HK1222391B - Oxoquinazolinyl-butanamide derivatives - Google Patents

Description

Oxoquinazolinyl-butyramide derivatives

Background of the Invention

The invention had the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.

The present invention relates to oxoquinazolinyl-butyramide derivatives that inhibit the activity of tankyrase (TANK) and poly (ADP-ribose) polymerase PARP-1. Thus, the compounds of the present invention are useful in treating diseases, such as cancer, multiple sclerosis, cardiovascular disease, central nervous system damage, and various forms of inflammation. The present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods of using pharmaceutical compositions containing these compounds to treat diseases.

The nuclear enzyme poly (ADP-ribose) polymerase-1 (PARP-1) is a member of the PARP enzyme family. This growing family of enzymes consists of PARPs (e.g., PARP-1, PARP-2, PARP-3, and Vault-PARP) and Tankyrases (TANKs) (e.g., TANK-1 and TANK-2). PARP is also known as poly (adenosine 5'-diphosphate-ribose) polymerase or PARS (poly (ADP-ribose) synthetase).

TANK-1 appears to be required for the polymerization of poly(ADP-ribose) associated with the mitotic spindle. The poly ADP-ribosylation activity of TANK-1 is critical for the precise formation and maintenance of spindle bipolarity. Furthermore, it has been demonstrated that normal telomere separation prior to anaphase requires the PARP activity of TANK-1. Interference with tankyrase PARP activity results in aberrant mitosis, causing temporary cell cycle arrest, which may be due to spindle checkpoint activation and subsequently cell death. Therefore, inhibition of tankyrases is expected to have a cytotoxic effect on proliferating tumor cells (WO2008/107478).

M. Rouleau et al., Clinical Cancer Research, Nature Reviews, Volume 10, 293-301 (Table 2, page 298), describe PARP inhibitors.

According to a review by Horvath and Szabo (Drug News Perspect 20(3), April 2007, pp. 171-181), recent studies have demonstrated that PARP inhibitors increase cancer cell death, primarily because they interfere with DNA repair at various levels. More recent studies have also demonstrated that PARP inhibitors inhibit angiogenesis by inhibiting growth factor expression or by suppressing growth factor-induced cell proliferation responses. These findings also correlate with the pattern of anticancer effects of PARP inhibitors in vivo.

Tentori et al. (Eur. J. Cancer, 2007, 43(14)2124-2133) also showed that PARP inhibitors can abolish VEGF- or placental growth factor-induced migration, prevent the formation of tubular networks in cell-based systems, and reduce angiogenesis in vivo. The study also demonstrated that growth factor-induced angiogenesis is insufficient in PARP-1 knockout mice. The results provide evidence for targeting PARP for anti-angiogenesis, adding new therapeutic significance to the use of PARP inhibitors in cancer treatment.

It is well known that defects in conserved signaling pathways play a key role in the origin and nature of essentially all cancers (E.A.Fearon, Cancer Cell, Vol. 16, Issue 5, 2009, 366-368). The Wnt pathway is a target for anti-cancer therapy. A key feature of the Wnt pathway is that the proteolysis (degradation) of β-catenin by the β-catenin destruction complex is controlled. Proteins such as WTX, APC or Axin are involved in the degradation process. Proper degradation of β-catenin is important for avoiding inappropriate activation of the Wnt pathway observed in many cancers. Tankyrases inhibit the activity of Axin and thereby inhibit the degradation of β-catenin. Therefore, tankyrase inhibitors increase the degradation of β-catenin. The Nature article not only provides important new insights into the proteins that control Wnt signaling but also further supports the approach of antagonizing the levels and location of β-catenin through small molecules (Huang et al., 2009; Nature, Vol. 461, 614-620). The compound XAV939 inhibits the growth of DLD-1 cancer cells. They found that XAV9393 blocks Wnt-stimulated accumulation of β-catenin by increasing the levels of AXIN1 and AXIN2 proteins. Subsequent work by the authors demonstrated that XAV939 controls AXIN levels by inhibiting tankyrases 1 and 2 (TNKS1 and TNKS2), both members of the poly(ADP-ribose) polymerase (PARP) protein family (S.J. Hsiao et al., Biochimie 90, 2008, 83-92).

It has been found that the compounds according to the invention and their salts possess very valuable pharmacological properties and are at the same time very well tolerated.

The present invention particularly relates to compounds of formula I that inhibit Tankyrases 1 and 2, compositions comprising these compounds, and methods of use thereof for treating TANK-induced diseases and disorders.

Furthermore, the compounds of formula I can be used for the isolation and study of the activity or expression of TANKs. In addition, they are particularly suitable for use in diagnostic methods for diseases associated with unregulated or disturbed TANK activity.

The host or patient can be any mammal, for example, primates, especially humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are meaningful models for experimental research and provide models for treating human diseases.

The sensitivity of specific cells to treatment according to the compounds of the present invention can be determined by in vitro testing. Typically, a culture of cells is combined with various concentrations of the compounds of the present invention for a period of time, allowing the active agent (e.g., anti-IgM) to be sufficient to induce a cellular response, e.g., expression of surface markers, typically between about an hour and a week. In vitro testing can be performed using cultured cells obtained from blood or biopsy samples. The amount of the expressed surface markers is evaluated by flow cytometry using specific antibodies that recognize the markers.

The dosage varies depending on the specific compound used, the specific disease, the patient's condition, etc. The therapeutic dose is typically sufficient to significantly reduce the unwanted cell population in the target tissue while maintaining the patient's vitality. Treatment is generally continued until a significant reduction occurs, for example, a reduction of at least about 50% in the cell burden, and can be continued until substantially no unwanted cells are detected in the body.

Existing technology

E. Wahlberg et al., Nature Biotechnology(2012), 30(3), 283.

The following quinazolinones are described as tankyrase inhibitors:

IC ₅₀₍ TNKS1)=590 nM, IC ₅₀₍ TNKS2)=600 nM; Cell assay: Ineffective at 30µM.

M. D. Shultz et al., Journal of Medicinal Chemistry 2013 (published November 7, 2013).

The following quinazolinones are described as tankyrase inhibitors:

Literature data: IC ₅₀₍ TNKS1)=50 nM, IC ₅₀₍ TNKS2)=22 nM.

In the same publication the following benzoylpiperidine derivatives are described as tankyrase inhibitors:

IC ₅₀₍ TNKS1)=2 nM, IC ₅₀₍ TNKS2)=0.6 nM; Cell assay: EC ₅₀ =35 nM.

H. Bregman et al., Journal of Medicinal Chemistry(2013), 56(3), 1341.

The following quinazolinones are described as tankyrase inhibitors:

IC ₅₀₍ TNKS1)=7.4 nM, IC ₅₀₍ TNKS2)=4.4 nM; Cell assay: EC ₅₀ =320 nM.

The compounds of the present invention are significantly more active.

Further tankyrase inhibitors are described in WO 2013/012723, WO 2013/010092 and WO 2013/008217.

Summary of the Invention

The present invention relates to compounds of formula I:

in

Z stands for

or

X represents CH or N,

R ¹ and R ² each independently represent H, F or Cl,

R ³ represents H, F, Cl, CH ₃ or OCH ₃ ,

^R4 represents H, F, A, CN, OA or Y,

R ⁵ represents H, F, A or OA,

R ⁶ represents CN or 2-pyrimidinyl,

R ⁷ represents Het ² ,

A represents a straight-chain or branched alkyl group having 1 to 8 C atoms, wherein one or two non-adjacent CH- and/or CH ₂ -groups may be replaced by N- and/or O-atoms, wherein 1 to 7 H atoms may be replaced by F, Cl and/or OH,

Y represents a pyrazolyl group which may be substituted by A or (CH ₂ ) _n Het ¹ ,

Het ¹ represents a pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl group, each of which may be substituted by A,

^Het2 represents pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrrolyl, thiazolyl, furyl or thienyl, each of which may be substituted by A,

n is 0, 1, 2, 3, or 4,

and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

The present invention also relates to optically active forms (stereoisomers), enantiomers, racemates, diastereomers and hydrates and solvates of these compounds.

Furthermore, the invention relates to pharmaceutically usable derivatives of the compounds of formula I.

The term "solvate of a compound" is understood to mean an addition of inert solvent molecules to the compound which forms owing to their mutual attractive force. Solvates are, for example, mono- or dihydrates or alcoholates.

It will be understood that the present invention also relates to solvates of the salts.

The term "pharmaceutically usable derivatives" is taken to mean, for example, the salts of the compounds according to the invention and also so-called prodrug compounds.

Unless otherwise indicated, the term "prodrug" as used herein refers to a derivative of a compound of formula I that can hydrolyze, oxidize, or react under biological conditions (in vitro or in vivo) to provide an active compound (particularly a compound of formula I). Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds of formula I that include a biohydrolyzable moiety, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. In certain embodiments, the prodrug of a compound with a carboxyl functional group is a lower alkyl ester of a carboxylic acid. Carboxylic acid esters are conveniently formed by esterification of any carboxylic acid moiety present on the molecule. Prodrugs can typically be prepared using well-known methods, for example, those described in Burger's Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

The term "effective amount" means the amount of a drug or a pharmaceutically active ingredient that elicits the biological or medical response in a tissue, system, animal or human that is being studied or desired by the researcher or physician.

Additionally, the term "therapeutically effective amount" refers to an amount that has the following consequences, compared to a corresponding patient who does not receive such amount:

Improved treatment, cure, prevention or elimination of a disease, syndrome, condition, disorder, disorder or side effect, or also slowing the progression of a disease, disorder or condition.

The term "therapeutically effective amount" also includes amounts effective to enhance normal physiological function.

The invention also relates to the use of mixtures of compounds of formula I, e.g., mixtures of two diastereomers, e.g., mixtures in a ratio of 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

Especially preferably, these are mixtures of stereoisomeric compounds.

"Tautomers" refer to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms depend on the environment in which the compound is obtained and may vary, for example, depending on whether the compound is a solid or in an organic or aqueous solution.

The present invention relates to compounds of formula I and salts thereof, as well as methods for preparing compounds of formula I and pharmaceutically acceptable salts, solvates, tautomers and stereoisomers thereof, characterized in that:

Compound of formula II

Wherein, Z has the meaning as set forth in claim 1,

reacting with a compound of formula III,

wherein R ¹ , R ² and R ³ have the meanings as shown in claim 1,

L represents Cl, Br, I, or a free or reactive functionally modified OH group,

and/or

A base or acid of formula I is converted into one of its salts.

Above and below, the radicals R ¹ , R ² , R ³ and Z have the meanings indicated for the formula I, unless expressly stated otherwise.

A represents an alkyl group, which is unbranched (straight-chain) or branched and has 2, 3, 4, 5, 6, 7 or 8 C atoms. Preferably, A represents ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, further preferably, for example, trifluoromethyl or 1-hydroxy-1-methylethyl.

Particularly preferably, A represents alkyl having 2, 3, 4, 5 or 6 C atoms, preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1,1,1-trifluoroethyl.

Furthermore, preferably, A represents CH ₂ OCH ₃ , CH ₂ CH ₂ OH or CH ₂ CH ₂ OCH ₃ .

Preferably, R ¹ represents H.

Preferably, ^R2 represents H or F.

Preferably, R ³ represents H, CH ₃ or F.

Preferably, R ⁴ represents H, CN, OCH ₃ , 1-ethyl-1H-pyrazol-4-yl, 1-(2-methoxy-ethyl)-1H-pyrazol-4-yl or 1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl.

Preferably, R ⁵ represents H, CH ₃ , F or OCH ₃ ,

Preferably, Het ¹ represents pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, each of which may be substituted by methyl.

Preferably, Het ² represents pyrazolyl or imidazolyl, each of which may be substituted by methyl.

Particularly preferably, Het ¹ represents pyrrolidinyl or piperidinyl.

Preferably, n represents 1, 2 or 3.

Throughout the invention, all radicals which occur more than once may be identical or different, ie they are independent of one another.

The compounds of formula I may have one or more chiral cores and may therefore occur in various stereoisomeric forms. Formula I encompasses all these forms.

Accordingly, the present invention relates in particular to compounds of formula I, in which at least one of the groups has one of the preferred meanings mentioned above. Some preferred groups of compounds can be represented by the following sub-formulae Ia to Ic, which correspond to formula Ia, wherein the groups not represented in greater detail have the meanings indicated for formula I, but wherein

In Ia, A represents a straight-chain or branched alkyl group having 1 to 6 C atoms, wherein one or two non-adjacent CH ₂ -groups may be replaced by an O-atom, wherein 1 to 7 H atoms may be replaced by F and/or OH;

In Ib, R ¹ and R ² each independently represent H, F or Cl,

R ³ represents H, F, Cl, CH ₃ or OCH ₃ ,

^R4 represents H, F, A, CN, OA or Y,

R ⁵ represents H, F, A or OA,

A represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms, wherein 1 to 3 hydrogen atoms may be replaced by fluorine and/or hydroxyl groups;

Y represents pyrazolyl which may be substituted by A, methoxyethyl or (CH ₂ ) _n Het ¹ ,

Het ¹ represents a pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl group, each of which may be substituted by A,

^Het2 represents pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrrolyl, thiazolyl, furyl or thienyl, each of which may be substituted by A,

n is 0, 1, 2, 3, or 4;

In Ic, ^R1 represents H,

^R2 represents H or F,

R ³ represents H, CH ₃ or F,

R ⁴ represents H, CN, OCH ₃ , 1-ethyl-1H-pyrazol-4-yl, 1-(2-methoxy-ethyl)-1H-pyrazol-4-yl or 1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl,

R ⁵ represents H, CH ₃ , F or OCH ₃ ,

Het ² represents a pyrazolyl group or an imidazolyl group, each of which may be substituted by A,

A represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms, wherein 1 to 3 hydrogen atoms may be replaced by fluorine and/or hydroxyl groups;

and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

Preferably, the present invention relates to compounds of formula Id

in

R ¹ and R ² each independently represent H, F or Cl,

R ³ represents H, F, Cl, CH ₃ or OCH ₃ ,

^R4 represents H, F, A, OA or Y,

R ⁵ represents H, F, A or OA,

A represents a straight-chain or branched alkyl group having 1 to 8 C atoms, wherein one or two non-adjacent CH- and/or CH ₂ -groups may be replaced by N- or O-atoms, wherein 1 to 7 H atoms may be replaced by F or Cl,

Y represents a pyrazolyl group which may be substituted by A or (CH ₂ ) _n Het ¹ ,

Het ¹ represents a pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl group, each of which may be substituted by A,

n is 0, 1, 2, 3, or 4,

and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

Accordingly, the present invention relates in particular to compounds of the formula Id, in which at least one of the groups has one of the preferred meanings given above. Some preferred groups of compounds can be represented by the following subformulae Ida to Idc, which correspond to formula Id, wherein the groups not specified in greater detail have the meanings indicated for formula Id, but wherein

In Ida, A represents a straight-chain or branched alkyl group having 1 to 6 C atoms, wherein one or two non-adjacent CH ₂ -groups may be replaced by an O-atom, wherein 1 to 7 H atoms may be replaced by F;

In Idb, R ¹ and R ² each independently represent H, F or Cl,

R ³ represents H, F, Cl, CH ₃ or OCH ₃ ,

^R4 represents H, F, A, OA or Y,

R ⁵ represents H, F, A or OA,

A represents a straight-chain or branched alkyl group having 1 to 6 C atoms,

Y represents pyrazolyl which may be substituted by A, methoxyethyl or (CH ₂ ) _n Het ¹ ,

Het ¹ represents a pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl group, each of which may be substituted by A,

n is 0, 1, 2, 3, or 4;

In Idc, R ¹ represents H,

^R2 represents H or F,

R ³ represents CH ₃ or F,

R ⁴ represents H, OCH ₃ , 1-ethyl-1H-pyrazol-4-yl, 1-(2-methoxy-ethyl)-1H-pyrazol-4-yl or 1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl,

R ⁵ represents H, CH ₃ , F or OCH ₃ ;

and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

In addition, the compounds of formula I and the starting materials for their preparation are prepared by methods known per se, as described in the literature (e.g., in standard reference books, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), specifically under reaction conditions known and suitable for the reactions described. It is also possible to use variants known per se that are not mentioned in greater detail herein.

The starting compounds of the formula II and III are generally known compounds. However, if they are novel compounds, they can be prepared by methods known per se.

Preferably, the compound of formula I can be obtained by reacting a compound of formula II with a compound of formula III.

In the compounds of the formula III, L preferably represents Cl, Br, I or a free or reactively modified OH group, for example, an active ester, an imidazolide or an alkylsulfonyloxy group having 1 to 6 C atoms (preferably methanesulfonyloxy or trifluoromethylsulfonyloxy) or an arylsulfonyloxy group having 6 to 10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).

The reaction is generally carried out in the presence of an acid-binding agent, preferably an organic base, for example, DIPEA, triethylamine, xylidine, pyridine or quinoline.

It may also be advantageous to add alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates, or other weak acid salts of alkali metals or alkaline earth metals, preferably potassium, sodium, calcium or cesium.

Depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature is between about -30° and 140°, usually between -10° and 90°, in particular between about 0° and about 70°.

Examples of suitable inert solvents are hydrocarbons, for example, hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, for example, trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, for example, methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, for example, diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, for example, ethylene glycol monomethyl or monoethyl ether, glyme (diglyme); ketones, for example, acetone or butanone; amides, for example, acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles, for example, acetonitrile; sulfoxides, for example, dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, for example, formic acid or acetic acid; nitro compounds, for example, nitromethane or nitrobenzene; esters, for example, ethyl acetate, or mixtures of the solvents mentioned.

Particular preference is given to acetonitrile, 1,2-dichloroethane, dichloromethane and/or DMF.

Pharmaceutical salts and other forms

The compounds according to the invention may be used in their final non-salt form. On the other hand, the present invention also includes the use of pharmaceutically acceptable salts of these compounds, which can be derived from various organic and inorganic acids and bases by methods known in the art. Most of the pharmaceutically acceptable salts of the compounds of formula I are prepared by conventional methods. If the compound of formula I contains a carboxyl group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base addition salt. Such bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides, for example, barium hydroxide and calcium hydroxide; alkali metal alcoholates, for example, potassium ethoxide and sodium propoxide; and various organic bases, for example, piperidine, diethanolamine and N-methylglutamine. Also included are aluminum salts of the compounds of formula I. In the case of certain compounds of Formula I, acid addition salts can be formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids, for example, hydrohalic acids, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, other inorganic acids and their corresponding salts, for example, sulfates, nitrates or phosphates and the like, as well as alkyl- and monoarylsulfonates, for example, ethanesulfonates, toluenesulfonates and benzenesulfonates, and other organic acids and their corresponding salts, for example, acetates, trifluoroacetates, tartrates, maleates, succinates, citrates, benzoates, salicylates, ascorbates and the like. Accordingly, pharmaceutically acceptable acid addition salts of the compounds of formula I include the following: acetate, adipate, alginate, arginine, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, octanoate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, fumarate, formate, mucate (derived from mucic acid), galacturonate, glucoheptonate, gluconate, glutamate, glycerophosphate, The invention also includes, but is not limited to, bisphenol A, bisphenol B, bisphenol C, bisphenol A ...

In addition, base salts of the compounds according to the present invention include, but are not limited to, aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium, and zinc salts. Of these salts, ammonium salts, alkali metal sodium and potassium salts, and alkaline earth metal calcium and magnesium salts are preferred. Salts of the compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases also include salts of primary, secondary, and tertiary amines, substituted amines, and also naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as, but not limited to, arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzalexane), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, trihydroxyethylamine, triethylamine, trimethylamine, tripropylamine, and tris(hydroxymethyl)methylamine (tromethamine).

The compounds of the invention containing basic nitrogen groups can be quaternized, for example, using reagents (C ₁ -C ₄ ) alkyl halides, such as methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; di(C ₁ -C ₄ ) alkyl sulfates, such as dimethyl, diethyl and diamyl sulfate; (C ₁₀ -C ₁₈ ) halogenated hydrocarbons, such as decyl, dodecyl, lauryl, tetradecyl and stearyl chloride, bromide and iodide; and aryl(C ₁ -C ₄ ) alkyl halides, such as benzyl chloride and phenethyl bromide. Water- and oil-soluble compounds according to the invention can be prepared using such salts.

Preferred pharmaceutically acceptable salts include acetate, trifluoroacetate, benzenesulfonate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, but are not limiting.

Particularly preferred are the hydrochloride, dihydrochloride, hydrobromide, maleate, methanesulfonate, phosphate, sulfate and succinate salts.

The acid addition salts of the basic compounds of Formula I are prepared by contacting the basic compound of Formula I in free base form with a sufficient amount of target acid to form a salt in a conventional manner. The salt form is contacted with a base and the free base is separated in a conventional manner, and the free base can be regenerated. According to certain physical properties, for example, solubility in polar solvents, the free base form differs from its corresponding salt form in some aspects; however, for the present invention, the salt corresponds to its corresponding free base form.

As described, pharmaceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines, for example, alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium, and calcium. Preferred organic amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine, and procaine.

Base addition salts of the acidic compounds according to the invention are prepared by contacting the free acid form of the acidic compound according to the invention with a sufficient amount of the desired base to form the salt in a conventional manner. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid form may differ in some respects from its corresponding salt form due to certain physical properties, such as solubility in polar solvents; however, for the purposes of the present invention, the salt corresponds to its corresponding free acid form.

If the compound according to the invention contains more than one group capable of forming pharmaceutically acceptable salts of this type, the invention also includes double salts. Typical double salt forms include, for example, bitartrate, diacetate, hydrogen fumarate, dimeglumine, hydrogen phosphate, disodium and trihydrochloride, but this is not restrictive.

With regard to the above, it can be seen that, in the present invention, the term "pharmaceutically acceptable salt" refers to an active ingredient comprising a salt form of a compound of formula I, in particular, if such salt form confers improved pharmacokinetic properties on the active ingredient compared to the free active ingredient or any other salt form of the active ingredient previously used. A pharmaceutically acceptable salt form of the active ingredient may also enable the active ingredient to possess previously unattainable desired pharmacokinetic properties for the first time, and may even have a positive effect on the efficacy of the active ingredient in terms of its in vivo therapeutic efficacy.

isotope

In addition, it is intended that the compounds of formula I include isotopically labeled forms thereof. The isotopically labeled forms of the compounds of formula I are identical to these compounds, except that one or more atoms of the compound are replaced by atoms having an atomic weight or mass number different from that of the atoms normally present in nature. Examples of isotopes that are readily commercially available and that can be incorporated into the compounds of formula I by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, respectively ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl. Compounds of formula I comprising one or more of the above-mentioned isotopes and/or other isotopes of other atoms, their prodrugs, or pharmaceutically acceptable salts are all part of the present invention. Isotopically labeled compounds of formula I can be used in many advantageous approaches. For example, isotope-labeled compounds of formula I that have been combined with an isotope, for example, a radioactive isotope, such as ³ H or ¹⁴ C, are suitable for drug and/or substrate tissue distribution assays. These radioactive isotopes, i.e., tritium ( ³ H) and carbon 14 ( ¹⁴ C), are particularly preferred radioactive isotopes because their preparation methods are simple and have excellent detection limits. Heavy isotopes (e.g., deuterium ( ² H)) are incorporated into compounds of formula I to provide therapeutic advantages because such isotope-labeled compounds have higher metabolic stability. Higher metabolic stability translates directly into increased half-life in vivo or reduced dosage, which in most cases represents a preferred embodiment of the present invention. Isotope-labeled compounds of formula I can generally be prepared according to the methods disclosed in the synthetic reaction schemes and the relevant specifications, examples, and preparation sections of the present invention, replacing non-isotope-labeled reactants with readily available isotope-labeled reactants.

Deuterium ( ² H) can also be incorporated into compounds of Formula I to control their oxidative metabolism via the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction caused by the exchange of isotopic nuclei, which in turn is caused by a change in the ground state energy required for covalent bond formation following isotope exchange. Exchange of heavy isotopes generally results in a decrease in the ground state energy of a chemical bond, and thus in a decrease in the rate of rate-limiting bond cleavage. If bond cleavage occurs in or near a coordinated saddle point region along a multi-product reaction, the product distribution ratio can be substantially altered. Explanation: If deuterium is bonded to a carbon atom at a non-exchangeable position, the k _M /k _D rate difference is typically 2-7. If this rate difference is successfully applied to oxidation-sensitive compounds of Formula I, the in vivo properties of such compounds can be dramatically altered, leading to improved pharmacokinetic properties.

When developing and preparing therapeutic agents, those skilled in the art attempt to optimize pharmacokinetic parameters while maintaining desired in vitro performance. It is reasonable to assume that many compounds with poor pharmacokinetic properties are sensitive to oxidative metabolism. Current in vitro liver microsome assays provide valuable information about this type of oxidative metabolic process, which also enables the rational design of deuterated compounds of Formula I that have increased stability by withstanding this oxidative metabolism. The pharmacokinetic properties of compounds of Formula I are thus significantly improved and can be quantitatively expressed based on an increase in in vivo half-life (t/2), the concentration at maximum therapeutic effect ( _Cmax ), the area under the dose-response curve (AUC) and F, as well as based on reduced clearance, dosage, and raw material consumption.

The following is used to illustrate the above: Compounds of Formula I that have multiple potential attack sites for oxidative metabolism (e.g., benzylic hydrogen atoms and hydrogen atoms bonded to nitrogen atoms) are prepared as a series of analogs in which various combinations of hydrogen atoms are replaced with deuterium atoms, such that some, most, or all of these hydrogen atoms are replaced with deuterium atoms. Half-life determinations can advantageously and accurately determine the degree of increased tolerance to oxidative metabolism. In this way, it has been determined that the half-life of the parent compound can be extended by up to 100% due to this type of deuterium-hydrogen exchange.

Deuterium-hydrogen exchange can also be used to achieve favorable changes in the metabolite profile of the starting compound in order to reduce or eliminate undesirable toxic metabolites in compounds of Formula I. For example, if toxic metabolites occur by oxidative carbon-hydrogen (C-H) bond cleavage, it is reasonable to assume that the deuterated analog will greatly reduce or eliminate the production of the unwanted metabolite, even if the specific oxidation is not the rate-determining step. Detailed information on the prior art of deuterium-hydrogen exchange can be found in, for example, Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al., Biochemistry 33(10)2927-2937, 1994, and Jarman et al., Carcinogenesis 16(4), 683-688, 1993.

Furthermore, the invention relates to medicaments containing at least one compound of the formula I and/or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or adjuvants.

Pharmaceutical preparations can be administered in dosage unit form, each dosage unit containing a predetermined amount of the active ingredient. Depending on the condition being treated, the method of administration, and the age, weight, and condition of the patient, such units may contain, for example, 0.5 mg to 1 g of the compound according to the invention, preferably 1 mg to 700 mg, and particularly preferably 5 mg to 100 mg, or pharmaceutical preparations can be administered in dosage unit form, each dosage unit containing a predetermined amount of the active ingredient. Preferred dosage unit formulations are those that contain the above-mentioned daily doses or partial doses of the active ingredient or corresponding fractions thereof. In addition, pharmaceutical preparations of this type can be prepared using methods generally known in the pharmaceutical art.

The pharmaceutical formulations may be suitable for administration by any suitable method of interest, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations may be prepared using all methods known in the pharmaceutical art, for example, by combining the active ingredient with an excipient or adjuvant.

Pharmaceutical formulations suitable for oral administration may be administered in the form of discrete units, for example, capsules or tablets; powders or granules; solutions or suspensions in water or non-aqueous liquids; edible foams or foam-like foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral tablet or capsule forms, the active ingredient can be mixed with an oral non-toxic and pharmaceutically acceptable inert excipient, such as ethanol, glycerol, water, etc. Powders are prepared by grinding the compound to a powder of a suitable size and mixing it with a pharmaceutical excipient (e.g., an edible carbohydrate, such as starch or mannitol) ground in a similar manner. Flavorings, preservatives, dispersants, and dyes may also be present.

The powder mixture is prepared and filled into a shaped gelatin shell to prepare a capsule. A glidant and a lubricant (e.g., highly dispersed silicic acid, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol) may be added to the powder mixture before filling. In order to improve the utilization of the drug after ingestion of the capsule, a disintegrant or solubilizing agent, such as agar, calcium carbonate, or sodium carbonate, may also be added.

In addition, if desired or necessary, suitable binders, lubricants and disintegrants and dyes can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, for example, glucose or beta-lactose, sweeteners made from corn, natural and synthetic rubbers, for example, gum arabic, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, paraffin, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include (but are not limited to) starch, methylcellulose, agar, bentonite, xanthan gum, etc. Tablets are prepared as follows: for example, a powder mixture is prepared, the mixture is granulated or dry-pressed, a lubricant and disintegrant are added, and the entire mixture is squeezed to obtain tablets. The powder mixture is prepared by mixing the compound, ground in a suitable manner, with a diluent or base as described above, optionally with a binder (e.g., carboxymethylcellulose, alginate, gelatin, or polyvinylpyrrolidone), a dissolution retardant (e.g., paraffin), an absorption enhancer (e.g., a quaternary salt), and/or an absorbent (e.g., bentonite, kaolin, or dicalcium phosphate). The powder mixture can be granulated by wetting it with a binder such as syrup, starch paste, acadia mucilage, or a solution of a cellulose or polymeric substance and pressing it through a sieve. As an alternative granulation method, the powder mixture can be passed through a tablet press to form uneven lumps, which are broken up to form granules. To prevent sticking to the tablet mold, the granules can be lubricated by adding stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then extruded to give tablets. The compounds according to the invention can also be mixed with free-flowing inert excipients and then extruded directly to give tablets without a granulation or dry pressing step. A transparent or opaque protective layer may be present comprising a sealing layer of sheet glue, a layer of sugar or polymer material and a wax gloss layer. In order to be able to distinguish different unit doses, dyes may be added to these coatings.

Oral liquids in dosage unit form, for example, solutions, syrups, and elixirs can be prepared so that a given amount contains a predetermined amount of compound. Syrups can be prepared by dissolving the compound in an aqueous solution containing a suitable flavoring, while elixirs are prepared using a non-toxic alcohol carrier. Suspensions can be prepared by dispersing the compound in a non-toxic carrier. Solubilizers and emulsifiers (for example, ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether), preservatives, flavoring additives (for example, peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, etc.) can also be added.

If desired, the oral dosage unit formulation can be enclosed in microcapsules. Extended or delayed release preparations can also be prepared in this way, for example, by coating or embedding particulate materials in polymers, paraffin, etc.

The compounds of Formula I and pharmaceutically acceptable salts, tautomers and stereoisomers thereof can also be administered in the form of liposome delivery systems, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids, for example, cholesterol, octadecylamine or phosphatidylcholines.

The monoclonal antibody (compound molecule is combined with it) as an independent carrier can also be used to deliver the compound of formula I and its salt, tautomer and stereoisomer. The compounds of this invention can also be combined with a soluble polymer as a targeted drug carrier. This polymer can include: polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamidophenol, polyhydroxyethyl asparagine phenol or the polyethylene oxide polylysine substituted with palmitoyl. In addition, the compounds of this invention can further be combined with a biodegradable polymer suitable for obtaining the controlled release of medicine, for example, polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphiphilic hydrogel block copolymers.

Pharmaceutical formulations adapted for transdermal administration may be administered as a separate plaster in prolonged close contact with the epidermis of the recipient, whereby the active ingredient may be delivered from the plaster, for example, by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.

For treatment of the eye or other external tissues, for example, the oral cavity and the skin, the formulation is preferably administered in the form of a topical ointment or cream. Where the formulation is an ointment, the active ingredient may be used with a paraffin or water-miscible cream base. Alternatively, the active ingredient may be formulated with an oil-in-water cream base or a water-in-oil base to produce a cream.

Pharmaceutical formulations adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration to the oral cavity include lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration may be administered as suppositories or as enemas.

Pharmaceutical formulations suitable for nasal administration (wherein the carrier is a solid) include coarse powders having a particle size in the range of, for example, 20-500 microns, which are administered by snorting, i.e., rapid inhalation through the nasal cavity from a powder container held close to the nose. Suitable formulations for administration as nasal sprays or nose drops containing a liquid as a carrier substance include aqueous or oily solutions of the active ingredient.

Pharmaceutical formulations suitable for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of pressurized dispensers with nebulizers, atomizers or insufflators.

Pharmaceutical formulations adapted for vaginal administration may be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations suitable for parenteral administration include water and sterile anhydrous injection solutions, which may contain antioxidants, buffers, antibacterial agents, and solutes to make the formulation isotonic with the blood of the recipient being treated; and water and non-aqueous sterile suspensions, which may contain a suspending medium and a thickening agent. The formulations can be administered in single-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile carrier, for example, water for injection, immediately prior to use. Injectable solutions and suspensions prepared according to the formulation can be prepared using sterile powders, granules, and tablets.

It will be apparent that in addition to the ingredients particularly mentioned above the formulations may include other agents conventional in the art for that particular type of formulation; thus, for example, formulations suitable for oral administration may include flavoring agents.

The therapeutically effective amount of compound of formula I depends on many factors, including, for example, the age and body weight of the animal, the exact disease to be treated and its severity, the characteristics of the preparation and the method of administration, and is ultimately determined by the treating doctor or veterinarian. However, the effective amount according to the compound of the present invention is usually in the scope of 0.1 to 100 mg/kg recipient (mammal) body weight every day, especially typically in the scope of 1 to 10 mg/kg body weight every day. Thus, for an adult mammal weighing 70 kg, the actual quantity every day is usually between 70 and 700 mg, wherein, this quantity of a single dose can be given every day, or (for example, two, three, four, five or six dosages) are usually given every day in the form of a series of partial doses so that total daily dose is identical. The effective amount of its salt or solvate or physiologically functional derivative can be determined according to the effective amount ratio of the compound of the present invention itself. It can be considered that similar dosage is suitable for treating other diseases mentioned above.

