find use in patients with FSD that results from: i) Vasculogeneic etiologies, e.g. cardiovascular or atherosclerotic diseases, hypercholesterolaemia, cigarette smoking, diabetes, hypertenesis, radiation and perineal trauma, traumatic injury to the ilio-hypogastric pudendale vascular system.

ii) Neurogenic etiologies such as spinal cord injury or diseases of the central nervous system, including multiple sclerosis, diabetes, Parkinsonism, cerebrovascular accidents, peripheral neuropathies, trauma or radical pelvic surgery.

Iii) Hormal / endocrine aetiologies such as dysfunction of the axis of hypothalamus / pituitary / glands, or dysfunction of the ovaries, dysfunction of the pancreas, surgical or medical castration, androgen deficiency, high circulating levels of prolactin, e.g. hyperprolactinaemia, natural menopause, premature ovarian failure, hyper and hypothyroidism.

iv) Psychogenic aetiologies such as depression, obsessive-compulsive disorder, anxiety disorder, post-natal depression / "baby blues", emotional and relational problems, fear of failure, marital problems, dysfunctional attitudes, sexual phobias, religious taboos or traumatic past experiences .

V) Drug-induced sexual dysfunction resulting from therapy with selective inhibitors of re-uptake of serotonin (SSRis) and other antidepressant therapies (tricyclic compounds and major sedatives), antihypertensive therapies, sympatholytic drugs, chronic therapy of oral contraceptives .

1029139.

71

The compounds of the present invention are also useful in the treatment of depression.

Dopamine D3 receptors are almost only expressed in the limbic region of the brain, an area that is involved in reward, emotional and cognitive processes. Chronic treatment with various classes of antidepressants is known to increase expression of D3 in the limbic region, and antidepressant effects of desipramine can be blocked by sulpride (a D2 / D3 antagonist) when injected into the nucleus accumbens (an area rich in D3), but not in the caudate putamen (an area rich in dopamine D2 receptors). In addition, antidepressant effects were observed in preclinical models for depression and in patients treated with pramipexole, a D2 / D3 agonist with a preference for D3. The available information suggests that D3 receptors promote 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 may have the potential to treat psychiatric illnesses.

Suitable disorders include depression (e.g., pressure in cancer patients, depression in patients suffering from Parkinson's disease, depression in postmycardial infarction, subsyndromal symptomatic depression, depression in infertile women, major depression, depression caused by child abuse) , postnatal depression and grumpy old man syndrome, a single episode of recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, early morning awakening or psychomotor retardation atypical depression (or reactive depression), including increased 10 29 1 39.

72 appetite, hypersomnia, psychomotor agitation or irritability, affective seasonal disorder and pediatric depression; bipolar disorder or manic depression, for example bipolar disorder I, bipolar disorder II and cyclothymic disorder; behavioral disorder; disorder that manifests itself in disruptive behavior; trichotillomania, kleptomania, attention deficit hyperactivity disorder (ADHD), behavioral disorders associated with mental retardation, autistic disorder; borderline personality disorder; personality disorders that consist of avoidance behavior; anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia with or without history of panic disorder, specific phobias, for example specific animal phobias, social anxiety, social phobia, obsessive-compulsive disorder, stress disorders, including post-traumatic stress disorder and acute stress disorder disorder, and generalized anxiety disorders; emotional lability, pathological crying, schizophrenia and other psychotic disorders, for example schizophreniform disorders, schizoaffective disorders, delusional disorders, short-term psychotic disorders, shared psychotic disorders, psychotic disorders with delusions or hallucinations, psychotic episodes of anxiety, anxiety associated with psychosis psychotic mood disorders such as major depressive disorder; mood disorders associated with psychotic disorders such as acute mania and depression associated with bipolar disorder; mood disorders associated with schizo-30 frenie; eating disorders (e.g., anorexia nervosa and bulimia nervosa); obesity; movement disorders, such as akinesias, dyskinesias, including familial paroxistic dyskinesias, spasticities, De la Tourette syndrome, Scott syndrome, PALSYS and akinetic rigid syndrome; ex-35 trapyramidal movement disorders such as medication-induced movement disorders, for example neuroleptically induced Parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute acathision, neuroleptic-induced tardines, and induced postural tremor; chemical dependencies and addictions (e.g., dependencies on or addictions to alcohol, heroin, cocaine, benzodiazepines, nicotine or phenobarbitol) and behavioral addictions, such as gambling addiction; harvest disorders such as glaucoma and ischemic retinopathy; sleep disorder (cataplexia) and shock.

In another preferred embodiment, the present invention provides for the use of a compound of formula (I) in the preparation of a medicament for the treatment of depression or psychiatric disorders.

Suitable depressive disorders and psychiatric disorders are described above.

In a further embodiment, the present invention provides for the use of the compounds 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; sources of neurodegeneration include poisoning by neurotoxins; loss of vision caused by neurodegeneration of the visual route, such as by stroke in the visual route, eg in the retina, the optic nerve and / or the occipital lobe; seizures, and when the glucose and / or oxygen supply of the brain is impeded.

Disorders associated with neurodegeneration include restless leg syndrome, Hunting-ton's disease, multiple sclerosis, mild cognitive decline, Down syndrome, stroke, hereditary hemorrhage with Dutch-type amyloidosis, cerebral amyloid angiopa-thie, delirium , dementia, cognitive decline due to age (age-related cognitive decline; ARCD), and amniotic 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 impairment, loss of executive function, vascular dementia, dementia of mixed vascular and degenerative origin, dementia related to Parkinson's disease, dementia related with progressive supranuclear palsy, dementia associated with cortical basal degeneration, dementia due to various infarctions, alcoholic mementia or other dementia related to drugs, dementia associated with intracranial tumors or brain trauma, dementia associated with Huntington's disease, Peak disease, Creutzfeldt-Jakob disease, dementia associated with HIV 15 or AIDS, diffuse Lewy body disease or Alzheimer's disease, frontotemporal dementias with parkinsonism (FTDP), head trauma, spinal cord injury, demyelinating diseases of the central nervous system, peripheral neuropathy, pain, cerebral amyloid angiopathy, amyotrophic lateral sclerosis, multiple sclerosis, multiple sclerosis dyskinesia associated with dopamine agonist therapy, mental retardation, learning disability, including reading disorder, mathematical disorder, or a written expression disorder; cognitive deterioration due to age-25, amnestic disorders, neuroleptically induced parkinsonism, tardive dyskinesias and acute and chronic neurodegenerative disorders.

Accordingly, the present invention provides for the use of a compound of formula (I) in the preparation of a medicament for the treatment of neurodegeneration.

Suitable neurodegenerative disorders are described above.

In addition to their role in treating sexual dysfunction, depression, neurodegeneration, and psychiatric disorders, the compounds of the present invention are likely to be effective in a number of indications.

The present invention thus provides for the use of compounds of formula (I) in the preparation of a medicament for the treatment of hypertension, premature ejaculation, obesity, cluster headache, migraine, pain, endocrine disorders (e.g. hyperprolactinaemia) ), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (including changes in motility and secretion), premenstrual syndrome, fibromyalgia syndrome, stress incontinence, trichotillomania and chronic paroxoxic hemicrania , headache (in connection with vascular disorders).

It will be understood that all references herein to treatment include curative, palliative and prophylactic treatment.

ASSAY OF D3 / D2 AGONIST

The activity on the dopamine D3 receptor can be determined by the methods described in WO 2004/052372. Using this assay, the compounds of the present invention all exhibit a functional potency on the D3 receptor expressed as an EC50 of less than 1000 nM and a 10-fold selectivity for D3 over D2. The selectivity is calculated as the EC 50 value for D2, divided by the EC 50 value for D3. When the EC 50 value of D 2 was> 10,000, a value of 10,000 was used in the calculation.

The compound of Example 14 has a functional potency on the D3 receptor expressed as an EC50 of 20 nM, with an Emav (maximum response value) of 98% (relative to the maximum effect of the standard pramipexole agent). Against the D2 receptor, this compound gave a response of only 22% (relative to the maximum effect of pramipexole) at 10,000 nM.

1, 29139j 76

Suitable active auxiliaries for use in the combinations of the present invention include: 1) Naturally occurring or synthetic prostaglanins or esters thereof. Suitable prostaglandins for use herein include compounds such as alpha prostadil, prostaglandin, prostaglandin E0, 13, 14 - dihydroprostaglandin E1, prostaglandin E2,

eprostinol, natural, synthetic, and semi-synthetic prostaglandins and derivatives thereof, including those described in WO

00033825 and / or US 6,037,346, published March 14, 2000, all of which are incorporated herein by reference, PGE0, PGEi, PGAi, PGBi, PGFi a, 19-hydroxy-PGAi, 19-hydroxy-PGBi, PGE2, PGB2, 19-hydroxy-PGA2, 19-hydroxy-15 PGB2, PGE3a, carboprosttromethamine, dinoprosttromethamine, dinoprostone, lipoprost, gemstrost, measuring oprost, sulprostune, tiaprost and moxisate.

2) antagonistic compounds of the α-adrenergic receptor, also known as α-adrenoreceptors or α-receptors or α-blockers. Suitable compounds for use herein include: α-adrenergic receptor blockers as described in PCT patent application WO 99/30697, published June 14, 1998, the descriptions of α-adrenergic receptors are incorporated herein by reference, and these include selective αχ-adrenoceptor blockers or α2-adrenoceptor blockers and non-selective adrenoceptor blockers; suitable αχ-adreno-30 receptor blockers include: phentolamine, phentolamine

mesylate, trazodone, alfuzosin, indoramine, naphthopidin, tamsulosin, dapiprazole, phenoxybenzamine, ida-zoxan, epharaxan, yohimbine, Rauwolfia alkaloids, Re-cordati 15/2739, SNAP 1069, SNAP 5089, RS17053, SL

89,0591, doxazosin, terazosin, abanoquil and prazosin; α2 blockers from US 6,037,346 [March 14, 2000]: dibenamine, tolazoline, trimazosin and dibenarnine; 1029139 77 α-adrenergic receptors as described in U.S. Pat. Nos. 4,188,390, 4,026,894, 3,511,836, 4,315,007, 3,527,761, 3,997,666, 2,503,059, 4,703,063, 3,381,009, 4,252,721 and 5,599,000, each of which is incorporated herein by reference; α 2 -adrenoceptor blockers include: clonidine, papaverine, papaverine hydrochloride, optionally in the presence of a cariotonic agent such as piraxamine.

3) NO donor (NO agonist) compounds. Suitable NO donor compounds for use herein include organic nitrates, such as mono-, di- or tri-nitrates, or organic nitrate esters, including glyceryl trinitrate (also known as nitroglycerin), isosorbide-5 mononitrate, isosorbide dinitrate, pentaery-tritol tetranitrate , erythritol tetranitrate, sodium nitroprusside (SNP), 3-morpholinosydnonimine, molsidomine, S-nitroso-N-acetylpenicillamine (SNAP), S-nitroso-N-glutathione (SNO-GLU), N-hydroxy-L -arginine, amyl nitrate, linsidomine, linsidomine chlorohydrate, (SIN-1), S-nitroso-N-cysteine, diazenium diolates, (NONOates), 1,5-pentanedinitrate, L-arginene, gin seng, zizphi fructus , molsidomine, Re-2047, nitrosylated maxisylite derivatives, such as NMI-678-11 and NMI-937, described in published PCT patent application WO 0012075.

4) Potassium channel openers or modulators. Suitable potassium channel openers / modulators for use herein include nicorandil, cromokalim, levcro-makalim, lemakalim, pinacidil, cliazoxide, minoxidil, charybdotoxin, glyburide, 4-aminopyridine, BaCl2.5) Vasodilators. Suitable vasodilators for use herein include nimodepine, pip 1029139.

78 nacidil, cylandelate, isoxsuprine, chloroprumazine, Ree 15/2739, trazodone.

6) Thromboxane A2 agonists.

5) Resources active on the CNS.

8) Ergot alkaloids; suitable ergot alkaloids are described in U.S. Patent No. 6,037,346, published March 14, 2000, and include acetergamine, brazergoline, bromerguride, cianergoline, del-orgotril, disulergine, ergonovine maleate, ergotamine netartrate, etisulergine, lergotril, lysergide, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride and terguride.

9) Compounds that modulate the action of natruretic factors, in particular atrial natruretic factor (also known as atrial natruretic peptide), naturetic factors of the B-type and C-type, such as inhibitors of neutral endopeptidase.

10) Compounds that inhibit angiotensin converting enzyme, such as enapril, and combined inhibitors of angiotensin converting enzyme and neutral endopeptidase, such as omapatrilat.

11) Angiotensin receptor antagonists, such as lo-sartan.

12) Substrates for NO synthase, such as L-arginine.

13) Blockers of the calcium channel, such as amlodipine.

14) Antagonists of endothelin receptors and inhibitors of endothelin converting enzyme.

1029139 79 15) Agents that lower the amount of cholesterol, such as statins (e.g., atorvastatin / Lipitor trademark) and fibrates.

16) Agents that inhibit platelet aggregation and antithrombotic agents, e.g. tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin, inhibitors of thromboplastin activating factor.

17) Means sensitizing insulin such as rezulin and hypoglycaemic agents such as glipizide, 18) Acetylcholinesterase inhibitors such as donezipil.

19) Steroid or non-steroidal anti-inflammatory drugs.

20) Modulators of the estrogen receptor and / or agonists of estrogen and / or antagonists of estrogen, preferably raloxifene or lasofoxifene, (-) - cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl] -5,6,7,8-tetrahydronaphthalene-2-ol and the pharmaceutically acceptable salts thereof, the preparation of which is disclosed in WO 96/21656.

21) A PDE inhibitor, more particularly an inhibitor of PDE 2, 3, 4, 5, 7 or 8, preferably an inhibitor of PDE2 or PDE5, and most preferably an inhibitor of PDE5 (see below), wherein the inhibitors preferably have an IC 50 against the respective enzyme of less than 100 nM (provided that inhibitors of PDE 3 and 4 are administered only topically or by injection into the penis). 1 1029139

Vasoactive intestinal protein (vasoactive intestinal protein; VIP), VIP mimetics, VIP analogues, on which more

in particular, one or more of the VIP receptor subtypes VPAC1, VPAC or PACAP intervenes

80 (pituitory adenylate cyclase activating peptide), one or more of an agonist of the VIP receptor or a VIP analogue (e.g. Ro-125-1553) or a VIP fragment, one or more of an antagonist of the α-adrenoceptor 5 with a VIP combination (e.g. Invicorp, Aviptadil).

23) An agonist or modulator of the melanocortin receptor (in particular of the MC3 or MC4 subtype) or an enhancer of melanocortin, such as melanotan II, PT-14, PT-141 or compounds claimed in WO 09964002 , WO 00074679, WO 9955679, WO 00105401, WO 00058361, WO 00114879, WO 00113112, WO 09954358.

