HK1222650B - Piperidine urea derivatives - Google Patents

Description

Piperidine urea derivatives

Background

The object of the present invention was to find novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.

The present invention relates to piperidine urea derivatives which inhibit the activity of Tankyrase (TANK) and poly (ADP-ribose) polymerase PARP-1. The compounds of the invention are therefore useful in the treatment of diseases such as cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury and different forms of inflammation. The invention also provides processes for preparing these compounds, pharmaceutical compositions comprising these compounds and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.

The ribozyme poly (ADP-ribose) polymerase-1 (PARP-1) is a member of the PARP enzyme family. This growing family of enzymes consists of: PARPs such as PARP-1, PARP-2, PARP-3 and Vault-PARP; and TANK polymerases (TANK) such as 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 essential for the polymerization of mitotic spindle-associated poly (ADP-ribose). The poly (ADP-ribose) activity of TANK-1 may be critical for the accurate formation and maintenance of both polarities of the spindle. Furthermore, the PARP activity of TANK-1 has been shown to be essential for normal telomere segregation prior to anaphase disruption. Interference of tankyrase PARP activity results in mitotic abnormalities that cause transient cell cycle arrest, possibly due to spindle checkpoint activation, followed by cell death. Inhibition of tankyrase is therefore expected to have a cytotoxic effect on proliferating tumor cells (WO 2008/107478).

In clinical cancer studies, PARP inhibitors are described by M. Rouleau et al in Nature Reviews, Volume 10,293-301 (Table 2, page 298).

According to a review by Horvath and Szabo (Drug News Perspectrum 20(3), 4.2007, 171-. More recent studies have also demonstrated that PARP inhibitors inhibit angiogenesis by inhibiting growth factor expression or by inhibiting growth factor-induced cell proliferation responses. These findings may also suggest an in vivo anti-cancer mode of action of PARP inhibitors.

Studies by Tentori et al (Eur. J. Cancer, 2007, 43 (14) 2124-2133) also demonstrated that PARP inhibitors abrogate VEGF-or placental growth factor-induced migration and prevent the formation of tubule-like networks in cell-based systems and impair angiogenesis in vivo. Studies also demonstrated that growth factor-induced angiogenesis is absent in PARP-1 knockout mice. The results of the study provide evidence of targeting PARP against angiogenesis, adding new therapeutic implications for the use of PARP inhibitors in cancer therapy.

It is well known that defects in the conserved signaling pathway play a key role in the origin and behavior of essentially all cancers (e.a. fearon, Cancer Cell, Vol. 16, Issue 5, 2009, 366-368) the Wnt pathway is the target of anti-Cancer therapy the key feature of the Wnt pathway is the regulated proteolysis (degradation) of β -catenin caused by β -catenin disrupting complexes-proteins like axx, APC or Axin are involved in this degradation process the correct degradation of β -catenin is important to avoid the inappropriate activation of the Wnt pathway observed in many cancers end-anchored polymerases inhibits the activity of ax5630-catenin and thus inhibits the degradation of ax β -catenin-thus end anchored polymerase inhibitors increase the degradation of β -catenin-a paper in Nature not only provides important new insight for proteins regulating Wnt signaling but also supports the inhibition of Wnt signaling through small molecules of genes β -catenin and their localization of proteins (axv-dockerin) by the subsequent inhibition of growth of axv-dockerin 3-9-dockerin 2, atxas 23-8-ctn-8-atn-2-atn-8-atn-h-a view of inhibiting the inhibition of the subsequent inhibition of the inhibition of Wnt signaling pathway of the growth of proteins identified by the growth of atn-8, atn-g, atn-9-atn-8, atn-8.

It has been found that the compounds according to the invention and their salts have very valuable pharmacological properties while being very tolerable.

The invention relates inter alia to compounds of formula I which inhibit tankyrase 1 and 2, compositions comprising these compounds and methods of their use for the treatment of TANK-induced diseases and conditions (compaint).

The compounds of formula I are additionally useful for isolating and studying TANK activity or expression. In addition, they are particularly suitable for use in diagnostic methods for diseases associated with dysregulated or disturbed TANK activity.

The host or patient may belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats, and hamsters; a rabbit; horses, cattle, dogs, cats, etc. The animal model has the significance of experimental research and provides a model for treating human diseases.

The sensitivity of a particular cell to treatment with a compound according to the invention can be determined by in vitro assays. Typically, a culture of cells is mixed with a compound according to the invention at various concentrations for a period of time sufficient to allow the active agent (e.g., anti-IgM) to induce a cellular response (e.g., expression of surface markers), typically about 1 hour to 1 week. In vitro tests can be performed using cultured cells from blood or from biopsy samples. The amount of surface marker expressed was assessed by flow cytometry using specific antibodies that recognize the marker.

The dosage will vary depending on the particular compound used, the particular disease, the patient's condition, and the like. The therapeutic dose is typically sufficient to significantly reduce the unwanted cell population in the target tissue while maintaining the viability of the patient. The treatment is generally continued until a significant reduction occurs, for example, a reduction in cell load of at least about 50%, and may be continued until substantially no more unwanted cells are detected in the body.

Prior Art

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

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

Other tankyrase inhibitors are described in WO 2013/012723, WO 2013/010092, WO 2012/076898 and in WO 2013/008217.

WO2004/033427 describes the preparation of 1, 4-disubstituted piperidine derivatives and their use as 11- β HSD1 inhibitors for the treatment of diabetes and related diseases:

4- (4-fluorobenzoyl) -N-methyl-N-phenyl-piperidine-1-carboxamide

And

4- (4-fluorobenzoyl) -N- (4-fluorophenyl) -N-methyl-piperidine-1-carboxamide

。

Summary of The Invention

The invention relates to compounds of formula I

Wherein

R¹Represents A or CH₂COOA，

R²、R³Independently of one another, each represents Ar or Het¹，

R¹And R²Together with the N atom to which they are attached representA heterocycle selected from 2, 3-dihydro-indolyl or 3, 4-dihydro-quinolinyl,

Het¹represents pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which may be mono-, di-or trisubstituted by Hal, A, OH, CN and/or OA,

ar represents phenyl which is unsubstituted or substituted by Hal, NO₂、CN、A、OR⁴、S(O)_mR⁴、N(R⁴)₂、COA、COOR⁴、CON(R⁴)₂、SO₂N(R⁴)₂、NR⁴COR⁴、NR⁴SO₂A、NR⁴CON(R⁴)₂And/or Het²Mono-, di-or tri-substituted,

R⁴represents H or A',

a represents an unbranched or branched alkyl radical having 1 to 8C atoms in which one or two non-adjacent CH and/or CH₂The radical may be replaced by an N or O atom and 1 to 7H atoms may be replaced by F or Cl,

a' represents unbranched or branched alkyl having 1,2,3 or 4C atoms,

Het²represents pyrazolyl, which can be substituted by A or (CH)₂)_nHet³The substitution is carried out by the following steps,

Het³represents pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, each of which may be substituted by A,

hal represents F, Cl, Br or I,

m represents 0, 1 or 2,

n represents 1,2,3 or 4,

provided that the exclusion is

4- (4-fluorobenzoyl) -N-methyl-N-phenyl-piperidine-1-carboxamide and 4- (4-fluorobenzoyl) -N- (4-fluorophenyl) -N-methyl-piperidine-1-carboxamide,

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

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

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

The term solvate of a compound is used to refer to the adduction of inert solvent molecules to a compound, which is formed due to their mutual attraction. Solvates are for example mono-or dihydrate or alkoxides.

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

The term pharmaceutically acceptable derivatives is used to refer to, for example, salts of the compounds according to the invention as well as so-called prodrug compounds.

As used herein and unless otherwise indicated, the term "prodrug" refers to derivatives of a compound of formula I that can hydrolyze, oxidize, or otherwise 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 biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. In certain embodiments, prodrugs of compounds having carboxyl functionality are lower alkyl esters of carboxylic acids. The carboxylic acid ester is suitably formed by esterifying any carboxylic acid moieties present on the molecule. Prodrugs are typically prepared using well known methods, such as those described in Burger's medicinal chemistry and Drug Discovery, 6 th edition (ed by Donald J. Abraham, 2001, Wiley) and design and Application of precursors (coded by H.Bundgaard, 1985, Harwood Academic publishers Gmfh).

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

In addition, the expression "therapeutically effective amount" denotes an amount which has the following result compared to the corresponding individual not receiving the amount:

improving the treatment, curing, preventing or eliminating a disease, syndrome, condition, symptom, disorder or side effect or also reducing the progression of a disease, symptom or disorder.

The expression "therapeutically effective amount" also encompasses an amount effective to increase normal physiological function.

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

These are particularly preferably mixtures of stereoisomeric compounds.

"tautomer" refers to isomeric forms of a compound that are in equilibrium with each other. The concentration of the isomeric form will depend on the environment in which the compound is present and may vary depending on, for example, whether the compound is a solid or in an organic or aqueous solution.

The invention relates to compounds of formula (I) and salts thereof, and to a process for the preparation of compounds of formula (I) and pharmaceutically acceptable salts, solvates, tautomers and stereoisomers thereof, characterized in that

Reacting a compound of formula II

Wherein R is¹And R²Having the meaning indicated in claim 1,

with compounds of the formula III

Wherein R is³Having the meaning indicated in claim 1,

and reacting with phosgene or triphosgene,

and/or

Converting a base or acid of formula I into one of its salts.

In this context, the radical R¹、R²、R³Have the meanings indicated in formula I, unless otherwise specifically indicated.

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

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

Further, A preferably represents CH₂OCH₃、CH₂CH₂OH or CH₂CH₂OCH₃。

A also preferably represents unbranched or branched alkyl having 1 to 8C atoms in which one or two non-adjacent CH groups₂The radical may be replaced by an O atom.

R¹Preferably represents methyl, ethyl, 2-hydroxyethyl or CH₂COOEt。

R²Preferably represents Ar.

R³Preferably represents Ar.

R³Particularly preferably Ar or Het¹。

R⁴Preferably represents H, methyl, ethyl, propyl or butyl.