This type of combined treatment may be obtained by simultaneous, sequential or separate administration of the individual components of the treatment.Combination products of this type employ the compounds according to the invention.

The invention furthermore relates to medicaments containing at least one compound of the formula I and/or pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient.

The present invention also relates to a device (kit) consisting of the following individually packaged components:

(a) an effective amount of a compound of formula I and/or its pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios,

and

(b) an effective amount of other pharmaceutically active ingredients.

The device comprises a suitable container, such as a box, an independent bottle, a bag or an ampoule. For example, the device can include independent ampoules, each ampoule containing an effective amount of a compound of Formula I and/or its pharmaceutically acceptable salts, tautomers and stereoisomers (including mixtures thereof in all ratios) in dissolved or lyophilized form, and an effective amount of other pharmaceutically active ingredients.

As used herein, "treating" refers to completely or partially alleviating the symptoms associated with a disorder or disease, or slowing or halting the further development or worsening of those symptoms, or preventing or prophylaxis of the disease or condition in a patient at risk of developing the disease or condition.

The term "effective amount" in conjunction with a compound of formula (I) can refer to an amount that completely or partially alleviates the symptoms associated with a condition or disease, or an amount that can slow or halt the further development or worsening of those symptoms, or an amount that can prevent or provide prophylaxis for a disease or condition disclosed herein (e.g., an inflammatory disorder, an immune disorder, a cancer, or a metabolic disorder) in a patient who has or is at risk of developing the disease or condition.

In one embodiment, the effective amount of a compound of formula (I) is the amount that inhibits (e.g., in vitro or in vivo) telomerase in a cell. In some embodiments, an effective amount of a compound of formula (I) inhibits 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99% telomerase in a cell compared to the activity of telomerase in untreated cells. The effective amount of a compound of formula (I), for example, in a pharmaceutical composition, can be at a level that produces the desired effect; for example, in a unit dose for oral and parenteral administration, it can be at a level of about 0.005 mg/kg patient weight to about 10 mg/kg patient weight.

use

The compounds of the present invention are suitable as pharmaceutical active ingredients for mammals, especially humans, for the treatment of cancer, multiple sclerosis, cardiovascular diseases, central nervous system damage and various forms of inflammation.

The present invention includes the use of compounds of formula I and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof for the preparation of medicaments for the treatment or prevention of cancer, multiple sclerosis, cardiovascular disease, central nervous system damage and various forms of inflammation.

Examples of inflammatory diseases include rheumatoid arthritis, psoriasis, contact dermatitis, delayed hypersensitivity reactions, and the like.

Also included is the use of a compound of formula I and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof for the preparation of a medicament for treating or preventing a tankyrase-induced disease or tankyrase-induced condition in a mammal, wherein the method comprises administering to the diseased mammal in need of such treatment a therapeutically effective amount of a compound according to the invention. The therapeutic amount will vary depending on the specific disease and can be determined by one skilled in the art without undue effort.

The term "tankyrase-induced disease or condition" refers to a pathological condition that depends on the activity of one or more tankyrases. Diseases associated with tankyrase activity include cancer, multiple sclerosis, cardiovascular disease, central nervous system damage, and various forms of inflammation.

The invention relates in particular to compounds of the formula I and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for use in the treatment of diseases in which the inhibition, control and/or regulation of tankyrase inhibition plays a role.

The invention particularly relates to compounds of formula I and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for use in inhibiting tankyrases.

The present invention particularly relates to compounds of formula I and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for use in the treatment of cancer, multiple sclerosis, cardiovascular diseases, central nervous system damage and various forms of inflammation.

The present invention particularly relates to a method for treating or preventing cancer, multiple sclerosis, cardiovascular disease, central nervous system damage and various forms of inflammation, which comprises administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt, tautomer, stereoisomer or solvate thereof.

Representative cancers that can be treated or prevented by the compounds of Formula I include, but are not limited to, cancers of the head, neck, eyes, mouth, throat, esophagus, bronchi, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, cervix, breast, ovary, testicles or other reproductive organs, cancers of the skin, thyroid, blood, lymph nodes, kidneys, liver, pancreas, brain, central nervous system, solid tumors and blood-borne tumors.

Representative cardiovascular diseases that can be treated or prevented by the compounds of Formula I include, but are not limited to, restenosis, atherosclerosis and its sequelae, such as stroke, myocardial infarction, ischemic injury to the heart, lung, intestine, kidney, liver, pancreas, spleen or brain.

The present invention relates to a method for treating proliferative, autoimmune, anti-inflammatory or infectious diseases, said method comprising administering a therapeutically effective amount of a compound of formula I to a patient in need thereof.

Preferably, the present invention relates to a method wherein the disease is cancer.

Particularly preferably, the present invention relates to a method wherein the disease is cancer and wherein administration is simultaneous, sequential or staggered with administration of at least one other active pharmaceutical agent.

The disclosed compounds of formula I can be administered in combination with other known therapeutic agents, including anticancer agents. As used herein, the term "anticancer agent" refers to any agent that is administered to a cancer patient to treat the cancer.

The anticancer treatment defined above may be used as a monotherapy or may include, in addition to the compounds of Formula I disclosed herein, conventional surgery or radiation therapy or drug therapy. Such drug therapy, for example, chemotherapy or targeted therapy, may include one or more of the following antineoplastic agents, but preferably one of the following antineoplastic agents:

Alkylating agents

For example, altretamine, bendamustine, busulfan, carmustine, chlorambucil, mechlorethamine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, lomustine, phenylalanine mustard, dibromomannitol, dibromodulcitol, pyrimidine nitrosourea, ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine, carboquinone, apaziquone, fotemustine, glufosfamide, palifosfamide, bisbromopropylpiperazine, clofosfamide, uracil mustard, TH-302 ⁴ , VAL-083 ⁴ ;

Platinum compounds

For example, carboplatin, cisplatin, etaplatin, miriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin;

Lobaplatin, Nedaplatin, Picoplatin, Satraplatin;

DNA-altering agents

For example, amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrin, brostallicin, pixantrone, laromustine ^1,3 ;

Topoisomerase inhibitors

For example, etoposide, irinotecan, aprotinoxate, sobuzoxan, teniposide, topotecan; aminafide, belotecan, elixirsium acetate, voreloxin;

microtubule regulators

For example, cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabulin, tesetaxel;

metabolic antagonists

For example, asparaginase ³ , azacitidine, leucovorin, capecitabine, cladribine, cytarabine, enocitabine, azauridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed, sapacitabine, tegafur ^2,3 , trimetrexate;

anticancer antibiotics

For example, bleomycin, actinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozotocin, valrubicin, jinsistatin, daunorubicin, plicamycin; aclarubicin, peclorubicin sulfate, pirarubicin;

Hormones/antagonists

For example, abarelix, abiraterone, bicalutamide, buserelin, captestosterone, chlorethoxyquin, degarelix, dexamethasone, estradiol, fluocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol acetate, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyroxine alfa, toremifene citrate, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, cyclothiocarbamate, orteronel, enzalutamide ^1,3 ;

Aromatase inhibitors

For example, aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane;

Small molecule kinase inhibitors

For example, crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enza staurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tipifarnib, tivantinib, tivozanib, trametinib, pimasertib, brivanib, cediranib, apatinib ⁴ , Cabozantinib S-malate ^1,3 , ibrutinib ^1,3 , icotinib ^{4 , buparlisib 2 ,} cipatinib ⁴ , cobimetinib ^1,3 , idelalisib ^1,3 , fedratinib ¹ , XL-647 ⁴ ;

photosensitizers

For example, methoxyfuroxine ³ ; porfimer sodium, talaporfin, temoporfin;

Antibody

For example, alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, and pertuzumab ^2,3 Catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab 1,2,3 , onartuzumab ^1,3 , racotumomab1, tabalumab ^1,3 , EMD-525797 ^{4 ,} nivolumab ^1,3 ;

Cytokines

For example, aldesleukin, interferon alfa ² , interferon alfa2a ³ , interferon alfa2b ^2,3 ; simoleukin, tasonermin, teceleukin, oprelvekin ^1,3 , recombinant interferon beta-1a ⁴ ;

Drug conjugates

For example, denileukin diftitox, ibritumomab tiuxetan, iodobenzylguanidine sulfate I123, phenylephrine, trastuzumab emtansine, estramustine, gemtuzumab, ozogamicin, aflibercept, cintredekin besudotox, edotreotide, inotuzumabozogamicin, naptumomab estafenatox, oportuzumab monatox, technetium (99mTc) acitumomab ^1,3 , vintafolide ^1,3 ;

vaccine

For example, sipuleucel ³ ; vitespen ³ , emepepimut-S ³ , oncoVAX ⁴ , rindopepimut ³ , troVax ⁴ , MGN-1601 ⁴ , MGN-1703 ⁴ ;

other

alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, mushroom polysaccharides, metirosine, mifamurtide, pamidronate, pegaptase, pentostatin, sipuleucel ³ , sizoran, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat; Celebrex, cilengitide, entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib, lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin, pomalidomide, procodazol, ridaforolimus, tasquinimod, telotristat, thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar, ^Gendicine , picibanil ⁴ , reolysin ⁴ , retaspimycin hydrochloride ^1,3 , trebananib ^2,3 , virulizin ⁴ , carfilzomib ^1,3 , endostatin ⁴ , immucothel ⁴ , belinostat ³ , MGN-1703 ⁴ ;

¹ Prop. INN (Proposed International Nonproprietary Name)

² Rec. INN (Recommended International Nonproprietary Names)

³ USAN (United States Adopted Name)

⁴ no INN.

The following abbreviations refer to the following definitions:

aq (aqueous solution), h (hour), g (gram), L (liter), mg (milligram), MHz (megahertz), min. (minute), mm (millimeter), mmol (millimole), mM (millimolar), mp (melting point), eq (equivalent), mL (milliliter), L (microliter), ACN (acetonitrile), AcOH (acetic acid), CDCl ₃ (deuterated chloroform), CD ₃ OD (deuterated methanol), CH ₃ CN (acetonitrile), c-hex (cyclohexane), DCC (dicyclohexylcarbodiimide), DCM (dichloromethane), DIC (diisopropylcarbodiimide), DIEA (diisopropylethylamine), DMF (dimethylformamide), DMSO (dimethyl sulfoxide), DMSO-d ₆ (deuterated dimethyl sulfoxide), EDC (1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI (electrospray ionization), EtOAc (ethyl acetate), Et ₂ O (diethyl ether), EtOH (ethanol), HATU (dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate), HPLC (high performance liquid chromatography), i-PrOH (2-propanol), K ₂ CO ₃ (potassium carbonate), LC (liquid chromatography), MeOH (methanol), MgSO ₄ (magnesium sulfate), MS (mass spectrometry), MTBE (methyl tert-butyl ether), NaHCO ₃ (sodium bicarbonate), NaBH _{4 (} sodium borohydride), NMM (N-methylmorpholine), NMR (nuclear magnetic resonance), PyBOP (benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), RT (room temperature), Rt (retention time), SPE (solid phase extraction), TBTU (2-(1-H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TLC (thin layer chromatography), UV (ultraviolet).

Description of in vitro tests

Abbreviations:

GST = glutathione-S-transferase

FRET = Fluorescence Resonance Energy Transfer

HTRF® = (Homogeneous Time-Resolved Fluorescence)

HEPES = 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer

DTT = dithiothreitol

BSA = bovine serum albumin

CHAPS = detergent;

CHAPS = 3-[(3-cholamidopropyl)dimethylammonium]-1-propanesulfonate.

Streptavidin-XLent® is an advanced streptavidin-XL665 conjugate whose coupling conditions have been optimized to yield a conjugate with improved performance for certain assays, particularly those requiring high sensitivity.

Determination of cellular inhibition of tankyrase

Since Tankyrases have been described to regulate cellular levels of Axin2 (Huang et al., 2009; Nature), the increase in Axin2 levels was used as a readout to determine cellular inhibition of Tankyrases in the Luminex-based assay.

DLD1 colon cancer cell line cells were plated in 96-well plates at 1.5 x ^10⁴ cells per well. The next day, cells were treated with test compounds serially diluted in seven steps in triplicate, with a final DMSO concentration of 0.3%. After 24 hours, cells were lysed in lysis buffer (20 mM Tris/HCl, pH 8.0, 150 mM NaCl, 1% NP40, 10% glycerol) and the lysates were cleared by centrifugation through 96-well filter plates (0.65 µm). Axin2 protein was isolated from the cell lysates by incubation with a monoclonal anti-Axin2 antibody (R & D Systems #MAB6078) conjugated to fluorescent carboxybeads. Bound Axin2 was then specifically detected using a polyclonal anti-Axin2 antibody (Cell Signaling #2151) and an appropriate PE-fluorescent secondary antibody. The amount of isolated Axin2 protein was determined by counting 100 conditions per well in a Luminex ²⁰⁰ instrument (Luminex Corporation) according to the manufacturer's instructions. Test compounds inhibit tankyrase, resulting in higher levels of Axin2, which is directly related to an increase in detectable fluorescence. As controls, cells were treated with solvent alone (neutral control) and with the tankyrase reference inhibitor IWR-2 (3E-06 M) as a control for maximum increase in Axin2. For analysis, the data obtained were normalized to the untreated solvent control using AssayExplorer software (Accelrys) and fitted to the measured EC50 values.

Description of the PARP1 trial

PARP-1 biochemical activity test: Autoparsylation test

The auto-PARylation assay is a two-step process: an enzyme reaction in which His-tagged Parp-1 transfers biotinylated ADP-ribose/ADP-ribose from biotinylated NAD/NAD (as a co-substrate) to itself; and a detection reaction in which time-resolved FRET is analyzed between a cryptate-labeled anti-His antibody bound to the enzyme's His tag and the biotin-PARylated residue bound to Xlent®-labeled streptavidin. Auto-PARylation activity is directly detected by an increase in the HTRF signal.

The automated PARylation assay was performed in a 384-well HTRF® (Cisbio, Codolet, France) assay format in Greiner low-volume nb 384-well microplates. A mixture of 35 nM His-tagged Parp-1 (human, recombinant, Enzo Life Sciences GmbH, Lörrach, Germany) and 125 nM bio-NAD (Biolog, Life science Inst., Bremen, Germany) with 800 nM NAD as a co-substrate was incubated in the absence or presence of test compounds (10 dilutions) at 23°C for 150 min in a total volume of 6 µl (100 mM Tris/HCl, 4 mM MgCl2, 0.01% IGEPAL® CA630, 1 mM DTT, 0.5% DMSO, pH 8, 13 ng/µl activated DNA (BPS Bioscience, San Diego, US). The reaction was terminated by adding 4 µl of stop/detection solution (70 nM SA-Xlent® (Cisbio, Codolet, France), 2.5 nM anti-His-K® (Eu-labeled anti-His, Cisbio, Codolet, France) in 50 mM HEPES, 400 mM KF, 0.1% BSA, 20 mM EDTA, pH 7.0). After incubation for 1 hour at room temperature, HTRF was measured using an Envision multimode reader (Perkin Elmer LAS Germany GmbH) with excitation at 340 nm (laser mode) and emission at 615 nm and 665 nm. The ratio of the emission signal was determined. The full value used was the reaction without inhibitor. The pharmacological zero value used was olaparib (LClabs, Woburn, US) at a final concentration of 1 µM. Inhibition values (IC50 values) were determined using the programs Symyx AssayExplorer® or Condosseo® (available from GeneData).

Description of TNKS1 and TNKS2 ELISA assays

Biochemical activity test of TNKS 1 and 2: Activity ELISA (automated PAR assay)

To analyze the auto-PARylation activity of TNKS 1 and 2, an activity ELISA was performed: In the first step, GST-tagged TNKS was collected on glutathione-coated plates. Subsequently, activity was assayed using biotinylated NAD in the absence or presence of the compound. During the enzymatic reaction, GST-tagged TNKS transfers biotinylated ADP-ribose from biotinylated NAD (as a co-substrate) to itself. For detection, a streptavidin-HRP conjugate was added, allowing it to bind to the biotinylated TNKS and thus be collected on the plate. The amount of biotinylated, resp. auto-PARylated TNKS was detected using a fluorescent substrate for HRP. The level of fluorescent signal directly correlates with the amount of auto-PARylated TNKS and, therefore, the activity of the TNKS.

