US 2016.0318876A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0318876A1 BUCHSTALLER et al. (43) Pub. Date: Nov. 3, 2016

(54) PHTHALAZINE DERVATIVES Publication Classification (71) Applicant: MERCK PATENT GMBH, Darmstadt (51) Int. Cl. C07D 237/34 (2006.01) (DE) A63L/502 (2006.01) (52) U.S. Cl. (72) Inventors: Hans-Peter BUCHSTALLER, CPC ...... C07D 237/34 (2013.01); A61K3I/502 Griesheim (DE); Dieter DORSCH, (2013.01) Ober-Ramstadt (DE); Christina ESDAR, Mainz (DE); Birgitta (57) ABSTRACT LEUTHNER, Darmstadt (DE) Compounds of the formula I

(73) Assignee: Marck Patent GmbH, Darmstadt (DE)

(21) Appl. No.: 14/392,145 (22) PCT Fed: May 30, 2014 (86) PCT No.: PCT/EP2014/OO1467 S 371 (c)(1), (2) Date: Dec. 23, 2015 in which R', X and n have the meanings indicated in Claim 1, are inhibitors of Tankyrase, and can be employed, inter (30) Foreign Application Priority Data alia, for the treatment of diseases such as cancer, cardiovas cular diseases, central nervous system injury and different Jun. 24, 2013 (EP) ...... 130O3205.5 forms of inflammation. US 2016/0318876 A1 Nov. 3, 2016

PHTHALAZINE DERVATIVES anti-cancer therapy. A key feature of the Wnt pathway is the regulated proteolysis (degradation) of B-catenin by the BACKGROUND OF THE INVENTION B-catenin destruction complex. Proteins like WTX, APC or 0001. The invention had the object of finding novel AXin are involved in the degradation process. A proper compounds having valuable properties, in particular those degradation of B-catenin is important to avoid an inappro which can be used for the preparation of medicaments. priate activation of the Wnt pathway which has been 0002 The present invention relates to quinazolinone observed in many cancers. Tankyrases inhibit activity of derivatives which inhibit the activity of Tankyrases AXin and hence inhibit the degradation of B-catenin. (TANKs) and poly(ADP-ribose)polymerase PARP-1. The 0009 Consequently, tankyrase inhibitors increase degra compounds of this invention are therefore useful in treating dation of B-catenin. A paper in the journal Nature not only diseases Such as cancer, multiple Sclerosis, cardiovascular offers important new insights into proteins regulating Wnt diseases, central nervous system injury and different forms signaling but also further Supports the approach to antago of inflammation. The present invention also provides meth nize B-catenin levels and localization via Small molecules ods for preparing these compounds, pharmaceutical compo (Huang et al., 2009; Nature, Vol 461, 614-620). The com sitions comprising these compounds, and methods of treat pound XAV939 inhibits growth of DLD-1-cancer cells. ing diseases utilizing pharmaceutical compositions They found that XAV9393 blocked Wnt-stimulated accu comprising these compounds. mulation of B-catenin by increasing the levels of the AXIN1 0003. The nuclear enzyme poly(ADP-ribose) poly and AXIN2 proteins. Subsequent work by the authors estab merase-1 (PARP-1) is a member of the PARP enzyme lished that XAV939 regulates AXIN levels via inhibition of family. This growing family of enzymes consist of PARPs tankyrases 1 and 2 (TNKS1 and TNKS2), both of which are such as, for example: PARP-1, PARP-2, PARP-3 and Vault members of the poly(ADP-ribose) polymerase (PARP) pro PARP, and Tankyrases (TANKs), such as, for example: tein family (S. J. Hsiao et al., Biochimie 90, 2008, 83-92). TANK-1 and TANK-2. PARP is also referred to as poly 0010. It has been found that the compounds according to (adenosine 5'-diphospho-ribose) polymerase or PARS (poly the invention and salts thereof have very valuable pharma (ADP-ribose) synthetase). cological properties while being well tolerated. 0004 TANK-1 seems to be required for the polymeriza tion of mitotic spindle-associated poly(ADP-ribose). The 0011. The present invention specifically relates to com poly(ADP-ribosyl)ation activity of TANK-1 might be cru pounds of the formula I which inhibit Tankyrase 1 and 2, to cial for the accurate formation and maintenance of spindle compositions which comprise these compounds, and to bipolarity. Furthermore, PARP activity of TANK-1 has been processes for the use thereof for the treatment of TANK shown to be required for normal telomere separation before induced diseases and complaints. anaphase. Interference with tankyrase PARP activity results 0012. The compounds of the formula I can furthermore in aberrant mitosis, which engenders a transient cell cycle be used for the isolation and investigation of the activity or arrest, probably due to spindle checkpoint activation, fol expression of TANKS. In addition, they are particularly lowed by cell death. Inhibition of tankyrases is therefore Suitable for use in diagnostic methods for diseases in con expected to have a cytotoxic effect on proliferating tumor nection with unregulated or disturbed TANK activity. cells (WO 2008/107478). 0013 The host or patient can belong to any mammalian 0005 PARP inhibitors are described by M. Rouleau et al. species, for example a primate species, particularly humans; in Nature Reviews, Volume 10, 293-301 in clinical cancer rodents, including mice, rats and hamsters; rabbits; horses, studies (Table 2, page 298). cows, dogs, cats, etc. Animal models are of interest for 0006. According to a review by Horvath and Szabo (Drug experimental investigations, providing a model for treatment News Perspect 20(3), April 2007, 171-181) most recent of human disease. studies demonstrated that PARP inhibitors enhance the can cer cell death primarily because they interfere with DNA 0014. The susceptibility of a particular cell to treatment repair on various levels. More recent studies have also with the compounds according to the invention can be demonstrated that PARP inhibitors inhibit angiogenesis, determined by in vitro tests. Typically, a culture of the cell either by inhibiting growth factor expression, or by inhib is combined with a compound according to the invention at iting growth factor-induced cellular proliferative responses. various concentrations for a period of time which is suffi These findings might also have implications on the mode of cient to allow active agents such as anti IgM to induce a PARP inhibitors anticancer effects in vivo. cellular response Such as expression of a Surface marker, 0007 Also a study by Tentorietal. (Eur. J. Cancer, 2007, usually between about one hour and one week. In vitro 43 (14) 2124-2133) shows that PARP inhibitors abrogate testing can be carried out using cultivated cells from blood VEGF or placental growth factor-induced migration and or from a biopsy sample. The amount of Surface marker prevent formation of tubule-like networks in cell-based expressed is assessed by flow cytometry using specific systems, and impair angiogenesis in vivo. The study also antibodies recognising the marker. demonstrates that growth factor-induced angiogenesis is 0015 The dose varies depending on the specific com deficient in PARP-1 knock-out mice. The results of the study pound used, the specific disease, the patient status, etc. A provide evidence for targeting PARP for anti-angiogenesis, therapeutic dose is typically sufficient considerably to adding novel therapeutic implications to the use of PARP reduce the undesired cell population in the target tissue inhibitors in cancer treatment. while the viability of the patient is maintained. The treat 0008 Defects in conserved signaling pathways are well ment is generally continued until a considerable reduction known to play key roles in the origins and behavior of has occurred, for example an at least about 50% reduction in essentially all cancers (E. A. Fearon, Cancer Cell, Vol. 16, the cell burden, and may be continued until essentially no Issue 5, 2009, 366-368). The Wnt pathway is a target for more undesired cells are detected in the body. US 2016/0318876 A1 Nov. 3, 2016

PRIOR ART 0033. The term solvates of the compounds is taken to 0016 E. Wahlberg et al., Nature Biotechnology (2012), mean adductions of inert solvent molecules onto the com 30(3), 283. pounds which form owing to their mutual attractive force. 0017 M. Elagawany et al. describe in Bioorganic & Solvates are, for example, mono- or dihydrates or alkoxides. Medicinal Chemistry Letters 23 (2013) 2007-2013 the 0034. It is understood, that the invention also relates to compound the Solvates of the salts. The term pharmaceutically accept able derivatives is taken to mean, for example, the salts of the compounds according to the invention and also so-called prodrug compounds. 0035. As used herein and unless otherwise indicated, the term “prodrug' means a derivative of a compound of \ stO formula I that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an SN N active compound, particularly a compound of formula I. C Examples of prodrugs include, but are not limited to, deriva tives and metabolites of a compound of formula I that 0018. This compound is inactive in inhibiting tankyrase. include biohydrolyzable moieties such as biohydrolyzable 0019. Other tankyrase inhibitors are described in WO amides, biohydrolyzable esters, biohydrolyzable carbam 2013/012723, WO 2013/010092 and in WO 2013/082217. ates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. In certain SUMMARY OF THE INVENTION embodiments, prodrugs of compounds with carboxyl func tional groups are the lower alkyl esters of the carboxylic 0020. The invention relates to compounds of the formula acid. The carboxylate esters are conveniently formed by I esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well known methods, such as those described by Burger's I Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic O Publishers Gmfh.). 0036. The expression “effective amount denotes the amount of a medicament or of a pharmaceutical active ingredient which causes in a tissue, system, animal or human a biological or medical response which is sought or desired, in which for example, by a researcher or physician. 0021) R' denotes H. Hal, CH, OCH or CH-OH, 0037. In addition, the expression “therapeutically effec 0022 X denotes Ar or Cyc, tive amount denotes an amount which, compared with a 0023 Ar denotes phenyl, biphenyl or naphthyl, each of corresponding Subject who has not received this amount, has which is unsubstituted or mono-, di- or trisubstituted by the following consequence: Hal, NO, CN, A, C(R), OR, S(O),R, ICR).N improved treatment, healing, prevention or elimination of a (R), C(R), COOR, C(R), CONCR), C(R), disease, syndrome, condition, complaint, disorder or side SO.N(R), NRCOR2, NR°SO.R.?, NR°CON(R°), effects or also the reduction in the advance of a disease, NHCOOA, OC(R), N(R), CHO and/or COA, complaint or disorder. 0024 R denotes Hoder A, 0038. The expression “therapeutically effective amount 0025. A denotes unbranched or branched alkyl with 1-10 also encompasses the amounts which are effective for C-atoms, wherein two adjacent carbon atoms may form a increasing normal physiological function. double bond and/or one or two non-adjacent CH- and/or 0039. The invention also relates to the use of mixtures of CH2-groups may be replaced by N-, O- and/or S-atoms the compounds of the formula I, for example mixtures of and wherein 1-7 H-atoms may be replaced by F. Cl and/or two diastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, OH, 1:5, 1:10, 1:100 or 1:1000. 0026 Cyc denotes cycloalkyl with 3, 4, 5, 6 or 7 C-atoms, 0040. These are particularly preferably mixtures of ste 0027 Hal denotes F, Cl, Br or I, reoisomeric compounds. 0028 m denotes 0, 1 or 2, 0041. “Tautomers’ refers to isomeric forms of a com 0029 in denotes 1, 2 or 3, pound that are in equilibrium with each other. The concen 0030 p denotes 0, 1, 2, 3 or 4, trations of the isomeric forms will depend on the environ and pharmaceutically acceptable salts, tautomers and Ste ment the compound is found in and may be different reoisomers thereof, including mixtures thereof in all ratios. depending upon, for example, whether the compound is a 0031. The invention also relates to the optically active Solid or is in an organic or aqueous solution. forms (stereoisomers), the enantiomers, the racemates, the 0042. The invention relates to the compounds of the diastereomers and the hydrates and Solvates of these com formula I and salts thereof and to a process for the prepa pounds. ration of compounds of the formula I and pharmaceutically 0032 Moreover, the invention relates to pharmaceuti acceptable salts, Solvates, tautomers and stereoisomers cally acceptable derivatives of compounds of formula I. thereof, characterised in that US 2016/0318876 A1 Nov. 3, 2016 a compound of the formula II 0054 Accordingly, the invention relates, in particular, to the compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated

