HK1154241A

HK1154241A - Substituted heteroarylamide diazepinopyrimidone derivatives

Info

Publication number: HK1154241A
Application number: HK11108073.0A
Authority: HK
Inventors: Aude Fayol; Alistair Lochead; Mourad Saady; Julien Vache; Philippe Yaiche
Original assignee: 赛诺菲-安万特; 田边三菱制药株式会社
Priority date: 2008-01-29
Filing date: 2009-01-27
Publication date: 2012-04-13

Description

Substituted heteroaryl amide diaza  pyrimidinone derivatives

Technical Field

The present invention relates to a compound for use as an active ingredient of a medicament for prophylactic and/or therapeutic treatment of a neurodegenerative disease caused by abnormal activity of GSK3 β.

Background

GSK3 β (glycogen synthase kinase 3 β) is a proline-directed serine/threonine kinase that plays an important role in controlling metabolism, differentiation, and survival. It was initially identified as an enzyme that is capable of phosphorylating and thus inhibiting glycogen synthase. Later, it was recognized that GSK3 β is consistent with tau kinase 1(TPK1), an enzyme that phosphorylates tau (tau protein), and that epitopes within it were also found to be hyperphosphorylated in alzheimer's disease and some tauopathies (tauopathies).

Interestingly, protein kinase b (akt) phosphorylation of GSK3 β results in a loss of its kinase activity, and it has been hypothesized that this inhibition may mediate some of the effects of neurotrophic factors. In addition, phosphorylation by GSK3 β of β -catenin, a protein involved in cell survival, leads to its degradation through ubiquitination-dependent proteasome pathways.

Thus, this shows that inhibition of GSK3 β activity results in neurotrophic activity. Indeed, there is evidence that non-competitive inhibitors of lithium, GSK3 β, enhance neuritogenesis (neuritogenesis) and also improve neuronal survival in some models by inducing the expression of survival factors such as Bcl-2 and inhibiting pro-apoptotic factors such as p53 and Bax.

Recent studies have shown that β -amyloid increases the activity of GSK3 β and phosphorylation of tau protein. In addition, this hyperphosphorylation and the neurotoxic effects of β -amyloid are blocked by lithium chloride and by GSK3 β antisense mRNA. These observations strongly suggest that GSK3 β may be the link of two major pathological processes in alzheimer's disease: abnormal APP (amyloid precursor protein) processing (processing) and hyperphosphorylation of tau protein.

Although hyperphosphorylation of tau results in instability of the neuronal cytoskeleton, the pathological consequences of aberrant GSK3 β activity are highly likely not only due to pathological phosphorylation of tau protein, but also because, as noted above, excessive activity of this kinase can affect survival via the expression regulation of apoptotic and anti-apoptotic factors. Furthermore, it has been shown that the β -amyloid-induced increase in GSK3 β activity causes phosphorylation and thus inhibits pyruvate dehydrogenase, a key enzyme in energy production and acetylcholine synthesis.

Together, these experimental observations suggest that GSK3 β can be used to treat neuropathological outcomes (consequences) and cognitive and attention deficits associated with Alzheimer's disease, as well as other pathologies when acute and chronic neurodegenerative diseases and other GSK3 β abnormalities (Nature Reviews Vol.3, 6 2004, p.479-487; Trends in pharmaceutical Sciences Vol.25No.9, 9 2004, p.471-480; Journal of neurochemistry 2004, 89, 1313-.

Neurodegenerative diseases, including, by way of non-limiting example: parkinson's disease, tauopathies (e.g., frontotemporal dementia, corticobasal degeneration), Pick's disease, progressive supranuclear palsy, Wilson's disease, Huntington's disease (The journal of biological chemistry Vol.277, No.37, Issue of September 13, pp.33791-33798, 2002), Prion disease (Prion disease) (biochemistry. J.372, p.129-136, 2003), and other dementias including vascular dementias; acute stroke and other traumatic injuries; cerebrovascular accidents (e.g., age-related macular degeneration); brain and spinal cord injuries (brain and spinal cord traumas); amyotrophic lateral sclerosis (European Journal of Neuroscience, Vol.22, pp.301-309, 2005); peripheral neuropathy; retinopathy and glaucoma. Recent studies have also shown that inhibition of GSK3 β causes neuronal differentiation of Embryonic Stem Cells (ESCs) and supports renewal of human and mouse ESCs and maintains their pluripotency. This suggests that inhibitors of GSK3 β can be applied in regenerative Medicine (Nature Medicine 10, p.55-63, 2004).

Inhibitors of GSK3 β may also be useful in the treatment of other neurological disorders, such as bipolar disorders (manic-depressive illness). For example, lithium has been used as a mood stabilizer and for the primary treatment of bipolar affective disorders for over 50 years. The therapeutic effect of lithium was observed at doses (1-2mM), when it was a direct GSK3 β inhibitor. Although the mechanism of action of lithium is unclear, inhibitors of GSK3 β can be used to mimic the mood stabilising effect of lithium. Alterations in Akt-GSK3 beta signaling have also been implicated in the pathogenesis of schizophrenia.

In addition, inhibition of GSK3 β may be useful in the treatment of cancers such as colorectal, prostate, breast, non-small cell lung, thyroid, T or B cell leukemia and some virus-induced tumors. For example, the active form of GSK3 β has been shown to be elevated in tumors in colorectal cancer patients, and inhibition of GSK3 β in colorectal cancer cells activates p 53-dependent apoptosis and antagonizes tumor growth. Inhibition of GSK3 β also increased TRAIL-induced apoptosis in prostate cancer cell lines. GSK3 β also plays a role in mitotic spindle dynamics, and inhibitors of GSK3 β prevent chromosomal movement and lead to stabilization of microtubules and prometaphase-like arrest (arrest), similar to what is observed with low doses of paclitaxel. Other possible uses for GSK3 β inhibitors include the treatment of non-insulin dependent diabetes (such as type II diabetes), obesity and alopecia.

Inhibitors of human GSK3 β also inhibit pfGSK3, and homologues of this enzyme are found in Plasmodium falciparum (Plasmodium falciparum), and thus they may be used to treat malaria (Biochimica et Biophysica Acta 1697, 181-196, 2004).

Recently, both human genetics and animal studies have indicated the role of the Wnt/LPR5 pathway as a major regulator of bone mass increase (bone increase). Inhibition of GSK3 β results in the subsequent activation of conventional Wnt signaling. Since Wnt signaling deficiencies have been implicated in osteopenic diseases, GSK3 β inhibitors may also be used to treat osteopenic diseases, bone-related pathologies, osteoporosis.

According to recent data, GSK3 β inhibitors may be useful in the treatment or prevention of pemphigus vulgaris.

Recent studies have shown that treatment with GSK3 β inhibitors improves the recovery of neutrophils and megakaryocytes. Therefore, GSK3 β inhibitors would be useful in the treatment of neutropenia induced by cancer chemotherapy.

Previous studies have shown that GSK3 activity decreases LTP, an electrophysiology associated with memory consolidation, suggesting that inhibitors of this enzyme may have pro-cognitive (cognitive) activity. The pro-cognitive effects of the compounds can be used to treat Alzheimer's disease, Parkinson's disease, age-related memory impairment, mild cognitive impairment, brain damage, schizophrenia and other conditions where these deficits are observed, which are characterized by memory deficits.

Inhibitors of GSK3 β may also be useful in the treatment of parenchymal renal diseases (Nelson PJ, Kidney International advanced online publication 19 dec2007) and in the prevention or treatment of muscle atrophy (j.biol. chem (283)2008, 358-.

