KR20130109936A - Compounds - Google Patents

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof: wherein R ¹ is CN; R ² is H or F; R ³ And R ⁴ is independently hydrogen, fluorine, chlorine, or OR ⁸ ; R ⁵ is hydrogen, C _{1 - 6} alkyl, C _{1 - 6} alkenyl or C _{1 - 6} alkynyl, and; R ⁶ And R ⁷ is independently hydrogen, halogen, OR ⁸ Or NR ⁹ R ¹⁰ ; R ⁸ is hydrogen or C _{1 - 6} alkyl; R ⁹ And R ¹⁰ is independently hydrogen or C _{1 - 6} alkyl; Or group R ⁹ And R ¹⁰ may together form a 5- or 6-membered ring when they are attached to a nitrogen atom, which optionally contains one further heteroatom selected from NR ⁸ , S and O, wherein said 5 or 6 membered ring is optionally a hydroxyl or C _{1 - 6} alkoxy is optionally substituted by; Or group R ⁹ And R ¹⁰ is hydroxyl or C ₁ they together when attached to nitrogen _atoms can form an optionally substituted azetidinyl ring substituted by a _6-alkoxy, is provided. The use of such compounds in the treatment of amyloid-related diseases is also disclosed.

Description

Compound {COMPOUNDS}

The present invention relates to novel heterocyclic compounds useful for the prevention and treatment of neurodegenerative disorders such as, for example, Alzheimer's disease, Parkinson's disease and Huntington's disease as well as type 2 diabetes.

Many refractory, age-related or degenerative diseases are involved in the general and basic pathogenic processes of protein or peptide misfolding and aggregation. This includes Alzheimer's disease, Parkinson's disease and Huntington's disease, and type 2 diabetes. Amyloid deposits present in these diseases consist of specific peptides that are characteristic for each of these diseases, but have a β-sheet structure characterized by amyloid fibrils, regardless of their sequence, and a common aggregation Share the path In each disease, specific proteins or peptides misfold, adopt β-strand structures and oligomerize to finally insoluble amyloid fibers, plaques or inclusions During the formation of fibrils ( en route ) to form a soluble aggregate intermediate. These insoluble forms of aggregated proteins or peptides are formed by the intermolecular association of β-strands into β-sheets. Current evidence suggests that soluble amyloid oligomers may be a major cause of neurotoxicity (Cleary et al., 2005; Walsh and Selkoe, 2007).

This "amyloid-related" disease is characterized by the fact that normally soluble proteins accumulate in various tissues as insoluble deposits of fibrils that are rich in β-sheet structures and have characteristic dye-binding properties. (Glenner, 1980a, 1980b). Although the specific polypeptides, including the deposits, are different for each disease, they have some common characteristics in common. The most characteristic of these is the ability of the protein to be highly soluble in biological fluids to be gradually converted to insoluble filamentous polymers rich in the β-sheet arrangement. Moreover, they tend to be formed by similar molecular mechanisms (by intermolecular association of β-strands to extended β-sheets), so that they are for example Congo Red and Thioflavin-T (Thioflavin T). There is a tendency to share a similar molecular structure and common ability to bind some pigments, such as (Selkoe, 2003; Stefani, 2004).

Amyloid-related diseases fall into two main categories: diseases affecting the brain and other parts of the central nervous system and diseases affecting other organs or tissues of the body outside the brain. Examples of amyloid-related diseases falling into these two categories are listed in the following two sections, but many other examples of rare hereditary amyloid-related diseases not included herein are known and more types of amyloid-related diseases are known. It will be found in the future.

Amyloidosis  Related Neurodegenerative Diseases

Many different neurodegenerative diseases are associated with misfolding and aggregation of specific proteins or peptides in certain parts of the brain, or in other parts of the central nervous system, depending on the particular disease (LeVine, 2004; Caughey and Lansbury, 2003; Dev et al. , 2003; Taylor et al., 2002; Wood et al., 2003; Masino, 2004; Ross and Poirier, 2004; Soto and Castilla, 2004; Forman et al., 2004). For example:

Down's syndrome, hereditary cerebral hemorrhage with amyloidosis (HCHWA, Dutch type), cerebral amyloid angiopathy, and possibly also various forms of Alzheimer's disease (AD / FAD) Mild cognitive impairment and another form of dementia are associated with aggregation of β-amyloid, ie 40 / 42-residue peptides called Aβ (1-40) or Aβ (1-42), which are specific diseases Accordingly, to form insoluble amyloid fibers and plaques in the cerebral cortex, hippocampus or another site of the brain;

Alzheimer's disease is also associated with the formation of neurofibrillary tangles by aggregation of hyperphosphorylated proteins called tau, which also occurs in frontotemporal dementia (Pick's disease ));

Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are involved in the aggregation of proteins called α-synuclein, which is called Resulting in the formation of an insoluble inclusion body called "Lewy bodies";

Huntington's disease (HD), spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, thalamus-nucleus-pale-nucleus-subthalamic atrophy (DRPLA), Glutamin repeats (extended tracks of polyglutamine) with abnormally prolonged different types of spinocerebellar ataxia (SCA, types 1, 2, 3, 6 and 7), and possibly another inherited neurodegenerative disease (tract) associated with aggregation of various proteins and peptides containing;

Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE), sheep scrapie, kuru, gerstmann-strau Gersmann-Straussler-Scheinker disease (GSS), fatal familial insomnia, and possibly another form of transmissible encephalopathy, are self-contained prion proteins. related to misfolding and flocculation;

Amyotrophic lateral sclerosis (ALS), and possibly another form of motor neuron disease (MND), are associated with aggregation of proteins called superoxide dismutases;

Familial British dementia (FBD) and familial Danish dementia (FDD) are associated with aggregation of ABri and ADan peptide sequences derived from BRI proteins, respectively; And

Amyloid hereditary cerebral hemorrhage (Icelandic type) (HCHWA, Icelandic type) is involved in the aggregation of a protein called cystatin C.

Amyloidosis  Related Systemic Diseases

In addition to the neurodegenerative diseases listed above, a wide range of systemic age-related or degenerative diseases are involved in misfolding and aggregation of specific proteins or peptides in various other tissues around the body outside the brain (Gejyo et al., 1985; Jaikaran and Clark, 2001; Buxbaum, 2004). For example:

Type 2 diabetes (also known as adult-onset diabete, or non-insulin dependent diabetes mellitus) is an islet amyloid polypeptide, IAPP, or "amylin (amylin) "), which is associated with the aggregation of 37-residue peptides, which form insoluble deposits associated with the progressive destruction of insulin-secreting β cells in the pancreas islets of Langerhans. ; There is also evidence that toxic species are IAPP oligomers (Haataja et al., 2008).

Dialysis-related amyloidosis (DRA) and prostatic amyloid are present in the bones, joints and tendons in the case of DRAs, in which case the proteins are prolonged during hemodialysis Developing, or in the prostate in the case of prostate amyloid, involves the aggregation of a protein called β ₂ -microglobulin;

Primary systemic amyloidosis, systemic AL amyloidosis, and myeloma-associated amyloidosis are insoluble in immunoglobulin light chains (or in some cases immunoglobulin heavy chains). Associated with aggregation into amyloid deposits, which gradually accumulate in various major organs such as the liver, kidney, heart and gastrointestinal (GI) tract;

Reactive systemic AA amyloidosis, secondary systemic amyloidosis, familial Mediterranean fever and chronic inflammatory disease are associated with aggregation of serum amyloid A protein. Forming insoluble amyloid deposits that accumulate in major organs such as liver, kidney and spleen;

Senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP), and familial amyloid cardiomyopathy (FAC) are different variants of the transthyretin protein (TTR). Associated with misfolding and aggregation, which forms insoluble inclusion bodies in various organs and tissues such as the heart (particularly in the case of FAC), peripheral nerves (particularly in the case of FAP), and the gastrointestinal (GI) tract;

Another form of familial amyloid polyneuropathy (FAP, type II) is involved in the aggregation of apolipoprotein AI in peripheral nerves;

Familial visceral amyloidosis and hereditary non-neuropathic systemic amyloidosis are associated with misfolding and aggregation of various strains of lysozyme, such as liver, kidney and spleen. Forming insoluble deposits in major organs;

Finnish hereditary systemic amyloidosis is associated with the aggregation of a protein called gelsolin in the eye (especially in the cornea);

Fibrinogen α-chain amyloidosis is associated with the aggregation of fibrinogen A α-chains, which form insoluble amyloid deposits in several organs such as the liver and kidneys;

Insulin-related amyloidosis is caused by aggregation of insulin at the injection site in the case of diabetes;

Medullary carcinoma of the thyroid gland is associated with the aggregation of calcitonin in the surrounding tissues;

Isolated atrial amyloidosis is associated with the aggregation of atrial natriuretic peptide (ANP) in the heart; And

Various types of cataracts are involved in the aggregation of γ-crystallin protein in the lens of the eye.