II above. Some preferred groups of compounds may be expressed by the following sub-formulae Ia to Id, which conform to the formula I and in which the radicals not designated in greater detail have the meaning indicated for the formula I, but in which

in Ia RI denotes H, HaI or CH: in which R' has the meanings indicated in claim 1, in Ib Air denotes phenyl, which is unsubstituted or mono-, di- or is reacted trisubstituted by Hal, NO, CN, A and/or C(R)-OR: in Ic A. denotes unbranched or branched alkyl with 1-6 C with a compound of formula III atoms, wherein 1-5 H-atoms may be replaced by F: in Id R denotes H, Hal or CH, Air denotes phenyl, which is unsubstituted or mono-, di- or III trisubstituted by Hal, NO, CN, A and/or C(R)-OR, (CH2)-X R2 denotes Hoder A, A. denotes unbranched or branched alkyl with 1-6 C atoms, wherein 1-5 H-atoms may be replaced by F, HaI denotes F, Cl, Br or I, O p denotes 0, 1, 2, 3 or 4 in which X and n have the meanings indicated in claim 1, and pharmaceutically acceptable salts, tautomers and Ste and L denotes Cl, Br, I or a free or reactively functionally reoisomers thereof, including mixtures thereof in all ratios. modified OH group, 0055. The compounds of the formula I and also the and/or starting materials for their preparation are, in addition, a base or acid of the formula I is converted into one of its prepared by methods known per se, as described in the literature (for example in the standard works, such as salts. Houben-Weyl, Methoden der organischen Chemie Methods I0043. Above and below, the radicals R' and Ar have the of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart), to meanings indicated for the formula I, unless expressly stated be precise under reaction conditions which are known and otherwise. suitable for the said reactions. Use can also be made here of 0044) A denotes alkyl, this is unbranched (linear) or variants known per se which are not mentioned here in branched, and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A greater detail. preferably denotes ethyl, propyl, isopropyl, butyl, isobutyl, 0056. The starting compounds of the formula II and III sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or are generally known. If they are novel, however, they can be 3-methylbutyl, 1,1-, 1.2- or 2,2-dimethylpropyl, 1-ethylpro prepared by methods known per se. pyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1.2-, 1.3-, 2.2-, 0057 Compounds of the formula I can preferably be 2.3- or 3.3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1- obtained by reacting a compound of the formula II with a methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1.2.2-trim compound of the formula III. ethylpropyl, furthermore preferably, for example, trifluo 0058. In the compounds of the formula III, L preferably romethyl. denotes Cl, Br, I or a free or reactively modified OH group, Such as, for example, an activated ester, an imidazolide or 0045. A very particularly preferably denotes alkyl having alkylsulfonyloxy having 1-6 C atoms (preferably methyl 2, 3, 4, 5 or 6 C atoms, preferably ethyl, propyl, isopropyl. sulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfony butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluo loxy having 6-10 C atoms (preferably phenyl- or p-tolylsul romethyl, pentafluoroethyl or 1,1,1-trifluoroethyl. More fonyloxy). over. A denotes preferably CHOCH, CHCH-OH or 0059. The reaction is generally carried out in the presence CHCHOCH. of an acid-binding agent, preferably an organic base. Such as 0046) R' preferably denotes H. Hal or CH. DIPEA, triethylamine, dimethyl-aniline, pyridine or quino 0047 R’ preferably denotes H. methyl, ethyl, propyl, line. butyl oder trifluoromethyl. 0060. The addition of an alkali or alkaline earth metal 0048 Ar preferably denotes phenyl, which is unsubsti hydroxide, carbonate or bicarbonate or another salt of a tuted or mono-, di- or trisubstituted by Hal, NO, CN, A weak acid of the alkali or alkaline earth metals, preferably of potassium, sodium, calcium or caesium, may also be and/or |C(R), ORi. favourable. 0049 p preferably denotes 0, 1 or 2. 0061. Depending on the conditions used, the reaction 0050 Hal preferably denotes F, C1 or Br, but also I, time is between a few minutes and 14 days, the reaction particularly preferably F or Cl. temperature is between about -30° and 140°, normally 0051 Cyc preferably denotes cylopentyl or cyclohexyl. between -10° and 90°, in particular between about 0° and 0052 Throughout the invention, all radicals which occur about 70°. more than once may be identical or different, i.e. are 0062) Examples of suitable inert solvents are hydrocar independent of one another. bons, such as hexane, petroleum ether, benzene, toluene or 0053. The compounds of the formula I may have one or Xylene; chlorinated hydrocarbons, such as trichloroethylene, more chiral centres and can therefore occur in various 1,2-dichloroethane, carbon tetrachloride, chloroform or Stereoisomeric forms. The formula I encompasses all these dichloromethane; alcohols, such as methanol, ethanol, iso forms. propanol, n-propanol, n-butanol or tert-butanol; ethers. Such US 2016/0318876 A1 Nov. 3, 2016