Ar preferably represents o-, m-or p-tolyl, o-, m-or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m-or p-isopropylphenyl, o-, m-or p-tert-butylphenyl, o-, m-or p-hydroxyphenyl, o-, m-or p-nitrophenyl, o-, m-or p-aminophenyl, o-, m-or p- (N-methylamino) phenyl, o-, m-or p- (N-methylaminocarbonyl) phenyl, o-, m-or p-methoxyphenyl, o-, m-or p-ethoxyphenyl, o-, m-or p-ethylphenyl, o-, m-or p-isopropylphenyl, o-, m-or p-tert-butylphenyl, M-or p-ethoxycarbonylphenyl, o-, m-or p- (N, N-dimethylamino) phenyl, o-, m-or p- (N, N-dimethylaminocarbonyl) phenyl, o-, m-or p- (N-ethylamino) phenyl, o-, m-or p- (N, N-diethylamino) phenyl, o-, m-or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m-or p-chlorophenyl, o-, m-or p- (methylsulfonylamino) phenyl, o-, m-or p- (methylsulfonyl) phenyl, o-, m-or p-cyanophenyl, o-, m-or p-dimethylamino-phenyl, o-, m-or p-diethylamino-phenyl, o-, m-or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m-or p-chlorophenyl, o-, o-, m-or p-carboxyphenyl, o-, m-or p-methoxycarbonylphenyl, o-, m-or p-formylphenyl, o-, m-or p-acetylphenyl, o-, m-or p-aminosulfonylphenyl, furthermore preferably 2,3-, 2,4-,2,5-, 2,6-, 3, 4-or 3, 5-difluorophenyl, 2,3-, 2,4-,2,5-, 2,6-, 3, 4-or 3, 5-dichlorophenyl, 2,3-, 2,4-,2,5-, 2,6-, 3, 4-or 3, 5-dibromophenyl, 2, 4-or 2, 5-dinitrophenyl, 2, 5-or 3, 4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro-or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino-or 3-nitro-4-N, N-dimethylaminophenyl, 2, 3-diaminophenyl, 2,3,4-, 2,3,5-,2,3,6-, 2,4, 6-or 3,4, 5-trichlorophenyl, trichlorophenyl, 2,4, 6-trimethoxyphenyl, 2-hydroxy-3, 5-dichlorophenyl, p-iodophenyl, 3, 6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2, 5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2, 5-dimethyl-4-chlorophenyl.

Ar furthermore preferably represents phenyl which is unsubstituted or substituted by Hal, CN, A, OA, NHSO₂A and/or Het²Mono-or di-substituted.

Het¹Preferably represents pyridyl, which may be monosubstituted by OA.

Throughout the present invention, all groups appearing more than once may be the same or different, i.e. independent of each other.

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

The present invention therefore relates in particular to compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of the compounds can be represented by the following sub-formulae Ia to Id, which correspond to formula I and in which the groups not specified in more detail have the meaning indicated for formula I, but wherein

In Ia Ar represents phenyl which is unsubstituted or substituted by Hal, CN, A, OA, NHSO₂A and/or Het²Mono-or di-substituted;

in Ib A represents unbranched or branched alkyl having 1 to 8C atoms,

in which one or two non-adjacent CH₂The radical may be replaced by an O atom;

in Ic R¹Represents A or CH₂COOA，

R²、R³Represents Ar, and represents the compound of formula (I),

R¹and R²Together with the N atom to which they are attached represent a heterocycle selected from 2, 3-dihydro-indolyl or 3, 4-dihydro-quinolyl,

ar represents phenyl which is unsubstituted or substituted by Hal, CN, A, OA, NHSO₂A and/or Het²Mono-, di-or tri-substituted,

R⁴represents H or A',

a represents an unbranched or branched alkyl radical having 1 to 8C atoms in which one or two non-adjacent CH groups₂The radical may be replaced by an O atom,

a' represents unbranched or branched alkyl having 1,2,3 or 4C atoms,

Het²represents pyrazolyl, which can be substituted by A or (CH)₂)_nHet³The substitution is carried out by the following steps,

Het³represents pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, each of which may be substituted by A,

hal represents F, Cl, Br or I,

m represents 0, 1 or 2,

n represents 1,2,3 or 4;

in Id R¹Represents A or CH₂COOA，

R²Represents Ar, and represents the compound of formula (I),

R³represents Ar or Het¹，

R¹And R²Together with the N atom to which they are attached represent a heterocycle selected from 2, 3-dihydro-indolyl or 3, 4-dihydro-quinolyl,

ar represents phenyl which is unsubstituted or substituted by Hal, CN, A, OA, NHSO₂A and/or Het²Mono-or diThe substitution is carried out by the following steps,

R⁴represents H or A',

a represents an unbranched or branched alkyl radical having 1 to 8C atoms in which one or two non-adjacent CH groups₂The radical may be replaced by an O atom,

a' represents unbranched or branched alkyl having 1,2,3 or 4C atoms,

Het¹represents pyridyl, which may be monosubstituted by OA,

Het²represents pyrazolyl, which can be substituted by A or (CH)₂)_nHet³The substitution is carried out by the following steps,

Het³represents pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, each of which may be substituted by A,

hal represents F, Cl, Br or I,

m represents 0, 1 or 2,

n represents 1,2,3 or 4;

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

Furthermore, the compounds of the formula I and the starting materials for their preparation are prepared by processes known per se, as described in the literature (for example in standard textbooks, such as Houben-Weyl, Methoden der organischen Chemistry [ methods of Organic Chemistry ], Georg-Thieme-Verlag, Stuttgart), in particular under reaction conditions which are known and suitable for the reaction in question. Variants known per se, which are not mentioned in more detail herein, can also be used here.

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

Preferably, the compounds of formula I can be obtained by reacting a compound of formula II with a compound of formula III and with phosgene or triphosgene.

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

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

Depending on the conditions used, the reaction time is from minutes to 14 days and the reaction temperature is from about-30 to 140 °, usually from-10 to 60 °, in particular from about 0 to about 30 °.

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

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

Pharmaceutically salts and other forms

The compounds according to the invention can be used in their final non-salt form. In another aspect, the invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts, which can be obtained from a variety of organic and inorganic acids and bases by methods known in the art. The pharmaceutically acceptable salt forms of the compounds of formula I are prepared in large part by conventional methods. If the compound of formula I contains a carboxyl group, one of its suitable salts may be formed by reacting the compound with a suitable base to give the corresponding base addition salt. The base is, for example, an alkali metal hydroxide including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alkoxides such as potassium ethoxide and sodium propoxide; and various organic bases such as 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 may be formed by treating these compounds with the following pharmaceutically acceptable organic and inorganic acids: for example hydrogen halides, such as hydrogen chloride, hydrogen bromide or hydrogen iodide; other inorganic acids and their corresponding salts, such as sulfates, nitrates or phosphates, etc.; and alkyl and monoaryl sulfonates such as ethane sulfonate, toluene sulfonate and benzene sulfonate; and other organic acids and their corresponding salts, such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate, and the like. Thus, pharmaceutically acceptable acid addition salts of the compounds of formula I include the following: acetate, adipate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, formate, galactarate (galactarate) (from mucic acid), galacturonate, glucoheptonate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, etc, Lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmitate (palmoate), pectate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this does not represent a limitation.

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

The compounds of the invention containing basic nitrogen-containing groups may be quaternized using, for example, the following reagents: (C)₁-C₄) Alkyl halides such as methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; two (C)₁-C₄) Alkyl sulfates such as dimethyl, diethyl, and diamyl sulfates; (C)₁₀-C₁₈) Alkyl halides such as decyl, dodecyl, lauryl, myristyl and octadecyl chlorides, bromides and iodides; and aryl (C)₁-C₄) Alkyl halides, such as benzyl chloride and phenethyl bromide. Water-solubility according to the invention andboth oil soluble compounds can be prepared using the salts.

Preferred such pharmaceutical salts include, but are not intended to be limiting, 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.

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

Acid addition salts of the basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid to cause the salt to form in conventional form. The free base may be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base form differs from its corresponding salt form in some respect with respect to certain physical properties such as solubility in polar solvents; however, for the purposes of the present invention, the salts are otherwise identical to their corresponding free base forms.

As mentioned, pharmaceutically acceptable base addition salts of compounds of formula I are formed with metals or amines, such as alkali 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.

The base addition salts of acidic compounds according to the invention are prepared by contacting the free acid form with a sufficient amount of the desired base to cause the salt to form in a conventional manner. The free acid may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid form differs from its corresponding salt form in some respect with respect to certain physical properties such as solubility in polar solvents; however, for the purposes of the present invention, the salts are otherwise identical to their corresponding free acid forms.

If the compounds according to the invention contain more than one group capable of forming a pharmaceutically acceptable salt of this type, the invention also covers multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, hydrogen fumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to represent a limitation.

With regard to the above, it can be seen that the expression "pharmaceutically acceptable salt" in this respect is used to refer to an active ingredient which comprises a compound of formula I in the form of one of its salts, which salt form confers improved pharmacokinetic properties on the active ingredient, in particular if compared to the free form of the active ingredient or any other salt form of the active ingredient used previously. The pharmaceutically acceptable salt forms of the active ingredients may also provide the active ingredient for the first time with desirable pharmacokinetic properties not previously present and may even have a favorable effect on the pharmacodynamics of the active ingredient with respect to its therapeutic efficacy in vivo.

Isotope of carbon monoxide

It is further intended that the compounds of formula I include isotopically labeled forms thereof. Isotopically-labelled forms of the compounds of formula I are identical to those of the compounds described except for the fact that one or more atoms of the compound have been replaced by one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the atom(s) usually found in nature. Examples of readily available isotopes which can be incorporated into compounds of formula I by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example each²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Compounds of formula I containing one or more of the foregoing isotopes and/or other isotopes of other atoms, and methods of making the sameA prodrug or a pharmaceutically acceptable salt of either is intended to be part of the present invention. Isotopically-labelled compounds of formula I can be used in a number of advantageous ways. For example, having incorporated therein, for example, radioactive isotopes such as³H or¹⁴The isotopically labeled compounds of formula I of C are suitable for use in drug and/or substrate tissue distribution assays. These radioactive isotopes, i.e. tritium (A)³H) And carbon-14 (¹⁴C) This is particularly preferred due to the simplicity of preparation and excellent detectability. By reaction of heavier isotopes such as deuterium (²H) The incorporation of compounds of formula I has therapeutic advantages due to the higher metabolic stability of the isotopically labeled compounds. Higher metabolic stability translates directly into an increased in vivo half-life or a decreased dose, which in most cases will represent a preferred embodiment of the invention. Isotopically labeled compounds of formula I can generally be prepared by carrying out the procedures disclosed in the synthetic schemes and associated descriptions, examples, and preparations herein to replace a non-isotopically labeled reactant with a readily available isotopically labeled reactant.

Deuterium (D) for the purpose of manipulating the oxidative metabolism of compounds by the first-order kinetic isotope effect²H) May also be incorporated into the compounds of formula I. The first order kinetic isotope effect is a rate change in chemical reactions caused by the exchange of isotope nuclei, which in turn is caused by a change in ground state energy necessary for covalent bond formation after the isotope exchange. Exchange of heavier isotopes generally causes a reduction in the ground state energy of the chemical bonds and hence a reduction in the rate of rate-limiting bond cleavage. If bond breakage occurs in or near the saddle point region along the coordinates of the multi-product reaction, the product distribution ratio will change significantly. For purposes of explanation: if deuterium is bonded to a carbon atom in a position which is not exchangeable, k_M/k_DA rate difference of = 2-7 is typical. If this difference is successfully applied to a compound of formula I that is sensitive to oxidation, the profile of the compound in vivo can be dramatically altered and result in improved pharmacokinetic properties.