Disclosure of Invention

It is an object of the present invention to provide compounds for use as active ingredients in medicaments for the prophylactic and/or therapeutic treatment of diseases caused by abnormal GSK3 β activity, more particularly neurodegenerative diseases. More specifically, the object of the present invention is to provide a novel compound useful as an active ingredient of a medicament capable of preventing and/or treating neurodegenerative diseases such as alzheimer's disease.

Accordingly, the present inventors have identified compounds having inhibitory activity against GSK3 β. As a result, they found that a compound represented by the following formula (I) has a desired activity and is useful as an active ingredient of a medicament for the prophylactic and/or therapeutic treatment of the above-mentioned diseases.

Accordingly, as an object of the present invention, there is provided a pyrimidone derivative represented by formula (I) and a salt thereof, or a solvate or hydrate thereof:

wherein:

y represents a sulfur atom, an oxygen atom, two hydrogen atoms, or C_1-2Alkyl and hydrogen atoms;

z represents a bond, an oxygen atom, a hydrogen atom or C_1-3An alkyl-substituted nitrogen atom, a sulfur atom, a methylene group optionally substituted with 1 or 2 groups selected from: c_1-6Alkyl, hydroxy, C_1-6Alkoxy, perhalogenated C_1-2Alkyl or amino;

r1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, said ring being optionally substituted by C_1-6Alkyl radical, C_1-6Alkoxy or halogen atoms;

r2 represents a hydrogen atom, C_1-6An alkyl group or a halogen atom;

r3 represents a 4-15 membered heterocyclyl group, which group is optionally substituted by 1 to 4 substituents selected from: c_1-6Alkyl, halogen atom, perhalogenated C_1-2Alkyl, halogenated C_1-6Alkyl, hydroxy, C_1-6Alkoxy, C (O) O (C)_1-6Alkyl) group, C: (O) O (aryl) group, halogenated C_1-6Alkoxy, nitro, cyano, amino, C_1-6Monoalkylamino group, C_2-12Dialkylamino group, S- (C)_1-6-alkyl), 4-15 membered heterocyclyl, aryl, O-aryl or S-aryl, said groups being optionally substituted with 1 to 4 substituents selected from the group consisting of: c_1-6Alkyl group, halogen atom, (C)_1-6) An alkoxy group;

r4 represents a hydrogen atom; c_1-6An alkyl group; benzyl, phenethyl, benzyloxycarbonyl, C_1-4Alkoxycarbonyl, phenyl, naphthyl, 5, 6, 7, 8-tetrahydronaphthyl, benzenesulfonyl, benzoyl, 4-15 membered heterocyclyl, said groups optionally substituted with 1 to 4 substituents selected from the group consisting of: halogen atom, hydroxy group, C_1-4An alkoxy group; perhalogenated C_1-2Alkyl radical, C_1-6Alkyl, phenyl, halogen atom, halogenated C_1-3Alkyl, nitro, cyano, amino, C_1-6Monoalkylamino or C_2-10A dialkylamino group;

r5 represents a hydrogen atom or C_1-6An alkyl group;

n represents 0 to 3.

According to another aspect of the present invention, there is provided a medicament comprising a pyrimidone derivative selected from the group consisting of those represented by formula (I) and physiologically acceptable salts thereof, and solvates thereof and hydrates thereof as an active ingredient. As preferred embodiments of the medicament, there are provided the above-mentioned medicament for prophylactic and/or therapeutic treatment of diseases caused by abnormal GSK3 β activity, and the above-mentioned medicament for prophylactic and/or therapeutic treatment of neurodegenerative diseases and other diseases, such as: non-insulin dependent diabetes (e.g., type II diabetes) and obesity; malaria, bipolar disorder (manic depression); schizophrenia; alopecia or cancer such as colorectal cancer, prostate cancer, breast cancer, non-small cell lung cancer, thyroid cancer, T-cell or B-cell leukemia, some virus-induced tumors and bone-related pathologies; treatment of parenchymal renal disease and prevention or treatment of muscle atrophy; treating cognitive impairment and memory loss. The medicine can also be used for regenerative medicine.

As a further embodiment of the present invention, there is provided the above-mentioned medicament, wherein the disease is a neurodegenerative disease and is selected from alzheimer's disease, parkinson's disease, tauopathies (such as frontotemporal dementia, corticobasal degeneration, pick's disease, progressive supranuclear palsy), wilson's disease, huntington's disease, prion diseases and other dementias, including vascular dementia; acute stroke and other traumatic injuries; cerebrovascular accidents (e.g., age-related macular degeneration); brain and spinal cord injuries; amyotrophic lateral sclerosis; peripheral neuropathy; retinopathy and glaucoma, and the above-mentioned drugs in the form of pharmaceutical compositions containing the above-mentioned substances as active ingredients and one or more pharmaceutically acceptable additives.

As a further embodiment of the present invention, there is provided the above medicament, wherein the bone-related pathology is osteoporosis.

The present invention also provides an inhibitor of GSK3 β activity, which contains as an active ingredient a substance selected from the group consisting of pyrimidone derivatives of formula (I) and salts thereof, and solvates and hydrates thereof.

According to another aspect of the present invention there is provided a method for the prophylactic and/or therapeutic treatment of a neurodegenerative disease caused by abnormal GSK3 β activity, the method comprising the steps of: administering to a patient a prophylactically and/or therapeutically effective amount of a substance selected from the group consisting of pyrimidone derivatives of formula (I) and physiologically acceptable salts thereof, and solvates thereof and hydrates thereof; also provided is the use of a substance selected from the group consisting of pyrimidone derivatives of formula (I) and physiologically acceptable salts thereof, and solvates and hydrates thereof, for the preparation of the aforementioned medicament.

As used in the present invention, C_1-6Alkyl denotes straight-chain or branched or cyclic alkyl having 1 to 6 carbon atoms, optionally substituted by straight-chain, branched or cyclic C_1-6Alkyl radicals substituted, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso-pentylPentyl, neopentyl, 1-dimethylpropyl, n-hexyl, isohexyl, cyclopropylmethyl, and the like.

