JP4198183B2 - Aminopyridine derivatives as selective dopamine D3 agonists - Google Patents

Description

  The present invention relates to a class of dopamine agonists, and more specifically to a class of agonists that are selective for D3 over D2. These compounds are sexual dysfunctions such as female sexual dysfunction (FSD), especially female sexual arousal disorder (FSAD), hyposexual desire disorder (HSDD; lack of interest in sex), female Useful for the treatment and / or prevention of orgasmic disorder (FOD; unable to reach orgasm); and male sexual dysfunction, especially male erectile dysfunction (MED). As mentioned herein, male sexual dysfunction may be ejaculatory disorders such as premature ejaculation, lack of pleasure (cannot reach orgasm), or impaired sexual desire disorder (HSDD; lack of interest in sex) It is meant to include craving disorders such as

The present invention relates to formula (I):
[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
{Where,
A represents O, S or CH ₂ ;
n is 1 or 2;
R ⁴ is selected from H and (C ₁ -C ₆ ) alkyl; wherein said (C ₁ -C ₆ ) alkyl is (C ₁ -C ₆ ) alkyl, OR ⁷ , phenyl, substituted phenyl And optionally substituted with one or two substituents each independently selected from heteroaryl;
R ⁵ is selected from H and (C ₁ -C ₆ ) alkyl; wherein said (C ₁ -C ₆ ) alkyl is 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 said (C ₁ -C ₆ ) alkyl is optionally substituted with phenyl or a substituted phenyl group;
R ⁸ is selected from H, methyl, ethyl, methoxy, and ethoxy;
R ⁹ represents (C ₁ -C ₆ ) alkyl; and
R ¹⁰ is selected from H and (C ₁ -C ₆ ) alkyl; wherein said (C ₁ -C ₆ ) alkyl is each independently selected from OR ⁷ , phenyl or substituted phenyl 1 or Optionally substituted with two substituents;
Here, heteroaryl means a 5- to 7-membered aromatic ring containing 1 to 4 heteroatoms, each heteroatom being independently selected from O, S and N. Said heteroaryl may be optionally substituted with one or more substituents each independently selected from (C ₁ -C ₆ ) alkyl, halo and OR ⁷ , wherein each substituent is the same; Or may be different; and
Here, substituted phenyl means phenyl substituted with one or more substituents each independently selected from (C ₁ -C ₆ ) alkyl, halo and OR ⁷ , and each substituent is the same Or may be different;
However:
R ¹ and R ² are H, R ³ is moiety (II), A is O, R ⁵ is H or (C ₁ -C ₆ ) alkyl, and R ⁶ is H or (C _1- C ₆ ) if alkyl, R ⁴ cannot be n-propyl}
Selected from]
Or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.

Unless otherwise indicated, (C ₁ -C ₆ ) alkyl may be linear or branched.
Suitable heteroaryl groups include pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl.

Unless otherwise indicated, the term “halo” means fluoro, chloro, bromo, or iodo.
Unless otherwise indicated, the term “substituted” means substituted by one or more defined groups. If the group can be selected from a number of alternative groups, the selected group may be the same or different.

Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and basic salts thereof.
Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetic acid, adipic acid, aspartic acid, benzoic acid, besylic acid, bicarbonate / carbonic acid, bisulfuric acid / sulfuric acid, boric acid, camsylic acid, citric acid, cyclamic acid, edicylic acid, esylic acid, formic acid, fumaric acid , Glucoceptate, gluconic acid, glucuronic acid, hexafluorophosphoric acid, hibenzic acid, hydrochloric acid / chloride, hydrobromic acid / bromide, hydroiodic acid / iodide, isethionic acid, lactic acid, malic acid, maleic Acid, malonic acid, mesylic acid, methyl sulfate, naphthylic acid, 2-naphthyl acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid / monohydrogen, phosphoric acid / dihydrogen, phosphoric acid Pyroglutamic acid, saccharate, stearic acid, succinic acid, tannic acid, tartaric acid, tosylic acid, trifluoroacetic acid and quinofoate (xinofo Salt of te) is included.

Hemisalts of acids can also be formed, for example hemisulfate.
For an overview on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002) by Stahl and Wermuth.

Pharmaceutically acceptable salts of the compound of formula I are:
(I) reacting a compound of formula I with the desired acid or base;
(Ii) removing an acid or base labile protecting group from a suitable precursor of the compound of formula I, or opening a suitable cyclic precursor, such as a lactone or lactam, with the desired acid or base. Or (iii) one of three methods of converting one salt of a compound of formula I into another salt by reaction with a suitable acid or base, or by means of a suitable ion exchange column. Or more.

  All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt may vary from fully ionized to hardly ionized.

  In the compound of the present invention, a solid state ranging from completely non-crystalline to completely crystalline can exist as one body. The term “amorphous” means a state in which a substance lacks long-range order at the molecular level and can exhibit physical properties of a solid or liquid depending on temperature. Typically, such materials do not give a characteristic X-ray diffraction pattern, while exhibiting solid properties and more formally expressed as liquids. Heating causes a change from solid to liquid properties, characterized by a change in state, typically second order ("glass transition"). The term “crystalline” means a solid phase in which a substance has a characteristic ordered X-ray diffraction pattern with a well-ordered internal structure at the molecular level and with distinct peaks. Such materials, when fully heated, will also exhibit liquid properties at the same time, but the change from solid to liquid is a phase change, typically first order ("melting point"). Is characterized by

  The compounds of the invention can also exist in unsolvated forms as well as solvated forms. The term “solvate” is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term “hydrate” is used when the solvent is water.

Pharmaceutically acceptable solvates of the compounds of formula (I) include the hydrates thereof.
The currently accepted classification system for organic hydrates is to define hydrates coordinated with isolated sites, channels, or metal ions—K. R. See Polymerism in Pharmaceutical Solids by Morris (HG Britain, edited by Marcel Dekker, 1995). An isolated site hydrate is one in which water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, water molecules are located in lattice channels adjacent to other water molecules. In a hydrate coordinated with a metal ion, water molecules bind to the metal ion.

  If the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of moisture. However, if the solvent or water is weakly bound, the water / solvent content will depend on moisture and drying conditions, as seen in channel solvates and hygroscopic compounds. In such cases, non-stoichiometry will be the basis.

Hereinafter all references to compounds of formula I include references to salts and solvates thereof.
The compounds of the present invention include compounds of formula I as defined above, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof defined below (optical isomers, geometric isomers and tautomers). And variants of the formula I labeled with isotopes.

  Within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula I, including compounds presenting more than one isomeric form, and mixtures of one or more thereof . Also included are acid addition salts or basic salts in which the counter ion is optically active (eg, d-lactate or l-lysine) or racemic (eg, dl-tartrate or dl-arginine). It is.

The compounds of formula (I) contain one or more asymmetric central carbon atoms and therefore there are two or more stereoisomeric forms. Furthermore, the person skilled in the art knows that moiety (II) is in all stereoisomeric and diastereoisomeric forms, in particular:
Will be understood to encompass.

  Separation of diastereoisomers can be achieved by conventional techniques such as fractional crystallization, chromatography or HPLC of stereoisomeric mixtures of compounds of formula (I), or suitable salts or derivatives thereof. Individual enantiomers of compounds of formula (I) can also be prepared from the corresponding optically pure intermediates, or separation of the corresponding racemate using a suitable chiral support, eg HPLC Or, if necessary, by fractional crystallization of diastereomeric isomer salts formed by reaction of the corresponding racemate with a suitable optically active acid or salt.

  The present invention includes all compounds of formula I labeled with a pharmaceutically acceptable isotope, wherein one or more atoms are replaced by atoms having the same atomic number, but the atomic mass or mass number. Is different from the atomic mass or mass number, which is naturally dominant.

Examples of isotopes suitable for incorporation into the compounds of the present invention include isotopes of hydrogen, such as ² H and ³ H, carbon isotopes, such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine isotopes, such as ³⁶ Cl, fluorine isotopes such as ¹⁸ F, iodine isotopes such as ¹²³ I and ¹²⁵ I, nitrogen isotopes such as ¹³ N and ¹⁵ N, oxygen isotopes such as ¹⁵ O, ¹⁷ O and ¹⁸ O, It includes an isotope of phosphorus, such as ³² P, and an isotope of sulfur, such as ³⁵ S.

Compounds of formula I labeled with certain isotopes, for example, incorporate radioisotopes and are useful in drug and / or substrate tissue distribution assays. The radioactive isotopes tritium, ie ³ H, and carbon-14, ie ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ready-to-use means for detection.

Substitution with heavier isotopes such as deuterium, ² H, can give certain therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, Therefore, it may be preferable under certain circumstances.

Substitution with positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N can be useful for assays by Positron Emission Topography (PET) to examine substrate receptor occupancy.

The isotope-labeled Formula I is prepared by the conventional methods known to those skilled in the art or by using appropriate isotope-labeled reagents in place of previously used unlabeled reagents. Can be prepared generally by methods analogous to those described in.
In accordance with the present invention, Pharmaceutically acceptable solvates include those wherein the solvent of crystallization may solvates be substituted isotopes, for example D _{2 O,} d 6 _- acetone, an d _6-DMSO.

The following aspects of the invention are particularly preferred:
Preferably R ¹ is selected from H, methyl and ethyl;
More preferably, R ¹ is selected from H and methyl;
Most preferably, R ¹ is H.

Preferably R ² is selected from H, methyl and ethyl;
More preferably, R ² is selected from H and methyl;
Most preferably R ² is H.

When R ³ is moiety (II):
Portions (IIa) and (IIb) are preferred.
Preferably A is O or CH ₂
More preferably, A is O.

Preferably, R ⁴ is (C ₁ -C ₆ ) alkyl, optionally substituted with phenyl, or a substituted phenyl group,
More preferably, R ⁴ is (C ₁ -C ₄ ) alkyl, optionally substituted with phenyl,
Even more preferably, R ⁴ is selected from methyl, ethyl, n-propyl, or n-butyl;
Most preferably R ⁴ is selected from methyl, ethyl, and n-propyl.

In a first preferred embodiment, R ⁵ is selected from H and (C ₁ -C ₄ ) alkyl; wherein the (C ₁ -C ₄ ) alkyl is optionally 1 or 2 OR ⁷ groups May be replaced,
More preferably, R ⁵ is selected from H, methyl and ethyl; wherein the methyl and the ethyl may optionally be substituted with an OR ⁷ group;
Most preferably R ⁵ is selected from H, methyl and ethyl.

In a second preferred embodiment, R ⁵ is (C ₁ -C ₄ ) alkyl, optionally substituted with 1 or 2 OR ⁷ groups;
More preferably, R ⁵ is selected from methyl and ethyl; wherein the methyl and the ethyl are optionally substituted with an OR ⁷ group,
Most preferably R ⁵ is selected from methyl and ethyl.

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

Preferably, R ⁷ is selected from H and (C ₁ -C ₄ ) alkyl; wherein said (C ₁ -C ₄ ) alkyl is optionally 1 or 2 phenyl or substituted phenyl groups Replaced by
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 moiety (III):
Preferably n is 1,
Preferably, R ⁴ represents a (C ₁ -C ₄ ) alkyl, substituted phenyl or heteroaryl group optionally substituted with 1 or 2 phenyl.

More preferably, R ⁴ represents ethyl, propyl or butyl, the group is optionally substituted with a phenyl group,
Most preferably R ⁴ represents ethyl or propyl and the group is optionally substituted with a phenyl group.

When R ³ is moiety (IV):
Preferably R ⁸ is selected from H, methyl and methoxy;
More preferably, R ⁸ is selected from H and methoxy,
Most preferably R ⁸ is H.

Preferably R ⁹ is selected from (C ₁ -C ₄ ) alkyl;
More preferably, R ⁹ is selected from methyl, ethyl and n-propyl,
Most preferably R ⁹ is n-propyl.

Preferably, R ¹⁰ is selected from H and (C ₁ -C ₃ ) alkyl; wherein the (C ₁ -C ₃ ) alkyl is optionally substituted with one or two OR ⁷ or phenyl groups May be,
More preferably, R ¹⁰ is selected from H and methyl;
Most preferably R ¹⁰ is H.

Preferably R ³ is selected from moieties (II) and (III);
More preferably, R ³ is selected from moieties (IIa), (IIb), and (III)
Most preferably R ³ is selected from moieties (IIa) and (IIb).

Preferably, the heteroaryl is a 5- or 6-membered aromatic ring containing 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from O and N;
More preferably, the heteroaryl is a 5 or 6 membered aromatic ring and contains 1 to 2 nitrogen atoms.

Particularly preferred compounds of the invention (and salts thereof) are exemplified herein;
More preferably,
5- (morpholin-2-yl) pyridin-2-amine (Example 2);
5- [4- (3-Phenylpropyl) morpholin-2-yl] pyridin-2-amine (Example 3);
5-[(2R, 5S) -5-methylmorpholin-2-yl] pyridin-2-amine (Example 7a);
5-[(2S, 5S) -5-methyl-4- (3-phenylpropyl) morpholin-2-yl] pyridin-2-amine (Example 9);
5-[(2S, 5S) -4-butyl-5-methylmorpholin-2-yl] pyridin-2-amine (Example 10);
5-{(2R, 5S) -5-[(benzyloxy) methyl] -4-propylmorpholin-2-yl} pyridin-2-amine (Example 13);
[6- (6-Aminopyridin-3-yl) -4-propylmorpholin-3-yl] methanol (Example 14);
4-methyl-5- (4-propylmorpholin-2-yl) pyridin-2-amine (Examples 18 &19);
5-[(2S, 5S) -4,5-diethylmorpholin-2-yl] pyridin-2-amine (Example 21);
5-[(2R, 5S) -4,5-diethylmorpholin-2-yl] pyridin-2-amine (Example 22);
5- (2R, 5S)-(4-Ethyl-5-methylmorpholin-2-yl) -pyridin-2-ylamine (Example 25)
It is.

  In an alternative embodiment, the present invention additionally provides compounds (+)-5- (4-propylmorpholin-2-yl) -1,3-thiazol-2-amine and (−)-5- (4- Propylmorpholin-2-yl) -1,3-thiazol-2-amine (Examples 26 and 27).

  The compound of the present invention can be produced by various methods by known methods. The following pathways describe methods for synthesizing compounds of formula (I); one skilled in the art will appreciate that other methods are equally feasible.

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

Formula (I) (wherein R ¹ , R ² , R ⁴ and R ⁶ are as defined above, and R ³ , R ⁵ and A are as defined herein. Can be prepared according to Reaction Scheme 1.

Reaction step 1. Compounds of aminopyridine protection formula (V) (wherein, for example, NPG is a 2,5-dimethylpyrrole system [described in J. Chem. Soc. Perkin Trans. 1, 1984, 2801-2807, VIa) is as explained by]]) with 1-2 equivalents of aminopyridine of formula (V) in toluene at reflux with azeotropic removal of water and an acid catalyst such as para-toluenesulfonic acid. Can be introduced through reaction with 2,5-hexanedione.

Reaction step 2. Aromatic halides of the aldehyde formula (VI) from the halide can be generated, for example, by generating an organometallic reagent from the halogenated pyridine of the formula (VI) followed by a formylating agent such as dimethylformamide or morpholine-4-carbaldehyde. Can be converted to the aldehyde of formula (VII).

Suitable organometallic pyridine derivatives include Grignard reagents (organomagnesium) or organolithium reagents and can be prepared from bromides (or iodides) by halogen-metal exchange. Typical conditions are to use isopropylmagnesium chloride (or butyllithium) in bromide (VI) in an anhydrous ether solvent such as tetrahydrofuran at room temperature (isopropylmagnesium chloride as the metallizing reagent) to perform the halogen metal exchange reaction. Heating may be required in some cases) or below (eg, -78 ° C. if butyl lithium is used), and adding the formylating agent at 0 ° C. or lower.

Reaction step 3. Conversion of Aldehyde to Amino Alcohol A compound of formula (VIII) is prepared by reacting an aldehyde of formula (VII) with a cyanide source such as potassium cyanide or trimethylsilyl cyanide, or a base such as nitromethane and sodium hydroxide. Intermediate addition compounds can be formed which can be reduced by treatment with borane, lithium aluminum hydride, or hydrogenation in an ether solvent. Typical conditions include reacting 1.0 equivalent of aldehyde in 1.5 equivalents of 3M HCl at room temperature with sodium sulfite (1.5 equivalents) followed by potassium cyanide (1.5 equivalents). The resulting cyanohydrin intermediate is then treated with 1.2-3.0 equivalents of borane in THF at reflux and then treated with a strong acid to hydrolyze the boron complex of the initially formed product. Is reduced by One skilled in the art will recognize that other non-acidic methods, such as treatment with diethanolamine, can be used to disrupt the boron complex.

Reaction step 4. The compound of the reductive amination formula (IX) can be prepared by using standard amide bond formation conditions followed by reduction of the intermediate amide with a hydride reducing agent such as borane or lithium aluminum hydride. ).

For example, the acid chloride can be used in the amide formation step in the presence of a suitable base such as triethylamine or 4-methylmorpholine. Typical reaction conditions are: 1.0 eq amine (VIII) in dichloromethane, 1.2-2.0 eq base (preferably triethylamine), 1.1-1.3 eq acid in dichloromethane at 25 ° C. Contains chloride. A reducing agent such as borane or lithium aluminum hydride can be used in the amide reduction step. Typical conditions are 1.0 equivalent of amide in THF, 1.2-3.0 equivalents of borane at reflux followed by a strong acid to hydrolyze the boron complex of the initially formed product. Including processing. One skilled in the art will recognize that other non-acidic methods, such as treatment with diethanolamine, can be used to disrupt the boron complex.

  The compound of formula (IX) is also suitable at room temperature in the presence of a hydride reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in an alcoholic solvent such as ethanol. Or more) can be prepared by reductive amination of compounds of formula (VIII).

Reaction step 5. The morpholinone-forming compound of formula (X) is a compound of formula (IX) in the presence of a base such as triethylamine, sodium carbonate or potassium hydroxide with chloroacetyl chloride or a 2-substituted α-chloroacyl chloride (eg, 2-chloropropinoyl chloride or 2-chlorobutyryl chloride). Typical conditions include 1.0 equivalents of amine (IX) in dichloromethane at 25 ° C., 1.0-1.3 equivalents of acid chloride, 1.2-2.0 equivalents of triethylamine, then The crude reaction mixture is dissolved in IPA using 1.2-3.0 equivalents of aqueous potassium hydroxide.

Reaction step 6. The morpholinone reduced formula (XI) compound can be prepared by reacting the compound of formula (X) with a reducing agent such as borane or lithium aluminum hydride. Typical conditions include 1.0 equivalent of amide (X) in THF, 1.2-3.0 equivalents of borane at reflux followed by hydrolysis of the initially formed boron complex. Treat with strong acid. One skilled in the art will recognize that other non-acidic methods, such as treatment with diethanolamine, can be used to disrupt the boron complex.

Reaction step 7. Aminopyridine deprotection The compound of formula (I) can be prepared from the compound of formula (XI) by deprotection. The nature of this reaction will depend on the protecting group selected for use.
For example, if a 2,5-dimethylpyrrole system is used to deprotect the aminopyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions include 1.0 equivalent of compound (XI) and 5 equivalents of hydroxylamine hydrochloride in ethanol at reflux.

Alternatively, compounds of formula (IX), where R ¹ , R ² , and R ⁴ are as defined above, can be prepared according to Reaction Scheme 2.

Reaction step 8. Chloroketones from halides Chloroketones of formula (XII) can be formed from halides of formula (VI) through the generation of reactive organometallic intermediates. Suitable organometallic pyridine derivatives include Grignard reagents (organomagnesium) or organolithium reagents and can be prepared from bromides (or iodides) by halogen-metal exchange. That is, treatment of (VI) with 1.1 (or more) equivalents of butyl lithium in an ether solvent such as tert-butyl methyl ether at low temperature (−78 ° C.) was An organometallic intermediate that can be treated with N-methoxy-N-methylacetamide is provided to provide chloroketones of formula (XII).

Reaction step 9. Chloroketones of epoxide formula (XII) from chloroketones can be converted to epoxides of formula (XIII) through reduction of the intermediate to chlorohydrin and base-promoted epoxide formation. That is, reaction of (XII) with sodium borohydride (0.3 equivalents or more) in dioxane followed by treatment with excess aqueous sodium hydroxide gives the epoxide of formula (XIII).