Activity ELISAs were performed in 384-well glutathione-coated microplates (Express capture glutathione-coated plates, Biocat, Heidelberg, Germany). The plates were pre-equilibrated with PBS. The plates were then incubated overnight at 4°C with 50 μl of 20 ng/well of GST-tagged Tnks-1 (1023-1327 aa, prepared in-house) and GST-tagged Tnks-2 (873-1166 aa, prepared in-house) in assay buffer (50 mM HEPES, 4 mM MgCl2, 0.05% Pluronic F-68, 2 mM DTT, pH 7.7). The plates were washed three times with PBS-Tween-20. The wells were blocked by incubating with 50 μl of blocking buffer (PBS, 0.05% Tween-20, 0.5% BSA) for 20 minutes at room temperature. The plates were then washed three times with PBS-Tween-20. The enzyme reaction was allowed to proceed for 1 hour at 30°C in the absence or presence of test compounds (10 dilutions) in 50 µl of reaction solution (50 mM HEPES, 4 mM MgCl2, 0.05% Pluronic F-68, 1.4 mM DTT, 0.5% DMSO, pH 7.7) containing 10 µM bio-NAD (Biolog, Lifescience Inst., Bremen, Germany) as a co-substrate. The reaction was terminated by washing three times with PBS-Tween-20. For detection, 50 µl of 20 ng/µl streptavidin was added with HRP conjugate (MoBiTec, Göttingen, Germany) in PBS/0.05% Tween-20/0.01% BSA, and the plate was incubated at room temperature for 30 minutes. After washing three times with PBS-Tween-20, 50 µl of SuperSignal ELISA Femto Maximum Sensitivity Substrate Solution (ThermoFisher Scientific (Pierce), Bonn, Germany) was added. After incubation at room temperature for 1 minute, the fluorescence signal was measured at 700 nm using an Envision multimode reader (Perkin Elmer LAS Germany GmbH). The full value used was the reaction without inhibitor. The pharmacological zero value used was XAV-939 (Tocris) at a final concentration of 5 µM. Inhibition values (IC50 values) were determined using the programs Symyx Assay Explorer® or Condosseo® (available from GeneData).

Above and below, all temperatures are expressed in °C. In the following examples, "conventional workup" means: adding water, if necessary, adjusting the pH to between 2 and 10, if necessary, depending on the composition of the final product, extracting the mixture with ethyl acetate or dichloromethane, separating the phases, drying the organic phase over sodium sulfate, evaporating, and purifying the residue by silica gel chromatography and/or by crystallization. Rf values on silica gel; eluent: 9:1 ethyl acetate/methanol.

^1H NMR spectrometers were recorded on a Bruker DPX-300, DRX-400, or AVII-400 spectrometer using the residual signal of the deuterated solvent as an internal standard. Chemical shifts (δ) are reported in ppm relative to the residual solvent signal (δ = 2.49 ppm for ^1H NMR in DMSO- _d6 ). ^1H NMR data are reported as follows: chemical shift (multiplicity, coupling constant, and hydrogen number). Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

Microwave chemistry was performed on a CEM microwave reactor.

HPLC/MS Condition A

Column: Chromolith PerformanceROD RP-18e, 100 x 3 mm ²

Gradient: A:B = 9:1 to 0:100, 1.8 min

Flow rate: 2.0 mL/min

Eluent A: water + 0.05% formic acid

Eluent B: acetonitrile + 0.04% formic acid

Wavelength: 220 nm

Mass spectrometry: positive ion mode

HPLC/MS Condition B

Column: XBridge C8, 3.5 µm, 4.6 x 50 mm

Gradient: 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min: 5% B

Flow rate: 2.0 mL/min

Eluent A: water + 0.1% TFA

Eluent B: acetonitrile + 0.1% TFA

HPLC/MS Conditions C:

Gradient: A:B = 96:4 to 0:100, 3.4 min; flow rate: 2.40 ml/min

A: Water + Formic acid (0.05%); B: Acetonitrile + Formic acid (0.04%)

Column: Chromolith SpeedROD RP-18e, 50 x 4.6 mm ²

Wavelength: 220 nm.

Pharmacology data

Table 1: Some representative compounds of formula I inhibit tankyrases

The compounds shown in Table 1 are particularly preferred compounds according to the invention.

Table 2: Some representative compounds of formula I inhibit tankyrases

The compounds shown in Table 2 are particularly preferred compounds according to the invention.

Synthesis of intermediates

Synthesis of 4-(6,8-difluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-butyric acid

A mixture of 2-amino-3,5-difluoro-benzamide (1.72 g, 10.0 mmol) and glutaric anhydride (1.48 g, 13.0 mmol) in toluene (37 ml) was refluxed for 2 days. The solvent was removed in vacuo, and 2N NaOH (25 ml) was added. The resulting suspension was heated to 80°C and stirred at this temperature for 1 day. The mixture was cooled to room temperature and acidified to pH 5 with acetic acid. The solid was collected by filtration, washed with water, and dried in vacuo to provide light brown crystals of 4-(6,8-difluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-butyric acid; HPLC/MS 1.48 min (A), [M+H] 269.

4-(4-Oxo-3,4-dihydro-quinazolin-2-yl)-butyric acid was prepared similarly as a beige solid; HPLC/MS 1.37 min (A), [M+H] 233.

Synthesis of 4-(6-fluoro-8-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)-butyric acid

A mixture of 2-amino-5-fluoro-3-methyl-benzamide (1.56 g, 9.3 mmol) and glutaric anhydride (1.38 g, 12.1 mmol) in toluene (32 ml) was refluxed for 3 hours. The mixture was cooled to room temperature and stirred for 9 days. The solid was collected by filtration, washed with toluene, and dried under vacuum to provide white crystals of 4-(6-fluoro-8-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)-butyric acid; HPLC/MS 1.63 min (A), [M+H] 265;

¹ H NMR (400 MHz, DMSO-d ₆ )δ 12.25(bs, 1H), 7.80 – 7.38(m, 2H), 2.65(t, J =7.4 Hz, 2H), 2.53(s, 3H), 2.34(t, J =7.3 Hz, 2H), 1.98(p, J =7.4 Hz, 2H).

4-(6-Fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-butanoic acid was prepared similarly as a white solid; LC/MS(B): 251.3 (M+H), Rt 1.91 min, ¹ H NMR (400 MHz, DMSO-d ₆ )δ 11.82(brs, 1H), 7.73(dd, J =1.8, 8.6 Hz, 1H), 7.66-7.64(m, 2H), 2.62(t, J =7.4 Hz, 2H), 2.27(t, J =7.4 Hz, 2H), 1.95-1.91(m, 2H).

4-(8-Fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-butanoic acid was prepared similarly as a colorless solid; LC/MS(B): 251.3 (M+H), Rt 2.05 min, ¹ H NMR (400 MHz, DMSO-d ₆ )δ 12.36(bs, 1H), 11.90(bs, 1H), 7.88-7.87(d, J =7.8 Hz, 1H), 7.66-7.61(dd, J =8.2, 6.9 Hz, 1H), 7.45-7.40(m, 1H), 2.67-2.63(m, 2H), 2.33-2.30(m, 2H), 1.99-1.96(m, 2H).

Synthesis of (4-methoxy-3-methyl-phenyl)-piperidin-4-yl-methanone hydrochloride

To a solution of mono-tert-butyl piperidine-1,4-dicarboxylate (25.00 g, 107.72 mmol) in DMF (250 ml) were added N,N-diisopropylethylamine (57.01 ml, 323.16 mmol), 1-hydroxybenzotriazole hydrate (1.67 g, 10.77 mmol), and (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (25.03 g, 129.27 mmol). Subsequently, O,N-dimethylhydroxylamine hydrochloride (11.68 g, 118.49 mmol) was added in small portions at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (300 ml) and washed with 10% sodium bicarbonate (2 x 200 ml), 0.5N HCl (2 x 100 ml), water (200 ml) and brine (200 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to provide 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester as a colorless liquid;

¹ H NMR (400 MHz, CDCl ₃ ): δ 4.15-4.09(m, 2H), 3.70(s, 3H), 3.17(s, 3H), 2.79-2.72(m, 3H), 1.72-1.60(m, 4H), 1.44(s, 9H);

LC/MS (Method B): 173.2 (M+H; BOC-cleaved mass), Rt. 3.54 min.

Under a nitrogen atmosphere, iodine (0.93 mg) dissolved in THF (40 ml) and 5 ml of 4-bromo-2-methylanisole (5.96 g, 29.06 mmol) were added to a suspension of magnesium turnings (0.72 g, 29.06 mmol) in anhydrous THF (40 ml). The mixture was stirred at room temperature for 15 minutes and then warmed to 50°C. The mixture was cooled to room temperature, and the remaining 4-bromo-2-methylanisole in THF was added dropwise over 20 minutes. The mixture was stirred at room temperature for an additional 2 hours to allow the magnesium to completely dissolve. The Grignard reagent solution was added dropwise to a solution of tert-butyl 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylate (4.00 g, 14.53 mmol) in THF (40.00 ml) at -78°C. The reaction mixture was stirred at room temperature for 15 hours. Then, it was cooled to 0 ° C, quenched with saturated ammonium chloride solution (100 ml), and extracted with ethyl acetate (2 x 100 ml). The organic layer was washed with 10% sodium bicarbonate (100 ml), water (100 ml) and brine (100 ml), dried over anhydrous Na ₂ SO ₄ , and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (230-400) with petroleum ether/ethyl acetate (0-30%) as a gradient eluent to provide a colorless solid of tert-butyl 4-(4-methoxy-3-methyl-benzoyl)-piperidine-1-carboxylate;

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.82(dd, J =2.2, 8.6 Hz, 1H), 7.76(d, J =1.6Hz, 1H), 6.86(d, J =8.6 Hz, 1H), 4.17(d, J =13.0 Hz, 2H), 3.90(s, 3H), 3.41-3.34(m, 1H), 2.93-2.86(m, 2H), 2.26(s, 3H), 1.83-1.80(m, 2H), 1.76-1.65(m,2H), 1.45(s, 9H):

LC/MS (Method B): 234.3 (M+H; BOC-cleavage mass), Rt. 5.31 min.

A solution of tert-butyl 4-(4-methoxy-3-methyl-benzoyl)-piperidine-1-carboxylate (1.50 g, 4.36 mmol) in dioxane/HCl (3M, 14.53 ml, 43.60 mmol) was stirred at room temperature under nitrogen for 6 hours. The solvent was evaporated to dryness under reduced pressure to provide (4-methoxy-3-methyl-phenyl)-piperidin-4-yl-methanone hydrochloride as a colorless solid;

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.25(brs, 1H), 8.92(brs, 1H), 7.90(dd, J =2.2, 8.6 Hz, 1H), 7.81(d, J =1.6 Hz, 1H), 7.05(d, J =8.6 Hz, 1H), 3.87(s, 3H),3.75-3.67(m, 1H), 3.29-3.25(m, 2H), 3.06-2.97(m, 2H), 2.19(s, 3H), 1.89-1.86(m, 2H), 1.81-1.78(m, 2H);

LC/MS (Method B): 234.3 (M+H), Rt. 2.65 min.

The following compounds were prepared similarly:

Piperidin-4-yl-m-tolyl-methanone hydrochloride

Colorless amorphous solid;

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.27(brs, 1H), 8.98(brs, 1H), 7.80(d, J =8.4 Hz, 2H), 7.48-7.40(m, 2H), 3.79-3.71(m, 1H), 3.27(d, J =12.6 Hz, 2H), 3.06-2.97(m, 2H), 2.38(s, 3H), 1.92-1.89(m, 2H), 1.81-1.74(m, 2H).

LC/MS (Method B): 204.3 (M+H), Rt. 2.48 min;

(3-Methoxy-phenyl)-piperidin-4-yl-methanone hydrochloride

Colorless solid;

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.15(brs, 1H), 8.83(brs, 1H), 7.60(d, J =7.9 Hz, 1H), 7.47(t, J =7.9 Hz, 2H), 7.24(dd, J =2.6, 8.2 Hz, 1H), 7.22(s, 3H),3.79-3.73(m, 1H), 3.30-3.27(m, 2H), 3.10-2.95(m, 2H), 1.94-1.91(m, 2H), 1.81-1.71(m, 2H);

LC/MS (Method B): 220.3 (M+H), Rt. 2.19 min;

(3-Fluoro-4-methoxy-phenyl)-piperidin-4-yl-methanone hydrochloride

Colorless amorphous solid;

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.17(brs, 1H), 8.86(brs, 1H), 7.89-7.81(m,2H), 7.31(t, J =8.5 Hz, 1H), 3.93(s, 3H), 3.74-3.68(m, 1H), 3.29-3.26(m, 2H), 3.05-2.96(m, 2H), 1.91-1.88(m, 2H), 1.80-1.73(m, 2H).

LC/MS (Method B): 238 (M+H), Rt. 2.32 min.

Synthesis of (4-bromo-phenyl)-piperidin-4-yl-methanone

At room temperature, under a nitrogen atmosphere, a mixture of 1-acetyl-piperidine-4-carboxylic acid (10.00 g, 57.24 mmol) and thionyl chloride (20.85 g, 171.73 mmol) was stirred for 6 hours. The thionyl chloride was removed under reduced pressure, and the residue was co-distilled with dichloromethane (2 x 200 ml). Then, at 0 ° C, under a nitrogen atmosphere, the acid chloride was added dropwise to a suspension of bromobenzene (27.24 g, 171.73 mmol) and anhydrous aluminum chloride (9.25 g, 68.69 mmol) in 1,2-dichloroethane (200 ml). The resulting mixture was stirred at room temperature for 16 hours, quenched in ice, and extracted with dichloromethane (2 x 200 ml). The organic layer was washed with water (2 x 200 ml), brine (200 ml), dried over anhydrous Na ₂ SO ₄ , and evaporated in vacuo. The resulting black residue was taken up in 6M aqueous HCl (200 ml), refluxed for 12 hours, and concentrated to half its original volume. The aqueous portion was basified with 10% sodium bicarbonate, extracted with dichloromethane (2 x 200 ml), washed with water (2 x 200 ml), brine (200 ml), dried over anhydrous Na ₂ SO ₄ , and evaporated in vacuo. The crude product was purified by column chromatography on silica gel (60-120) using a gradient of dichloromethane/methanol to provide (4-bromo-phenyl)-piperidin-4-yl-methanone as a yellow gum.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.95-7.92 (m, 2H), 7.78-7.74 (m, 2H), 3.71-3.68 (m, 1H), 3.25-3.22 (m, 2H), 2.98-2.92 (m, 2H), 1.90-1.87 (m, 2H), 1.76-1.70 (m, 2H); LC/MS (method B): 268/270 (M+H), Rt. 2.73 min.

Synthesis of (6-methoxy-pyridin-3-yl)-piperidin-4-yl-methanone hydrochloride

1.1: 4-(6-Methoxy-pyridine-3-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 5-bromo-2-methoxy-pyridine (6.60 g; 34.40 mmol) in THF (132 ml) was added n-butyllithium (1.6 M in hexane) (25.80 ml; 41.28 mmol) dropwise at -78°C under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hour. A solution of tert-butyl 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylate (10.52 g; 37.84 mmol) in THF (25 ml) was added dropwise at -78°C, and the mixture was stirred at -78°C for 4 hours. The reaction mixture was then allowed to slowly reach room temperature and stirred for 12 hours. The reaction mixture was quenched with saturated _NH4Cl (250 mL) and extracted with ethyl acetate (2 x 300 ml). The combined organic layers were washed with water (200 ml), brine solution (200 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified using silica gel (60-120) column chromatography with petroleum ether/ethyl acetate as gradient eluent to provide 4-(6-methoxy-pyridine-3-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (5.00 g; 44.5%) as a light yellow oil;

¹ H NMR(400 MHz, CDCl ₃ )δ 8.80(d, J =2.3 Hz, 1H), 8.14(dd, J =2.4, 8.7 Hz,1H), 6.82(d, J =8.8 Hz, 1H), 4.20-4.17(m, 2H), 4.02(s, 3H), 3.35-3.27(m, 1H),2.92-2.86(m, 2H), 1.85-1.82(m, 2H), 1.76-1.66(m, 2H), 1.47(s, 9H);

LC/MS(B): 265 (M+H; BOC-fragmentation mass), Rt: 4.64 min.

1.2: (6-Methoxy-pyridin-3-yl)-piperidin-4-yl-methanone hydrochloride

Colorless solid; LC/MS (Method B): 221.0 (M+H), Rt 1.84 min;

¹ H NMR(400 MHz, DMSO-d ₆ )δ 9.21(s, 1H), 8.91(d, J =1.08 Hz, 2H), 8.23-8.20(m, 1H), 6.95(d, J =8.76 Hz, 1H), 6.55(bs, 3H), 6.09(bs, 2H), 3.94(s, 3H), 3.78-3.67(m, 1H), 3.29-3.26(m, 2H), 3.04-2.95(m, 2H), 1.93-1.90(m, 2H), 1.82-1.71(m, 2H).

(1-Methyl-1H-pyrazol-4-yl)-piperidin-4-yl-methanone hydrochloride

Under argon, 4-iodo-1-methyl-1H-pyrazole (1.12 g; 5.385 mmol) and tert-butyl 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylate (1.47 g; 5.385 mmol) were dissolved in anhydrous THF (15 ml). While stirring, the clear, pale yellow solution was cooled to -60°C, and butyllithium (15% solution in n-hexane) (3.72 ml; 5.923 mmol) was added dropwise at this temperature over 10 minutes. The reaction mixture was stirred between -60 and -45°C for 30 minutes, then slowly warmed to room temperature and stirred for 14 hours. The reaction mixture was cooled to 0°C, quenched with 10% citric acid solution, diluted with ethyl acetate (70 ml), washed with water and brine, _dried over _Na₂SO₄ , filtered, and evaporated to dryness.