Pathogenic Mechanisms of Amyloid-Related Diseases

While all these amyloid-related diseases share a common connection with the pathogenic process of amyloidosis, the exact molecular mechanisms involved in the progressive degeneration of tissues affected by this general process of protein / peptide misfolding and aggregation are unclear. In some cases, including systemic amyloid-related diseases, the sheer mass of insoluble protein or peptide simply overwhelms the affected tissue, which is considered to eventually cause acute organ failure. In other cases, including most of the neurodegenerative diseases listed above, the toxic form of the amyloidogenic protein is a soluble oligomer species, which, in size, dimers and trimers, to tens or even hundreds or It is further considered a range up to a much larger species containing thousands of protein or peptide monomers. Moreover, oligomers are inherently toxic to cells in vitro in the absence of insoluble aggregates, all of which are considered identical antibodies despite the fact that they can be formed by proteins or peptides having very different amino acid sequences. They are believed to share common structural features (Kayed et al., 2003; Glabe, 2004; Walsh et al., 2002; Walsh and Selkoe, 2004). For Alzheimer's disease, some studies have shown that the severity of the disease is more closely related to the soluble form of Aβ than the fibrillar form of the peptide (Lue et al., 1999; McLean et al., 1999; Wang et al., 1999). It has been found to point to a key pathogenic role for soluble oligomers of Αβ.

Accumulating evidence (Estrada and Soto, 2007) provides a convincing argument that compounds that prevent A [beta] aggregation and prevent the production of toxic A [beta] assemblies can provide a successful new treatment for AD. Unlike current therapies that only treat symptoms of the disease (Melnikova, 2007; Shah et al., 2008; Wilcock, 2008), these 'disease-modifying' therapies can slow or even stop disease progression. You may have the ability. Molecules that inhibit A [beta] aggregation and prevent oligomerization or bind to toxic A [beta] assemblies and neutralize these toxic effects can be useful in the treatment of AD. Moreover, preventing Aβ aggregation is therapeutically attractive because this process is considered an exclusive pathological event and compounds that target this mechanism tend to have superior stability properties compared to some other approaches currently pursued. Because it is larger.

The molecular structure of these toxic soluble oligomers is unknown and the exact mechanism by which they kill cells is unclear, but some theories have been proposed. According to only one theory, for example, called "channel hypothesis," oligomers form heterogeneous void or leaky ion channels, which allow ions to flow freely through the cell membrane, thereby Destroys its integrity and eventually causes cell death (Kagan et al., 2002).

However, regardless of the exact pathogenic mechanism, an overwhelming amount of evidence has accumulated that suggests that the general process of protein / peptide aggregation is the main cause of all, and possibly, another, different amyloid-related disorder.

The present invention relates to chemical compounds and compositions having inhibitors of amyloid toxicity and thus having use in the treatment of amyloid-related diseases and disorders.

WO2007125351 discloses a class of 2,5-disubstituted pyrimidine derivatives that have been found to inhibit amyloid toxicity. In drug design, functional groups can be grouped into clusters according to their physicochemical properties. For example, hydrophobic (π), electron (σ) and molar refractive properties can be used to group substituents with potentially similar biological activities. Nitrile, carboxylic acid and carboxylic ester functional groups belong to the same cluster and are therefore expected to exhibit similar biological activity. Previous studies have shown that electron withdrawing carboxyl-like substituents in the aniline ring of the claimed formula are very detrimental to the desired activity. However, unexpectedly, we now believe that the stoichiometric ratio of the β-amyloid: inhibitor of 1: 2 to 1: 3 by the SEN1500 where the nitrile group in the aniline ring exhibits an IC ₅₀ of 26 μM in protection against β-amyloid toxicity. , It has a very positive effect on this type of ability. In contrast, typical carboxyl derivatives SEN1521, SEN1538 and SEN1547 are inert.

Thus, in a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof:

here

R ¹ is CN;

R ² is H or F;

R ³ And R ⁴ is independently hydrogen, fluorine, chlorine, or OR ⁸ ;

R ⁵ is hydrogen, C _{1 - 6} alkyl, C _{1 - 6} alkenyl or C _{1 - 6} alkynyl, and;

R ⁶ And R ⁷ is independently hydrogen, halogen, OR ⁸ Or NR ⁹ R ¹⁰ ;

R ⁸ is hydrogen or C _{1 - 6} alkyl;

R ⁹ And R ¹⁰ is independently hydrogen or C _{1 - 6} alkyl;

Or group R ⁹ And R ¹⁰ may together form a 5- or 6-membered ring when they are attached to a nitrogen atom, which optionally contains one further heteroatom selected from NR ⁸ , S and O, wherein said 5 or 6 membered ring is optionally a hydroxyl or C _{1 - 6} alkoxy is optionally substituted by;

Or group R ⁹ And R ¹⁰ may together form an azetidinyl ring optionally substituted by hydroxyl or C _1-6 alkoxy when they are attached to a nitrogen atom.

The term "alkyl" includes both straight and branched chain radicals as used herein per se or as part of a larger group, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl , sec-butyl and tert-butyl. The term alkyl also includes these radicals, such as CF ₃ , in which one or more hydrogen atoms are replaced with fluorine.

The terms "alkenyl" and "alkynyl" as used herein include both straight and branched chain radicals.

The term "halogen" as used herein includes fluorine, chlorine and bromine.

Preferred compounds are as follows:

3- [5- (3-morpholin-4-ylphenoxy) pyrimidin-2-ylamino] -benzonitrile

2-Fluoro-5- [5- (3-morpholin-4-ylphenoxy) -pyrimidin-2-ylamino] -benzonitrile

2-fluoro-5-methyl- [5- (3-morpholin-4-ylphenoxy) -pyrimidin-2-yl] amino-benzonitrile

2,6-difluoro-3- [5- (3-morpholin-4-ylphenoxy) -pyrimidin-2-ylamino] benzonitrile

2-Chloro-5- [5- (3-morpholin-4-ylphenoxy) -pyrimidin-2-ylamino] -benzonitrile

3-Fluoro-5- [5- (3-morpholin-4-ylphenoxy) -pyrimidin-2-ylamino] -benzonitrile

2-Fluoro-3- [5- (3-morpholin-4-ylphenoxy) -pyrimidin-2-ylamino] -benzonitrile

4-Fluoro-3- [5- (3-morpholin-4-ylphenoxy) -pyrimidin-2-ylamino] -benzonitrile

2-methoxy-5- [5- (3-morpholin-4-ylphenoxy) -pyrimidin-2-ylamino] -benzonitrile

2-Fluoro-5- [5- (3-pyrrolidin-1-ylphenoxy) -pyrimidin-2-ylamino] -benzonitrile

2-fluoro-4- (5- (3- (3-hydroxyazetidin-1-yl) phenoxy) pyrimidin-2-yl-amino) benzonitrile

The present invention includes any salts of the compounds of the present invention, in particular any pharmaceutically acceptable salts. Preferred salts for the present invention are hydrohalogenates (e.g. hydrochloride, hydrobromide, hydroiodide, etc.), inorganic acid salts (e.g. sulfate salts, nitrate salts, perchlorate salts, phosphate salts, carbonates) Salts, bicarbonate salts, and the like), organic carboxylic acid salts (e.g., acetate salts, maleate salts, tartrate salts, fumarate salts, citrate salts, etc.), organic sulfonic acid salts (e.g. methanesulfo Nate salts, ethane sulfonate salts, benzene sulfonate salts, toluenesulfonate salts, camphorsulfonate salts, and the like), amino acid salts (eg, aspartate salts, glutamate salts, etc.), quaternary ammonium salts, alkali metal salts (Eg, sodium salts, potassium salts, and the like), alkaline earth metal salts (eg, magnesium salts, calcium salts, and the like) and the like.

Salts can be prepared according to conventional methods using methods known in the art. Acid addition salts of these basic compounds can be prepared by dissolving the free base compound according to the first aspect of the invention in an aqueous solution or an aqueous alcohol solution or another suitable solvent containing the required acid. When the compound of the present invention has an acidic functional group, the basic salt of the compound can be prepared by reacting the compound with an appropriate base. Acidic or basic salts can be obtained by direct separation or by concentrating the solution, for example by evaporation.

The compounds of the present invention may exist in optical isomeric forms, such as diastereomers and mixtures of all proportions of isomers, such as racemic mixtures. The present invention particularly includes isomeric forms (R or S). Different isomeric forms may be separated or resolved from either by conventional methods, or any given isomer may be obtained by conventional synthesis or by stereospecific or asymmetric synthesis. If the compound contains a portion of the alkene, the alkene may be present as the cis (cis) or trans (trans) isomer or a mixture thereof. When an isomeric form of a compound of the invention is provided substantially free of other isomers, it contains another isomer less than 5% w / w, more preferably less than 2% w / w and especially less than 1% w / w. It would be desirable.

Since the compounds of the invention are intended for use in pharmaceutical compositions, they are each preferably in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, It will be readily understood that in particular it is provided as at least 98% pure (% is based on weight-weight). Non-pure preparations of the compounds can be used to prepare the more pure forms used in pharmaceutical compositions; Such less pure preparations of compounds should contain at least 1%, more suitably at least 5%, for example from 10 to 59% of the compound of formula (I).

Compounds of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are defined for formula (I) above are compounds of formula (II)

Wherein R ⁶ and R ⁷ are as defined in formula (I), from suitable catalysts such as tris (dibenzylideneacetone) -palladium (0), phosphine ligands such as 4,5- bis In the presence of phenylphosphino) -9,9-dimethylxanthene and a base such as cesium carbonate, in a solvent such as 1,4-dioxane, it can be prepared by treatment with an appropriate aniline.