  Enantiomerically pure or enantiomerically enriched epoxides of the formula (XIII) can be obtained by using asymmetric reducing agents. For example, reaction of a chloroketone of general formula (XIII) with (−)-B-chlorodiisopinocinfeylborane (1.5 or more equivalents) in tetrahydrofuran at low temperature (eg −30 ° C.), and Subsequent treatment of the intermediate chlorohydrin with sodium hydroxide gives the enantiomerically enriched epoxide of formula (XIII).

Reaction step 10. Epoxide ring opening When heated with a suitable primary amine in an inert solvent such as DMSO at 90 ° C., an epoxide of formula (XIII) gives a compound of formula (IX).
Formula (I) wherein R ¹ , R ² , R ⁴ , and R ⁵ are as defined above, and R ³ , R ^6, and A are as described herein. ) Can be prepared according to Reaction Scheme 3.

Reaction step 11. The compound of the amide forming formula (XV) is prepared by reacting an amino acid ester of formula (XIV) and an acid chloride (R = (C ₁ -C ₆ ) alkyl) in the presence of a suitable base such as triethylamine and 4-methylmorpholine ( Or other suitable amide formation conditions). 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 formula (XV) are also commercially available.

Reaction step 12. Amide and ester reduction, followed by N-Boc forming formula (XVI) compound, reaction of compound of formula (XV) with borane-THF complex, followed by hydrolysis of the resulting boron complex with the product Can be prepared by treatment with a strong acid (eg, 5M HCl). Other non-acidic methods such as treatment with diethanolamine can be used to disrupt the boron complex. This follows the t-butyloxycarbonyl protection of the amine formed. Typical reaction conditions, 1 equivalent of the amide with 3 equivalents of _BH 3-THF in THF at reflux temperature (XV), cooling, cautious addition of 6M HCl aqueous solution, and further heated up to 6 hours reflux including. Subsequent evaporation of the solvent, redissolving in a methanol: water (8: 1) mixture and addition of a base such as 5 equivalents of potassium hydroxide and 1.5 equivalents of di-tert-butyl bicarbonate and the mixture For 72 hours.

Reaction step 13. A compound of N-Boc deprotection formula (XVII) can be prepared by reacting a compound of formula (XVI) with an organic solution of HCl. Typical reaction conditions include 1 equivalent of carbamate (XVI) and 1-10 equivalents of 4M HCl solution in dioxane at 25 ° C. Examples of compounds of formula (XVII) are also commercially available.

Reaction step 14. If necessary, the compound of formula (XVIII) with chloroketone can be reacted with a compound of formula (XVII) and an α-haloketone of formula (XII) in the presence of a base such as triethylamine or 4-methylmorpholine. Can be manufactured by. Typical conditions include 1 equivalent of aminoalcohol (XVII) with 1-3 equivalents of triethylamine and 1 equivalent of compound of formula (XII) at 65 ° C.

Reaction step 15. Reduction to the diol The morpholinol intermediate of formula (XVIII) is obtained by reaction with a hydride reducing agent such as sodium borohydride (1 equivalent or more) in an alcoholic solvent such as ethanol at room temperature. XIX) diol.

Reaction step 16. The morpholine closed ring (XIX) diol compound can be closed to the morpholine compound of formula (XI) using a number of methods. For example, reacting a solution of (XIX) in dichloromethane with excess concentrated sulfuric acid at room temperature will achieve crystallization.

  Instead, ring closure employs the use of 1.1 equivalents of an azodicarboxylic acid reagent such as diisopropyl azodicarboxylate (DIAD) and 1.1 equivalents of triphenylphosphine in an inert solvent such as tetrahydrofuran. It can be achieved using Mitsunobu type conditions.

  A further alternative is described in Org. Lett. 2004, 6 (6), 1045-1047, a sulfonylating agent such as p-toluenesulfonylimidazole in an inert solvent such as tetrahydrofuran in the presence of a strong acid such as sodium hydroxide. Is to use.

Reaction step 7. Aminopyridine deprotection Compounds of formula (I) can be prepared from compounds of formula (XI) by deprotection. The nature of this reaction will depend on the protecting group selected for use.
For example, if a 2,5-dimethylpyrrole system is used to protect an aminopyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions include 1.0 equivalent of compound (XI) and 5 equivalents of hydroxylamine hydrochloride in ethanol at reflux temperature.

Instead, in some cases it may prove advantageous to deprotect the aminopyridine group (PGN) prior to ring closure to form a morpholine group. This is most likely when acidic conditions are used to achieve crystallization. In this case, the formula (I) (where R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ are as defined above, and R ³ and A are described herein. Can be prepared from the compound of formula (XIX) according to Reaction Scheme 4.

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

Reaction step 18. Morpholine ring closure The compound of formula (I) can then be prepared by crystallization of the compound of formula (XX) by treatment with acid. Typical conditions use concentrated sulfuric acid and dichloromethane at room temperature or above.

Other methods can also be used to form the morpholine ring, such as the method described for reaction step 16 in Scheme 3.
Scheme 5 is an alternative to converting a compound of formula (XVIII) into a compound of formula (XI), where R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ are as defined above. The method is described.

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

Similarly, if a protecting group is not present in the compound of formula (XVIII), this method step provides an alternative route to the compound of formula (I).
An alternative approach for the formation of compounds of formula (XIX) is shown in Scheme 6, where R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ are as defined above.

The compound of formula (XIX) can be derived by reaction of reaction step 20— an amine of formula (XVII) with an epoxide of formula (XIII). The reaction is generally carried out at an elevated temperature in an inert solvent such as toluene or DMSO. Typical reaction conditions: involving heating (XIII) and (XVII) together in DMSO at 90 ° C.

An alternative method for the synthesis of compounds of formula (XVIII) is shown in Scheme 7, where R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ are as defined above.

Compounds of formula (XVIII) can be prepared by reaction of reaction step 21— an organometallic reagent derived from a halogenated pyridine compound of formula (VI) with a morpholino compound of formula (XXI) (see Scheme 8). Wanna) Suitable organometallic pyridine derivatives include Grignard reagents (organomagnesium) or organolithium reagents and can be prepared from bromides (or iodides) by halogen-metal exchange. Typical conditions are room temperature (which may require heating when using isopropylmagnesium chloride as a metallizing reagent) or lower (eg when using butyllithium to perform a halogen metal exchange reaction). Includes the addition of isopropylmagnesium chloride (or butyllithium) to bromide (VI) in an absolute ethanol solvent such as tetrahydrofuran, followed by the addition of morpholinone (XXI) at 0 ° C or lower.

Morpholinone compounds of formula (XXI), where R ⁴ , R ⁵ and R ⁶ are as defined above can be prepared as shown in Scheme 8.

The morpholinone compound of formula (XXI) is a reaction step 22- an α-haloester compound such as amino alcohol of formula (XVII) and methyl bromoacetate (XXII) in the presence of a base such as triethylamine or 4-methylmorpholine. It can manufacture by reaction with. Typical conditions include 1 equivalent of aminoalcohol (XVII) with 1-3 equivalents of triethylamine and 1 equivalent of methyl bromoacetate using toluene as the solvent at room temperature or above. In some cases, heating with azeotropic removal of methanol is required to achieve good conversion to the desired product (XXI).

An alternative method for the synthesis of epoxides of formula (XIII) where R ¹ and R ² are as defined above is shown in Scheme 9.

Compounds of formula (XIII) can be prepared by reaction of reaction step 23— aldehydes of formula (VII) with sulfur ylides such as those derived from trimethylsulfonium iodide and a suitable base. Typical reaction conditions are to react trimethylsulfonium iodide (1 equivalent) with sodium hydroxide (1 equivalent) in DMSO at 0 ° C., followed by addition of aldehyde (VII), and to validate the reaction at room temperature. Accompany.

A further alternative for the synthesis of epoxide compounds of formula (XIII), where R ¹ and R ² are as defined above, is shown in Scheme 10.

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

Alkenes of formula (XXIII), where R ¹ and R ² are as defined above, can be prepared according to Scheme 11.

Alkene compounds of formula (XIII) can be prepared from aldehydes of formula (VII) by reaction step 25 , Wittig reaction or similar olefination reactions. Typical reaction conditions are 1 equivalent of aldehyde (VII) using 1-2 equivalents of ylide resulting from the reaction of equimolar amounts of methyltriphenylphosphonium iodide and butyllithium in tetrahydrofuran at room temperature or lower. With processing.

Alternatively, alkenes of formula (XXIII), where R ¹ and R ² are as defined above, can be prepared according to Scheme 12.

The alkene compound of formula (XXIII) can be prepared by reaction step 26-a palladium-catalyzed vinylation reaction using a halogen compound of formula (VI). Typical vinyl sources that can be used in this process include vinyl tributylstannane, ethene gas (at high pressure), or vinyl boronate. Many Pd (0) or Pd (II) catalysts such as Pd (PPH ₃ ) ₄ are suitable for this conversion. Typical conditions are elevated temperature (eg 80 ° C.), Pd catalyst (1.5 mol%) such as Pd (OAc) ₂ , phosphine ligand such as tri-o-tolylphosphine (5 mol%), and triethylamine Reaction of a halogenated pyridine of formula (VI) (1 equivalent) with ethylene gas (high pressure, eg at 120 psi) in the presence of an amine base (large excess) such as

It will be apparent to those skilled in the art that in the preparation of compounds of formula (I), the R ⁴ group (as defined above) can be introduced into any of several intermediates in the synthetic procedure. This is most commonly accomplished by reaction step 27 , the reductive amination method. Examples of intermediates suitable for use in such transformations are shown in Scheme 13, where R ¹ , R ² , R ⁵ and R ⁶ are as defined above. Other intermediates useful for the preparation of compounds of formula I can be practiced as well.

A typical method is to use one equivalent of a secondary amine (eg, (XIX), (XI), or (I)) and one equivalent of an aldehyde in an inert solvent such as tetrahydrofuran or dichloromethane at room temperature. The reaction involves the addition of the next 1 equivalent (or more) sodium triacetoxyborohydride or sodium cyanoborohydride.

In some cases, for example, formula (I) (where R ⁴ is H, R ³ and A are as defined herein, and R ¹ , R ² , R ⁵ and In the preparation of the compound of R ⁶ as defined above, it may be advantageous to use the protecting group PG ′ prior to the formation of the morpholine ring. This is illustrated in Scheme 14.

Any suitable nitrogen protecting group can be used (as described in “Protecting Groups in Organic Synthesis” 3rd edition TW Greene and PG Wuts, Wiley-Interscience, 1999). . A common nitrogen protecting group (PG ′) suitable for use herein is tert-butoxycarbonyl, by treatment with an acid such as trifluoroacetic acid or hydrochloric acid in an organic solvent such as dichloromethane. Easily removed.

Reaction step 28. N-protected compounds of formula (XXIV) can be prepared by reaction step 28-N-protection. A compound of formula (XIX) (where R ⁴ = H) is reacted with a nitrogen atom protecting agent such as benzyl chloroformate to produce the protected compound. Typical reaction conditions are at room temperature 1 equivalent of secondary amine (XIX) and (1 equivalent or more) benzyl chloroformate and triethylamine (1 equivalent or more) in an inert solvent such as dichloromethane. With the above).

Reaction step 16. Ring closure of ring - closing diol (XXIV) to morpholine (XXV) can be accomplished using a number of methods previously described herein, see Reaction Step 16, Scheme 3. A Mitsunobu-type ring closure reaction through the action of a dialkyl azodicarboxylate reagent (1.1 eq) + triphenylphosphine (1.1 eq) in an inert solvent such as tetrahydrofuran at room temperature Is suitable.

Reaction step 29. Removal of the protecting group Compounds of formula (I) can be prepared by reaction step 29-deprotection of morpholine (XXV) under conditions depending on the nature of the protecting group used. For example, then, when benzyloxycarbonyl is used as a protecting group, hydrogen is used under an atmospheric pressure of 1 atmosphere or higher using a palladium catalyst such as palladium on carbon in an inert solvent such as ethanol. It can be removed by addition decomposition. When the morpholine nitrogen is protected with a benzyl group, it can be deprotected by transfer hydrogenation. Typical conditions are treatment of 1 equivalent of a compound of formula (XXV) with ammonium formate (10 equivalents) in the presence of 10% palladium on carbon as catalyst (10% weight) in ethanol for 3 hours at reflux. Including doing.

Compounds of formula (XVII) (R ⁴ , R ⁵ and R ⁶ are as defined above) can be prepared according to Scheme 15.

Compounds of formula (XVII) (wherein R ⁴ is not H) can be prepared by reaction step 30 , reductive amination method. Typical conditions include the reaction of 1 equivalent of an aminoalcohol of formula (XVI) with 1.1 equivalents of aldehyde in the presence of dry 4 乾燥 molecular sieves in dichloromethane at room temperature. After filtration and evaporation of the reaction mixture, the residue is dissolved in methanol and reacted with sodium borohydride (2 equivalents or more) at room temperature.

  Instead, reductive amination is performed in two steps via formation of an intermediate amide and subsequent reduction, similar to that described for reaction step 4 (Scheme 1) and reaction steps 11 and 12 (Scheme 3). Can be achieved.

  One skilled in the art will recognize that many amino alcohol compounds of formula (XVI) and (XVII) are commercially available. Instead, they can be made according to myriad methods known to those skilled in the art, such as those described in Tetrahedron 2000, 56, 2561-2576 and the references cited therein.

Formula (I) (wherein R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ are as defined above, and R ³ , R ⁵ and A are as described herein. Can be prepared from chloropyridines of formula (XXVI) according to Scheme 16.

  It will be apparent to those skilled in the art that the chloropyridine intermediate of formula (XXVI) can be reached through the application of analogous synthetic methods to the methods previously described herein for the preparation of protected aminopyridine compounds of formula (XI). Let's go.

Reaction step 31. A metal-catalyzed amination formula (XXVII) compound is prepared by reaction step 31 , reaction of a compound of formula (XXVI) with a benzophenone imine in the presence of a suitable base and a metal catalyst, such as a Pd complex. be able to. Typical reaction conditions are chloropyridine (XXVI) (1 eq) and benzophenone imine (1.2 eq), sodium tert-butoxide (1.4 eq), tris (dibenzylideneacetone) in toluene at 80-120 ° C. ) With reaction with dipalladium (0) (1 mol%) and 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP) (3 mol%).

Reaction step 32. The compound of the bezophenone deprotection formula (XXVII) can be hydrocracked (using a solvent inert at one atmospheric pressure or higher of hydrogen and a heterogeneous catalyst such as palladium on carbon), or alternatively Can be converted to a compound of formula (I) by treatment with an aqueous acid, for example 2M HCl, in the presence of an organic solvent such as tetrahydrofuran or dioxane mixed with. Transfer hydrogenation can also be used to accomplish this conversion. Typical conditions are 3 hours at reflux, ethanol, and 1 equivalent of compound of formula (XXVII) with ammonium formate (10 equivalents) in the presence of 10% palladium on carbon as catalyst (10% weight). Processing.

A compound of formula (I) wherein R ¹ , R ² and R ⁴ are as defined above and R ³ is as defined herein is prepared according to Scheme 17 can do.

Reaction step 33. The zincate coupling formula (XXX) compound is prepared by reacting the compound of formula (XXIX) with a Zn / Cu couple (or other activated Zn source) with sonication and then 2-chloro-4 It can be prepared by adding iodopyridine and a suitable palladium catalyst and ligand and heating at 70 ° C. for 18 hours. Typical conditions are 1 equivalent of azetidine (XXIX), 1.05 equivalents of halogenated pyridine (VI), 0.05 equivalents with 40 wt% Zn / Cu couple in DMF with sonication for 4 hours at room temperature. Of tris (dibenzylideneacetone) dipalladium (0) and 0.1 equivalent of tri-o-furylphosphine and heating to 70 ° C. for 18 hours. Compounds of formula (XXIX) can be prepared as described in Synlett, 4, 1998, 379.

Reaction step 34. The compound of the Boc deprotection formula (XXXI) can be synthesized in a suitable solvent such as dichloromethane or diethyl ether at room temperature or above, if necessary in the presence of a cation scavenger such as Et ₃ SiH. XXX) can be prepared by reacting with a suitable acid such as HCl or TFA. Typical conditions include 1 equivalent of azetidine (XXX) and CH ₂ Cl ₂ saturated with HCl gas at 0 ° C. and then left at room temperature overnight.

Reaction step 27. The compound of the reductive amination formula (XXXII) is converted to a suitable 1- 1 such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as dichloromethane or tetrahydrofuran with optional addition of acetic acid. It can be prepared by reacting a compound of formula (XXXI) with 1-5 equivalents of the required aldehyde in a suitable solvent at room temperature in the presence of 5 equivalents of a reducing agent. Typical conditions include reacting 1 equivalent of azetidine (XXXI) with 3.1 equivalents of aldehyde and 3.1 equivalents of sodium triacetoxyborohydride in dichloromethane at room temperature for 18 hours.

Reaction step 31. A metal-catalyzed amination reaction formula (XXXII) can be converted to a compound of formula (I) via an intermediate (XXXIII). Conversion of (XXXII) to (XXXIII) can be accomplished using benzophenone imine and a suitable salt and metal catalyst, such as a Pd (0) complex. Typical reaction conditions are chloropyridine (XXXII) (1 eq), benzophenone imine (1.2 eq), sodium tert-butoxide (1.4 eq), tris (di- Reacting with benzylideneacetone) dipalladium (0) (1 mol%) and 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP) (3 mol%).

Reaction step 32. A compound of the benzophenone deprotection formula (XXXIII) can be hydrocracked (using an inert solvent at 1 atmospheric pressure or higher of hydrogen and a heterogeneous catalyst such as Pd on carbon) or water admixed, It can be converted to a compound of formula (I) by either treatment with an acidic aqueous solution in the presence of an organic solvent such as tetrahydrofuran or dioxane. Transfer hydrogenation can also be used to accomplish this conversion. Typical conditions are: reflux in ethanol in the presence of 10% palladium on carbon as a catalyst (10% weight) in ethanol for 3 hours and 1 equivalent of a compound of formula (XXVII) with ammonium formate (10 equivalents). With processing.

Instead, the compound of formula (I), wherein R ¹ , R ² and R ⁴ are as defined above and R ³ is as defined herein, It can be prepared according to Scheme 18.

Reaction step 33. A compound of the zincate coupling formula (XXXIV) is reacted with a Zn / Cu couple (or other activated Zn source) while sonicating the compound of the formula (XXIX), followed by the formula (VI And a suitable palladium catalyst and ligand and heating to 70 ° C. for 18 hours. Typical conditions are 1 eq. Azetidine (XXIX) and 40 wt% Zn / Cu couple in DMF with sonication for 4 hours at room temperature followed by 1.05 eq. Halogenated pyridine (VI), 0.05 Adding an equivalent of tris (dibenzylideneacetone) dipalladium (0), and 0.1 equivalent of tris-o-furylphosphine, and heating to 70 ° C. for 18 hours. Compounds of formula (XXIX) can be prepared as described in Synlett, 4, 1998, 379.

Reaction step 34. Compounds of N-Boc deprotection formula (XXXV) is a suitable solvent, such as dichloromethane or diethyl ether, at room temperature or above, optionally in the presence of a cation scavenger such as Et 3 _SiH, It can be prepared by reacting a compound of formula (XXXIV) with a suitable acid such as HCl or TFA. Typical conditions include 1 equivalent of azetidine (XXXIV) at 0 ° C. and CH ₂ Cl ₂ saturated with HCl gas, then left at room temperature overnight.

Reaction step 27. A compound of the reductive amination formula (XXXVI) is prepared at room temperature with 1-5 equivalents of a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as dichloromethane or tetrahydrofuran. It can be prepared by reacting a compound of formula (XXXV) with 1-5 equivalents of the required aldehyde in a suitable solvent, optionally in the presence of acetic acid. Typical conditions include reacting 1 equivalent of n-azetidine (XXXV) with 3.1 equivalents of aldehyde in dichloromethane and 3.1 equivalents of sodium triacetoxyborohydride at room temperature for 18 hours.

Reaction step 7. The compound of aminopyridine deprotection formula (XXXVI) can be converted to the compound of formula (I) by deprotection. The nature of this reaction will depend on the protecting group selected for use. For example, if a 2,5-dimethylpyrrole system is used to protect the aminopyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions include 1.0 equivalent of compound (XXXVI) and 5 equivalents of hydroxylamine hydrochloride in ethanol at reflux.