24) An agonist, antagonist or modulator of the serotonin receptor, more particularly agonists, antagonists or modulators for 5HT1A - (including VML 670), 5HT2A, 5HT2C, 5HT3 and / or 5HT6 receptors, including those which are described in WO 09902159, WO 00002550 and / or WO 00028993.

25) A substitute for testosterone (including de-hydroandrostenedione), testosternone (Tostrelle), dihydrototestosterone or a testosterone implant.

26) Estrogen, estrogen and medroxyprogesterone or hydroxyprogesterone acetate (MPA) (ie as a combination) or a hormone replacement therapy agent for estrogen and methyl testosterone (e.g. HRT, in particular Premarin, Cenestin,

Oestrofeminal, Equin, Estrace, Estrofem, Elleste Solo, Estring, Eastraderm TTS, Eastradérm Matrix, Der-mestrile, Premphase, Preempro, Prempak, Premique, Es-tratest, Estratest HS, Tibolone).

1029139 81 27) A modulator of the transporters of noradrenaline, dopamine and / or serotonin, such as bupropion, GW-320659.

28) An agonist and / or modulator of the purinergic receptor.

29) An antagonist of the neurokinin (NK) receptor, including those described in WO

10 09964008.

30) An opioid receptor agonist, antagonist or modulator, preferably ORL-1 receptor agonists.

31) An agonist, antagonist or modulator of oxytocin receptors, preferably a selective agonist or modulator of oxytocin.

32) Modulators of cannabinoid receptors.

33) A SEP inhibitor (SEPi), for example a SEPi with an IC50 of less than 100 nanomolar, preferably of less than 50 nanomolar

The SEP inhibitors of the present invention preferably have a selectivity to SEP of more than 30 times, and more preferably of more than 50 times that of neutral endopeptidase NEP EC 3.4.24.11 and angiotensin converting enzyme (ACE). Preferably, the SEPi also has a selectivity of more than 100 times that for endothelin-converting enzyme (ECE).

34) An antagonist or modulator for the NPY (in particular of the Y1 and Y5 subtype) receptor.

1029139 82 35) An antagonist or modulator of the binding of globulin to sex hormones, which prevents estrogens and / or androgens from being bound.

36) An inhibitor of arginase II.

37) An agonist, antagonist or modulator of vasopressin receptors, which is preferably selective for the V1a receptor.

38) A PDE5 inhibitor. More suitable PDE5 inhibitors include: 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7 H -pyrazolo [4.3 -d] -pyrimidin-7-one (sildenafil), in particular sildenafil citrate, (6R, 12aR) -2.3, 6, 7.12,12a-hexahydro-2-methyl-6- (3, 4-methylenedioxyphenyl) pyrazino [2 ', 1': 6.1] pyrido [3,4-b] indole-1,4-dione (IC-351 or tadalafil), 2- [2-ethoxy-5- ( 4-ethylpiperazin-1-yl-1-sulfonyl) phenyl] -5-methyl-7-propyl-3 H -imidazo [5,1-f] [1,2,4] triazine-4-one (vardenafil); 5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7tf-pyrazolo [4,3-d] pyrimidine-7- on; 5- (5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-77 / pyrazolo [4,3-d] pyrimidine-7-one and 5- [2-ethoxy-5- (4-ethyl-piperazin-1-yl-sulfonyl) -pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro -7 H -pyrazolo [4,3-d] pyrimidine-7-δ; 4 - [(3-chloro-4-methoxybenzyl) amino] -2 - [{2 S) -2- (hydroxy-methyl) pyrrolidin-1-yl] -N- (pyrimidin-2-ylmethyl) pyrimidine- 5-carboxamide (TA-1790); 3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1 H -pyrazolo [4,3-d] pyrimidin-5-yl) -N- [2- (1-methylpyrrolidine) 2-yl) ethyl] -4-propoxybenzenesulfonamide (DA 8159), and pharmaceutically acceptable salts thereof.

1029139 83 39) A selective agonist of the dopamine D4 receptor, such as 2 - [(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole (ABT724).

By referring herein to compounds occurring in patents and patent applications, and which may be used in accordance with the present invention, we mean therapeutically active compounds as defined in the claims (in particular in claim 1) and the specific examples (which are herein) all are included by reference).

If a combination of active agents is administered, these can be administered simultaneously, separately or sequentially.

The compounds of the formula (I) should be evaluated for their biopharmaceutical properties, such as solubility and stability in solution (over the pH range), permeability, etc., in order to determine the most suitable dosage form and route of administration for treatment of the precursor. -20 suggested choosing an indication.

The compounds of the present invention intended for pharmaceutical use can be administered as crystalline or amorphous products. These 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-drying can be used for this purpose.

These can be administered alone or in combination with one or more other compounds of the present invention, or in combination with one or more other drugs (or as a combination thereof). In general, these will be administered as a preparation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to subscribe to any component other than the compound (s) of the present invention. The choice of the excipient 1029139 84 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 the release of compounds of the present invention and methods of 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 Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

The present invention thus provides a pharmaceutical composition comprising a compound of formula (I), and a pharmaceutically acceptable diluent or carrier.

The compounds of the present invention can be administered orally. Oral administration may involve ingestion such that the compound enters the gastrointestinal tract, and / or buccal, linguistic or sublingual administration whereby the compound enters the blood stream directly from the mouth.

Preparations suitable for oral administration include solid, semi-solid and liquid systems, such as tablets, soft or hard capsules containing various particles or nanoparticles, liquids or powders, pastilles (including liquid-filled), chewing gums, gels, rapidly dispersing dosage forms, films, ovules, sprays and buccal / mucoadhesive patches.

Liquid preparations include suspensions, solutions, syrups and elixirs. Such compositions may be used as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropyl methylcellulose) and typically include a carrier, e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifiers and / or suspending agents. Liquid preparations can also be prepared by reconstituting 102913a 85 with a solid, for example from a sachet.

The compounds of the present invention can also be used in rapidly dissolving, rapidly disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001) .

For dosage forms such as tablets, depending on the dose, the medicament may represent 1 to 80% by weight of the dosage form, and in a more typical case 5 to 60% by weight of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrating agents include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinyl pyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. In general, the disintegrant will comprise from 1 to 25% by weight and preferably from 5 to 20% by weight of the dosage form.

Binders are generally used to impart cohesion to a tablet preparation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. 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.

Tablets may optionally also contain surfactants such as sodium lauryl sulfate and polysorbate 80, and lubricants such as silica and talc. When present, surfactants may comprise 0.2% to 5% by weight of the tablet, and lubricants 0.2% to 1% by weight of the tablet.

1029139 86

The tablets also generally 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 to 10% by weight and preferably from 0.5 to 3% by weight of the tablet.

Other possible ingredients include antioxidants, colorants, fragrances and flavors, preservatives and taste masking agents.

Examples of tablets contain up to about 80% drug, about 10 to about 90% binder, about 0 to about 85% diluent, about 2 to about 10% disintegrant, and about 0.25 to about 10% by weight. % lubricant.

Tablet mixtures can be compressed directly or by means of a roller to form tablets. Tablet blends or portions of blends can alternatively be tableted wet, dry, or melted, granulated, and allowed to melt and solidify or extrude again. The final composition may comprise one or more layers and may or may not be coated; it may even be encapsulated.

The formulation of tablets is discussed in Phar-maceutical Dosage Forms: Tablets, vol. 1, by H. Lieber-25 male and L. Lachman (Marcel Dekker, New York, USA, 1980).

Digestible oral films for human or veterinary use are typically flexible, water-soluble or water-swellable thin films, dosage forms that can dissolve rapidly, or are mucoadhesive, and in a typical case include a compound of the formula I, a polymer that forms a film, a binder, a solvent, a wetting agent, a plasticizer, a stabilizer or emulsifier, a viscosity modifier and a solvent. Some components of the composition may perform more than one function.

The compound of the formula I may or may not be water-soluble. A water-soluble compound 1029139 87 typically accounts for 1 to 80% by weight, and more typically 20 to 50% by weight of the dissolved substances. Less soluble compounds can make up a larger proportion of the composition, typically up to 88% by weight of the dissolved substances. Alternatively, the compound of the formula I can be in the form of multi-particle beads.

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 99% by weight and in a more typical case in the range of 30 to 80% by weight %.

Other possible ingredients include antioxidants, colorants, flavorings and flavor enhancers, preservatives, saliva secretion agents, coolants, co-solvents (including oils), emollients, bulk agents, anti-foaming agents, surfactants, and taste masking agents.

Films in accordance with the present invention are typically prepared by drying by evaporation of thin aqueous films coated on a peelable backing layer or paper. This can be done in a drying oven or tunnel, typically a combination of a coater and a dryer, or by freeze drying, or under vacuum.

Solid compositions for oral administration can be formulated for immediate and / or modified release. Modified-release preparations include those for delayed, continuous, pulsed, controlled, targeted, and programmed release.

Suitable modified release formulations for the purposes of the present invention are described in U.S. Patent No. 6,106,864. Details of other suitable delivery technologies, such as high-energy dispersions and osmotic and coated particles, can be found in Pharmaceutical Technology On-Line, 25 (2), 1-14, by Verma et al (2001). The use of chewing gum to obtain a controlled release is described in WO 00/35298.

The compounds of the present invention can also be administered directly into the blood stream, into the muscles or into an internal organ. Such methods of parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intra-uretral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration. Suitable means for parenteral administration include needle (including micro needle) injectors, needle free injectors and infusion techniques.

Parenteral preparations are typically aqueous solutions that may contain excipients such as salts, carbohydrates and buffering agents (preferably with a pH of 3 to 9), but for some applications these may be better formulated as a sterile non-aqueous solution or as a dried form that will be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral compositions under sterile conditions, for example by lyophilization, can be easily achieved with standard pharmaceutical techniques known to those skilled in the art.

The solubility of compounds of the formula I, which are used in the preparation of parenteral solutions, can be increased by the use of suitable formulation techniques, such as incorporating agents that increase the solubility.

Preparations for parenteral administration can be formulated for immediate and / or modified release. Modified-release preparations include those for delayed, continuous, pulsed, controlled, targeted, and programmed release. The compounds of the present invention can thus be formulated as a suspension or as a solid, a semi-solid or a thixotropic liquid for administration as an implanted depot providing for the modified release of the active link. Examples of such compositions include drug-coated stents and semi-solids and suspensions and poly (dl-milk-cogly-5-col) acid (PGLA) microspheres containing drug.

The compounds of the present invention can also be topically applied to the skin or mucous membranes, i.e., (intra) dermal or transdermal. Typical compositions for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, spreads, foams, films, skin patches, waffles, implants, sponges, fibers, dressings and micro-emulsions. Liposomes can also be used. Tyopic carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers can be included - see, for example, J. Pharm. Sci., £ 8 (10), 955-958, by Finnin and Morgan (October 1999).

Other modes of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and injection with a micro needle or needle free (e.g., Powderject ™, Bioject ™, etc.) injection.

Preparations for topical administration can be formulated for immediate and / or modified release. Modified-release preparations include those for delayed, continuous, pulsed, controlled, targeted, and programmed release.

The compounds of the present invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example in a dry lactose mixture, or as a mixture composed of from particles, for example mixed with phospholipids such as phosphatidylcholine) from a dry powder inhaler or as an arosol spray from a pressurized container, pump, syringe, nebulizer (preferably a nebulizer that uses to produce a fine mist) electrohydrodynamics), 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 contain a bioadhesive agent, for example chitosan or cyclodèxtrin.

The pressurized container, pump, syringe or nebulizer contains a solution or suspension of the compound (s) of the present invention which include, for example, ethanol, aqueous ethanol or a suitable alternative means for dispersing, solubilizing or extending the release of the active ingredient, propellant (s) as solvent and an optional surfactant such as sorbitan trioleate, oleic acid or an oligoleic acid.

Prior to use in a dry powder or suspension preparation, the drug product is reduced to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by a suitable method of reduction, such as grinding with a screw jet, grinding with a fluidized bed jet, processing with supercritical fluid, which forms nanoparticles, homogenization under high pressure or spray drying.

Capsules (made for example from gelatin or hydroxypropylmethylcellulose), blister packs, and cartridges for use in an inhaler or insufflator can be formulated to be a powder blend of the compound of the present invention, a suitable powder raw material such as lactose or starch and a performance modifier such as 1-leucine, mannitol or magnesium stearate. The lactose can be in anhydrous form or in the form of the monohydrate, and preferably in the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution, a composition for use in a nebulizer that uses electrohydrodynamics to produce a fine mist, 1029139 91 may contain 1 pg to 20 mg of the compound of the present invention per stroke, and the stroke volume may vary from 1 μΐ to 100 μΐ. A typical preparation may consist of a compound of the 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 fragrances and flavors, such as menthol and vomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to compositions of the present invention intended for inhaled / intranasal administration.

Preparations for inhaled / intranasal administration may be formulated for immediate and / or modified release with, for example, PGLA. Modified-release preparations include those for delayed, continuous, pulsed, controlled, targeted, and programmed release.

With dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that delivers a metered amount. Units of the present invention are typically set to deliver a metered dose or "puff" containing ... to ... pg of the compound of formula (I). The total daily dose will typically be in the range of ... pg to ... mg, which can be administered in a single dose or, more usually, as a divided dose throughout the day.

The compounds of the present invention can be administered rectally or vaginally, for example in the form of a suppository, pessary or clysma. Cocoa butter is the traditional raw material for a suppository, but if desired various alternatives can be used.

Preparations for rectal / vaginal administration can be formulated for immediate and / or modified release. Modified-release preparations include 1029139 92 for delayed, continuous, pulsed, controlled, targeted, and programmed release.

The compounds of the present invention can typically also be administered directly to the eye or ear, in the form of drops of a crushed suspension or a solution in isotonic, adjusted pH, sterile saline. Other compositions suitable for ocular and aural administration include ointments, gels, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, waffles, lenses, and particulate or vesicle systems , such as niosomes or liposomes. A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulose polymer, for example hydroxypropyl methylcellulose, hydroxyethylcellulose or methylcellulose, or a heteropolysaccharide polymer, e.g. Such compositions can also be delivered by iontophoresis.

Preparations for ocular / aural administration can be formulated for immediate and / or modified release. Modified-release preparations include those for delayed, continuous, pulsed, controlled, targeted, or programmed release.

The compounds of the present invention can be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polymers containing polyethylene glycol, to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in one of the aforementioned methods of administration.

For example, drug-cyclodextrin complexes generally prove useful for most dosage forms and administration routes. Both 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 carrier, diluent or solubilizer. For these purposes, alpha, beta and gamma cyclodextrins are most often used, examples of which can be found in International Patent Application No. WO 91/11172, WO 94/02518 and WO 98/55148.