The oily residue was purified by flash chromatography (Companion RF; 120 g Si50 silica gel column); yield: 999 mg (63%) of a light green oil (purity: 99.4; Rt: 2.33 min); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 7.94 (d, J =0.7 Hz, 1H), 3.97 (d, J =12.6 Hz, 2H), 3.87 (s, 3H), 3.15 (tt, J =11.4,3.6 Hz, 1H), 2.93 – 2.75 (m, 2H), 1.76 – 1.67 (m, 2H), 1.33-1.46 (m, 11H); LC/MS(C), Rt: 1.93 min; 238.1 (M+H; BOC-fragmentation mass).

Boc-cleavage afforded the title compound as a colorless solid; LC/MS (C): 194.2 (M+H), Rt: 0.34/0.47 min.

(1-Methyl-1H-imidazol-2-yl)-piperidin-4-yl-methanone dihydrochloride

Prepared in a manner similar to that described above; yield: 484 mg (96%) of a colorless solid; LC/MS (C): 194.2 (M+H), Rt: 0.47/0.61 min.

Synthesis of 6-amino-1',2',3',4',5',6'-hexahydro-[3,4']bipyridine-5-carbonitrile dihydrochloride

1.1: 2-amino-5-bromo-nicotinonitrile

To a solution of 2-amino-nicotinonitrile (0.50 g; 4.11 mmol) in acetic acid (10 ml) at 0°C was added sodium carbonate (0.48 g; 4.52 mmol), followed by the dropwise addition of bromine (0.74 g; 4.52 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The solvent was evaporated in vacuo, and the residue was suspended in water (50 ml), filtered, and dried to provide the title compound (0.60 g; 73%). The product was used in the next step without further purification; ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.26 (d, J = 2.5 Hz, 1H), 8.14 (d, J = 2.5 Hz, 1H), 7.13 (brs, 2H); LC/MS(B), Rt: 2.59 min; (M+2H)200.

1.2: tert-Butyl 6-amino-5-cyano-3',6'-dihydro-2'H-[3,4']bipyridine-1'-carboxylate

To a solution of 2-amino-5-bromo-nicotinonitrile (0.60 g; 3.02 mmol) in dioxane (24 ml) and water (6 ml) was added tert-butyl 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.04 g; 3.32 mmol) and _Na₂CO₃ ( _0.98 g; 9.05 mmol), and the mixture was degassed for 30 minutes. 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.13 g; 0.15 mmol) was added, and the reaction mixture was heated to 90°C for 10 hours. The reaction mixture was cooled to ambient temperature, filtered through celite, and the solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether and ethyl acetate (5:5) to provide the title compound (450.0 mg; 50%) as a light yellow solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (d, J =2.5 Hz, 1H), 7.92 (d, J =2.5 Hz, 1H), 6.92 (s, 2H), 6.08 (s, 1H), 3.94 (s, 2H), 3.49 (t, J =5.6 Hz, 2H), 2.37 (d, J =1.5 Hz, 2H), 1.40 (s, 9H); LC/MS(B), Rt: 3.50 min; (M+H)301.2.

1.3: tert-Butyl 6-amino-5-cyano-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate

Tert-butyl 6-amino-5-cyano-3',6'-dihydro-2'H-[3,4']bipyridine-1'-carboxylate (5.00 g; 16.63 mmol) was dissolved in methanol (150 ml) and hydrogenated with palladium on carbon (10% w/w) (1.77 g; 1.66 mmol) for 15 hours. The reaction mixture was concentrated and the residue was used in the next step without further purification; yield: 4.50 g (87%) of a light yellow solid (purity: 97%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.11 (d, J =2.4 Hz, 2H), 7.76 (d, J =2.4 Hz, 2H), 4.05-4.01 (m, 2H), 2.85-2.55 (m, 2H), 2.59-2.53 (m, 1H), 1.67 (d, J =12.2 Hz, 2H), 1.47-1.38 (m, 11H); LC/MS(B), Rt: 3.27 min; (M+H-tert-butyl) 247.

1.4: 6-Amino-1',2',3',4',5',6'-hexahydro-[3,4']bipyridine-5-carbonitrile dihydrochloride

To a solution of tert-butyl 6-amino-5-cyano-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate (4.50 g; 14.43 mmol) in 1,4-dioxane (45 ml) was added HCl (4M in 1,4-dioxane) (10.82 ml; 43.30 mmol) at 0°C, and the reaction was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to provide the title compound (3.50 g; 85%) as a colorless solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.22-8.95 (m, 2H), 8.15-7.98 (m, 5H), 3.38-3.29 (m, 2H), 2.95-2.87 (m, 2H), 2.85-2.70 (m, 1H), 1.92-1.81 (m,2H), 1.80-1.58 (m, 2H); LC/MS(B), Rt: 2.13 min; (M+H)203.2.

Synthesis of 5-pyrimidin-2-yl-1',2',3',4',5',6'-hexahydro-[3,4']bipyridin-6-ylamine hydrochloride

1.1: 2-(2-Fluoro-pyridin-3-yl)-pyrimidine

To a solution of (2-fluoro-3-pyridyl)boronic acid (6.00 g; 40.45 mmol) in 1,4-dioxane (108 ml) and water (12 ml) was added 2-bromo-pyrimidine (6.56 g; 40.45 mmol) and Na ₂ CO ₃ (13.12 g; 121.36 mmol), and the solution was degassed for 30 minutes. Then, 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1.70 g; 2.02 mmol) was added, and the reaction mixture was heated to 90°C for 6 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether and ethyl acetate (8:2) to provide the title compound (3.00 g; 42%) as an off-white solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.99 (d, J =4.9 Hz, 2H), 8.57 (t, J =9.8 Hz, 1H), 8.39 (d, J =8.0 Hz, 1H), 7.57-7.52 (m, 2H); LC/MS(B), Rt: 1.77 min; (M+H)176.

1.2: 3-pyrimidin-2-yl-pyridin-2-ylamine

To a solution of 2-(2-fluoro-pyridin-3-yl)-pyrimidine (11.0 g; 62.55 mmol) in THF (110 ml) was added ammonia (6M in THF) (330 ml) at -20°C. The reaction mixture was heated to 70°C in an autoclave for 40 hours. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (230-400) with petroleum ether-ethyl acetate (2:8) as eluent to afford the title compound (6.50 g; 60%) as an off-white solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (d, J =4.9 Hz, 2H), 8.64 (d, J =7.8 Hz, 1H), 8.12 (d, J =6.6 Hz, 1H), 7.40 (t, J =4.8 Hz, 1H), 6.70-6.67 (m, 1H); LC/MS(B), Rt: 1.49 min; (M+H)173.

1.3: 5-Bromo-3-pyrimidin-2-yl-pyridin-2-ylamine

To a solution of 3-pyrimidin-2-yl-pyridin-2-ylamine (6.30 g; 36.22 mmol) in acetonitrile (315 ml) was added NBS (7.89 g; 43.47 mmol) at 0°C under a nitrogen atmosphere over 5 minutes. The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to 50 ml and then filtered hot. The residue was washed with petroleum ether to provide 5-bromo-3-pyrimidin-2-yl-pyridin-2-ylamine (8.50 g; 93%) as a yellow solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (d, J =4.9 Hz, 2H), 8.72 (s, 1H), 8.20 (d, J =2.6 Hz, 1H), 7.46 (t, J =4.9 Hz, 1H); LC/MS(B), Rt: 2.25 min; (M+2H)253/255.

1.4: tert-Butyl 6-amino-5-pyrimidin-2-yl-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylate

To a solution of 5-bromo-3-pyrimidin-2-yl-pyridin-2-ylamine (4.80 g; 19.03 mmol) in 1,4-dioxane (192 ml) and water (48 ml) was added tert-butyl 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (6.54 g; _20.94 mmol) and _Na₂CO₃ (6.18 g; 57.10 mmol), and the solution was degassed for 30 minutes. Then, 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.80 g; 0.95 mmol) was added to the reaction mixture, and the mixture was heated to 90°C for 10 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography using petroleum ether-ethyl acetate (5:5) to provide the title compound (6.20 g; 90%) as a light yellow solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (s, 2H), 8.70 (s, 1H), 8.27 (s, 1H), 7.94 (bs, 2H), 7.42 (t, J =4.8 Hz, 1H), 6.06 (s, 1H), 3.98-3.98 (m, 2H), 3.56-3.53 (m, 2H), 2.49-2.48 (m, 2H), 1.42 (s, 9H); LC/MS(B), Rt: 3.52 min; (M+H)354.2.

1.5: tert-Butyl 6-amino-5-pyrimidin-2-yl-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate

Tert-butyl 6-amino-5-pyrimidin-2-yl-3',6'-dihydro-2'H-[3,4']bipyridine-1'-carboxylate (1.20 g; 3.31 mmol) was dissolved in methanol (36 ml) and hydrogenated with palladium/carbon (10% w/w) (0.24 g; 0.23 mmol) at room temperature for 10 hours. The reaction mixture was evaporated to dryness to provide the title compound (1.00 g; 77%) as a light yellow solid; LC/MS (B), Rt: 3.51 min; (M+H) 356.3.

1.6: 5-Pyrimidin-2-yl-1',2',3',4',5',6'-hexahydro-[3,4']bipyridin-6-ylamine hydrochloride

To a solution of tert-butyl 6-amino-5-pyrimidin-2-yl-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylate (1.00 g; 2.54 mmol) in 1,4-dioxane (10 ml) was added HCl (4M in 1,4-dioxane) (5.00 ml; 20.00 mmol) at 0°C, and the reaction was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to provide 5-pyrimidin-2-yl-1',2',3',4',5',6'-hexahydro-[3,4']bipyridin-6-ylamine hydrochloride (0.80 g; 94%) as a yellow solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.15-9.14 (m, 1H), 9.05-9.02 (m, 3H), 8.95-8.92 (m, 1H), 8.14 (s, 1H), 7.62 (t, J =4.9 Hz, 1H), 3.38-3.35 (m, 1H), 2.98-2.93 (m, 3H), 2.01-1.98 (m, 2H), 1.92-1.82 (m, 2H); LC/MS(B), Rt: 1.31 min;(M+H)256.2.

Synthesis of [4-(1-hydroxy-1-methyl-ethyl)-phenyl]-piperidin-4-yl-methanone hydrochloride

1.1: 4-[4-(1-Hydroxy-1-methyl-ethyl)-benzoyl]-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 2-(4-bromo-phenyl)-propan-2-ol (5.00 g; 22.78 mmol) in THF (100 ml) at -78°C under a nitrogen atmosphere was added n-butyllithium (23% in hexane) (13.92 ml; 50.12 mmol) dropwise, and the mixture was stirred at the same temperature for 15 minutes. A solution of tert-butyl 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylate (6.96 g; 25.06 mmol) in THF (100 ml) was added dropwise at -78°C, and the mixture was stirred at -78°C for 2 hours. The reaction mixture was stirred at -78°C for 4 hours and quenched with saturated _NH4Cl solution (100 ml). The reaction mixture was extracted with ethyl acetate (2 x 100 ml). The combined extracts were washed with water (200 ml), brine solution (100 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (60-120) with petroleum ether-ethyl acetate (1:1) as a gradient eluent to afford the title compound (2.30 g; 29%) as a light yellow oil; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.92 (d, J =8.48 Hz, 2H), 7.60 (d, J =8.52 Hz, 2H), 5.18 (s, 1H), 3.96 (d, J =12.56 Hz, 2H), 3.63-3.57 (m, 1H), 2.90 (s, 2H), 1.74 (d, J =11.52 Hz, 2H), 1.43-1.38 (m, 17H); LC/MS(B), Rt: 4.50 min; (M+H-BOC) 248.3.

1.2: [4-(1-Hydroxy-1-methyl-ethyl)-phenyl]-piperidin-4-yl-methanone hydrochloride

A solution of 4-[4-(1-hydroxy-1-methyl-ethyl)-benzoyl]-piperidine-1-carboxylic acid tert-butyl ester (2.30 g; 6.69 mmol) in HCl/1,4-dioxane (22.28 ml; 66.85 mmol) was stirred at ambient temperature under nitrogen for 6 hours. The solvent was evaporated under reduced pressure to provide a crude product, which was triturated with diethyl ether to give the title compound (1.90 g; 99%) as a colorless solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (s, 1H), 8.77 (s, 1H), 7.94 (d, J =8.48 Hz, 2H), 7.62 (d, J =8.48 Hz, 2H), 5.21 (s, 1H), 3.78-3.70 (m, 1H), 3.34-3.27 (m,2H), 3.02 (q, J =12.32 Hz, 2H), 1.99-1.90 (m, 2H), 1.80-1.70 (m, 2H), 1.43 (s,6H); LC/MS (B), Rt: 1.95 min;(M+H)248.3.

Example 1

Synthesis of 2-{4-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A1")

To 4-(4-oxo-3,4-dihydro-quinazoline-2-yl)-butyric acid (51.0 mg, 0.22 mmol), (4-methoxy-phenyl)-piperidin-4-yl-methanone hydrochloride (84.4 mg, 0.33 mmol) and benzotriazole-1-ol hydrate (50.5 mg, 0.33 mmol) in DMF (0.5 ml) solution, add N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (74.8 mg, 0.30 mmol) and 4-methylmorpholine (39.5 mg, 0.39 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was distributed between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column using methanol/dichloromethane as eluent to provide 2-{4-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one as a colorless, amorphous solid; HPLC/MS 1.71 min (A), [M+H] 435;

¹ H NMR(400 MHz, DMSO-d ₆ )δ 12.15(s, 1H), 8.08(dd, J =8.1, 1.5 Hz, 1H), 8.04 – 7.95(m, 2H), 7.76(ddd, J =8.5, 7.1, 1.6 Hz, 1H), 7.59(dt, J =8.1, 0.8Hz, 1H), 7.45(ddd, J =8.1, 7.1, 1.2 Hz, 1H), 7.12 – 6.99(m, 2H), 4.40(d, J =12.9 Hz, 1H), 3.93(d, J =13.7 Hz, 1H), 3.85(s, 3H), 3.65(tt, J =11.2, 3.6 Hz, 1H), 3.25 – 3.11(m, 1H), 2.73(td, J =12.8, 2.8 Hz, 1H), 2.65(t, J =7.4 Hz, 2H), 2.42(td, J =7.3, 2.9 Hz, 2H), 1.98(p, J =7.2 Hz, 2H), 1.77(m, 2H), 1.51(qd, J =12.1, 4.0 Hz, 1H), 1.34(qd, J =12.1, 4.1 Hz, 1H).