Scheme 19-29
Compounds of formula I wherein R ³ is moiety IV, and R ¹ , R ² , R ⁸ , R ⁹ and R ¹⁰ are as defined above unless otherwise indicated It can be produced using the method described in 19-29.

Reaction step 35. The compound of formula (VII) forming the nitrile can be converted to the nitrile compound of formula (XXXVII) by reaction with tosylmethyl isocyanide (TosMic). Typical conditions are treatment of aldehyde (VII) (1 eq) with TosMic (1 eq) and potassium tert-butoxide (2 eq) in ethylene glycol dimethyl ether at −45 ° C. and after 30 min methanol Is added to allow the reaction mixture to reach room temperature.

Reaction step 36. Nitrile reduction formula (XXXVII) nitriles can be converted to amines of formula (XXXVIII) by reduction of the nitrile group. This reduction can be achieved through the action of a hydride reducing agent such as lithium aluminum hydroxide 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 using a transition metal catalyst such as Raney Nickel or carbon-supported Pd.

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

Reaction step 27. The reductive aminated primary amine (XXXVIII) is converted to a compound of formula (XXXIX) by a reductive amination method, reaction with an aldehyde such as sodium triacetoxyborohydride or sodium borohydride and a hydroxide reducing agent. Can be converted.

Typical conditions include the reaction of a compound of formula (XXXVIII) with a suitable aldehyde (in the presence of a hydride reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in an alcoholic solvent such as ethanol. With 1 equivalent or more).

Reaction step 7. Aminopyridine deprotection compound of formula (XXXIX) is converted to a compound of formula I by using a reaction to deprotect the nitrogen of the aminopyridine group (PGN) to liberate NH ₂ of compound (I). Can be converted. The nature of this reaction will depend on the protecting group selected for use. For example, if a 2,5-dimethylpyrrole system is used to protect the aminopyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions include 1.0 equivalent of compound (XXXIX) and 5 equivalents of hydroxylamine hydrochloride in ethanol at reflux.

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

Reaction step 37. The intermediate of the reductive alkylation formula (XXXVII) can be reduced using, for example, sodium borohydride and nickel chloride in the presence of an alkylating agent such as a carboxylic acid anhydride, and the amide of formula (XL) An intermediate is obtained. Typical conditions include reacting nitrile (XXXVII) (1 equivalent) with nickel chloride (1 equivalent) and carboxylic anhydride (1 equivalent or more) in methanol followed by sodium borohydride (3 With careful addition of equivalents or more).

Reaction step 38. Amide Reduction Amides of the general formula (XL) can be reduced to amines using borane or lithium aluminum hydride. Typical conditions include 1.0 equivalent of amide (XL) in THF, 1.2-3.0 equivalents of borane followed by heating in an aqueous strong acid such as 5M HCl at reflux. The resulting amine intermediate is then deprotected as described above in Reaction Step 7 to provide the aminopyridine compound of formula (I).

An alternative method for preparing a nitrile compound of formula (XXXVII) is shown in Scheme 21.

The compound of formula (XXXVII) is prepared by reaction step 39- Chem. It can be prepared by reacting a halogenated pyridine (VI) with tributyl (cyanomethyl) stannane and a palladium catalyst according to the method described in Lett 1984, 1511-1512. Typical conditions are that 1 equivalent of (VI) is converted to 1.5 equivalents of tributyl (cyanomethyl) stannane, bis (acetonitrile) dichloropalladium (II) (2.5 mol%) and tri-o- With treatment with tolylphosphine (5 mol%).

An alternative method for preparing compounds of formula (XXXVIII) is shown in Scheme 22.

Reaction step 40. Protected amides of the B-alkyl Suzuki coupling formula (XLII) are described in J. Am. Org. Chem. 1999, 64, 8743-8744 in a manner similar to that described by B-alkyl Suzuki coupling between vinyl carbamate (XLI) and halogenated pyridine (VI). In typical methods, benzyl vinyl carbamate [commercially available, or J. Org. Org. Chem. 1999, 64, 8743-8744] was treated with 1 equivalent of 9BBN solution in tetrahydrofuran at -10 ° C. After completion of the hydroboration step, the resulting organoboron intermediate is treated with sodium hydroxide. The PdCl ₂ (dppf) CH ₂ Cl ₂ complex is added along with the halogenated pyridine of formula (VI).

Reaction step 29. Compounds of amine deprotection formula (XLII) can be converted to compounds of formula (XXXVIII) by deprotection. The nature of this reaction will depend on the protecting group selected for use. For example, if benzyloxycarbonyl is then used as a protecting group, it can be removed by hydrogenolysis using a palladium catalyst such as palladium on carbon in an inert solvent such as ethanol. Typical reaction conditions include reacting a compound of formula (XLII) in an alcohol solvent (eg ethanol) using hydrogen (at 1 atmospheric pressure or higher) in the presence of a transition metal catalyst such as Pd on carbon. Including.

An alternative method for preparing compounds of formula (XXXIX) is shown in Scheme 23.

The compound of formula (XXXIX) is reacted in reaction step 41 —for example hydrogenation (at atmospheric pressure hydrogen in an inert solvent such as ethanol in the presence of a transition metal catalyst such as Pd on carbon (1 atm Or higher)) by deoxygenation of the compound of formula (IX). Alternatively, a hydride source such as triethylsilane in combination with a suitable acid can be used (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 one equivalent (or more) of triethylsilane.

A further method for preparing the compound of formula (XXXVII) is shown in Scheme 24.

Reaction step 42. The aldehyde of formula (VII) converted to a benzyl electrophile can be reduced by treatment with a hydride reducing agent such as sodium borohydride in an alcoholic solvent such as ethanol at room temperature. The resulting alcohol can be activated for nucleophilic substitution by conversion to group X (generally a halide or sulfonate ester). Typical conditions involve the reaction of 1 equivalent of methanesulfonyl chloride and 1 equivalent of an amine base such as triethylamine in an inert solvent such as dichloromethane at 0 ° C.

Reaction step 43. The intermediate of the cyanide substitution formula (XLIII) is nucleophilically supplied by a cyanide such as KCN in an inert solvent such as dimethylformamide in a manner similar to that described in US Pat. No. 5,914,319. It can be converted to a compound of formula (XXXVII) by the action of the source.

A further method for preparing compounds of formula (XXXIX) is shown in Scheme 25.

Reaction step 44. The halogenated pyridines of methyl ketone forming formula (VI) are first treated with butyllithium (or other reagent capable of promoting the halogen metal exchange reaction) and the resulting organometallic intermediate is acetylmorpholine. Alternatively, it can be converted to methyl ketones of the formula (XLIV) by treatment with Weingreb amide derived from acetic acid.

Reaction step 45. The methyl ketones of Willgerodt-Kindler scheme (XLIV) can be converted to aryl acetic acids of formula (XLV) by treatment with sulfur and morpholine. A typical method involves reacting 1 equivalent of methyl ketone (XLIV) with sulfur (2 equivalents) in excess morpholine at reflux followed by hydrolysis by refluxing either 2M hydrochloric acid or 2M NaOH. .

Reaction step 46. Pyridyl acetic amide formation formula (XLV), the reaction of an amine with a suitable amide coupling reaction of the formula (XLVII), for example, reaction with acidic chloride or anhydride, the addition of the next suitable amine, or dicyclohexyl Peptide coupling reagents such as carbodiimide or other carbodiimide reagents can be used to convert to an amide of formula (XLVI). For example, in the presence of a suitable base such as triethylamine or 4-methylmorpholine, the acid chloride can be used for the amide formation step. Typical reaction conditions include conversion of the acid (XLV) to the acid chloride by treatment with oxalyl chloride using a trace amount of dimethylformamide as a catalyst in an inert solvent such as dichloromethane. After evaporation of solvent and excess oxalyl chloride, 1.0 equivalent of amine (XLVII), 1.2-2.0 equivalents of base (preferably triethylamine) is 1.0 equivalent of acidification in dichloromethane at 25 ° C. React with things.

Reaction step 38. Amide Reduction Amides of the general formula (XLVI) can be converted to compounds of the formula (XXXIX) by reduction with a hydride reducing agent such as a borane-tetrahydrofuran complex. Typical conditions are to hydrolyze 1.0 equivalent of amide (XLVI) in THF, 1.2-3.0 equivalents of borane at reflux and then the borane complex initially formed with the product. Treatment with a strong acid such as 5M HCl at elevated temperature. Other non-acidic methods can be used to decompose the boron complex, for example, treatment with diethanolamine.

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

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

Compounds of formula (XLVIII) (where R ⁸ is OMe) can be prepared by reaction step 48 --methylation of alcohol (IX) using a suitable electrophilic methyl source such as iodomethane. It can be formed from a compound. In general, a strong base such as sodium hydroxide is also required. Typical conditions include treating 1 equivalent of (IX) with 1.1 equivalent (or more) sodium hydroxide in an inert solvent such as tetrahydrofuran or dimethylformamide, then 1 With the addition of (or more) an equivalent amount of iodomethane.

  Compounds of general formula (XLVIII) can then be converted to compounds of formula (I) using similar methods described for the conversion of compounds of formula (XXXIX) as shown in Scheme 19.

Further examples of compounds of formula (I) where R ⁶ is not hydrogen can be prepared according to Scheme 28.

Reaction step 44. The halogenated pyridine compound of the ketone forming formula (VI) can be readily converted to the ketone of formula (XLIX) using a method similar to the formation of the methyl ketone compound of formula (XLIV) (Scheme 25). That is, it is first treated with butyllithium (or other reagent capable of promoting a halogen metal exchange reaction) and acylmorpholine or winelevamide (both are easily prepared using methods well known to those skilled in the art). By treating the resulting organometallic intermediate with a suitable acyl source such as

Reaction step 45. The nitrile forming formula (XLIX) ketone can then be converted to the nitrile (XXXVII) by reaction with tosylmethyl isocyanide (TosMic). Typical conditions involve treating ketone (XLIX) (1 eq) with TosMic (1 eq) and potassium tert-butoxy (2 eq) in ethylene glycol dimethyl ether at −45 ° C. After 30 minutes, methanol is added and the reaction mixture is allowed to reach room temperature.

The nitrile of formula (XXXVII) can then be converted to the compound of formula (I) using the method described above in Scheme 19.

Formula (XXXIX) or (I) ^{(wherein, R 10} = is H) Compounds of the reaction process 50 - by reductive amination as shown in Scheme 29, further formula (XXXIX) or (I) ( Where R ¹⁰ is not H). A typical method is to react one equivalent of a secondary amine (eg (XXXIX) or (I)) with one equivalent of an aldehyde in an inert solvent such as tetrahydrofuran or dichloromethane at room temperature, then With the addition of 1 equivalent (or more) sodium triacetoxyborohydride or sodium cyanoborohydride.

Alternatively, the reductive amination can be carried out in two steps via an intermediate amide in the same manner as described for reaction step 4 in Scheme 1.
Formula (I) wherein R ¹ , R ² , R ⁴ and R ⁵ are as defined above, and R ³ , R ⁵ and A are as defined herein. Can be prepared according to Reaction Scheme 30.

Reaction step 51. Thioether-forming thioethers of formula (LI) can be synthesized in the presence of a base in an alcoholic solvent with compounds of formula (L) [commercially available or J. Org. Chem. Formed as described in Soc Perkin I, 1987, 111-120] by reacting a compound of formula (XLIII), where X is generally a halogen or a sulfonate ester. can do.

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

Reaction step 52. The compound of N-Boc deprotection formula (LII) is prepared in HCl in a suitable solvent such as dichloromethane or diethyl ether at room temperature or above, if necessary, in the presence of a cation scavenger such as Et ₃ SiH. Alternatively, it can be prepared by reacting a compound of formula (LI) with a suitable acid such as TFA. Typical conditions include adding 1 equivalent of protected amine (LI) to CH ₂ Cl ₂ saturated with HCl gas at 0 ° C. and then allowing to stand overnight at room temperature.

Reaction step 4. The compound of the reductive amination formula (LIII) is obtained from the compound of the formula (LII) by reduction of the intermediate amide using a hydride reducing agent such as borane or lithium aluminum hydride using standard amide bond formation conditions. Can be manufactured.

For example, acid chlorides in the presence of a suitable base such as triethylamine or 4-methylmorpholine can be used for the AND formation step. Typical reaction conditions are: 1.0 equivalent of amine (LII), 1.2-2.0 equivalents of base (preferably triethylamine), 1.1-1.3 equivalents of acidification in dichloromethane at 25 ° C. Including things. A reducing agent such as borane or lithium aluminum hydride can be used for the amide formation step. Typical conditions are treatment with a strong acid to hydrolyze 1.0 equivalents of amide in THF, 1.2-3.0 equivalents of borane, followed by the boron complex of the initially formed product at reflux. Including that. Other non-acidic methods can utilize decomposition of the boron complex, for example treatment with diethanolamine.

Reaction step 53. Compounds of the carbamate forming formula (LIV) (where R ¹¹ is benzyl or (C ₁ -C ₆ ) alkyl) can be prepared in chloroform in an inert solvent such as dichloromethane or diethyl ether in the presence of a base. It can be formed by treating a compound of formula (LIII) with an acid alkyl or benzyl.

Typical conditions include 1.0 equivalent of amine (LIII) in diethyl ether at 25 ° C., 1.0 equivalent of an alkyl chloroformate such as methyl chloroformate, and 1.0-3.0 equivalents of triethylamine. Such quaternary amine bases.

Reaction step 54. The compound of thiomorpholinone ring forming formula (LV) is formed by treating thioether (LIV) with a strong base such as lithium diisopropylamide in an inert solvent such as diethyl ether or THF. Can do.

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

Reaction step 55. The compound of amide reduction formula (LVI) can be prepared by reacting the compound of formula (LV) with a reducing agent such as borane or lithium aluminum hydride. Typical conditions are 1.0 equivalent of amide (LV), 1.2-3.0 equivalents of borane in THF at reflux followed by treatment with a strong acid to hydrolyze the initially formed boron complex. Including that. Other non-acidic methods can be used to disrupt the boron complex, for example, treatment with diethanolamine.

Reaction step 7. Aminopyridine deprotected formula (LVI) compounds can be converted to compounds of formula (I) by deprotection. The nature of this reaction will depend on the protecting group selected for use.

For example, if a 2,5-dimethylpyrrole system is used to protect the aminopyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions include 1.0 equivalent of the compound of formula (LVI) and 5 equivalents of hydroxylamine hydrochloride in ethanol at reflux temperature.

Compounds of formula (LIX), wherein R ¹ , R ² and R ⁵ are as defined above can be prepared according to Reaction Scheme 31.

Reaction step 56. A compound of primary alcohol activity formula (LVII) can be obtained by selective conversion of a primary hydroxyl group to a group X (generally a halide or sulfonate ester), where formula (XXIV) (where PG ′ is which is a carbamate protecting group such as tert-butyloxycarbonyl or benzyloxycarbonyl). Typical conditions involve the reaction of 1 equivalent of toluene sulphonine chloride and 1 equivalent of an amine base such as triethylamine at 0 ° C. in an inert solvent such as dichloromethane.

Reaction step 57. The compound of formula (LVIII) forming thioacetic acid is reacted with a suitable nucleophile such as thioacetic acid in an inert solvent such as acetonitrile in the presence of a suitable base. Wherein PG ′ is a carbamate protecting group such as tert-butyloxycarbonyl or benzyloxycarbonyl). Typical conditions include one equivalent of a compound of formula (LVII) in the presence of a suitable base such as 1.0-1.5 equivalents of potassium carboxylate in an inert solvent such as acetonitrile. With reaction with 1.0-2.0 equivalents of thioacetic acid, and heating the mixture at reflux temperature.

Reaction step 58. Cyclic (LVIII) compounds can be achieved for nucleophilic substitution at the benzene center by conversion to the group X (generally a halide or sulfonate ester). The ring closure can then occur in the original position to provide a compound of formula (LIX). Typical conditions involve reacting 1 equivalent of toluenesulfonyl chloride and 1 equivalent of an amine base such as triethylamine in an inert solvent such as dichloromethane at 0 ° C. Removal of the solvent followed by redissolving in a higher boiling solvent such as acetonitrile with 0-5.0 equivalents of a suitable base such as potassium carboxylate and heating the mixture to reflux temperature achieves ring closure. May be necessary for.

  Compounds of formula (LIX) (where PG ′ is a carbamate protecting group such as tert-butyloxycarbonyl or benzyloxycarbonyl) can be used to convert compounds of formula (XXXIV) to compounds of formula (I) Can be converted to compounds of formula (I) using methods analogous to those described in Scheme 18.

The compound of formula (I), wherein R ¹ , R ² and R ⁴ are as defined above and R ³ is as defined herein, is according to reaction scheme 32 Can be manufactured.

Reaction step 59. The compound of cycloaddition formula (LX) is prepared from N-10-benzyl-N- (methoxymethyl)-in an inert solvent such as dichloromethane, acetonitrile, tetrahydrofuran or toluene from -10 ° C to the reflux temperature of the reaction mixture. It can be formed from an alkene of formula (XXIII) by reacting with a catalytic amount of an acid such as trimethylsilylmethylamine and trifluoroacetic acid. Alternative catalysts include anhydrous potassium or cesium fluoride, tetra-n-butylammonium fluoride, trifluoromethanesulfonic acid, trimethylsilyl trifluoromethanesulfonate, and iodotrimethylsilane. Typical conditions are the reaction of 1 equivalent of alkene (XXIII) with 1.5 equivalents of N-benzyl-N- (methoxymethyl) -trimethylsilylmethylamine and 0.1 equivalent of trifluoroacetic acid in dichloromethane. Accompany.

Reaction step 60. The compound of the pyrrolidine debenzylation formula (LX) is obtained by hydrogenolysis with a palladium catalyst such as palladium on carbon in an inert solvent such as ethanol at one atmospheric pressure or higher hydrogen pressure. It can be deprotected to secondary amines of (LXI). Instead, deprotection is possible by transfer hydrogenation. Typical conditions involve treating 1 equivalent of a compound of formula (LX) with ammonium formate (10 equivalents) in ethanol in the presence of 10% palladium on carbon as a catalyst (10% weight). .

Reaction step 27. The compound of the reductive amination formula (LXII) is prepared in the presence of a suitable reducing agent such as 1-5 equivalents of sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as dichloromethane or tetrahydrofuran. Can be prepared by reacting a compound of formula (LXI) with 1-5 equivalents of the required aldehyde in a suitable solvent, optionally with acetic acid. Typical conditions include reacting 1 equivalent of pyrrolidine (LX) with 3.1 equivalents of aldehyde and 3.1 equivalents of sodium triacetoxyborohydride in dichloromethane at room temperature for 18 hours.

Reaction step 7. Compounds of aminopyridine deprotection formula (LXI) can be converted to compounds of formula (I) by deprotection. The nature of this reaction will depend on the protecting group selected for use. For example, when a 2,5-dimethylpyrrole system is used to protect an aminopyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions include 1.0 equivalent of compound (LXI) and 5 equivalents of hydroxylamine hydrochloride in ethanol at reflux.

Formula (I) (wherein R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ are as defined above, and R ³ and A are as defined herein). Can be prepared according to Reaction Scheme 33.

Reaction Step 61.3-Pyridylborane A compound of formula (LXIII) is reacted with 3-pyridylborane (or similar boronic acid) in the presence of a suitable base and a suitable palladium catalyst to produce a compound of formula (LXIII) VI). Typical conditions are the addition of 3-pyridylborane to the compound of formula (VI) in toluene / ethanol as solvent in the presence of tetrakis (triphenylphosphine) palladium (0) and sodium carboxylate, followed by reflux temperature. Including heating. Examples of 3-pyridylboranes (or similar boronic acids) are commercially available.

Reaction step 62. Alkylated compounds of formula (LXIV) can be prepared from compounds of formula (LXIII) by addition of alkyl iodide. Typical conditions include adding an alkyl iodide to a compound of formula (LXIII) in a suitable solvent such as acetonitrile and heating to the next reflux temperature.

Reaction step 63. Compounds of hydrogenation formula (LXV) can be prepared from compounds of formula (LXIV) by hydrogenation. Typical conditions, the boost, in a suitable solvent such as ethanol, in the presence of a suitable catalyst as PtO _2, including hydrogenation of a compound of formula (LXIV).