4-15 membered heterocyclyl means an unsaturated, fully saturated or partially saturated monocyclic or polycyclic group (e.g. 4-10 membered) containing 1 to 7 heteroatoms selected from N, O and S. Examples of heterocyclic groups include pyridine, 4-indolizine, pyrimidine, pyrazine, pyridazine, triazine, pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole,Oxazole, isoAzole,Oxadiazole, thiazole, isothiazole, thiadiazole, pyrrolopyrrole, pyrroloimidazole, pyrrolopyrazole, pyrrolotriazole, imidazoimidazole, imidazopyrazole, imidazotriazole, quinoline, isoquinoline, cinnoline, 2, 3-naphthyridine, quinoxaline, quinazoline, 1, 5-naphthyridine, benzotriazine, pyridopyrimidine, pyridopyrazine, pyridopyridazine, pyridotriazine, pyrimidopyrimidine, pyrimidopyridazine, pyrimidotriazine, pyrazinopyrazine, pyrazinopyridazine, pyrazinotriazine, pyridazinopyridazine, pyridazinotriazine, indole, isoindole, benzimidazole, indazole, indolizine, benzofuran, isobenzofuran, benzothiophene, benzo [ c ] indole]Thiophene, pyrrolopyridine, imidazopyridine, pyrazolopyridine, triazolopyridine, tetrazolopyridine, pyrrolopyrimidine, imidazopyrimidine, pyrazolopyrimidine, triazolopyrimidine, pyrrolopyrimidine, pyrrolopyrazine, imidazopyrazine, pyrazolopyrazine, triazolooxazine tetrazolopyrizine, pyrrolopyridazine, imidazopyridazine, pyrazolopyridazine, triazolopyridazine, tetrazolopyridazine, pyrrolotriazine, imidazotriazine, pyrazolotriazine, triazolotriazine, tetrazolotriazine, furopyridine, furopyrimidine, furopyrazine, furopyridazine, furotriazine, furo-pyrimidine, furo-triazine,A pyrazolopyridine,A pyrazolopyrimidine,Azolopyrazines, pyrazolopyrazines, pyrazolopyrimidines,Azolopyridazine,Azolotriazine, isoAzolopyridine, isoAzolopyrimidine, isoAzolopyrazine, isoAzolopyridazine, isoAn azolo-triazine,Diazolopyridine,Diazolo-pyrimidines,Oxadiazole pyrazine, pyrazine and pyrazine,Diazolopyridazines,Oxadiazotriazines, benzolsAzole, benzisohAzole and benzolOxadiazole, thienopyridine, thienopyrimidine, thienopyrazine, thienopyridazine, thienotriazine, thiazolopyridine, thiazolopyrimidine, thiazolopyrazine, thiazolopyridazine, thiazolotriazine, isothiazolopyridine, isothiazolopyrimidine, isothiazolopyrizine, isothiazolopyridazine, isothiazolotriazine, thiadiazolopyridine, thiadiazolopyrimidine, thiadiazolopyridazine, thiadiazolotriazine, benzothiazole, benzisothiazole, benzothiadiazole, benzotriazole, benzodioxadiazine(benzodioxine) and benzodiazepineAlkanes (benzodioxane), benzodioxines (benzodioxine), diazepanes. These heterocycles can also be present in partially or fully saturated forms, such as, for example, dihydrobenzofuran, tetrahydroisoquinoline, dihydrobenzodioxin, and the like.

C_1-6Alkoxy represents alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like;

halogen atom represents fluorine, chlorine, bromine or iodine atom;

perhalogenated C_1-2Alkyl represents an alkyl group in which all the hydrogen atoms are presentHaving been substituted by halogen atoms, e.g. CF₃Or C₂F₅；

Halogenated C_1-3Alkyl represents an alkyl group in which at least one hydrogen is not substituted by a halogen atom;

C_1-6monoalkylamino radicals represented by a C_1-6Alkyl-substituted amino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, isopentylamino and the like;

C_2-12dialkylamino represents a group represented by two C_1-6Alkyl-substituted amino groups such as dimethylamino, ethylmethylamino, diethylamino, methylpropylamino, diisopropylamino, and the like;

the leaving group L represents a group which can be easily removed and substituted; such groups may be, for example, tosyl, mesyl, bromo substituents, and the like.

The compound represented by the above formula (I) may form a salt. When an acidic group is present, examples of the salt include salts of alkali metals and alkaline earth metals such as lithium, sodium, potassium, magnesium, and calcium; salts of ammonia and amines such as methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine and L-glucosamine; or salts with basic amino acids such as lysine, delta-hydroxylysine and arginine. Base addition salts of acidic compounds are prepared by standard methods well known in the art.

When a basic group is present, examples include salts with inorganic acids such as hydrochloric acid, hydrobromic acid; salts with organic acids such as acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, and the like.

Acid addition salts of base compounds are prepared according to standard procedures well known in the art, including, but not limited to: the free base is dissolved in an aqueous solution of an alcohol containing a suitable acid and the resulting salt is isolated by evaporating the solution, or by reacting the free base with an acid in an organic solvent, at which point the resulting salt is isolated directly or precipitated with a second organic solvent or can be obtained by concentrating the solution. Acids which may be used to prepare acid addition salts preferably include those which, when combined with the free base, form a pharmaceutically acceptable salt, that is, the anion of such a salt is relatively non-toxic to animal organisms in pharmaceutically acceptable dosages of the salt, so that the beneficial properties inherent in the free base are not compromised by side effects attributable to the anion (complex). Although pharmaceutically acceptable salts of the base compounds are preferred, all acid addition salts are within the scope of the invention.

In addition to the pyrimidone derivatives represented by the above formula (I) and salts thereof, their solvates or hydrates are also within the scope of the present invention.

The pyrimidone derivative represented by the above formula (I) may have one or more asymmetric carbon atoms. With respect to the stereochemistry of these asymmetric carbon atoms, they may independently be in the (R) or (S) configuration, and the derivatives may exist as stereoisomers such as optical isomers or diastereomers. Any stereoisomer, mixture of stereoisomers, racemic compound, etc., in pure form is within the scope of the present invention.

In a first embodiment of the invention, there is provided a compound in free base form or in addition to an acid to form a salt, wherein:

y represents an oxygen atom;

z represents a chemical bond;

r1 represents an unsubstituted 4-pyridine ring or an unsubstituted 4-pyrimidine ring;

r2 represents a hydrogen atom;

r3 represents naphthyridinyl, pyridyl, dihydrobenzofuranyl, tetrahydroisoquinolinyl, pyridazinyl, dihydrobenzodioxinyl or benzodioxinyl, wherein the above groups are optionally substituted1 to 4 substituents selected from: c_1-6Alkyl group, halogen atom, C_1-6Alkoxy, amino, C (O) O (C)_1-6Alkyl) groups;

r4 represents a hydrogen atom, C_1-6Alkyl radical, C_1-4Alkoxycarbonyl, benzyl;

r5 represents a hydrogen atom;

n represents 0.

Examples of the compounds of the present invention are shown in table 1 below. The scope of the present invention is not limited to these compounds. Names are named according to the IUPAC rules.

A further aspect of the invention includes compounds of formula (la) of table 1 as defined below:

(+/-) -9- [ ([1, 5] naphthyridine-2-carbonyl) -amino ] -4-oxo-2-pyrimidin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

(+/-) -4-oxo-9- [ (pyridine-2-carbonyl) -amino ] -2-pyrimidin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

(+/-) -9- [ (2, 2-dimethyl-2, 3-dihydro-benzofuran-7-carbonyl) -amino ] -4-oxo-2-pyrimidin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

(+/-) -pyridine-2-carboxylic acid (4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -2, 6-dimethoxy-N- (7-methyl-4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -nicotinamide

(+/-) -4-methoxy-pyridine-2-carboxylic acid (4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -4-methoxy-pyridine-2-carboxylic acid (7-methyl-4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -9- [ (2, 3-dihydro-benzofuran-7-carbonyl) -amino ] -4-oxo-2-pyridin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

(+/-) -9- [ (2-tert-butoxycarbonyl-1, 2, 3, 4-tetrahydro-isoquinoline-7-carbonyl) -amino ] -4-oxo-2-pyridin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

(+/-) -9- [ (4-methoxy-pyridine-2-carbonyl) -amino ] -4-oxo-2-pyridin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

(+/-) -2, 3-dihydro-benzofuran-7-carboxylic acid (4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -3, 6-dimethoxy-pyridazine-4-carboxylic acid (4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -2, 3-dihydro-benzofuran-7-carboxylic acid (7-methyl-4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -2-methoxy-N- (4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -nicotinamide

(+/-) -2-methoxy-N- (7-methyl-4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -nicotinamide

(+/-) -3, 6-dimethoxy-pyridazine-4-carboxylic acid (7-methyl-4-oxo-2-pyrimidin-4-yl 4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -5-bromo-2, 3-dihydro-benzofuran-7-carboxylic acid (4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -5-bromo-2, 3-dihydro-benzofuran-7-carboxylic acid (7-methyl-4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -6-fluoro-4H-benzo [1, 3] dioxin-8-carboxylic acid (4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -8-amino-7-chloro-2, 3-dihydro-benzo [1, 4] dioxine-5-carboxylic acid (4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -4-oxo-2-pyridin-4-yl-9- [ (1, 2, 3, 4-tetrahydro-isoquinoline-7-carbonyl) -amino ] -5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