To the extent that it may be desirable 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, of which at least at least one containing a compound of the present invention can be easily combined in the form of a kit suitable for co-administration of the compositions.

The kit of the present invention thus comprises two or more separate pharmaceutical preparations, at least one of which contains a compound of the formula (I) in accordance with the present invention, and means for keeping such preparations apart, such as a container, a subdivided bottle or subdivided foil package. An example of such a kit is the well-known blister pack used for the packaging of tablets, capsules and the like.

The kit of the present invention is suitable in particular for administering different dosage forms, for example oral and parenteral, for administering the separate preparations at different dosing intervals, or for titrating the separate preparations against each other . In order to better meet the requirements, in a typical case the kit contains instructions for administration and may be provided with a so-called memory support.

The present invention is illustrated by the following non-limiting examples, wherein the following abbreviations and definitions are used: 1 u 2 913 9 94 aD optical rotation at 587 nm.

AC2O acetic anhydride APCI chemical ionization at atmospheric pressure

Arbocel® filter medium 5 Br wide

Bert-butoxycarbonyl

Butyl CDCl3 chloroform-dl CD3OD methanol-d4 10 δ chemical shift d doublet dd double doublet DCM dichloromethane DMF Ν, Ν-dimethylformamide DMSO dimethylsulfoxide eq. (mol) equivalents of ESI electrospray ionization

Ethyl

EtOAc ethyl acetate 20 H hours or hours HCl hydrogen chloride HPLC high performance liquid chromatography HR M / S high resolution mass spectrum I PA isopropyl alcohol 25 KOAc potassium acetate m multiplet

Me methyl

MeCN acetonitrile M / S mass spectrum 30 min minutes NMR nuclear magnetic resonance k quartet k.t. room temperature s singlet 35 sat. saturated t triplet td triplet of doublets 1029139 95

Tf trifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran TIPS triisopropylsilyl TLC / t.l.c. thin layer chromatography. Nuclear magnetic resonance (NMR) spectra corresponded to the proposed structures in all cases. The characteristic chemical shifts (δ) are given in parts per million δΗ from tetramethylsilane, the main peaks being used for the designation of the main peaks: eg s, singlet; d, doublet; t, triplet; k, quartet; m, multiplet; bro, wide. The following abbreviations have been used for the usual solvents: CDCl3, deuterochloroform; DMSO, dimethyl sulfoxide. The abbreviation psi means pounds per square inch and LRMS means low-resolution mass spectrometry. When thin layer chromatography (TLC) is used, this relates to silica gel TLC with silica gel 60 F254 plates, Rf is the distance covered by a compound divided by the distance covered by the liquid front on a TLC plate.

Example 1 5- [(21?) - 4-Benzylmorpholin-2-yl] pyridine-2-amine

HjN '^ NT

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 overnight (~ 16 hours) for 1029139 96 up to 80 ° C. After cooling to room temperature, the reaction mixture was evaporated to a yellow, oily residue that was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol / NH 3 (s.d. = 0.880) = 98: 2: 0.

after which the polarity was increased to 95: 5: 0, then to 95: 5: 0.5 and then to 90: 10: 1 to give the title compound (645 mg, 40%).

1 H NMR (400 MHz, CDCl 3) δΗ 8.01 (1 H, s), 7.43 (1 H, d), 7.33 (5 H, m), 6.46 (1 H, d), 4.45 (3 H, brm), 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 - [(2R) -Morpholin-2-yl] pyridine-2-amine 20, η, νΛ, Χ The benzyl morpholine from Example 1 (990 mg, 3.7 mmol) was dissolved in methanol (20 ml ammonium formate (1.16 g, 18.5 mmol) and then 10% Pd-on-carbon (495 mg) were added, after which the mixture was heated under reflux for 2 hours. The cooled reaction mixture was filtered through a layer of Arbocel® and evaporated to give an orange solid (1.49 g). This material was purified by flash chromatography on silica gel (compound pre-absorbed on silica), eluting with dichloromethane / methanol / NH 3 35 (sd = 0.880) = 90: 10: 1 to give the title compound as a white solid (467 mg, 70%).

1029139 97 X H NMR (400 MHz, CD3 OD) δΗ 7.82 (1 H, s), 7.45 (1 H, d), 6.58 (1 H, d), 4.34 (1 H, d), 3, 95 (1H, d), 3.72 (1H, t), 2.95-2.80 (3H, m), 2.7 (1H, t).

MS (APCl +): 180 (MH +) δ [α] 25d = -39.4 ° (c ≤ 0.12, MeOH)

Example 3 5- [(2.R) -4- (3-Phenylpropyl) morpholin-2-yl] pyridine-2-amine

The morpholine from Example 2 (80 mg, 0.45 mmol) was dissolved in tetrahydrofuran (15 mL) and 3-phenylpropion-20 aldehyde (59 μΐ, 0.45 mmol) was added as a solution in tetrahydrofuran for 15 minutes (15 ml). Once the addition was complete, sodium triacetoxyborohydride (227 mg, 1 mmol) was added and the reaction mixture stirred at room temperature for 6 hours. The reaction mixture was then diluted with saturated sodium hydrogen carbonate solution (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic fractions were dried (MgSO 4), filtered and evaporated to give a yellow oil. Purification by flash chromatography on silica gel, eluting with dichloromethane / methanol / NH 3 (sd = 0.880) = 98: 2: 0.2, after which the polarity was increased to 95: 5: 0.5, yielded the title compound (51 mg, 38%).

1 H NMR (400 MHz, CD3 OD) δΗ 7.86 (1H, d), 7.45 (1H, dd), 35 7.27-7.10 (5H, m), 6.55 (1H, 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 (2 H, m).

1029139 98 MS (APCI +): 298 (MH +) [a] 25d = + 6.9 ° (c - 0.13, MeOH)

Example 4 5- [(22?) -4-Butyl-morpholin-2-yl] pyridine-2-amine 1 x y -

H2 N

The morpholine from Example 2 {80 mg, 0.45 mmol) was mixed with tetrahydrofuran (10 ml) (only partially soluble) and butyraldehyde (40 μΐ, 0.45 mmol) was added, resulting in a homogeneous solution. The reaction mixture was stirred for an additional 30 minutes before sodium triacetoxyborohydride (227 mg, 1 mmol) was added. The reaction mixture was then stirred overnight (~ 16 hours) at room temperature before being diluted with saturated sodium hydrogen carbonate solution (100 ml) and extracted with ethyl acetate (100 ml). The combined organic layer was separated, dried (MgSO 4), filtered and evaporated to give a yellow oil. Purification by flash chromatography on silica gel, eluting with dichloromethane / metha-ηο1 / ΝΗ3 (sd = 0.880) = 98: 2: 0.2, after which the polarity was increased to 95: 5: 0.5, yielded the title compound (17 mg, 16%).

1 H NMR (400 MHz, CD3 OD) δΗ 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 (2 H, t), 2.41 (2 H, t), 2.21 (1 H, t), 2.07 (1 H, t), 1.50 (2H, m), 1.35 (2H, m), 0.95 (3H, t).

MS (APCI +): 236 (MH +).

1029139

Example 5 5- [(21?) -4-Pentyl-morpholin-2-yl] pyridine-2-amine 99 x 10 - 10

The morpholine from Example 2 (80 mg, 0.45 mmol) was mixed with tetrahydrofuran (15 ml), and pentanal (47 μΐ, 0.45 mmol) was added dropwise over 15 minutes as a solution in tetrahydrofuran (15 ml) . After the addition was complete, sodium triacetoxyborohydride (227 mg, 1 mmol) was added and the reaction mixture stirred overnight at room temperature ("16 hours). The reaction mixture was then diluted with saturated sodium hydrogen carbonate solution (75 ml) and extracted with ethyl acetate ( 100 ml) The combined organic layer was separated, dried (MgSO 4), filtered and evaporated to give a yellow oil Purification by flash chromatography on silica gel, eluting with dichloromethane / methanol / NH 3 (sd = 0.880 = 98: 2: 0.2, after which the polarity was increased to 95: 5: 0.5, yielded the title compound (67 mg, 61%).

1 H NMR (400 MHz, CD 3 OD) δΗ 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 (2 H, t), 2.39 (2 H, t), 2.21 (1 H, t), 2.06 (1 H, t) , 1.54 (2H, m), 1.34 (4H, m), 0.92 (3H, t) MS (APCl +): 250 (MH +) [a] 25d = + 4.42 ° (c = 0 13, MeOH) 35 102 9 1 39.

Example 6 5 - [(2R) -4- (2-Phenylethyl) morpholin-2-yl] pyridine-2-amine 100 5 10

The morpholine from Example 2 (80 mg, 0.45 mmol) was mixed with tetrahydrofuran (15 ml), and phenylacetaldehyde (52 μΐ, 0.4 mmol) was added dropwise over 15 minutes as a solution in tetrahydrofuran ( 15 ml). After the addition was complete, the mixture was allowed to stir for 1 hour at room temperature before sodium triacetoxyborohydride (227 mg, 1 mmol) was added. The mixture was stirred at room temperature overnight (~ 16 hours) and then diluted with saturated sodium hydrogen carbonate solution (100 ml) and dried with ethyl acetate (100 ml). The combined organic layer was separated, dried (MgSO 4), filtered and evaporated to give a yellow oil. Purification by flash chromatography on silica gel, eluting with dichloromethane / methanol / NH 3 (s.d. = 0.880) 98: 2: 0.2 gave the title compound (31 mg, 24%). 1 H NMR (400 MHz, CD 3 OD) 5 H 7.87 (1 H, s), 7.47 (1 H, d), 7.20 (5 H, m), 6.55 (1 H, d), 4.42 ( 1 H, d), 3.97 (1 H, d), 3.78 (1 H, t), 2.93 (2 H, t), 2.82 (2 H, m), 2.66 (2 H, t) , 2.30 (2H, t), 2.21 (1H, t), 2.15 (1H, t) MS (APCI +): 284 (MH +) 35 1029139

Example 7a 5- [(2R, 5S) -5-Methylmorpholin-2-yl] pyridine-2-amine 101 5

The material from preparation 10 (410 mg, 1.25 mmol) was dissolved in ethanol (10 ml), 5% Pd-on-carbon (40 mg) was added and the mixture was hydrogenated at 1 atmosphere overnight. The mixture was then filtered through a layer of Arbocel®, the layer was washed with ethanol and the combined filtrates and washings were evaporated to a pale yellow solid. Purification by flash chromatography on silica gel, eluting with dichloromethane / methanol / NH 3 (sd = 20, 880) = 93: 7: 0.5, gave the title compound as a white solid (110 mg, 45%) ).

1 H NMR: δΗ (400 MHz, CD3 OD) 7.85 (1H, d), 7.45 (1H, dd), 6.55 (1H, d), 4.29 (1H, m), 3.90 (1 H, m), 3.30 (1 H, m), 2.95-2.85 (2 H, m), 2.75 (1 H, m), 1.01 (3 H, d) 25 MS (ES +) : 1.94 (MH +).

Alternatively, the morpholine ring can be formed by the following conditions, which gives a mixture of diastereoisomers.

30

Example 7b 5- [(5S) -5-Methylmorpholin-2-yl) pyridine-2-amine (diastereomeric mixture) 1029139 a 102 ρΧί

5 Η, Ν-V

The diol from preparation 11 (1.26 g, 5.96 mmol) was dissolved in dichloromethane (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 the careful addition of water, basified to pH ~ 9 with NH 3 solution (s.d. = 0.880) and extracted with dichloromethane (2 x 150 ml). The combined organic liquids were dried over magnesium sulfate, filtered and evaporated to provide the title compounds as a 3: 1 mixture of the (R, S) and (5, S) diastereomers, respectively. 1 H NMR: δΗ (400 MHz, CD3 OD) 7.85 (1H, m), 7.52-7.45 (1H, 2 x xdd), 6.60-6.52 (1H, 2xd), 4, 38-4.22 (1H, 2xdd), 3.95-3.80 (1H, 2xdd), 3.30 (1H, m), 3.10-2.83 (2H, m), 2.75 ( 1 H, m), 1.39-0.99 (3 H, 2xd)

Examples 8 and 9 A mixture of morpholine compounds from Example 7b (240 mg, 1.2 mmol) was dissolved in tetrahydrofuran (45 ml) and to the stirred solution was added 3-phenylpropionaldehyde (165 µl, 1.2 mmol) dropwise added as a solution in tetrahydrofuran (45 ml). Once the addition was complete, sodium acetoxy borohydride (270 mg, 1.2 mmol) was added and the reaction mixture was allowed to stir overnight at room temperature. The solvent was evaporated, 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 ca. 2: 1 mixture of trans: cis distereoisomers.

1 h y y 1 39 - 103

The diastereoisomers were separated by HPLC over a Chiralcel AD-H column with a mobile phase of methanol: ethanol = 50:50 and a flow rate of 15 ml / min.

5

Example 8 (diastereomer 1) 5- [(2R, SS) -5-Methyl-4- (3-phenylpropyl) morpholin-2-yl] -pyridine-2-amine

Retention time: 4.80 min.

^ -NMR: δΗ (400 MHz, CD3 OD) 7.83 (1H, s), 7.44 (1H, d), 7.29-7.08 (m, 5H), 6.52 (1H, d) , 4.40 (1 H, d), 3.79 (1 H, 20 d), 3.30 (1 H, m), 2.91-2.78 (2 H, m), 2.60-2.50 ( 2 H, m), 2.40 (1 H, m), 2.29 (1 H, m), 2.19 (1 H, m), 1.88-1, 68 (2 H, m), 0.95 (3 H , d) MS (APCl +): 312 (MH +) Example 9 (diastereomer 2) 5- [(25.55) -5-Methyl-4- (3-phenylpropyl) morpholin-2-yl) -pyridine-2- amine

HJN N

35

Retention time: 7.60 min.

* 029 f39 104 ^ NMR: δΗ (400 MHz, CD3 OD) 7.89 (1H, s), 7.49 (1H, 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 (2 H , m), 2.60-2.42 (4H, m), 1.90-1.75 (2H, m), 1.09 (3H, d) 5 MS (APCI4): 312 (MH +)

Examples 10 and 11

The diol from preparation 31 (350 mg, 1.3 mmol) was dissolved in dichloromethane (5 ml) and to the stirred solution was added concentrated H 2 SO 4 (2.5 ml). The reaction mixture was stirred at room temperature for 2 hours, then the reaction was terminated by the careful addition of water (10 ml) and the reaction mixture basified to pH = 8-9 by the addition of NH3 (sd = 0.880) ). The mixture was then extracted with dichloromethane (2 x 50 ml) and the combined extracts were dried (MgSO 4), filtered and evaporated, yielding a brown oil of a mixture of cis and trans-morpholine diastereomers (275 mg, 85%) 20 took care.