Reaction step 7. Compounds of aminopyridine deprotection formula (LXV) can be converted to compounds of formula (I) by deprotection. The nature of this reaction will depend on the protecting group selected for use.
For example, when a 2,5-dimethylpyrrole system is used to protect an aminopyridine group, it can be deprotected by treatment with hydroxylamine. Typical conditions include 1.0 equivalent of compound (LXV) and 5 equivalents of hydroxylamine hydrochloride in ethanol at reflux temperature.

Methods for Analyzing Racemates Where the above methods lead to racemic products, many methods are available for separating racemates into 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 with chiral stationary phase-many commercially available (3) Formation of diastereomeric adducts by reaction of racemates with enantiomerically pure chiral compounds or reagents, followed by physics Separation of the component enantiomers by an enzymatic method, crystallization or chromatography of the separated adduct to release the desired compound in an enantiomerically enriched form, and resolution. This is often referred to as classical analysis. For example, racemic alcohols can be reacted with enantiomerically pure chiral acids to form diastereomeric esters using standard ester forming reactions. These esters can then be separated, for example, by selective crystallization. The separated diastereomeric esters can then be individually hydrolyzed under standard ester hydrolysis conditions to release the chiral alcohol in an enantiomerically enriched form.
(4) Selective reaction of chiral reagents (including enzymes) with one enantiomer of a racemic mixture—referred to as kinetic analysis.

  The compounds of the present invention have utility as selective D3 agonists in the treatment of disease states. There are many compounds that have activity as both D2 and D3 agonists; however, the use of such compounds is associated with the majority of side effects including nausea, vomiting, syncope, hypotension and bradycardia, of which Some cause serious concerns.

It has previously been mentioned that the effectiveness of prior art compounds is due to the ability to act on D2; however, D2 activity is implicated as a cause of the side effects detailed above.
The present invention provides selective D3 agonists. Unexpectedly, they have been found to be effective; while reducing the side effects associated with non-selective prior art compounds.

Accordingly, a further aspect of the present invention provides a compound of formula (I) for use as a medicament.
The compounds of the present invention are particularly useful for female sexual dysfunction, including female sexual dysfunction, female sexual arousal disorder, female sexual arousal disorder, female orgasmic disorder and sexual pain disorder, male erectile dysfunction, hypertension Useful for the treatment of neurodegenerative disorders, depression, and psychosis.

The present invention therefore provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment or prevention of sexual dysfunction.
The compounds of the present invention are useful for male sexual dysfunction, particularly male erectile dysfunction. Others known as male erectile dysfunction (MED), male erectile dysfunction,
“Unable to achieve and / or maintain penile erection for sufficient sexual activity” (NIH Consensus Development Panel on Impactence, 1993)
Is defined as

  The prevalence of erectile dysfunction (ED) of any degree (minimal, moderate and complete impotence) is 52% in men aged 40-70 years, and higher in people over 70 years (Melma 1999, J. Urology, 161, p5-11). The symptoms have a significant negative impact on the quality of life of individuals and their partners, often resulting in increased anxiety and tension leading to depression and low self-assessment. Twenty years ago, MED was initially thought to be a psychological disorder (Benet et al., 1994, Comp. Ther., 20: 669-673), but now for most individuals It is known that there is an underlying biological cause. As a result, considerable methods have been made to identify the mechanism of normal penile erection and the pathophysiology of MED.

  Penile erection is a hemodynamic event that depends on the balance of smooth and vascular contraction and relaxation of the cavernous corpus cavernosum (Lerner et al., 1993, J. Urology, 149, 1256-1255). Cavernous smooth muscle also refers herein to body smooth muscle, or plural corpus cavernosum. The relaxation of the smooth muscle of the cavernous body leads to increased blood flow to the trabecular space of the cavernous body, resulting in dilation to the envelope and compression of the drainage vein. This results in a significant increase in blood pressure resulting in an erection (Naylor, 1998, Br. J. Urology, 81, 424-431).

The changes that occur during the erection 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). Body smooth muscle is regulated by noradrenergic innervation of the sympathetic nervous system through active compounds of the postsynaptic α ₁ adrenergic receptor. MED may be associated with increased endogenous smooth muscle tone in the corpus cavernosum. However, the process of relaxation of the body's smooth muscle is mediated, in part, by non-adrenergic, non-cholinergic (NANC) neurotransmission. There are many other NANC neurotransmitters found in penis other than NO, such as calcitonin hereditary related peptide (CGRP) and vasoactive intestinal peptide (VIP). The main relaxing factor involved in mediating 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 the reduction of body smooth muscle tension can assist in the induction of cavernous relaxation by NO. During sexual arousal in males, NO is released from neurons and endothelium and binds to and activates soluble guanylate cyclase (sGC) localized in smooth muscle cells and endothelium, resulting in intracellular cyclic guanosine 3 ′, This leads to an increase in 5′-monophosphate (cGMP) levels. This increase in cGMP is in intracellular calcium concentration ([Ca ²⁺ ] _i ) via an unknown mechanism (possibly due to Ca ²⁺ pumps and Ca ²⁺ activated K ⁺ channels) that is thought to be associated with protein kinase G activation. It leads to relaxation of the corpus cavernosum due to the decrease.

  A number of potential sites have been identified within the central nervous system for modulation of sexual behavior. The major neurotransmitters are thought to be serotonin, norepinephrine, oxytocin, nitric oxide and dopamine. Sexual function can be modulated by mimicking the action of one of these major neurotransmitters. Dopamine D3 receptors are almost over-expressed in the brain, areas involved in reward, emotional and marginal areas of the cognitive process.

  Without being bound by any theory, “By virtue of its role in controlling motor activity, the integrity of the nigrostriatal dopaminergic pathway also appears to be essential for the presentation of mating behavior. Minutes, more specifically by sexual function, dopamine causes penile erections by acting on oxytocin neurons located in the periventricular nucleus of the hypothalamus, and possibly in the parasympathetic central part of the pre-erection sacrum in the spinal cord It seems that they can do it. " Currently, the important site is D3, not D2, which was previously considered.

In essence, D3 is an initiator of sexual behavior.
The present invention therefore provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment or prevention of sexual dysfunction.

  Patients with mild to moderate MED should benefit from treatment with compounds according to the present invention, and patients with severe MED can also be accommodated. However, early studies suggest that the response rate of patients with mild, moderate and severe MED is greater with selective D3 agonist / PDE5 inhibitor combinations. Mild, moderate and severe MED will be a term known to those skilled in the art, but the The Journal of Urology, vol. 151, 54-61 (Jan 1994) can find guidance.

Early studies suggest that the MED patient groups mentioned below should benefit from treatment with selective D3 agonists and PDE5i (or other combinations described below). These patient groups are more particularly described in Clinical Andology vol. 23, no. 4, p773-782, and I.I. Eardley and K.M. It is described in Chapter 3 of the book “Electile Dysfunction-Current Investigation and Management” by Setia, and includes: psychogenic, organ system, vascular system, endocrine system, neurological, arterial system, drug-induced sexual dysfunction (milking) And sexual dysfunction associated with cavernous factors, particularly venous.
Thus, the present invention provides the use of a compound of formula (I) in the manufacture of a medicament in combination with a PDE5 inhibitor for sexual dysfunction.

Suitable PDE5 inhibitors are described herein.
The compounds of the present invention may be used in female sexual dysfunction (FSD), particularly female sexual arousal disorder (FSAD), hyposexual desire disorder (HSDD; lack of interest in sex), FSAD with concomitant HSDD, And in the treatment or prevention of female orgasmic disorders (FOD; unable to reach orgasm).

  According to the present invention, FSD can be defined as the difficulty or inability of a woman to find satisfaction in sexual expression. FSD is a collective term for several diverse female sexual disorders (Leiblum, SR (1998)-Definition and Classification of female sex disorders. Int. J. Implant Res., 10, S104-S106; Berman, JR, Berman, L. & Goldstein, I. (1999)-Female sex dysfunction: Incidence, pathophysiology, evaluations and treatment options, 54, Urology 39, Urology 39. The woman may have lack of desire, excitement or difficulty in orgasm, pain during intercourse, or a combination of these problems. Several types of diseases, medications, injuries, or physiological problems can cause FSD. Treatments under development are aimed at treating specific FSD subtypes, primarily desire and arousal disorders.

  The category of FSD is best defined by contrasting them to the normal female sexual response: desire, arousal, and orgasm stages (Leiblum, SR (1998) -Definitions and Classification of female sexual disorders.Int.J.Impotence Res., 10, S104-S106). Desire or libido is an impulse for sexual expression. The expression often includes sexual thinking when in a relationship with an interested partner or when exposed to other sexual stimuli. Excitement is the response of the vasculature to sexual stimulation (an important component of which is genital hyperemia) and includes increased vaginal lubrication, vaginal dilation, and increased genital sensation / sensitivity. Orgasm is the release of sexual tension that culminates during arousal.

  Thus, FSD occurs when a woman has an inadequate or unsatisfactory response in any of these phases, usually desire, excitement, orgasm. The categories of FSD include hypo libido disorder, sexual arousal disorder, orgasm disorder, and sexual pain disorder. The compounds of the present invention improve genital response to sexual stimulation (such as in female sexual arousal disorders), but when doing so, also improve pain, anxiety and discomfort associated with sexual intercourse Other sexual disorders can also be treated.

  Decreased libido is present when a woman has no or little desire to be sexual and has little or no sexual thought or illusion. This type of FSD may be caused by low testosterone levels due to either natural menopause or surgical menopause. Other causes include illness, medication, fatigue, depression, and anxiety.

  Female sexual arousal disorder (FSAD) is characterized by inadequate genital response to sexual stimulation. The genitals do not lead to hyperemia characterizing normal sexual arousal. Intercourse is painful because the vaginal wall hardly lubricates. Orgasm can also be disturbed. Arousal disorders can be caused by estrogen reduction during menopause or after childbirth, and during lactation, and due to illnesses with vascular components such as diabetes and arteriosclerosis. Other causes arise from treatment with diuretics, antihistamines, antidepressants such as selective serotonin reuptake inhibitors (SSRIs), or antihypertensive agents.

  Sexual pain disorders (including sexual pain and vaginal spasticity) are characterized by pain resulting from insertion and do not lubricate, endometriosis, pelvic inflammatory disease, inflammatory bowel disease, or urinary tract problems Can be caused by.

  As discussed above, D3 is believed to be an initiator of sexual behavior. The clitoris is thought to be a penile homolog (Levin, RJ (1991), Exp. Clin. Endocrinol., 98, 61-69); the same mechanism that gives an erectile response in men is directed against FSD Produces increased genital blood flow in women with associated effects. In addition, there are changes in active and passive sexual behavior.

  That is, according to a preferred embodiment of the present invention, treatment or prevention of female sexual dysfunction, more specifically, sexual desire disorder, female sexual arousal disorder, female orgasmic disorder, and sexual pain disorder. There is provided the use of a compound of formula (I) in the manufacture of a medicament for

  Preferably, the compound of formula (I) is for the treatment or prevention of female sexual arousal disorder (FSAD), FSAD with concomitant hyposexual desire disorder, orgasmic disorder, and hyposexual desire disorder, and most Preferably, it is useful for the treatment or prevention of female sexual arousal disorder.

In a preferred embodiment, the compounds of formula (I) are useful in the treatment of patients with female sexual arousal disorders and concomitant hyposexual desire disorders.
Female Sexual Arousal Disorder (FSAD) has been identified by the American Psychiatric Diagnosis and Statistical Manual (DSM) IV as “continuing to achieve or maintain a sufficient lubrication-swelling response of sexual arousal by the completion of sexual activity. Sexual or recurrent disability. This disorder must cause significant anxiety and interpersonal difficulties. "
It is said that.
The evoked response consists of vascular congestion in the pelvis, vaginal lubrication, and dilation and expansion of the external genitalia. This disorder causes significant anxiety and / or difficulties between individuals.

  FSAD is a highly prevalent sexual disorder that affects women before, during, and after menopause (± hormone replacement therapy (HRT)). This is associated with comorbidities such as depression, cardiovascular disease, diabetes, and genitourinary (UG) disorders.

  The primary consequences of FSAD are lack of hyperemia / inflation, lack of lubrication, and lack of enjoyable genital sensation. The secondary consequences of FSAD are reduced sexual desire, pain during intercourse, and difficulty in reaching orgasm.

  Recently, the hypothesis that at least some patients with FSAD symptoms have a basal cause of the vasculature has been proposed (Goldstein et al., Int. J. Impot. Res., 10, S84-S90, 1998), Animal data supports this view (Park et al., Int. J. Impot. Res., 9, 27-28, 1997).

  R. J. et al. Levin argues that “male and female genital organs develop from a common tissue primordium, and that male and female genital structures are homologous to each other. "It is a penile homolog and the scrotum is a labia homolog" (Levin, RJ (1991), Exp. Clin. Endocrinol., 98, 61-69).

Candidate drugs for treating FSAD that are being investigated for efficacy are primarily erectile dysfunction drugs that promote circulation to the male reproductive tract.
The compounds of the present invention are advantageous by providing a means to restore a normal sexual arousal response, i.e., increased genital blood flow resulting in redness of the vagina, clitoris, and labia. This will result in increased vaginal lubrication through plasma filtration, increased vaginal compliance, and increased genital sensitivity. Thus, the compounds of the present invention provide a means to restore or enhance normal sexual arousal responses.

  Thus, according to a preferred aspect of the present invention, the formula (I) in the manufacture of a medicament for the treatment or prevention of female sexual arousal disorder and female sexual arousal disorder with concomitant hyposexual desire disorder Use of the compound is provided.

  As used herein for female reproduction, Applicant states, “The reproductive organs consist of internal and external groups. The internal organs are located in the pelvis and consist of the ovaries, fallopian tubes, uterus and vagina. , On the surface of the urogenital septum, below the pelvic arch, they constitute the pubic cone, the large and small labia, the clitoris, the vestibule, the vestibular bulb, and the large vestibular gland. " C.D. Elemente, 13th edition, American edition).

The compounds of the invention are applied to the following subpopulations of patients with FSD: young, elderly, premenopausal, menopausal, postmenopausal women who are or are not receiving hormone replacement therapy.
The compounds of the present invention find application in patients with FSD resulting from:
i) Angiogenic etiology such as cardiovascular or arteriosclerotic disease, hypercholesterolemia, smoking, diabetes, hypertension, radiation and perineal trauma, traumatic damage to the genital vasculature of the lower iliac abdomen.
ii) Neurogenic etiology such as spinal cord injury or central nervous system disease (including multiple sclerosis, diabetes, Parkinson's disease, cerebrovascular accident, peripheral neuropathy, trauma, or radical pelvic surgery).
iii) Hypothalamic / pituitary / gonadal dysfunction, or ovarian dysfunction, pancreatic dysfunction, surgical or medical castration, androgen deficiency, high circulating levels of prolactin such as hyperprolactinemia, natural Hormonal / endocrine etiology such as menopause, premature ovarian failure, hyperthyroidism and hypothyroidism.
iv) depression, obsessive-compulsive disorder, anxiety disorder, postpartum depression / "baby blue", emotional and relationship issues, performance anxiety, gender disagreement, sexual dysfunction attitudes, sex phobia, religious inhibition, Or psychogenic etiology such as previous trauma experience.
v) Drug induction resulting from treatment with selective serotonin reuptake inhibitors (SSRIs) and other antidepressants (tricyclic compounds and major tranquilizers), antihypertensive, sympathetic blockade, and chronic oral contraceptive therapy Sexual dysfunction.

The compounds of the present invention are also useful in the treatment of depression.
Dopamine D3 receptors are almost over-expressed in the peripheral regions of the brain, regions involved in reward, emotional and cognitive processes. Chronic treatment with several classes of antidepressants is known to increase the expression of D3 in the surrounding area, and the effect of desipramine antidepressants has been demonstrated on the nucleus accumbens (D3 rich) It was possible to block when sulpiride (D2 / D3 antagonist) was injected into the region), but not when injected into the caudate nuclear putamen (region rich in dopamine D2 receptor). In addition, the effects of antidepressants were observed in patients treated with a preclinical model of depression, pramipexole (D3 preferred D2 / D3 agonist). Available information suggests that D3 receptors mediate antidepressant activity and that selective D3 receptor agonists represent a new class of antidepressants. Since antidepressants are known to be effective for other psychiatric disorders, D3 agonists have the potential to treat psychosis.

  Suitable symptoms include depression (eg, depression in cancer patients, depression in Parkinson's disease patients, depression after myocardial infarction, subsyndromic depression, depression in infertile women, severe depression, child abuse induction Depression, postpartum depression, and dysphoric geriatric syndrome), one-time seizure or recurrent severe depression disorder, dysthymic disorder, depressive neurosis and neurotic depression, anorexia Melancholic depression including weight loss, insomnia, early morning awakening or psychomotor delay; appetite, hypersomnia, psychomotor agitation or excitability, seasonal emotional disorder, and atypical depression (including childhood depression) (or Reactive depression); bipolar disorder or manic depression, eg bipolar I disorder, bipolar II disorder and circulatory disease; behavioral disorder; disruptive behavioral disorder; hair loss, stealing, hyperactivity disorder (ADHD); Behavioral disorder, autistic disorder associated with intellectual disability; Sexual personality disorder; avoidance personality disorder; anxiety disorder with or without agoraphobia, agoraphobia with no history of anxiety disorder, specific phobias such as specific animal phobia, social anxiety, social phobia, obsessive Stress disorders including neuropathy, post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorder; emotional anxiety, pathological crying; schizophrenia and other mental disorders such as schizophrenia-like disorder, schizophrenia Psychosis such as disability, delusional disorder, short-term mental disorder, common mental disorder, mental disorder with delusions and fantasy, anxiety psychiatric symptoms, anxiety associated with psychosis, severe serious depressive disorder Disorders; mood disorders associated with psychotic disorders such as acute mania and depression associated with bipolar disorders; mood disorders associated with schizophrenia; eating disorders (eg anorexia and bulimia), obesity; movement disorders Eg immobility, dyskinesia, familial paroxysmal dyskinesia, spasm, Tourette syndrome, Scott syndrome, PALSYS and immobility stiff syndrome; extrapyramidal movement disorders such as drug-induced movement disorders such as neuroleptic drug-induced parkinsonism , Neuroleptic malignant syndrome, neuroleptic-induced acute ataxia, neuroleptic-induced acute restlessness, neuroleptic-induced delayed dyskinesia and drug-induced postural vibration; drug dependence and addiction (eg, alcohol, heroin, Cocaine, benzodiazepine, nicotine, or phenobarbitol dependence or addiction), and behavioral addiction, such as gambling addiction; eye disorders such as glaucoma and ischemic retinopathy; sleep disorders (weakness attacks) and shock.

In a further preferred embodiment, the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment of depression or psychiatric disorder.
Suitable depression symptoms and mental disorders are described above.
In an additional further aspect, the present invention provides the use of a compound of formula I in the manufacture of a medicament for the treatment of obesity.

  The compounds of the present invention also have utility in the treatment of neurodegeneration; the source of neurodegeneration is neurotoxic effects; visual pathways, such as cerebral infarctions in the retina, optic nerve and / or occipital lobe Blindness caused by neurodegeneration of the brain; including epileptic seizures; and from dysfunction of glucose and / or oxygen supply to the brain.

  Symptoms associated with neurodegeneration include restless leg syndrome, Huntington's disease, multiple sclerosis, mild cognitive impairment, Down's syndrome, cerebral infarction, hereditary cerebral hemorrhage with Dutch amyloidosis, cerebral amyloid angiopathy, hallucinations, cognition , Age-related cognitive decline (ARCD), and amnesia and other cognitive or neurodegenerative disorders such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, Alzheimer type cognition Dysfunction, memory impairment, loss of executive function, vascular dementia, mixed vascular and degenerative dementia, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, cortical basal degeneration Dementia, multiple infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumor or brain trauma, hunting Dementia associated with dermatitis, Pick disease, Creutzfeldt-Jakob disease, dementia associated with HIV or AIDS, extensive Lewy bodies of Alzheimer's disease, frontotemporal dementia with Parkinson's syndrome, head trauma, spinal cord Injury, demyelinating disease of the nervous system, peripheral neuropathy, pain, cerebral amyloid angiopathy, amyotrophic lateral sclerosis, multiple sclerosis, movement disorder associated with dopamine agonist treatment, intellectual disability, reading disorder, arithmetic Disability or learning disabilities, including written expression disorders; including age-related cognitive decline, amnestic disorders, nerve blockade-induced Parkinsonism, tardive dyskinesia, and acute and chronic neurodegenerative disorders.