Compounds of formula (II), wherein R ⁶ and R ⁷ are defined in formula (I), comprise one equivalent of 2-chloro-5-hydroxypyrimidine in equivalent boronic acid of formula (III), wherein R ⁶ and R ⁷ is as defined in formula (I) and can be prepared by treatment in a suitable solvent such as dichloromethane in the presence of triethylamine and copper (II) acetate. 2-Chloro-5-hydroxypyrimidine can be prepared by methods known to those skilled in the art.

Instead, a compound of formula (I), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are defined for Formula (I) above, is derived from a compound of Formula (IV) , Boric acid of formula (III), wherein R ⁶ and R ⁷ are as defined in formula (I), in a suitable solvent in the presence of triethylamine and copper (II) acetate, for example dichloromethane It can be prepared by.

Compounds of formula (IV) are de-benzylation using conventional hydrocracking conditions of hydrogen gas from compounds of formula (V) in the presence of a suitable catalyst such as palladium-on-carbon in a suitable solvent such as ethanol. It can be prepared by.

The compound of the formula (V) can be prepared from 2-chloro-5-benzyloxypyrimidine with a suitable catalyst such as tris (dibenzylideneacetone) -palladium (0), phosphine ligands such as 4,5- bis In the presence of diphenylphosphino) -9,9-dimethylxanthene and a base such as cesium carbonate, in a solvent such as 1,4-dioxane, it can be prepared using an appropriate aniline with heating.

Unstable functional groups in the intermediate compound, such as hydroxyl and amino groups, may be protected during the synthesis of the compound of formula (I). The protecting group may be removed at any stage of the synthesis of the compound of formula (I) or may be present in the final compound of formula (I). A comprehensive discussion of how different labile functional groups can be protected and methods for isolating the resulting protected derivatives is given, for example, in Protective Groups in Organic Chemistry, are given in TW Greene and PGM Wuts (Wiley- Interscience, New York, 2 nd edition, 1991).

It will be understood by those skilled in the art that by using the methods described above in various combinations it is possible to synthesize another derivative included in the general formula (I).

It will also be appreciated that the aniline and boronic acid forming blocks used in the synthesis of the general formula (I) compounds are commercially available or can be synthesized by methods known in the art.

Pharmaceutically effective compounds of formula (I) may be administered in conventional formulations prepared by mixing a standard pharmaceutical carrier or excipient with a compound of formula (I) (“active ingredient”) according to conventional procedures known in the art. The process may include mixing, granulating and compressing or dissolving the ingredients as appropriate for the desired formulation.

Thus, in a third aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, with one or more pharmaceutically acceptable carriers or excipients .

The active ingredient of the pharmaceutical composition may be administered simultaneously, separately or sequentially with another suitable therapeutic agent for the amyloid-related disease to be treated.

The active ingredient or pharmaceutical composition may be administered to the subject by any of the routes conventionally used for drug administration, for example they are oral administration (including buccal administration, sublingual administration), nasal to mammals, including humans. It may be suitable for administration (including inhalation administration) or parenteral administration (including subcutaneous administration, intramuscular administration, intravenous administration or intradermal administration). The best route for administration in any given case will depend on the particular compound or pharmaceutical composition, the subject, and the nature and composition, and the severity of the disease and the physical state of the subject. Such compositions can be prepared by any method known in the art of pharmacy, such as by combining the active ingredient with a carrier or excipient. Preferred routes of administration are oral and intravenous administration.

Pharmaceutical compositions suitable for oral administration may be presented as discrete units such as capsules or tablets; Powder or granules; A solution or suspension in an aqueous or non-aqueous liquid; Edible foams or whips; Or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

Tablets and capsules for oral administration may be in unit dosage form, and include conventional excipients such as binders such as syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidine; Fillers such as lactose, sugar, corn-starch, calcium phosphate, sorbitol or glycine; Tabletting lubricants such as magnesium stearate, talc, polyethylene glycol or silica; Disintegrants such as potato starch; Or an acceptable wetting agent such as sodium lauryl sulfate. Tablets can usually be coated according to methods known in the pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsion syrups or elixirs, or may be present as a dry product for reconstitution with water or another suitable carrier prior to use. . Such liquid preparations are conventional additives such as suspending agents such as sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsifiers such as lecithin, Sorbitan monooleate, acacia; Non-aqueous carriers (which may contain edible oils) such as almond oils, oily esters such as glycerin, propylene glycol, or ethyl alcohol; Preservatives such as methyl or propyl p -hydroxybenzoate or sorbic acid and, if desired, conventional flavoring or coloring agents.

Pharmaceutical compositions suitable for controlled release or sustained release may be administered by injection, eg, by a subcutaneous route.

Pharmaceutical compositions suitable for nasal administration in which the carrier is a solid are coarse, for example, administered by rapid inhalation through the nasal passages from a powder container which has a particle size in the range of 20-500 microns and is kept close to the nose. Powder. Compositions in which the carrier is liquid and suitable for administration as a nasal spray or nasal drop comprise an aqueous or oily solution of the active ingredient.

Pharmaceutical compositions suitable for administration by inhalation include fine particle dust or mist, which can be generated by various types of metered dose pressurized aerosols, nebulizers or insulators.

Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions which may contain antioxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the intended recipient's blood; And aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be present in unit-dose or multi-dose containers, eg sealed ampoules or vials, and freeze-dried (freeze-drying) requiring only the addition of a sterile liquid carrier, eg water, for injection immediately prior to use. May be stored in a closed state. Instant injection solutions and suspensions can be prepared from sterile powders, granules and tablets.

For parenteral administration, fluid unit dosage forms are prepared using the active ingredient and a sterile carrier, with water being preferred. Depending on the carrier and concentration used, the active ingredient may be suspended or dissolved in the carrier. In solution preparation, the active ingredient is dissolved in water for injection and filter sterilized and sealed before filling into a suitable vial or ampoule.

Advantageously, reagents such as local anesthetics, preservatives and buffers can be dissolved in the carrier. To enhance stability, the composition can be filled into vials and then frozen and the water removed under reduced pressure. The dry lyophilized powder may then be sealed in a vial and a vial accompanied with water for injection may be supplied for reconstitution into a liquid phase before use. Parenteral suspensions are prepared in substantially the same manner except that the active ingredient is suspended in a carrier instead of dissolved and sterilization cannot be achieved by filtration. The active ingredient may be sterilized by exposure to ethylene oxide prior to suspension in sterile carriers. Advantageously, surfactants or wetting agents are included in the composition to promote uniform distribution of the active ingredient.

The pharmaceutical composition according to the invention is preferably suitable for oral administration, intravenous administration or subcutaneous administration.

In addition to the components described above in particular, it is to be understood that the composition may comprise another reagent customary in the art with respect to the type of preparation in question, for example, those suitable for oral administration may include flavoring agents. do. They may also contain therapeutically active reagents in addition to the compounds of the present invention. Such carriers may be present from about 1% up to about 98% of the formulation. More generally, they will form up to about 80% of the formulation.

The composition may contain 0.1% by weight, preferably 10-60% by weight of active substance, depending on the method of administration.

The pharmaceutical composition may be present in unit dosage form containing a predetermined amount of active ingredient per dose. Such units may contain, for example, 0.1 mg / kg to 100 mg / kg, more preferably 0.1 mg / kg to 10 mg / kg, depending on the condition being treated, the route of administration and the age, weight and condition of the patient. Preferred unit dosage compositions are those containing a daily dose or sub-dosage of the active ingredient, or an appropriate fraction thereof, as recited above.

In the first and second aspects of the invention, the optimal amount and interval of individual doses of the compound will be determined by the nature and extent of the disease being treated, the dosage form, the route and site, and the particular subject being treated, and such optimal conditions It will be appreciated by those skilled in the art that this may be determined by the prior art. It will also be understood by those skilled in the art that the optimal route of treatment, i. will be.

Depending on the route of administration, the chemical compound or composition may be required to be coated with a substance to protect it from the action of an enzyme, an acid or another neutral condition that can inactivate it.

To administer a chemical compound or composition in addition to parenteral administration, it may be coated with a substance to prevent its deactivation or may be administered with such a substance. For example, it may be administered in an adjuvant, co-administered with an enzyme inhibitor, or in liposomes. Adjuvants contemplated herein include resorcinol, non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether.

Liposomes include conventional liposomes as well as water-in-oil-in-water CGF emulsions.

The active chemical compound or composition may also be administered parenterally or intraperitoneally. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and combinations thereof, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical compositions or formulations suitable for injectable use contain sterile aqueous solutions (which are water soluble) or dispersions and sterile powders for immediate preparation of sterile injectable solutions or dispersions. In all cases the formulation must be sterile and must be fluid to the extent that easy syringability exists. The formulation must be stable under the conditions of manufacture and storage and must be conservative against the contaminating activity of microorganisms such as bacteria and fungi. Carriers include, for example, solvents containing water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyetheylene gloycol, etc.), suitable combinations thereof, and vegetable oils Or dispersion medium. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

Prevention of microbial action can be carried out by various antibacterial and antibacterial agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example sugars or sodium chloride. Prolonged absorption of the injectable compositions can be performed using reagents that prolong absorption in the composition, such as aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active chemical compound or composition in the required amount in a suitable solvent with the various other desired ingredients enumerated above, followed by filtered sterilization. In general, dispersions may be prepared by incorporating the sterile active ingredient into a sterile carrier which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying and freeze-drying techniques which yield any additional desired ingredients from their previous sterile-filtered solution together with the powder of the active ingredient.