In discovering and developing therapeutic agents, one skilled in the art attempts to optimize pharmacokinetic parameters while preservingMaintaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are sensitive to oxidative metabolism. The currently available in vitro liver microsomal assays provide valuable information on this type of oxidative metabolic processes, which in turn allows rational design of deuterated compounds of formula I with improved stability via resistance to said oxidative metabolism. A significant improvement in the pharmacokinetic profile of the compound of formula I is thus obtained, and may be based on the in vivo half-life (t/2), the concentration at which the maximum therapeutic effect is achieved (C)_max) Increase in area under the dose response curve (AUC) and F; and quantitatively expressed in terms of clearance, dosage and reduction in material costs.

The following is intended to illustrate the above: compounds of formula I having multiple potential sites of oxidative metabolic attack, such as benzylic hydrogen atoms and hydrogen atoms bonded to nitrogen atoms, are prepared as a series of analogs in which the hydrogen atoms of various combinations are replaced by deuterium atoms such that some, most, and all of these hydrogen atoms are replaced by deuterium atoms. The half-life measurement enables a favorable and accurate measurement of the degree of improvement in resistance to oxidative metabolism. In this way, it was determined that the half-life of the parent compound could be extended up to 100% due to this type of deuterium-hydrogen exchange.

Deuterium-hydrogen exchange in the compounds of formula I can also be used to achieve an advantageous modification of the metabolite profile of the starting compounds to reduce or eliminate unwanted toxic metabolites. For example, if toxic metabolites are produced via the cleavage of oxidized carbon-hydrogen (C-H) bonds, it is reasonable to assume that deuterated analogs will greatly reduce or eliminate the production of unnecessary metabolites, even if the particular oxidation is not a rate limiting step. Further information on the state of the art for deuterium-hydrogen exchange can be found, for example, in: hanzlik et al, J.org. chem. 55, 3992-; 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-; and Jarman et al, Carcinogenesis 16(4), 683-.

The invention furthermore relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or auxiliaries.

Pharmaceutical formulations may be administered in dosage unit form containing a predetermined amount of active ingredient per dosage unit. Such units may comprise, for example, from 0.5 mg to 1 g, preferably from 1mg to 700 mg, particularly preferably from 5 mg to 100 mg, of a compound according to the invention, depending on the condition to be treated, the method of administration and the age, weight and condition of the patient, or pharmaceutical preparations may be administered in dosage unit form comprising a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those containing a daily dose or a divided dose of the active ingredient as indicated above, or a corresponding fraction thereof. In addition, pharmaceutical formulations of this type may be prepared using methods generally known in the pharmaceutical art.

The pharmaceutical formulation may be adapted for administration via any desired suitable method, 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. The formulations may be prepared using all methods known in the pharmaceutical art, for example by combining the active ingredient with excipients or auxiliaries.

Pharmaceutical formulations adapted for oral administration may be administered as discrete units, such as capsules or tablets; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

Thus, for example, in the case of oral administration in the form of tablets or capsules, the active ingredient component may be combined with an oral, non-toxic and pharmaceutically acceptable inert excipient such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable small size and mixing it with a pharmaceutical excipient, such as an edible carbohydrate, for example starch or mannitol, which is comminuted in a similar manner. Flavoring, preservative, dispersing and coloring agents may also be present.

Capsules are produced by preparing a powder mixture as described above and filling shaped gelatin shells with it. Glidants and lubricants, for example highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. Disintegrating or solubilizing agents such as agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after taking the capsule.

The present invention relates to a process for the preparation of a pharmaceutical composition comprising a mixture of a starch, gelatin, a natural sugar such as glucose or β -lactose, a sweetening agent made from corn, natural and synthetic rubbers such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like, a process for the preparation of a pharmaceutical composition comprising the step of granulating or press-drying the mixture, adding a lubricant and a disintegrating agent and pressing the whole mixture to give a tablet, a process for the preparation of a powder mixture by mixing a suitably comminuted compound with a diluent or matrix as described above and optionally a binder such as carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a dissolution retardant such as paraffin, an absorption accelerating agent such as a quaternary salt, and/or an absorption accelerating agent such as bentonite, a bentonite or a talc, and optionally a wetting agent.

Oral liquids such as solutions, syrups and elixirs may be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution with a suitable flavoring agent, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions may be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether; a preservative; flavoring additives, such as peppermint oil; or natural sweeteners or saccharin; or other artificial sweeteners, and the like.

Dosage unit formulations for oral administration may be encapsulated in microcapsules, if desired. The formulations may also be prepared in a delayed or retarded release manner, for example by coating or embedding the particulate material in a polymer, wax or the like.

The compounds of formula I and pharmaceutically salts, tautomers and stereoisomers thereof can also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, octadecylamine or phosphatidylcholine.

The compounds of formula I and salts, tautomers and stereoisomers thereof can also be delivered using monoclonal antibodies as separate carriers to which the compound molecules are coupled. The compounds may also be coupled to soluble polymers as targeted drug carriers. The polymer may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamylphenol, or polyethylene oxide polylysine (substituted with palmitoyl groups). The compounds may additionally be coupled to a class of biodegradable polymers suitable for achieving controlled release of drugs, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphiphilic block copolymers of hydrogels.

Pharmaceutical formulations suitable for transdermal administration may be administered as a separate ointment for prolonged intimate contact with the epidermis of the recipient. Thus, for example, the active ingredient may be delivered from the paste by iontophoresis, as described in general terms in pharmaceutical research, 3(6), 318 (1986).

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

For the treatment of the eye or other external tissues such as mouth and skin, the formulation is preferably applied as a topical ointment or cream. In the case of formulations which produce ointments, the active ingredient may be employed with either a paraffinic or a water-miscible cream base. Alternatively, the active ingredients may be formulated together with an oil-in-water cream base or a water-in-oil base to produce a cream.

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

Pharmaceutical formulations suitable for topical administration in the mouth include lozenges, pastilles and mouthwashes.

Pharmaceutical preparations suitable for rectal administration may be administered in the form of suppositories or enemas.

Pharmaceutical preparations suitable for nasal administration in which the carrier material is a solid include coarse powders having a particle size, for example, in the range of 20-500 microns, which are administered by inhalation of the olfactory formulation, i.e., by rapid inhalation through the nasal passage from a powder-containing container held close to the nose. Suitable formulations for administration as nasal sprays or nasal drops with liquid as carrier material include solutions of the active ingredient in water or oil.

Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of pressurised dispensers, nebulisers or insufflators, with aerosols.

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 aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions which may contain a suspending medium and a thickening agent. The formulations may be administered in single-or multi-dose containers, such as sealed ampoules and vials, and stored in a freeze-dried (lyophilized) condition, so that only a sterile carrier liquid, for example water for injection purposes, needs to be added immediately prior to use. Injections and suspensions prepared according to this formulation can be prepared from sterile powders, granules and tablets.

It goes without saying that, with regard to the particular formulation type, the formulation may contain, in addition to the ingredients specifically mentioned above, other agents commonly used in the art; thus, for example, formulations suitable for oral administration may contain flavoring agents.

The therapeutically effective amount of a compound of formula I will depend on a number of factors including, for example, the age and weight of the animal, the precise condition to be treated and its severity, the nature of the formulation and the method of administration, and will ultimately be determined by the treating physician or veterinarian. However, an effective amount of a compound according to the invention is generally in the range of 0.1-100 mg/kg body weight of the recipient (mammal) per day and particularly typically in the range of 1-10 mg/kg body weight per day. Thus, the actual amount per day for an adult mammal having a body weight of 70 kg is typically 70-700 mg, wherein the amount may be administered in a single daily dose or typically in a series of multiple doses per day (e.g. 2,3,4, 5 or 6), such that the total daily dose is the same. An effective amount of a salt or solvate, or physiologically functional derivative thereof, may be determined as part of the effective amount of the compound of the invention itself. Similar dosages may be assumed to be appropriate for the treatment of the other conditions described above.

This type of combination therapy can be achieved by means of simultaneous, sequential or separate dispensing of the individual components of the therapy. This type of combination product employs the compounds according to the invention.

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

The invention also relates to a set (kit) consisting of the following individual packages:

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

and

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

The kit comprises suitable containers, such as boxes (boxes), individual bottles, bags or ampoules. The kit may for example comprise separate ampoules, each containing an effective amount of a compound of formula I and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios,

and an effective amount of other pharmaceutically active ingredients in dissolved or lyophilized form.

As used herein, "treating" or "treatment" refers to alleviating, in whole or in part, symptoms associated with a disorder or disease, or slowing or halting further progression or worsening of those symptoms, or preventing a disease or disorder in an individual at risk of developing the disease or disorder.

The term "effective amount" with respect to a compound of formula (I) may refer to an amount capable of completely or partially alleviating the symptoms associated with a disorder or disease, or slowing or halting further progression or worsening of those symptoms, or preventing or providing prophylaxis of a disease or disorder in an individual having or at risk of developing a disease disclosed herein, such as an inflammatory condition, an immune condition, a cancer, or a metabolic condition.

In one embodiment, an effective amount of a compound of formula (I) is an amount that inhibits tankyrase in a cell, e.g., in vitro or in vivo. In some embodiments, the effective amount of the compound of formula (I) inhibits tankyrase in a cell by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 99% compared to the activity of tankyrase in an untreated cell. An effective amount of a compound of formula (I), for example in a pharmaceutical composition, may be at a level to produce the desired effect; for example, for both oral and parenteral administration, from about 0.005 mg/kg to about 10 mg/kg of the individual's body weight in a unit dose.

Use of

The compounds of the invention are suitable as pharmaceutically active ingredients for mammals, in particular humans, for the treatment of cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury and different forms of inflammation.

The invention includes the use of a compound of formula I and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof in the manufacture of a medicament for the treatment or prevention of cancer, multiple sclerosis, cardiovascular disease, central nervous system injury, and different forms of inflammation.

Examples of inflammatory diseases include rheumatoid arthritis, psoriasis, contact dermatitis, delayed type 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, wherein for this method a therapeutically effective amount of a compound of the invention is administered to a diseased mammal in need of such treatment, in the manufacture of a medicament for the treatment or prevention of a tankyrase-induced disease or a tankyrase-induced condition in a mammal. The amount of treatment will vary depending on the particular disease and can be determined by one skilled in the art without undue effort.

The expression "tankyrase-induced disease or condition" refers to a pathological condition which is dependent on the activity of one or more tankyrase enzymes. Diseases associated with tankyrase activity include cancer, multiple sclerosis, cardiovascular disease, central nervous system injury and different forms of inflammation.

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

The invention relates in particular to compounds of the formula I and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for use in the inhibition of tankyrase.

The invention relates in particular to compounds of the formula I and to their pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all ratios, for use in the treatment of cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury and different forms of inflammation.

The present invention relates inter alia to a method for the treatment or prevention of cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury and different forms of inflammation, comprising administering to a subject in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt, tautomer, stereoisomer or solvate thereof.