The following compounds were prepared similarly:

2-[4-(4-Benzoyl-piperidin-1-yl)-4-oxo-butyl]-3H-quinazolin-4-one ("A2")

HPLC/MS 1.68 min(A),[M+H]404;

¹ H NMR (400 MHz, DMSO-d ₆ )δ 12.15 (s, 1H), 8.07 (dd, J =8.0, 1.5 Hz, 1H), 8.04 – 7.94 (m, 2H), 7.76 (ddd, J =8.5, 7.1, 1.6 Hz, 1H), 7.71 – 7.62(m, 1H),7.62 – 7.51(m, 3H), 7.45(ddd, J =8.1, 7.2, 1.2 Hz, 1H), 4.39(d, J =13.0 Hz,1H), 3.93(d, J =13.6 Hz, 1H), 3.70(tt, J =11.2, 3.6 Hz, 1H), 3.27 – 3.08(m,1H), 2.75(td, J =12.5, 2.8 Hz, 1H), 2.65(t, J =7.4 Hz, 2H), 2.42(td, J =7.3, 3.1Hz, 2H), 1.98(p, J =7.2 Hz, 2H), 1.80(m, 2H), 1.59 – 1.44(m, 1H), 1.35(qd, J =12.3, 4.1 Hz, 1H);

2-[4-(4-Benzoyl-piperidin-1-yl)-4-oxo-butyl]-6-fluoro-8-methyl-3H-quinazolin-4-one ("A3")

HPLC/MS 1.91 min(A),[M+H]436;

¹ H NMR(400 MHz, DMSO-d ₆ )δ 12.26(s, 1H), 8.26 – 7.84(m, 2H), 7.76 –7.60(m, 1H), 7.61 – 7.47(m, 4H), 4.39(d, J =13.1 Hz, 1H), 3.91(d, J =13.6 Hz,1H), 3.70(tt, J =11.2, 3.6 Hz, 1H), 3.26 – 3.09(m, 1H), 2.74(ddd, J =12.8,10.9, 2.8 Hz, 1H), 2.66(t, J =7.3 Hz, 2H), 2.53(s, 3H), 2.46(td, J =7.3, 3.1Hz, 2H), 1.99(p, J =7.4 Hz, 2H), 1.80(d, J =13.2 Hz, 2H), 1.50(qd, J =12.1, 3.9Hz, 1H), 1.34(qd, J =12.3, 4.2 Hz, 1H);

6-Fluoro-2-{4-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-8-methyl-3H-quinazolin-4-one ("A4")

HPLC/MS 1.91 min(A),[M+H]466;

¹ H NMR(500 MHz, DMSO-d ₆ )δ 12.23(s, 1H), 8.09 – 7.88(m, 2H), 7.56(m,2H), 7.12 – 6.99(m, 2H), 4.48 – 4.30(m, 1H), 3.91(d, J =13.6 Hz, 1H), 3.85(s,3H), 3.64(tt, J =11.2, 3.6 Hz, 1H), 3.17(td, J =13.0, 2.7 Hz, 1H), 2.73(td, J =12.6, 2.8 Hz, 1H), 2.66(t, J =7.3 Hz, 2H), 2.53(s, 3H), 2.45(td, J =7.3, 4.2Hz, 2H), 1.99(p, J =7.4 Hz, 2H), 1.76(dt, J =13.0, 3.5 Hz, 2H), 1.49(qd, J =12.0, 4.0 Hz, 1H), 1.41 – 1.26(m, 1H);

6,8-Difluoro-2-{4-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A5")

HPLC/MS 1.81 min(A),[M+H]440;

¹ H NMR(400 MHz, DMSO-d ₆ )δ 12.45(s, 1H), 8.08 – 7.93(m, 2H), 7.76(ddd, J =10.5, 9.0, 2.9 Hz, 1H), 7.69 – 7.58(m, 2H), 7.55(dd, J =8.3, 7.0 Hz, 2H), 4.39(dd, J =12.9, 3.7 Hz, 1H), 3.95(d, J =13.5 Hz, 1H), 3.70(tt, J =11.3, 3.6Hz, 1H), 3.19(td, J =13.5, 12.9, 2.7 Hz, 1H), 2.74(td, J =12.7, 2.7 Hz, 1H),2.67(t, J =7.4 Hz, 2H), 2.44(td, J =7.2, 1.8 Hz, 2H), 1.97(p, J =7.4 Hz, 2H),1.80(dd, J =11.6, 7.2 Hz, 2H), 1.50(qd, J =12.0, 4.0 Hz, 1H), 1.34(qd, J =12.1,4.1 Hz, 1H);

2-[4-(4-Benzoyl-piperidin-1-yl)-4-oxo-butyl]-6,8-difluoro-3H-quinazolin-4-one ("A6")

HPLC/MS 1.82 min(A),[M+H]470;

¹ H NMR(400 MHz, DMSO-d ₆ )δ 12.46(s, 1H), 8.11 – 7.93(m, 2H), 7.76(ddd, J =10.5, 9.0, 2.9 Hz, 1H), 7.61(ddd, J =8.4, 2.9, 1.4 Hz, 1H), 7.13 – 6.98(m,2H), 4.39(d, J =13.1 Hz, 1H), 3.95(d, J =13.6 Hz, 1H), 3.85(s, 3H), 3.65(tt, J =11.2, 3.6 Hz, 1H), 3.18(t, J =12.3 Hz, 1H), 2.80 – 2.59(m, 3H), 2.48 – 2.37(m,2H), 1.97(p, J =7.4 Hz, 2H), 1.75(m, 2H), 1.50(qd, J =12.1, 4.0 Hz, 1H), 1.34(tt, J =12.2, 6.0 Hz, 1H).

Example 2

Synthesis of 2-{4-[4-(3-methyl-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A7")

To a DMF (4 ml) solution of 4-(4-oxo-3,4-dihydro-quinazolin-2-yl)-butyric acid (167 mg, 0.72 mmol) and piperidin-4-yl-m-tolyl-methanone hydrochloride (173 mg, 0.72 mmol) was added triethylamine (0.31 ml, 2.2 mmol), and then at 0 ° C, under a nitrogen atmosphere, propanephosphonic anhydride (T3P, 50%, in ethyl acetate; 794 mg, 1.08 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 15 hours. The solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (50 ml) and washed with 10% sodium bicarbonate solution and water. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column using methanol/dichloromethane as eluent to provide 2-{4-[4-(3-methyl-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one as an off-white solid; HPLC/MS 3.53 min (B), [M+H] 418;

¹ H NMR(400 MHz, DMSO-d ₆ )δ 12.15(s, 1H), 8.06(dd, J=1.2, 7.9 Hz, 1H), 7.79-7.73(m, 3H), 7.58(d, J=7.9 Hz, 1H), 7.57-7.39(m, 3H), 4.37(d, J= Hz,1H), 3.92(d, J=13.5 Hz, 1H), 3.71-3.65(m, 1H), 3.16(t, J=11.8 Hz, 1H), 2.75-2.69(m, 1H), 2.63(t, J=7.32 Hz, 2H), 2.41-2.37(m, 5H), 1.99-1.92(m, 2H), 1.79-1.75(m, 2H), 1.53-1.44(m, 1H), 1.33(td, 1H).

The following compounds were prepared similarly:

2-{4-[4-(3-Fluoro-4-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A8")

HPLC/MS 3.40 min(B),[M+H]452;

¹ H NMR(400 MHz, DMSO-d ₆ )δ 12.18(s, 1H), 8.06(dd, J=1.1, 7.9 Hz, 1H), 7.87(d, J=8.6 Hz, 1H), 7.82(dd, J=1.9, 12.3 Hz, 1H), 7.78-7.74(m, 1H), 7.59(d, J=8.0 Hz, 1H), 7.46-7.42(m, 1H), 7.29(t, J=8.6 Hz, 1H), 4.37(d, J=13.0Hz, 1H), 3.93-3.90(m, 4H), 3.68-3.63(m, 1H), 3.16(t, , 1.53-1.47(m, 1H), 1.36-1.29(m, 1H);

2-{4-[4-(3-Methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A9")

HPLC/MS 3.36 min(B),[M+H]434;

¹ H NMR(400 MHz, DMSO-d ₆ )δ 12.17(s, 1H), 8.07(d, J=7.8 Hz, 1H), 7.76(t,J=7.6 Hz, 1H), 7.61-7.58(m, 2H), 7.48-7.45(m, 3H), 7.22(d, J=7.6 Hz, 1H), 4.38(d, J=12.6 Hz, 1H), 3.93-3.90(m, 1H), 3.86(s, 3H), 3.72-3.63(m, 1H), 3.17(t, J=12.28 Hz, 1H), 2.73(t, J=11.60 Hz, 1H), 2.63(t, J=7.24 Hz, 2H), 2.41-2.32(m, 2H), 1.96(t, J=7.16 Hz, 2H), 1.85-1.72(m, 2H), 1.53-1.45(m, 1H), 1.36-1.28(m, 1H).

Example 3

Synthesis of 2-(4-{4-[4-(1-ethyl-1H-pyrazol-4-yl)-benzoyl]-piperidin-1-yl}-4-oxo-butyl)-3H-quinazolin-4-one ("A10")

To a solution of 4-(4-oxo-3,4-dihydro-quinazolin-2-yl)-butyric acid (671 mg, 2.89 mmol) and (4-bromo-phenyl)-piperidin-4-yl-methanone (852 mg, 3.18 mmol) in DMF (16 ml) was added triethylamine (1.23 ml, 4.34 mmol), and then T3P (50% in ethyl acetate; 3.18 g, 4.34 mmol) was added dropwise at 0 ° C. under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 15 hours. The solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (50 ml) and washed with 10% sodium bicarbonate solution and water. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column using methanol/dichloromethane as eluent to provide 2-{4-[4-(4-bromo-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one as a light yellow solid; HPLC/MS 3.79 min (B), [M+H] 482/484;

¹ H NMR(400 MHz, DMSO-d ₆ )δ 12.18(s, 1H), 8.06(dd, J=1.3, 7.9 Hz, 1H), 7.94-7.92(m, 2H), 7.78-7.74(m, 3H), 7.58(d, J=7.8 Hz, 1H), 7.46-7.42(m, 1H),4.36(d, J=13.0 Hz, 1H), 3.92(d, J=13.4 Hz, 1H), 3.70-3.64(m, 1H), 3.19-3.13(m, 1H), 2.74-2.66(m, 1H), 2.63(t, J=7.36 Hz, 2H), 2.43-2.38(m, 2H), 1.82-1.60(m, 2H), 1.55-1.40(m, 1H), 1.33-1.29(m, 1H).

A solution of 2-{4-[4-(4-bromo-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one (183 mg, 0.38 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (102 mg, 0.46 mmol) and cesium carbonate (379 mg, 1.15 mmol) in dioxane (4 ml) and water (0.4 ml) was purged with nitrogen. 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (32 mg, 0.040 mmol) was then added. Under a nitrogen atmosphere, the mixture was heated to 100° C. and stirred at this temperature for 18 hours. The reaction mixture was cooled to room temperature and filtered through a celite pad. The filtrate was evaporated and the residue was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column using methanol/dichloromethane as eluent to provide 2-(4-{4-[4-(1-ethyl-1H-pyrazol-4-yl)-benzoyl]-piperidin-1-yl}-4-oxo-butyl)-3H-quinazolin-4-one as an off-white solid; HPLC/MS 3.36 min (B), [M+H] 498;

¹ H NMR(400 MHz, DMSO-d ₆ )δ 12.17(s, 1H), 8.36(s, 1H), 8.07(d, J=7.2 Hz,1H), 8.00-7.97(m, 3H), 7.78-7.71(m, 3H), 7.59(d, J=8.0 Hz, 1H), 7.44(t, J=7.6Hz, 1H), 4.40(d, J=12.8 Hz, 1H), 4.16(q, J=7.2 Hz, 2H), 3.93(d, J=12.9 Hz,1H), 3.72-3.66(m, 1H), 3.18(t, J=12.12 Hz, 1H), 2.74(t, J=12.08 Hz, 1H), 2.64(t, J=7.32 Hz, 2H), 2.44-2.40(m, 2H), 2.0(q, J=7.0 Hz, 2H), 1.85-1.72(m, 2H),1.55-1.50(m, 1H), 1.42-1.40(m, 3H), 1.35-1.33(m, 1H).

The following compounds were prepared similarly:

2-[4-(4-{4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidin-1-yl)-4-oxo-butyl]-3H-quinazolin-4-one ("A11")

HPLC/MS 4.60 min(B),[M+H]528;

¹ H NMR(400 MHz, DMSO-d ₆ )δ 12.10(s, 1H), 8.06(dd, J=1.2, 7.9 Hz, 1H), 8.02-7.97(m, 3H), 7.78-7.71(m, 3H), 7.59(d, J=8.0 Hz, 1H), 7.44(t, J=7.8 Hz,1H), 4.39(d, J=13.0 Hz, 1H), 4.28(t, J=5.2 Hz, 2H), 3.93(d, J=13.4 Hz, 1H), 3.71(t, J=5.2 Hz, 3H), 3.23(s, 3H), 3.19-3.15(m, 1H), 2.76-2.74(m, 1H), 2.63(t, J=7.36 Hz, 2H), 2.41-2.39(m, 2H), 2.00-1.92(m, 2H), 1.85-1.73(m, 2H),1.52-1.49(m, 1H), 1.35-1.33(m, 1H);

2-[4-Oxo-4-(4-{4-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidin-1-yl)-butyl]-3H-quinazolin-4-one ("A12")

HPLC/MS 2.52 min(B),[M+H]567;

¹ H NMR(400 MHz, DMSO-d ₆ )δ 12.09(s, 1H), 8.36(s, 1H), 8.06(dd, J=1.3,7.9 Hz, 1H), 8.01-7.97(m, 3H), 7.78-7.71(m, 3H), 7.59(d, , 3.21-3.18(m, 1H), 2.90-2.80(m, 2H), 2.76-2.70(m, 1H),2.65-2.63(m, 2H), 2.43-2.41(m, 4H), 1.99-1.90(m, 2H), 2.85-2.70(m, 2H), 1.70-1.52(m, 4H), 1.55-1.46(m, 1H), 1.37-1.32(m, 1H).

Analogously to Example 1, the following compounds were prepared:

2-[4-[4-(4-Methoxy-3-methyl-benzoyl)-1-piperidinyl]-4-oxo-butyl]-3H-quinazolin-4-one ("A13")

¹ H NMR(400 MHz, DMSO-d ₆ )δ 8.06(dd, J =1.24, 7.94 Hz, 1H), 7.89(dd, J =2.12, 8.58 Hz, 1H), 7.80-7.78(m, 1H), 7.76-7.74(m, 1H), 7.59(d, J =7.88 Hz, 1H), 7.47-7.42(m, 1H), 7.05(d, J =8.68 Hz, 1H), 4.37(d, J =0.32 Hz, 1H), 3.92(d, J =13.24 Hz, 1H), 3.87(s, 3H), 3.66-3.63(m, 1H), 3.23(t, J =12.36 Hz, 1H), 2.75-2.65(m, 1H), 2.64-2.62(m, 2H), 2.49-2.39(m, 2H), 2.19(s, 3H), 1.97(q, J =7.24 Hz, 2H), 1.74(d, J =10.76 Hz, 2H), 1.50(t, J =9.68 Hz, 1H), 1.33(t, J =9.08Hz, 1H);

6,8-Difluoro-2-[4-[4-(4-methoxy-3-methyl-benzoyl)-1-piperidinyl]-4-oxo-butyl]-3H-quinazolin-4-one ("A14")

HPLC/MS 1.91 min(A),[M+H]484; ¹ H NMR(500 MHz, DMSO-d ₆ )δ 12.48(s, 1H),7.90(dd, J =8.6, 2.3 Hz, 1H), 7.85 – 7.80(m, 1H), 7.78(ddd, J =10.5, 9.0, 2.9Hz, 1H), 7.62(ddd, J =8.4, 2.9, 1.2 Hz, 1H), 7.06(d, J =8.6 Hz, 1H), 4.44 –4.35(m, 1H), 3.99 – 3.91(m, 1H), 3.89(s, 3H), 3.66(tt, J =11.2, 3.6 Hz, 1H), 3.19(td, J =13.2, 12.8, 2.7 Hz, 1H), 2.80 – 2.70(m, 1H), 2.68(t, J =7.4 Hz, 2H), 2.44(td, J =7.3, 2.3 Hz, 2H), 1.98(p, J =7.4 Hz, 2H), 1.82 – 1.71(m, 2H), 1.50(qd, J =12.1, 4.0 Hz, 1H), 1.40 – 1.28(m, 1H);

6-Fluoro-2-[4-[4-(4-methoxy-3-methyl-benzoyl)-1-piperidinyl]-4-oxo-butyl]-8-methyl-3H-quinazolin-4-one ("A15")

HPLC/MS 2.01 min(A),[M+H]480; ¹ H NMR(500 MHz, DMSO-d ₆ )δ 12.28(s, 1H),7.90(dd, J =8.6, 2.3 Hz, 1H), 7.85 – 7.77(m, 1H), 7.64 – 7.49(m, 2H), 7.06(d, J =8.6 Hz, 1H), 4.41(dt, J =13.3, 3.7 Hz, 1H), 3.89(m, 4H), 3.66(tt, J =11.2,3.6 Hz, 1H), 3.18(td, J =13.1, 2.6 Hz, 1H), 2.74(td, J =12.9, 2.7 Hz, 1H), 2.67(t, J =7.4 Hz, 2H), 2.54(s, 3H), 2.46(td, J =7.3, 4.2 Hz, 2H), 1.99(p, J =7.2Hz, 2H), 1.76(dt, J =12.9, 3.4 Hz, 2H), 1.50(qd, J =12.1, 4.0 Hz, 1H), 1.34(qd, J =12.2, 4.1 Hz, 1H).