When the chemical compound or composition is properly protected as described above, it may be administered orally, for example, with an inert diluent or with an assimilable edible carrier, or it may be included in a hard or soft shell gelatin capsule. Or it may be compressed to be a tablet, or it may be directly included in a dietary food. For oral therapeutic administration, the active compounds may be included in excipients and used in the form of ingestible tablets, oral tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. have. The amount of active compound in such therapeutically useful compositions is such that an appropriate dose is obtained.

Tablets, troches, pills, capsules, and the like may also include the following: binders such as gum tragacanth, acacia, corn starch or gelatin; Excipients such as dicalcium phosphate; Disintegrants such as corn starch, potato starch, alginic acid and the like; Glidants such as magnesium stearate; And sweetening agents such as sucrose, lactose or saccharin may be added or flavoring agents such as peppermint, wintergreen oil, or cherry flavoring agent. If the dosage unit form is a capsule, it may contain a liquid carrier in addition to this type of substance.

Various other materials may be present as coatings or otherwise to modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated by shellac, sugar or both. Syrups or elixirs may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as a preservative, dyes and flavoring agents such as cherry or orange flavoring agents. Of course, all materials used to prepare any dosage unit form must be pharmaceutically pure and substantially non-toxic in the amount used. In addition, the active compounds may be included in sustained release preparations or products.

As used herein, "pharmaceutically acceptable carriers and / or diluents" include any and all solvents, dispersion media, coatings, antibacterial and antibacterial agents, isotonic and absorption delaying agents, and the like. The use of such media and reagents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or reagent is incompatible with the active ingredient, their use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be included in the compositions.

It is particularly advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. As used herein, dosage unit form means physically discrete units suited as a single dosage for the mammalian subject to be treated; Each unit contains a predetermined amount of active substance calculated to combine with the required pharmaceutical carrier to produce the desired therapeutic effect. The specifications for the novel dosage unit forms of the present invention are: (a) the unique properties of the active substance and the specific therapeutic effect to be achieved, and (b) the activity for the treatment of the disease in surviving subjects with a disease state in which physical health is impaired. It is defined by the inherent limitations in the field of compounds such as materials and depends directly on them.

The main active ingredient is combined with a suitable pharmaceutically acceptable carrier in dosage unit form in an effective amount for convenient and effective administration. In the case of compounds containing supplementary active ingredients, the dosage is determined by reference to the general manner of administration and administration of these ingredients.

In another aspect, the present invention provides:

1. Compounds of the invention for use in the treatment of amyloid-related diseases. In particular, the medicament is for the treatment of:

a) any form of Alzheimer's disease (AD or FAD);

b) any form of mild cognitive impairment (MCI) or senile dementia;

c) Down syndrome;

d) cerebral amyloid angiopathy, inclusion body myositis, amyloid hereditary cerebral hemorrhage (Dutch type) (HCHWA, Dutch type), or age-related macular degeneration (ARMD) ;

e) fronto-temporal dementia;

f) any form of Parkinson's disease (PD) or dementia with Lewy bodies;

g) Huntington's disease (HD), thalamus-nucleus-pale-nucleus-subthalamic atrophy (DRPLA), spinocerebellar ataxia (SCA, types 1, 2, 3, 6 and 7), spine and training Spinal and bulbar muscular atrophy (SBMA), Kennedy's disease, or any other polyglutamine disease;

h) Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE), sheep scrapie, kuru, gerstmann-Straussler- Gersmann-Straussler-Scheinker disease (GSS), fatal familial insomnia, or any other transmissible encephalopathy associated with aggregation of prion proteins;

i) Amyotrophic lateral sclerosis (ALS) or any other form of motor neuron disease;

j) Familial British dementia (FBD) or familial Danish dementia (FDD);

k) amyloidogenic cerebral hemorrhage (Icelandic type) (HCHWA, Icelandic type);

l) type 2 diabetes (adult-onset diabetes, or non-insulin dependent diabetes mellitus (NIDDM));

m) dialysis-related amyloidosis (DRA) or prostatic amyloid;

n) primary systemic amyloidosis, systemic AL amyloidosis, or nodular AL amyloidosis;

o) myeloma-associated amyloidosis;

p) systemic (reactive) AA amyloidosis, secondary systemic amyloidosis, chronic inflammatory disease, or familial Mediterranean fever;

q) senile systemic amyloidosis, familial amyloid polyneuropathy, or familial cardiac amyloid;

r) Familial visceral amyloidosis, hereditary non-neuropathic systemic amyloidosis, or any other lysozyme-related amyloidosis;

s) Finnish hereditary systemic amyloidosis;

t) fibrinogen α-chain amyloidosis;

u) insulin-related amyloidosis;

v) medullary carcinoma of the thyroid gland;

w) isolated atrial amyloidosis;

x) cataract in any form; And

y) Any other amyloid-related disease associated with misfolding or aggregation of certain target amyloid-forming proteins or peptides into toxic soluble oligomers, protofibrils, ion channels, insoluble amyloid fibers, plaques or inclusions.

2. A method of treating an amyloid-related disease, comprising administering to a subject an effective amount of a compound or pharmaceutical composition of the present invention.

Example

The following examples are considered to be exemplary only and are not to be construed as limiting the scope of the invention in any way.

Intermediate 1: 2, 4- Dihydroxy -5- Methoxypyrimidine

A mixture of methyl methoxyacetate (104 g. 1.0 mol) and ethyl formate (74 g. 1.0 mol) is added dropwise to a stirred suspension of sodium (23 g. 1.0 mol) in toluene (300 mL) and the temperature kept below 30 ° C. I was. After 24 h the toluene layer was discarded and ethanol (150 mL) and urea (60 g. 1.0 mol) were added to the crude, viscous methyl sodium-β-hydroxy-α-methoxyacrylate. The mixture was stirred for 1 h at room temperature and then heated under reflux for 5 h. After cooling, the solids were collected and dissolved in water (500 mL) and the solution was washed with 6N aq. Neutralized with hydrochloric acid. The resulting precipitate was collected by filtration and dried at 100 ° C. This material 2, 4-dihydroxy-5-methoxypyrimidine (47 g, 33%) was pure enough for direct use in the next step.

NMR : δ _H ( d ₆ -DMSO) 3.57 (3H, s), 7.00 (1H, s), 10.45 (1H, br) and 11.20 (1H, br).

Intermediate 2: 2, 4- Dichloro -5- Methoxypyrimidine

2, 4-dihydroxy-5-methoxypyrimidine (45 g, 0.316 mol), phosphorus oxychloride (225 mL, 0.88 mol), and N, N-dimethylaniline (45 mL, 0.391 mol) were added under reflux for 2 h. Heated. The mixture was poured into crushed ice (80 g.) And the product collected in ether. Recrystallization from light petroleum (b.p: 40-60 ° C.) yielded 2,4-dichloro-5-methoxypyrimidine (43 g, 75%).

Mass spectrometry: (ES +) 179 (M + H) ⁺

Intermediate 3: 2- Chloro -5- Methoxypyrimidine

2,4-dichloro-5-methoxypyrimidine (43 g, 0.24 mol), zinc dust (86 g, 1.32 mol), ethanol (200 mL) and water (200 mL) were heated under reflux for 4 h. . The hot mixture was filtered and ethanol was removed under reduced pressure. After cooling, the product was collected in ether. Recrystallization from light oil (b.p .: 40-60 ° C.) yielded 2-chloro-5-methoxypyrimidine (20 g, 58%).

Mass spectrometry: (ES +) 145 (M + H) ⁺

NMR : δ _H ( d ₆ -DMSO) 3.92 (3H, s) and 8.55 (2H, s).

Intermediate 4: 2- Chloro -5- Hydroxypyrimidine

To a solution of 2-chloro-5-methoxypyrimidine (10 g, 0.069 mol) in dichloromethane (84 mL) was added dropwise boron tribromide (104 mL, 1M solution in dichloromethane) at -78 ° C. The mixture was stirred at room temperature for 20 h and then methanol (150 mL) was added dropwise at -78 ° C. The reaction mixture was concentrated under reduced pressure and the pH was adjusted to 5 with aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent was removed under reduced pressure to yield 2-chloro-5-hydroxypyrimidine (5.0 g, 55%).

Mass spectrometry: (ES-) 129

NMR : δ _H ( d ₆ -DMSO) 8.27 (2H, s) and 10.85 (1H, br s).