Representative cancers for which compounds of formula I may be useful in the treatment or prevention include, but are not limited to, cancers of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, cervix, breast, ovary, testis or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, central nervous system, solid tumors, and blood-borne tumors (blood-borne tumors).

Representative cardiovascular diseases for which compounds of formula I may be useful include, but are not limited to, restenosis, atherosclerosis, and its consequences such as stroke, myocardial infarction, ischemic injury to the heart, lung, intestine, kidney, liver, pancreas, spleen, or brain.

The present invention relates to methods of treating proliferative, autoimmune, anti-inflammatory, or infectious disease conditions comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I.

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

Particularly preferred the invention relates to a method wherein the disease is cancer, wherein the administration is simultaneous, sequential or alternating with the administration of the at least one further active agent.

The disclosed compounds of formula I may be administered in combination with other known therapeutic agents, including anticancer agents. As used herein, the term "anti-cancer agent" relates to any agent administered to a cancer patient for the purpose of treating cancer.

The anti-cancer treatment defined above may be applied as monotherapy or may involve conventional surgery or radiotherapy or drug treatment in addition to the compounds of formula I disclosed herein. Such drug therapies, such as chemotherapy or targeted therapy, may include one or more, but preferably are one of the following antineoplastic agents:

alkylating agent

Such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, mechlorethamine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosylate, lomustine, melphalan, dibromomannitol, dibromodulcitol, nimustine, ramustine, temozolomide, thiotepa, busulfan, mechlororetamine, carboquone, apaziquone, fotemustine, glufosfamide, palimide, palivamide, piprazine, trofosfamide, uracil mustard, TH-302⁴、VAL-083⁴；

Platinum compounds

Such as carboplatin, cisplatin, eptaplatin, miriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin;

DNA altering agents

Such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine, Bronstallicin, Pickerosetron, and larmoustine^1,3；

Topoisomerase inhibitors

Such as etoposide, irinotecan, razoxane, sobuzole, teniposide, topotecan; amonafide, belotecan, etiloamine, voreloxin;

microtubule modulators

Such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine, combretastatin (fosbreetallin), tesetaxel;

antimetabolites

Such as asparaginase³Azacitidine, levofolinic acid calcium, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed, sapatibine, tegafur^2,3Trimetrexate;

anticancer antibiotics

Such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, setastatin, zorubicin, daunomycin, mithramycin; doxorubicin, pelargycin, doxorubicin pyrans;

hormone/antagonist

Such as abarelix, abiraterone, bicalutamide, buserelin, carroterone, tris-metoxychloroethylene, degarelix, dexamethasone, estradiol, fluocortolone, flutolmetin, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyroid stimulating hormone α, toremifene, tromestane, triptorelin, diethylstilbestrol, acolbifene, danazol, dessertraline, epitioandrostel, enzel, enzalutamide^1,3；

Aromatase inhibitors

Such as aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; 2, fulvestrant;

small molecule kinase inhibitors

Such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, doratinib, enzastarin, nintedanib, lenvatinib, linitinib, masitinib, midostaurin, motexenib, neratinib, oranatinib, pirifosfacin, ponatinib, ladostitinib, rigoretinib, tipifarnib, alanatinib, cedanib, apatinib, apratinib, tipifanib, tivatinib, tivozanib, trametinib, pimasetib, alaninebrib, sildenib, apatinib, dacatinib, dacetinib, getinib, etc⁴Carbometinib S-malate salt^1,3Ibrutinib, ibrutinib^1,3Icotinib⁴、buparlisib²、cipatinib⁴、cobimetinib^1,3、idelalisib^1,3、fedratinib¹、XL-647⁴；

Photosensitizers

Such as methoxsalen³Porfimer sodium, talaporfin, temoporfin;

antibodies

Such as alemtuzumab, bexisoma, bernetuzumab-vedottin, cetuximab, dinosememe, yiprizumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab^2,3Rituzumab, elotuzumab, epratuzumab, farlettuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, ocatatuzumab, ogovazumab, ramucirumab, rituximab, stetuximab, tositumumab, zalutumab, zamumab, matuzumab, trastuzumab^1,2,3、onartuzumab^1,3Ratumocumab¹、tabalumab^1,3、EMD-525797⁴、nivolumab^1,3；

Cytokine

Such as aldesleukin, interferon α²Interferon α 2a³Interferon α 2b^2,3Simethin, tasolomin, tesil, olpril^1,3Recombinant interferon β -1a⁴；

Drug conjugates

Such as a dinil-toxin linker, ibritumomab tiuxetan, robenidine I123, prednimustine, trastuzumab-emtansine, estramustine, gemtuzumab, oxzolmitrin, aflibercept; cintredekin besedotox, edrotacin, obinutuzumab, namomab, moebizumab, technetium (99mTc), acipimox mab^1,3、vintafolide^1,3；

Vaccine

Such as sipuleucel³Vietsbone, vietsbone³、emepepimut-S³、oncoVAX⁴、rindopepimut³、troVax⁴、MGN-1601⁴、MGN-1703⁴；

Other drugs

Aliretin A acid, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lentinan, methyltyrosine, mivampicin, pamidronic acid, pegapase, pentostatin, sipuleucel³Cilostase, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib, lonidamine, nimorazole, panobinostat, peretinoin, plipidepsin, pomalidomide, procodazol, ridaforolimus, taqimod, telotristat, thymalfasin, tirapazamine, tolodestat, trabedersen, ubenimex, valceplata, today's (genicine)⁴Streptococcus lysis⁴、reolysin⁴Ruitamycin hydrochloride^1,3、trebananib^2,3Viluliqin, viluliqin⁴Carfilzomib^1,3Endostatin⁴、immucothel⁴、belinostat³、MGN-1703⁴；

¹Prop. INN (proposed International non-exclusive name)

²Rec, INN (International non-exclusive name for recommendation)

³USAN (names adopted in the United states)

⁴No INN.

The following abbreviations refer to the following definitions, respectively:

aq (aqueous), h (hours), g (g), L (L), mg (mg), MHz (megahertz), min. (min), mM (mM), mmol (mmol), mM (mmol equivalents), m.p. (melting point), eq (equivalents),mL (mL), L (microliter), ACN (acetonitrile), AcOH (acetic acid), CDCl₃(deuterated chloroform), CD₃OD (deuterated methanol), CH₃CN (acetonitrile), c-hex (cyclohexane), DCC (dicyclohexylcarbodiimide), DCM (dichloromethane), DIC (diisopropylcarbodiimide), DIEA (diisopropylethylamine), DMF (dimethylformamide), DMSO (dimethyl sulfoxide), DMSO-d₆(deuterated dimethyl sulfoxide), EDC (1- (3-dimethyl-amino-propyl) -3-ethylcarbodiimide), ESI (electrospray ionization), EtOAc (ethyl acetate), Et₂O (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), K₂CO₃(Potassium carbonate), LC (liquid chromatography), MeOH (methanol), MgSO₄Magnesium sulfate, MS (Mass Spectrometry), MTBE (methyl Tert-butyl Ether), NaHCO₃(sodium bicarbonate), NaBH₄(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 assays

Abbreviations:

GST = glutathione-S-transferase

FRET = fluorescence resonance energy transfer

HTRF = (homogeneous phase time resolved fluorescence)

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

DTT = dithiothreitol

BSA = bovine serum albumin

CHAPS = detergent;

CHAPS = 3- [ (3-cholamido (cholenamido) propyl) dimethylammonio (ammonio) ] -1-propanesulfonate.

streptavidin-XLent is a high grade streptavidin-XL 665 conjugate for which coupling conditions have been optimized to produce conjugates with enhanced performance for some assays, particularly assays requiring high sensitivity.

Biochemical activity testing of tankyrase 1 and 2: automated poly ADP nuclear glycation (autopropsy) assay

The autopolyadp ribosylation assay was performed in two steps: enzymatic reactions (where GST-labeled tankyrase-1, resp tankyrase-2 transfer biotinylated ADP-ribose to itself from biotinylated NAD as a common substrate) and detection reactions (where time resolved FRET between cryptate-labeled anti-GST bound to GST tags of the enzyme and Xlent @ labeled-streptavidin bound to biotin-poly ADP riboylated residues) were analyzed. Autopolyadp ribosylation activity can be detected directly via an increase in HTRF signal.

The automated poly ADP ribosylation assay was performed as a 384-well HTRF (Cisbio, Codolet, France) assay format in Grarner low (Greiner low volume) nb 384-well microtiter plates and used for high throughput screening. 250 nM GST-labeled Takara polymerase-1 (1023 + 1327 aa), approximately 250 nM GST-labeled Takara polymerase-2 (873 + 1166 aa) and 5 μ M bio-NAD (Biolog, Life science Inst., Bremen, Germany), respectively, were incubated in a total volume of 5 μ l (50 mEPMHES, 4 mM magnesium chloride, 0.05% Prorhenike F-68, 1.4 mM DTT, 0.5% DMSO, pH 7.7) at 30 ℃ for 90 min in the absence or presence of test compounds (10-fold dilution). The reaction was stopped by adding 1 μ l of 50mM EDTA solution. 2 μ l of detection solution (1.6 μ M SA-Xlent ® (Cisbio, Codolet, France), 7.4 nM anti-GST-K (Eu-labeled anti-GST, Cisbio, Codolet, France) was added in 50mM HEPES, 800 mM KF, 0.1% BSA, 20mM EDTA, 0.1% CHAPS, pH 7.0). After 1 hour incubation at room temperature, HTRF was measured with an Envision multimode reader (Perkin Elmer LASGermany GmbH) at an excitation wavelength of 340 nm (laser mode) and emission wavelengths of 615 nm and 665 nm. The ratio of the emitted signals is determined. The full value used is the inhibitor-free reaction. The pharmacological zero value used was XAV-939 (Tocris) in a final concentration of 5 μ M. The inhibition values (IC50) were determined using the program Symyx Assay Explorer @orCondosseo @fromGeneData.

Determination of the cytostatic Effect of tankyrase

Since tankyrase has been described as modulating the cellular level of Axin2 (Huang et al, 2009; Nature), an increase in Axin2 levels was used as a readout to determine the cytostatic effect of tankyrase in a Luminex-based assay.

Cells of colon cancer cell line DLD1 were plated at 1.5x10 per well⁴Individual cells were seeded in 96-well plates. The following day, cells were treated with serially diluted test compounds in triplicate at 0.3% final DMSO concentration in 7 steps. After 24 hours, cells were lysed in lysis buffer (20mM Tris/HCl pH 8.0, 150mM NaCl, 1% NP40, 10% glycerol) and the lysate was cleared by centrifugation through 96-well filter plates (0.65 μm). By binding to monoclonal anti-Axin 2 antibody (R) bound to fluorescent carboxyl beads (carboxybeads)&D Systems # MAB6078) were incubated together to isolate Axin2 protein from the cell lysate. Bound Axin2 was then specifically detected with polyclonal anti-Axin 2 antibody (Cell Signaling #2151) and a suitable PE-fluorescent secondary antibody. In Luminex, according to the manufacturer's instructions²⁰⁰The amount of Axin2 protein isolated was determined on the machine (Luminex Corporation) by counting 100 events per well. Inhibition of tankyrase by test compounds resulted in higher levels of Axin2, which was directly correlated with an increase in detectable fluorescence. As a control, cells were treated with solvent only (neutral control) and with the tankyrase reference inhibitor IWR-2 (3E-06M), which refers to the control as the maximum increase to Axin 2. For analysis, the data obtained were normalized to untreated solvent controls and fitted using Assay Explorer software (Accelrys) to determine EC₅₀The value is obtained.