The present invention therefore provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment of neurodegeneration.
Suitable neurodegenerative symptoms are described above.
In addition to their role in the treatment of sexual dysfunction, depression, neurodegeneration and psychiatric disorders, the compounds of the present invention may be effective for a number of additional indications.

Therefore, the present invention relates to hypertension, premature ejaculation, obesity, cluster headache, migraine, pain, endocrine disorders (eg hyperprolactinemia), vasospasm (especially in the cerebral vasculature), cerebellar ataxia, digestion Drugs for the treatment of vascular disorders (related to changes in movement and secretion), premenstrual syndrome, fibromyalgia syndrome, stress urinary incontinence, hair loss and chronic paroxysmal migraine, headache (related to vascular disorders) Use of a compound of formula (I) in the manufacture of
It should be appreciated that all references to treatment herein include treatment, pain relief and prophylactic treatment.

D3 / D2 agonist assay The activity at the dopamine D3 receptor can be determined using the method described in WO2004 / 052372. Using this assay, all of the compounds of the present invention can display functional potential at the D3 receptor expressed as EC ₅₀ , lower than 1000 nM and 10 times higher than D3 compared to D2. There is selectivity. Selectivity is calculated as a value obtained by dividing an _{EC 50} value of D2 with _{an EC 50} value of D3. If the EC _{50 for} D2 was greater than 10,000, a number of 10,000 was used in the calculation.

The compound of Example 14 was expressed as an EC ₅₀ of 20 nM using an Emax (maximum response value) of 98% (compared to the maximum effect of the standard reagent pramipexole). For the D2 receptor, the compound gave only a 22% response (compared to the maximum effect of pramipexole) at 10000 nM.
Pre-active reagents suitable for use in the combinations of the present invention include:

1) Naturally occurring or synthetic prostaglandins or their esters. Prostaglandins suitable for use herein include alprostadil, prostaglandin E ₁ , prostaglandin E ₀ , 13,14-dihydroprostaglandin E ₁ , prostaglandin E ₂ , eprostinol ), Natural, synthetic and semi-synthetic prostaglandins, including those described in WO-00033825 and / or US Pat. No. 6,037,346 (issued March 14, 2000), all incorporated herein by reference. And their derivatives, PGE ₀ , PGE ₁ , PGA ₁ , PGB ₁ , PGF ₁ α, 19-hydroxy PGA ₁ , 19-hydroxy-PGB ₁ , PGE ₂ , PGB ₂ , 19-hydroxy-PGA ₂ , 19 - hydroxy -PGB _2, PGE ₃ α, carboxymethyl Prost-door Including Metamin-dinoprost, tromethamine, dinoprostone, Ripopurosuto (lipoprost), gemeprost, compounds such as Metenopurosuto (metenoprost), sulprostone (sulprostune), Chiapurosuto and Mokishishireto (moxisylate).

2) α-Adrenergic receptor antagonist compounds are also known as α-adrenergic receptors or α-receptors or α-blockers. Compounds suitable for use herein are alpha-adrenergic receptor blockers described in PCT application WO 99/30697 published Jun. 14, 1998 (the disclosure relating to adrenergic receptors therein). Are incorporated herein by reference), including selective α ₁ -adrenergic receptors or α ₂ -adrenergic blockers and non-selective adrenergic blockers, suitable α ₁ -adrenergic receptor blockers include phentolamine , Phentolamine mesylate, trazodone, alfuzosin, indolamin, naphthopidyl, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan, efaraxan, yohimbine, lauolfa alkaloids, Record 15/2739, SNAP1069, SNAP5089, RS17053, SL89.0591, doxazosin, terazosin, Abanokiru (abanoquil), and prazosin; US6,037,346 [2000 March 14] of alpha ₂ - blockers blocking agents Jibenarunin (Dibenarnine ), Tolazoline, trimazosin and dibenarnin; U.S. Pat. Nos. 4,188,390; 4,026,894; 3,511,836; 4,315,007; 3, each incorporated herein by reference. 527,761; 3,997,666; 2,503,059; 4,703,063; 3,381,009; 4,252,721 and 2,599,000 including α-adrenergic receptors ; α ₂ - ad Nalin receptor blockers, optionally in the presence of a cardiotonic like Pirukisamin (pirxamine), including clonidine, papaverine, and papaverine.

3) NO donor (NO agonist) compound. NO donor compounds suitable for use herein include trinitroglycerin (also known as nitroglycerin), isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, nitroprusside Sodium (SNP), 3-morpholinoside nonimine molsidomine, S-nitroso-N-acetylpenicillamine (SNAP), S-nitroso-N-glutathione (SNO-GLU), N-hydroxy-L-arginine, amylni Tratate, linsidomine, linsidomine chlorohydrate, (SIN-1) S-nitroso-N-cysteine, diazeniumdiolate, (NONO art), 1,5-pentanedinitrate, L-arginine Nitrosylated maxilyte derivatives such as NMI-678-11 and NMI-937 described in published PCT application WO0012075, Ginseng, zizphi fructus, molsidomine, Re-2047. Including organic nitrates or organic nitrates such as mono-, di- or tri-nitrates.

4) Potassium channel opener and regulator. Suitable potassium channel openers / modulators for use herein include nicorandil, cromokalim, lebucromacarim, remakalim, pinacidil, clearazoxide, minoxidil, caribodotoxin, glyburide, 4-aminipyridine, a ₂ is included.

5) Vasodilator. Vasodilators suitable for use herein include nimodipine, pinacidil, cyclandelate, isoxsuprine, chloroplumazine, Rec 15/2739, trazodone.
6) Thromboxane A2 agonists.
7) CNS activator.

8) ergot alkaloids; suitable ergot alkaloids are described in US Pat. No. 6,037,346 issued on March 14, 2000, and include acetergamine, brazergoline, bromerguride, Cyanergoline, delorgotrile, disulerginine, ergotamine maleate, ergotamine tartrate, etherergine, erysergerine, erysergerine ) Including nicergoline, pergolide, Puropiserujido (propisergide), the proterguride (proterguride) and terguride.

9) Modulate the action of sodium utilization factors, specifically atrial natriuretic factor (also known as atrial sodium peptide), B and C type natriuretic factors such as inhibitors or neutral endopeptidases Compound.

10) A compound that inhibits an angiotensin converting enzyme such as enapril, and an angiotensin converting enzyme such as omapatrilate and a neutral endopeptidase combined inhibitor.

11) Angiotensin receptor antagonists such as losartan.
12) Substrate for NO synthase such as L-arginine.
13) Calcium channel blockers such as amlodipine.

14) Endothelin receptor antagonists and inhibitors or endothelin converting enzymes.
15) Cholesterol lowering agents such as statins (eg atorvastatin / Lipior-trademark) and fibrates.

16) Antiplatelet and antithrombotic agents such as tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin, thromboplastin activator inhibitors.
17) Insulin sensitizers such as resulin and hypoglycemic agents such as glipizide.
18) Acetylcholinesterase inhibitors such as donezipil.

19) A steroidal or non-steroidal anti-inflammatory agent.
20) Estrogen receptor modulators and / or estrogen agonists and / or estrogen antagonists, preferably raloxifene or lasofoxifene, (−)-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl) -Ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol and pharmaceutically acceptable salts thereof, the preparation thereof is detailed in WO 96/21656.

21) PDE inhibitors, more specifically PDE2, 3, 4, 5, 7 or 8 inhibitors, preferably PDE2 or PDE5 inhibitors, and most preferably PDE5 inhibitors (see below), preferably each Inhibitors with an IC ₅₀ of less than 100 nM for enzymes (however, PDE3 and PDE4 inhibitors are administered topically or only injected into the penis).

22) By vasoactive intestinal protein (VIP), VIP mimetics, VIP analogs, more specifically by one or more VIP receptor subtypes VPAC1, VPAC or PACAP (pituitary adenylate cyclase activating peptide) Mediated, one or more VIP receptor agonists or VIP analogs (eg Ro-125-1553) or VIP fragments, one or more alpha-adrenergic receptor antagonists and VIP combinations (eg Invicorp, Avidadil) .

23) Melanocortin receptors (specifically MC3 or MC4 subtype) agonists or modulators or melanocortin potentiators, such as melanotan II, PT-14, PT-141, or WO-09644002, WO-00074679, WO Such as the compounds claimed in -0995679, WO-00105401, WO-00058361, WO-00114879, WO-00113112, WO-0995358.

24) Serotonin receptor agonists, antagonists or modulators, more specifically 5HT1A (including VML670), 5HT2A, 5HT2C, 5HT3, and those described in WO-09902159, WO-0000002550 and / or 00002993 An agonist, antagonist or modulator for the 5HT6 receptor.

25) Testosterone supplements (including dehydroandrostenedione), testosterone, dihydrotestosterone or testosterone implants.

26) Estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) (ie as a combination), or estrogen and methyltestosterone hormone replacement therapy (eg HRT, especially premarin, senestine, oestrofeminal), Equin, Estrace, Estrofem, Eleste Solo, Estring, Eastradarm TTS, Eastradarm Matrix, Dermestril, Premphase, Preempro (Preempro), Prempak, Premix, Stra test, es tiger test HS, tibolone).

27) Modulators of noradrenaline, dopamine and / or serotonin transporters, such as bupropion, GW-320659.
28) Purine receptor agonists and / or modulators.

29) Neurokinin (NK) receptor antagonists, including those described in WO-09964008.
30) Opioid receptor agonists, antagonists or modulators, preferably agonists for the ORL-1 receptor.

31) An agonist, antagonist or modulator for the oxytocin receptor, preferably a selective oxytocin agonist or modulator.
32) Modulator of cannabinoid receptor.

33) SEP inhibitors (SEPi), eg SEPi having an IC ₅₀ of less than 100 nM, more preferably less than 50 nM.
Preferably, the SEP inhibitors according to the present invention have a selectivity greater than 30-fold, more preferably greater than 50-fold over SEP compared to neutral endopeptidase NEP EC 3.4.24.11 and angiotensin converting enzyme (ACE). Have Preferably, SEPi also has a selectivity greater than 100-fold compared to endothelin converting enzyme (ECE).

34) Antagonists or modulators for NPY (especially Y1 and Y5 subtype) receptors.
35) A sex hormone binding globulin antagonist or modulator that inhibits estrogen and / or androgen from binding.

36) Arginase II inhibitor.
37) An agonist, antagonist or modulator for the vasopressin receptor, preferably selective for the V1a receptor.

38) PDE5 inhibitor. Suitable PDE inhibitors are
5- [2-Ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] Pyrimidin-7-one (sildenafil), 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-ethyl-piperazin-1-yl-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2 , 4] Triazin-4-one (Vardenafil);
5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine- 7-on;
5- (5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine- 7-on; and
5- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one;
4-[(3-Chloro-4-methoxybenzyl) amino] -2-[(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -N- (pyrimidin-2-ylmethyl) pyrimidine-5-carboxamide (TA-1790);
3- (1-Methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -N- [2- (1-methylpyrrolidine-2 -Yl) ethyl] -4-propoxybenzenesulfonamide (DA8159)
And pharmaceutically acceptable salts thereof.
39) A selective dopamine D4 receptor agonist such as 2-[(4-pyridin-2-ylpiperazin-1-yl) methyl] -1H-benzimidazole (ABT724).

  By cross-reference in this specification to the compounds contained in patents and patent applications that can be used according to the invention, Applicants can claim the claims (especially claim 1) and specific examples (all by reference). Means a therapeutically active compound as defined in (incorporated herein).

Then, when combinations of active agents are administered, they can be administered simultaneously, separately or sequentially.
The compounds of formula I are suitable for selecting the most suitable dosage form and route of administration for the treatment of the proposed indications, in order to select their biopharmaceutical properties such as solubility and solution stability (over the whole pH range). ) And should be evaluated for permeability.

  The compounds of the present invention intended for pharmaceutical use can be administered as crystalline or amorphous products. They can be obtained as solid plugs, powders, or coatings by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporation drying. Microwave or high frequency drying can be used for this purpose.

  They can be administered alone or in combination with one or more compounds of the invention, or in combination with (or as any combination thereof) one or more other agents. Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term “excipient” is used herein to describe any ingredient other than the compound (s) of the invention. The choice of excipient will to a large extent depend on 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 delivery of the compounds of the present invention and methods for their production will be readily apparent to those skilled in the art. Such compositions and methods for their production can be found, for example, in Remington's Pharmaceutical Sciences , 19th Edition (Mack Publishing Company, 1995).

Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable diluent or carrier.
The compounds of the present invention can be administered orally. Oral administration involves swallowing the compound to enter the gastrointestinal tract and / or the compound enters the bloodstream directly from the mouth by mouth, tongue, or sublingual administration.

  Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particles, liquids or powders; lozenges (including those filled with liquids) Gels; immediate dispersion dosage forms; films; ovules; sprays; and mouth / mucoadhesive patches.

  Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as soft or hard capsule dressings (eg made from gelatin or hydroxypropylmethylcellulose) and are typically carriers such as water, ethanol, polyethylene glycol, propylene Includes glycols, methylcellulose, or suitable oils, and one or more emulsions and / or suspensions. Liquid formulations can also be manufactured by reconstitution from a solid, for example a sachet.

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

  For tablet dosage forms, depending on dosage, the drug can be prepared from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium glycolate starch, carboxymethylcellulose sodium, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, Contains α-starch and sodium alginate. Generally, the disintegrant will comprise 1% to 25%, preferably 5% to 20% by weight of the dosage form.

  Binders are commonly used to give cohesiveness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, saccharides, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, α-starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets can also contain diluents such as lactose (monohydrate, spray dried monohydrate, anhydride, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dicalcium phosphate Contains dihydrate.

  Tablets also optionally include surface active agents such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactant may consist of 0.2% to 5% by weight of the tablet and the glidant may consist of 0.2% to 1% by weight of the tablet. Good.

  Tablets also typically contain a lubricant, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, a mixture of magnesium stearate and sodium lauryl sulfate. The lubricant is generally composed of 0.25 wt% to 10 wt%, preferably 0.5 wt% to 3 wt% of the tablet.

Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and flavor masking agents.
Typical tablets have up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegration. And 0.25 wt% to about 10 wt% lubricant.

  Tablet blends can be compressed directly or by roller to form tablets. The tablet blend or portion of the blend may alternatively be wet, dry or melt granulated, melt solidified, or molded prior to tableting. The final formulation may constitute one or more layers and may or may not be coated; further encapsulated.

Tablet formulation is described in H.C. Lieberman and L.L. Pharmaceutical Dosage Forms by Lachman : Tables , Vol. 1 (Marcel Dekker, New York, 1980).

  Oral films consumed for human or veterinary use are typically flexible water-soluble or water-swellable film dosage forms that can rapidly dissolve or adhere to the mucosa, and typically Is composed of a compound of formula I, a film-forming polymer, a binder, a solvent, a wetting agent, a plasticizer, a stabilizer or emulsifier, a viscosity modifier, and a solvent. Some components of the formulation can perform more than one function.

  The compound of formula I can be water-soluble or insoluble. The water soluble compound typically constitutes 1% to 80% by weight of the solute, more typically 20% to 50% by weight. Slightly soluble compounds comprise a greater proportion of the composition, typically up to 88% by weight of the solute. Alternatively, the compound of formula I may be in the form of multiparticulate beads.

  The film-forming polymer can be selected from natural polysaccharides, proteins, or synthetic hydrocolloids, and typically ranges from 0.01 to 99% by weight, more typically 30 to 80% by weight. It exists in the range.

  Other possible ingredients are antioxidants, colorants, flavors and flavor enhancers, preservatives, saliva stimulants, cooling agents, cosolvents (including oils), softeners, fillers, antifoaming agents, surfaces Contains active agent and flavor masking agent.

  Films according to the present invention can typically be prepared by evaporating and drying a thin water-soluble film coated on a peelable backing support or paper. This can be done in a dryer or drying room, typically by a coater dryer combination, or by lyophilization or vacuum.

  Solid formulations for oral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed compounded releases.

A modified release formulation suitable for the purposes of the present invention is described in US Pat. No. 6,106,864. Details of other suitable release technologies such as high energy dispersants and osmotic and coated particles should be found in Pharmaceutical Technology On-line , 25 (2), 1-14 (2001) by Verma et al. . The use of chewing gum to achieve controlled release is described in WO 00/35298.

  The compounds of the present invention can also be administered directly, into the bloodstream, intramuscularly, or into the viscera. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for parenteral use include needle (including microneedle) injection devices, needleless injection devices and infusion techniques.

  Parenteral preparations are typically aqueous solutions that can contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of 3-9), but for some applications For, they can be more suitably formulated as sterile non-aqueous solutions or dry forms for use with a suitable vehicle such as sterile pyrogen-free water.

Preparation of parenteral formulations under aseptic conditions, such as lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.
The solubility of compounds of formula I used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques, such as the introduction of solubility enhancers.

  Formulations for parenteral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release. That is, the compounds of the invention can be administered as a suspension for administration, or as a solid, semi-solid, or thixotropic liquid, as an embedded reservoir that provides controlled release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions containing drug-filled poly (dl-lactic-co-glycolic acid) (PGLA) microspheres.

  The compounds of the present invention can also be administered topically, dermally (in the skin), or transdermally to the skin or mucosa. Topical administration for this purpose includes gels, hydrogels, lotions, solutions, creams, ointments, sprays, dressings, foams, films, skin patches, water, implants, sponges, fibers, bandages, and microemulsions including. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers can be introduced, see for example J Pharm Sci, 88 (10), 955-958 (October 1999) by Finnin and Morgan.

  Other means of local administration include electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (eg, Powderject ™, Bioject ™, etc.) infusion devices.

  Formulations for topical administration can be formulated to be immediate and / or controlled release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

  The compounds of the present invention may also be administered intranasally or by inhalation, typically from a dry powder inhaler, to a dry powder (alone, as a mixture, eg, as a dry blend with lactose, or as a mixed component particle, eg, phosphatidylcholine). In the form of a phospholipid such as, a pressurized container, a pump, a spray, a nebulizer (preferably a nebulizer using electrohydrodynamics to produce a fine mist), or 1,1,1,2-tetrafluoro It can be administered as a nebulizer with or without a suitable propellant such as ethane or 1,1,1,2,3,3,3-heptanefluoropropane, or nasal drops. For intranasal use, the powder may constitute a bioadhesive agent, for example, chitosan or cyclodextrin.

  Pressurized containers, pumps, sprays, nebulizers, or nasal drops contain solutions or suspensions of the compound (s) of the invention, eg, ethanol, aqueous ethanol solutions, or dispersion, solubilization, or active agents. Alternative agents suitable for extended release of the drug, penetration enhancer (s) such as solvents, and optional surfactants such as sorbitan trioleate, oleic acid, or oligolactic acid.

  Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for transport by inhalation (typically less than 5 microns). This can be achieved by suitable grinding methods such as spiral jet mill, supercritical fluid processing, forming nanoparticles, high pressure homogenization, or spray drying.

  Capsules (eg prepared from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator are powder mixtures, lactose or starches of the compounds of the invention And a suitable performance base such as l-leucine, mannitol, or magnesium stearate can be formulated. Lactose can be anhydrous or in the form of a monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

  Suitable solution formulations for use in nebulizers with electrohydrodynamics to generate fine mist contain 1 μg to 20 mg of the compound of the invention per actuation, and the working volume may vary from 1 μl to 100 μ. it can. A typical formulation may comprise a compound of formula I, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

Suitable flavoring agents such as menthol and levomensole, or sweetening agents such as saccharin or saccharin sodium can be added to the formulations of the invention intended for inhaled / intranasal administration.
Formulations for inhalation / intranasal administration can be formulated to be immediate and / or controlled release using, for example, PGLA. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

  In the case of dry powder inhalers and nebulizers, the dosing unit is determined using the value that transports the measured amount. The unit according to the invention is typically a compound of the formula I. . . ~. . . A measured dose containing μg is arranged to be administered or “puffed”. The total daily dose can typically be administered as a single dose or, more usually, as divided doses throughout the day. . . μg˜. . . It will be in the μg range.

  The compounds of the present invention can be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate.