MS (ES4): 250 (MH +).

The mixed diastereoisomer sample was subjected to HPLC with a Chiralcel OD-H column, the mobile phase was 30:70 = IPA / hexane with 0.1% diethyl amine, and a flow rate of 20 ml / min.

Example 10 (diastereomer 1) 5- [(2S, 5S) -4-Butyl-5-iaethyl-morpholin-2-yl] pyridine-2-amine

fV

jcr * -

HJN N

35

Retention time: 4.90 min.

1029129 105 X H NMR: δΗ (400 MHz, CD3 OD) 7.86 (1 H, d), 7.49 (1 H, dd), 6.56 (1 H, d), 4.44 (1 H, m), 3 , 86 (1H, ra), 3.39 (1H, m), 2.99 (1H, m), 2.88 (1H, m), 2.52 (1H, brm), 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] pyridine-2-amine

Retention time: 7.20 min.

1 H NMR: δΗ (400 MHz, CD3 OD) 7.88 (1 H, d), 7.48 (1 H, dd), 6.55 (1 H, d), 4.41 (1 H, 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 +).

25

Example 12 5- {(2R, 5S) -5 - [(Benzyloxy) methyl] morpholin-2-yl} pyridine-2-amine

rJX ^ O

35 1 υ 2 9 1 39.

106

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 overnight (~ 16 hours) heated to 80 ° C. After cooling to room temperature, the mixture was diluted with 10% aqueous K 2 CO 3 solution (100 ml) and extracted with dichloromethane (2 x 100 ml). The combined organic fractions were dried over magnesium sulfate, filtered and taken in; evaporates, yielding a brown oil of the crude protected 2-aminopyridine intermediate (3.6 g).

This Boc-group-protected morpholine (3.6 g, 9 mmol) was treated with 4M HCl in dioxane (30 mL) and the mixture stirred at room temperature for 4 hours. The solvent was then evaporated and the residue treated with 2M 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 a light brown solid which was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol / NH 3 (s.d.

0.880) (93: 7: 0.5), which gave the title compound as a light brown solid (1.43 g, 51%).

1 H NMR: 6H (400 MHz, CD3 OD) 7.85 (1H, d), 7.45 (1H, dd), 7.36-7.25 (5H, m), 6.54 (1H, d) , 4.52 (2 H, s), 4.28 (1 H, 25 m), 3.97 (1 H, m), 3.49-3.38 (3 H, m), 3.06 (1 H, m) , 2.96 (1H, m), 2.76 (1H, m) MS (ES +): 300 (MH +)

Example 13 5- {(2R, SS) -5- [(Benzyloxy) methyl] -4-propyl-morpholin-2-yl} -pyridine-2-amine nucleo.

35 ¥ V ^ JO 29 f 39 107

The morpholine from Example 11 (1.4 g, 4.8 mmol) was dissolved in THF (200 mL) and propanal (350 μΐ, 4.8 mmol) in THF (150 mL) was added dropwise to the stirred mixture. After the addition was complete, 5 NaBH (OAc) 3 (1.02 g, 4.8 mmol) were added in one portion and the reaction mixture was stirred at room temperature overnight (~ 16 hours). TLC analysis showed that starting material was still remaining, so that additional NaBH (OAc) 3 (1 g was added and the reaction mixture was stirred for an additional 24 hours. Saturated NH 4 Cl in water (200 ml) was added, the organic layer, dried over magnesium sulfate, filtered, and evaporated The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / NH 3 (sd = 0.880) (95: 5: 0.5) to the title compound as a light brown oil (540 mg, 33%).

1 H NMR: δΗ (400 MHz, CD3 OD) 7.86 (1 H, d), 7.46 (1 H, dd), 7.36-7.26 (5 H, m), 6.53 (1 H, d) , 4.52 (2H, m), 4.38 (1H, 20 m), 4.00 (1 H, m), 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 (2 H, m), 1 , 60-1.37 (2 H, m), 0.84 (3 H, t).

MS (ES +): 342 (MH +).

Examples 14-17 [6- (6-Aminopyridin-3-yl) -4-propyl-morpholin-3-yl] methanol

OH, OH

The diol from 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.

11> 2 9 t 39.

_l .. - 108

The mixture was stirred at room temperature for 2 hours before the reaction was terminated by the addition of ice, and then basified to pH -9 with NH 3 (s.d. = 0.880). 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 / NH 3 (sd = 0.880) (95: 5: 0.5), after which the polarity was increased to 93: 7: 0.5) which gave 110 mg of a light brown oil, the title compound, as a mixture of four diastereoisomers. The diastereoisomers were separated by HPLC over a Chiralpak AD column, and a mobile phase of 20:80 = 15 IPA / hexane with 0.1% DEA, yielding four stereoisomers.

Example 14

Stereo isomer-1 (retention time: 9.50 min.) Trans enantiomer 1 1 H-NMR: 5 h (400 MHz, CD 3 OD) 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 (1H, m), 2.47 (1H, m), 2.34 (1H, m), 2.26 (2H, m), 2.27-1.42 (2H, m), 0.90 (3H, 25t).

Example 15

Stereo isomer-2 (retention time: 11.90 min.) Cis enantiomer 1 30 1 H-NMR: (400 MHz, CD 3 OD) δ (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, 1 H), 6.6 (d, 1 H), 7.5 (d, 1 H), 7.85 (s, 1 H).

Example 16 35 Stereo isomer-3 (retention time: 16.60 min.) Cis enantiomer 2 1 UZ9139 109 1 H-NMR: (400 MHz, CD3 OD) δ (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 17

Stereo isomer-4 (retention time: 19.70 min.) Trans enantiomer 2 1 H-NMR: δΗ (400 MHz, CD3 OD) 7.86 (1H, d), 7.49 (1H, 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 (1H, m), 2.47 (1H, m), 2.34 (1H, m), 2.26 (2H, m), 2.27-1.42 (2H, m) , 0.90 (3 H, t).

Examples 18-19 4-Methyl-5- (4-propyl-morpholin-2-yl) pyridine-2-ainine

iVO

H2 N

The diol from preparation 21 (950 mg, 3.7 mmol) was dissolved in dichloromethane (15 ml) and treated with concentrated sulfuric acid (7 ml) at room temperature. The mixture was stirred for an additional 2 hours. The reaction was then terminated by the addition of ice and the mixture then made basic to pH ~ 9 by the dropwise addition of NH 3 (s.d. = 0.880). The mixture was then extracted with dichloromethane (4 x 50 mL) and the combined organic liquids were dried with magnesium sulfate, filtered and evaporated to give the title compound as a pale brown oil (700 mg, 79%).

1 H NMR: δΗ (400 MHz, CD3 OD) 7.85 (1 H, d), 6.38 (1 H, d), 4.60 (1 H, m), 3.99 (1 H, m), 3, 78 (1H, m), 2.92-2.82 (2H, 1029139 1 -------- ---- 110 m), 2.38 (2Η, m), 2.28-2, 18 (4Η, m), 2.12 (1Η, m), 1.62-1.50 (2H, m), 0.93 (3H, t).

MS (APCI +): 236 (MH +).

The racemic morpholine was subjected to HPLC 5 using a Chiralcel OD-H column eluted with acetonitrile. This yielded two enantiomers.

Example 18 (enantioxiner 1) Retention time: 5.1 min.

X H NMR: δΗ (400 MHz, CD 3 OD) 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, 62-150 (2H, m), 0.93 (3H, t).

MS (APCI +): 236 (MH +).

Example 19 (eiiantiomer 2)

Retention time: 6.5 minutes

20 H NMR: δΗ (400 MHz, CD3 OD) 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 (2 H, m), 2.38 (2 H, m), 2.28-2.18 (4 H, m), 2.12 (1 H, m), 1 , 62-1.50 (2 H, m), 0.93 (3 H, t).

MS (APCI +): 236 (MH +).

25

Example 20 3-Methyl-5- [(5S) -5-methyl-4-propyl-morpholin-2-yl] pyridine-2-amine 35 102 9139 111

The diol from preparation 29 (200 mg, 0.74 mmol) was dissolved in dichloromethane (4 ml) and treated with concentrated sulfuric acid (2 ml) at room temperature. The mixture was stirred for 2 hours overnight. The reaction was then terminated by the careful addition of water and the mixture was then made basic to pH ~ 9 by the dropwise addition of NH 3 (s.d. = 0.880). The mixture was then extracted with dichloromethane (3 x 70 ml) and the combined organic liquids were dried with magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel to provide the title compound as a clear oil, a mixture of diastereoisomers (35 mg, 19%).

1 H NMR: δΗ (400 MHz, CD3 OD) 7.77 (1 H, d), 7.38 (1 H, d), 4.41 (1 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), 2.11 (3H (2xs), 1.61-1.39 (2H, m), 1.18-1.00 (3H, 2xd), 0.91 (3H, m).

MS (ESI +): 250 (MH +).

20

Examples 21 and 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 hours before the reaction was terminated by the addition of ice and the mixture was made basic to pH ~ 9 by the addition of NH 3 (s.d. = 0.880). The mixture was then extracted with dichloromethane (3 x 150 ml), the combined organic liquids were dried over magnesium sulfate, filtered and the solvents were evaporated. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol / NH 3 (sd = 0.880) (95: 5: 0.5) to give the title compound as a mixture of diastereoisomers (470 mg, 51%).

MS (ES +): 236 (MH +).

1029139 112

The diastereoisomers were separated by chiral HPLC over a Chiralcel OD-H column eluted with 30% IPA in hexanes with 0.1% diethylamine. This yielded: 5

Example 21 (diastereomer 1) 5- [(25.55) -4,5-diethylmorpholin-2-yl] pyridine-2-amine

HJN N

15

Retention time: 4.1 minutes

1 H NMR: δΗ (400 MHz, CD3 OD) 7.88 (1 H, d), 7.48 (1 H, dd), 6.57 (1 H, d), 4.43 (1 H, 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, 20t).

MS (ESI +): 236 (MH +).

Example 22 (diastereomer 2) 5- [(2R, 55) -4,5-Diethylmorpholin-2-yl] pyridine-2-amine

Retention time: 7.3 minutes

1 H NMR: δΗ (400 MHz, CD3 OD) 7.87 (1 H, d), 7.47 (1 H, dd), 6.56 (1 H, d), 4.40 (1 H, 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, 1 ° 29139 m), 1.78 (1 H, m), 1.32 (1 H, m), 1.06 (3 H, t), 0.93 (3 H, t).

MS (ESI +): 236 (MH +).

Example 23 5- (1-Propylazetidin-3-yl) pyridine-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, 10 eq.) Were added and the mixture was heated under a calm reflux for 3 hours. More 10% Pd / C (10 20 mg) and ammonium formate (168 mg, 2.67 mmol, 10 eq.) Were added and the mixture was heated under reflux for an additional 4 8 hours. The catalyst was filtered off 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), 2M HCl (aq) was added and stirred for 3 hours at r.t. The mixture was evaporated in vacuo, basified with K 2 CO 3 (10 wt% / vol. aq) and extracted with CH 2 Cl 2 (3 x 20 mL), dried (MgSO 4), filtered and evaporated to give a colorless oil. This oil was purified by flash chromatography on silica gel, eluting with a gradient of 100% CH 2 Cl 2 to 90: 10: 1 = CH 2 Cl 2: MeOH: ΝΗ <0Η, giving the product as a colorless oil that solidified after standing ( 21 mg, 41%).

35 Tic, Rf = 0.24 (90:10: 1 = CH 2 Cl 2: MeOH: NH 4 OH; visualizing with UV).

MS (APCI +): 192 (MH +) 02 9 139.

114 ...........

1 H NMR: δΗ (400 MHz, CD3 OD) 7.95 (1 H, s), 7.45 (1 H, d), 6.5 (1 H, d), 4.2-4.6 (2 H, br s ), 3.5-3.8 (3 H, m), 3.05 (2 H, t), 2.45 (2 H, t), 1.3-1.5 (2 H, m), 0.9 ( 3H, t) Examples 24 and 25

5- (2R, 5S) -4-Ethyl-5-inethylxnorpholin-2-yl) pyridin-2-yl-amine & 5- (2S, 5S) -4-ethyl-5-methyl-morpholin-2-yl) pyridine 2-ylamine I

10 i! ΙΧΛ jCj ^ \ 15

The morpholine from preparation 38 (1 g, 4.17 in mol) was dissolved in CH 2 Cl 2 (15 ml) and concentrated sulfuric acid (7.5 ml) was added. The mixture was stirred at r.t. for 2 hours, basified by careful addition of NH 3 (sd = 0.880), extracted with CH 2 Cl 2 (2x200 ml), the organic liquids were combined, dried over magnesium sulfate, filtered and purified by flash. chromatography on silica gel, eluting with CH 2 Cl 2: MeOH / NH 4 OH = 97: 3: 1 to give the title compound as a light brown oil (560 mg, 61%).

The diastereoisomers were separated on a Chi-cell cell OD-H column (500 * 50 mm) with a mobile phase of 30% IPA, 80% hexane, 0.1% DEA, at a flow rate of 80 ml / min which gave:

Diastereoisomer 1 - retention time 5.47 min. (Example 24, (2S, 5S) diastereoisomer) 1 H-NMR: δΗ (400 MHz, CD3OD) 7.88 (1H, s), 7.46-7 52 (1H, 35 m), 6.58 (1 H, d), 4.40-4.46 (1 H, m), 3.84-3, 92 (1H, m), 3.75-3, 79 (1H, m), 2.91-2.98 (1H, m), 2.47-2, 60 (4H, m), 1.08-1.18 (m, 6H).

1 »2 9139.

115 MS (APCI +): 222 (MH +).

Diastereoisomer 2 retention time 7.96 min. (Example 25, (2R, 5S) diastereoisomer) 1 H-NMR: δΗ (400 MHz, CD3OD) 7.88 (1H, s), 7.44-7 , 50 (1H, 5 m), 6.56 (1 H, d), 4.40-4.46 (m, 1 H), 3.80-3.88 (1 H, m), 3.28-3, 41 (1H, 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 (APCl +): 222 (MH +) Examples 26 & 27 (+) - 5- (4-Propyl-morpholin-2-yl) -1,3-thiazole-2-amine & (- ) -5- (4-propyl-morpholin-2-yl) -1,3-thiazole-2-amine

w - T X

20

To 2- (2-bromo-1,3-thiazol-5-yl) -4-propylmorpholine (2.5 g, 8.56 mmol) in ethylene glycol (60 ml) were added CU2O (61 mg, 0.43 mmol, 0.05 eq.) And NH 3 (d (20 ml) added in a bomb. The vessel was closed and heated to 80 ° C for 18 hours. The vessel was allowed to cool, vented and the contents were partitioned between EtOAc (2 x 200 ml) and water (100 ml), the organic layers were combined, dried over MgSC 4. The solvent was evaporated to give a brown oil, this material was chromatographed on an Isco Companion Combiflash autocar chromatography system, eluting with a gradient from 99/1 / 0.1 = CH 2 Cl 2 / MeOH / NH 3 to 95/5 / 0.5 = 02012 / Μβ0Η / ΝΗ3, giving the product as a brown oil (1.1 g) gave.