Description of the PARP1 assay

Biochemical activity assay of PARP-1: automated poly ADP ribosylation assay

The autopolyadp ribosylation assay was performed in two steps: enzymatic reactions (where His-tagged Parp-1 transfers biotinylated ADP-ribose/ADP-ribose to itself from biotinylated NAD/NAD as a co-substrate) and detection reactions (where time resolved FRET between cryptate-tagged anti-His antibodies bound to the enzyme's His tag and Xlent @ tagged-streptavidin bound to biotin-poly ADP riboylated residues) were analyzed. Autopolyadp ribosylation activity can be detected directly via an increase in HTRF signal.

Automatic poly ADP ribosylation Assay was performed as 384-well HTRF [ [ Cisbio, Codolet, France ] Assay format in Graham low-volume nb 384-well microtiter plates in the absence or presence of test compounds (10-fold dilution concentration.) A mixture of 35 nM His-tagged Parp-1 [ human, recombinant, Enzo Life Sciences GmbH, L ö rrach, Germany ] and 125 nM bio-NAD [ Biolog, Life Sciences ] Inst, Bremen, Germany ] as co-substrate in a total volume of 6 μ L of total volume of 6 mM Tris HCl, 4 mM magnesium chloride, 0.01% IGEPAL CA630, 1mM DTT, 0.5% DMSO, pH 8, 13 ng/μ L activated DNA [ BPS Bioscience, Sanego, US ] CA630, 1mM DTT, 0.5% DMSO, pH 8, 13 ng/μ L [ mu ] incubated in a multi-mode anti-frequency probe reaction with a final anti-emission rate of 0mM EDTA-5 mM EDTA from a Colint reader after addition of 5mM HESbsoS Biotech probe (Invitro) in a 1mM Biolag Biotech probe, 4 mM Biotech, 1,4 mM EDTA, 5mM, or 1mM EDTA-type probe in a final emission rate of a final anti-L-5 mM reaction.

Description of TNKS1 and TNKS2 ELISA assays

Biochemical activity test of TNKS1 and 2: activity ELISA (automatic poly ADP ribolysis assay)

To analyze the autopolyadp-ribosylation activity of TNKS1 and 2, an activity ELISA was performed: in the first step, GST-tagged TNKS was captured on glutathione-coated plates. The activity assay was then performed with biotinylated NAD in the absence/presence of the compound. During the enzymatic reaction GST-tagged TNKS transferred biotinylated ADP-ribose to itself from biotinylated NAD as co-substrate. For detection, streptavidin-HRP conjugate bound to biotinylated TNKS was added, and thus captured to the plate. The amount of biotinylated resp autopolyadp ribosylated TNKS was detected with a luminescent substrate of HRP. The level of the luminescence signal is directly related to the amount of autopolyadp ribosylated TNKS and thus also to TNKS activity.

The activity ELISA was performed on 384 well Glutathione coated microtiter plates (Express capture Glutathione coated plates), Biocat, Heidelberg, Germany.) the plates were pre-equilibrated with PBS after which the plates were incubated with 50 μ l 20 ng/well GST-labeled Tnks-1 (1023-1327 aa, prepared in-house), GST-labeled Tnks-2 (873-1166 aa, prepared in-house) in Assay buffer (50 mM HEPES, 4 mM magnesium chloride, 0.05% data Pluronic F-68, 2mM DTT, pH 7.7) overnight at 4 ℃ the Assay plates were washed 3 times with PBS-Tween-20. after incubation with PBS-Tween-20. the plates were incubated with 50 μ l blocking buffer (PBS, 0.05% Tween-20, 0.5% BSA) for 20 minutes at room temperature in a luminescence reaction buffer (PBS), after incubation with a maximum 10% Biotech-10 μ G PBS-10 μ M pH test, the reaction was performed with a maximum luminescence detection of the ELISA Assay buffer (10 μ G-10 mM Biotech-10 μ G-PBS) after incubation with a final test for the addition of the pH 1 μ G-10 mM pH-1-PBS, the Assay buffer, the reaction was performed with a luminescence-10-labeled Biotech-labeled protein-labeled protein-labeled.

In this context, all temperatures are expressed in degrees Celsius. In the following examples, "conventional post-processing (work-up)" means: if desired with addition of water, if desired to adjust the pH to 2-10, depending on the composition of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or crystallization. Rf value on silica gel; eluent: ethyl acetate/methanol 9: 1.

¹H NMR was recorded on a Bruker 400 MHz spectrometer using the residual signal of the deuterated solvent as an internal standard. Chemical shifts (. delta.) are reported in ppm relative to residual solvent signal (for the samples in DMSO-d)₆In (1)¹H NMR，δ = 2.49 ppm)。¹H NMR data are reported below: chemical shifts (multiplicity, coupling constants and hydrogen numbers). Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

LCMS-analysis:

method AComprises solvent A of water and 0.1% TFA, solvent B of ACN and 0.1% TFA, flow rate of 2 ml/min, gradient of 0min of 5% B, 8 min of 100% B, 8.1 min of 100% B, 8.5 min of 5% B and 10 min of 5% B.

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

method B10 mM NH as solvent A₄HCO₃Solvent B is ACN, and the flow rate is 1.0 ml/min

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

HPLC:

the method A comprises the following steps:A-0.1 % TFA/H₂o, B-0.1% TFA/ACN flow-2.0 mL/min.

Column XBridge C8 (50X 4.6 mm, 3.5 μm).

Examples

Phenyl (piperidin-4-yl) methanones

1-Acetylpiperidine-4-carboxylic acid (3.0 g, 0.018 mol) was added in small portions to thionyl chloride (10 mL,0.143 mol) and stirred at room temperature for 4 h. The reaction was concentrated under vacuum and co-evaporated with toluene (2 × 200 mL). The residue was dissolved (slightly soluble) in1, 2-dichloroethane and added to a stirred suspension of anhydrous aluminum chloride in benzene (20 mL). The resulting mixture was refluxed for 2h, poured into crushed ice and extracted with chloroform (2 × 200 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried and evaporated to give a brown gum. The resulting gel was refluxed with 6N hydrochloric acid (60 mL) for 6 h. The reaction was cooled to room temperature and washed with diethyl ether (100 mL). The aqueous portion was made basic with 10% sodium hydroxide and extracted with ether (2 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried and evaporated to dryness. The residue was purified by column chromatography eluting with silica gel (60-120) and petroleum ether/ethyl acetate as a gradient to provide the title compound; yield: 1.5g (45%); LCMS (method B) 190.3 (M + H), Rt 2.01 min, purity 85.3%;

。

example 1

4-benzoyl-piperidine-1-carboxylic acid methyl-m-tolyl-amide ("A1")

To a suspension of phenyl (piperidin-4-yl) methanone (0.15 g, 0.79mmol) in DCM (10 mL) was added diisopropylethylamine (0.30 g, 2.37 mmol) followed by the dropwise addition of triphosgene (0.23 g, 0.79mmol) at 0 deg.C. After stirring for 30 min, the reaction was cooled to 0 ℃ and methyl-m-tolyl-amine (0.093 g,0.87 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (20 mL) and washed with 10% sodium bicarbonate (50 mL), 1.5N HCl (50 mL), water (50 mL) and brine (50 mL). Through anhydrous Na₂SO₄The organic layer was dried and evaporated to dryness. The residue was purified by column chromatography using silica gel (60-120) and petroleum ether/ethyl acetate as a gradient elution to provide the title compound in 58 mg (26%); LCMS (method A): 337.2 (M + H), Rt.4.93 min, 99.8% purity (254 nm); HPLC (method A): Rt. 4.84.84 min, 99.8% purity (254 nm);

。

example 2

4-benzoyl-piperidine-1-carboxylic acid methyl-p-tolyl-amide ("A2")

The compound was prepared in analogy to example 1.

Yield 79 mg (35%), (LCMS (method A): 337.3 (M + H), Rt. 5.57.57 min, purity 98.2% (254 nm); HPLC (method A): Rt. 4.86.86 min, purity 97.8% (254 nm);

。

example 3

4-benzoyl-piperidine-1-carboxylic acid (3-methoxy-phenyl) -methyl-amide ("A3")

The compound was prepared in analogy to example 1.

Yield 56 mg (29%), (LCMS (method A): 367.0 (M + H), Rt. 4.73.73 min, purity 96% (254 nm); HPLC (method A): Rt. 4.57.57 min, purity 98.5% (254 nm);

。

example 4

4-benzoyl-piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide ("A4")

The compound was prepared in analogy to example 1.

Yield 28 mg (12%), (LCMS (method A): 353.2 (M + H), Rt. 4.47.47 min, purity 98.9% (254 nm); HPLC (method A): Rt. 4.45.45 min, 99% (254 nm);

。

example 5

4- (4-methyl-benzoyl) -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide ("A5")

The compound was prepared in analogy to example 1.

Yield 132 mg (29%), (LCMS (method A): 367.3 (M + H), Rt. 4.80.80 min, purity 99.9% (254 nm); HPLC (method A): Rt. 4.74.74 min, 99.8% (254 nm);

。

example 6

4- (4-methoxy-benzoyl) -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide ("A6")

The compound was prepared in analogy to example 1.

Yield 8 mg (16%), (LCMS (method A): 383.3 (M + H), Rt. 4.43.43 min, purity 99.7% (254 nm); HPLC (method A): Rt. 4.42.42 min, 99.7% (254 nm);

。

example 7

4- (3-fluoro-benzoyl) -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide ("a7")

The compound was prepared in analogy to example 1.

Yield 77 mg (17%), (LCMS (method A): 371.3 (M + H), Rt. 4.59.59 min, purity 98.3% (254 nm); HPLC (method A): Rt. 4.76.76 min, 98.2% (254 nm);

。

example 8

4- (4-fluoro-benzoyl) -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide ("A8")

The compound was prepared in analogy to example 1.

Yield 8 mg (16%), (LCMS (method A): 371.2 (M + H), Rt. 4.63.63 min, purity 99.6% (254 nm); HPLC (method A): Rt. 4.60.60 min, 99.8% (254 nm);

。

example 9

4- (4-chloro-benzoyl) -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide ("A9")

The compound was prepared in analogy to example 1.