(+/-) -8-amino-7-chloro-2, 3-dihydro-benzo [1, 4] dioxine-5-carboxylic acid (7-methyl-4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -6-fluoro-4H-benzo [1, 3] dioxin-8-carboxylic acid (7-methyl-4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -9- [ ([1, 5] naphthyridine-2-carbonyl) -amino ] -4-oxo-2-pyridin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

(+/-) -5-chloro-2, 3-dihydro-benzofuran-7-carboxylic acid (4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -6-fluoro-4H-benzo [1, 3] dioxin-8-carboxylic acid (4-oxo-2-pyridin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -5-chloro-2, 3-dihydro-benzofuran-7-carboxylic acid (7-methyl-4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -2, 2-dimethyl-2, 3-dihydro-benzofuran-7-carboxylic acid (4-oxo-2-pyridin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -6-fluoro-4H-benzo [1, 3] dioxin-8-carboxylic acid (7-methyl-4-oxo-2-pyridin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -2-methoxy-N- (4-oxo-2-pyridin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -nicotinamide

(+/-) -2-methoxy-N- (7-methyl-4-oxo-2-pyridin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -nicotinamide

(+/-) -N- (7-isopropyl-4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -2-methoxy-nicotinamide

(+/-) -N- (7-cyclopropylmethyl-4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -2-methoxy-nicotinamide

(+/-) -pyridine-2-carboxylic acid (4-oxo-2-pyridin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -N- (7-benzyl-4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -2-methoxy-nicotinamide

(+/-) -2, 2-dimethyl-2, 3-dihydro-benzofuran-7-carboxylic acid (7-benzyl-4-oxo-2-pyridin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -6-fluoro-4H-benzo [1, 3] dioxin-8-carboxylic acid (7-isopropyl-4-oxo-2-pyridin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -6-fluoro-4H-benzo [1, 3] dioxin-8-carboxylic acid (7-benzyl-4-oxo-2-pyridin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -2, 6-dimethoxy-N- (4-oxo-2-pyridin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -nicotinamide

(+/-) -2, 6-dimethoxy-N- (4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -nicotinamide

As another aspect, the present invention also relates to a process for producing the pyrimidone compound represented by the above formula (I).

These compounds can be prepared according to the methods described below.

Preparation method

The pyrimidone compound represented by the above formula (I) can be prepared according to the method described in scheme 1.

Scheme 1

(in the above schemes, R1, R2, R3, R4, R5, n, Y and Z have the same definitions as already described for the compounds of formula (I)).

According to this method, pyrimidone derivatives represented by the above formula (III), wherein R1, R2, R4 and R5 are as defined as formula (I), are used as intermediates. Alternatively, a compound of formula (I) is reacted with a base such as triethylamine, sodium carbonate or potassium carbonate in a solvent such as tetrahydrofuran, N-methylpyrrolidone, N-dimethylacetamide or chloroform at a suitable temperature of 0-130 ℃ in ordinary air and then with a compound of formula (II) wherein R3, Z, Y and N are as defined for the compound of formula (I) and L represents a leaving group, preferably chlorine, bromine or methylsulfonyl, to give the compound of formula (I) above.

Alternatively, the compounds of formula (I) wherein Y represents two hydrogen atoms may be prepared by reductive amination of a compound of formula (II) wherein Y represents an oxygen atom and L represents a hydrogen atom, with a compound of formula (III) wherein R1, R2, R4 and R5 are as defined for the compound of formula (I), according to methods well known to those skilled in the art.

The compounds of formula (II) are commercially available or may be synthesized according to methods well known to those skilled in the art.

The compound of formula (III) may be prepared according to the method of scheme 2 starting from the compound of formula (IV). Conditions that can be used are given in the chemical examples.

Scheme 2

As another object, the present invention also relates to intermediates (III), (VI) and (VII) for producing the pyrimidone compound represented by the above formula (I).

(in the above scheme, R1, R2 and R4 are as defined above).

According to this process, a 3-ketoester of formula (IV) (wherein R1 and R2 have the same meaning as for the compound of formula (I) and R is an alkyl group such as methyl or ethyl) is reacted with a compound of formula (V) (wherein R4 has the same meaning as for the compound of formula (I)). The reaction may be carried out in the presence of a base such as potassium carbonate in an alcohol solvent such as methanol, ethanol, etc. or in the absence of an alcohol solvent at a suitable temperature of 25 to 140 ℃ in ordinary air to give the compound of formula (VI) above.

Compounds of formula (VI) in which R1, R2 and R4 have the same meanings as compounds of formula (I) may be deprotonated with a strong base such as lithium bis (trimethylsilyl) amide or lithium diisopropylamide and the resulting anion reacted with bromine or N-bromosuccinimide to give compounds of formula (VII).

Compounds of formula (VII) wherein R1, R2 and R4 have the same meanings as compounds of formula (I) may be reacted with a suitable nucleophilic nitrogen source such as 4-methoxybenzylamine in ammonia to give compounds of formula (III).

Further, the compound of formula (III) wherein R2 represents a hydrogen atom may be halogenated, thereby obtaining a compound of formula (III) wherein R2 is a halogen atom such as a bromine atom or a chlorine atom. The reaction may be carried out in an acidic medium such as acetic acid or propionic acid in the presence of bromosuccinimide or chlorosuccinimide or bromine.

Further, the compound of the formula (IV) wherein R2 represents a fluorine atom can be obtained by a method similar to that described in Tetrahedron Letters, Vol.30, No.45, pp 6113-6116, 1989.

Furthermore, the compounds of formula (IV) wherein R2 represents a hydrogen atom can be obtained by a method similar to that described in patent DE 2705582.

The compounds of formula (IV) are commercially available or may be synthesized according to methods well known to those skilled in the art.

For example, compounds of formula (IV) wherein R1 represents optionally substituted C_1-6Alkyl radical, C_1-6An alkoxy or halogen atom-substituted pyridine or pyrimidine ring, which can be prepared as follows: respectively enable to be optionally substituted by C_1-6Alkyl radical, C_1-6Alkoxy or halogen substituted isonicotinic acid or pyrimidine-carboxylic acid is reacted with the corresponding malonic acid monoester. The reaction can be carried out using those skilled in the artWell known methods are carried out, for example, in the presence of a coupling agent such as 1, 1' -carbonyldi-1H-imidazole in a solvent such as tetrahydrofuran at a temperature of from 20 to 70 ℃.

The compounds of formula (V) can be synthesized according to the methods described in WO97/16430 and Tetrahedron Letters, Vol.32, No.22, pp 2469-2470, 1991.

In the above reaction, protection or deprotection of a functional group may sometimes be necessary. Suitable protecting groups Pg may be selected according to the type of functional group, and methods described in the literature may be applied. Examples of protecting Groups, protecting and deprotecting methods are described, for example, in Greene's Protective Groups in organic Synthesis, Greene et al, 4^th Ed.(John Wiley &Sons, inc., New York) 2007.