This material was separated by HPLC

over a Chiralcel OJ column (250 * 21.5) with a mobile F029t3S_ 116 se of 70:30 = hexane: IPA, at a flow rate of 18 ml / min, which gave two enantiomers.

Enantiomer 1: retention time 5,140 minutes.

1 H NMR (400 MHz, CD3 OD) δ (ppm): 6.99 (s, 1H), 4.63 (d, 5H), 3.87-3.93 (m, 1H), 3.70- 3.77 (m, 1H), 2.95 (d, 1H), 2.78 (d, 1H), 2.31-2.39 (m, 2H), 2.10-2.23 (m, 2H) , 1.48-1.60 (m, 2H), 0.92 (t, 3H).

M / S (APCl +): 228 (MH +).

Optical rotation [a] D 25 = + 48.45 ° (c = 1.45 mg / ml MeOH) Elemental analysis + 0.55 H 2 O; total MW = 237.24

Calculated: C (50.63), H (7.69), N (17.71)

In fact: 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, CD3 OD) δ (ppm): 6.99 (s, 1H), 4.63 (d, 1H), 3.87-3, 93 (m, 1H), 3.70-3 , 77 (m, 1H), 2.95 (d, 1H), 2.78 (d, 1H), 2.31-2.39 (m, 2H), 2.10-2.23 (m, 2H), 1.48-160 (m, 2H), 0.92 (t, 3H) 20 M / S (APCI4): 228 (MH +)

Optical rotation [a] D25 = + 43.56 ° (c = 2.6 mg / ml MeOH) Elemental analysis + 1 H2O total MW = 245.35 Calculated: C (48.96), H (7.81), N (17.13)

Actually: C (49.05, 49.07), H (7.83, 7.85), N (17.00, 16.99)

The following preparations illustrate the synthesis of certain intermediates used in the preparation of the preceding examples: Preparation 1 5-Bromo-2- (2,5-dimethylpyrrole-1-yl) pyridine bt; 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 mixture was heated under reflux for 24 hours with Dean-Stark conditions. para-5 Toluenesulfonic acid (100 mg) was added and the reaction mixture was refluxed for an additional 18 hours. 8 ml of water was removed, after which the reaction mixture was allowed to cool to room temperature. The mixture was washed with water (100 ml) and the mixture was allowed to pass a layer of silica gel, eluting with toluene. The eluent was evaporated in vacuo and the residue dissolved in pentane: dichloromethane (1: 1 by volume) and a layer of silica gel was passed, eluting with pentane: dichloromethane (1: 1 by volume). . The eluent was evaporated in vacuo to give a red liquid which solidified upon standing. The solid was recrystallized (isopropanol) to give the title compound as a pale yellow solid (54.4 g).

1 H NMR (400 MHz, CDCl 3): δΗ 8.66 (1 H, s), 7.93-7.92 (1 H, 20 d), 7.13-7.11 (1 H, d), 5.91 (2 H, s), 2.13 (6 H, s).

LRMS (thermospray): m / z [M + H] + = 252.

Preparation 2 2-Chloro-1- [6- (2,5-dimethylpyrrol-1-yl) pyridine-3-2 yl] ethanone

A solution of 2.5 M n-butyl lithium in hexanes (35 ml, 87.6 mmol) was added under nitrogen at -78 ° C in 10 minutes to a solution of bromide from preparation 1 (20.0 g, 79.7 mmol) in tert-butyl methyl ether (300 ml).

1029139 118

The reaction mixture was stirred for an additional 10 minutes and 2-chloro-7,7-methoxy-.beta.-methylacetamide (12.1 g, 87.6 mmol) in tert-butyl methyl ether (40 ml) was added slowly. The reaction mixture was stirred for 20 minutes at -5 78 ° C and then 1M hydrochloric acid (200 ml) was added.

The mixture was allowed to warm to room temperature, stirred for 2 hours and the organic phase separated. The aqueous phase was extracted with tert-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 purified by flash column chromatography on silica gel, eluting with pentane: dichloromethane / methanol (75: 25: 0, changing to 0: 99: 1). by volume). The residue 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): δ H 9.11 (1 H, s), 8.34-8.33 (1 H, d), 7.32-7.30 (1 H, d), 5.91 (2H, s), 4.66 (2H, s), 2.17 (6H, s).

LRMS (electrospray): m / z [M + H] + s = 247.

Preparation 3 2- (2,5-Dimethylpyrrol-1-yl) -5 - [(2R) oxiranyl] pyridine 30 ixy A solution of the chloride from preparation 2 (12.0 g, 48.1 mmol) in tetrahydrofuran (20 ml) was slowly added at -30 ° C under nitrogen to a solution of 119 (-) - S-chlorodiisopinocamphorylborane (20.1 g, 62.5 mmol) in tert-butyl methyl ether (15 ml) and tetrahydrofuran (30 ml). The reaction mixture was stirred at -30 ° C for 6 hours, and then sodium perborate tetrahydrate (7.4 g, 5 48.1 mmol), and then tert-butyl methyl ether (50 ml) were added. The reaction mixture was stirred at room temperature for 18 hours, treated with 2M aqueous sodium hydroxide (190 ml) and stirred for an additional 6 hours. The organic phase was separated and the aqueous phase extracted with more tert-butyl methyl ether (50 ml). The combined organic extracts were washed with 1M 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 pentane: dichloromethane (80: 2, changing to 100: 0 by volume) to give the crude epoxide (65% b / w, 11.0 g ) was used without further purification.

20 H H NMR (400 MHz, CDCl 3): δΗ 8.58 (1H, brs), 7. 68-7, 66 (1H, dd), 7.22-7.20 (1H, d), 3.97 -3.96 (1 H, m), 3.26-3.24 (1 H, m), 2.91-2.89 (1 H, m), 2.12 (6 H, s).

LRMS (electrospray): m / z [M + H) + = 215, [M + Na] 4 = 237.

Preparation 4 (1.R) -2- (Benzylamino) -1- [6- (2,5-dimethyl-1ff-pyrrol-1-yl) pyridine-3-1] ethanol

30 ^ XkJO

n "35

The epoxide from preparation 3 (2.66 g, 12 mmol) was dissolved in DMSO (30 ml), treated with benzylamine (1.62 1029139 120 ml, 15 mmol) and the mixture heated overnight (~ 16 hours) to 90 ° C. After cooling to room temperature, the reaction mixture was evaporated at 60 ° C under high vacuum, the majority of the DMSO being removed. The residue was diluted with ethyl acetate (150 ml) and washed with water (100 ml). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (100 ml). The combined organic fractions were dried (MgSO 4), 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 (5 H, m), 7.2 (1 H, d), 5 , 9 (2H, s), 4.8 (1H, m), 3.89 (2H, s), 3.01 (1H, dd), 2.78 (1H, t), 2.1 (6H, s).

MS (APCI +): 322 (MH +).

15

Preparation 5 N-Benzyl-2-chloro-N - {(2 R) -2- [6- (2,5-dimethyl-11-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl} acetamide 20 OH 1 ^ 25

The amino alcohol from Preparation 4 (3.22 g, 10 mmol) was dissolved in dichloromethane (100 mL), sodium hydroxide (2 g, 50 mmol) in water (35 mL) was added and the mixture stirred vigorously. Chloroacetyl chloride (0.96 ml, 12 mmol) was added dropwise and stirring was then continued overnight (-16 hours). 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 1 H NMR spectrum 1029f 39 121 indicated that a mixture of chloramide and morpholinone (product of preparation 5) was formed, so that the mixture was used without further purification.

MS (APCI +): 398 (MH +, chloramide), 362 (MH +, ring-locked morpholinone).

Preparation 6 (6R) -4-Benzyl-6- [6- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] morpholin-3-one 10, pjXo 15

The crude mixture from preparation 5 was dissolved in propan-2-ol (100 ml), water (5 ml) was added, followed by potassium hydroxide (573 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, yielding a dark orange oil. Purification by flash chromatography on silica gel, eluting with dichloromethane / methanol = 99: 1, 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 (1H , dd), 2.09 (6H, s) MS (APCI +): 362 (MH +) 35 12139 122

Preparation 7 (2R) -4-Benzyl-2- [6- (2, 5-dimethyl-1-pyrrole-1-yl-pyridin-S-yl] morpholine 5

-CuO

10

The morpholinone from Preparation 6 (2.47 g, 6.8 mmol) was dissolved in tetrahydrofuran (100 mL) and cooled (flask 15 in ice / water bath). Lithium aluminum hydride (1M in tetrahydrofuran, 10.2 ml, 10.2 mmol) was added dropwise and after the addition, the reaction mixture was allowed to stir overnight (~ 16 hours) at room temperature. The reaction was stopped by the 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 separated, dried over MgSO 4 and evaporated to give the title compound as a yellow oil (2.09 g, 89%).

25 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 (1H, d), 2.35 (1H, t), 2.19 (1H, t), 2.1 (6H, s).

MS (APCI +): 348 (MH +).

30

Preparation 8 (2S) -2 - ({(2R) -2- [6- (2,5-Dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl} amino) propane-1 -ol 35 123

OH

9HV

! v jor ° "

The epoxide from preparation 3 (5.4 g, 20 in mol) was dissolved in DMSO (50 ml) together with (S) -2-aminopropan-1-ol (2.0 g, 20 mmol) and the mixture was heated to 90 ° C overnight (approx. 16 hours). After cooling to room temperature, the mixture was evaporated under high vacuum and the residue purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (95: 5, after which the polarity was increased to 90:10) to give the title compound as a pale yellow oil (5.0 g, 75%).

Preparation 9

Benzyl- (2R, 5S) -2- [6- (2,5-dimethyl-ΙΗ-pyrrol-1-yl) pyridin-3-yl] -5-methylmorpholine-4-carboxylate 25 fr n br ° 30

The diol from 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 hours) before the reaction was terminated by the addition of 2M sodium hydroxide (100 ml). The mixture was extracted with dichloromethane (2 x 100 ml) and the 91 I9.

124 combined organic fractions were dried (MgSO 4), filtered and evaporated. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 25 to 60% ethyl acetate in pentane to give the CB2 group-protected intermediate as a light brown oil (2.56) g, 35%).

MS (ES +): 446 (MNa +) MS (ES +): 422 (M-H +)

A sample of the above with a CB2 group protected diol (2 g, 4.7 mmol) was dissolved in toluene (30 mL) together with triphenylphosphine (1.5 g, 5.6 mmol). Diisopropylazodicarboxylate (1.12 ml, 5.6 mmol) was added dropwise and the reaction mixture was stirred overnight (~ 16 hours). 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 4), filtered and evaporated. The residue was purified by flash chromatography on silica gel, eluting with 20% ethyl acetate in pentane to give the title compound as a clear oil (1.68 g). 1 H NMR shows that the sample contains ~ 3 equivalents of diisopropylhydrazine-1,2-dicarboxylate and the title compound. ~ 40% by weight of the material is thus the title compound, which corresponds to a yield of approximately 36%.

1 H NMR: δΗ (400 MHz, CDCl 3) 8.62 (1H, d), 7.80 (1H, dd), 7.37-7.27 (5H, m), 7.11 (1H, d) , 5.88 (2 H, s), 5.18 (1 H, d), 5.10 (1 H, d), 4.26 (1 H, m), 4.08 (1 H, m), 3.72 ( 2 H, m), 3.46-3.40 (2 H, m), 2.09 (6 H, s), 1.37 (2 H, d) 30 MS (ES +): 406 (MH +)

Preparation 10 2- (6-Aminopyridin-3-yl) -5-methylmorpholine-4-carboxylic acid benzyl ester 35 1029139 9 125 <rr π 5 XX χ Η2Ν Ν

The morpholine from preparation 9 (680 mg, 1 mmol) was dissolved in ethanol (12 ml), treated with hydroxylamine-10 hydrochloride (600 mg, 8.4 mmol) and the mixture heated to 80 ° C overnight ~ 16 hours . After cooling to room temperature, the solvent was evaporated and the residue was purified by flash chromatography on silica gel, eluting with 0% methanol in dichloromethane, and the polarity increased to 2% to give the title compound as a purple-colored oil (410 mg, 95%).

1 H NMR: (400 MHz, CD 3 OD) δ 7 7.91 (1 H, d), 7.43 (1 H, dd), 7.37-7.28 (5 H, m), 6.52 (1 H, d) , 5.13 (2H, 2xd), 4.79 (1H, 20 m), 4.12 (1 H, m), 4.04 (2 H, m), 3.37 (2 H, m), 1.30 (3 H, d) MS (ES +): 328 (MH +)

Preparation 11 (2S) -2- {[(21?) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -25 amino) propan-1-ol

Jr »xy ~" h2n n

The diol from preparation 8 (1 g, 3.35 mmol) was dissolved in ethanol, treated with hydroxylamine hydrochloride (1.2 g, 16.75 mmol) and the mixture heated to 80 over night (~ 16 hours) ° C. After cooling to room temperature 1029139 126, the solvent was evaporated and the residue purified by flash chromatography on silica gel, eluting with dichloromethane / methanol / NH 3 (sd = 0.880) (85: 15: 1, after which the polarity was increased to 82: 17: 1), which gave the title compound as a light brown oil (670 mg, 95%).

1 H NMR: (400 MHz, CD3 OD) δΗ 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 (3 H, m), 1.15 (3 H, d) 10 MS (ES +): 212 (MH +), 234 (MNa +) )

Preparation 12 (2R) -3- (Benzyloxy) -2- ({(2R) -2- [6- (2,5-diraethyl-1H-pyrrole-1-yDpyridin-3-yl) -2-hydroxyethyl} amino propan-1-ol 15

OH

ohS ^ o ^ O i NH ^! 20

The epoxide from preparation 3 (5.4 g, 25 mol) 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 to 90 ° C overnight (approx. 16 hours). After cooling to room temperature, the mixture was evaporated under high vacuum to give a brown oil. ~ 12 g of the desired title compound contained some remaining DMSO, but was sufficiently pure to be used in the next step without further purification.