Yield 183 mg (16%), (LCMS (method A): 387.0 (M + H), Rt. 4.93.93 min, purity 99.5% (254 nm); HPLC (method A): Rt. 4.90.90 min, 99.6% (254 nm);

。

example 10

4-benzoyl-piperidine-1-carboxylic acid (3-cyano-phenyl) -methyl-amide ("A10")

The compound was prepared in analogy to example 1.

Yield 4 mg (2%), (LCMS (method A): 405.2 (M + H), Rt. 4.76.76 min, purity 96.8% (254 nm); HPLC (method A): Rt. 4.34.34 min, 94.9% (254 nm);

。

example 11

4-benzoyl-piperidine-1-carboxylic acid (4-cyano-phenyl) -methyl-amide ("A11")

The compound was prepared in analogy to example 1.

Yield 12 mg (5%), (LCMS (method A): 348.0 (M + H), Rt. 4.30.30 min, purity 98.6% (254 nm); HPLC (method A): Rt. 4.46.46 min, 94.9% (254 nm);

。

example 12

4-benzoyl-piperidine-1-carboxylic acid (3-fluoro-phenyl) -methyl-amide ("A12")

The compound was prepared in analogy to example 1.

Yield 23 mg (10%), (LCMS (method A): 341.3 (M + H), RT. 4.68.68 min, purity 99% (254 nm); HPLC (method B): Rt. 6.09.09 min, 94.7% (254 nm);

。

example 13

4-benzoyl-piperidine-1-carboxylic acid (4-fluoro-phenyl) -methyl-amide ("A13")

The compound was prepared in analogy to example 1.

Yield 26 mg (11%), (LCMS (method A): 341.2 (M + H), Rt. 4.70.70 min, purity 98.8% (254 nm); HPLC (method A): Rt. 4.61.61 min, 98.6% (254 nm);

。

example 14

4-benzoyl-piperidine-1-carboxylic acid ethyl- (4-methoxy-phenyl) -amide ("A14")

The compound was prepared in analogy to example 1.

Yield 103 mg (42%), (LCMS (method A): 367.2 (M + H), Rt. 4.82.82 min, purity 100% (254 nm); HPLC (method A): Rt. 4.75.75 min, 100% (254 nm);

。

example 15

4-benzoyl-piperidine-1-carboxylic acid (2-hydroxy-ethyl) - (4-methoxy-phenyl) -amide ("A15")

The compound was prepared in analogy to example 1, and purified by preparative HPLC, yield 13 mg (17%), (LCMS (method A): 383.2 (M + H), Rt. 4.07.07 min, purity 98.2% (254 nm); HPLC (method A): Rt.4.04 min, 98% (254 nm);

。

example 16

(4-benzoyl-piperidin-1-yl) - (2, 3-dihydro-indol-1-yl) -methanone ("A16")

The compound was prepared in analogy to example 1.

Yield 59 mg (26%), (LCMS (method A): 335.2 (M + H), Rt. 4.78.78 min, purity 98.5% (254 nm): HPLC (method A): Rt. 4.74.74 min, 98.5% (254 nm);

。

example 17

(2, 3-dihydro-indol-1-yl) - [4- (4-methyl-benzoyl) -piperidin-1-yl ] -methanone ("A17")

The compound was prepared in analogy to example 1.

Yield 221 mg (52%), (LCMS (method A): 349.2 (M + H), Rt. 5.11.11 min, purity 98.6% (254 nm); HPLC (method A): Rt. 5.05.05 min, 97.2% (254 nm);

。

example 18

(2, 3-dihydro-indol-1-yl) - [4- (4-methoxy-benzoyl) -piperidin-1-yl ] -methanone ("A18")

The compound was prepared in analogy to example 1.

Yield 8 mg (16%), (LCMS (method A): 365.0 (M + H), Rt. 4.70.70 min, purity 99.9% (254 nm); HPLC (method A): Rt. 4.71.71 min, 99.7% (254 nm);

。

example 19

(2, 3-dihydro-indol-1-yl) - [4- (3-fluoro-benzoyl) -piperidin-1-yl ] -methanone ("A19")

The compound was prepared in analogy to example 1.

Yield 60 mg (14%), (LCMS (method A): 353.2 (M + H), Rt. 5.01.01 min, purity 96.8% (254 nm); HPLC (method A): Rt. 5.19.19 min, 96.9% (254 nm);

。

example 20

(2, 3-dihydro-indol-1-yl) - [4- (4-fluoro-benzoyl) -piperidin-1-yl ] -methanone ("A20")

The compound was prepared in analogy to example 1.

Yield 8 mg (16%), (LCMS (method A): 353.2 (M + H), Rt. 4.93.93 min, purity 98.9% (254 nm); HPLC (method A): Rt. 5.19.19 min, 96.9% (254 nm);

。

example 21

[4- (4-chloro-benzoyl) -piperidin-1-yl ] - (2, 3-dihydro-indol-1-yl) -methanone ("A21")

The compound was prepared in analogy to example 1.

Yield 108 mg (26%), (LCMS (method A): 369.0 (M + H), Rt. 5.18.18 min, purity 98% (254 nm); HPLC (method A): Rt. 5.19.19 min, 96.9% (254 nm);

。

example 22

(4-benzoyl-piperidin-1-yl) - (3, 4-dihydro-2H-quinolin-1-yl) -methanone ("A22")

The compound was prepared in analogy to example 1.

Yield 8 mg (16%), (LCMS (method A): 349.2 (M + H), Rt. 4.85.85 min, purity 97.3% (254 nm); HPLC (method A): Rt. 4.84.84 min, 97.6% (254 nm);

。

example 23

Synthesis of 4- (4-methoxy-3-methyl-benzoyl) -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide ("A23")

23.1 piperidine-1, 4-dicarboxylic acid mono-tert-butyl ester

To a solution of piperidine-4-carboxylic acid (20.00 g, 150.20 mmol) in water (200mL) was added sodium hydroxide (18.21 g, 450.61 mmol) followed by dropwise addition of BOC anhydride (38.34 mL, 165.23 mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 16 h and acidified with 10% citric acid. The precipitated solid was collected by filtration, washed with water (100mL) and dried under suction, yield 25.0 g (72%) of a colorless solid (crude product);

LC/MS (method A) 130.2 (M + H; mass of BOC-cleavage), Rt. 3.29.29 min, purity 99%.

23.24- (methoxy-methyl-carbamoyl) -piperidine-1-carboxylic acid tert-butyl ester

To a solution of mono-tert-butyl piperidine-1, 4-dicarboxylate (25.00 g, 107.72 mmol) in DMF (250 mL) was added N, N-diisopropylethylamine (57.01 mL, 323.16 mmol), 1-hydroxybenzotriazole hydrate (1.67 g,10.77 mmol), (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride (25.03 g, 129.27 mmol), followed by O, N-dimethyl-hydroxylamine hydrochloride (11.68 g, 118.49 mmol) in small portions at 0 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 h. 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 x200 mL), 0.5N HCl (2 x100 mL), water (200mL) and brine (200 mL). Through anhydrous Na₂SO₄The organic layer was dried and evaporated in vacuo, yield 24.0 g (81%) of a colorless liquid (crude);

LC/MS (method A): 173.2 (M + H; mass of BOC-cleavage), Rt. 3.54.54 min, purity 99%.

23.34- (4-methoxy-3-methyl-benzoyl) -piperidine-1-carboxylic acid tert-butyl ester

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 dry THF (40 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 min and then warmed to 50 ℃. The mixture was cooled to room temperature and the remaining solution of 4-bromo-2-methylanisole in THF was added dropwise over a period of 20 min. The mixture was stirred at room temperature for a further 2h until the magnesium was completely dissolved. The grignard reagent solution was added dropwise to a solution of 4- (methoxy-methyl-carbamoyl) -piperidine-1-carboxylic acid tert-butyl ester (4.00 g, 14.53 mmol) in THF (40.00 mL) at-78 ℃. The reaction mixture was stirred at room temperature for 15 h. Then, it was cooled to 0 ℃, quenched by saturated ammonium chloride solution (100mL) and extracted with ethyl acetate (2 × 100 mL). The organic layer was washed with 10% sodium bicarbonate (100mL), water (100mL) and brine (100mL) over anhydrous Na₂SO₄Dried and evaporated under vacuum. The crude material was purified by flash chromatography using silica gel (230-;

yield 1.50 g (30%);

LC/MS (method A) 234.3 (M + H; mass of BOC-cleavage), Rt. 5.31.31 min, purity 99%.

23.4 (4-methoxy-3-methyl-phenyl) -piperidin-4-yl-methanone hydrochloride

A solution of 4- (4-methoxy-3-methyl-benzoyl) -piperidine-1-carboxylic acid tert-butyl ester (1.50 g, 4.36 mmol) in dioxane/HCl (3M, 14.53 ml, 43.60 mmol) was stirred at room temperature under a nitrogen atmosphere for 6 h. The solvent was evaporated to dryness under reduced pressure to give the title compound in a yield of 1.10 g (92% crude product);

LC/MS (method A) 234.3 (M + H), Rt. 2.65.65 min, 98% purity.

23.54- (4-methoxy-3-methyl-benzoyl) -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide ("A23")

To a solution of 4-methoxy-N-methylaniline (0.28 g, 2.01mmol) in DCM (10 mL) was added ethyl-diisopropyl-amine (1.61 mL, 9.15 mmol) followed by triphosgene (0.66g, 2.20 mmol) at 0 deg.C under a nitrogen atmosphere. After stirring at 0 ℃ for 1h, (4-methoxy-3-methyl-phenyl) -piperidin-4-yl-methanone hydrochloride (0.50 g, 1.83 mmol) was added and stirred at room temperature for 16 h. The reaction was diluted with DCM (100mL), washed with water (100mL), 10% sodium bicarbonate (2X 100mL), brine (100mL), and dried over anhydrous Na₂SO₄Dried and evaporated under vacuum. The crude material was purified by flash column using silica gel (230- & 400) and petroleum ether/ethyl acetate (0-40%) as eluent in 60 mg (8%);

LC/MS (method A) 397 (M + H), Rt. 4.76.76 min, 100% purity.

Example 24

4- (4-methoxy-3-methyl-benzoyl) -piperidine-1-carboxylic acid ethyl- (4-methoxy-phenyl) -amide ("A24")

The compound was prepared in analogy to example 22 from ethyl- (4-methoxy-phenyl) -amine (0.31 g, 2.01mmol), ethyl-diisopropyl-amine (1.61 mL, 9.15 mmol), triphosgene (0.66g, 2.20 mmol) and (4-methoxy-3-methyl-phenyl) -piperidin-4-yl-methanone hydrochloride (0.50 g, 1.83 mmol) in DCM (10 mL);

purification by preparative HPLC, yield 40 mg (5%);

LC/MS (method A) 411 (M + H), Rt. 5.06.06 min, 100% purity.

Example 25

25.1 piperidin-4-yl-m-tolyl-methanone hydrochloride

The compound was prepared analogously to example 23.1-23.4.

Yield 2.80 g (95% crude);

LC/MS (method A) 204.3 (M + H), Rt. 2.48.48 min, 100% purity.