as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or 0.066 Furthermore, the base salts of the compounds dioxane; glycol ethers, such as ethylene glycol monomethyl according to the invention include aluminium, ammonium, or monoethyl ether, ethylene glycol dimethyl ether (dig calcium, copper, iron(III), iron(II), lithium, magnesium, lyme), ketones. Such as acetone or butanone; amides, such as manganese(III), manganese(II), potassium, Sodium and Zinc acetamide, dimethylacetamide or dimethylformamide salts, but this is not intended to represent a restriction. Of the (DMF): nitriles, such as acetonitrile; sulfoxides, such as above-mentioned salts, preference is given to ammonium; dimethyl sulfoxide (DMSO); carbon di-sulfide; carboxylic the alkali metal salts sodium and potassium, and the alkaline acids, such as formic acid or acetic acid; nitro compounds, earth metal salts calcium and magnesium. Salts of the Such as nitromethane or nitrobenzene, esters, such as ethyl compounds of the formula I which are derived from phar acetate, or mixtures of the said solvents. maceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, Substituted 0063 Particular preference is given to acetonitrile, 1,2- amines, also including naturally occurring Substituted dichloroethane, dichloromethane and/or DMF. amines, cyclic amines, and basic ion exchanger resins, for 0.064 Pharmaceutical Salts and Other Forms example arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohex 0065. The said compounds according to the invention can ylamine, diethanolamine, diethylamine, 2-diethylamin be used in their final non-salt form. On the other hand, the oethanol, 2-dimethylaminoethanol, ethanolamine, ethylene present invention also encompasses the use of these com diamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, pounds in the form of their pharmaceutically acceptable glucosamine, histidine, hydrabamine, isopropylamine, lido salts, which can be derived from various organic and inor caine, lysine, meglumine, N-methyl-D-glucamine, morpho ganic acids and bases by procedures known in the art. line, piperazine, piperidine, polyamine resins, procaine, Pharmaceutically acceptable salt forms of the compounds of purines, theobromine, triethanolamine, triethylamine, trim the formula I are for the most part prepared by conventional ethylamine, tripropylamine and tris(hydroxymethyl)methyl methods. If the compound of the formula I contains a carboxyl group, one of its suitable salts can be formed by amine (tromethamine), but this is not intended to represent reacting the compound with a suitable base to give the a restriction. corresponding base-addition salt. Such bases are, for 0067 Compounds of the present invention which contain example, alkali metal hydroxides, including potassium basic nitrogen-containing groups can be quaternised using hydroxide, sodium hydroxide and lithium hydroxide; alka agents such as (C-C)alkyl halides, for example methyl, line earth metal hydroxides, such as barium hydroxide and ethyl, isopropyl and tert-butyl chloride, bromide and iodide; calcium hydroxide; alkali metal alkoxides, for example di(C-C)alkyl sulfates, for example dimethyl, diethyl and potassium ethoxide and sodium propoxide; and various diamyl Sulfate; (Co-Cs)alkyl halides, for example decyl. organic bases, such as piperidine, diethanolamine and dodecyl, lauryl, myristyl and Stearyl chloride, bromide and N-methyl-glutamine. The aluminium salts of the compounds iodide; and aryl(C-C)alkyl halides, for example benzyl of the formula I are likewise included. In the case of certain chloride and phenethyl bromide. Both water- and oil-soluble compounds of the formula I, acid-addition salts can be compounds according to the invention can be prepared using formed by treating these compounds with pharmaceutically Such salts. acceptable organic and inorganic acids, for example hydro 0068. The above-mentioned pharmaceutical salts which gen halides, such as hydrogen chloride, hydrogen bromide are preferred include acetate, trifluoroacetate, besylate, cit or hydrogen iodide, other mineral acids and corresponding rate, fumarate, gluconate, hemisuccinate, hippurate, hydro salts thereof. Such as Sulfate, nitrate or phosphate and the chloride, hydrobromide, isethionate, mandelate, meglumine, like, and alkyl- and monoarylsulfonates, such as ethanesul nitrate, oleate, phosphonate, pivalate, sodium phosphate, fonate, toluenesulfonate and benzenesulfonate, and other Stearate, Sulfate, Sulfosalicylate, tartrate, thiomalate, tosylate organic acids and corresponding salts thereof. Such as and tromethamine, but this is not intended to represent a acetate, trifluoroacetate, tartrate, maleate, Succinate, citrate, restriction. benzoate, salicylate, ascorbate and the like. Accordingly, 0069 Particular preference is given to hydrochloride, pharmaceutically acceptable acid-addition salts of the com dihydrochloride, hydrobromide, maleate, mesylate, phos pounds of the formula I include the following: acetate, phate, Sulfate and Succinate. adipate, alginate, arginate, aspartate, benzoate, benzenesul 0070 The acid-addition salts of basic compounds of the fonate (besylate), bisulfate, bisulfite, bromide, butyrate, formula I are prepared by bringing the free base form into camphorate, camphorsulfonate, caprylate, chloride, chlo contact with a sufficient amount of the desired acid, causing robenzoate, citrate, cyclopentanepropionate, digluconate, the formation of the salt in a conventional manner. The free dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, eth base can be regenerated by bringing the salt form into anesulfonate, fumarate, formate, galacterate (from mucic contact with a base and isolating the free base in a conven acid), galacturonate, glucoheptanoate, gluconate, glutamate, tional manner. The free base forms differ in a certain respect glycerophosphate, hemisuccinate, hemisulfate, heptanoate, from the corresponding salt forms thereof with respect to hexanoate, hippurate, hydrochloride, hydrobromide, certain physical properties, such as solubility in polar Sol hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, vents; for the purposes of the invention, however, the salts isobutyrate, lactate, lactobionate, malate, maleate, malonate, otherwise correspond to the respective free base forms mandelate, metaphosphate, methanesulfonate, methylben thereof. Zoate, monohydrogenphosphate, 2-naphthalenesulfonate, 0071. As mentioned, the pharmaceutically acceptable nicotinate, nitrate, oxalate, oleate, palmoate, pectinate, per base-addition salts of the compounds of the formula I are Sulfate, phenylacetate, 3-phenylpropionate, phosphate, formed with metals or amines, such as alkali metals and phosphonate, phthalate, but this does not represent a restric alkaline earth metals or organic amines. Preferred metals are tion. Sodium, potassium, magnesium and calcium. Preferred US 2016/0318876 A1 Nov. 3, 2016 organic amines are N,N'-dibenzylethylenediamine, chloro advantages owing to the higher metabolic stability of this procaine, choline, diethanolamine, ethylenediamine, isotope-labelled compound. Higher metabolic stability N-methyl-D-glucamine and procaine. translates directly into an increased in vivo half-life or lower 0072 The base-addition salts of acidic compounds dosages, which under most circumstances would represent a according to the invention are prepared by bringing the free preferred embodiment of the present invention. An isotope acid form into contact with a sufficient amount of the desired labelled compound of the formula I can usually be prepared base, causing the formation of the salt in a conventional by carrying out the procedures disclosed in the synthesis manner. The free acid can be regenerated by bringing the salt schemes and the related description, in the example part and form into contact with an acid and isolating the free acid in in the preparation part in the present text, replacing a a conventional manner. The free acid forms differ in a certain non-isotope-labelled reactant by a readily available isotope respect from the corresponding salt forms thereof with labelled reactant. respect to certain physical properties, such as solubility in 10077. Deuterium (H) can also be incorporated into a polar solvents; for the purposes of the invention, however, compound of the formula I for the purpose in order to the salts otherwise correspond to the respective free acid manipulate the oxidative metabolism of the compound by forms thereof. way of the primary kinetic isotope effect. The primary 0073. If a compound according to the invention contains kinetic isotope effect is a change of the rate for a chemical more than one group which is capable of forming pharma reaction that results from exchange of isotopic nuclei, which ceutically acceptable salts of this type, the invention also in turn is caused by the change in ground state energies encompasses multiple salts. Typical multiple salt forms necessary for covalent bond formation after this isotopic include, for example, bitartrate, diacetate, difumarate, dime exchange. Exchange of a heavier isotope usually results in glumine, diphosphate, disodium and trihydrochloride, but a lowering of the ground state energy for a chemical bond this is not intended to represent a restriction. and thus cause a reduction in the rate in rate-limiting bond 0074. With regard to that stated above, it can be seen that breakage. If the bond breakage occurs in or in the vicinity of the expression “pharmaceutically acceptable salt in the a saddle-point region along the coordinate of a multi-product present connection is taken to mean an active ingredient reaction, the product distribution ratios can be altered sub which comprises a compound of the formula I in the form of stantially. For explanation: if deuterium is bonded to a one of its salts, in particular if this salt form imparts carbon atom at a non-exchangeable position, rate differences improved pharmacokinetic properties on the active ingredi of k/ki 2-7 are typical. If this rate difference is Success ent compared with the free form of the active ingredient or fully applied to a corn-pound of the formula I that is any other salt form of the active ingredient used earlier. The susceptible to oxidation, the profile of this compound in vivo pharmaceutically acceptable salt form of the active ingredi can be drastically modified and result in improved pharma ent can also provide this active ingredient for the first time cokinetic properties. with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the 0078. When discovering and developing therapeutic pharmacodynamics of this active ingredient with respect to agents, the person skilled in the art attempts to optimise its therapeutic efficacy in the body. pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many com 0075 Isotopes pounds with poor pharmacokinetic profiles are susceptible to 0076. There is furthermore intended that a compound of the formula I includes isotope-labelled forms thereof. An oxidative metabolism. In vitro liver microsomal assays isotope-labelled form of a compound of the formula I is currently available provide valuable information on the identical to this compound apart from the fact that one or course of oxidative metabolism of this type, which in turn more atoms of the compound have been replaced by an atom permits the rational design of deuterated compounds of the or atoms having an atomic mass or mass number which formula I with improved stability through resistance to such differs from the atomic mass or mass number of the atom oxidative metabolism. Significant improvements in the phar which usually occurs naturally. Exam-pies of isotopes which macokinetic profiles of compounds of the formula I are are readily commercially available and which can be incor thereby obtained, and can be expressed quantitatively in porated into a compound of the formula I by well-known terms of increases in the in vivo half-life (t/2), concentration methods include isotopes of hydrogen, carbon, nitrogen, at maximum therapeutic effect (C), area under the dose oxygen, phosphorus, fluorine and chlorine, for example H, response curve (AUC), and F; and in terms of reduced H, 13C, 14C, 15N, 18O, 17O, 3P 32P 35s, F and 36C1, clearance, dose and materials costs. respectively. A compound of the formula I, a prodrug, (0079. The following is intended to illustrate the above: a thereof or a pharmaceutically acceptable salt of either which compound of the formula I which has multiple potential sites contains one or more of the above-mentioned isotopes of attack for oxidative metabolism, for example benzylic and/or other iso-topes of other atoms is intended to be part hydrogen atoms and hydrogen atoms bonded to a nitrogen of the present invention. An isotope-labelled compound of atom, is prepared as a series of analogues in which various the formula I can be used in a number of beneficial ways. For combinations of hydrogen atoms are replaced by deuterium example, an isotope-labelled compound of the formula I into atoms, so that some, most or all of these hydrogen atoms which, for example, a radioisotope, such as H or ''C, has have been replaced by deuterium atoms. Half-life determi been incorporated is suitable for medicament and/or sub nations enable favourable and accurate determination of the strate tissue distribution assays. These radioisotopes, i.e. extent of the extent to which the improvement in resistance tritium (H) and carbon-14 (''C), are particularly preferred to oxidative metabolism has improved. In this way, it is owing to simple preparation and excellent detectability. deter-mined that the half-life of the parent compound can be Incorporation of heavier isotopes, for example deuterium extended by up to 100% as the result of deuterium-hydrogen (H), into a compound of the formula I has therapeutic exchange of this type. US 2016/0318876 A1 Nov. 3, 2016

0080 Deuterium-hydrogen exchange in a compound of I0086 Capsules are produced by preparing a powder the formula I can also be used to achieve a favourable mixture as described above and filling shaped gelatine shells modification of the metabolite spectrum of the starting therewith. Glidants and lubricants, such as, for example, compound in order to diminish or eliminate undesired toxic highly disperse silicic acid, talc, magnesium Stearate, cal metabolites. For example, if a toxic metabolite arises cium Stearate or polyethylene glycol in Solid form, can be through oxidative carbon-hydrogen (C-H) bond cleavage, added to the powder mixture before the filling operation. A it can reasonably be assumed that the deuterated analogue disintegrant or solubiliser, Such as, for example, agar-agar, will greatly diminish or eliminate production of the calcium carbonate or Sodium carbonate, may likewise be unwanted metabolite, even if the particular oxidation is not a rate-determining step. Further information on the state of added in order to improve the availability of the medicament the art with respect to deuterium-hydrogen exchange may be after the capsule has been taken. found, for example in Hanzlik et al., J. Org. Chem. 55, I0087. In addition, if desired or necessary, suitable bind 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326 ers, lubricants and disintegrants as well as dyes can likewise 3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette be incorporated into the mixture. Suitable binders include et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et starch, gelatine, natural Sugars, such as, for example, glucose al. Carcinogenesis 16(4), 683-688, 1993. or beta-lactose, Sweeteners made from maize, natural and 0081. The invention furthermore relates to medicaments synthetic rubber, Such as, for example, acacia, tragacanth or comprising at least one compound of the formula I and/or Sodium alginate, carboxymethylcellulose, polyethylene gly pharmaceutically acceptable derivatives, Solvates and Ste col, waxes, and the like. The lubricants used in these dosage reoisomers thereof, including mixtures thereof in all ratios, forms include Sodium oleate, sodium Stearate, magnesium and optionally excipients and/or adjuvants. Stearate, Sodium benzoate, sodium acetate, sodium chloride 0082 Pharmaceutical formulations can be administered and the like. The disintegrants include, without being in the form of dosage units which comprise a predetermined restricted thereto, starch, methylcellulose, agar, bentonite, amount of active ingredient per dosage unit. Such a unit can xanthan gum and the like. The tablets are formulated by, for comprise, for example, 0.5 mg to 1 g, preferably 1 mg to 700 example, preparing a powder mixture, granulating or dry mg, particularly preferably 5 mg to 100 mg. of a compound pressing the mixture, adding a lubricant and a disintegrant according to the invention, depending on the condition and pressing the entire mixture to give tablets. A powder treated, the method of administration and the age, weight mixture is prepared by mixing the compound comminuted in and condition of the patient, or pharmaceutical formulations a suitable manner with a diluent or a base, as described can be administered in the form of dosage units which above, and optionally with a binder, Such as, for example, comprise a predetermined amount of active ingredient per carboxymethylcellulose, an alginate, gelatine or polyvi dosage unit. Preferred dosage unit formulations are those nylpyrrolidone, a dissolution retardant. Such as, for example, which comprise a daily dose or part-dose, as indicated paraffin, an absorption accelerator, Such as, for example, a above, or a corresponding fraction thereof of an active quaternary salt, and/or an absorbant, Such as, for example, ingredient. Furthermore, pharmaceutical formulations of bentonite, kaolin or dicalcium phosphate. The powder mix this type can be prepared using a process which is generally ture can be granulated by wetting it with a binder, such as, known in the pharmaceutical art. for example, syrup, starch paste, acadia mucilage or solu 0083) Pharmaceutical formulations can be adapted for tions of cellulose or polymer materials and pressing it administration via any desired Suitable method, for example through a sieve. As an alternative to granulation, the powder by oral (including buccal or Sublingual), rectal, nasal, topical mixture can be run through a tabletting machine, giving (including buccal, Sublingual or transdermal), vaginal or lumps of non-uniform shape, which are broken up to form parenteral (including Subcutaneous, intramuscular, intrave granules. The granules can be lubricated by addition of nous or intradermal) methods. Such formulations can be Stearic acid, a stearate salt, talc or mineral oil in order to prepared using all processes known in the pharmaceutical art prevent sticking to the tablet casting moulds. The lubricated by, for example, combining the active ingredient with the mixture is then pressed to give tablets. The compounds excipient(s) or adjuvant(s). according to the invention can also be combined with a 0084 Pharmaceutical formulations adapted for oral free-flowing inert excipient and then pressed directly to give administration can be administered as separate units, such tablets without carrying out the granulation or dry-pressing as, for example, capsules or tablets; powders or granules; steps. A transparent or opaque protective layer consisting of Solutions or Suspensions in aqueous or non-aqueous liquids; a shellac Sealing layer, a layer of Sugar or polymer material edible foams or foam foods; or oil-in-water liquid emulsions and a gloss layer of wax may be present. Dyes can be added or water-in-oil liquid emulsions. to these coatings in order to be able to differentiate between 0085 Thus, for example, in the case of oral administra different dosage units. tion in the form of a tablet or capsule, the active-ingredient I0088 Oral liquids, such as, for example, solution, syrups component can be combined with an oral, non-toxic and and elixirs, can be prepared in the form of dosage units so pharmaceutically acceptable inert excipient, such as, for that a given quantity comprises a pre-specified amount of the example, ethanol, glycerol, water and the like. Powders are compound. Syrups can be prepared by dissolving the com prepared by comminuting the compound to a suitable fine pound in an aqueous solution with a suitable flavour, while size and mixing it with a pharmaceutical excipient commi elixirs are prepared using a non-toxic alcoholic vehicle. nuted in a similar manner, Such as, for example, an edible Suspensions can be formulated by dispersion of the com carbohydrate, such as, for example, starch or mannitol. A pound in a non-toxic vehicle. Solubilisers and emulsifiers, flavour, preservative, dispersant and dye may likewise be Such as, for example, ethoxylated isostearyl alcohols and present. polyoxyethylene sorbitol ethers, preservatives, flavour addi US 2016/0318876 A1 Nov. 3, 2016