Intermediate 5: 3- Morpholine -4- Monophenylboronic acid

1,3-dibromobenzene (50 g, 0.212 mol), morpholine (15.88 mL, 0.191 mol) and anhydrous toluene (200 mL) were placed into the flask by syringe under argon. After thoroughly mixing the solution, add R-BINAP (1.32 g, 0.0021 mol) and tris (dibenzylideneacetone) palladium (0) (0.640 g, 0.006 mol) and finally inject DBU (25.83 mL, 0.1726) into the syringe Added through. The reaction mixture was stirred at 60 < 0 > C. Sodium tert -butoxide (30.55 g, 0.3178 mol) was added and the reaction heated to 100 ° C. overnight. The suspension was diluted with ethyl acetate, filtered through celite and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica (ethyl acetate: hexane, 1: 1) to yield 4- (3-bromophenyl) morpholine as a yellow oil (31 g, 60%). .

Mass spectrometry: (ES +) 242 (M + H) ⁺

To a stirred mixture of 4- (3-bromophenyl) morpholine (16.5 g, 0.068 mol) in dry THF (300 mL) add n-BuLi (98.1 mL, 0.102 mol, 1.6 M in n-hexane) to -70 ° C. Dropwise at -78 ° C. The mixture was stirred at the same temperature for 2 h. Tri-isopropyl borate (30.5 mL, 0.150 mol) was added dropwise to this reaction mixture while maintaining the temperature. The dry ice-acetone bath was removed and the mixture was allowed to warm to room temperature and stirred overnight at room temperature. The mixture was poured into a saturated solution of ammonium chloride, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was dried (MgSO ₄ ) and the solvent removed at reduced pressure and below 40 ° C. The residue was triturated with n-hexane and diethyl ether to give 3-morpholin-4-ylphenylboronic acid (12 g, 85%) as off-white solid.

Mass spectrometry: (ES +) 208 (M + H) ⁺

NMR : δ _H ( d ₆ -DMSO) 3.05 (4H, m), 3.72 (4H, m), 6.95 (1H, d), 7.18 (1H, t), 7.21 (1H, d), 7.38 (1H, br s) and 7.94 (2H, s).

Intermediate 6: 4- [3- (2- Chloropyrimidine -5-yloxy) Phenyl ] Morpholine

2-chloro-5-hydroxypyrimidine (12.61g, 0.097mol), dimorpholinylphenylboronic acid (20.0g, 0.097mol) in dichloromethane (600mL), copper (II) acetate (19.28g, 0.097 mmol), triethylamine (47.13 mL, 0.34 mol) and powdered 4mm molecular sieve were stirred in air for 3 days. Calcium chloride guard tubes were used to protect the reactants from moisture. The suspension was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica (ethyl acetate: hexane 1: 1) to give 4- {3-[(2-chloropyrimidin-5-yl) oxy] phenyl} morpholine (5.0 g, 18 %) Was calculated as a colorless oil.

Mass spectrometry: (ES +) 292 (M + H) ⁺

NMR : δ _H ( d ₆ -DMSO) 3.15 (4H, m), 3.84 (4H, m), 6.50 (1H, d), 6.58 (1H, s), 6.75 (1H, d), 7.28 (1H, t ) And 8.35 (2H, s).

Intermediate 7: 2- Chloro -5- (3- ( Pyrrolidine -1 day) Phenoxy Pyrimidine

2-chloro-5-hydroxypyrimidine (2.69 g, 0.0206 mol), 3- (pyrrolidin-1-yl) phenylboronic acid (3.95 g, 0.0206 mol) in dichloromethane (70 mL), copper (II) A mixture of acetate (3.75g, 0.0206mmol), triethylamine (14.40mL, 0.0721mol) and powdered 4mm molecular sieve was stirred in air for 3 days. Calcium chloride guard tubes were used to protect the reaction from moisture. The suspension was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica (ethyl acetate: hexane, 1: 1) to give 2-chloro-5- (3- (pyrrolidin-1-yl) phenoxy) -pyrimidine as a colorless oil Calculated as (1.3 g, 18%).

Mass spectrometry: (ES +) 275 (M + H) ⁺

Intermediate 8: 2- Chloro -5- Benzyloxypyrimidine

Benzyl chloride (2.6 mL, 0.023 mol) was added to a stirred mixture of 2-chloro 5-hydroxypyrimidine (2.0 g, 0.01532 mol), K ₂ CO ₃ (4.23 g, 0.0307 mol) in dry THF (30 mL) at room temperature. Dropped at The mixture was heated at reflux overnight. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent was removed under reduced pressure to yield 2-chloro-5-benzyloxypyrimidine (1.3 g), which was of sufficient purity for direct use in the synthesis of intermediate 9.

Mass spectrometry: (ES +) 221 (M + H) ⁺

Intermediate 9: 5- [5- ( Benzyloxy Pyrimidine-2- Amino ]-2- Fluoro - Benzonitrile

2-chloro-5-benzyloxypyrimidine (2.0 g, 9.074 mmol), 5-amino-2-fluorobenzonitrile (1.24 g, 9.074 mmol) in de-gassed 1,4-dioxane (15 mL), tris (dibenzylideneacetone) palladium (0) (415 mg, 0.45 mmol), 4,5- bis (diphenylphosphino) -9,9-dimethylxanthene (525 mg, 0.90 mol) and cesium carbonate (5.9 g, 18.1 mmol) were heated at 80 ° C. for 2 days. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent removed under reduced pressure. The crude product was purified by flash chromatography using 0-5% ethyl acetate: hexane as eluent to give 5- [5- (benzyloxy) pyrimidin-2-ylamino] -2-fluoro-benzonitrile (2.88 g) was calculated as a yellow solid.

Mass spectrometry: (ES +) 321 (M + H) ⁺

Intermediate 9: 2- Fluoro -5- (5- Hydroxypyrimidine -2- Amino ) - Benzonitrile

A stirred mixture of 5- [5- (benzyloxy) pyrimidin-2-ylamino] -2-fluoro-benzonitrile (2.88 g), palladium-on-carbon (0.8 g) in dry ethanol (40 mL) Purge with hydrogen gas for 20 minutes. The suspension was filtered through celite, washed with ethanol and the solvent removed under reduced pressure to yield 2-fluoro-5- (5-hydroxypyrimidin-2-ylamino) -benzonitrile (1.5 g, 72%). It was.

Mass spectrometry: (ES +) 230 (M + H) ⁺

Example  1: 3- [5- (3- Morpholine -4- Ilphenoxy Pyrimidine-2- Amino ] - Benzonitrile  synthesis

4- [3- (2-chloro-pyrimidin-5-yloxy) phenyl] morpholine (150 mg, 0.515 mmol), 3-aminobenzonitrile (60.9 mg in degassed 1,4-dioxane (4 mL) , 0.515 mmol), tris (dibenzylideneacetone) -palladium (0) (23.6 mg, 0.025 mmol), 4,5- bis (diphenylphosphino) -9,9-dimethylxanthene (30 mg, 0.0515 mmol) And a suspension of cesium carbonate (336 mg, 1.030 mmol) was heated at 80 ° C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica (ethyl acetate: hexane 1: 1) to give 3- [5- (3-morpholin-4-ylphenoxy) pyrimidin-2-yl] aminobenzonitrile ( 30 mg, 16%) was calculated as an off-white solid.

Mass spectrometry: (ES +) 374 (M + H) ⁺

HPLC: 98.4%

NMR: δ _H ( d ₆ -DMSO) 3.12 (4H, m), 3.71 (4H, m), 6.41 (1H, dd), 6.64 (1H, br s), 6.73 (1H, dd), 7.20 (1H, t), 7.38 (1H, d), 7.50 (1H, t), 7.98 (1H, d), 8.30 (1H, br s), 8.48 (2H, s) and 10.13 (1H, s).

Example  2: 2- Fluoro -5- [5- (3- Morpholine -4- Ilphenoxy ) -Pyrimidine-2- Amino ] - Benzo Nitrile

4- [3- (2-chloro-pyrimidin-5-yloxy) phenyl] morpholine (150 mg, 0.515 mmol), 5-amino-2-fluoro in degassed 1,4-dioxane (4 mL) Robenzonitrile (70.2 mg, 0.515 mmol), tris (dibenzylideneacetone) -palladium (0) (23.6 mg, 0.025 mmol), 4,5- bis (diphenylphosphino) -9,9-dimethylxanthene (30 mg, 0.0515 mmol) and cesium carbonate (336 mg, 1.03 mmol) were heated at 80 ° C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica (ethyl acetate: hexane 1: 1) to give 2-fluoro-5- [5- (3-morpholin-4-ylphenoxy) pyrimidin-2-yl Amino] benzonitrile was calculated as a light yellow solid (70 mg, 35%).

Mass spectrometry: (ES +) 392 (M + H) ⁺

HPLC: 97%

NMR: δ _H ( d ₆ -DMSO) 3.08 (4H, m), 3.69 (4H, m), 6.39 (1H, dd), 6.61 (1H, br s), 6.70 (1H, dd), 7.18 (1H, t), 7.47 (1H, t), 7.95 (1H, m), 8.30 (1H, m), 8.44 (2H, s) and 10.10 (1H, s).