25.24- (3-methyl-benzoyl) -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide ("A25")

Prepared as described in example 22 from 4-methoxy-N-methylaniline (0.32 g, 2.27mmol), ethyl-diisopropyl-amine (1.82 mL, 10.33 mmol), triphosgene (0.75 g, 2.48 mmol) and piperidin-4-yl-m-tolyl-methanone hydrochloride (0.50 g, 2.07 mmol) in DCM (10 mL).

Purification by flash column chromatography using silica gel (230-;

LC/MS (method A): 367 (M + H), Rt. 4.76.76 min, purity 97%.

Example 26

4- (3-methyl-benzoyl) -piperidine-1-carboxylic acid ethyl- (4-methoxy-phenyl) -amide ("A26")

This compound was prepared in analogy to example 22 from ethyl- (4-methoxy-phenyl) -amine (0.35 g, 2.27mmol), ethyl-diisopropyl-amine (1.82 mL, 10.33 mmol), triphosgene (0.75 g, 2.48 mmol) and piperidin-4-yl-m-tolyl-methanone hydrochloride (0.50 g, 2.07 mmol) in DCM (10 mL).

Purification by flash column chromatography using silica gel (230-;

。

example 27

4- (3-methoxy-benzoyl) -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide ("A27")

This compound was prepared in analogy to example 22 from 4-methoxy-N-methylaniline (0.30 g, 2.15mmol), ethyl-diisopropyl-amine (1.72 mL, 9.76 mmol), triphosgene (0.71 g, 2.34 mmol) and (3-methoxy-phenyl) -piperidin-4-yl-methanone hydrochloride (0.50 g, 1.95 mmol) in DCM (10 mL).

Purification by flash column chromatography using silica gel (230-;

。

example 28

4- (3-methoxy-benzoyl) -piperidine-1-carboxylic acid ethyl- (4-methoxy-phenyl) -amide ("A28")

This compound was prepared in analogy to example 22 from ethyl- (4-methoxy-phenyl) -amine (0.33 g, 2.15mmol), ethyl-diisopropyl-amine (1.72 mL, 9.76 mmol), triphosgene (0.71 g, 2.34 mmol) and (3-methoxy-phenyl) -piperidin-4-yl-methanone hydrochloride (0.50 g, 1.95 mmol) in DCM (10 mL).

Purification by preparative HPLC, yield 17 mg (22%);

LC/MS (method A) 397 (M + H), Rt. 4.81.81 min, 99% purity.

Example 29

4- (3-fluoro-4-methoxy-benzoyl) -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide ("A29")

The compound was prepared in analogy to example 22 from 4-methoxy-N-methylaniline (0.28 g, 1.97mmol), ethyl-diisopropyl-amine (1.57 mL, 8.93 mmol), triphosgene (0.65 g, 2.14 mmol) and (3-fluoro-4-methoxy-phenyl) -piperidin-4-yl-methanone hydrochloride (0.50 g, 1.79 mmol) in DCM (10 mL).

Purification by flash column chromatography using silica gel (230-;

LC/MS (method A) 401.2 (M + H), Rt. 4.55.55 min, 97% pure.

Examples30

Synthesis of 4- {4- [1- (2-methoxy-ethyl) -1H-pyrazol-4-yl ] -benzoyl } -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide ("A30")

30.1 (4-bromo-phenyl) -piperidin-4-yl-methanones

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 at room temperature under a nitrogen atmosphere for 6 h. Thionyl chloride was removed under reduced pressure and the residue co-distilled with DCM (2 × 200 mL). The acid chloride was then added dropwise to a suspension of bromobenzene (27.24 g,171.73 mmol) and anhydrous aluminum chloride (9.25 g, 68.69 mmol) in DCE (200mL) at 0 ℃ under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h, quenched into ice and extracted with DCM (2 × 200 mL). The organic layer was washed with water (2X 200mL), brine (200mL), and dried over anhydrous Na₂SO₄Dried and evaporated under vacuum. The resulting black residue was taken up in 6M HCl (200mL), refluxed for 12 h and concentrated to half of its original volume. Basified aqueous portion with 10% sodium bicarbonate and extracted with DCM (2 × 200mL), washed with water (2 × 200mL), brine (200mL), over anhydrous Na₂SO₄Dried and evaporated under vacuum. The crude material was purified by column chromatography eluting with silica gel (60-120) and DCM/methanol as a gradient with a yield of 3.50 g (21%);

LC/MS (method A) 268/270 (M + H), Rt. 2.73.73 min, 93% purity.

30.24- (4-bromo-benzoyl) -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide

This compound was prepared in analogy to example 22 from 4-methoxy-N-methylaniline (0.81 g, 5.78mmol), ethyl-diisopropyl-amine (4.62 mL, 26.28 mmol), triphosgene (1.91 g, 6.31 mmol) and (4-bromo-phenyl) -piperidin-4-yl-methanone (1.50 g, 5.26 mmol) in DCM (30 mL).

Purification by flash column chromatography using silica gel (230-;

LC/MS (method A) 431/433 (M + H), Rt. 4.99.99 min, 94% pure.

30.34- {4- [1- (2-methoxy-ethyl) -1H-pyrazol-4-yl ] -benzoyl } -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide ("A30")

4- (4-bromo-benzoyl) -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide (100.0 mg,0.22 mmol), 1- (2-methoxy-ethyl) -4- (4,4,5, 5-tetramethyl- [1,3, 2)]A solution of dioxaborolan-2-yl) -1H-pyrazole (93.5 mg, 0.24 mmol) and cesium carbonate (216 mg, 0.66 mmol) in dioxane (2 mL)/water (0.20 mL) was degassed for 5 min. Then, 1' -bis (diphenylphosphino) ferrocene complexed with dichloromethane (18.43 mg, 0.02 mmol) was added]Palladium (II) dichloride and refluxed under nitrogen atmosphere for 16 h. The reaction was cooled to room temperature and filtered through celite. The filtrate was evaporated under vacuum. The residue was dissolved in ethyl acetate (50 mL), washed with water (50 mL) and brine (50 mL), and dried over anhydrous Na₂SO₄Dried and evaporated under vacuum. The crude material was purified by preparative HPLC, yield 69 mg (62%);

LC/MS (method A) 477.2 (M + H), Rt. 4.2.2 min, 93% pure.

Example 31

31.14- (4-methoxy-benzoyl) -piperidine-1-carboxylic acid (4-bromo-phenyl) -methyl-amide

This compound was prepared in analogy to example 22 from (4-bromo-phenyl) -methyl-aniline (1.96 g, 10.22mmol), ethyl-diisopropyl-amine (6.06 g, 46.43 mmol), triphosgene (3.37 g, 11.14 mmol) and (4-methoxy-phenyl) -piperidin-4-yl-methanone hydrochloride (2.50 g, 9.29 mmol) in DCM (50 mL). Purification by flash column chromatography using silica gel (230-;

LC/MS (method A) 430/432 (M + H), Rt. 4.98.98 min, 98% purity.

31.24- (4-methoxy-benzoyl) -piperidine-1-carboxylic acid {4- [1- (2-methoxy-ethyl) -1H-pyrazol-4-yl ] -phenyl } -methyl-amide ("A31")

This compound was prepared in analogy to example 29 from 4- (4-methoxy-benzoyl) -piperidine-1-carboxylic acid (4-bromo-phenyl) -methyl-amide (100.0 mg, 0.23 mmol), 1- (2-methoxy-ethyl) -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-hex-ane) -1H-pyrazole (96.4 mg; 0.25 mmol), cesium carbonate (222.8 mg,0.68 mmol) and 1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) complexed with dichloromethane (1.90 mg) in dioxane/water.

Purification by preparative HPLC, yield 14 mg (13%);

LC/MS (method A) 477.2 (M + H), Rt. 4.16.16 min, purity 95%.

Example 32

32.14- (4-bromo-benzoyl) -piperidine-1-carboxylic acid (4-bromo-phenyl) -methyl-amide

This compound was prepared in analogy to example 22 from (4-bromo-phenyl) -methyl-aniline (1.11 g, 5.78mmol), ethyl-diisopropyl-amine (4.62 mL, 26.28 mmol), triphosgene (1.91 g, 6.31 mmol) and (4-bromo-phenyl) -piperidin-4-yl-methanone (1.50 g, 5.26 mmol) in DCM (30 mL).

Purification by flash column chromatography using silica gel (230-;

LC/MS (method A) 480/482 (M + H), Rt. 5.52.52 min, purity 95%.

32.24- {4- [1- (2-methoxy-ethyl) -1H-pyrazol-4-yl ] -benzoyl } -piperidine-1-carboxylic acid {4- [1- (2-methoxy-ethyl) -1H-pyrazol-4-yl ] -phenyl } -methyl-amide ("A32")

This compound was prepared in analogy to example 29 from 4- (4-bromo-benzoyl) -piperidine-1-carboxylic acid (4-bromo-phenyl) -methyl-amide (100.0 mg, 0.20 mmol), 1- (2-methoxy-ethyl) -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole (169.6 mg, 0.44 mmol), cesium carbonate (391.9mg, 1.19 mmol) and 1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) complexed with dichloromethane (3.3 mg) in dioxane/water.

Purification by preparative HPLC, yield 21 mg (17%);

LC/MS (method A) 571.3 (M + H), Rt. 3.96.96 min, purity 93%.

Example 33

4- [4- (1-ethyl-1H-pyrazol-4-yl) -benzoyl ] -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide ("A33")

This compound was prepared in analogy to example 29 from 4- (4-bromo-benzoyl) -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide (150.0 mg; 0.33 mmol), 1-ethyl-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole (139.3 mg, 0.39 mmol), cesium carbonate (324.2 mg, 0.99mmol) and 1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) complexed with dichloromethane (27.6 mg, 0.03 mmol) in dioxane/water.

Purification by column chromatography using silica gel (230- & 400) and DCM/methanol as a gradient, yield 19 mg (12%),

LC/MS (method A) 447.3 (M + H), Rt. 4.38.38 min, 96% purity.

Example 34

4- (4-methoxy-benzoyl) -piperidine-1-carboxylic acid [4- (1-ethyl-1H-pyrazol-4-yl) -phenyl ] -methyl-amide ("A34")

This compound was prepared in analogy to example 29 from 4- (4-methoxy-benzoyl) -piperidine-1-carboxylic acid (4-bromo-phenyl) -methyl-amide (150.0 mg, 0.34 mmol), 1-ethyl-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole (143.6 mg, 0.41 mmol), cesium carbonate (334.1 mg, 1.02mmol) and 1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) complexed with dichloromethane (28.5 mg, 0.03 mmol) in dioxane/water.

Purification by column chromatography using silica gel (230-400) and DCM/methanol as a gradient and a yield of 52 mg (32%);

LC/MS (method A) 447.3 (M + H), Rt. 4.31.31 min, 96% purity.