The compounds of the invention have inhibitory activity against GSK3 β. Therefore, the compounds of the present invention can be used as active ingredients for the preparation of medicaments capable of prophylactic and/or therapeutic treatment of diseases caused by abnormal GSK3 β activity, more specifically neurodegenerative diseases such as alzheimer's disease. Furthermore, the compounds of the invention can also be used as active ingredients for the preparation of medicaments for the prophylactic and/or therapeutic treatment of neurodegenerative diseases such as parkinson's disease, tauopathies (such as frontotemporal dementia, corticobasal degeneration, pick's disease, progressive supranuclear palsy), wilson's disease, huntington's chorea, prion diseases and other dementias including vascular dementia; acute stroke and other traumatic injuries; cerebrovascular accidents (e.g., age-related macular degeneration); brain and spinal cord injuries; amyotrophic lateral sclerosis, peripheral neuropathy; retinopathy and glaucoma; and other diseases such as non-insulin dependent diabetes (e.g., type II diabetes) and obesity; malaria, manic depression; schizophrenia; alopecia; cancers, such as colorectal, prostate, breast, non-small cell lung, thyroid, T-cell or B-cell leukemias, some virus-induced tumors, and bone-related pathologies; parenchymal renal disease or muscle atrophy. The medicine can also be used for regenerative medicine. The medicament may also be used for the treatment or prevention of pemphigus vulgaris. The medicine can also be used for treating neutropenia induced by cancer chemotherapy. The medicament may also be used in the therapeutic treatment of conditions characterised by cognitive deficits and memory deficits, such as Alzheimer's disease, Parkinson's disease, age-related memory impairment, mild cognitive impairment, brain trauma, schizophrenia and other conditions in which such deficits or deficits are observed.

The present invention also relates to methods of treating neurodegenerative diseases caused by abnormal activity of GSK3 β and the diseases mentioned above, which methods comprise administering to a mammalian organism in need thereof an effective amount of a compound of formula (I).

As the active ingredient of the medicament of the present invention, a substance selected from the group consisting of the compounds represented by the above formula (I) and pharmacologically acceptable salts thereof, and solvates and hydrates thereof can be used. The substance itself may be administered as a medicament according to the invention; however, it is desirable to administer the drug in the form of a pharmaceutical composition comprising the above-mentioned substance as an active ingredient and one or more pharmaceutically acceptable additives. As the active ingredient of the medicament of the present invention, two or more of the above-mentioned substances may be used in combination. The pharmaceutical composition can be supplemented with other active ingredients of medicines for treating the diseases. The type of the pharmaceutical composition is not particularly limited, and the composition may be provided in any formulation form for oral or parenteral administration. For example, the pharmaceutical composition may be formulated, for example, in the form of a pharmaceutical composition for oral administration, such as granules, fine granules (fine granules), powders, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions, etc., or in the form of a pharmaceutical composition for parenteral administration, such as intravenous, intramuscular, or subcutaneous injection, drip infusion, transdermal (transdermal), transmucosal (transmucosal), nasal drops, inhalants, suppositories, etc. Injections or drip infusions may be prepared in the form of powdery preparations such as lyophilized preparations, and may be used by dissolving in a suitable aqueous medium such as physiological saline before use. Sustained release formulations, such as those coated with polymers, can be administered directly intracerebrally.

The type of the pharmaceutical additive used for preparing the pharmaceutical composition, the content ratio of the pharmaceutical additive to the active ingredient, and the method for preparing the pharmaceutical composition may be appropriately selected by those skilled in the art. Inorganic or organic substances or solid or liquid substances can be used as pharmaceutical additives. In general, the pharmaceutical additives may be mixed in a proportion of 1 to 90% by weight based on the weight of the active ingredient.

Examples of excipients used in the preparation of solid pharmaceutical compositions include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate, and the like. For the preparation of liquid compositions for oral administration, conventional inert diluents such as water or vegetable oils may be used. In addition to inert diluents, the liquid compositions may also contain adjuvants such as wetting agents, suspending aids, sweeteners, aromatics, colorants and preservatives. The liquid composition may be filled in capsules made of an absorbable material such as gelatin. Examples of solvents or suspending media for preparing compositions for parenteral administration (e.g., injections, suppositories) include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin, and the like. Base materials for suppositories include, for example, cocoa butter, emulsified cocoa butter, lauryl butter (lauricilipid), witepsol.

The administration dose and frequency of the medicament of the present invention are not particularly limited and are appropriately selected depending on the purpose of prophylactic and/or therapeutic treatment, the type of disease, the body weight or age of a patient, the severity of disease, and the like. In general, the daily dose for oral administration to an adult may be 0.01 to 1000mg (weight of active ingredient), and the dose may be administered once a day or in divided portions several times a day, or once a plurality of days. When the medicament is used as an injection, it is preferably administered to an adult continuously or intermittently at a daily dose of 0.001 to 100mg (weight of active ingredient).

Chemical examples

Example 1 (Compound 2 of Table 1)

1.14-oxo-2-pyrimidin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

To a solution of 13.4g (60.45mmol) of 5-amino-2, 3, 6, 7-tetrahydro- [1, 4]]Diaza derivativesTo a suspension of ethyl-1-carboxylate monohydrochloride (synthesized as described in WO 9716430) in 50ml of ethanol was added 10.29g (74.50mmol) of potassium carbonate. The reaction mixture was stirred at room temperature for 10 minutes, 14.47g (74.50mmol) of ethyl 3- (4-pyrimidinyl) -3-oxopropanoate were added and the resulting mixture was stirred at reflux for 2.5 hours. The cooled solution was evaporated to remove the solvent. The mixture was dissolved with water and diethyl ether. After stirring, the resulting solid was filtered, washed with water and diethyl ether to give 8.80g (46%) of the desired compound as a powder.

Mp：144-146℃。

RMN¹H(DMSO-d⁶；400MHz)

δ(ppm)：9.34(s，1H)，9.06(d，1H)，8.28(d，1H)，7.29(s，1H)，4.42(m，2H)，4.10(m，2H)，3.72(m，4H)，3.29(m，2H)，1.20(t，3H)。

1.2(+/-) -9-bromo-4-oxo-2-pyrimidin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

To a solution of 4.5g (14.27mmol) of 4-oxo-2-pyrimidin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester in dry tetrahydrofuran (140ml) was added 15.70ml (15.70mmol) of lithium bis (trimethylsilyl) amide (1M in tetrahydrofuran) under an argon atmosphere at-30 ℃. The solution was stirred at-30 ℃ for 5 minutes and 0.77mL (14.98mmol) of bromine was added. The reaction was stirred at-30 ℃ to room temperature for 3 hours. The mixture was quenched by addition of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (dichloromethane with 1 to 3% methanol) to yield 2.6g (46%) of product.

RMN¹H(DMSO-d⁶；400MHz)

δ(ppm)：9.35(s，1H)，9.08(d，1H)，8.23(d，1H)，7.35(s，1H)，5.68(m，1H)，5.21(m，1H)，4.31(m，3H)，4.11(m，2H)，3.95(m，2H)，1.21(t，3H)。

1.3(+/-) -9- (4-methoxy-benzylamino) -4-oxo-2-pyrimidin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

To a suspension of 8.20g (20.80mmol) of ethyl 9-bromo-4-oxo-2-pyrimidin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylate in 208mL of toluene were added 8.56g (62.40mmol) of 4-methoxybenzylamine and 14.77mL (208.00mmol) of dimethyl sulfoxide. The reaction mixture was stirred at 85 ℃ for 15 hours. The cooled solution was evaporated to remove the solvent. The mixture was quenched by addition of saturated ammonium chloride solution and extracted with dichloromethane, washed with saturated sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (dichloromethane/methanol/ammonia, 98/2/0.2 to 97/3/0.3) to yield 5.80g (62%) of product.