Example  3: 2- Fluoro -5- methyl -[5- (3- Morpholine -4- Ilphenoxy ) -Pyrimidin-2-yl-] Aminobenzonitrile

A suspension of 2-fluoro-5- [5- (3-morpholin-4-ylphenoxy) pyrimidin-2-ylamino] -benzonitrile (84 mg, 0.214 mmol) in dry THF for 5 minutes to 0 ° C. Cooled. Sodium hydride (26 mg, 0.644 mmol) was added followed by methyl iodide (0.25 mL, 2.148 mmol). The reaction was stirred at 0 ° C for 2 h. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent removed under reduced pressure. The crude product was purified by preparative TLC (ethylacetate: hexane, 1: 1) to give 2-fluoro-5-methyl- [5- (3-morpholin-4-ylphenoxy) -pyrimidine-2- General] aminobenzonitrile was calculated as a solid (44 mg, 38%).

Mass spectrometry: (ES +) 406 (M + H) ⁺

HPLC: 95%

NMR: δ _H ( d ₆ -DMSO) 3.08 (4H, m), 3.48 (3H, s), 3.69 (4H, m), 6.40 (1H, dd), 6.59 (1H, br s), 6.68 (1H, dd), 7.17 (1H, t), 7.53 (1H, t), 7.82 (1H, m), 8.00 (1H, m), 8.32 (2H, s) and 10.10 (1H, s).

Example  4: 2,6- Difluoro -3- [5- (3- Morpholine -4- Ilphenoxy ) -Pyrimidine-2- Amino ] - Benzonitrile

4- [3- (2-chloro-pyrimidin-5-yloxy) phenyl] morpholine (180 mg, 0.619 mmol), 3-amino-2,6- in degassed 1,4-dioxane (4 mL) Difluorobenzonitrile (95.3 mg, 0.619 mmol), tris (dibenzylidene-acetone) palladium (0) (28.3 mg, 0.030 mmol), 4,5- bis (diphenylphosphino) -9,9-dimethyl A suspension of xanthene (35.8 mg, 0.061 mmol) and cesium carbonate (403 mg, 1.238 mmol) was heated at 80 ° C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica (ethyl acetate: hexane, 1: 1) to give 2,6-difluoro-3- [5- (3-morpholin-4-ylphenoxy) pyrimidine -2-ylamino] benzonitrile was calculated as a solid (110 mg, 44%).

Mass spectrometry: (ES +) 410 (M + H) ⁺

HPLC: 99.2%

NMR: δ _H ( d ₆ -DMSO) 3.08 (4H, m), 3.69 (4H, m), 6.34 (1H, dd), 6.60 (1H, br s), 6.69 (1H, dd), 7.18 (1H, t), 7.40 (1H, t), 8.10 (1H, m), 8.35 (2H, s) and 9.59 (1H, s).

Example 5: 2-Chloro-5- [5- (3-morpholin-4-ylphenoxy) -pyrimidin-2-ylamino] -benzo-nitrile

4- [3- (2-chloro-pyrimidin-5-yloxy) phenyl] morpholine (180 mg, 0.619 mmol), 5-amino-2-chlorobenzo in degassed 1,4-dioxane (4 mL) Nitrile (94.3 mg, 0.619 mmol), tris (dibenzylidene-acetone) palladium (0) (28.3 mg, 0.030 mmol), 4,5- bis (diphenylphosphino) -9,9-dimethyl-xanthene ( 35.8 mg, 0.061 mmol) and cesium carbonate (403 mg, 1.238 mmol) were heated at 80 ° C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica (ethyl acetate: hexane, 1: 1) to give 2-chloro-5- [5- (3-morpholin-4-ylphenoxy) -pyrimidine-2- Ilamino] benzonitrile was calculated as a solid (40 mg, 16%).

Mass spectrometry: (ES +) 408 (M + H) ⁺

HPLC: 92%

NMR : δ _H ( d ₆ -DMSO) 3.08 (4H, m), 3.69 (4H, m), 6.39 (1H, dd), 6.62 (1H, br s), 6.70 (1H, dd), 7.19 (1H, t), 7.63 (1H, d), 7.96 (1H, dd), 8.40 (1H, d), 8.46 (2H, s) and 10.22 (1H, s).

Example  6: 3- Fluoro -5- [5- (3- Morpholine -4- Ilphenoxy ) -Pyrimidine-2- Amino ] - Benzo Nitrile

4- [3- (2-chloro-pyrimidin-5-yloxy) phenyl] morpholine (180 mg, 0.619 mmol), 3-amino-5-fluoro in degassed 1,4-dioxane (4 mL) Benzonitrile (84 mg, 0.619 mmol), Tris (dibenzylideneacetone) -palladium (0) (28.3 mg, 0.030 mmol), 4,5- bis (diphenylphosphino) -9,9-dimethylxanthene (35.8 mg, 0.061 mmol) and cesium carbonate (403 mg, 1.238 mmol) were heated at 80 ° C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica (ethyl acetate: hexane, 1: 1) to give 3-fluoro-5- [5- (3-morpholin-4-ylphenoxy) -pyrimidine-2 -Ylamino] -benzonitrile was calculated as a solid (98 mg, 41%).

Mass spectrometry: (ES +) 392 (M + H) ⁺

HPLC: 97.4%

NMR : δ _H ( d ₆ -DMSO) 3.10 (4H, m), 3.69 (4H, m), 6.40 (1H, dd), 6.62 (1H, br s), 6.71 (1H, dd), 7.18 (1H, t), 7.36 (1H, m), 8.00 (1H, s), 8.03 (1H, m), 8.48 (2H, s) and 10.32 (1H, s).

Example  7: 2- Fluoro -3- [5- (3- Morpholine -4- Ilphenoxy ) -Pyrimidine-2- Amino ] - Benzo Nitrile

4- [3- (2-chloro-pyrimidin-5-yloxy) phenyl] morpholine (180 mg, 0.619 mmol), 3-amino-2-fluoro in degassed 1,4-dioxane (4 L) Robenzonitrile (76 mg, 0.557 mmol), tris (dibenzylidene-acetone) palladium (0) (28.3 mg, 0.030 mmol), 4,5- bis (diphenylphosphino) -9,9-dimethyl-xanthene (35.8 mg, 0.061 mmol) and cesium carbonate (403 mg, 1.238 mmol) were heated at 80 ° C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica (ethyl acetate: hexane, 1: 1) to give 2-fluoro-3- [5- (3-morpholin-4-ylphenoxy) -pyrimidine-2 -Ylamino] -benzonitrile was calculated as a solid (70 mg, 29%).

Mass spectrometry: (ES +) 392 (M + H) ⁺

HPLC: 98.5%

NMR : δ _H ( d ₆ -DMSO) 3.08 (4H, m), 3.69 (4H, m), 6.38 (1H, dd), 6.61 (1H, br s), 6.70 (1H, dd), 7.18 (1H, t), 7.36 (1H, m), 7.58 (1H, m), 8.13 (1H, t), 8.38 (2H, s) and 9.60 (1H, s).

Example  8: 4- Fluoro -3- [5- (3- Morpholine -4- Ilphenoxy ) -Pyrimidine-2- Amino ] - Benzonitrile

4- [3- (2-chloro-pyrimidin-5-yloxy) phenyl] morpholine (180 mg, 0.619 mmol), 3-amino-4-fluoro in degassed 1,4-dioxane (4 mL) Benzonitrile (75.8 mg, 0.557 mmol), tris (dibenzylidene-acetone) palladium (0) (28.3 mg, 0.030 mmol), 4,5- bis (diphenylphosphino) -9,9-dimethylxanthene ( 35.8 mg, 0.061 mmol) and cesium carbonate (403 mg, 1.238 mmol) were heated at 80 ° C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica (ethyl acetate: hexane, 1: 1) to afford 4-fluoro-3- [5- (3-morpholin-4-ylphenoxy) -pyrimidine-2 -Ylamino] -benzonitrile was calculated as a colorless oil (111 mg, 46%).

Mass spectrometry: (ES +) 392 (M + H) ⁺

HPLC: 94.1%

NMR : δ _H ( d ₆ -DMSO) 3.08 (4H, m), 3.69 (4H, m), 6.38 (1H, dd), 6.61 (1H, br s), 6.70 (1H, dd), 7.18 (1H, t), 7.47 (1H, t), 7.59 (1H, m), 8.40 (2H, s), 8.43 (1H, m) and 9.55 (1H, s).

Example  9: 2- Methoxy -5- [5- (3- Morpholine -4- Ilphenoxy ) -Pyrimidine-2- Amino ] - Benzonitrile

4- [3- (2-chloro-pyrimidin-5-yloxy) phenyl] morpholine (180 mg, 0.619 mmol), 5-amino-2-methoxy in degassed 1,4-dioxane (4 mL) Benzonitrile (91.7 mg, 0.557 mmol), tris (dibenzylidene-acetone) palladium (0) (28.3 mg, 0.030 mmol), 4,5- bis (diphenylphosphino) -9,9-dimethyl-xanthene (35.8 mg, 0.061 mmol) and cesium carbonate (403 mg, 1.238 mmol) were heated at 80 ° C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica (ethyl acetate: hexane, 1: 1) to give 2-methoxy-5- [5- (3-morpholin-4-ylphenoxy) -pyrimidine-2 -Ylamino] -benzonitrile was calculated as a solid (113 mg, 46%).