  Formulations for rectal / vaginal administration can be formulated to be immediate and / or controlled release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

  The compounds of the invention may also be administered directly to the eye or ear, typically in the form of a finely divided suspension or solution dropwise in an isotonic, pH-adjusted sterile buffer. it can. Other formulations suitable for ophthalmic and otic administration include ointments, gels, biodegradable (eg absorbable gel sponges, collagen) and non-biodegradable (eg silicon) implants, wafers, lenses and microparticles or vesicle systems, For example, niosomes or liposomes are included. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, heteropolysaccharide polymers such as gellan gum can be introduced with preservatives such as benzalkonium chloride it can. Such formulations can also be transported by iontophoresis.

  Formulations for ophthalmic / ear administration can be formulated for immediate and / or controlled release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, or programmed release.

  The compounds of the present invention may be soluble polymeric entities to improve their solubility, dissolution rate, flavor masking, bioavailability and / or stability for use in any of the foregoing modes of administration. For example cyclodextrin and suitable derivatives thereof, or polyethylene glycol-containing polymers.

  Drug-dextrin complexes are found to be generally useful, for example, in the best dosage form and route of administration. Both encapsulated and non-encapsulated complexes can be used. As an alternative to affecting complexation with the drug, cyclodextrin can be used as a preliminary adduct, ie, carrier, diluent, or solubilizer. The most commonly used for these purposes are α-, β- and gamma-cyclodextrins, examples of which are described in International Patent Application No. It can be found in WO91 / 11172, WO94 / 02518 and WO98 / 55148.

  For example, for the purpose of treating a particular disease or condition, it is desired to administer a combination of active compounds, so that two or more pharmaceutical compositions contain at least one compound according to the present invention, and the composition It is within the scope of the present invention that it can be conveniently combined in the form of a kit suitable for simultaneous administration of products.

  That is, the kit of the invention contains two or more separate pharmaceutical compositions, at least one contains a compound of formula I according to the invention and can be a container, divided bottle, or divided foil. Means for holding the compositions separately, such as packets. An example of such a kit is the familiar blister pack used to pack tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different compositions at different dosing intervals or for administering different dosage forms, eg oral and parenteral, to balance the balance of the different compositions with respect to each other. ing. To assist compliance, the kit typically includes instructions for administration and can provide so-called memory aids.
The invention is illustrated by the following non-limiting examples, in which the following abbreviations and definitions are used.

¹ H nuclear magnetic resonance (NMR) spectra were consistent with the proposed structure in all cases. Characteristic chemical shifts (δ) are conventional abbreviations for indicating the main peak: eg, s, singlet; d, doublet; t, triplet; q, quadruple; m, multiple line; br, using broad, given from tetramethylsilane downfield in parts per million of [delta] _H. The following abbreviations are used for common solvents: CDCl ₃ , 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, it means silica gel TLC using silica gel 60F ₂₅₄ plates, where R _f is the distance traveled by the compound on the TLC plate divided by the distance traveled by the solvent front. Is.

Example 1
5-[(2R) -4-Benzylmorpholin-2-yl] pyridin-2-amine

Morpholine from product 7 (2.05 g, 6 mmol) was dissolved in ethanol (75 mL), hydroxylamine hydrochloride (2.05 g, 30 mmol) was added and the mixture was heated at 80 ° C. overnight (about 16 hours). . After cooling to room temperature, the reaction mixture was evaporated to dryness to a yellow oily residue, dichloromethane / methanol / 0.880 NH ₃ 98: 2: 0 to 95: 5: 0, then 95: 5: 0. Purification by flash chromatography on silica gel eluting with 5 and then increasing polarity to 90: 10: 1 gave the title compound (645 mg, 40%).

Example 2
5-[(2R) -morpholin-2-yl] pyridin-2-amine

Benzylmorpholine from Example 1 (990 mg, 3.7 mmol) is dissolved in methanol (20 mL), ammonium formate (1.16 g, 18.5 mmol) is added followed by 10% Pd on carbon (495 mg) and the mixture is refluxed. And heated for 2 hours. The cooled reaction mixture was filtered through a plug of arbocel® and evaporated to give an orange solid (1.49 g). This material is purified by flash chromatography on silica gel (compound pre-absorbed onto silica) eluting with dichloromethane / methanol / 0.880 NH ₃ 90: 10: 1 to give the title compound as a white solid. (467 mg, 70%).

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

Morpholine from Example 2 (80 mg, 0.45 mmol) was dissolved in tetrahydrofuran (15 mL) and 3-phenylpropionaldehyde (59 μL, 0.45 mmol) was added as a solution in tetrahydrofuran (15 mL) over 15 minutes. After the addition was complete, sodium triacetoxyborohydride (227 mg, 1 mmol) was added and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was then diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (2 × 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 / 0.880 NH ₃ 98: 2: 0.2 with increasing polarity to 95: 5: 0.5 gave the title compound (51 mg, 38 %).

Example 4
5-[(2R) -4-butylmorpholin-2-yl] pyridin-2-amine

Morpholine from Example 2 (80 mg, 0.45 mmol) was mixed with tetrahydrofuran (10 mL) (partially dissolved) and butyraldehyde (40 μL, 0.45 mmol) was added to give a homogeneous solution. The reaction mixture was stirred for an additional 30 minutes and sodium triacetoxyborohydride (227 mg, 1 mmol) was added. The reaction mixture was then stirred at room temperature overnight (about 16 hours), diluted with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were separated, dried (MgSO ₄ ), filtered and evaporated to give a yellow oil. Purification by flash chromatography on silica gel eluting with dichloromethane / methanol / 0.880 NH ₃ 98: 2: 0.2 with increasing polarity to 95: 5: 0.5 gave the title compound (17 mg, 16 %).

Example 5
5-[(2R) -4-pentylmorpholin-2-yl] pyridin-2-amine

Morpholine (80 mg, 0.45 mmol) from Example 2 was mixed with tetrahydrofuran (15 mL) and pentanal (47 μL, 0.45 mmol) was added dropwise as a solution in tetrahydrofuran (15 mL) over 15 minutes. After the addition was complete, sodium triacetoxyborohydride (227 mg, 1 mmol) was added and the reaction mixture was stirred at room temperature overnight (about 16 hours). The reaction mixture was then diluted with saturated aqueous sodium bicarbonate (75 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were separated, dried (MgSO ₄ ), filtered and evaporated to give a yellow oil. Purification by flash chromatography on silica gel eluting with dichloromethane / methanol / 0.880 NH ₃ 98: 2: 0.2 with increasing polarity to 95: 5: 0.5 gave the title compound (67 mg, 61 %).

Example 6
5-[(2R) -4- (2-Phenylethyl) morpholin-2-yl] pyridin-2-amine

Morpholine from Example 2 (80 mg, 0.45 mmol) was mixed with tetrahydrofuran (15 mL) and phenylacetaldehyde (52 μL, 0.45 mmol) was added dropwise as a solution in tetrahydrofuran (15 mL) over 15 minutes. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour and sodium triacetoxyborohydride (227 mg, 1 mmol) was added. The reaction mixture was stirred at room temperature overnight (about 16 hours), then diluted with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were separated, dried (MgSO ₄ ), filtered and evaporated to give a yellow oil. Purification by flash chromatography on silica gel eluting with dichloromethane / methanol / 0.880 NH ₃ 98: 2: 0.2 gave the title compound (31 mg, 24%).

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

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 room temperature overnight at 1 atmosphere. The mixture was then filtered through an Arbocel (R) plug, the plug was washed with ethanol, and the combined filtrate and wash were evaporated to a pale yellow solid. Purification by flash chromatography on silica gel eluting with dichloromethane / methanol / 0.880 NH ₃ 93: 7: 0.5 gave the title compound as a white solid (110 mg, 45%).

  Instead, the morpholine ring is formed under the following conditions to give a mixture of diastereoisomers.

Example 7b
5-[(5S) -5-Methylmorpholin-2-yl] pyridin-2-amine (diastereomeric mixture)

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, quenched by careful addition of water, basified with 880NH ₃ until the pH was approximately 9, and extracted with dichloromethane (2 × 150 mL). The combined organics were dried over magnesium sulfate, filtered and evaporated to give the title compound as a 3: 1 mixture of (R, S) and (S, S) diastereomers, respectively.

Examples 8 and 9
A mixture of morpholine compounds according to Example 7b (240 mg, 1.2 mmol) was dissolved in tetrahydrofuran (45 mL) and to the stirred solution 3-phenylpropionaldehyde (165 μL, 1.2 mmol) as a solution in tetrahydrofuran (45 mL). Added dropwise. When the addition was complete, sodium triacetoxyborohydride (270 mg, 1.2 mmol) was added and the reaction mixture continued to stir at room temperature overnight. The solvent was evaporated, diluted with water (30 mL) and extracted with dichloromethane (2 × 100 mL). The combined organic fractions were dried (MgSO ₄ ), filtered and evaporated to give a clear oil of an approximately 2: 1 mixture of trans: cis diastereomers.
Diastereomers were separated by HPLC on a Chiralcel AD-H column with a moving bed of methanol: ethanol 50:50 at a flow rate of 15 ml / min.

Example 8 (Diastereomer 1)
5-[(2R, 5S) -5-Methyl-4- (3-phenylpropyl) morpholin-2-yl] pyridin-2-amine

Retention time 4.80 minutes.

Example 9 (Diastereomer 2)
5-[(2S, 5S) -5-Methyl-4- (3-phenylpropyl) morpholin-2-yl] pyridin-2-amine

Retention time 7.60 minutes.

Examples 10 and 11
The diol from Production Example 31 (350 mg, 1.3 mmol) was dissolved in dichloromethane (5 mL) and concentrated H ₂ SO ₄ (2.5 mL) was added to the stirred solution. The reaction mixture was kept stirring at room temperature for 2 hours, then quenched by careful addition of water (10 mL) and then basified to pH 8-9 by addition of 0.880 NH ₃ . The mixture was then extracted with dichloromethane (2 × 50 mL) and the combined extracts were dried (MgSO ₄ ), filtered and evaporated to give a brown oil of a mixture of cis and trans morpholine diastereomers. Obtained (275 mg, 85%).
MS (ES ⁺ ) 250 (MH ⁺ )

  A sample of the mixed diastereoisomers was subjected to HPLC using a Chiralcel OD-H column, the moving bed was 30:70 IPA / hexane containing 0.1% diethylamine, and the flow rate was 20 mL / min.

Example 10 (Diastereomer 1)
5-[(2S, 5S) -4-butyl-5-methylmorpholin-2-yl] pyridin-2-amine

Retention time 4.90 minutes.

Example 11 (Diastereomer 2)
5-[(2R, 5S) -4-butyl-5-methylmorpholin-2-yl] pyridin-2-amine

Retention time 7.20 minutes.

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

Morpholine according to Preparation 14 (4.4 g, 9.21 mmol) is dissolved in ethanol (50 mL), hydroxylamine hydrochloride (3.2 g, 46 mmol) is added, and the mixture is allowed to stand at 80 ° C. overnight (about 16 hours). Heated. After cooling to room temperature, the mixture was diluted with 10% aqueous K ₂ CO ₃ (100 mL) and extracted with dichloromethane (2 × 100 mL). The combined organic fractions were dried over magnesium sulfate, filtered and evaporated to give a deprotected crude 2-aminopyridine intermediate brown oil (3.6 g).

The boc protected morpholine (3.6 g, 9 mmol) was treated with 4M HCL in dioxane (30 mL) and the mixture was stirred at room temperature for 4 hours. The solvent was then evaporated and the residue was treated with 2M sodium hydroxide (100 mL) and extracted with dichloromethane (4 × 100 mL). The combined organic fractions are dried over magnesium sulfate, filtered, evaporated to a light brown solid and eluted on silica gel eluting with dichloromethane / methanol / 880NH ₃ (93: 7: 0.5). Of the title compound as a light brown solid (1.43 g, 51%).

Example 13
5-{(2R, 5S) -5-[(benzyloxy) methyl] -4-propylmorpholin-2-yl} pyridin-2-amine

Morpholine according to Example 11 (1.4 g, 4.8 mmol) was dissolved in THF (200 mL) and propanal (350 μL, 4.8 mmol) in THF (150 mL) was added dropwise to the stirred mixture. After the addition was complete, NaBH (OAc) ₃ (1.02 g, 4.8 mmol) was added in one portion and the reaction mixture was stirred at room temperature overnight (about 16 hours). TLC analysis showed that starting material still remained, so additional NaBH (OAc) ₃ (1 g) was added and the reaction mixture was stirred for an additional 24 hours. Saturated aqueous NH ₄ Cl (200 mL) was added and the organic layer was separated, dried over magnesium sulfate, filtered and the solvent was evaporated. Purification of the residue by flash chromatography on silica gel eluting with dichloromethane / methanol / 880NH ₃ (95: 5: 0.5) gave the title compound as a light brown oil (540 mg, 33%).

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

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. The mixture was stirred for 2 hours at room temperature, the reaction by the addition of ice was stopped and basified to pH of about 9 by then using 880NH _3. The mixture was extracted with dichloromethane (3 × 150 mL) and the combined organic layers were dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880NH ₃ (95: 5: 0.5 increasing in polarity to 93: 7: 0.5) to give four title compounds. As a diastereoisomer, 110 mg of a light brown oily substance was obtained.
Diastereoisomers were separated by HPLC on a Chiralpak AD column with 20:80 IPA / hexanes containing 0.1% DEA in moving bed to give four stereoisomers.

Example 14
Stereoisomer 1 (retention time: 9.50 minutes) trans enantiomer 1

Example 15
Stereoisomer 2 (Retention time: 11.90 minutes) Cis enantiomer 1

Example 16
Stereoisomer 3 (Retention time: 16.60 minutes) Cis enantiomer 2

Example 17
Stereoisomer 4 (retention time: 19.70 minutes) trans enantiomer 2

Examples 18-19
4-Methyl-5- (4-propylmorpholin-2-yl) pyridin-2-amine

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 and the mixture was stirred for an additional 2 hours. Then, the reaction by the addition of ice to stop, then basified to pH of about 9 by dropwise addition 880NH _3. The mixture was then extracted with dichloromethane (4 × 50 mL) and the combined organics were dried over magnesium sulfate, filtered and evaporated to give the title compound as a light brown oil (700 mg, 79%). .

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

Example 18 (Enantiomer 1)
Retention time: 5.1 minutes

Example 19 (Enantiomer 2)
Retention time: 6.5 minutes

Example 20
3-Methyl-5-[(5S) -5-methyl-4-propylmorpholin-2-yl] pyridin-2-amine

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 and the mixture was stirred for an additional 2 hours. The reaction was then quenched by careful addition of water and then basified by addition of 880NH ₃ dropwise until the pH was about 9. The mixture was then extracted with dichloromethane (3 × 70 mL) and the combined organics were dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography on silica gel to give the title compound as a mixture of diastereoisomers as a clear oil (35 mg, 19%).

Examples 21 and 22
The diol from Preparation Example 24 (990 mg, 3.9 mmol) was dissolved in dichloromethane (10 mL) and treated with concentrated sulfuric acid at room temperature. The mixture was kept stirring for 2 hours, the reaction by the addition of ice was stopped and basified to pH of about 9 by the addition of 880NH _3. The mixture was then extracted with dichloromethane (3 × 150 mL) and the combined organics were dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880NH ₃ (95: 5: 0.5) to give the title compound as a mixture of diastereoisomers (470 mg, 51%). .

MS (ES ⁺ ) 236 (MH ⁺ )
Diastereoisomers were obtained by eluting with chiral HPLC on a Chiralcel OD-H column eluting with 30% IPA in hexane containing 0.1% diethylamine.

Example 21 (Diastereomer 1)
5-[(2S, 5S) -4,5-diethylmorpholin-2-yl] pyridin-2-amine

Retention time: 4.1 minutes.

Example 22 (Diastereomer 2)
5-[(2R, 5S) -4,5-diethylmorpholin-2-yl] pyridin-2-amine

Retention time: 7.3 minutes.

Example 23
5- (1-propylazetidin-3-yl) pyridin-2-amine

Aminopyridineimine (95 mg, 0.267 mmol, 1.0 eq) from Preparation 35 was dissolved in EtOH (2 ml) and 10% Pd / C (10 mg) and ammonium formate (168 mg, 2.67 mmol, 10 eq) were added. And the mixture was slowly refluxed and heated for 3 hours. Further 10% Pd / C (10 mg) and ammonium formate (168 mg, 2.67 mmol, 10 eq) were added and the mixture was heated to reflux for 48 hours. The catalyst was removed by filtration through arbocel and washed with ethanol. The filtrate was evaporated under vacuum to give a colorless oil. This material was dissolved in THF (5 mL) and 2M HCl (aq) was added and stirred at room temperature for 3 h. The mixture was evaporated under vacuum, basified with K ₂ CO ₃ (10% w / v aqueous solution), extracted with CH ₂ Cl ₂ (3 × 20 ml), dried (MgSO ₄ ), filtered and evaporated. A colorless oil was obtained. The oil was purified by flash chromatography on silica gel using a gradient elution from 100% CH ₂ Cl ₂ to 90: 10: 1 CH ₂ Cl ₂ : MeOH: NH ₄ OH and left to solidify The obtained product was obtained as a colorless oil (21 mg, 41%).
_{Tlc Rf = 0.24 (90: 10} : 1 CH 2 Cl 2: MeOH: NH 4 OH UV visualization).

Examples 24 and 25
5- (2R, 5S) -4-Ethyl-5-methylmorpholin-2-yl) -pyridin-2-ylamine & 5- (2S, 5S) -4-ethyl-5-methylmorpholin-2-yl) -pyridine -2-ylamine

Morpholine (1 g, 4.17 mmol) from Preparation 38 was dissolved in CH ₂ Cl ₂ (15 mL) and concentrated sulfuric acid (7.5 mL) was added. The mixture was stirred at room temperature for 2 hours, basified by careful addition of 0.880 NH ₃ , extracted with CH ₂ Cl ₂ (2 × 200 ml), the combined organics were dried over magnesium sulfate, filtered, Purification by flash chromatography on silica gel eluting with CH ₂ Cl ₂ : MeOH: NH ₄ OH 97: 3: 1 gave the title compound as a light brown oil (560 mg, 61%).

Diastereoisomers were obtained by separation on a Chiralcel OD-H column (500 × 50 mm) using a moving bed of 20% IPA, 80% hexane, 0.1 DEA at a flow rate of 80 ml / min:
Diastereomer 1—Retention time 5.47 minutes (Example 24, (2S, 5S) diastereoisomer)

Diastereomer 2—Retention time 7.96 minutes (Example 25, (2R, 5S) diastereoisomers)

Examples 26 & 27
(+)-5- (4-Propylmorpholin-2-yl) -1,3-thiazol-2-amine & (−)-5- (4-propylmorpholin-2-yl) -1,3-thiazole- 2-Amine

2- (2-Bromo-1,3-thiazol-5-yl) -4-propylmorpholine (2.5 g, 8.56 mmol) in ethylene glycol (60 ml) at −78 ° C. with Cu ₂ O (61 mg, 0 .43 mmol, 0.05 eq) and NH3 _(l) (20 ml) were added in a bomb. The vessel was sealed and heated at 80 ° C. for 18 hours. Cool the vessel, puncture and separate between EtOAc (2 × 200 mL) and water (100 mL), combine the organic layers, dry over MgSO ₄ , evaporate the solvent and remove a brown oil. Got. This material is Isco companion combination flash autochromatography using a gradient elution from 99/1 / 0.1 CH ₂ Cl ₂ / MeOH / NH ₃ to 95/5/0 · 5 CH ₂ Cl ₂ / MeOH / NH ₃ Chromatography on the system gave the product as a brown oil (1.1 g).
This material was separated by HPLC on a Chiralcel OJ column (250 × 21.5) with a moving bed of 70:30 hexane: IPA at a flow rate of 18 ml / min to give two enantiomers.

Enantiomer 1 Retention time 5.140 minutes.

Optical rotation [α] ^D ₂₅ +48.45 (c = 1.45 mg / ml MeOH)
Basic analysis + 0.55H ₂ O Total MW = 237.24
Calculated value C (50.63), H (7.69), N (17.71)
Measured value C (50.90, 50.79), H (7.48, 7.51), N (17.35, 17.38)

Enantiomer 2 Retention time 10.750 minutes.