Mp：217-219℃。

RMN¹H(DMSO-d⁶；400MHz)

δ(ppm)：9.31(s，1H)，9.04(d，1H)，8.28(d，1H)，7.21(m，3H)，6.82(d，2H)，4.72(m，1H)，4.38(m，1H)，4.20(m，1H)，4.02(m，2H)，3.78(m，5H)，3.70(s，3H)，3.52(m，1H)，1.12(t，3H)。

4(+/-) -9-amino-4-oxo-2-pyrimidin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

To a solution of 10.75g (23.86mmol) of ethyl 9- (4-methoxy-benzylamino) -4-oxo-2-pyrimidin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylate in acetonitrile/water (160/80mL) was added 26.16g (47.73mmol) of cerium ammonium nitrate. The reaction was stirred at room temperature for 2 hours. 13.08g (23.86mmol) of ammonium cerium nitrate was added and the reaction was stirred at room temperature for 0.5 hours. After acid-base treatment and extraction with dichloromethane, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to give 5.15g (65%) of a powder.

Mp：185-187℃。

RMN¹H(DMSO-d⁶；400MHz)

δ(ppm)：9.32(s，1H)，9.05(d，1H)，8.44(d，1H)，7.28(s，1H)，4.89(m，1H)，4.40(m，1H)，4.12-4.01(m，3H)，3.90(m，1H)，3.75(m，1H)，3.50(m，2H)，2.32(br s，2H)，1.15(t，3H)。

1.5(+/-) -4-oxo-9- [ (pyridine-2-carbonyl) -amino ] -2-pyrimidin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

To a solution of 0.100g (0.30mmol) of (+/-) -9-amino-4-oxo-2-pyrimidin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester dissolved in 1.50mL of dimethylformamide was added 0.041g (0.33mmol) of 2-pyridinecarboxylic acid. To the resulting mixture were added 50. mu.l (0.33mmol) of diethyl cyanophosphonate and 130. mu.l (0.91mmol) of triethylamine at 0 ℃. The resulting mixture was stirred at room temperature for 15 hours. Water and ethyl acetate were added and the mixture was stirred. The resulting residue was filtered and washed with water, ethyl acetate and diethyl ether to give 0.098g (76%) of the pure product as a white powder.

Mp：250-252℃。

RMN¹H(DMSO；400MHz)

δ(ppm)：9.98(m，1H)，9.40(s，1H)，9.20(d，1H)，8.94(m，1H)，8.41(m，1H)，8.12(m，2H)，7.75(m，1H)，7.35(s，1H)，5.52(m，1H)，5.11(m，1H)，4.41(m，1H)，4.10(m，4H)，3.99(m，1H)，3.51(m，1H)，1.20(t，3H)。

Example 2 (Compound 4 of Table 1)

To a solution of 0.075g (0.17mmol) of ethyl (+/-) -4-oxo-9- [ (pyridine-2-carbonyl) -amino ] -2-pyrimidin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylate (example 1) dissolved in 0.6ml (3.44mmol) of hydrobromic acid (33% by weight in glacial acetic acid). The resulting mixture was stirred at 100 ℃ for 8 hours, cooled and evaporated to dryness. Toluene was added to the residue and evaporated. MeOH was added to the residue and evaporated. After acid-base treatment, the crude product was triturated with ether and filtered to give 0.035g (45%) of the product as a white powder and free base.

Mp：256-258℃。

RMN¹H(DMSO；400MHz)

δ(ppm)：9.95(br s，1H)，9.38(s，1H)，9.22(d，1H)，8.91(m，1H)，8.48(m，1H)，8.12(m，2H)，7.72(m，1H)，7.32(m，1H)，5.45(m，1H)，4.98(m，1H)，3.92(m，1H)，3.14(m，2H)，2.91(m，1H)，2.70(m，1H)。

Example 3 (Compound 14 of Table 1)

3.1(+/-) -9-amino-2-pyrimidin-4-yl-6, 7, 8, 9-tetrahydro-5H-1, 4a, 7-triaza-benzocyclohepten-4-one dihydrobromide salt (2: 1)

To a solution of 9.70g (23.59mmol) of (+/-) -9-amino-4-oxo-2-pyrimidin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester (step 1.4) dissolved in 118mL of glacial acetic acid was added 41.38mL (235.86mmol) of hydrobromic acid (33 wt% solution in glacial acetic acid). The resulting mixture was stirred at 90 ℃ for 16 hours, cooled and evaporated to dryness. Toluene was added to the residue and evaporated. Ethanol was added to the residue and evaporated. The crude product was triturated with ether and filtered to give 12.40g of product as a brown powder.

Mp：225-235℃。

RMN¹H(DMSO；400MHz)

δ(ppm)：9.40(s，1H)，9.20(d，1H)，9.06(br s，2H)，8.61(m，1H)，7.40(s，1H)，5.28(m，2H)，4.55-4.18(m，2H)，4.03(m，1H)，3.82-3.52(m，2H)，3.32(m，1H)。

3.2(+/-) -2-methoxy-N- (4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -nicotinamide

To a solution of 0.040g (0.26mmol) of 6-methoxy-pyridine-2-carboxylic acid dissolved in 8ml of anhydrous dichloromethane were added 0.11ml (0.79mmol) of triethylamine, 0.050g (0.26mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 0.035g (0.26mmol) of 1-hydroxybenzotriazole. The resulting mixture was stirred at room temperature for 10 minutes and slowly added at-10 deg.C to a solution of 0.110g (0.26mmol) of (+/-) -9-amino-2-pyrimidin-4-yl-6, 7, 8, 9-tetrahydro-5H-1, 4a, 7-triaza-benzocyclohepten-4-one dihydrobromide (2: 1) dissolved in a mixture of 17mL of anhydrous dichloromethane and 0.15mL (1.05mmol) of triethylamine. The resulting mixture was stirred at-10 ℃ for 1 hour and at room temperature for 16 hours. After addition of water, extraction with dichloromethane; the reaction mixture was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue is eluted by chromatography on silica gel with a mixture of dichloromethane/methanol/aqueous ammonia (29%) in a ratio 90/10/1 to give 0.100g (90%) of pure product in the form of a powder.

Mp：236-238℃

RMN¹H(DMSO；400MHz)

δ(ppm)：9.42(m，2H)，9.21(d，1H)，8.41(m，3H)，7.38(s，1H)，7.30(m，1H)，5.61(m，1H)，4.98(m，1H)，4.15(s，3H)，4.01(m，1H)，3.18(m，2H)，2.94(m，1H)，2.71(m，1H)。

Example 4 (Compound 15 of Table 1)

To a solution of 0.055g (0.14mmol) of (+/-) -2-methoxy-N- (4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -nicotinamide (example 3) in 3.00mL of dichloroethane was added 0.050mL (0.70mmol) of formaldehyde (37% in water), 0.089g (0.42mmol) of sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 12 hours. Sodium hydroxide solution (35%) was added and the mixture was extracted with dichloromethane, washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated. The residue is eluted by chromatography on silica gel with a mixture of dichloromethane/methanol/aqueous ammonia (29%) in a ratio 90/10/1 to give 0.014g (24%) of pure product.

Mp：228-230℃

RMN¹H(DMSO；400MHz)

δ(ppm)：9.45(m，1H)，9.38(s，1H)，9.18(d，1H)，8.43(m，2H)，8.32(m，1H)，7.32(s，1H)，7.22(m，1H)，5.65(m，1H)，5.01(m，1H)，4.12(s，3H)，3.95(m，1H)，3.08(m，2H)，2.58(m，1H)，2.38(s，3H)，2.37(m，1H)。

Example 5 (Compound 9 of Table 1)

5.14-oxo-2-pyridin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

By a method similar to that described in example 1 (step 1.1), using ethyl 3-oxo-3-pyridin-4-yl-propionate instead of ethyl 3- (4-pyrimidinyl) -3-oxopropanoate, 9.45g (44%) of the compound were obtained as a white powder.