tives, such as, for example, peppermint oil or natural Sweet tered in the manner in which snuff is taken, i.e. by rapid eners or saccharin, or other artificial Sweeteners and the like, inhalation via the nasal passages from a container containing can likewise be added. the powder held close to the nose. Suitable formulations for 0089. The dosage unit formulations for oral administra administration as nasal spray or nose drops with a liquid as tion can, if desired, be encapsulated in microcapsules. The carrier Substance encompass active-ingredient solutions in formulation can also be prepared in Such a way that the water or oil. release is extended or retarded. Such as, for example, by 0099 Pharmaceutical formulations adapted for adminis coating or embedding of particulate material in polymers, tration by inhalation encompass finely particulate dusts or wax and the like. mists, which can be generated by various types of pres 0090 The compounds of the formula I and pharmaceu Surised dispensers with aerosols, nebulisers or insufflators. tically salts, tautomers and stereoisomers thereof can also be 0100 Pharmaceutical formulations adapted for vaginal administered in the form of liposome delivery systems. Such administration can be administered as pessaries, tampons, as, for example, Small unilamellar vesicles, large unilamellar creams, gels, pastes, foams or spray formulations. vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as, for example, 0101 Pharmaceutical formulations adapted for parent cholesterol, Stearylamine or phosphatidylcholines. eral administration include aqueous and non-aqueous sterile 0091. The compounds of the formula I and the salts, injection solutions comprising antioxidants, buffers, bacte tautomers and stereoisomers thereof can also be delivered riostatics and Solutes, by means of which the formulation is using monoclonal antibodies as individual carriers to which rendered isotonic with the blood of the recipient to be the compound molecules are coupled. The compounds can treated; and aqueous and non-aqueous sterile Suspensions, also be coupled to soluble polymers as targeted medicament which may comprise Suspension media and thickeners. The carriers. Such polymers may encompass polyvinylpyrroli formulations can be administered in single-dose or multi done, pyran copolymer, polyhydroxypropylmethacrylami dose containers, for example sealed ampoules and vials, and dophenol, polyhydroxyethylaspartamidophenol or polyeth stored in freeze-dried (lyophilised) state, so that only the ylene oxide polylysine, Substituted by palmitoyl radicals. addition of the sterile carrier liquid, for example water for The compounds may furthermore be coupled to a class of injection purposes, immediately before use is necessary. biodegradable polymers which are suitable for achieving Injection solutions and Suspensions prepared in accordance controlled release of a medicament, for example polylactic with the recipe can be prepared from sterile powders, acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, granules and tablets. polyorthoesters, polyacetals, polydihydroxypyrans, poly 0102. It goes without saying that, in addition to the above cyanoacrylates and crosslinked or amphipathic block copo particularly mentioned constituents, the formulations may lymers of hydrogels. also comprise other agents usual in the art with respect to the 0092 Pharmaceutical formulations adapted for transder particular type of formulation; thus, for example, formula mal administration can be administered as independent tions which are suitable for oral administration may com plasters for extended, close contact with the epidermis of the prise flavours. recipient. Thus, for example, the active ingredient can be 0103) A therapeutically effective amount of a compound delivered from the plaster by iontophoresis, as described in of the formula I depends on a number of factors, including, general terms in Pharmaceutical Research, 3(6), 318 (1986). for example, the age and weight of the animal, the precise 0093I Pharmaceutical compounds adapted for topical condition that requires treatment, and its severity, the nature administration can be formulated as ointments, creams, of the formulation and the method of administration, and is Suspensions, lotions, powders, solutions, pastes, gels, ultimately determined by the treating doctor or vet. How sprays, aerosols or oils. ever, an effective amount of a compound according to the 0094 For the treatment of the eye or other external tissue, invention is generally in the range from 0.1 to 100 mg/kg of for example mouth and skin, the formulations are preferably body weight of the recipient (mammal) per day and particu applied as topical ointment or cream. In the case of formu larly typically in the range from 1 to 10 mg/kg of body lation to give an ointment, the active ingredient can be weight per day. Thus, the actual amount per day for an adult employed either with a paraffinic or a water-miscible cream mammal weighing 70 kg is usually between 70 and 700 mg. base. Alternatively, the active ingredient can be formulated where this amount can be administered as a single dose per to give a cream with an oil-in-water cream base or a day or usually in a series of part-doses (such as, for example, water-in-oil base. two, three, four, five or six) per day, so that the total daily 0095 Pharmaceutical formulations adapted for topical dose is the same. An effective amount of a salt or Solvate or application to the eye include eye drops, in which the active of a physiologically functional derivative thereof can be ingredient is dissolved or Suspended in a Suitable carrier, in determined as the fraction of the effective amount of the particular an aqueous solvent. compound according to the invention per se. It can be 0096 Pharmaceutical formulations adapted for topical assumed that similar doses are suitable for the treatment of application in the mouth encompass lozenges, pastilles and other conditions mentioned above. mouthwashes. 0104. A combined treatment of this type can beachieved 0097 Pharmaceutical formulations adapted for rectal with the aid of simultaneous, consecutive or separate dis administration can be administered in the form of Supposi pensing of the individual components of the treatment. tories or enemas. Combination products of this type employ the compounds 0098 Pharmaceutical formulations adapted for nasal according to the invention. administration in which the carrier Substance is a Solid 0105. The invention furthermore relates to medicaments comprise a coarse powder having a particle size, for comprising at least one compound of the formula I and/or example, in the range 20-500 microns, which is adminis pharmaceutically acceptable salts, tautomers and stereoiso US 2016/0318876 A1 Nov. 3, 2016