Optical rotation [α] ^D ₂₅ -43.56 (c = 2.6 mg / ml MeOH)
Basic analysis + 1H ₂ O Total MW = 245.35
Calculated value C (48.96), H (7.81), N (17.13)
Measured value C (49.05, 49.07), H (7.83, 7.85), N (17.00, 16.99)

The following preparation examples illustrate the synthesis of certain intermediates used in the preparation of the preceding examples.
Production Example 1
5-Bromo-2- (2,5-dimethyl-pyrrol-1-yl) pyridine

2,5-Hexanedione (46.2 g, 0.41 mol) is added to a suspension of 2-amino-5-bromopyridine (50.0 g, 0.29 mol) and the reaction is run under Dean & Stark conditions. Heat at reflux for 24 hours. Para-toluenesulfonic acid (100 mg) was added and the reaction was refluxed for an additional 18 hours. 8 mL of water was removed and the reaction was cooled to room temperature, washed with water (100 mL) and passed through a plug of silica gel eluting with toluene. The eluate was concentrated under vacuum and the residue was dissolved in pentane: dichloromethane (1: 1 by volume) and passed through a plug of silica gel eluting with pentane: dichloromethane (1: 1 by volume). The eluate was concentrated under vacuum to obtain a red liquid that solidified on standing. The solid was recrystallized (isopropanol) to give the title compound as a yellow solid (54.4 g).

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

Production Example 2
2-Chloro-1- [6- (2,5-dimethyl-pyrrol-1-yl) -pyridin-3-yl] -ethanone

A solution of 2.5 M n-butyllithium in hexane (35 mL, 87.6 mmol) at −78 ° C. under nitrogen for 10 minutes in tert-butyl methyl ether (300 mL) bromide according to Preparation 1 (20. 0 g, 79.7 mmol). The reaction was stirred for an additional 10 minutes and 2-chloro-N-methoxy-N-methylacetamide (12.1 g, 87.6 mmol) in tert-butyl methyl ether (40 mL) was added slowly. The reaction was stirred at −78 ° C. for 20 minutes, after which 1M hydrochloric acid (200 mL) was added. The mixture was warmed to room temperature and stirred for 2 hours, and the organic layer was separated. The aqueous layer was extracted with tert-butyl methyl ether, and the combined organic extracts were washed with water (100 mL), saturated aqueous sodium chloride solution (100 mL), and 1M sodium hydroxide (100 mL). The organic layer is dried (magnesium sulfate), concentrated in vacuo, and the residual oil is eluted with pentane: dichloromethane: methanol (volume ratio changing from 75: 25: 0 to 0: 99: 1). Purified by flash column chromatography on silica gel. The residue was recrystallized from pentane: dichloromethane to give the title compound as a yellow solid (14.37 g, 73%).

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

Production Example 3
2- (2,5-Dimethyl-pyrrol-1-yl) -5-[(2R) -oxiranyl] pyridine

A solution of the chloride from Preparation 2 (12.0 g, 48.1 mmol) in tetrahydrofuran (20 ml) under nitrogen at −30 ° C. under (−) in tert-butyl methyl ether (15 mL) and tetrahydrofuran (30 mL). Slowly added to a solution of -B-chlorodiisopinocinfeylborane (20.1 g, 62.5 mmol). The reaction was stirred at −30 ° C. for 6 hours, then sodium peroxoborate tetrahydrate (7.4 g, 48.1 mmol) was added followed by tert-butyl methyl ether (50 mL). The reaction 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 layer was separated and the aqueous layer was further extracted with tert-butyl methyl ether (50 mL). The combined organic extracts were washed with 1M sodium hydroxide (50 mL), saturated aqueous sodium chloride solution (50 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with pentane: dichloromethane (volume ratio changing from 80: 2 to 100: 0) to give the crude epoxide (65% b / w, 11.0 g). ), Used without further purification.

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

Production Example 4
(1R) -2- (Benzylamino) -1- [6- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] ethanol

The epoxide according to Preparation 3 (2.66 g, 12 mmol) was dissolved in DMSO (30 mL), treated with benzylamine (1.62 mL, 15 mmol), and the mixture was heated at 90 ° C. overnight (about 16 hours). After cooling to room temperature, the reaction mixture was evaporated at 60 ° C. under high vacuum to remove most of the DMSO. The residue was diluted with ethyl acetate (150 mL) and washed with water (100 mL). The organic layer was separated and the aqueous layer was extracted again 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%).

MS (APCI ⁺ ) 322 (MH ⁺ )
Production Example 5
N-benzyl-2-chloro-N-{(2R) -2- [6- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl} acetamide

Amino alcohol (3.22 g, 10 mmol) from Preparation 4 was dissolved in dichloromethane (100 mL), sodium hydroxide (2 g, 50 mmol) in aqueous solution (35 mL) was added and the mixture was stirred vigorously. Chloroacetyl chloride (0.96 mL, 12 mmol) was added dropwise, followed by continued stirring at room temperature overnight (about 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 formed a mixture of chloroamide and morpholinone (product of Preparation 5), which was used previously without further purification.
MS (APCI ^<+> ) 398 (MH ^<+> , chloroamide), 362 (MH ^<+> , cyclized morpholinone).

Production Example 6
(6R) -4-Benzyl-6- [6- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] morpholin-3-one

The crude mixture from Preparation 5 was dissolved in propan-2-ol (100 mL) and water (5 mL) was added followed by potassium hydroxide (673 mg). The mixture was stirred vigorously at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate (200m) and water (150mL). The organic layer was separated, washed with brine (150 mL), dried (MgSO ₄ ), filtered and evaporated to give a dark orange oil. Purification by flash chromatography on silica gel eluting with dichloromethane / methanol 99: 1 gave the title compound as a yellow oil (69%).

Production Example 7
(2R) -4-benzyl-2- [6- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] morpholine

Morpholine according to Preparation 6 (2.47 g, 6.8 mmol) was dissolved in tetrahydrofuran (100 mL) and cooled (flask in ice / water bath). Lithium aluminum hydroxide (1M in tetrahydrofuran, 10.2 mL, 10.2 mmol) was added dropwise, after which the reaction mixture was stirred at room temperature overnight (about 16 hours). The reaction was quenched by careful addition of 1M sodium hydroxide (10 mL), then diluted with water (150 mL) and stirred for 10 minutes. Ethyl acetate (200 mL) was added and the organic layer was separated, dried over MgSO ₄ and evaporated to give the title compound as a yellow oil (2.09 g, 89%).

Production Example 8
(2S) -2-({(2R) -2- [6- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl} amino) propane-1- Oar

  The epoxide according to Preparation 3 (5.4 g, 20 mmol) was dissolved in DMSO (50 mL) together with (S) -2-aminopropan-1-ol (2.0 g, 20 mmol) and the mixture was stirred at 90 ° C. Heated overnight (approximately 16 hours). After cooling to room temperature, the mixture was purified by flash chromatography on silica gel, evaporating the solvent under high vacuum and eluting with dichloromethane / methanol (increased polarity from 95: 5 to 90:10), The title compound was obtained as a pale yellow oil (5.0 g, 75%).

Production Example 9
Benzyl (2R, 5S) -2- [6- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] -5-methylmorpholine-4-carboxylate

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 (about 16 hours) and quenched by the addition of 2M sodium hydroxide (100 mL). The mixture was extracted with dichloromethane (2 × 100 mL) and the combined organic fractions were dried (MgSO ₄ ), filtered and the solvent was 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 CBz protected intermediate as a light brown oil (2.56 g, 35%).
MS (ES ⁺ ) 446 (MNa ⁺ )
MS (ES ⁻ ) 422 (M−H ⁺ )

A sample of the above CBz protected diol (2 g, 4.7 mmol) was dissolved in toluene (30 mL) along with triphenylphosphine (1.5 g, 5.6 mmol). Diisopropyl azodicarboxylate (1.12 mL, 5.6 mmol) was added dropwise and the reaction mixture continued to stir overnight (about 16 hours). The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic fractions were dried (MgSO ₄ ), filtered and the solvent was 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). 1H NMR indicates that the sample contains about 3 equivalents of diisopropylhydrazine-1,2-dicarboxylate and the title compound. That is, about 40% by weight of the material is the title compound, corresponding to an approximate yield of 36%.

Production Example 10
2- (6-Amino-pyridin-3-yl) -5-methyl-morpholine-4-carboxylic acid benzyl ester

Morpholine according to Preparation 9 (680 mg, 1. mmol) was dissolved in ethanol (12 mL), treated with hydroxylamine hydrochloride (600 mg, 8.4 mmol) and the mixture was heated at 80 ° C. overnight (about 16 hours). . After cooling to room temperature, the solvent is evaporated and the residue is purified by flash chromatography on silica gel eluting with dichloromethane in methanol of increasing polarity from 0% to 2% to give the title compound as a purple oil. (410 mg, 95%).

Production Example 11
(2S) -2-{[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] amino} propan-1-ol

Diol (1 g, 3.35 mmol) was dissolved in ethanol and treated with hydroxylamine hydrochloride (1.2 g, 16.75 mmol) as in Preparation 8 and the mixture was heated at 80 ° C. overnight (about 16 hours). . After cooling to room temperature, the solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880NH ₃ (increasing polarity from 85: 15: 1 to 82: 17: 1). The title compound was obtained as a light brown oil (670 mg, 95%).

MS (ES ^<+> ) 212 (MH ^<+> ) 234 (MNa +)

Production Example 12
(2R) -3- (Benzyloxy) -2-({(2R) -2- [6- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl } Amino) propan-1-ol

The epoxide according to Preparation Example 3 (5.4 g, 25 mmol) was dissolved in DMSO (50 mL) together with (S) -2-amino-3-benzyloxypropan-1-ol (5.0 g, 27.6 mmol), The mixture was heated at 90 ° C. overnight (approximately 16 hours). After cooling to room temperature, the mixture was evaporated under high vacuum to give about 12 g of the desired title compound containing some residual DMSO as a brown oil, but without further purification It is sufficiently pure for use in

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

The crude diol from Preparation 12 (10 g, about 25 mmol) was dissolved in dichloromethane (150 mL) and treated with di-tert-butyl dicarboxylate (5.52 g, 25 mmol) and the mixture was allowed to stand at room temperature overnight (about 16 hours). Stir. The reaction mixture was diluted with 10% aqueous K ₂ CO ₃ (200 mL), the organic layer was separated and the aqueous layer was extracted with dichloromethane (2 × 300 mL). The combined organic fractions were dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with increasing eluent polarity from 35% ethyl acetate in pentane to 50% ethyl acetate in pentane to give the title compound as a pale yellow oil ( 6.2 g, 50% yield over two steps, steps 12 and 13.)

Production Example 14
tert-Butyl (2R, 5S) -5-[(benzyloxy) methyl] -2- [6- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] morpholine-4-carboxy rate

The diol from Preparation Example 13 (6.2 g, 12.5 mmol) was dissolved in toluene (100 mL) and treated with triphenylphosphine (4 g, 15 mmol) at room temperature. Diisopropyl azodicarboxylate (DIAD) (3 mL, 15 mmol) was added dropwise and the mixture was stirred overnight (about 16 hours). The reaction mixture was then diluted with water (200 mL), the organic layer was separated and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with increasing polarity from 10% ethyl acetate in pentane to 15% ethyl acetate in pentane to give the title compound as a clear oil (4.4 g, 74%).

Production Example 15
(2R) -3- (Benzyloxy) -2-[{(2R) -2- [6- (2,5-dimethyl-1H-pyrrol-1-yl (pyridin-3-yl) -2-hydroxyethyl] } (Propyl) amino] propan-1-ol

The crude diol from Preparation 12 (3 g, 7.6 mmol) was dissolved in dichloromethane and propanal (1.1 mL, 15.2 mmol) and NaBH (OAc) ₃ (3.25 g, 15.2 mmol) were added. The reaction mixture was stirred at room temperature overnight (about 16 hours), after which the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880NH ₃ (97: 3: 0.5) to give the title compound as a light brown oil, but from about the previous step. It still contained 3 equivalents of DMSO contamination (4.5 g, corrected for about 2.95 g of product DMSO, 89% yield).

Production Example 16
(2R) -2-[[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] (propyl) amino] -3- (benzyloxy) propan-1-ol

The diol from Preparation 15 (2.95 g, 6.7 mmol) is dissolved in ethanol (50 mL) and treated with hydroxylamine hydrochloride (2.34 g, 33.7 mmol) and the mixture is stirred at 80 ° C. overnight (ca. 16 Heated). After cooling to room temperature, the solvent was evaporated and the residue was flash chromatographed on silica gel eluting with dichloromethane / methanol / 880NH ₃ (increasing polarity from 95: 5: 0.5 to 91: 9: 0.5). Purification by chromatography gave the title compound as a light brown oil (1.4 g, 58%).

Production Example 17
5-Bromo-2- (2,5-dimethyl-1H-pyrrol-1-yl) -4-methylpyridine

2-Amino-5-bromo-4-methylpyridine [commercially available] (6 g, 32 mmol) is dissolved in toluene (100 mL) and hexane-2,5-dione (5.3 mL, 45 mmol) and Para-toluenesulfonic acid monohydrate (50 mg) was added and the mixture was heated to reflux using a suitable Dean-Stark apparatus. If the water recovery is interrupted, the reaction mixture is cooled and diluted with water (50 mL) and 10% aqueous K ₂ CO ₃ (50 mL), the organic layer is separated and the aqueous layer is extracted with ethyl acetate (200 mL). did. The combined organic fractions were dried over magnesium sulfate, filtered and the solvent was 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%).

Production Example 18
4-propylmorpholin-2-one

Methyl 2-bromoacetate (50 mL, 0.54 mol, 1 eq) was added at 0 ° C. with N-propylaminoethanol (62.4 ml, 0.54 mol, 1 eq) and Et ₃ N (75 ml, 0.54 mol, 1 eq) in toluene. 1 equivalent) and stirred overnight at room temperature. Water (1 L) was added and the mixture was extracted with EtOAc (2 × 500 mL). Brine (500 mL) was added to the aqueous layer and extracted again with EtOAc (2 × 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.

Production Example 19
2- [6- (2,5-Dimethyl-1H-pyrrol-1-yl) -4-methylpyridin-3-yl] -4-propylmorpholin-2-ol

Bromopyridine (5 g, 18.8 mmol) according to Preparation Example 17 was dissolved in THF (80 mL) and cooled to -78 ° C. To the stirred solution was added tert-butyllithium (22 mL, 37.7 mmol) dropwise. Immediately after the addition was complete, morpholine (according to Preparation 18) (2.7 g, 18.8 mmol) was added as a solution in THF (20 mL) and the reaction mixture continued to stir at −78 ° C. for 1 h. The reaction was then quenched and saturated aqueous NH ₄ Cl (100 mL) was added followed by extraction with ethyl acetate (100 mL). The organic fraction was dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with increasing eluent polarity from 35% ethyl acetate in pentane to 40% ethyl acetate in pentane to give the title compound as a pale yellow oil ( 1.95 g, 32%).

Production Example 20
1- [6- (2,5-Dimethyl-1H-pyrrol-1-yl) -4-methylpyridin-3-yl] -2-[(2-hydroxyethyl) (propyl) amino] ethanol

Morpholinol from Preparation 19 (1.95 g, 5.9 mmol) was dissolved in ethanol (25 mL) and water (10 mL) and sodium borohydride (900 mg, 23.6 mmol) were added to the stirred mixture at room temperature. Stirring was continued overnight (about 16 hours), quenched by addition of saturated aqueous ammonium chloride (100 mL) and extracted with dichloromethane (2 × 100 mL). The combined organic fractions were dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880NH ₃ (96: 4: 0.5) to give the title compound as a yellow oil (1.4 g, 71%). .

MS (ESI ⁺ ) 332 (MH ⁺ )

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

The diol from Preparation 20 (1.4 g, 4.22 mmol) was dissolved in ethanol (30 mL) and treated with hydroxylamine hydrochloride (1.12 g, 16.9 mmol) and the mixture was refluxed overnight (about 16 Heated). After cooling to room temperature, the mixture was diluted with 10% aqueous K ₂ CO ₃ and extracted with dichloromethane (2 × 200 mL). The combined organic fractions were dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880NH ₃ (93: 7: 1) to give the title compound as a light brown oil (950 mg, 89%).

Production Example 22
(2S) -2-({(2R) -2- [6- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl} amino) butane-1- Oar

Epoxide (10.6 g, 49.4 mmol) from Preparation 3 was added to DMSO (100 mL) along with (S) -2-aminobutan-1-ol (5.6 g, 59.4 mmol) [commercially available]. ) And the mixture was heated at 90 ° C. overnight (approximately 16 hours). After cooling to room temperature, the mixture was evaporated under high vacuum to give a dark oil (17.7 g) of the title compound containing the remaining DMSO, which was pure enough for subsequent steps. .

Production Example 23
(2S) -2-[{(2R) -2- [6- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl} (ethyl) amino] butane -1-ol

The diol according to Preparation 22 was dissolved in dichloromethane (50 mL) and treated with ethanal (1.66 mL, 29.6 mmol) and NaBH (OAc) ₃ (6.3 g, 29.6 mmol), and the mixture was stirred overnight at room temperature ( Stir for about 16 hours. The solvent was then evaporated and the residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880NH ₃ (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 methanol in 1% ethyl acetate increasing in polarity to 2% to give the title compound as a clear oil (1.42 g, 43% ).

Production Example 24
(2S) -2-[[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] (ethyl) amino] butan-1-ol

The diol from Preparation 23 (1.42 g, 4.3 mmol) was dissolved in ethanol (50 mL) and treated with hydroxylamine hydrochloride (1.5 g, 21.4 mmol) and the mixture was allowed to stand at 80 ° C. overnight (about 16 Heated). After cooling to room temperature, the solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880NH ₃ (91: 9: 0.5) to give the title compound as a light brown oil. (990 mg, 91%).

Production Example 25
5-Bromo-2- (2,5-dimethyl-1H-pyrrol-1-yl) -3-methylpyridine

2-Amino-3-methyl-5-bromopyridine (5.86 g, 31.3 mmol) is dissolved in toluene (50 mL), hexane-2,5-dione (5.15 mL, 43.9 mmol) and para-toluene. Sulfonic acid monohydrate (20 mg) was added and the mixture was heated to reflux using a suitable Dean-Stark apparatus. When water recovery was discontinued, the reaction mixture was evaporated and the residue was purified by flash chromatography on silica gel eluting with 5% ethyl acetate in pentane to give the title compound as a pale yellow oil ( 5.1 g, 61%).

Production Example 26
(5S) -5-Methyl-4-propylmorpholin-2-one

The material from Preparation 36 (4 g, 26 mmol) was dissolved in benzene (80 mL) followed by addition of N-ethyldiisopropylamine (9.07 mL, 52 mmol) and methyl bromoacetate (2.4 mL, 26 mmol). The mixture was heated to reflux with azeotropic removal of water. After cooling to room temperature, the solvent is removed by evaporation and the crude material is dissolved in methanol, preabsorbed on SiO ₂ and purified by flash chromatography on SiO ₂ eluting with 40% EtOAc in pentane, The title compound was obtained as a clear oil (1.78 g).

Production Example 27
(5S) -2- [6- (2,5-Dimethyl-1H-pyrrol-1-yl) -5-methylpyridin-3-yl] -5-methyl-4-propylmorpholin-2-ol

Bromopyridine (2.5 g, 9.4 mmol) from Preparation Example 25 was dissolved in THF (60 mL) and cooled to -78 ° C. To the stirred solution was added tert-butyllithium (1.5M in pentane, 12.6 mL, 18.8 mmol) dropwise. Immediately after the addition was complete, morpholinone (according to Preparation 26) (1.5 g, 9.4 mmol) was added as a solution in THF (10 mL) and the reaction mixture continued to stir at −78 ° C. for 1 h. The reaction was then quenched by the addition of saturated aqueous NH ₄ Cl (100 mL) and then extracted with ethyl acetate (80 mL). The organic fraction was dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with increasing eluent polarity from 10% ethyl acetate in pentane to 40% then 70% ethyl acetate in pentane to give the title compound as a pale yellow oil (590 mg, 18%).