1 H NMR: (400 MHz, CD3 OD) δΗ 8.54 (1H, d), 7.99 (1H, 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 MH + 1029139 127

Preparation 13 tert-Butyl - [(IR) -2- (benzyloxy) -1- (hydroxymethyl) ethyl] - {(2R) -2- [6- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl} carbamate 5

rj5CfO

The crude diol from preparation 12 (10 g, ~ 25 alcohol) was dissolved in dichloromethane (150 ml), treated with di-tert-butyl dicarbonate (5.52 g, 25 mmol) and the mixture overnight (~ 16 hours ) stirred at room temperature. The reaction mixture was diluted with 10% aqueous K 2 CO 3 solution (200 ml), the organic layer separated and the aqueous layer 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, after which the polarity of the eluent was increased to 50% ethyl acetate in pentane. This gave the title compound as a pale yellow oil (6.2 g, 50% yield over two steps of preparations 12 and 13).

^ -NMR: δΗ (400 MHz, CD3 OD) 8.55 (1H, d), 8.04-7.95 (1H, 30 m), 7.38-7.23 (6H, m), 5.81 (2H, s), 5.05 (1H, brm), 4.54 (2H, m), 3.93 (1H, brm), 3.83 (1H, brm), 3.78-3, 60 ( 5 H, m), 3.44-3, 32 (1 H, m), 2.05 (6 H, s), 1.44 and 1.40 (9 H, two singlets).

MS (APCI +): 496 (MH +) 35 1029139 128

Preparation 14 tert-Butyl- [(ZR, 5S) -5- [(benzyloxy) methyl] -2- [6- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] morpholine- 4-carboxylate 5

The diol from 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. Diisopropylazodi-carboxylate (DIAD) (3 ml, 15 mmol) was added dropwise and the mixture stirred overnight (-16 hours). The reaction mixture was then diluted with water (200 ml), the organic layer separated and the water layer 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, after which the polarity was increased to 15% ethyl acetate in pentane. This gave the title compound as a clear oil (4.4 g, 74%).

1 H NMR: 5 H (400 MHz, CDCl 3) 8.64 (1 H, d), 7.88 (1 H, dd), 7.36-7.27 (5 H, m), 7.22 (1 H, d) ), 5.89 (2 H, s), 4.96 (1 H, m), 4.62 (1 H, d), 4.54 (1 H, d), 4.28 (1 H, m), 4.12 (1 H, m), 3.82-3.68 (4 H, m), 3.60 (1 H, dd), 2.12 (6 H, s), 1.44 (9 H, s).

MS (APCI +): 478 MH + 35 1029139 129

Preparation 15 (2R) -3- (Benzyloxy) -2 - [{(ZR) -2- [6- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl (propyl) amino] propan-1-ol 5

The crude diol from preparation 12 (3 g, 7.6 mmol) was dissolved in dichloromethane, and propanal (1.1 mL, 15.2 nunol) and NaBH (OAc) 3 (3.25 g, 15.2 mmol) ) were added. The reaction mixture was stirred at room temperature overnight (~ 16 hours) and then the solvents were evaporated. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol / NH 3 (sd = 0.880) (97: 3: 0.5) to give the title compound as a light brown oil which still ~ 3 equivalents of contamination of DMSO from the previous step (4.5 g, corrected for DMSO ~ 2.95 g of product, 89% yield).

X H NMR: δΗ (400 MHz, CDCl 3) 8.52 (1H, d), 8.81 (1H, dd), 7.38-7.22 (5H, m), 7.17 (1H, d) , 5.86 (2 H, s), 4.72 (1 H, m), 4.54 (2 H, s), 3. 48-3, 68 (4 H, m), 3.16 (1 H, m), 2.88-2.95 (1H, m), 2.82-2.55 (3H, m), 2.07 (6H, s), 1.50 (2H, 30 m), 0.87 (3H , t).

MS (APCI +): 438 (MH +), 460: (MNa +)

Preparation 16 (2R) -2- [[(ZR) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -35 (propyl) amino] -3- (benzyloxy) propan-1-ol 139- 130

OH

ohVo ^ P)

The diol from 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 overnight (-16 hours) heated to 80 ° C. 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 3 (sd = 0.880) (95: 5: 0.5, after which the polarity was increased to 91: 9: 0.5). The yielded the title compound as a light brown oil (1.4 g, 58%).

1 H NMR: δΗ (400 MHz, CD3 OD) 7.82 (1H, d), 7.46 (1H, dd), 7.38-7.22 (5H, m), 6.57 (1H, d) ), 4.57-4, 44 (3 H, m), 3.63 - 3.46 (4 H, m), 3.07 (1 H, m), 2.77 (2 H, 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 30 \ xVBr 35 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), and para-102 9 1 131 toluene sulfonic acid monohydrate (50 mg) was added and the mixture was heated under reflux with a Dean-Stark device installed. When the water collection stopped, the reaction mixture was cooled and diluted with water (50 ml) and 10% K 2 CC> 3 aqueous solution (50 ml). The organic layer was separated and the aqueous layer 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 pale yellow oil (8 g, 95%).

1 H NMR: δΗ (400 MHz, CDCl 3) 8.62 (1 H, s), 7.11 (1 H, s), 5.90 (2 H, s), 2.45 (3 H, s), 2.15 (6H, s).

MS (ESI +): 267 (MH +).

Preparation 18 4-Propylmorpholine-2-one 20

Methyl 2-bromoacetate (50 ml, 0.54 mol, 1 eq) was slowly added at 0 ° C to W-propylaminoethanol (62.4 ml, 0.54 mol, 1 eq.) And Et3 N (75 ml, 0 54 moles, 1 eq.) In toluene and allowed to stir overnight at room temperature. Water (1 L) was added and the mixture extracted with EtOAc (2 x 500 ml). Concentrated saline (500 ml) was added to the water layer, which was again extracted with EtOAc (2 x 500 ml). The organic layers were combined, dried (MgSO 4), filtered and the solvent removed in vacuo to give 62.7 g (81%) of the title compound as a clear oil.

1029139 132 TLC, EtOAc, Rf = 0.5 M / S (APCI +): 14 4 (MH +) 1 H-NMR: (400 MHz, CD3 OD) δΗ 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, 5 2H) ).

Preparation 19 2- [6- (2,5-Dimethyl-1H-pyrrol-1-yl) -4-methylpyridin-3-yl] -4-propylmorpholine-2-ol 10 <> xp

15 ° rH ° H

The bromopyridine from preparation 17 (5 g, 18.8 mmol) was dissolved in THF (80 ml) and cooled to -78 ° C. To the stirred solution was added dropwise tert-butyl lithium (22 ml, 37.7 mmol). Immediately after the addition was completed, morpholinone (from preparation 18) (2.7 g, 18.8 mmol) was added as a solution in THF. (20 ml). The reaction mixture was allowed to stir for 1 hour at -78 ° C. The reaction was then terminated by the addition of saturated aqueous NH 4 Cl solution (100 ml) and 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, after which the polarity of the eluent was increased to 40% ethyl acetate in pentane. This gave the title compound as a pale yellow oil (1.95 g, 32%).

029139 133 1 H NMR: δΗ (400 MHz, CDCl 3) 8.78 (1 H, s), 7.00 (1 H, s), 5.86 (2 H, s), 5.21 (1 H, brs), 4 23 (1H, m), 3.85 (1H, m), 3.03 (1H, m), 2.82 (1H, m), 2.62 (3H, s), 2.56-2, 37 (4 H, m), 2.08 (6 H, s), 1.58 (2 H, m), 0.97 (3 H, t).

MS (ESI +): 330 (MH +).

Preparation 20 1- [6- (2,5-Dimethyl-1H-pyrrol-1-yl) -4-methylpyridin-3-yl] -2 - [(2-hydroxyethyl) (propyl) amino] ethanol 10 yr. Py oh oh 15

The morpholinol from preparation 19 (1.95 g, 5.9 inmol) was dissolved in ethanol (25 ml) and water (10 ml). Sodium boron hydride (900 mg, 23.6 mmol) was added to the stirred mixture at room temperature. Stirring was continued overnight (~ 16 hours) before the reaction was terminated by the addition of saturated aqueous ammonium chloride (100 ml). 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 / NH 3 (sd = 0.880) (96: 4: 0.5), yielding the title compound as a yellow oil (1.4 g, 71 %).

1 H NMR: δ (400 MHz, CD3 OD) 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 +).

102913 * 134

Preparation 21 1- (6-Amino-4-methylpyridin-3-yl) -2- [(2-hydroxyethyl) - (propyl) amino] ethanol 5

^ JpV ^ OH ^ OH

io 2

The diol from preparation 20 (1.4 g, 4.22 mmol) was dissolved in ethanol (30 mL), treated with hydroxyl-15 amine hydrochloride (1.12 g, 16.9 mmol), and the mixture overnight ( ~ 16 hours) heated under reflux. After cooling to room temperature, the mixture was diluted with 10% aqueous K 2 CO 3 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 / NH 3 (sd = 0.880) (93: 7: 1) to give the title compound as a pale brown oil (950 mg, 89%) ) on-25.

X H NMR: δΗ (400 MHz, CD3 OD) 7.90 (1 H, s), 6.39 (1 H, s), 4.81 (1 H, m), 3.66-3.57 (2 H, m) , 2.80-2.72 (1 H, m), 2.67 - 2.48 (5 H, m), 2.24 (3 H, s), 1.58-1.46 (2 H, m), 0 , 91 (3 H, 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) butane-1 -ol 35 1U * 9139.

135

OH

ohV ^ hty

The epoxide from 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 to 90 ° C overnight (approx. 16 hours). After cooling to room temperature, the mixture was evaporated under high vacuum, yielding a dark oil of the title compound (17.7 g) containing residual DMSO, but sufficiently pure to be used in the next step.

1 H NMR: δΗ (400 MHz, CDCl 3) 8.56 (1H, d), 7.82 (1H, dd), 7.18 (1H, d), 5.83 (2H, 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, brs), 2.70 (1 H, m), 2.58 (1 H, m), 2.05 (6 H, s), 1.54-1.38 (2 H, m), 0.92 (3 H, t).

MS (ESI +): 304 (MH +).

Preparation 23 (2S) -2 - [{(21?) - 2- [6- (2,5-Dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl} (ethyl) amino] butan-1-ol JU.

30

ijCn

cC

35 1029139 136

The diol from preparation 22 was dissolved in dichloromethane (50 ml), treated with ethanol (1.66 ml, 29.6 mmol) and NaBH (OAc) 3 (6.3 g, 29.6 mmol), and the The mixture was stirred at room temperature overnight (~ 16 hours). The solvents were then evaporated and the residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol / NH 3 (sd = 0.880) (97: 3: 0.5) to give the title compound as a light brown oil (2.8 g). The material was purified again by flash chromatography on silica gel, eluting with 1% methanol in ethyl acetate, then increasing the polarity to 2% to give the title compound as a clear oil (1.42 g, 43%).

1 H NMR: δΗ (400 MHz, CDCl 3) 8.58 (1H, d), 7.95 (1H, dd), 7.21 (1H, d), 5.87 (2H, s), 4, 98 (3H, brm), 3.72 (1H, dd), 3.57 (1H, m), 3.10 (1H, dd), 2.95 (2H, m), 2.78 (2H, m) ), 2.10 (6 H, s), 1.57 (1 H, m), 1.43 (1 H, m), 1.18 (3 H, t), 0.97 (3 H, t).

MS (ESI +): 332 (MH +). I

Preparation 24 (2S) -2 - [[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] - (ethyl) amino] butane-1-O 25

OH

OH ^ Y ^

JCT ^ I

H 2 N · ^

The diol from preparation 23 (1.42 g, 4.3 mmol) was dissolved in ethanol (50 ml), treated with hydroxylamine hydrochloride (1.5 g, 21.4 mmol) and the mixture overnight (~ 16 hours) to 80 ° C. After cooling to room temperature, the solvents were evaporated and the 10291sg 137 residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol / NH 3 (sd = 0.880) (91: 9: 0.5), using the title compound as a light brown oil (990 mg, 91%).

1 H NMR: δΗ (400 MHz, CD3 OD) 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, t), 0.92 (3H, t).

MS (ESI +): 254 (MH +), 276 (MNa +) 10

Preparation 5 5-Bromo-2- (2,5-dimethyl-1ff-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) and para-toluenesulfonic acid monohydrate (20 mg) were added and the mixture was heated under reflux with a Dean-Stark device that was installed. When the water collection stopped, the reaction mixture was evaporated and the residue purified by flash chromatography on silica gel, eluting with 5% ethyl acetate in pentane to give the title compound 30 as a pale yellow oil (5.1 g, 61%) yielded.

1 H NMR: δΗ (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 (5% EtOAcpentane).

Preparation 26 (5S) -5-Methyl-4-propyl-morpholin-2-one 10 2 9 1 31, 138 ° 5;

The material from preparation 36 (4 g, 26 mmol) was dissolved in benzene (80 ml), after which the addition of N-10 ethyl diisopropylamine (9.07 ml, 52 mmol) and methyl bromoacetate (2.4 ml, 26 mmol) ) follow the. The mixture was heated under reflux overnight with azeotropic removal of water. After cooling to room temperature, the solvent was removed by evaporation, the unsaturated material dissolved in methanol, pre-absorbed in SiC> 2 and purified by flash chromatography on SiC> 2, eluting with 40% EtOAc in pentane. This gave the title compound as a clear oil (1.78 g). 1 H-NMR: (CDCl 3, 400 MHz) δΗ 0.9 (t, 3H), 1.1 (d, 3H), 1.5 (m, 2H), 2.25 (m, 1H), 2, 6 (m, 1H), 2.8 (m, 1H), 3.2 (d, 1H), 3.6 (d, 1H), 4.05 (dd, 1H), 4.3 (dd, 1H) ).

TLC, Rf = 0.18 (50% EtOAc in pentane, visualized with UV).

Preparation 27 (5S) -2- [6- (2,5-Dimethyl-1-pyrrole-1-yl) -5-methylpyridin-3-yl] -5-methyl-4-propyl-morpholine-2-ol y-NYN-2 oh 30 'ΑΛ1.0.

s 35 1029139- 139

The bromopyridine from preparation 25 (2.5 g, 9.4 mmol) was dissolved in THF (60 mL) and cooled to -78 ° C. To the stirred solution was added dropwise tert-butyl lithium (1.5 M in pentane, 12.6 ml, 18.8 mmol). Immediately after the addition was complete, the morpho-linone (from preparation 26) (1.5 g, 9.4 mmol) was added as a solution in THF (10 ml) and the reaction mixture stirred at -78 for 1 hour ° C. The reaction was then stopped by the addition of saturated NH 4 Cl-10 aqueous solution (100 ml) and then the mixture was 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, after which the polarity of the eluent was increased to 40% and then to 70% ethyl acetate in pentane. This gave the title compound as a pale yellow oil (590 mg, 18%).