mers thereof, including mixtures thereof in all ratios, and at medicament for the treatment or prevention of a tankyrase least one further medicament active ingredient. induced disease or a tankyrase-induced condition in a mam 0106 The invention also relates to a set (kit) consisting of mal, in which to this method a therapeutically effective separate packs of amount of a compound according to the invention is admin 0107 (a) an effective amount of a compound of the istered to a sick mammal in need of Such treatment. The formula I and/or pharmaceutically acceptable salts, tau therapeutic amount varies according to the specific disease tomers and stereoisomers thereof, including mixtures and can be determined by the person skilled in the art thereof in all ratios, and without undue effort. 0108 (b) an effective amount of a further medicament 0118. The expression “tankyrase-induced diseases or active ingredient. conditions' refers to pathological conditions that depend on 0109 The set comprises suitable containers, such as the activity of one or more tankyrases. Diseases associated boxes, individual bottles, bags or ampoules. The set may, for with tankyrase activity include cancer, multiple Sclerosis, example, comprise separate ampoules, each containing an cardiovascular diseases, central nervous system injury and effective amount of a compound of the formula I and/or different forms of inflammation. pharmaceutically acceptable salts, tautomers and stereoiso 0119 The present invention specifically relates to com mers thereof, including mixtures thereof in all ratios, and an pounds of the formula I and pharmaceutically acceptable effective amount of a further medicament active ingredient salts, tautomers and stereoisomers thereof, including mix in dissolved or lyophilised form. tures thereof in all ratios, for the use for the treatment of 0110. “Treating as used herein, means an alleviation, in diseases in which the inhibition, regulation and/or modula whole or in part, of symptoms associated with a disorder or tion inhibition of tankyrase plays a role. disease, or slowing, or halting of further progression or 0.120. The present invention specifically relates to com worsening of those symptoms, or prevention or prophylaxis pounds of the formula I and pharmaceutically acceptable of the disease or disorder in a subject at risk for developing salts, tautomers and stereoisomers thereof, including mix the disease or disorder. tures thereof in all ratios, for the use for the inhibition of 0111. The term “effective amount” in connection with a tankyrase. compound of formula (I) can mean an amount capable of I0121 The present invention specifically relates to com alleviating, in whole or in part, symptoms associated with a pounds of the formula I and pharmaceutically acceptable disorder or disease, or slowing or halting further progression salts, tautomers and stereoisomers thereof, including mix or Worsening of those symptoms, or preventing or providing tures thereof in all ratios, for the use for the treatment of prophylaxis for the disease or disorder in a subject having or cancer, multiple Sclerosis, cardiovascular diseases, central at risk for developing a disease disclosed herein, such as nervous system injury and different forms of inflammation. inflammatory conditions, immunological conditions, cancer 0.122 The present invention specifically relates to meth or metabolic conditions. ods for treating or preventing cancer, multiple Sclerosis, 0112. In one embodiment an effective amount of a com cardiovascular diseases, central nervous system injury and pound of formula (I) is an amount that inhibits a tankyrase different forms of inflammation, comprising administering in a cell. Such as, for example, in vitro or in vivo. In some to a subject in need thereof an effective amount of a embodiments, the effective amount of the compound of compound of formula I or a pharmaceutically acceptable formula (I) inhibits tankyrase in a cell by 10%, 20%, 30%, salt, tautomer, Stereoisomer or Solvate thereof. 40%, 50%, 60%, 70%, 80%, 90% or 99%, compared to the I0123 Representative cancers that compounds of formula activity of tankyrase in an untreated cell. The effective I are useful for treating or preventing include, but are not amount of the compound of formula (I), for example in a limited to, cancer of the head, neck, eye, mouth, throat, pharmaceutical composition, may be at a level that will esophagus, bronchus, larynx, pharynx, chest, bone, lung, exercise the desired effect; for example, about 0.005 mg/kg colon, rectum, stomach, prostate, urinary bladder, uterine, of a subject’s body weight to about 10 mg/kg of a subjects cervix, breast, ovaries, testicles or other reproductive organs, body weight in unit dosage for both oral and parenteral skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, administration. brain, central nervous system, Solid tumors and blood-borne 0113 Use tumors. 0114. The present compounds are suitable as pharmaceu 0.124 Representative cardiovascular diseases that com tical active ingredients for mammals, especially for humans, pounds of formula I are useful for treating or preventing in the treatment of cancer, multiple Sclerosis, cardiovascular include, but are not limited to, restenosis, atherosclerosis diseases, central nervous system injury and different forms and its consequences such as stroke, myocardial infarction, of inflammation. ischemic damage to the heart, lung, gut, kidney, liver, 0115 The present invention encompasses the use of the pancreas, spleen or brain. compounds of the formula I and/or pharmaceutically accept 0.125. The present invention relates to a method of treat able salts, tautomers and stereoisomers thereof for the prepa ing a proliferative, autoimmune, anti inflammatory or infec ration of a medicament for the treatment or prevention of tious disease disorder that comprises administering to a cancer, multiple Sclerosis, cardiovascular diseases, central subject in need thereof a therapeutically effective amount of nervous system injury and different forms of inflammation. a compound of formula I. 0116 Examples of inflammatory diseases include rheu 0.126 Preferably, the present invention relates to a matoid arthritis, psoriasis, contact dermatitis, delayed hyper method wherein the disease is a cancer. sensitivity reaction and the like. I0127 Particularly preferable, the present invention 0117. Also encompassed is the use of the compounds of relates to a method wherein the disease is a cancer, wherein the formula I and/or pharmaceutically acceptable salts, tau administration is simultaneous, sequential or in alternation tomers and stereoisomers thereof for the preparation of a with administration of at least one other active drug agent. US 2016/0318876 A1 Nov. 3, 2016

0128. The disclosed compounds of the formula I can be 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) administered in combination with other known therapeutic and compounds that work by other mechanisms (for agents, including anticancer agents. As used here, the term example linomide, inhibitors of integrin CVB3 function and 'anticancer agent' relates to any agent which is adminis angiostatin): tered to a patient with cancer for the purposes of treating the (vi) vessel-damaging agents, such as combretastatin A4 and CaCC. compounds disclosed in international patent applications 0129. The anti-cancer treatment defined herein may be WO 99/02166, WO 00/40529, WO 00/41669, WO applied as a sole therapy or may involve, in addition to the O1/92224, WO 02/04434 and WO 02/08213; compound of the invention, conventional Surgery or radio (vii) antisense therapies, for example those which are therapy or chemotherapy. Such chemotherapy may include directed to the targets listed above, such as ISIS 2503, an one or more of the following categories of anti-tumour anti-Ras antisense; agents: (viii) gene therapy approaches, including, for example, (i) antiproliferative/antineoplastic/DNA-damaging agents approaches for replacement of aberrant genes, such as and combinations thereof, as used in medical oncology, Such aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene as alkylating agents (for example cis-platin, carboplatin, directed enzyme pro-drug therapy) approaches, such as cyclophosphamide, nitrogen mustard, melphalan, chloroam those using cytosine deaminase, thymidine kinase or a bucil, buSulphan and nitrosoureas); antimetabolites (for bacterial nitroreductase enzyme, and approaches for increas example antifolates such as fluoropyrimidines like 5-fluo ing patient tolerance to chemotherapy or radiotherapy. Such rouracil and tegafur, raltitrexed, methotrexate, cytosine ara as multi-drug resistance gene therapy; and binoside, hydroxyurea and gemcitabine); antitumour antibi (ix) immunotherapy approaches, including, for example, otics (for example anthracyclines, like adriamycin, ex-vivo and in-vivo approaches for increasing the immuno bleomycin, doxorubicin, daunomycin, epirubicin, idarubi genicity of patient tumour cells, such as transfection with cin, mitomycin-C, dactinomycin and mithramycin); antimi cytokines, such as interleukin 2, interleukin 4 or granulo totic agents (for example Vinca alkaloids, like Vincristine, cyte-macrophage colony Stimulating factor, approaches for vinblastine, Vindesine and vinorelbine, and taxoids, like decreasing T-cell anergy, approaches using transfected taxol and taxotere); topoisomerase inhibitors (for example immune cells. Such as cytokine-transfected dendritic cells, epipodophyllotoxins, like etoposide and teniposide, amsa approaches using cytokine-transfected tumour cell lines, and crine, topotecan, irinotecan and camptothecin) and cell approaches using anti-idiotypic antibodies. differentiating agents (for example all-trans-retinoic acid, 0.130. The anti-cancer treatment defined above may be 13-cis-retinoic acid and fenretinide); applied as a monotherapy or may involve, in addition to the (ii) cytostatic agents, such as antioestrogens (for example herein disclosed compounds of formula I, conventional tamoxifen, toremifene, raloxifene, droloxifene and iodoxy Surgery or radiotherapy or medicinal therapy. Such medici fene), oestrogen receptor downregulators (for example full nal therapy, e.g. a chemotherapy or a targeted therapy, may Vestrant), antiandrogens (for example bicalutamide, fluta include one or more, but preferably one, of the following mide, nilutamide and cyproterone acetate), LHRH antitumor agents: antagonists or LHRH agonists (for example goserelin, leu I0131 Alkylating Agents prorelin and buserelin), progesterones (for example mege (0132 Such as altretamine, bendamustine, busulfan, car strol acetate), aromatase inhibitors (for example as anastro mustine, chlorambucil, chlormethine, cyclophosphamide, Zole, letrozole, vorazole and exemestane) and inhibitors of dacarbazine, ifosfamide, improSulfan tosilate, lomustine, 5C-reductase, such as finasteride; melphalan, mitobronitol, mitolactol, nimustine, ranimustine, (iii) agents which inhibit cancer cell invasion (for example temozolomide, thiotepa, treosulfan, mechloretamine, carbo metalloproteinase inhibitors, like marimastat, and inhibitors quone, apaziquone, fotemustine, glufosfamide, palifosf of urokinase plasminogen activator receptor function); amide, pipobroman, trofosfamide, uramustine; (iv) inhibitors of growth factor function, for example such 0.133 Platinum Compounds inhibitors include growth factor antibodies, growth factor 0.134. Such as carboplatin, cisplatin, eptaplatin, miripla receptor antibodies (for example the anti-erbb2 antibody tine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, trastuzumab HerceptinTM and the anti-erbbl antibody satraplatin: cetuximab C225), farnesyl transferase inhibitors, tyrosine I0135) DNA. Altering Agents kinase inhibitors and serine/threonine kinase inhibitors, for 0.136 Such as amrubicin, bisantrene, decitabine, mitox example inhibitors of the epidermal growth factor family antrone, procarbazine, trabectedin, clofarabine, amsacrin, (for example EGFR family tyrosine kinase inhibitors, such brostallicin, pixantrone, laromustine; aS N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-mor 0.137 Topoisomerase Inhibitors pholinopropoxy) quinazolin-4-amine (gefitinib, AZD1839), 0.138. Such as etoposide, irinotecan, razoxane, sobuzox N-(3-ethynylphenyl)-6,7-bis (2-methoxyethoxy)guinazolin ane, teniposide, topotecan, amonafide, belotecan, ellip 4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3- tinium acetate, Voreloxin; chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)guinaZo 0.139 Microtubule Modifiers lin-4-amine (CI 1033)), for example inhibitors of the 0140. Such as cabazitaxel, docetaxel, eribulin, ixabepi platelet-derived growth factor family and for example lone, paclitaxel, vinblastine, Vincristine, Vinorelbine, Vin inhibitors of the hepatocyte growth factor family; desine, Vinflunine, fosbretabulin, tesetaxel: (v) antiangiogenic agents, such as those which inhibit the 0.141 Antimetabolites effects of vascular endothelial growth factor, (for example 0142. Such as asparaginase, azacitidine, calcium levoflo the anti-vascular endothelial cell growth factor antibody linate, capecitabine, cladribine, cytarabine, enocitabine, bevacizumab AvastinTM, compounds such as those dis floXuridine, fludarabine, fluorouracil, gemcitabine, mercap closed in published international patent applications WO topurine, methotrexate, nelarabine, pemetrexed, pralatrex US 2016/0318876 A1 Nov. 3, 2016 ate, azathioprine, thioguanine, carmofur, doxifluridine, ela etanidazole, ganetespib, idronoxil, iniparib, ixazomib, cytarabine, raltitrexed, sapacitabine, tegafur, trimetrexate; lonidamine, nimorazole, panobinostat, peretinoin, pliti 0143 Anticancer Antibiotics depsin, pomalidomide, procodaZol, ridaforolimus, tasquini 0144. Such as bleomycin, dactinomycin, doxorubicin, mod, telotristat, thymalfasin, tirapazamine, tosedostat, tra epirubicin, idarubicin, levamisole, miltefosine, mitomycin bedersen, ubenimex, Valspodar, gendicine, picibanil, C, romidepsin, streptozocin, valrubicin, Zinostatin, Zorubi reolysin, retaspimycin hydrochloride, trebananib, virulizin. cin, daunurobicin, plicamycin, aclarubicin, peplomycin, 0163 The following abbreviations refer respectively to pirarubicin; the definitions below: 0145 Hormones/Antagonists 0.164 aq (aqueous), h (hour), g (gram), L (liter), mg 0146 Such as abarelix, abiraterone, bicalutamide, buser (milligram), MHZ (Megahertz), min. (minute), mm (milli elin, calusterone, chlorotrianisene, degarelix, dexametha meter), mmol (millimole), mM (millimolar), m.p. (melting Sone, estradiol, fluocortolone, fluoxymesterone, flutamide, point), eq (equivalent), mL (milliliter), L (microliter), ACN fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mito (acetonitrile), AcOH (acetic acid), CDC1 (deuterated chlo tane, nafarelin, nandrolone, nilutamide, octreotide, predni roform), CDOD (deuterated methanol), CHCN (acetoni Solone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trile), c-hex (cyclohexane), DCC (dicyclohexyl carbodiim trilostane, triptorelin, diethylstilbestrol, acolbifene, danazol, ide), DCM (dichloromethane), DIC (diisopropyl deslorelin, epitiostanol, orteronel, enZalutamide; carbodiimide), DIEA (diisopropylethyl-amine), DMF (dim 0147 Aromatase Inhibitors ethylformamide), DMSO (dimethylsulfoxide), DMSO-d 0148 Such as aminoglutethimide, anastrozole, exemes (deuterated dimethylsulfoxide), EDC (1-(3-dimethyl tane, fadrozole, letrozole, testolactone, formestane; amino-propyl)-3-ethylcarbodiimide), ESI (Electro-spray 0149 Small Molecule Kinase Inhibitors ionization), EtOAc (ethyl acetate), EtO (diethyl ether), 0150. Such as crizotinib, dasatinib, erlotinib, imatinib, EtOH (ethanol), HATU (dimethylamino-(1.2.3 triazolo4. lapatinib, nilotinib, paZopanib, regorafenib, ruXolitinib, 5-b]pyridin-3-yloxy)-methylene-dimethylammonium Sorafenib, Sunitinib, Vandetanib, venurafenib, bosutinib, hexafluorophosphate), HPLC (High Performance Liquid gefitinib, axitinib, afatinib, alisertib, dabrafenib, dacomi Chromatography). i-PrCH (2-propanol), KCO (potassium tinib, dinaciclib, dovitinib, enZastaurin, nintedanib, lenva carbonate), LC (Liquid Chromatography), MeOH (metha tinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, nol), MgSO4 (magnesium Sulfate), MS (mass spectrometry), neratinib, orantinib, perifosine, ponatinib, radotinib, rigos MTBE (Methyl tert-butyl ether), NaHCO, (sodium bicar ertib, tipifarnib, tivantinib, tivozanib, trametinib, pimasertib, bonate), NaBH (sodium borohydride), NMM (N-methyl brivanib alaninate, cediranib, apatinib, cabozantinib morpholine), NMR (Nuclear Magnetic Resonance), PyBOP S-malate, carfilzomib, ibrutinib, icotinib; (benzotriazole-1-yl-oxy-trispyrrolidino-phosphonium 0151. Photosensitizers hexafluorophosphate), RT (room temperature), Rt (retention 0152 Such as Methoxsalen, porfimer sodium, talaporfin, time), SPE (solid phase extraction), TBTU (2-(1-H-benzo temoporfin; triazole-1-yl)-1,1,3,3-tetramethyluromium tetrafluoro 0153. Antibodies borate), TEA (triethylamine), TFA (trifluoroacetic acid), 0154). Such as alemtuzumab, besilesomab, brentuximab THF (tetrahydrofuran), TLC (Thin Layer Chromatography), Vedotin, cetuximab, denosumab, ipilimumab. ofatumumab, UV (Ultraviolet). panitumumab, rituximab, to situmomab, trastuzumab, beva 0.165 Description of the In Vitro Assays cizumab, catumaXomab, elotuZumab, epratuZumab, farletu (0166 Abbreviations: Zumab, mogamulizumab, necitumumab, nimotuZumab, obi (0167 GST=Glutathione-S-transferase nutuZumab, ocaratuZumab, oregovomab, ramucirumab, 0168 FRET=Fluorescence resonance energy transfer rillotumumab, siltuximab, tocilizumab, Zalutumumab, Zano 0169 HTRF(R)=(homogenous time resolved fluores limumab, matuZumab, dalotuZumab, onartuzumab, pertu cence) Zumab, racotumomab, tabalumab, (0170 HEPES-4-(2-hydroxyethyl)-1-piperazine ethane (O155 Cytokines sulfonic acid buffer 0156 Such as aldesleukin, interferon alfa, interferon (0171 DTT=Dithiothreitol alfa2a, interferon alfa2b, tasonermin, teceleukin, oprelvekin; 0172 BSA=bovine serum albumin 0157 Drug Conjugates (0173 CHAPS=detergent; 0158. Such as denileukin diftitox, ibritumomab tiuxetan, 0.174 CHAPS-3-(3-cholamidopropyl)dimethylam iobenguane I123, prednimustine, trastuzumab emtansine, monio-1-propanesulfonate estramustine, gemtuzumab ozogamicin, aflibercept, cin 0.175 Streptavidin-XLent(R) is a high grade streptavidin tredekin besudotox, edotreotide, inotuZumab ozogamicin, XL665 conjugate for which the coupling conditions have naptumomab estafenatox, oportuZumab monatox, techne been optimized to yield a conjugate with enhanced perfor tium (99mTc) arcitumomab, vintafolide; mances for some assays, particularly those requiring high 0159 Vaccines sensitivity. 0160 Such as sipuleucel, Vitespen, emepepimut-S, onco 0176 Biochemical Activity Testing of Tankyrase 1 and 2: VAX, rindopepimut, troVax, stimuVax: Autoparsylation Assay 0161 Miscellaneous 0177. The autoparsylation assay is run in two steps: the 0162 alitretinoin, bexarotene, bortezomib, everolimus, enzymatic reaction in which GST-tagged Tankyrase-1, resp ibandronic acid, imiquimod, lenalidomide, lentinan, Tankyrase-2 transferred biotinylated ADP-ribose to itself metirosine, mifamurtide, pamidronic acid, pegaspargase, from biotinylated NAD as co-substrate and the detection pentostatin, Sipuleucel3, sizofiran, tamibarotene, temsiroli reaction where a time resolved FRET between cryptate mus, thalidomide, tretinoin, Vismodegib, Zoledronic acid, labelled anti-GST bound to the GST tag of the enzyme and thalidomide, Vorinostat, celecoxib, cilengitide, entinostat, Xlent(R) labelled-streptavidin bound the biotin-parsylation US 2016/0318876 A1 Nov. 3, 2016