Mp：191-193℃。

RMN¹H(DMSO-d⁶；400MHz)

δ(ppm)：8.76(d，2H)，8.02(d，2H)，7.12(s，1H)，4.42(m，2H)，4.11(q，2H)，3.75(m，4H)，3.28(m，2H)，1.21(t，3H)。

5.2(+/-) 9-amino-4-oxo-2-pyridin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

By a method analogous to that described in example 1 (step 1.2, step 1.3, step 1.4), using ethyl 4-oxo-2-pyridin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylate instead of ethyl 4-oxo-2-pyrimidin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylate, the compound was obtained as a white powder.

Mp：171-173℃。

RMN¹H(DMSO-d⁶；400MHz)

δ(ppm)：8.72(d，2H)，8.11(d，2H)，7.29(s，1H)，4.85(m，1H)，4.40(m，1H)，4.08(m，3H)，3.90(m，1H)，3.75(m，1H)，3.48(m，2H)，2.35(br s，2H)，1.18(t，3H)。

5.3(+/-) -9- [ (2-tert-butoxycarbonyl-1, 2, 3, 4-tetrahydro-isoquinoline-7-carbonyl) -amino ] -4-oxo-2-pyridin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

By a method analogous to that described in example 1 (step 1.5), using ethyl 9-amino-4-oxo-2-pyridin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylate and 2-tert-butyl 3, 4-dihydro-1H-isoquinoline-2, 7-dicarboxylate instead of (+/-) -9-amino-4-oxo-2-pyrimidin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylate hydrobromide (1: 1) and 2-picolinic acid, 0.286g (80%) of the compound is obtained as a white powder.

Mp：242-244℃。

RMN¹H(DMSO-d⁶；400MHz)

δ(ppm)：8.95(br s，1H)，8.68(d，2H)，8.01(d，2H)，7.85(m，1H)，7.79(m，1H)，7.36(m，1H)，7.21(S11H)，5.50(m，1H)，5.05(m，1H)，4.62(m，2H)，4.20(m，1H)，4.08(m，4H)，3.66(m，1H)，3.64(m，2H)，3.41(m，1H)，2.89(m，2H)，1.45(s，9H)，1.15(m，3H)。

Example 6 (Compound 21 of Table 1)

(+/-) -4-oxo-2-pyridin-4-yl-9- [ (1, 2, 3, 4-tetrahydro-isoquinoline-7-carbonyl) -amino) -5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

To 0.0265g (0.mmol) of (+/-) -9- [ (2-tert-butoxycarbonyl-1, 2, 3, 4-tetrahydro-isoquinoline-7-carbonyl) -amino]To a solution of (E) -4-oxo-2-pyridin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester (example 5) in 1M1 of dichloromethane was added 1.13mL (4.50mmol) of hydrochloric acid (4M bisAn alkane solution). The resulting mixture was stirred at room temperature for 16 hours. The resulting residue was filtered and washed with dichloromethane and isopropyl ether to give 0.261g (100%) of pure product as a white powder.

Mp：258-260℃。

RMN¹H(D₂O；400MHz)

δ(ppm)：8.86(m，2H)，8.22(m，2H)，7.85(m，2H)，7.40(m，1H)，7.32(s，1H)，5.50(m，1H)，5.02(m，1H)，4.60(m，2H)，4.35(m，2H)，4.18(m，1H)，4.04(m，3H)，3.70(m，1H)，3.41(m，2H)，3.11(m，2H)，1.14(m，3H)。

Example 7 (Compound 26 of Table 1)

(+/-) -6-fluoro-4H-benzo [1, 3] dioxin-8-carboxylic acid (4-oxo-2-pyridin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide hydrochloride (1: 1).

7.1(+/-) -9-amino-2-pyridin-4-yl-6, 7, 8, 9-tetrahydro-5H-1, 4a, 7-triaza-benzocyclohepten-4-one dihydrobromide salt (2: 1)

By a method analogous to that described in example 3 (step 3.1), using ethyl 9-amino-4-oxo-2-pyridin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylate (step 5.2) instead of (+/-) -9-amino-4-oxo-2-pyrimidin-4-yl-5, 6, 8, 9-tetrahydro-4H-1, 4a, 7-triaza-benzocycloheptene-7-carboxylate, compound 2.5g (91%) was obtained as a powder.

Mp：286-288℃。

RMN¹H(DMSO-d⁶；400MHz)

δ(ppm)：9.10(m，3H)，9.01(d，2H)，8.59(d，1H)，7.51(s，1H)，5.36(m，1H)，5.26(m，1H)，4.08(m，1H)，3.80-3.58(m，3H)，3.32(m，1H)。

2(+/-) -6-fluoro-4H-benzo [1, 3] dioxin-8-carboxylic acid (4-oxo-2-pyridin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide hydrochloride (1: 1).

By a method similar to that described in example 3 (step 3.2), using (+/-) -9-amino-2-pyridin-4-yl-6, 7, 8, 9-tetrahydro-5H-1, 4a, 7-triaza-benzocyclohepten-4-one dihydrobromide salt and 6-fluoro-4H-benzo [1, 3] dioxin-8-carboxylic acid instead of (+/-) -9-amino-2-pyrimidin-4-yl-6, 7, 8, 9-tetrahydro-5H-1, 4a, 7-triaza-benzocyclohepten-4-one dihydrobromide salt (2: 1) and 6-methoxy-pyridine-2-carboxylic acid, 0.007g (50%) of the compound was obtained as a white powder.

Mp：232-234℃。

RMN¹H(DMSO-d⁶；400MHz)

δ(ppm)：9.48(m，1H)，8.90(d，2H)，8.20(d，2H)，7.65(m，1H)，7.38(s，1H)，7.34(m，1H)，5.80(m，1H)，5.47(m，2H)，5.31(m，1H)，5.12(s，2H)，4.11(m，1H)，3.72(m，2H)，3.49(m，1H)，3.26(m，1H)。

A list of chemical structures and physical data for the compounds of formula (I) above is given in table 1 to illustrate the invention. These compounds have been prepared according to the methods of the examples.

In the table, Me represents methyl, Et represents ethyl, (Rot.) represents the levorotatory or dextrorotatory nature of the enantiomeric compounds, and (dec.) represents the decomposition of these compounds.

TABLE 1

Test examples: the inhibitory activity of the medicine of the invention on GSK3 beta is as follows:

four different schemes may be used.

In a first scenario: 7.5 μ M of the pre-phosphorylated GS1 peptide and 10 μ M ATP (300000 cpm containing)³³P-ATP) in 25mM Tris-HCl, pH 7.5, 0.6mM DTT, 6mM MgCl₂0.6mM EGTA, 0.05mg/ml BSA buffer in the presence of GSK3 beta at room temperature for 1h (total reaction volume: 100 microliter).

In a second scenario: 4.1 μ M of the pre-phosphorylated GS1 peptide and 42 μ M ATP (containing 260000 cpm)³³P-ATP) was incubated in 80mM Mes-NaOH, pH 6.5, 1mM magnesium acetate, 0.5mM EGTA, 5mM 2-mercaptoethanol, 0.02% Tween 20, 10% glycerol buffer for 2 hours at room temperature in the presence of GSK3 beta.