Mass spectrometry: (ES +) 404 (M + H) ⁺

HPLC: 99%

NMR : δ _H ( d ₆ -DMSO) 3.08 (4H, m), 3.69 (4H, m), 3.88 (3H, s), 6.37 (1H, dd), 6.59 (1H, brs), 6.68 (1H, dd ), 7.17 (1H, d), 7.20 (1H, t), 7.86 (1H, dd), 8.12 (1H, d), 8.38 (2H, s) and 9.80 (1H, s).

Example  10: 2- Fluoro -5- [5- (3- Pyrrolidine -One- Ilphenoxy ) -Pyrimidin-2-ylamino]- Benzo Nitrile

2-chloro-5- (3- (pyrrolidin-1-yl) phenoxy) pyrimidine (150 mg, 0.545 mmol), 5-amino-2-fluoro in degassed 1,4-dioxane (4 mL) Robenzonitrile (74 mg, 0.545 mmol), tris (dibenzylidene-acetone) palladium (0) (24.9 mg, 0.027 mmol), 4,5- bis (diphenylphosphino) -9,9-dimethyl-xanthene (31.4 mg, 0.0545 mmol) and cesium carbonate (345.5 mg, 1.090 mmol) were heated at 80 ° C. for 2 days. The suspension was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica (ethyl acetate: hexane, 1: 1) to give 2-fluoro-5- [5- (3-pyrrolidin-1-ylphenoxy) -pyrimidine- 2-ylylamino] -benzonitrile was calculated as a solid (95 mg, 46%).

Mass spectrometry: (ES +) 376 (M + H) ⁺

NMR : δ _H ( d ₆ -DMSO) 1.90 (4H, m), 3.18 (4H, m), 6.13 (1H, dd), 6.15 (1H, br s), 6.28 (1H, dd), 7.10 (1H, t), 7.46 (1H, t), 7.95 (1H, m), 8.30 (1H, m) and 8.41 (2H, s).

Example  11: 2- Fluoro -5- [5- (3- Bromophenoxy Pyrimidine-2- Amino ] - Benzonitrile

2-Fluoro-5- (5-hydroxypyrimidin-2-ylamino) -benzonitrile (0.5 g, 0.00217 mol), 3-bromophenylboronic acid (0.497 g, 0.00217 mol) in dichloromethane (40 mL) ), A mixture of copper (II) acetate (0.394 g, 0.00217 mol), triethylamine (1.5 mL, 0.0109 mol), and powdered 4 ′ molecular sieve were stirred in air for 3 days. Calcium chloride guard tubes were used to protect the reaction from moisture. The reaction mixture was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent removed under reduced pressure. The crude product was purified by flash chromatography using 0-15% ethyl acetate: hexane as eluent to 2-fluoro-5- [5- (3-bromophenoxy) -pyrimidin-2-yl Amino] -benzonitrile (0.175 g, 21%) was calculated as a white solid.

Mass spectrometry: (ES +) 386 (M + H) ⁺

Example  12: 2- Fluoro -4- (5- (3- (3- Hydroxyacetidine -1 day) Phenoxy Pyrimidin-2-yl-amino) Benzonitrile

2-fluoro-5- [5- (3-bromophenoxy) -pyrimidin-2-ylamino] -benzonitrile (170 mg, 0.441 mmol in degassed 1,4-dioxane (5 mL) ), Azetidin-3-ol hydrochloride (58 mg, 0.529 mmol), tris (dibenzylidene-acetone) palladium (0) (20 mg, 0.022 mmol), 4,5- bis (diphenylphosphino) -9, A suspension of 9-dimethyl-xanthene (26 mg, 0.044 mmol) and cesium carbonate (288 mg, 0.88 mmol) was stirred at 80 ° C. for 2 days. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried (MgSO ₄ ) and the solvent removed under reduced pressure. The crude product was purified by flash chromatography using 0-15% ethyl acetate: hexane as eluent to afford 2-fluoro-4- (5- (3- (3-hydroxyazetidin-1-yl) Phenoxy) pyrimidin-2-ylamino) benzonitrile (71 mg, 44%) was calculated as a white solid.

Mass spectrometry: (ES +) 378 (M + H) ⁺

HPLC: 98.6%

NMR : δ _H ( d ₆ -DMSO) 3.48 (2H, m), 4.05 (2H, t), 4.55 (1H, m), 5.62 (1H, d), 6.10 (1H, brs), 6.0 (1H, dd ), 6.26 (1H, dd), 7.12 (1H, t), 7.50 (1H, t), 7.98 (1H, m), 8.30 (1H, m), 8.42 (2H, s) and 10.10 (1H, s) .

Example  13: Preparation of Stock Solution for Biological Assay

Aβ (1-42) formulation

Aβ (1-42) was prepared for amyloid aggregation and toxicity assays by dissolving the Aβ (1-42) HCl salt in hexafluoroisopropanol (HFIP) with brief ultrasound and vortexing. A solution of Aβ (1-42) peptide in this HFIP was stored at 4 ° C. × 2 mM. If desired, an aliquot of this stock solution was freeze-dried and dissolved in DMSO at 200 times the required final assay concentration (eg 2 mM for a final assay concentration of 10 μM).

Compound manufacturing

20 mM stock solutions of each test compound were prepared in DMSO and aliquots of these solutions were used to prepare additional stock solutions of each test compound in DMSO, ranging in concentration from 3 μM up to 10 mM. This stock solution was prepared for use when required as needed and stored at -20 ° C (maximum 3 freeze-thaw cycles). The 20 mM parent stock solution was stored frozen at -20 ° C.

Example  14: MTT  Cell Viability Assay for Amyloid Toxicity Using Reduction

The activity of the compounds in protecting SH SY5Y cells from toxic attacks of 10 μM Aβ (1-42) was assayed using inhibition of MTT reduction as a measure of cell viability. Aliquots (3 μL) of test compound [various concentrations] in DMSO are added to 294 μL of Opti-Mem (containing 2% FBS, 1% Pen / Strep, 1% L-Gln). Plate plate}. Mix wells thoroughly. An aliquot (3 μL) of Aβ (1-42) [2 mM] is then added to the offspring plate wells and mixed thoroughly again. 50 μL is then aspirated off and dispersed in wells containing 50 μL medium + SH SY5Y cells (cells are also plated at ˜30,000 cells / well / 50 μL in Opti-MM). For cells, the final concentration of the compound is [50 μM] to [˜15 nM] and the final concentration of Aβ (1-42) is [10 μM].

Cell plates are incubated for 24h and then MTT assay (Shearman, 1999) is performed. Simply add 15 μL of MTT (3- (4,5-dimethylthiazol-2-yl) -2, 5-diphenyl-tetrazolium bromide) dye (obtained from Promega) to each well And plate 5% CO ₂ Incubated at 37 ° C. for 4 h. 100 μL Stop / solubilsation solution (obtained from Promega) was added to each well and the plate was left overnight in a humidified box at room temperature. The plate was shaken and the absorbance was recorded at 570 nm and 650 nm. The ΔA value was calculated by subtracting the absorbance at 650 nm from the absorbance at 570 nm to reduce the nonspecific background absorbance. The ΔA values obtained from equivalent experiments were averaged and the% cell viability was determined as follows:

Viable Cell Control: 1% DMSO in Opti-Mem

Dead cell control: 0.1% Triton X-100 added to cells

Progeny plates were sealed with a silver seal and incubated at 37 ° C. for 24 and 48 hours for the Thioflavin T assay (LeVine and Scholten 1999).

Example  15 Thioflavin  T black

The activity of compounds in 10 μM Aβ (1-42) aggregate inhibition was assayed using a thioflavin-T fluorimetric assay. At each time point, 50 or 100 μL aliquots were taken from each well of the progeny plate and dispersed in black 96 well plates. Equal volume (50 or 100 μL) of thioflavin T [40 μM] ([50 mM] -NaOH pH 8.5 in glycine buffer) was added to each well. The plate was shaken and fluorescence was recorded using a top reader setting (10 × 1 msec) using excitation and emission filters of 440 (± 15) and 485 (± 10) nm, respectively. Fluorescence records from equivalent experiments were averaged and% amyloid formation was determined as follows:

Example  16 Thioflavin Using -T fluorescence assay 10 μM  Activity of compounds in inhibiting Aβ (1-42) aggregates

Example  17 As a measure of cell viability MTT  Using the suppression of reduction, SH -SY5Y cells 10 μM  Aβ (1-42)  Activity of compounds in protection from toxic attacks

Example 18 Activity of SEN1500 in Preventing Defects in Organ Enhancement Caused by Toxic Forms of Aβ

Long-term potentiation (LTP) is a natural, long-term electrophysiological response involving learning and short-memory neurological processes that affect Alzheimer's disease. Aβ (1-42) has been shown to act as a potential inhibitor of LTP and as a result LTP has been used as a model system for testing the efficacy of potential therapeutic reagents for diseases (Walsh et al. 2002; Rowan et al. 2004). LTP was measured using Schaffer collateral stimulation in rat hippocampal brain slices, as described below.

7PA2 cells are stably transfected CHO cells containing cDNA for APP (APP751) that is specific for the familial AD mutation Val717Phe (Walsh et al., 2002). The cells were grown up to just below joining DMEM, contained 10% FBS and 200 μg / ml G418 (Genetisin), 5% in a sufficient volume of DMEM to simply wash in DPS and just cover the cells. Incubate with CO ₂ at 37 ° C. for 18 hours. After incubation the medium was centrifuged at 3000 g for 15 minutes and used directly or snap frozen and stored at -20 ° C. Subsequently quantitation of low-n oligomers was performed using IP / WB.