1 H NMR: δΗ (400 MHz, CDCl 3) 8.70 (1 H, s), 7.92 (1 H, s), 5.88 (2 H, s), 3.77 (2 H, brs), 3, 0-2.37 (5H, m), 2.02 (3H, s), 1.90 (6H, s), 1.65-1.58 (2H, m), 1.10 (m, 3H) , 0.99-0.84 (3 H, m).

MS (ESI +): 344 (MH +).

Preparation 28 (2S) -2 - [{2- [6- (2,5-Dimethyl-1-pyrrol-1-yl) -5-methyl-pyridin-3-yl] -2-hydroxyethyl} (propyl) amino] propan-1-ol 30 / YN <1 35 1029 1 39 140

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 continued overnight (-16 hours) before the reaction was terminated by the addition of saturated aqueous ammonium chloride (100 ml), the reaction mixture 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, a mixture of diastereoisomers, as a yellow oil (450 mg, 75%) that was used directly without further purification.

MS (ESI +): 346 (MH +), 368 (MNa +).

Preparation 29 (2S) -2 - [[2- (6-Amino-5-methylpyridin-3-yl] -2-hydroxy-ethyl] (propyl) amino] propan-1-ol 20 v Η'ΝγΝ *, Α ^ ΛγΟΗ.ΟΗ s

The diol from preparation 28 (420 mg, 1.5 mmol) was dissolved in propanol (5 ml) and water (1.5 ml), treated with hydroxylamine hydrochloride (2.2 g, 31.4 mmol) and triethylamine (2 , 2 ml, 15.7 mmol), and the mixture heated under reflux for 12 hours. After cooling to room temperature, the mixture was evaporated and the residue purified by flash chromatography on silica gel, eluting with dichloromethane / methanol / NH 3 (s.d.

= 0.880) (90: 10: 1), after which the polarity was increased to 85: 15: 3. This yielded a white solid (1.3 g) which was triturated 1029139 141 with dichloromethane (3 x 50 ml). The remaining solvent was removed in vacuo to give 700 mg of white solid which was further purified by flash chromatography on silica gel, eluting with dichloromethane / methanol / NH 3 (sd = 0.880) (92.5: 7) , 5: 0). This gave the title compound as a clear oil (200 mg, 50%).

MS (ESI +): 254 (MH +).

Preparation 30 (2S) -2 - [{(2R) -2- [6- (2,5-Dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl} (butyl) amino propan-1-ol

OH

15 ohV

20

The diol from preparation 8 (1 g, 3.35 mmol, 1 eq.) Was dissolved in dichloromethane (20 ml), treated with butanal (910 μΐ, 10 mmol, 3 eq.) And NaBH (OAc) 3 (2, 1 g, 10 mmol, 3 eq.) And the mixture stirred overnight (~ 16 hours) at room temperature. The reaction was quenched with water (50 ml), the mixture extracted with CH 2 Cl 2 (2 x 100 ml), the organic layers were combined, dried (MgSO 4), filtered and evaporated. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol / NH 3 (sd = 0.880) (95: 5: 0.5) to give the title compound as a clear oil (900 mg, 86 %).

1 H NMR: 5h (400 MHz, CDCl3) 8.55 (1H, d), 7.85 (1H, dd), 7.20 (1H, d), 6.88 (2H, s), 4.85 (1 H, m), 3.10-2.97 (1 H, 35 m), 2.87-2, 94 (1 H, m), 2.43-2.70 (3 H, m), 2.10 ( 6H, s), 1.22-1.60 (6H, m), 0.87-1.0 (6H, m).

MS (ESI +): 346 (MH +), 368 (MNa +) 1 ° 29139 142

Preparation 31 (2S) -2- [[(2J) -2- (6-Aminopyridin-3-yl] -2-hydroxyethyl] - (butyl) amino] propan-1-ol

5 OH

OH ^ Y * 10

The diol from preparation 30 (900 mg, 2.6 mmol) was dissolved in ethanol (15 ml), treated with hydroxylamine hydrochloride (905 mg, 13 mmol) and the mixture heated overnight (~ 16 hours) up to 80 ° C. 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 dichloromethane / methanol / NH 2 gradient (sd = 0.880) (95: 5: 0) , 5 to 92: 8: 0.5) to give the title compound as a light brown oil (330 mg). 1 H NMR: δΗ (400 MHz, CD 3 OD) 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 tert-butyl ester rX \ nV "35 1029139 143

Zinc powder (127 mg, 1.94 mmol, 1.1 eq.) Was dried under vacuum at 100 ° C for 18 hours, transferred to a round bottom flask and heated under vacuum with a hair dryer. The flask was allowed to cool to room temperature and DMF (2 ml) and 1,2-dibromoethane (12 μΐ, 0.141 mmol, 0.08 eq.) Were added. The mixture was heated to 70 ° C for 10 minutes, allowed to cool to r.t. and TMSCl (18 μΐ, 0.141 mmol, 0.08 eq.) was added dropwise. This mixture was stirred at r.t. for 30 minutes. before 3-10 iodo-azetidine-1-carboxylic acid tert-butyl ester (Ref: SynLett, 1998, 4, 379) (500 mg, 1,766 mmol, 1.0 eq.) was added as a solution in DMF (2 ml). The mixture was stirred at 40 ° C for 1 hour. 2-Chloro-5-iodopyridine was dissolved in DMF (2 ml) and added, followed by Pd2dba3 (32 mg, 0.355 mmol, 0.02 eq.) And tri-2-furyl phosphine (17 mg, 0.071 mmol, 0.04 eq.), and the mixture was heated to 70 ° C for 4 hours. The mixture was allowed to cool, diluted with Et 2 O (40 ml) and NH 4 Cl (40 ml, sat in aq.), The layers were separated and the aqueous layer was re-extracted with Et 2 O (20 ml). The organic liquids were combined, washed with brine (2 x 30 mL), dried (MgSO 4), filtered and evaporated to give a yellow solid. This solid was flash chromatographed on silica gel, eluting with a gradient from 100% CH 2 Cl 2 to 99: 1 = CH 2 Cl 2: MeOH to give 235 mg of crude product. This material was further purified by flash chromatography on silica gel, eluting with a gradient of 100% toluene 30 to 95: 5 = toluene: EtOAc to give the title compound as a yellow solid (193 mg, 41%).

Tic, Rf = 0.13 (10% EtOAc / toluene, visualized with UV).

MS (APCI +): 269 (MH +).

1 H NMR: δ H (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 (2H, t), 3.65-3.8 (1H, m), 1.45 (9H, s).

1 ^ 29139.

144

Preparation 33 5-Azetidin-3-yl-2-chloropyridine dihydrochloride 5 '

H

jCN

CY ^ .2HCl

3- (6-Chloropyridin-3-yl) azetidin-1-carboxylic acid tert-butyl ester (190 mg, 0.707 mmol, 1.0 eq.) Was dissolved in CH 2 Cl 2 (4 mL), cooled to 0 ° C and HCl g) was passed through for 10 minutes to give a dark orange solution. This was stirred for 72 hours at r.t. The mixture was evaporated to give a light brown solid. This was triturated with Et 2 O, the resulting solid was filtered off and dried in vacuo at 60 ° C to give the title compound (141 mg, 83%).

Tic, Rf = 0.15 (CH 2 Cl 2: MeOH: NH 4 OH = 90: 10: 1) MS (APCI +): 169 (MH +) MS (ESI +): 169 (MH +) 1 H NMR: δΗ (400 MHz, CD 3 OD) 8.4 (1H, s), 7.95-8.05 (1H, m), 7.55 (1H, d), 4.2-4.5 (5H, m).

25

Preparation 34 2-Chloro-5- (1-propylazetidin-3-yl) pyridine 30

Xr 5-Azetidin-3-yl-2-chloropyridine dihydrochloride (131 mg, 0.542 mmol 1.0 eq.) Was partitioned between CH 2 Cl 2 (10 mL) 1029139 145 and K 2 CO 3 (10 mL, 10 wt% / vol., Aq .), the layers were separated and the aqueous layer was re-extracted with CH 2 Cl 2 (10 ml). The organic layers were combined, dried (MgSO 4), filtered and evaporated to a volume of approximately 2 ml. Propionaldehyde (79 μΐ, 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 hours. The reaction was quenched with H 2 O (0.5 mL) and the mixture partitioned between CH 2 Cl 2 (10 mL) and 10 K 2 CO 3 (10 mL, 10 wt% / vol., Aq.). The layers were separated and the aqueous layer was re-extracted with CH 2 Cl 2 (10 ml). The organic layers were combined, dried (MgSO 4), filtered and evaporated to give a dark brown oil. This oil was purified by flash chromatography on silica gel, eluting with a gradient of 100% CH 2 Cl 2 to 95: 5 = CH 2 Cl 2: MeOH to give the title compound as a yellow oil (41 mg, 36%).

TLC, Rf = 0.39 (CH 2 Cl 2: MeOH: NH 4 OH = 90: 10: 1, visualized with UV).

MS (APCI +): 211 (MH +).

1 H NMR: δΗ (400 MHz, CDCl 3) 8.25 (1H, s), 7.65-7.75 (1H, m), 7.25 (1H, d), 3.6-3.75 ( 3 H, m), 3.1 (t, 2 H), 2.4 (t, 2 H), 1.3-1.5 (m, 2 H), 0.9 (t, 3 H).

Preparation 35

Benzhydrylidene [5- (1-propylazetidin-3-yl) pyridin-2-yl] -amine 2-Chloro-5- (1-propylazetidin-3-yl) pyridine (100 mg, 0.475 mmol, 1.0 eq. ), 1,1-diphenylmethanimine (95 μΐ, 1029 t 39 146 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.) Were combined in toluene (2 ml) and heated to 80 ° C for 16 hours . More palladium (II) acetate (4.4 mg, 0.00475 mmol, 0.01 eq.) And BINAP (8.7 mg, 0.014 mmol, 0.03 eq.) Were added, and the mixture was added for 4 heated under reflux for 1 hour. The mixture was allowed to cool to r.t. and it was partitioned between EtOAc (25 ml) and K 2 CO 3 10 (20 ml, 10 wt% / vol., aq.). The layers were separated and the aqueous layer was re-extracted with EtOAc (2 x 25 mL). The organic layers were combined, dried (MgSO 4), filtered and evaporated to give an orange oil. This oil was purified by flash chromatography on silica gel, eluting with a gradient of 100% CH 2 Cl 2 to 95: 5: 0.5 = CH 2 Cl 2: MeOH: NH 4 OH to give the title compound as a yellow oil (110 mg, 66%) ) gave. TLC, Rf = 0.22 (90: 10: 1 = CH 2 Cl 2: MeOH: NH 4 OH, visualized with UV).

MS (APCI +): 356 (MH +) - NMR: δΗ (400 MHz, CDCl 3) 8.2 (1H, s), 7.8 (2H, m), 7.0-7.6 (9H, m ), 6.55 (1 H, d), 3.65-3.8 (3 H, m), 3.1 (2 H, t), 2.45 (t, 2 H), 1.3-1.5 ( m, 2H), 0.95 (t, 3H).

CHN + 0.75 H2 O: 25 Calculated: C (78.12) H (7.24) N (11.39)

Observed: C (77.85, 78.12) H (7.04 7.04) N (11, 18, 11.28)

Preparation 36 30 (2S) -2- (Propylamino) propane-1-ol hydrochloride HO.

HN ^ 'X

Γ * .HCl

35 1029139 147

To (2S) - (+) - 2-aminopropan-1-ol (19.6 g, 0.26 mol) dissolved in CH 2 Cl 2 (500 ml), propionaldehyde (20.9 ml, 0.28 mol) ) was added, followed by pre-dried, powdered 4A molecular sieves (40 g), and the mixture was stirred at room temperature overnight. The mixture was filtered through a layer of Celite® (filtering agent), the layer was washed with CH 2 Cl 2 and the solvent evaporated from the filtrate to give a clear oil. This oil was dissolved in methanol (200 ml), and 10 NaBH 4 was added portionwise in 15 minutes. The mixture was stirred overnight at r.t., the reaction was then terminated by careful addition of 2M HCl in water (200 ml). It was then made basic by the addition of 2M NaOH in water (200 ml) and the methanol removed by evaporation. Di-tert-butyl dicarbonate (115 g, 0.52 mol) was added to the residue, followed by 1,4-dioxane (200 ml) and the mixture was stirred overnight at r.t. 1,4-Dioxane was removed by evaporation and the residue 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 stirred overnight at r.t. The solvent was removed by evaporation to give the title compound as a white solid (24 g).

1 H NMR: (DMSO, 400 MHz) δ: 0.95 (3 H, t), 1.2 (3 H, d), 1.6 (2 H, m), 2.8 (2 H, m), 3, 15 (1H, m), 3.5 (1H, brm), 3.6 (1H, m), 5.4 (1H, b), 8.6-8.9 (2H, brd) 30 M / S (APCI +): 118 (MH +)

Preparation 37 (2S) -2 - ({2- [6- (2,5-Dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl} aroino) propan-1-ol 35 1029139 148

OH

OHΎ 5

The epoxide from preparation 40 (950 mg, 4.4 mmol) was dissolved in DMSO (10 mL) together with (S) -2-aminopropan-1-10 ol (380 µl, 4.9 mmol), and the mixture was the night (approx. 16 hours) is heated to 90 ° C. 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 / NH 3 (sd = 0.880) (98: 2: 0, after which the polarity was increased to 90 : 10: 1), which gave the title compound as a pale yellow oil (780 mg, 67% over 2 steps from preparation 40).

1 H NMR: 5h (400 MHz, CDCl 3) 8.61 (1H, d), 7.86 (1H, dd), 7.21 (1H, d), 5.90 (2H, s), 4, 90 (1H, m), 3.68 (1H, m), 3.46 (1H, m), 3.26-2.72 (4H, m), 2.11 (6H, s), 1.14 (3H, 2 xd).

M / S (APCl +): 290 (MH +) Preparation 38 (2S) -2 - [{2- [6- (2,5-Dimethyl-1ff-pyrrol-1-yl) pyridin-3-yl] -2 -hydroxyethyl} (ethyl) amino] propan-1-ol (diastereomeric mixture)

OH

ohV

35

The diol from preparation 37 (1.5 g, 5.2 mmol) was dissolved in dichloromethane (25 ml), treated with acetaldehyde (870 μΐ, 15.5 mmol) and sodium triacetoxyborohydride (3.3 g, 15 (5 mmol), and the reaction mixture stirred at room temperature overnight (-16 hours) The reaction mixture was diluted with saturated ammonium chloride solution and then made basic by the addition of 10% aqueous K2 CO3 solution and extracted with dichloromethane (2 x 150 ml) The combined organic liquids were dried (MgSO 4), filtered and evaporated The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol / NH 3 (sd = 0.880) ( 93: 7: 0.5) to give the title compound as a mixture of diastereoisomers, a slightly crude light brown oil (2.5 g), this material was used directly without further purification.