Example 35

4- {4- [1- (2-pyrrolidin-1-yl-ethyl) -1H-pyrazol-4-yl ] -benzoyl } -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide ("A35")

This compound was prepared in analogy to example 29 from 4- (4-bromo-benzoyl) -piperidine-1-carboxylic acid (4-methoxy-phenyl) -methyl-amide (150.0 mg, 0.33 mmol), 1- (2-pyrrolidin-1-yl-ethyl) -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole (118.0 mg, 0.39 mmol), cesium carbonate (324.2 mg, 0.99mmol) and 1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) complexed with dichloromethane (27.6 mg, 0.03 mmol) in dioxane/water. Purification by preparative HPLC, yield 16 mg (9%);

。

example 36

4- (4-methoxy-benzoyl) -piperidine-1-carboxylic acid methyl- {4- [1- (2-pyrrolidin-1-yl-ethyl) -1H-pyrazol-4-yl ] -phenyl } -amide ("A36")

This compound was prepared in analogy to example 29 from 4- (4-methoxy-benzoyl) -piperidine-1-carboxylic acid (4-bromo-phenyl) -methyl-amide (150.0 mg, 0.34 mmol), 1- (2-pyrrolidin-1-yl-ethyl) -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole (121.6 mg, 0.41 mmol), cesium carbonate (334.1 mg, 1.02mmol) and 1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) complexed with dichloromethane (28.5 mg, 0.03 mmol) in dioxane/water.

Purification by column chromatography using silica gel (230-400) and DCM/methanol as a gradient and a yield of 30 mg (16%);

。

example 37

4- {4- [1- (2-pyrrolidin-1-yl-ethyl) -1H-pyrazol-4-yl ] -benzoyl } -piperidine-1-carboxylic acid methyl- {4- [1- (2-pyrrolidin-1-yl-ethyl) -1H-pyrazol-4-yl ] -phenyl } -amide ("A37")

This compound was prepared in analogy to example 29 from 4- (4-bromo-benzoyl) -piperidine-1-carboxylic acid (4-bromo-phenyl) -methyl-amide (100.0 mg, 0.20 mmol), 1- (2-pyrrolidin-1-yl-ethyl) -4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole (130.8 mg, 0.44 mmol), cesium carbonate (391.9mg, 1.19 mmol) and 1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) complexed with dichloromethane (33.4 mg, 0.04 mmol) in dioxane/water. Purification by preparative HPLC, yield 6 mg (5%);

。

the following compounds were prepared analogously

4- (4-methanesulfonylamino-benzoyl) -piperidine-1-carboxylic acid methyl-phenyl-amide ("A38")

;

[ (4-benzoyl-piperidine-1-carbonyl) -phenyl-amino ] -acetic acid ethyl ester ("A39")

;

{ [4- (4-methoxy-benzoyl) -piperidine-1-carbonyl ] -phenyl-amino } -acetic acid ethyl ester ("A40")

;

N-ethyl-4- (3-fluoro-4-methoxy-benzoyl) -N- (4-methoxyphenyl) piperidine-1-carboxamide ("A41")

;

4- (3-fluoro-4-methoxy-benzoyl) -N- (6-methoxy-3-pyridyl) -N-methyl-piperidine-1-carboxamide ("A42")

N-Ethyl-N- (4-methoxyphenyl) -4- (6-methoxypyridine-3-carbonyl) piperidine-1-carboxamide ("A43")

4-benzoyl-N- (6-methoxy-3-pyridyl) -N-methyl-piperidine-1-carboxamide ("A44")

N- (6-methoxy-3-pyridyl) -N-methyl-4- (3-methylbenzoyl) piperidine-1-carboxamide ("A45")

N- (6-methoxy-3-pyridyl) -N-methyl-4- (4-methylbenzoyl) piperidine-1-carboxamide ("A46")

4- (3-methoxybenzoyl) -N- (6-methoxy-3-pyridyl) -N-methyl-piperidine-1-carboxamide ("A47")

4- [4- (1-ethylpyrazol-4-yl) benzoyl ] -N- (6-methoxy-3-pyridyl) -N-methyl-piperidine-1-carboxamide ("A48")

4- (4-methoxybenzoyl) -N- (6-methoxy-3-pyridyl) -N-methyl-piperidine-1-carboxamide ("A49")

4- (3-fluorobenzoyl) -N- (6-methoxy-3-pyridyl) -N-methyl-piperidine-1-carboxamide ("A50")

4- (4-fluorobenzoyl) -N- (6-methoxy-3-pyridyl) -N-methyl-piperidine-1-carboxamide ("A51")

4- (4-methoxy-3-methyl-benzoyl) -N- (6-methoxy-3-pyridyl) -N-methyl-piperidine-1-carboxamide ("A52")

N- (4-methoxyphenyl) -4- (6-methoxypyridine-3-carbonyl) -N-methyl-piperidine-1-carboxamide ("A53")

4- [4- (1-ethyl-1H-pyrazol-4-yl) -benzoyl ] -piperidine-1-carboxylic acid [4- (1-ethyl-1H-pyrazol-4-yl) -phenyl ] -methyl-amide („ A57 ")

N- (4-cyanophenyl) -4- (4-methoxybenzoyl) -N-methyl-piperidine-1-carboxamide ("A58")

;

N- (4-cyanophenyl) -N- (2-hydroxyethyl) -4- (4-methoxybenzoyl) piperidine-1-carboxamide ("A59")

;

N- (6-cyano-3-pyridinyl) -4- (4-methoxybenzoyl) -N-methyl-piperidine-1-carboxamide ("A60")

;

N- (4-cyanophenyl) -4- (3-fluoro-4-methoxy-benzoyl) -N-methyl-piperidine-1-carboxamide ("A61")

;

N- (4-cyanophenyl) -N- (2-hydroxyethyl) -4- (4-methoxy-3-methyl-benzoyl) piperidine-1-carboxamide ("A62")

;

N- (4-cyanophenyl) -4- (3-fluoro-4-methoxy-benzoyl) -N- (2-hydroxyethyl) piperidine-1-carboxamide ("A63")

;

N- (2-hydroxyethyl) -4- (4-methoxybenzoyl) -N- (4-methoxyphenyl) piperidine-1-carboxamide ("A64")

;

N- (2-hydroxyethyl) -4- (4-methoxy-3-methyl-benzoyl) -N- (4-methoxyphenyl) piperidine-1-carboxamide ("A65")

;

4- (3-fluoro-4-methoxy-benzoyl) -N- (2-hydroxyethyl) -N- (4-methoxyphenyl) piperidine-1-carboxamide ("A66")

;

N- (2-hydroxyethyl) -4- (4-methoxy-3-methyl-benzoyl) -N- (6-methoxy-3-pyridyl) piperidine-1-carboxamide ("A67")

;

4- (3-fluoro-4-methoxy-benzoyl) -N- (2-hydroxyethyl) -N- (6-methoxy-3-pyridyl) piperidine-1-carboxamide ("A68")

;

N- (2-hydroxyethyl) -4- (4-methoxybenzoyl) -N- (6-methoxy-3-pyridyl) piperidine-1-carboxamide ("A69")

;

4- (4-Methoxybenzoyl) -N- (6-methoxypyridazin-3-yl) -N-methyl-piperidine-1-carboxamide ("A70")

;

4- (4-Methoxybenzoyl) -N- (2-methoxypyrimidin-5-yl) -N-methyl-piperidine-1-carboxamide ("A71")

.

Synthesis of 4- [4- (1-hydroxy-1-methyl-ethyl) benzoyl ] -N- (4-methoxyphenyl) -N-methyl-piperidine-1-carboxamide ("A54")

。

The following compounds were prepared analogously:

n- [4- (1-hydroxy-1-methyl-ethyl) phenyl ] -4- (4-methoxybenzoyl) -N-methyl-piperidine-1-carboxamide ("A55")

;

4- [4- (1-hydroxy-1-methyl-ethyl) benzoyl ] -N- [4- (1-hydroxy-1-methyl-ethyl) phenyl ] -N-methyl-piperidine-1-carboxamide ("A56")

。

Pharmacological data

TABLE 1 inhibition of tankyrase by Compounds of formula I

IC₅₀:<0.3 μM = A 0.3 - 3 μM = B 3-50 μM=C。

TABLE 2 inhibition of tankyrase by Compounds of formula I

EC₅₀:<0.3 μM = A 0.3 - 3 μM = B 3-50 μM=C。

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

TABLE 3 inhibition of tankyrase by some representative compounds of formula I

IC₅₀:<0.3 μM = A 0.3 - 3 μM = B 3-50 μM=C。

The compounds shown in table 3 are particularly preferred compounds according to the invention.

The following examples relate to medicaments:

example A injection vial

A solution of 100 g of the active ingredient of the formula I and 5g of disodium hydrogen phosphate in 3 l of bidistilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile-filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contained 5 mg of active ingredient.

Example B suppository

A mixture of 20 g of the active ingredient of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into a mould and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: solutions of

Comprises 1 g of active ingredient of formula I, 9.38 g of NaH₂PO₄∙2 H₂O、28.48 g Na₂HPO₄∙12 H₂O and 0.1 g benzalkonium chloride in 940 ml double distilled water. The pH was adjusted to 6.8 and the solution was made up to 1 l and irradiatedSterilizing. This solution can be used in the form of eye drops.

Example D: ointment formulation

500 mg of the active ingredient of the formula I are mixed with 99.5 g of vaseline under sterile conditions.

Example E: tablet formulation

A mixture of 1 kg of active ingredient of the 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 way that each tablet contains 10 mg of active ingredient.

Example F: sugar-coated pill

Tablets were compressed analogously to example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G capsules

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

Example H: ampoule (CN)

A solution of 1 kg of the active ingredient of the formula I in 60 l of bidistilled water is sterile-filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

Claims (6)

1. A compound selected from

And pharmaceutically acceptable salts thereof, including mixtures thereof in all ratios.

2. A medicament comprising at least one compound of formula I according to claim 1 and/or a pharmaceutically acceptable salt thereof, including mixtures thereof in all ratios, and optionally a pharmaceutically acceptable carrier, excipient or vehicle.

3. Compounds of formula I according to claim 1 and their pharmaceutically acceptable salts, including mixtures thereof in all ratios, for use in the treatment and/or prevention of cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury and different forms of inflammation.

4. A compound according to claim 3 for use in the treatment and/or prevention of a disease selected from: head, neck, eye, mouth, throat, esophagus, bronchus, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, cervix, breast, ovary, testis, or other reproductive organs, skin, thyroid, blood, lymph node, kidney, liver, pancreas, brain, central nervous system, solid tumor, and blood-borne tumor.

5. A medicament comprising at least one compound of the formula I according to claim 1 and/or a pharmaceutically acceptable salt thereof, including mixtures thereof in all ratios, and at least one further pharmaceutically active ingredient.

6. A kit consisting of the following separate packages:

(a) an effective amount of a compound of the formula I according to claim 1 and/or its pharmaceutically acceptable salts and salts, including mixtures thereof in all ratios,

and

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