In a third scenario: 7.5 μ M of the pre-phosphorylated GS1 peptide and 10 μ M ATP (300000 cpm containing)³³P-ATP) at 50mM Hepes, pH 7.2, 1mM DTT, 1mM MgCl₂1mM EGTA, 0.01% Tween 20 buffer in GSK3 beta in the presence of room temperature 1h incubation (total reaction volume: 100 microliter).

In a fourth scenario: 7.5 μ M of the pre-phosphorylated GS1 peptide and 10 μ M ATP (300000 cpm in)³³P-ATP) at 50mM Hepes, pH 7.2, 1mM DTT, 1mM MgCl₂1mM EGTA, 0.01% Tween 20 buffer in commercial GSK3 beta (Mil)lipore) was incubated at room temperature for 90 minutes (total reaction volume: 100 microliters).

The inhibitor was dissolved in DMSO (final solvent concentration in the reaction medium, 1%).

The reaction was stopped with 100. mu.l of a solution containing 25g of polyphosphoric acid (85% P)₂O₅)、126ml85％H₃PO₄And H to 500ml₂O, and then diluted 1: 100 prior to use. An aliquot of the reaction mixture was then transferred to a Whatman P81 cation exchange filter and washed with the above solution. Mixed in³³The radioactivity of P was measured by liquid scintillation spectrometry (scintillation spectrometry).

The phosphorylated GS-1 peptide has the following sequence:

NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH(Woodgett，J.R.(1989)Analytical Biochemistry 180，237-241。

GSK3 beta inhibitory Activity of Compounds of the invention as IC₅₀Show, as an illustration, the respective ICs of the compounds in Table 1₅₀In the range of 0.1nM to 3. mu.M.

For example, for the fourth protocol, compound 1 of table 1 shows IC₅₀At 0.073. mu.M, IC shown for Compound 8 of Table 1₅₀At 0.109. mu.M, IC shown by Compound 22 of Table 1₅₀At 0.047. mu.M, IC shown by Compound 26 of Table 1₅₀It was 0.012. mu.M.

Formulation examples

(1) Tablet formulation

The following ingredients were mixed by a conventional method and tabletted using conventional equipment.

Compound of example 130 mg

Microcrystalline cellulose 60mg

Corn starch 100mg

Lactose 200mg

Magnesium stearate 4mg

(2) Soft capsule

The following ingredients were mixed by a general method and filled into a soft capsule.

Compound of example 130 mg

Olive oil 300mg

Lecithin 20mg

(1) Parenteral formulation

The following ingredients were mixed by a usual method to prepare an injection contained in a 1ml ampoule.

Compound of example 13 mg

Sodium chloride 4mg

1ml of distilled water for injection

Industrial applicability

The compounds of the present invention have GSK3 β inhibitory activity and can be used as active ingredients of medicaments for the prophylactic and/or therapeutic treatment of diseases caused by abnormal activity of GSK3 β, more particularly neurodegenerative diseases.

Claims

1. A pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof:

wherein:

z represents a bond, an oxygen atom, a hydrogen atomAtom or C_1-3An alkyl-substituted nitrogen atom, a sulfur atom, a methylene group optionally substituted with 1 or 2 groups selected from: c_1-6Alkyl, hydroxy, C_1-6Alkoxy, perhalogenated C_1-2Alkyl or amino;

r2 represents a hydrogen atom, C_1-6An alkyl group or a halogen atom;

r3 represents a 4-15 membered heterocyclyl group, which group is optionally substituted by 1 to 4 substituents selected from: c_1-6Alkyl, halogen atom, perhalogenated C_1-2Alkyl, halogenated C_1-6Alkyl, hydroxy, C_1-6Alkoxy, C (O) O (C)_1-6Alkyl), C (O) O (aryl) groups, halogenated C_1-6Alkoxy, nitro, cyano, amino, C_1-6Monoalkylamino group, C_2-12Dialkylamino group, S- (C)_1-6-alkyl), 4-15 membered heterocyclyl, aryl, O-aryl or S-aryl, said groups being optionally substituted with 1 to 4 substituents selected from the group consisting of: c_1-6Alkyl group, halogen atom, (C)_1-6) An alkoxy group;

r5 represents a hydrogen atom or C_1-6An alkyl group; and is

n represents 0 to 3.

2. A pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1, wherein:

y represents an oxygen atom;

z represents a chemical bond;

r2 represents a hydrogen atom;

r3 represents naphthyridinyl, pyridinyl, dihydrobenzofuranyl, tetrahydroisoquinolinyl, pyridazinyl, dihydrobenzodioxinyl or benzodioxinyl, wherein the above groups are optionally substituted by 1 to 4 substituents selected from: c_1-6Alkyl group, halogen atom, C_1-6Alkoxy, amino, C (O) O (C)_1-6Alkyl) groups;

r4 represents a hydrogen atom, C_1-6Alkyl radical, C_1-4Alkoxycarbonyl, benzyl;

r5 represents a hydrogen atom;

n represents 0.

3. A pyrimidone derivative or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1, which is selected from the group consisting of:

(+/-) -3, 6-dimethoxy-pyridazine-4-carboxylic acid (7-methyl-4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -8-amino-7-chloro-2, 3-dihydro-benzo [1, 4] dioxadiene-5-carboxylic acid (4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -8-amino-7-chloro-2, 3-dihydro-benzo [1, 4] dioxadiene-5-carboxylic acid (7-methyl-4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -amide

(+/-) -2, 6-dimethoxy-N- (4-oxo-2-pyrimidin-4-yl-4, 5, 6, 7, 8, 9-hexahydro-1, 4a, 7-triaza-benzocyclohepten-9-yl) -nicotinamide.

4. Pyrimidone derivatives represented by formulae (III), (VI) and (VII) wherein:

the definitions of R1, R2 and R4 follow those of the compounds of formula (I) according to claim 1.

5. A medicament containing, as an active ingredient, a substance selected from the pyrimidone derivatives represented by formula (I) or salts thereof, or solvates thereof or hydrates thereof according to claims 1 to 3.

A GSK3 β inhibitor selected from a pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof according to claim 1.

7. A compound according to claims 1-3 for use in the prophylactic and/or therapeutic treatment of diseases caused by abnormal GSK3 β activity.

8. A compound according to claims 1-3 for use in the prophylactic and/or therapeutic treatment of a neurodegenerative disease.

9. The compound according to claim 8, wherein said neurodegenerative disease is selected from the group consisting of alzheimer's disease, parkinson's disease, tauopathies, vascular dementia; acute stroke, traumatic injury; cerebrovascular accident, brain injury, spinal cord injury; peripheral neuropathy; retinopathy or glaucoma.

10. A compound according to claims 1-3 for use in the prophylactic and/or therapeutic treatment of non-insulin dependent diabetes mellitus; obesity; manic depression; schizophrenia; alopecia; cancer; parenchymal renal disease or muscle atrophy.

11. A compound according to claim 10, wherein the cancer is breast cancer, non-small cell lung cancer, thyroid cancer, T-cell or B-cell leukemia or a virus-induced tumor.

12. A compound according to claims 1-3 for use in the prophylactic and/or therapeutic treatment of malaria.

13. A compound according to claims 1-3 for use in the prophylactic and/or therapeutic treatment of bone disorders.

14. A compound according to claims 1-3 for use in the prophylactic and/or therapeutic treatment of pemphigus vulgaris.

15. A compound according to claims 1-3 for use in the prophylactic and/or therapeutic treatment of neutropenia induced by cancer chemotherapy.

16. A compound according to claims 1-3 for use in the therapeutic treatment of diseases characterized by cognitive deficits and memory deficits.

17. A process for the synthesis of a compound of general formula (I) as defined in claims 1 to 3, using an intermediate as defined in claim 4.