Analogously to Example 2, the following compounds were prepared:

2-{4-[4-(6-Methoxy-pyridine-3-carbonyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A16")

Colorless solid; HPLC/MS 2.93 min(B), [M+H]435; ¹ H NMR (400 MHz, DMSO-d ₆ )δ 8.90(s, 1H), 8.22(d, J =8.7 Hz, 1H), 8.07(d, J =7.9 Hz, 1H), 7.76(t, J =8.4 Hz, 1H),7.59(d, J =7.8 Hz, 1H), 7.44(t, J =8.0 Hz, 1H), 6.94(d, J =8.6 Hz, 1H), 4.40-4.34(m, 1H), 3.94(s, 3H), 3.93-3.90(m, 1H), 3.67-3.62(m, 1H), 3.16(t, J =11.92Hz, 1H), 2.72(t, J =10.60 Hz, 1H), 2.67-2.62(m, 2H), 2.44-2.39(m, 2H), 2.00-1.92(m, 2H), 1.78-1.76(m, 2H), 1.51-1.39(m, 1H), 1.34-1.29(m, 1H);

4-{1-[4-(4-Oxo-3,4-dihydro-quinazolin-2-yl)-butyryl]-piperidin-4-yloxy}-benzonitrile ("A17")

Colorless solid; HPLC/MS 3.34 min(B), [M+H]417; ¹ H NMR (400 MHz, DMSO-d ₆ )δ 12.16(s, 1H), 8.06(d, J =7.9 Hz, 1H), 7.78-7.74(m, 3H), 7.58(d, J =8.0 Hz, 1H), 7.45(t, J =7.9 Hz, 1H), 7.15(d, J =8.9 Hz, 2H), 4.77-4.73(m, 1H), 3.88-3.85(m, 1H),3.73-3.70(m, 1H), 3.35-3.32(m, 1H), 3.22-3.17(m, 1H), 2.64(t, J =7.48 Hz, 2H), 2.42(t, J =7.52 Hz, 2H), 2.00-1.88(m, 4H), 1.61-1.58(m, 1H), 1.49-1.47(m, 1H);

2-{4-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A18")

Colorless solid; HPLC/MS 3.40 min(B), [M+H]422; ¹ H NMR (400 MHz, DMSO-d ₆ )δ 12.12(s, 1H), 8.11-8.05(m, 3H), 7.76(d, J =8.3 Hz, 1H), 7.59(d, J =8.0 Hz, 1H), 7.45(t, J =7.8 Hz, 1H), 7.36(t, J =8.8 Hz, 2H), 4.40-4.37(m, 1H), 3.94-3.91(m, 1H),3.71-3.66(m, 1H), 3.17(t, J =11.8 Hz, 1H), 2.72(t, J =11.8 Hz, 1H), 2.64(t, J =7.36 Hz, 2H), 2.42-2.39(m, 2H), 2.00-1.92(m, 2H), 1.79-1.76(m, 2H), 1.53-1.44(m, 1H), 1.37-1.33(m, 1H);

6-Fluoro-2-{4-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A19")

Colorless solid; HPLC/MS 3.70 min(B), [M+H]452; ¹ H NMR (400 MHz, DMSO-d ₆ )δ 12.30(s, 1H), 7.98(d, J =8.9 Hz, 2H), 7.75-7.72(m, 1H), 7.67-7.62(m, 2H), 7.06-7.03(m, 2H), 4.45-3.35(m, 1H), 3.93-3.89(m, 1H), 3.84(s, 3H), 3.67-3.61(m, 1H),3.19-3.13(m, 1H), 2.74-2.62(m, 3H), 2.43-2.38(m, 2H), 1.70-1.60(m, 2H), 1.53-1.48(m, 1H), 1.36-1.28(m, 1H);

6-Fluoro-2-{4-[4-(3-fluoro-4-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A20")

Off-white solid; HPLC/MS 3.81 min(B),[M+H]470; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.30(s, 1H), 7.87(d, J =8.8 Hz, 1H), 7.82(dd, J =1.9, 12.3 Hz, 1H), 7.73(dd, J =1.2, 8.6 Hz, 1H), 7.67-7.62(m, 2H), 7.29(t, J =8.6 Hz, 1H), 4.38(d, J =12.7Hz, 1H), 3.93-3.90(m, 4H), 3.68-3.63(m, 1H), 3.19-3.13(m, 1H), 2.75-2.62(m,3H), 2.43-2.38(m, 2H), 1.80-1.70(m, 2H), 1.52-1.44(m, 1H), 1.36-1.32(m, 1H);

6-Fluoro-2-{4-[4-(6-methoxy-pyridine-3-carbonyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A21")

Off-white solid; HPLC/MS 3.29 min(B),[M+H]453; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.29(s, 1H), 8.90(d, J =2.2 Hz, 1H), 8.22(dd, J =2.5, 8.8 Hz, 1H), 7.75-7.72(m, 1H), 7.69-7.62(m, 2H), 6.94(d, J =8.8 Hz, 1H), 4.38(s, 1H), 3.94(s, 3H),3.93-3.89(m, 1H), 3.67-3.62(m, 1H), 3.19-3.13(m, 1H), 2.74-2.66(m, 1H), 2.63(t, J=7.40 Hz, 2H), 2.43-2.39(m, 2H), 1.99-1.92(m, 2H), 1.85-1.70(m, 2H), 1.58-1.40(m, 1H), 1.35-1.31(m, 1H);

4-{1-[4-(6-Fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-butyryl]-piperidin-4-yloxy}-benzonitrile ("A22")

Off-white solid; HPLC/MS 3.66 min(B),[M+H]435; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.44(s, 1H), 7.77-7.72(m, 3H), 7.66(d, J =9.6 Hz, 2H), 7.15(d, J =9.0 Hz, 2H),4.78-4.74(m, 1H), 3.88-3.85(m, 1H), 3.73-3.69(m, 1H), 3.33-3.32(m, 1H), 3.19-3.06(m, 1H), 2.67-2.62(m, 2H), 2.44-2.40(m, 2H), 2.00-1.88(m, 4H), 1.60-1.58(m, 1H), 1.51-1.44(m, 1H);

6-Fluoro-2-{4-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A23")

Off-white solid; HPLC/MS 3.79 min(B),[M+H]440; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.30(s, 1H), 8.11-8.07(m, 2H), 7.75-7.72(m, 1H), 7.67-7.64(m, 2H), 7.39-7.36(m, 2H), 4.38(d, J =13.8 Hz, 1H), 3.92(d, J =12.9 Hz, 1H), 3.71-3.66(m, 1H),3.19-3.13(m, 1H), 2.75-2.62(m, 3H), 2.42-2.38(m, 2H), 1.99-1.94(m, 2H), 1.85-1.71(m, 2H), 1.53-1.47(m, 1H), 1.36-1.30(m, 1H);

6-Fluoro-2-{4-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A24")

Off-white solid; HPLC/MS 4.03 min(B), [M+H]466; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.50(s, 1H), 7.89(dd, J =1.8, 8.6 Hz, 1H), 7.80(s, 1H), 7.73(dd, J =1.6, 8.6Hz, 1H), 7.67-7.64(m, 2H), 7.04(d, J =8.6 Hz, 1H), 4.38(d, J =12.9 Hz, 1H),3.93-3.87(m, 4H), 3.67-3.61(m, 1H), 3.19-3.13(m, 1H), 2.75-2.72(m, 1H), 2.65(t, J =13.56 Hz, 2H), 2.43-2.39(m, 2H), 1.99-1.92(m, 2H), 1.70-1.68(m, 2H), 1.53-1.45(m, 1H), 1.36-1.27(m, 1H);

8-Fluoro-2-{4-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A25")

Off-white solid; HPLC/MS 3.63 min(B),[M+H]452; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.35(bs, 1H), 7.99-7.97(m, 2H), 7.88-7.86(d, J =8.0 Hz, 1H), 7.65-7.60(m,1H), 7.45-7.40(m, 1H), 7.06-7.03(m, 2H), 4.39-4.36(d, 1H), 3.96-3.93(m, 1H),3,86(s, 3H), 3.66-3.61(m,1H), 3.20-3.14(m, 1H), 2.74-2.72(m, 1H), 2.68-2.64(m, 2H), 2.48-2.41(m, 2H), 2.00-1.92(m, 2H), 1.75-1.73(m, 2H), 1.53-1.45(m,1H), 1.37-1.30(m, 1H);

8-Fluoro-2-{4-[4-(3-fluoro-4-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A26")

Off-white solid; HPLC/MS 3.80 min(B),[M+H]470; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.35(bs, 1H), 7.88-7.82(m, 2H), 7.80-7.79(d, J =8.1 Hz, 1H), 7.66-7.61(m,1H), 7.45-7.40(m, 1H), 7.31-7.27(m, 1H), 4.39-4.36(d, 1H), 3.96-3.93(m, 1H),3,92(s, 3H), 3.68-3.61(m,1H), 3.17-3.14(m, 1H), 2.74-2.73(m, 1H), 2.68-2.64(m, 2H), 2.48-2.41(m, 2H), 2.00-1.92(m, 2H), 1.78-1.75(m, 2H), 1.53-1.45(m,1H), 1.37-1.32(m, 1H);

4-{1-[4-(8-Fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-butyryl]-piperidin-4-yloxy}-benzonitrile ("A27")

Colorless solid; HPLC/MS 3.76 min(B), [M+H]435; ¹ H NMR (400 MHz, DMSO-d ₆ )δ 12.35(bs, 1H), 7.88-7.86(d, J =8.0 Hz, 1H), 7.77-7.73(m, 2H), 7.66-7.61(m, 1H),7.45-7.40(m, 1H), 7.16-7.14(m, 2H), 4.77-4.73(m, 1H), 3.86-3.83(m, 1H),3.72-3.71(m, 1H), 3.34-3.32(m, 1H), 3.21-3.16(m, 1H), 2.68-2.64(m, 2H), 2.69-2.65(m, 2H), 2.46-2.42(m, 2H), 2.01-1.87(m, 4H), 1.62-1.55(m, 1H), 1.50-1.46(m, 1H);

8-Fluoro-2-{4-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A28")

Off-white solid; HPLC/MS 3.75 min(B),[M+H]440; ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.35(bs, 1H), 8.10-8.06(m, 2H), 7.88-7.86(m, 1H), 7.65-7.60(m, 1H), 7.45-7.40(m, 1H), 7.38-7.34(m, 2H), 4.39-4.36(m, 1H), 3.96-3.93(m, 1H), 3.71-3.64(m, 1H), 3.34-3.32(m, 1H), 3.21-3.14(m, 1H), 2.78-2.64(m, 3H), 2.43-2.40(m,2H), 2.01-1.92(m, 2H), 1.89-1.76(m, 2H), 1.53-1.43(m, 1H), 1.36-1.27(m, 1H);

8-Fluoro-2-{4-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A29")

Colorless solid; HPLC/MS 3.98(B),[M+H]466; ¹ H NMR (400 MHz, DMSO-d ₆ )δ 12.34(bs,1H), 7.90-7.87(m, 2H), 7.80-7.79(d, J=2.4 Hz, 1H), 7.66-7.61(m, 1H), 7.45-7.40(m, 1H), 7.05-7.03(d, J=8.1 Hz, 1H),4.39-4.36 (m, 1H), 3.96-3.92(m, 1H),3.86(s, 3H), 3.67-3.61(m, 1H), 3.20-3.14(m, 1H), 2.74-2.72(m, 1H), 2.68-2.64(m, 2H), 2.44-2.41(m, 2H), 2.19)s, 3H), 1.98-1.92(m, 2H),1.79-1.76(m, 2H),1.52-1.44(m, 1H), 1.36-1.27(m, 1H);

2-[4-(6-amino-5-pyrimidin-2-yl-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridin-1'-yl)-4-oxo-butyl]-3H-quinazolin-4-one ("A30")

Light yellow solid; HPLC/MS 2.32(B),[M+H]470; ¹ H NMR (400 MHz, DMSO-d ₆ )δ 12.17(s, 1H), 8.90(s, 2H), 8.51(s, 1H), 8.08-8.04(m, 2H), 7.76-7.72(m, 1H), 7.59(d, J =7.6 Hz, 2H), 7.46-7.42(m, 1H), 7.42-7.38(m, 1H), 4.55-4.52(m, 1H),4.02-3.99(m, 1H), 3.17-3.06(m, 1H), 2.76-2.73(m, 1H), 2.68-2.66(m, 2H), 2.66-2.60(m, 2H), 2.50-2.44(m, 2H), 2.03-1.97(m, 2H), 1.82-1.76(m, 2H), 1.59-1.54(m, 1H), 1.40-1.37(m, 1H);

6-Amino-1'-[4-(6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-butyryl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridine-5-carbonitrile ("A31")

Off-white solid; HPLC/MS 2.39(B),[M+H]435; ¹ H NMR (400 MHz, DMSO-d ₆ )δ 12.30(s, 1H), 8.11(d, J =2.4 Hz, 1H), 7.76-7.72(m, 2H), 7.67-7.64(m, 2H), 6.70(s,2H), 4.50(d, J =13.1 Hz, 1H), 3.96(d, J =13.3 Hz, 1H), 3.06-3.00(m, 1H), 2.64(t, J =7.4 Hz, 3H), 2.41(t, J= 7.3 Hz, 2H), 2.00-1.93(m, 2H), 1.73-1.67(m, 2H),1.55-1.45(m, 1H), 1.42-1.30(m, 1H);

2-[4-(6-amino-5-pyrimidin-2-yl-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridin-1'-yl)-4-oxo-butyl]-6-fluoro-3H-quinazolin-4-one ("A32")

Pale yellow solid; HPLC/MS 2.58(B),[M+H]488; ¹ H NMR (400 MHz, DMSO-d ₆ )δ 12.30(s, 1H), 8.89(d, J =4.9 Hz, 2H), 8.50(d, J =2.4 Hz, 1H), 8.04(d, J =2.4 Hz, 1H),7.74(dd, J =2.8, 8.6 Hz, 1H), 7.69-7.60(m, 3H), 7.39(t, J =4.9 Hz, 1H), 4.55-4.51(m, 1H), 4.01-3.98(m, 1H), 3.11-3.05(m, 1H), 2.76-2.64(m, 3H), 2.60-2.50(m, 1H), 2.46-2.42(m, 2H), 2.03-1.97(m, 2H), 1.82-1.76(m, 2H), 1.57-1.53(m,1H), 1.41-1.37(m, 1H);

8-Fluoro-2-{4-[4-(6-methoxy-pyridine-3-carbonyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A33")

Colorless solid; HPLC/MS 3.40(B),[M+H]453; ¹ H NMR (400 MHz, DMSO-d ₆ )δ 12.35(bs,1H), 8.89(bs,1H), 8.22-8.20(dd, J =8.8, 2.4 Hz,1H), 7.88-7.86(d, J =8.0 Hz,1H), 7.65-7.60(m,1H), 7.45-7.40(m,1H), 6.94-6.92(d, J =8.8 Hz,1H), 4.39-4.35(d,1H), 3.96-3.89(m,4H), 3.66-3.61(m,1H), 3.19-3.13(m, 1H), 3.17-3.14(m, 1H), 2.74-2.64(m, 1H), 2.68-2.64(m, 3H), 2.44-2.40(m, 2H), 1.98-1.92(m,2H), 1.78-1.75(m, 2H), 1.50-1.47(m, 1H), 1.34-1.28(m, 1H);

6-Amino-1'-[4-(8-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-butyryl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridine-5-carbonitrile ("A34")

Off-white solid; HPLC/MS 2.39(B),[M+H]435; ¹ H NMR (400 MHz, DMSO-d ₆ )δ 12.36(bs, 1H), 8.10(bs, 1H), 7.89-7.87(d, J =8.1 Hz, 1H), 7.75-7.74(d, J =2.4 Hz,1H), 7.65-7.60(m, 1H), 7.45-7.40(m, 1H), 6.69(s, 2H), 4.50-4.47(m, 1H), 4.01-3.97(m, 1H), 3.06-3.03(m, 1H), 2.74-2.73(m,4H), 2.44-2.41(m, 2H), 2.06-1.94(m, 2H), 1.75-1.67(m, 2H), 1.50-1.47(m, 1H), 1.35-1.33(m, 1H).