residue is analysed. The autoparSylation activity was detect biotinylated ADP-ribose/ADP-ribose to itself from bioti able directly via the increase in HTRF signal. nylated NAD/NAD as co-substrate and the detection reac 0.178 The autoparsylation assay is performed as 384-well tion where a time resolved FRET between cryptate labelled HTRF(R) (Cisbio, Codolet, France) assay format in Greiner anti-His antibody bound to the His tag of the enzyme and low volume nb 384-well microtiter plates and is used for Xlent(R) labelled-streptavidin bound the biotin parsylation high throughput screen. 250 nM GST-tagged Tankyrase-1 residue is analysed. The autoparsylation activity is detect (1023-1327 aa), respectively about 250 nM GST-tagged able directly via the increase in HTRF signal. Tankyrase-2 (873-1166 aa) and 5uMbio-NAD (Biolog, Life 0185. The autoparsylation assay is performed as 384-well Science Inst., Bremen, Germany) as co-substrate are incu HTRF(R) (Cisbio, Codolet, France) assay format in Greiner bated in a total volume of 5 ul (50 mM HEPES, 4 mM low volume nb 384-well microtiter plates. 35 nM His-tagged Mg-chloride, 0.05% Pluronic F-68, 1.4 mM DTT, 0.5% Parp-1 (human, recombinant, Enzo Life Sciences GmbH, DMSO, pH 7.7) in the absence or presence of the test Lörrach, Germany) and a mixture of 125 nM bio-NAD compound (10 dilution concentrations) for 90 min at 30° C. (Biolog, Life science Inst., Bremen, Germany) and 800 nM The reaction is stopped by the addition of 1 Jul 50 mM EDTA NAD as co-substrate are incubated in a total volume of 6 ul solution. 2 ul of the detection solution (1.6 uM SA-Xlent(R) (100 mM Tris/HCl, 4 mM Mg-chloride, 0.01% IGEPAL(R) (Cisbio, Codolet, France), 7.4 nM Anti-GST-KR (Eu-la CA630, 1 mM DTT, 0.5% DMSO, pH 8, 13 ng/ul activated belled anti-GST, Cisbio, Codolet, France) in 50 mM DNA (BPS Bioscience, San Diego, US)) in the absence or HEPES, 800 mM KF, 0.1° A. BSA, 20 mM EDTA, 0.1% presence of the test compound (10 dilution concentrations) CHAPS, pH 7.0) are added. After 1 h incubation at room for 150 min at 23°C. The reaction is stopped by the addition temperature the HTRF is measured with an Envision mul of 4 ul of the Stop/detection solution (70 nM SA-Xlent(R) timode reader (Perkin Elmer LAS Germany GmbH) at (Cisbio, Codolet, France), 2.5 nM Anti-His-KR (Eu-labelled excitation wavelength 340 nm (laser mode) and emission anti-His, Cisbio, Codolet, France) in 50 mM HEPES, 400 wavelengths 615 nm and 665 nm. The ratio of the emission mM KF, 0.1% BSA, 20 mM EDTA, pH 7.0). After 1 h signals is determined. The full value used is the inhibitor incubation at room temperature the HTRF is measured with free reaction. The pharmacological Zero value used is XAV an Envision multimode reader (Perkin Elmer LAS Germany 939 (Tocris) in a final concentration of 5uM. The inhibitory GmbH) at excitation wavelength 340 nm (laser mode) and values (IC50) are determined using either the program emission wavelengths 615 nm and 665 nm. The ratio of the Symyx Assay Explorer R or Condosseo(R) from GeneData. emission signals is determined. The full value used is the (0179 Measurement of Cellular Inhibition of Tankyrase inhibitor-free reaction. The pharmacological Zero value used 0180 Since Tankyrases have been described to modulate is Olaparib (LClabs, Woburn, US) in a final concentration of cellular level of Axin2 (Huang et al., 2009; Nature) the 1 uM. The inhibitory values (IC50) are determined using increase of Axin2 level is used as read-out for determination either the program Symyx Assay Explorer(R) or Condosseo(R) of cellular inhibition of Tankyrases in a Luminex based from GeneData. assay. 0186. Description of the TNKS1 and TNKS2 ELISA 0181 Cells of the colon carcinoma cell line DLD1 are Assay plated in 96 well plates with 1.5x10 cells per well. Next 0187 Biochemical Activity Testing of TNKS 1 and 2: day, cells are treated with a serial dilution of test compound Activity ELISA (Autoparsylation Assay) in seven steps as triplicates with a final DMSO concentration 0188 For analysis of autoparsylation activity of TNKS 1 of 0.3%. After 24 hours, cells are lysed in lysis buffer (20 and 2 an activity ELISA is performed: In the first step GST mM Tris/HCl pH 8.0, 150 mM NaCl, 1% NP40, 10% tagged TNKS is captured on a Glutathione coated plate. Glycerol) and lysates are cleared by centrifugation through Then the activity assay with biotinylated NAD is performed a 96 well filter plate (0.65 um). Axin2 protein is isolated in the absence/presence of the compounds. During the from cell lysates by incubation with a monoclonal anti enzymatic reaction GST tagged TNKS transfers biotinylated Axin2 antibody (R&D Systems #MAB6078) that is bound to ADP-ribose to itself from biotinylated NAD as co-substrate. fluorescent carboxybeads. Then, bound Axin2 is specifically For the detection streptavidin-HRP conjugate is added that detected with a polyclonal anti-Axin2 antibody (Cell Sig binds to the biotinylated TNKS and is thereby captured to naling #2151) and an appropriate PE-fluorescent secondary the plates. The amount of biotinylated resp. autoparSylated antibody. The amount of isolated Axin2 protein is deter TNKS is detected with a luminescence substrate for HRP. mined in a Luminex" machine (Luminex Corporation) The level of the luminescence signal correlates directly with according to the manufacturers instruction by counting 100 the amount of autoparsylated TNKS and therefore with events per well. Inhibition of Tankyrase by test compounds activity of TNKS. results in higher levels of Axin2 which directly correlates (0189 The activity ELISA is performed in 384 well with an increase of detectable fluorescence. As controls cells Glutathione coated microtiter plates (Express capture Glu are treated with solvent alone (neutral control) and with a tathione coated plate, Biocat, Heidelberg, Germany). The Tankyrase reference inhibitor IWR-2 (3E-06 M) which plates are pre-equilibrated with PBS. Then the plates are refers as control for maximum increase of Axin2. For incubated with 50 ul 20 ng/well GST-tagged Tnks-1 (1023 analysis, the obtained data are normalized against the 1327 aa, prepared in-house), respectively GST-tagged untreated solvent control and fitted for determination of the Tnks-2 (873-1166 aa, prepared in-house) in assay buffer (50 ECso values using the Assay Explorer software (Accelrys). mM HEPES, 4 mM Mg-chloride, 0.05% Pluronic F-68, 2 0182. Description of the PARP1 Assay mM DTT, pH 7.7) overnight at 4°C. The plates are washed 0183 Biochemical Activity Testing of PARP-1: Autopar 3 times with PBS-Tween-20. The wells are blocked by Sylation Assay incubation at room temperature for 20 minutes with 50 ul 0184 The autoparsylation assay is run in two steps: the blocking buffer (PBS, 0.05% Tween-20, 0.5% BSA). After enzymatic reaction in which His-tagged Parp-1 transfers wards the plates are washed 3 times with PBS-Tween-20. US 2016/0318876 A1 Nov. 3, 2016