Example 2 was prepared as a 6 mM stock in DMSO and stored at −20 ° C. until use. 7PA2 cell conditioned medium (7PA2 CM) and wild type Chinese hamster ovary cell conditioned medium (wtCHO CM, control) were stored at −80 ° C. until use. 7PA2 CM: 10 μL DMSO was added to stock 7PA2 CM (1 mL) and allowed to equilibrate for 1 hour before experiment. In the experiment for Example 2, 10 μL of 6 mM Example 2 was added to the stock solution 7PA2 CM. This final mixture was diluted to 20 mL in aCSF immediately before use. The final concentration of DMSO was 0.05% and the final concentration of Example 2 was 3 μΜ. For wtCHO CM control experiments, 10 μL DMSO was added to stock wtCHO CM (1 mL) and allowed to equilibrate for 1 hour before experiment. The final concentration of DMSO was 0.05%.

Extracellular fEPSP recordings were performed from 400 μm thick transverse hippocampal slices prepared from male Sprague-Dawley rats. After a minimum recovery period of 1 h, the slices were transferred to an interface chamber warmed to 30 ± 1 ° C. and aCSF was injected. Schaffer collateral was stimulated every 20 seconds with concentric bipolar electrodes and fEPSP was recorded from the stratum radiatum in the CA1 region using glass capillary microelectrodes. The stimulus intensity was set to produce a fEPSP of 40-50% of maximum amplitude. A stable basal period of at least 10 minutes was recorded, after which the test substance was administered and after 10 minutes, high frequency stimulation (HFS, 1 second, 100 Hz) was performed three times at 10 minute intervals followed by washing of the test substance (30 minutes Coverage period). fEPSP was recorded 80 minutes after the last HFS stimulation and the last 10 minutes of recording (30 sweeps) were selected for group comparison using an unpaired t-test.

The results obtained from Example 2 (FIGS. 1 and 2) show that the toxic effects of 7PA2 CM on LTP are effectively prevented by this compound at a concentration of 3 μM.

Description of the drawing:

1: Summary and histogram summary of Example 2 (3 μM) on 7PA2 CM-induced inhibition of LTP

Figure 2: Tabulated summary of the effect of Example 2 (3 μM) on LPA 7PA2 CM-induced inhibition

Statistical Analysis: Data is presented as mean SEM. Significant difference of the data was calculated using Student's t-test. A probability value of P <0.05 is considered to represent a significant difference.

references

Claims (9)

Compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof:

here
R ¹ is CN;
R ² is H or F;
R ³ And R ⁴ is independently hydrogen, fluorine, chlorine, or OR ⁸ ;
R ⁵ is hydrogen, C _{1 - 6} alkyl, C _{1 - 6} alkenyl or C _{1 - 6} alkynyl, and;
R ⁶ And R ⁷ is independently hydrogen, halogen, OR ⁸ Or NR ⁹ R ¹⁰ ;
R ⁸ is hydrogen or C _{1 - 6} alkyl;
R ⁹ And R ¹⁰ is independently hydrogen or C _{1 - 6} alkyl;
Or group R ⁹ And R ¹⁰ may together form a 5- or 6-membered ring when they are attached to a nitrogen atom, which optionally contains one further heteroatom selected from NR ⁸ , S and O, wherein said 5 or 6 membered ring is optionally a hydroxyl or C _{1 - 6} alkoxy is optionally substituted by;
Or group R ⁹ And R ¹⁰ may together form an azetidinyl ring optionally substituted by hydroxyl or C _1-6 alkoxy when they are attached to a nitrogen atom. Compound of formula (la) or a pharmaceutically acceptable salt or prodrug thereof:

here
R ¹ is CN;
R ² is H or F;
R ³ And R ⁴ is independently hydrogen, fluorine, chlorine, or OR ⁸ ;
R ⁵ is hydrogen or C _{1 - 6} alkyl, C _{1 - 6} alkenyl, C _{1 - 6} alkynyl, and;
R ⁶ And R ⁷ is independently hydrogen, halogen, OR ⁸ Or NR ⁹ R ¹⁰ ;
R ⁸ is hydrogen or C _{1 - 6} alkyl;
R ⁹ And R ¹⁰ is independently hydrogen or C _{1 - 6} alkyl;
Or group R ⁹ And R ¹⁰ may together form a 5- or 6-membered ring when they are attached to a nitrogen atom, which optionally contains one further heteroatom selected from NR ⁸ , S and O. Compounds selected from:
3- [5- (3-morpholin-4-ylphenoxy) pyrimidin-2-ylamino] -benzonitrile;
2-fluoro-5- [5- (3-morpholin-4-ylphenoxy) -pyrimidin-2-ylamino] -benzonitrile;
2-fluoro-5-methyl- [5- (3-morpholin-4-ylphenoxy) -pyrimidin-2-yl] amino-benzonitrile;
2,6-difluoro-3- [5- (3-morpholin-4-ylphenoxy) -pyrimidin-2-ylamino] benzonitrile;
2-chloro-5- [5- (3-morpholin-4-ylphenoxy) -pyrimidin-2-ylamino] -benzonitrile;
3-fluoro-5- [5- (3-morpholin-4-ylphenoxy) -pyrimidin-2-ylamino] -benzonitrile;
2-fluoro-3- [5- (3-morpholin-4-ylphenoxy) -pyrimidin-2-ylamino] -benzonitrile;
4-fluoro-3- [5- (3-morpholin-4-ylphenoxy) -pyrimidin-2-ylamino] -benzonitrile;
2-methoxy-5- [5- (3-morpholin-4-ylphenoxy) -pyrimidin-2-ylamino] -benzonitrile;
2-fluoro-5- [5- (3-pyrrolidin-1-ylphenoxy) -pyrimidin-2-ylamino] -benzonitrile;
2-fluoro-4- (5- (3- (3-hydroxyazetidin-1-yl) phenoxy) pyrimidin-2-yl-amino) benzonitrile. A pharmaceutical composition comprising a compound as claimed in claim 1 together with optionally at least one pharmaceutically acceptable carrier or excipient. A compound as claimed in claim 1 or a pharmaceutical composition as claimed in claim 4 for use in the treatment of amyloid-related diseases. A compound or pharmaceutical composition as claimed in claim 5 for use in the following treatment:

a) any form of Alzheimer's disease (AD or FAD);
b) any form of mild cognitive impairment (MCI) or senile dementia;
c) Down syndrome;
d) cerebral amyloid angiopathy, inclusion body myositis, amyloid hereditary cerebral hemorrhage (Dutch type) (HCHWA, Dutch type), or age-related macular degeneration (ARMD) ;
e) fronto-temporal dementia;
f) any form of Parkinson's disease (PD) or dementia with Lewy bodies;
g) Huntington's disease (HD), thalamus-nucleus-pale-nucleus-subthalamic atrophy (DRPLA), spinocerebellar ataxia (SCA, types 1, 2, 3, 6 and 7), spine and training Spinal and bulbar muscular atrophy (SBMA), Kennedy's disease, or any other polyglutamine disease;
h) Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE), sheep scrapie, kuru, gerstmann-Straussler- Gersmann-Straussler-Scheinker disease (GSS), fatal familial insomnia, or any other transmissible encephalopathy associated with aggregation of prion proteins;
i) Amyotrophic lateral sclerosis (ALS) or any other form of motor neuron disease;
j) Familial British dementia (FBD) or familial Danish dementia (FDD);
k) amyloidogenic cerebral hemorrhage (Icelandic type) (HCHWA, Icelandic type);
l) type 2 diabetes (adult-onset diabetes, or non-insulin dependent diabetes mellitus (NIDDM));
m) dialysis-related amyloidosis (DRA) or prostatic amyloid;
n) primary systemic amyloidosis, systemic AL amyloidosis, or nodular AL amyloidosis;
o) myeloma-associated amyloidosis;
p) systemic (reactive) AA amyloidosis, secondary systemic amyloidosis, chronic inflammatory disease, or familial Mediterranean fever;
q) senile systemic amyloidosis, familial amyloid polyneuropathy, or familial cardiac amyloid;
r) Familial visceral amyloidosis, hereditary non-neuropathic systemic amyloidosis, or any other lysozyme-related amyloidosis;
s) Finnish hereditary systemic amyloidosis;
t) fibrinogen α-chain amyloidosis;
u) insulin-related amyloidosis;
v) medullary carcinoma of the thyroid gland;
w) isolated atrial amyloidosis;
x) cataract in any form; or
y) Any other amyloid-related disease associated with misfolding or aggregation of certain target amyloid-forming proteins or peptides into toxic soluble oligomers, protofibrils, ion channels, insoluble amyloid fibers, plaques or inclusions. A method of treating amyloid-related disease, comprising administering to a subject an effective amount of a compound as claimed in claim 1 or a pharmaceutical composition as claimed in claim 4. 8. The method of claim 7, wherein the amyloid-related disease is any one of those defined in claim 6. Intermediates of formula (II) in the synthesis of compounds of claim 1:

Wherein R6 and R7 are as defined in claim 1.

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