1 H NMR: δΗ (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 (1H, m), 3.77-3.65 (1H, m), 3.18-3.05 (1H, m), 2.95-2.57 (5H, m), 2.10 (6H) , s), 1.18-1.10 (2 x 3 H, t), 1.00-0.92 (2 x 3 H, d).

20 M / S (ESI +): 318 (MH +).

Preparation 39 (2S) -2 - [[2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] (ethyl) -amino] propan-1-ol (diastereomeric mixture)

OH

ΟηΥ * Η, Ν Ν 30 2

The diol from preparation 38 (2.5 g, 7.8 mmol) was dissolved in ethanol (80 mL), treated with hydroxylamine hydrochloride (2.7 g, 21.4 mmol) and the mixture overnight (- 16 hours) to 80 ° C. 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 3 (sd = 0.880) (95: 5: 0.5, after which the polarity was increased to 90: 10: 1) to give the title compound as a light brown oil (1.5 g, 80%).

X H NMR: δΗ (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).

M / S (ESI +): 240 (MH +) 10

Preparation 40 2- (2,5-Dimethylpyrrol-1-yl) -5- [oxiranyl] pyridine 20

Ethanolamine (0.24 ml, 4 mmol) was added dropwise over 15 minutes to a solution of borane tetrahydrofuran complex (1M solution in tetrahydrofuran, 8 ml, 8 mmol) in tetrahydrofuran (5 m) that had been cooled to 0 ° C. The mixture was allowed to come to room temperature and then the chloride from preparation 2 (1 g, 4 mmol) in tetrahydrofuran was added dropwise to the stirred solution. The reaction mixture was stirred at room temperature for 30 minutes, after which time the reaction was stopped by the addition of 2M sodium hydroxide (10 ml) and the reaction mixture was stirred for another hour. The mixture was then extracted with ethyl acetate (2 x 50 ml), dried (MgSO 4), filtered and evaporated to give the racemic epoxide as a yellow oil (950 mg). The 1 H NMR spectrum was as from Preparation 3. The material was used directly without further purification.

10291J9 151

Preparation 41 4-Propyl-2-thiazol-5-yl-morpholine-2-ol 5 N ^ 10

To 2-trimethylsilylthiazole (9.5 g, 60.5 mmol, 1 eq.) In Et 2 O (200 mL) was added n-butyl lithium (36 mL, 2.5 M in hexanes, 90.7 mmol, 1) at -78 ° C. , 5 eq.) Added dropwise, and the mixture stirred at -15 78 ° C for 30 minutes. 4-Propylmorpholine-2-one (prepared according to the method described in WO 2004/052372 - 8.65 g, 60.5 mmol, 1 eq.) In Et 2 O (50 ml) was added in 5 minutes (the temperature during the addition to -55 ° C). The mixture was again cooled to -78 ° C and allowed to stir for 2 hours at -78 ° C. The reaction was stopped by the dropwise addition of water, allowed to warm to r.t. and was extracted with EtOAc (2 x 500 ml) and dichloromethane (2 x 300 ml). The organic extracts were combined, dried over MgSO4 and the solvent was evaporated, yielding a brown oil. The oil was chromatographed on an SiO2 column from an Isco Companion Combiflash autochromatography system eluting with a gradient of 98/2 / 0.5 = CH 2 Cl 2 / MeOH / NH 3 to 95/5 / 0.5 = CH 2 Cl 2 / MeOH / NH 3 to give a pale brown solid (8.5 g, 61%).

1 H NMR: (400 MHz, CD3 OD) δ (ppm): 8.91 (s, 1H), 7.91 (s, 1H), 4.13-4.22 (m, 1H), 3.68- 3.75 (m, 1H), 2.97 (d, 1H), 2.68-2.80 (m, 1H), 2.26-2.40 (m, 4H), 1.48-1, 60 (m, 2H), 0.93 (m, 3H).

35 M / S APCI +: 229 (MH +).

Tic, 95/5 / 0.5 = CH 2 Cl 2 / MeOH / NH 3, Rf = 0.35 Tic, EtOAc, Rf = 0.3.

1029139 152

Preparation 42 2- [(2-Hydroxyethyl) (propyl) amino] -1- (1,3-thiazol-5-yl) -ethanol J, 10

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 NaBH 1, and the mixture stirred for 1 hour at 15 kt The mixture was diluted with water (200 ml) and extracted with dichloromethane (3 x 250 ml). The organic layers were combined, dried over MgSO 4 and the solvent was evaporated, yielding a pale oil (6.2 g). 1 H NMR: (400 MHz, CD3 OD) δ (ppm): 8.92 (s, 1H), 7.80 (s, 1H), 5.05 (t, 1H), 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 +)

Tic, 90/10/1 = CH 2 Cl 2 / MeOH / NH 3, Rf = 0.45 Preparation 43 4-Propyl-2- (1,3-thiazol-5-yl) morpholine o 30 <NJ k 35 2- [( 2-Hydroxyethyl) (propyl) amino] -1- (1,3-thiazol-5-yl) ethanol (5.7 g, 25.8 mmol) in dichloromethane (20 ml) was treated with concentrated sulfuric acid (50 ml) . After 1029139 153 complete addition, the dichloromethane was removed in vacuo and the resulting mixture heated to 140 ° C for 1 hour. The mixture was allowed to cool to r.t., poured out into ice and the reaction carefully terminated by the addition of NH 3 (s.d. = 0.880) while the temperature was kept below 20 ° C by cooling in ice. The mixture was extracted with dichloromethane (2 x 250 ml), dried over MgSO 4 and the solvent evaporated, yielding a brown oil. This material was chromatographed with an Isco Companion Combiflash autochromatography system, eluting with an eluent of 98/2 / 0.5 = CH 2 Cl 2 / MeOH / NH 3 to give the product as a pale brown oil.

1 H NMR: (400 MHz, CD3 OD) δ (ppm): 8.94 (s, 1H), 7.84 (s, 1H), 4.93 (dd, 1H), 3.93-4.0 (m, 1H), 3.76-3, 84 (m, 1H), 3.07 (d, 1H), 2.81 (d, 1H), 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 +)

Tic, 95/5 / 0.5 = CH 2 Cl 2 / MeOH / NH 3, Rf = 0.55

Preparation 44 2- (2-Bromo-1,3-thiazol-5-yl) -4-propyl-morpholine 25

Fri 30

To 4-propyl-2- (1,3-thiazol-5-yl) morpholine (2.9 g, 13.7 inmol) in THF (50 ml) was added n-butyl lithium (5.5 ml, 2) at -78 ° C 5M in hexanes, 13.7 mmol, 1 eq.) And allowed to stir for 30 minutes at -78 ° C. A solution of carbon tetrabromide (4.5 g, 13.7 mmol) in THF (20 ml) was added keeping the temperature below -70 ° C during the addition. The mixture was allowed to stir at -70 ° C for 1 hour. The reaction was stopped by the careful addition of water and allowed to warm up to r.t. in 18 hours. The mixture was extracted with EtOAc (3 x 150 ml), dried over MgSO 4 and the solvent evaporated, yielding a brown oil. This material was chromatographed with an Isco Companion Combiflash autochromatography system, eluting with a gradient from 99/1 / 0.1 = CH 2 Cl 2 / MeOH / NH 3 to 95/5 / 0.5 = CH 2 Cl 2 / MeOH / NH 3, which is the product as a brown oil (2.5 g, 63%).

1 H NMR: (400 MHz, CD3 OD) 6 (ppm): 7.54 (s, 1H), 4.83-4.89 (m, 1H), 3.90-3.96 (m, 1H), 3.70-3.79 (m, 1H), 3.02 (d, 1H), 2.75 (d, 1H), 2.35-2.41 (m, 2H), 2.17-2, 30 (m, 2H), 1.50-1.62 (m, 2H), 0.94 (t, 3H).

15 M / S APCI +: 293 (MH +)

Tic, 95/5 / 0.5 = CH 2 Cl 2 / MeOH / NH 3, Rf = 0.75 1029139

Claims (16)

Compounds of the formula (I): R1 2. Compounds of the formula (I): "" V R (I) wherein: A compound according to claims 1 or 2, wherein R 1 and R 2 are each independently selected from H and methyl. 4-Methyl-5 - (4-propyl-morpholin-2-yl) pyridine-2-amine, 5- t (2S, SS) -4,5-Diethylmorpholin-2-yl] pyridine-2-amine, 5- [ (2R, 5S) -4,5-Diethylmorpholin-2-yl] pyridine-2-amine and 5 - [(2R, 5S) - (4-Ethyl-5-methylmorpholin-2-yl] pyridine-2-ylamine. The compound of claim 1, wherein R 5 is selected from methyl and ethyl, wherein the methyl and ethyl may be optionally substituted with an OR 7 group; and R6 is selected from H and methyl. The compound of claim 2, wherein R 3 is the radical (II). The compound of claim 5, wherein R 4 (C x C 4) is alkyl optionally substituted with phenyl, R 5 is selected from methyl and ethyl, wherein the methyl and ethyl may be optionally substituted with an OR 7 group and R 6 is selected from H and methyl. The compound of claim 2, wherein R 3 is the radical 35 (III). A compound according to claim 7, wherein η is 1 and R 4 is selected from ethyl, propyl or butyl, wherein the alkyl groups are optionally substituted with a phenyl group. The compound of claim 2, wherein R 3 is the radical (IV), R 8 is selected from H and methoxy, and R 10 is selected from H and methyl. 10. A compound according to claim 1, which is selected from: 5- (Morpholin-2-yl) pyridine-2-amine 5- [4- (3-Phenylpropyl) morpholin-2-yl] pyridine-2-amine, 5 - [(2R, 5S) -5-Methylmorpholin-2-yl] pyridine-2-amine, 5 - [(2S, 5S) -5-Methyl-4- (3-phenylpropyl) morpholin-2-yl] pyri- dine-2-amine, 5 - [(2S, 5S) -4-Butyl-5-methylmorpholin-2-yl] pyridine-2-amine, 5 - {(2R, SS) -5 - [(Benzyloxy) methyl ] -4-propyl-morpholin-2-yl] pyridine-2-amine, [6- (6-Aminopyridin-3-yl) -4-propyl-morpholin-3-yl] methanol, R 1 is selected from H and (C 1 -C 8) alkyl, R 2 is selected from H and (C 1 -C 8) alkyl, R 3 is selected from: R 4 (") R 4 OU)" R "(IV) wherein: AS or CH2, η is 1 or 2, R 4 is selected from H and (C 1 -C 8) alkyl, wherein the (C 1 -C 8) alkyl may be optionally substituted with 1 or 2 substituents each independently selected from OR 7, phenyl, substituted phenyl and hot-roaryl, R 8 is selected from H and (C 1 -C 8) alkyl, wherein the (C 1 -C 8) alkyl may be optionally substituted with 1 or 2 OR 7 groups, R 6 is selected from H and (C 1 -C 8) alkyl, R 7 is selected from H and (C 1 -C 8) alkyl, wherein the (C 1 -C 8) alkyl may be optionally substituted with a phenyl or a substituted phenyl group, R 8 is selected from H, methyl, ethyl, methoxy and ethoxy, R 9 ( C 1 -C 6) alkyl and R 10 is selected from H and (C 1 -C 6) alkyl, wherein the (C 1 -C 6) alkyl may be optionally substituted with 1 or 2 substituents each independently selected from OR 7, phenyl or substituted phenyl wherein heteroaryl means a five to seventy five aromatic ring containing 1 to 4 heteroatoms, each of which is selected independently from O, S and N, and the heteroaryl may be optionally substituted with one or more substituents each independently selected from (C 1 -C 6) alkyl, halogen and OR 7, and each substituent can be the same or different and wherein substituted phenyl means phenyl substituted with one or more substituents each independently selected from (C 1 -C 8) alkyl, halogen and OR 7, and each substituent may be the same or different, and the pharmaceutically acceptable salts, solvates, polymorphs and prodrugs thereof. R 7 is selected from H and (C 1 -C 6) alkyl, wherein the (C 1 -C 6) alkyl may be optionally substituted with a phenyl or a substituted phenyl group, R 8 is selected from H, methyl, ethyl, methoxy and ethoxy, A compound according to any of claims 1-10 for use as a medicine. 2 5 Use of a compound according to any of claims 1-10 in the preparation of a medicament for the treatment of sexual dysfunction. 13. Use according to claim 12, wherein the sexual dysfunction is male erectile dysfunction or female sexual dysfunction. Use of a compound according to any of claims 1-10 in the preparation of a medicament for the treatment of depression or psychiatric disorders. Use of a compound according to any of claims 1-10 in the preparation of a medicament for the treatment of neurodegeneration. · * ♦! R 9 represents (C 1 -C 6) alkyl and R 10 is selected from H and {C 1 -C 6) alkyl, wherein the (C 1 -C 6) alkyl may be optionally substituted with 1 or 2 substituents each independently selected from OR 7, phenyl or substituted phenyl, where heteroaryl means a five to seventy five aromatic ring containing 1 to 4 heteroatoms, each of which heteroatoms are independently selected from O, S and N, and the heteroaryl may be optionally substituted with one or more substituents each are independently selected from (C 1 -C 8) alkyl, halogen, and OR 7, and each substituent can be the same or different and wherein substituted phenyl means phenyl substituted with one or more substituents each independently selected from (C1 -C6) alkyl, halogen and OR7, and any substituent can be the same or different, provided that: when R1 and R2 are H, R5 is H or (C1 -C8) alkyl and R6 is H or (C1 -C6) ) is alkyl, R 4 cannot be n-propyl, and the far pharmaceutically acceptable salts, solvates, polymorphs and prodrugs thereof. H 2 N 4 yk> / R 2 R (O 20 wherein: R 1 is selected from H and (C 1 -C 8) alkyl, R 2 is selected from H and (C 1 -C 7 alkyl, R 3 is: n 2 R 5 R 4 (II) wherein: A represents O, 1029139 «R 4 is selected from H and (C 1 -C 6) straight chain alkyl, wherein the (C 1 -C 6) straight chain alkyl may be optionally substituted with 1 or 2 substituents each independently selected from OR 7, phenyl, substituted phenyl and heteroaryl, R 5 is selected from H and (C 1 -C 6) alkyl, wherein the (C 1 -C 6) alkyl may be optionally substituted with 1 or 2 OR 7 groups, R 6 is selected from H and (C 1 -C 8) alkyl, A pharmaceutical composition comprising a compound according to any of claims 1-10 and a pharmaceutically acceptable diluent or carrier. 5 -o-o-o-! 1029139