The enzymatic reaction is performed in 50 ul reaction viated as follows: S (singlet), d (doublet), t (triplet), q solution (50 mM HEPES, 4 mM Mg-chloride, 0.05% (quartet), m (multiplet), br (broad). Pluronic F-68, 1.4 mM DTT, 0.5% DMSO, pH 7.7) with 10 (0195 The microwave chemistry is performed on a CEM uMbio-NAD (Biolog, Life science Inst., Bremen, Germany) microwave reactor. as co-substrate in the absence or presence of the test com (0196. Phthalazines: Synthesis pound (10 dilution concentrations) for 1 hour at 30°C. The reaction is stopped by 3 times washing with PBS-Tween-20. For the detection 50 ul of 20 ng/ul Streptavidin, HRP C conjugate (MoBiTec, Göttingen, Germany) in PBS/0.05% Tween-20/0.01% BSA are added and the plates are incu n N --> bated for 30 minutes at room temperature. After three times washing with PBS-Tween-20 50 ul of SuperSignal ELISA - Femto Maximum sensitivity substrate solution (Thermo FisherScientific (Pierce), Bonn, Germany) are added. Fol C lowing a 1 minute incubation at room temperature lumines NH2 cence signals are measured with an Envision multimode reader (Perkin Elmer LAS Germany GmbH) at 700 nm. The n N --> full value used is the inhibitor-free reaction. The pharma cological Zero value used is XAV-939 (Tocris) in a final 2 N concentration of 5 uM. The inhibitory values (IC50) are determined using either the program Symyx Assay C Explorer(R) or Condosseo(R) from GeneData. NH2 0190. Above and below, all temperatures are indicated in C. In the following examples, “conventional work-up” means: water is added if necessary, the pH is adjusted, if SN - - necessary, to values between 2 and 10, depending on the 2 N constitution of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, O 21 the organic phase is dried over Sodium Sulfate and evapo rated, and the residue is purified by chromatography on HN S X silica gel and/or by crystallisation. Rf values on silica gel; R eluent: ethyl acetate/methanol 9:1. (0191 P: HPLC-Method: gradient: 5.5 min: flow: 2.75 ml/min from 99:1 to 0:100 s HO/acetonitrile; 2 N water+TFA (0.01% vol.); acetonitrile+TFA (0.01% vol.) column: Chromolith SpeedROD RP 18e 50-4.6 wavelength: 220 nm EXAMPLE 1. Merck HitachiLa Chrome Synthesis of 2-phenyl-N-phthalazin-1-yl-acetamide (“A1 ”) (0192 N: HPLC-Method: gradient: 5.5 min: flow: 2.75 ml/min from 90:10 to 0:100 0197) HO/acetonitrile; water+TFA (0.01% vol.); acetonitrile+TFA (0.01% vol.) O column: Chromolith SpeedROD RP 18e 50-4.6 H wavelength: 220 nm N \ Merck HitachiLa Chrome N A 0193 X: HPLC/MS Conditions RN column: Chromolith Performance ROD RP-18e, 100x3 2 gradient: A:B=99:1 to 0:100 in 1.8 min 1.1 4-Chloro-phthalazin-1-ylamine flow rate: 2.0 ml/min (0198 eluent A: water+0.05% formic acid eluent B: acetonitrile+0.04% formic acid wavelength: 220 nm N-N (0194 H NMR was recorded on Bruker DPX-300, DRX HN / \ C 400 or AVII-400 spectrometer, using residual signal of deuterated solvent as internal reference. Chemical shifts (8) are reported in ppm relative to the residual solvent signal (8–2.49 ppm for "H NMR in DMSO-d). "H NMR data are reported as follows: chemical shift (multiplicity, coupling constants, and number of hydrogens). Multiplicity is abbre US 2016/0318876 A1 Nov. 3, 2016

0199 Copper (II)-sulfate pentahydrate (632.4 mg. 2.53 EXAMPLE 2 mmol) was dissolved in an aqueous ammonia Solution (32%, 25 mL). A Suspension Von 1,4-dichlorophthalazine (2 g; Synthesis of 2-(3-methoxyphenyl)-N-phthalazin-1- 10.05 mmol) in THF (25 mL) was added and the 2-phase yl-acetamide (“A2) mixture was heated for 1.5 h at 65-80° C. (max. 13 bar) and 1.5 h at 100° C. in a microwave oven (CEM Discover). In the organic phase a precipitate was formed. The reaction 0204 mixture was cooled to room temperature, the precipitate was filtered off by suction, washed with water, little ethyl acetate and diethyl ether and dried in vacuo at 50° C. for 14 h; yield: O 1.6 g (89%), pink crystals (purity: 100%, Rt. 2.49 min). 1.2: Phthalazin-1-ylamine HN O 0200 s 2N

NN 0205 Phthalazin-1-ylamine (57 mg; 0.39 mmol) was Suspended in 1,2-dichloroethane (4 mL) under argon. N-eth - yldiisopropylamine (0.141 mL: 0.83 mmol) was added fol lowed by the dropwise addition of (3-methoxyphenyl)- 0201 4-Chloro-phthalazin-1-ylamine (750 mg; 4.18 acetyl chloride (0.123 ml, 0.79 mmol) via a syringe. During mmol) was hydrogenated in methanol (20 mL) and 2N the addition the temperature increased from 20°C. to 35° C. sodium hydroxide solution (3.7 mL) with Pd/C (5%) at room After one minute a clear light brown solution was obtained. temperature for 14 h. The reaction solution was filtered and The reaction was stirred for 18 h at room temperature. The concentrated. The aqueous residue was diluted with water (5 Solvent was removed under vacuum. The residue was puri mL) and extracted with ethyl acetate (3x). The organic fied by chromatography (column: 40 g RP18 silica gel; layers were combined, washed with brine, dried over sodium combiflash companion); yield: 6 mg (5%), colourless Solid sulfate, filtered and evaporated to dryness. The residue was (purity: 100%, Rt: 2.94 min); triturated with diethyl ether, filtered off by suction and dried. The aqueous phase from the extraction was evaporated to 0206 H NMR (400 MHz, DMSO-d) 8 ppm) 10.96 (s, dryness. The residue was dissolved in a mixture of water and 1H), 9.59 (s, 1H), 8.19 (d. J=8.0 Hz, 1H), 8.08-7.79 (m,3H), acetonitrile and lyophilized. The solid was suspended in 7.29 (t, J=7.9 Hz, 1H), 7.10-6.74 (m, 3H), 3.86 (s. 2H), 3.77 dichloromethane/methanol (10%), stirred for 30 min and (s, 3H). filtered off by suction. The filtrate was evaporated to dry ness. The residue was triturated with dichloromethane, fil tered off by suction, washed with diethyl ether and dried. EXAMPLE 3 Both solids were combined; yield: 545 mg (90%), light brown solid (purity: 100%, Rt. 2.25 min). Synthesis of 2-(4-methoxyphenyl)-N-phthalazin-1- yl-acetamide (“A3) 1.3 2-Phenyl-N-phthalazin-1-yl-acetamide 0202 Phthalazin-1-ylamine (50 mg; 0.34 mmol) was 0207 suspended in THF (2 mL) and treated under argon with N-ethyldiisopropylamine (76.2 ul: 0.45 mmol). Phenylace O tylchloride (54.6 ul: 0.41 mmol) was added dropwise at H room temperature and the mixture was heated to 70° C. For N a short time a clear yellow solution was formed, before a O solid precipitated. After stirring at 70° C. for 1 h THF (2 \ \ mL), N-ethyldiisopropylamine (76.2 ul; 0.45 mmol) and A phenylacetylchloride (54.6 ul: 0.41 mmol) were added and FN the reaction mixture was stirred at 70° C. for 14 h. The reaction mixture was cooled to room temperature, treated with methanol (0.5 mL) and evaporated to dryness. The 0208 “A3' was prepared from phthalazin-1-ylamine (60 light-brown residue was treated with acetonitrile (1 mL) and mg; 0.41 mmol), N-ethyldiisopropylamine (0.148 mL: 0.87 methanol (1 mL) and Sonicated. The formed precipitate was mmol) and (4-methoxyphenyl)-acetyl chloride (0.126 mL.; filtered by suction, washed with methanol and diethyl ether 0.83 mmol) in 1,2-dichlorethane (3 mL) according to pro and dried in vacuo at 50° C. Further product was isolated from filtrate via column chromatography; yield: 25 mg cedure for example 2: yield: 16 mg (13%), colourless solid (28%), colourless solid (purity: 100%, Rt. 2.89 min); (purity: 100%, Rt: 2.91 min); H NMR (400 MHz, DMSO 0203 H NMR (400 MHz, DMSO-d) 8 ppm. 10.97 (s, d) 8 ppm. 10.92 (s, 1H), 9.58 (s, 1H), 8.19 (d. J–7.9 Hz, 1H), 9.57 (s, 1H), 8.17 (d. J=7.9 Hz, 1H), 8.08-7.82 (m, 3H), 1H), 8.07-7.83 (m, 1H), 7.34 (d. J=8.5 Hz, 1H), 6.94 (d. 747-720 (m, 5H), 3.89 (s. 2H). J=8.6 Hz, 1H), 3.81 (s, 1H), 3.76 (s. 2H). US 2016/0318876 A1 Nov. 3, 2016 14