2-[4-(6-amino-5-pyrimidin-2-yl-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridin-1'-yl)-4-oxo-butyl]-8-fluoro-3H-quinazolin-4-one ("A35")

Colorless solid; HPLC/MS 2.63(B),[M+H]488; ¹ H NMR (400 MHz, DMSO-d ₆ )δ 12.36(bs,1H), 8.90(bs, 2H), 8.50(d, J =2.4 Hz, 1H), 8.04-8.03(d, J =2.4 Hz, 1H), 7.88-7.86(m, 1H), 7.64-7.59(m, 2H), 7.45-7.37(m, 2H), 4.50-4.47(m, 1H), 4.01-3.97(m, 1H), 3.06-3.03(m, 1H), 2.72-2.70(m, 4H), 2.44-2.41(m, 2H), 2.06-1.97(m,2H), 1.81-1.75(m, 2H), 1.50-1.47(m, 1H), 1.35-1.33(m, 1H);

6-Amino-1'-[4-(4-oxo-3,4-dihydro-quinazolin-2-yl)-butyryl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridine-5-carbonitrile ("A36")

Colorless solid; HPLC/MS 2.14(B),[M+H]417; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.23(s,1H), 8.12(s,1H), 8.07(d, J =8.0 Hz,1H), 7.78-7.74(m, 2H), 7.58(d, J =7.7 Hz,1H), 7.45(t, J =8.0 Hz,1H), 6.70(s, 2H), 4.52-4.48(m,1H), 3.99-3.95(m,1H),3.03(t, J =12.5 Hz,1H), 2.67-2.63(m, 4H), 2.43-2.40(m, 2H), 2.01-1.94(m, 2H),1.73-1.67(m, 2H), 1.53-1.49(m, 1H), 1.39-1.36(m, 1H);

8-Fluoro-2-(4-{4-[4-(1-hydroxy-1-methyl-ethyl)-benzoyl]-piperidin-1-yl}-4-oxo-butyl)-3H-quinazolin-4-one ("A37")

Colorless solid; HPLC/MS 3.32(B),[M+H]480; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.36(bs, 1H), 7.93(d, J =8.4 Hz, 2H), 7.88(d, J =2.4 Hz, 1H), 7.66-7.59(m, 3H),7.45-7.40(m, 1H), 5.18(s, 1H), 4.39-4.36(m, 1H), 3.96-3.92(m, 1H), 3.67-3.64(m, 1H), 3.20-3.14(m, 1H), 2.74-2.72(m, 1H), 2.68-2.64(m, 2H), 2.44-2.41(m,2H), 2.00-1.94(m, 2H),1.79-1.76(m, 2H), 1.53-1.43(m, 7H), 1.36-1.30(m, 1H);

2-(4-{4-[4-(1-hydroxy-1-methyl-ethyl)-benzoyl]-piperidin-1-yl}-4-oxo-butyl)-3H-quinazolin-4-one ("A38")

Colorless solid; HPLC/MS 2.98(B),[M+H]462; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.10(s,1H), 8.07(dd, J =1.24, 7.88 Hz, 1H), 7.93(d, J =8.44 Hz, 2H), 7.78-7.74(m, 1H),7.62-7.58(m, 3H), 7.47-7.43(m, 1H), 5.20(s, 1H), 4.38(d, J =13.00 Hz, 1H),4.15(d, J =171.00 Hz, 1H), 3.94-3.65(m, 1H), 3.33-3.14(m, 1H), 2.76-2.66(m, 1H), 2.66-2.50(m, 2H), 2.49-2.39(m, 2H), 2.00-1.94(m, 2H), 1.80-1.77(m, 2H),1.51-1.43(m, 1H), 1.35-1.33(m, 6H), 1.32-1.22(m, 1H);

6-Fluoro-2-(4-{4-[4-(1-hydroxy-1-methyl-ethyl)-benzoyl]-piperidin-1-yl}-4-oxo-butyl)-3H-quinazolin-4-one ("A39")

Yellow solid; HPLC/MS 3.28(B),[M+H]480; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.30(s,1H), 7.93(d, J =8.48 Hz, 2H), 7.75-7.72(m, 1H), 7.69-7.60(m, 4H), 5.18(s, 1H),4.38(d, J =12.88 Hz, 1H), 3.92(d, J =13.44 Hz, 1H), 3.90-3.65(m, 1H), 3.32-3.14(m, 1H), 2.76-2.64(m, 1H), 2.62-2.48(m, 2H), 2.43-2.39(m, 2H), 1.99-1.92(m,2H), 1.77-1.60(m, 2H), 1.51-1.43(m, 7H), 1.33-1.31(m, 1H).

Example 4

Synthesis of 2-{4-[4-(1-methyl-1H-imidazole-2-carbonyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A40")

To a suspension of 4-(4-oxo-3,4-dihydro-quinazolin-2-yl)-butyric acid (48.8 mg, 0.21 mmol), (1-methyl-1H-imidazol-2-yl)-piperidin-4-yl-methanone dihydrochloride (66.7 mg, 1.20 mmol), and [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate (HATU, 119 mg, 0.31 mmol) in DMF (2.0 ml) was added N-ethyldiisopropylamine (213 µl, 1.25 mmol), and the resulting clear solution was stirred at room temperature for 4 hours. The reaction mixture was directly chromatographed on a reverse phase silica gel column using water/acetonitrile/0.1% formic acid as the eluent. The fractions containing the product were combined. The acetonitrile was removed in vacuo and saturated NaHCO ₃ solution was added to the remaining solution. The aqueous suspension was extracted with dichloromethane. The organic phase was dried over sodium sulfate and evaporated to provide 2-{4-[4-(1-methyl-1H-imidazole-2-carbonyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one as a light yellow solid; HPLC/MS 1.53(C), [M+H]408; ¹ H NMR (400 MHz, T=363K, DMSO-d ₆ ) δ 11.85(brs, 1H), 8.10(dd, J =7.9, 1.3 Hz, 1H), 7.79-7.72(m, 1H), 7.62-7.57(m, 1H), 7.47-7.41(m, 2H), 7.13-7.09(m, 1H), 3.94(s, 3H), 3.83(tt, J =11.1, 3.9 Hz, 1H), 2.69(t, J =7.3 Hz,2H), 2.45(t, J =7.3 Hz, 2H), 2.03(d, J =7.4 Hz, 2H), 1.95-1.77(m, 2H), 1.53(d, J =9.2 Hz, 2H).

The following compounds were prepared similarly:

2-{4-[4-(1-methyl-1H-pyrazole-4-carbonyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A41")

HPLC/MS 1.49(C),[M+H]408; ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 12.12(s, 1H),8.42(s, 1H), 8.07(dd, J =7.9, 1.2 Hz, 1H), 7.95(d, J =0.6 Hz, 1H), 7.79-7.72(m,1H), 7.59(d, J =7.8 Hz, 1H), 7.48-7.42(m, 1H), 4.39(d, J =13.0 Hz, 1H), 3.93(d, J =13.6 Hz, 1H), 3.88(s, 3H), 3.22(tt, J =11.3 Hz, 3.7, 1H), 3.17-3.06(m, 1H), 2.74-2.61(m, 3H), 2.42(td, J =7.2, 2.5 Hz, 2H), 1.97(p, J =7.3 Hz, 2H), 1.76(d, J =13.0 Hz, 2H), 1.58-1.43(m, 1H), 1.43-1.27(m, 1H);

6,8-Difluoro-2-{4-[4-(1-methyl-1H-pyrazole-4-carbonyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one ("A42")

HPLC/MS 1.20(A);[M+H]444; ¹ H NMR(500 MHz, DMSO-d6)δ 12.45(s, 1H),8.43(s, 1H), 7.95(d, J =0.7 Hz, 1H), 7.76(ddd, J =10.4, 9.0, 2.9 Hz, 1H), 7.61(ddd, J =8.4, 2.9, 1.3 Hz, 1H), 4.47 – 4.29(m, 1H), 3.95(d, J =13.5 Hz, 1H), 3.88(s, 3H), 3.22(tt, J =11.4, 3.7 Hz, 1H), 3.12(t, J =11.9 Hz, 1H), 2.67(m,3H), 2.43(td, J =7.4, 1.9 Hz, 2H), 1.97(p, J =7.4 Hz, 2H), 1.81 – 1.71(m, 2H), 1.58 – 1.42(m, 1H), 1.40 – 1.27(m, 1H);

The following examples relate to pharmaceuticals:

Example A: Injection Vial

A solution of 100 g of the active ingredient of Formula I and 5 g of disodium hydrogen phosphate in 3 liters of double-distilled water is adjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered, transferred to injection vials, freeze-dried under aseptic conditions, and sealed under aseptic conditions. Each injection vial contains 5 mg of the active ingredient.

Example B: Suppositories

Melt a mixture of 20 g of the active ingredient of formula I with 100 g of soya lecithin and 1400 g of cocoa butter, pour into molds, and allow to cool. Each suppository contains 20 mg of the active ingredient.

Example C: Solution

Prepare a solution of 1 g of the active ingredient of Formula I, 9.38 g of _{NaH₂PO₄ ∙ 2H₂O} , 28.48 g _{of Na₂HPO₄} ∙ _12H₂O , and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. Adjust the pH to 6.8, make up to 1 liter, and sterilize by irradiation. This solution can be used as eye drops.

Example D: Ointment

Under sterile conditions, 500 mg of the active ingredient of formula I are mixed with 99.5 g of petrolatum.

Example E: Tablets

A mixture of 1 kg of the active ingredient of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in a conventional manner to give tablets in such a manner that each tablet contains 10 mg of the active ingredient.

Example F: Lozenge

Tablets are extruded analogously to Example E and subsequently coated with sucrose, potato starch, talc, tragacanth and dye in a conventional manner.

Example G: Capsules

2 kg of the active ingredient of the formula I are placed into hard gelatine capsules in a conventional manner in such a way that each capsule contains 20 mg of the active ingredient.

Example H: Ampoule

A solution of 1 kg of the active ingredient of formula I in 60 liters of double distilled water is sterile filtered, transferred into ampoules, freeze-dried under aseptic conditions, and sealed under aseptic conditions. Each ampoule contains 10 mg of the active ingredient.

Claims (9)

1. Compounds of Formula I in Z represents or X represents CH or N. ^R1 and ^R2 each independently represent H, F, or Cl. R ³ represents H, F, Cl, CH ₃ or OCH ₃ , R ⁴ represents H, F, A, CN, OA, or Y. R ⁵ represents H, F, A, or OA. ^R6 represents CN or 2-pyrimidinyl. R ⁷ represents Het ² . A represents an unbranched or branched alkyl group having 1-8 carbon atoms, wherein one or two non-adjacent CH- and/or _CH2- groups can be replaced by N- or O atoms, and wherein 1-7 H atoms can be replaced by F, Cl and/or OH. Y represents a pyrazol group that can be substituted by A or ( _CH2 ) _nHet1 ^. Het ¹ represents pyrrolidinyl, piperidinyl, morpholinyl, or piperazineyl, each of which may be substituted with A. Het ² represents pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrroleyl, thiazolyl, furanyl, or thiophenyl, each of which may be substituted with A. n is 0, 1, 2, 3, or 4. And its medicinal salts. 2. The compound according to claim 1, wherein A represents an unbranched or branched alkyl group having 1-6 carbon atoms, wherein one or two non-adjacent _CH₂- groups can be replaced by O- atoms, and wherein 1-7 H atoms can be replaced by F and/or OH. And its medicinal salts. 3. The compound according to claim 1, wherein ^R1 and ^R2 each independently represent H, F, or Cl. R ³ represents H, F, Cl, CH ₃ or OCH ₃ , R ⁴ represents H, F, A, CN, OA, or Y. R ⁵ represents H, F, A, or OA. A represents an unbranched or branched alkyl group having 1-6 carbon atoms, wherein 1-3 hydrogen atoms can be replaced by F and/or OH. Y represents a pyrazolyl group that can be substituted by A, methoxyethyl, or ( _CH2 ) _nHet1 ^. Het ¹ represents pyrrolidinyl, piperidinyl, morpholinyl, or piperazineyl, each of which may be substituted with A. Het ² represents pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrroleyl, thiazolyl, furanyl, or thiophenyl, each of which may be substituted with A. A represents an unbranched or branched alkyl group having 1-6 carbon atoms, wherein 1-3 hydrogen atoms can be replaced by F and/or OH. n is 0, 1, 2, 3, or 4. And its medicinal salts. 4. The compound according to claim 1, wherein ^R1 represents H, R ² represents H or F, R ³ represents H, CH ₃ , or F. R ⁴ represents H, CN, OCH ₃ , 1-ethyl-1H-pyrazole-4-yl, 1-(2-methoxy-ethyl)-1H-pyrazole-4-yl, or 1-(2-pyrrolidine-1-yl-ethyl)-1H-pyrazole-4-yl. R ⁵ represents H, CH ₃ , F, or OCH ₃ . Het ² represents a pyrazolyl or imidazole group, each of which can be substituted by A. A represents an unbranched or branched alkyl group having 1-6 carbon atoms, wherein 1-3 hydrogen atoms can be replaced by F and/or OH. And its medicinal salts. 5. Compounds, selected from serial number name “A1” 2-{4-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A2” 2-[4-(4-benzoyl-piperidin-1-yl)-4-oxo-butyl]-3H-quinazolin-4-one “A3” 2-[4-(4-benzoyl-piperidin-1-yl)-4-oxo-butyl]-6-fluoro-8-methyl-3H-quinazolin-4-one “A4” 6-Fluoro-2-{4-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-8-methyl-3H-quinazolin-4-one “A5” 6,8-Difluoro-2-{4-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A6” 2-[4-(4-benzoyl-piperidin-1-yl)-4-oxo-butyl]-6,8-difluoro-3H-quinazolin-4-one “A7” 2-{4-[4-(3-methyl-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A8” 2-{4-[4-(3-fluoro-4-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A9” 2-{4-[4-(3-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A10” 2-(4-{4-[4-(1-ethyl-1H-pyrazol-4-yl)benzoyl]-piperidin-1-yl}-4-oxo-butyl)-3H-quinazolin-4-one “A11” 2-[4-(4-{4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidin-1-yl)-4-oxo-butyl]-3H-quinazolin-4-one “A12” 2-[4-oxo-4-(4-{4-[1-(2-pyrrolidone-1-yl-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidin-1-yl)-butyl]-3H-quinazolin-4-one “A13” 2-[4-[4-(4-methoxy-3-methyl-benzoyl)-1-piperidinyl]-4-oxo-butyl]-3H-quinazolin-4-one “A14” 6,8-Difluoro-2-[4-[4-(4-methoxy-3-methylbenzoyl)-1-piperidinyl]-4-oxo-butyl]-3H-quinazolin-4-one “A15” 6-Fluoro-2-[4-[4-(4-methoxy-3-methyl-benzoyl)-1-piperidinyl]-4-oxo-butyl]-8-methyl-3H-quinazolin-4-one “A16” 2-{4-[4-(6-methoxy-pyridin-3-carbonyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A17” 4-{1-[4-(4-oxo-3,4-dihydro-quinazolin-2-yl)-butyryl]-piperidin-4-yloxy}-benzylnitrile “A18” 2-{4-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A19” 6-Fluoro-2-{4-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A20” 6-Fluoro-2-{4-[4-(3-fluoro-4-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A21” 6-Fluoro-2-{4-[4-(6-methoxy-pyridin-3-carbonyl)piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A22” 4-{1-[4-(6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-butyryl]-piperidin-4-yloxy}-benzylnitrile “A23” 6-Fluoro-2-{4-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A24” 6-Fluoro-2-{4-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A25” 8-Fluoro-2-{4-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A26” 8-Fluoro-2-{4-[4-(3-fluoro-4-methoxy-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A27” 4-{1-[4-(8-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-butyryl]-piperidin-4-yloxy}-benzylnitrile “A28” 8-Fluoro-2-{4-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A29” 8-Fluoro-2-{4-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A30” 2-[4-(6-amino-5-pyrimidin-2-yl-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridin-1'-yl)-4-oxo-butyl]-3H-quinazolin-4-one “A31” 6-Amino-1'-[4-(6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-butyryl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridine-5-carboxynitrile “A32” 2-[4-(6-amino-5-pyrimidin-2-yl-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridin-1'-yl)-4-oxo-butyl]-6-fluoro-3H-quinazolin-4-one “A33” 8-Fluoro-2-{4-[4-(6-methoxy-pyridin-3-carbonyl)piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A34” 6-Amino-1'-[4-(8-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-butyryl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridine-5-carboxynitrile “A35” 2-[4-(6-amino-5-pyrimidin-2-yl-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridin-1'-yl)-4-oxo-butyl]-8-fluoro-3H-quinazolin-4-one “A36” 6-Amino-1'-[4-(4-oxo-3,4-dihydro-quinazolin-2-yl)-butyryl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridine-5-carboxynitrile “A37” 8-Fluoro-2-(4-{4-[4-(1-hydroxy-1-methyl-ethyl)-benzoyl]-piperidin-1-yl}-4-oxo-butyl)-3H-quinazolin-4-one “A38” 2-(4-{4-[4-(1-hydroxy-1-methyl-ethyl)-benzoyl]-piperidin-1-yl}-4-oxo-butyl)-3H-quinazolin-4-one “A39” 6-Fluoro-2-(4-{4-[4-(1-hydroxy-1-methyl-ethyl)-benzoyl]-piperidin-1-yl}-4-oxo-butyl)-3H-quinazolin-4-one “A40” 2-{4-[4-(1-methyl-1H-imidazol-2-carbonyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A41” 2-{4-[4-(1-methyl-1H-pyrazole-4-carbonyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one “A42” 6,8-Difluoro-2-{4-[4-(1-methyl-1H-pyrazole-4-carbonyl)-piperidin-1-yl]-4-oxo-butyl}-3H-quinazolin-4-one And its medicinal salts. 6. A method for preparing compounds of formula I according to claims 1-5 and their pharmaceutically acceptable salts, characterized in that: Compounds of Formula II Wherein, Z has the meaning as shown in claim 1. Reaction with compounds of formula III Wherein, ^R1 , ^R2 , and ^R3 have the meanings shown in claim 1. L represents Cl, Br, I, or a free or reactive functionally modified OH group. and/or The base or acid of formula I is converted into a salt of it. 7. A medicament comprising at least one compound of formula I according to any one of claims 1-5 and/or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier, excipient or medium. 8. Use of a compound of formula I according to any one of claims 1-5 and its pharmaceutically acceptable salt in the preparation of a medicament for the treatment and/or prevention of cancer, multiple sclerosis, cardiovascular disease, central nervous system injury and various forms of inflammation. 9. The use according to claim 8, wherein the drug is used to treat and/or prevent diseases selected from the following: cancers of the head, neck, eyes, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bones, lungs, colon, rectum, stomach, prostate, bladder, uterus, cervix, breast, ovary, testis or other reproductive organs; cancers of the skin, thyroid, blood, lymph nodes, kidneys, liver, pancreas, brain, central nervous system, solid tumors and blood-borne tumors.