MS (ESI ⁺ ) 344 (MH ⁺ )

Production Example 28
(2S) -2-[{2- [6- (2,5-Dimethyl-1H-pyrrol-1-yl) -5-methylpyridin-3-yl] -2-hydroxyethyl} (propyl) amino] propane -1-ol

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 is continued overnight (about 16 hours), quenched by the addition of saturated aqueous ammonium chloride (100 mL), basified with 2M aqueous NaOH until the pH is about 9, and dichloromethane (2 × 200 mL) is added. Extracted using. The combined organic fractions were dried over magnesium sulfate, filtered and the solvent was evaporated to give the title compound as a mixture of diastereoisomers as a yellow oil (450 mg, 75%) without further purification. Used directly.
MS (ESI +) 346 (MH +), 368 (MNa +)

Production Example 29
(2S) -2-[[2- (6-Amino-5-methylpyridin-3-yl) -2-hydroxyethyl] (propyl) amino] propane] -1-ol

The diol from Preparation 28 (420 mg, 1.5 mmol) was dissolved in propanol (5 mL) and water (1.5 mL), hydroxylamide hydrochloride (2.2 g, 31.4 mmol) and triethylamine (2.2 mL, 15. 7 mmol) and the mixture was heated to reflux for 12 hours. After cooling to room temperature, the mixture was evaporated and the residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880NH ₃ (90: 10: 1) increasing in polarity to (85: 15: 3). Triturate with dichloromethane (3 × 50 mL) to give a white solid (1.3 g) and remove the remaining solvent under vacuum to give 700 mg of a white solid, dichloromethane / methanol / 880NH ₃ ( Further purification by flash chromatography on silica gel eluting with 92.5: 7.5: 0) gave the title compound as a clear oil (200 mg, 50%).
MS (ESI ⁺ ) 254 (MH ⁺ )

Production Example 30
(2S) -2-[{(2R) -2- [6- (2,5-dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl} (butyl) amino] propane -1-ol

The diol from Preparation 8 (1 g, 3.35 mmol, 1 eq) was dissolved in dichloromethane (20 mL) and with butanal (910 μl, 10 mmol, 3 eq) and NaBH (OAc) ₃ (2.1 g, 10 mmol, 3 eq). Worked and the mixture was stirred at room temperature overnight (about 16 hours). The reaction was quenched with water (500 ml), extracted with CH ₂ Cl ₂ (2 × 100 ml), the organic layers were combined, dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 880NH ₃ (95: 5 :: 0.5) to give the title compound as a clear oil (900 mg, 86%).

Production Example 31
(2S) -2-[[(2R)-(6-Aminopyridin-3-yl) -2-hydroxyethyl] (butyl) amino] propan-1-ol

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 was heated at 80 ° C. overnight (about 16 hours). After cooling to room temperature, the solvent is evaporated and the residue is preabsorbed on silica gel and eluted with a gradient of dichloromethane / methanol / 880NH ₃ (95: 5: 0.5 to 92: 8: 0.5). Purification by flash chromatography on silica gel gave the title compound as a light brown oil (330 mg).

Production Example 32
3- (6-Chloropyridin-3-yl) -azetidine-1-carboxylic acid tert-butyl ester

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 with a hot air gun under vacuum. The flask was cooled to room temperature and DMF (2 ml) and 1,2-dibromoethane (12 μl, 0.141 mmol, 0.08 equiv) were added. The mixture was heated at 70 ° C. for 10 minutes, cooled to room temperature, and TMSCI (18 μl, 0.141 mmol, 0.08 equiv) was added dropwise. The mixture was stirred at room temperature for 30 minutes and 3-iodoazetidine-1-carboxylic acid tert-butyl ester (see SynLett, 1998, 4, 379) (500 mg, 1.766 mmol, 1.0 eq) in DMF (2 ml). Added dropwise as a solution in. The mixture was stirred at 40 ° C. for 1 hour. 2-Chloro-5-iodopyridine dissolved in DMF (2 ml) was added followed by Pd ₂ dba ₃ (32 mg, 0.035 mmol, 0.02 equiv) and tri-2-furylphosphine (17 mg, 0 0.071 mmol, 0.04 eq) was added and the mixture was heated at 70 ° C. for 4 h.

Cool the mixture and dilute with Et ₂ O (40 ml) and NH ₄ Cl (40 ml, saturated aqueous solution), separate the layers, extract the aqueous layer again with Et ₂ O (20 ml), combine the organics, Washed with brine (2 × 30 ml), dried (MgSO ₄ ), filtered and the solvent was evaporated to give a yellow solid.

This solid was subjected to flash chromatography on silica gel using gradient elution from 100% CH ₂ Cl ₂ to 99: 1 CH ₂ Cl ₂ : MeOH to give a product containing 235 mg of impurities. This material was purified by flash chromatography on silica gel using a gradient elution from 100% toluene to 95: 5 toluene: EtOAc to give the title compound as a yellow solid (193 mg, 41%).
Tlc Rf = 0.13 (10% EtOAc / toluene UV visualization)

Production Example 33
5-Azetidin-3-yl-2-chloropyridine dihydrochloride

3- (6-Chloropyridin-3-yl) -azetidine-1-carboxylic acid tert-butyl ester (190 mg, 0.707 mmol, 1.0 eq) was dissolved in CH ₂ Cl ₂ (4 ml) and brought to 0 ° C. Cooled and bubbled HCl _(g) for 10 minutes to give a dark orange solution. This was stirred at room temperature for 72 hours. After evaporation of the mixture, a light brown solid was obtained, triturated with Et ₂ O, and the resulting solid was filtered and dried under vacuum at 60 ° C. to give the title compound (141 mg, 83%) .

Production Example 34
2-Chloro-5- (1-propylazetidin-3-yl) -pyridine

5-azetidin-3-yl-2-chloropyridine dihydrochloride (131mg, 0.542mmol, 1.0 eq.) _CH 2 _Cl 2 (10ml) and _{K 2 CO 3 (10ml, 10} % w / v aqueous solution of ), The layers were separated, and the aqueous layer was extracted again with CH ₂ Cl ₂ (10 ml). The organic layers were combined, dried (MgSO ₄ ), filtered and the solvent was evaporated to a volume of approximately 2 ml. Propionaldehyde (79 μl, 1.084 mmol, 2.0 equiv) and sodium triacetoxyborohydride (230 mg, 1.084 mmol, 2.0 equiv) were added and the mixture was stirred at room temperature for 2.5 hours. The mixture was quenched with H ₂ O (0.5 ml), partitioned between CH ₂ Cl ₂ (10 ml) and K ₂ CO ₃ (10 ml, 10% w / v aqueous solution), the layers were separated, The aqueous layer was extracted again 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 was purified by flash chromatography on silica gel using gradient elution from 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 UV visualization)

Production Example 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 equiv), 1,1-diphenylmethanimine (95 μl, 0.570 mmol, 1.2 equiv) , Palladium (II) acetate (4.4 mg, 0.00475 mmol, 0.01 equiv), BINAP (8.7 mg, 0.014 mmol, 0.03 equiv) and sodium tert-butoxide (49 mg, 0.665 mmol, 1 .4 equivalents) in toluene (2 ml) and heated at 80 ° C. for 16 hours. Further 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 heated to reflux for 4 hours. did. The mixture was cooled to room temperature, partitioned between EtOAC (25 ml) and K ₂ CO ₃ (20 ml, 10% w / v aqueous solution), the layers separated and the aqueous layer extracted again with EtOAc (2 × 25 ml). did. The organic layers were combined, dried (MgSO ₄ ), filtered and the solvent was evaporated to give an orange oil. The oil was purified by flash chromatography on silica gel eluting with a gradient from 100% CH ₂ Cl ₂ to 95: 5: 0.5 CH ₂ Cl ₂ : MeOH: NH ₄ OH to give the title compound yellow As an oil (110 mg, 66%).
Tlc Rf = 0.22 (90: 10: 1 CH ₂ Cl ₂ : MeOH: NH ₄ OH UV visualization)

Calculated value C (78.12) H (7.24) N (11.39)
Observation C (77.85, 78.12) H (7.04, 7.04) N (11.18, 11.28)

Production Example 36
(2S) -2- (Propylamino) propan-1-ol hydrochloride

(2S)-(+)-2-Aminopropan-1-ol (19.6 g, 0.26 mol) dissolved in CH ₂ Cl ₂ (500 mL) followed by propionaldehyde (20.9 mL, 0.28 mol) followed by 4 kg of molecular sieves (40 g) dried and powdered was added and the mixture was stirred at room temperature overnight. The mixture was filtered through a pad of Celite® (filter agent), the pad was washed with CH ₂ Cl ₂ and the solvent was evaporated from the filtrate to give a clear oil. This oil was dissolved in methanol (200 mL) and NaBH ₄ was added intermittently over 15 minutes. The mixture was stirred overnight at room temperature, then quenched by careful addition of 2M aqueous HCl (200 mL), basified by addition of 2M aqueous NaOH (200 mL), and 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 at room temperature overnight. 1,4-Dioxane was removed by evaporation and the residue was diluted with water (750 mL) and extracted with CH ₂ Cl ₂ (2 × 750 mL). The combined organic fractions were dried (MgSO ₄ ), filtered and evaporated to give a clear oil. To this oil was added 4M HCl in 1,4-dioxane (200 mL) and the mixture was stirred at room temperature overnight. The solvent was removed by evaporation to give the title compound as a white solid (24 g).

Production Example 37
(2S) -2-({2- [6- (2,5-Dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl} amino) propan-1-ol

The epoxide according to Preparation 40 (950 mg, 4.4 mmol) was dissolved in DMSO (10 mL) together with (S) -2-aminopropan-1-ol (380 μL, 4.9 mmol) and the mixture was stirred at 90 ° C. overnight. Heated (approximately 16 hours). After cooling to room temperature, the mixture is evaporated under high vacuum, and the residue is eluted with dichloromethane / methanol / 0.880 NH ₃ (increasing polarity from 98: 2: 0 to 90: 10: 1) on silica gel. Purification by flash chromatography above gave the title compound as a pale yellow oil (780 mg, 67% over 2 steps from Preparation 40).

Production Example 38
(2S) -2-[{2- [6- (2,5-Dimethyl-1H-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethyl} (ethyl) amino] propan-1-ol (Diastereomer mixture)

The diol from Preparation 37 (1.5 g, 5.2 mmol) was dissolved in dichloromethane (25 mL) and treated with acetaldehyde (870 μL, 15.5 mmol) and sodium triacetoxyborohydride (3.3 g, 15.5 mmol). The reaction mixture was kept stirring at room temperature overnight (about 16 hours). The reaction mixture was diluted with saturated aqueous ammonium chloride then basified by addition of 10% K ₂ CO ₃ solution and then extracted with dichloromethane (2 × 150 mL). The combined organics were dried (MgSO ₄ ), filtered and the solvent was evaporated. The residue is purified by flash chromatography on silica gel eluting with dichloromethane / methanol / 0.880 NH ₃ (93: 7: 0.5) and the title compound is slightly impure as a mixture of diastereoisomers. Obtained as a light brown oil (2.5 g). This material was used directly without further purification.

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

The diol from Preparation 38 (2.5 g, 7.8 mmol) was dissolved in ethanol (80 mL) and treated with hydroxylamine hydrochloride (2.7 g, 21.4 mmol) and the mixture was allowed to stand at 80 ° C. overnight (about 16 Heated). After cooling to room temperature, the solvent was evaporated and the residue was flash chromatographed on silica gel eluting with dichloromethane / methanol / 880NH ₃ (increasing polarity from 95: 5: 0.5 to 90: 10: 1). Purification gave the title compound as a light brown oil (1.5 g, 80%).

Production Example 40
2- (2,5-Dimethyl-pyrrol-1-yl) -5- [oxiranyl] pyridine

Ethanolamine (0.24 mL, 4 mmol) was added dropwise over 15 minutes to a solution of borane-tetrahydrofuran complex in tetrahydrofuran (5 mL) cooled to 0 ° C. (1M solution in tetrahydrofuran, 8 mL, 8 mmol). The mixture was allowed to reach room temperature and then chloride according to Preparation 2 (1 g, 4 mmol) in tetrahydrofuran was added dropwise to the stirred solution. The reaction mixture was then stirred at room temperature for 30 minutes, after which the reaction was quenched by the addition of 2M sodium hydroxide (10 mL) and the reaction mixture was stirred for an additional hour. The mixture was then extracted with ethyl acetate (2 × 50 mL), dried (MgSO ₄ ), filtered and the solvent was evaporated to give the racemic epoxide as a yellow oil (950 mg). ¹ H NMR was as in Production Example 3. The material proceeded directly without further purification.

Production Example 41
4-propyl-2-thiazol-5-yl-morpholin-2-ol

2-Trimethylsilylthiazole (9.5 g, 60.5 mmol, 1 eq) in Et ₂ O (200 ml) at −78 ° C. to n-butyllithium (36 ml, 2.5 M in hexane, 90.7 mmol, 1.5 eq) ) Was added dropwise and the mixture was stirred at -78 ° C for 30 min. 4-Propylmorpholin-2-one (prepared according to the method described in WO2004 / 052372—8.65 g, 60.5 mmol, 1 eq) in Et ₂ O (50 ml) was added over 5 min (addition) The temperature is raised to -55 ° C). The mixture was cooled again to -78 ° C and stirred at -78 ° C for 2 hours. The reaction was quenched by the dropwise addition of water, warmed to room temperature and extracted with EtOAc (2 × 500 ml) and dichloromethane (2 × 300 ml). The organic extracts were combined, dried over MgSO ₄ and the solvent was evaporated to give a brown oil. The oil was used with a gradient elution from 98/2 / 0.5 CH ₂ Cl ₂ / MeOH / NH ₃ to 95/5 / 0.5 CH ₂ Cl ₂ / MeOH / NH ₃ using an Isco Companion Combiflash autochromatography. Chromatography through a system SiO2 column gave a light brown solid (8.5 g, 61%).

Production Example 42
2-[(2-hydroxyethyl) (propyl) amino] -1- (1,3-thiazol-5-yl) ethanol

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 ₄ and the mixture was stirred at room temperature for 1 hour. Stir. The mixture was diluted with water (200 mL) and extracted with dichloromethane (3 × 250 ml). The organic layers were combined, dried over MgSO ₄ and the solvent was evaporated to give a pale oil (6.2 g).

Production Example 43
4-propyl-2- (1,3-thiazol-5-yl) morpholine

2-[(2-hydroxyethyl) (propyl) amino] -1- (1,3-thiazol-5-yl) ethanol (5.7 g, 24.8 mmol) in dichloromethane (20 ml) was concentrated sulfuric acid (50 ml). Was processed. When the addition was complete, the dichloromethane was removed in vacuo and the resulting mixture was heated at 140 ° C. for 1 hour. The mixture was cooled to room temperature, poured into ice and quenched by careful addition of 0.880 NH ₃ containing ice while cooling to maintain T <20 ° C. The mixture was extracted with dichloromethane (2 × 250 ml), dried over MgSO ₄ and the solvent was evaporated to give a brown oil. This material was chromatographed on the Isco Companion Combiflash Autochromatography system using 98/2 / 0.5 CH ₂ Cl ₂ / MeOH / NH ₃ eluent to give the product as a light brown oil. .

Production Example 44
2- (2-Bromo-1,3-thiazol-5-yl) -4-propylmorpholine

4-propyl-2- (1,3-thiazol-5-yl) morpholine (2.9 g, 13.7 mmol) in THF (50 ml) at −78 ° C. and n-butyllithium (5.5 ml, 2 in hexane). 0.5M, 13.7 mmol, 1 eq) was added and stirred at −78 ° C. for 30 min. A solution of carbon tetrabromide (4.5 g, 13.7 mmol) was added to maintain T <−70 ° C. during the addition and the mixture was stirred at −70 ° C. for 1 hour. The reaction was stopped by careful addition of water and allowed to warm to room temperature for 18 hours. The mixture was extracted with EtOAc (3 × 150 ml), dried over MgSO ₄ and the solvent was evaporated to give a brown oil. This material was subjected to a gradient elution from 99/1 / 0.1 CH ₂ Cl ₂ / MeOH / NH ₃ to 95/5 / 0.5 CH ₂ Cl ₂ / MeOH / NH ₃ using an Isco Companion Combiflash autochromatography system. And the product was obtained as a brown oil (2.5 g, 63%).

Claims (12)

Formula (I):
[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
{Where,
A represents O;
R ⁴ is selected from H and straight chain (C ₁ -C ₆ ) alkyl; wherein said straight chain (C ₁ -C ₆ ) alkyl is each from OR ⁷ , phenyl, substituted phenyl and heteroaryl Optionally substituted with 1 or 2 independently selected substituents;
R ⁵ is selected from H and (C ₁ -C ₆ ) alkyl; wherein said (C ₁ -C ₆ ) alkyl is optionally substituted with one or two 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 said (C ₁ -C ₆ ) alkyl may optionally be substituted with phenyl or a substituted phenyl group;
Here, heteroaryl means a 5- to 7-membered aromatic ring containing 1 to 4 heteroatoms, wherein the heteroatoms are independently selected from O, S and N; The heteroaryl may be optionally substituted with one or more substituents each independently selected from (C ₁ -C ₆ ) alkyl, halo and OR ⁷ , each substituent being the same or May be different;
And here, substituted phenyl means phenyl substituted with one or more substituents each independently selected from (C ₁ -C ₆ ) alkyl, halo and OR ^7. The groups may be the same or different;
However:
When R ¹ and R ² are H, R ⁵ is H or (C ₁ -C ₆ ) alkyl, and R ⁶ is H or (C ₁ -C ₆ ) alkyl, R ⁴ is n-propyl. Can't be}
Is]
Or a pharmaceutically acceptable salt, solvate or polymorph thereof. Formula (I):
[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
{Where,
n is 1;
R ⁴ is selected from H and (C ₁ -C ₆ ) alkyl; wherein (C ₁ -C ₆ ) alkyl is (C ₁ -C ₆ ) alkyl, OR ⁷ , phenyl, substituted phenyl And optionally substituted with one or two substituents each independently selected from heteroaryl;
R ⁷ is selected from H and (C ₁ -C ₆ ) alkyl; wherein said (C ₁ -C ₆ ) alkyl may optionally be substituted with phenyl or a substituted phenyl group;
Where heteroaryl means a 5-7 membered aromatic ring containing 1-4 heteroatoms, wherein the heteroatoms are independently selected from O, S and N; The aryl may be optionally substituted with one or more substituents each independently selected from (C ₁ -C ₆ ) alkyl, halo and OR ⁷ , each substituent being the same or different. May be; and
Here, substituted phenyl means phenyl substituted with one or more substituents each independently selected from (C ₁ -C ₆ ) alkyl, halo and OR ⁷ , wherein each substituent is May be the same or different}
Selected from]
Or a pharmaceutically acceptable salt, solvate or polymorph thereof. The compound according to claim 1 or 2, wherein R ¹ and R ² are each independently selected from H and methyl. 2. R ⁵ is selected from methyl and ethyl, wherein said methyl and said ethyl may be optionally substituted with an OR ⁷ group; and R ⁶ is selected from H and methyl. Compound described in 1. n is 1, and R ⁴ are ethyl, selected from propyl or butyl, said alkyl group is optionally substituted with a phenyl group, a compound of claim 2. 5- (morpholin-2-yl) pyridin-2-amine;
5- [4- (3-phenylpropyl) morpholin-2-yl] pyridin-2-amine;
5-[(2R, 5S) -5-methylmorpholin-2-yl] pyridin-2-amine;
5-[(2S, 5S) -5-methyl-4- (3-phenylpropyl) morpholin-2-yl] pyridin-2-amine;
5-[(2S, 5S) -4-butyl-5-methylmorpholin-2-yl] pyridin-2-amine;
5-{(2R, 5S) -5-[(benzyloxy) methyl] -4-propylmorpholin-2-yl} pyridin-2-amine;
[6- (6-aminopyridin-3-yl) -4-propylmorpholin-3-yl] methanol;
4-methyl-5- (4-propylmorpholin-2-yl) pyridin-2-amine;
5-[(2S, 5S) -4,5-diethylmorpholin-2-yl] pyridin-2-amine;
5-[(2R, 5S) -4,5-diethylmorpholin-2-yl] pyridin-2-amine; and 5- (2R, 5S)-(4-ethyl-5-methylmorpholin-2-yl)- 2. A compound according to claim 1 selected from pyridin-2-ylamine.   7. A compound according to any one of claims 1 to 6 for use as a medicament.   A medicament for treating sexual dysfunction comprising the compound according to any one of claims 1 to 6.   The medicament according to claim 8, wherein the sexual dysfunction is male erectile dysfunction or female sexual dysfunction.   A medicament for treating depression or psychiatric disorder, comprising the compound according to any one of claims 1 to 6.   The pharmaceutical for treating neurodegeneration containing the compound of any one of Claims 1-6.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 and a pharmaceutically acceptable diluent or carrier.