EXAMPLE 4 temperature the reaction mixture was diluted with water (40 mL) and extracted 3 times with ethyl acetate. The combined Synthesis of 2-(4-ethoxyphenyl)-N-phthalazin-1-yl organic layers were washed with brine, dried with sodium acetamide (A4) sulfate and evaporated to dryness. The residue was triturated in ethanol, filtered off, washed with diethyl ether and dried 0209 at 50° C. in vacuo. From the filtrate further product was obtained by chromatography (column: 40 g RP18 silica gel; combiflash companion); yield: 58 mg (39%), light yellow O solid (purity: 98%, Rt. 3.29 min); H N 0214) H NMR (400 MHz, DMSO-d) 8 ppm. 11.02 (s, 1H), 9.58 (s, 1H), 8.26-8.15 (m, 1H), 8.09-7.84 (m, 3H), \ O\— 7.58-7.38 (m, 3H), 7.34-7.22 (m. 1H), 3.98 (s. 2H). M EXAMPLE 6 RN Synthesis of 2-(3-cyanophenyl)-N-phthalazin-1-yl 0210 (4-Ethoxyphenyl)-acetic acid (74.5 mg; 0.41 acetamide (“A6) mmol), benzotriazol-1-ol hydrate (65.3 mg 0.41 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro 0215 chloride (103 mg: 0.54 mmol) were dissolved in DMF (2 mL) at room temperature. After stirring for 15 min O phthalazin-1-ylamine (60 mg 0.41 mmol) was added and H the reaction mixture was stirred for 2 h. The solid, which N precipitated during the reaction, was filtered off, washed \ with a small portion of DMF, acetonitrile and diethyl ether N and dried at 50° C. in vacuo. The filtrate was diluted with =y water (40 mL) and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried with \ sodium sulfate, filtered and evaporated to dryness. The residue (light yellow solid) was triturated with ethanol, 0216 “A6' was prepared from (3-cyanophenyl)-acetic filtered off, washed with ethanol and diethyl ether and dried acid (66.6 mg; 0.41 mmol), benzotriazol-1-ol hydrate (65.3 at 50° C. in vacuo. Both solids were combined; yield: 81 mg mg; 0.41), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (63%), amorphous colourless solid (purity: 100%, Rt: 3.03 hydrochloride (103 mg: 0.54 mmol) and phthalazin-1-ylam min); ine (60 mg; 0.41 mmol) in DMF (2 mL) as described for 0211 "H NMR (400 MHz, DMSO-d) 8 ppm) 10.91 (s, example 5: yield: 89 mg (75%), colourless solid (purity: 1H), 9.58 (s, 1H), 8.18 (d. J=7.9 Hz, 1H), 8.07-7.84 (m, 3H), 100%, Rt: 2.91 min): 7.33 (d. J=8.6 Hz, 2H), 6.92 (d. J=8.6 Hz, 2H), 4.03 (q, J–6.9 0217 H NMR (400 MHz, DMSO-d) 8 ppm. 11.03 (s, Hz, 2H), 3.81 (s. 2H), 1.33 (t, J=6.9 Hz, 3H). 1H), 9.60 (s, 1H), 8.26-8.15 (m, 1H), 8.12-7.94 (m, 3H), 7.92-7.52 (m, 4H), 4.03 (s. 2H). EXAMPLE 5 EXAMPLE 7 Synthesis of N-phthalazin-1-yl-2-(3-trifluo romethoxyphenyl)-acetamide (“A5') Synthesis of 2-(3-nitrophenyl)-N-phthalazin-1-yl acetamide (“A7') 0212 0218

O O H N HN O \ N NN 1. M F FN N+EO 2 N O 0219 “A7” was prepared from (3-nitrophenyl)-acetic 0213 “A5” was prepared from (3-trifluoromethoxyphe acid (62.4 mg. 0.34 mmol), benzotriazol-1-ol hydrate (54.4 nyl)-acetic acid (93.8 mg; 0.41 mmol), benzotriazol-1-ol mg; 0.34 mmol), 1-ethyl-3-(3-dimethylamino-propyl)carbo hydrate (65.3 mg; 0.41 mmol), 1-ethyl-3-(3-dimethylamino diimide hydrochloride (85.8 mg; 0.45 mmol) and propyl)carbodiimide hydrochloride (103 mg: 0.54 mmol) phthalazin-1-ylamine (50 mg 0.34 mmol) in DMF (2.5 mL) and phthalazin-1-ylamine (60 mg; 0.41 mmol) in DMF (2 as described for example 4; yield: 84 mg (79%), light yellow mL) as described for example 4. After 3 h stirring at room solid (purity: 100%, Rt: 3.01 min):

US 2016/0318876 A1 Nov. 3, 2016 18

3-(2,3-dichlorophenyl)-N-(8-methyl-phthalazin-1- TABLE 2-continued yl)-propionamide ("A26") Inhibition of tankyrases of some representative 0255 compounds of the formula I ICso ICso Compound ICso TNKS1 TNKS2 No. PARP ELISA ELISA

C. A15 C A. A. HN A16 C A. A. A17 A. A. A18 B A. A. NN A2O B A. A. 2N ICso: <0.3 M = A 0.3-3 uM = B 3-50 um = C 0258. The compounds shown in Table 2 are particularly 0256 Pharmacological Data preferred compounds according to the invention. 0259. The following examples relate to medicaments: TABLE 1. EXAMPLEA Inhibition of tankyrases of some representative compounds of the formula I Injection Vials Cso Cso Compound TNKS1 TNKS2 ICso 0260 A solution of 100 g of an active ingredient of the No. enzyme assay enzyme assay Cell assay formula I and 5 g of disodium hydrogenphosphate in 31 of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric A1 A2 acid, sterile filtered, transferred into injection vials, A3 lyophilised under sterile conditions and sealed under sterile A4 conditions. Each injection vial contains 5 mg of active A5 ingredient. A6 A7 A8 EXAMPLEB A9 A10 Suppositories A11 A12 A13 0261. A mixture of 20 g of an active ingredient of the A14 formula I with 100 g of soya lecithin and 1400 g of cocoa A15 butter is melted, poured into moulds and allowed to cool. A16 Each Suppository contains 20 mg of active ingredient. A17 A18 A19 EXAMPLE C A2O A21 Solution ICso: <0.3 uM = A 0.3-3 uM = B 3-50 um = C 0262. A solution is prepared from 1 g of an active ingredient of the formula I, 9.38g of NaH2PO2H.O. 28.48 0257 The compounds shown in Table 1 are particularly g of NaHPO.12H2O and 0.1 g of benzalkonium chloride in preferred compounds according to the invention. 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 1 and sterilised by irradiation. This TABLE 2 Solution can be used in the form of eye drops. Inhibition of tankyrases of some representative compounds of the formula I EXAMPLED ICso ICso Compound ICso TNKS1 TNKS2 Ointment No. PARP ELISA ELISA 0263 500 mg of an active ingredient of the formula I are A1 mixed with 99.5 g of Vaseline under aseptic conditions. A2 A3 A4 EXAMPLE E A5 A6 Tablets A7 A8 A9 0264. A mixture of 1 kg of active ingredient of the A10 formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of A13 talc and 0.1 kg of magnesium Stearate is pressed in a A14 conventional manner to give tablets in Such a way that each tablet contains 10 mg of active ingredient. US 2016/0318876 A1 Nov. 3, 2016 19

EXAMPLE F 3. Compounds according to claim 1 in which Ardenotes phenyl, which is unsubstituted or mono-, di- or Dragees trisubstituted by Hal, NO, CN, A and/or C(R), OR, 0265 Tablets are pressed analogously to Example E and and pharmaceutically acceptable Solvates, salts, tautomers Subsequently coated in a conventional manner with a coating and stereoisomers thereof, including mixtures thereof of Sucrose, potato starch, talc, tragacanth and dye. in all ratios. EXAMPLE G 4. Compounds according to claim 1 in which A denotes unbranched or branched alkyl with 1-6 C-at Capsules oms, wherein 1-5 H-atoms may be replaced by F. and pharmaceutically acceptable Solvates, salts, tautomers 0266 2 kg of active ingredient of the formula I are and stereoisomers thereof, including mixtures thereof introduced into hard gelatine capsules in a conventional in all ratios. manner in Such a way that each capsule contains 20 mg of 5. Compounds according to claim 1, in which the active ingredient. R" denotes H. Hal or CH, X denotes Ar or Cyc, EXAMPLE H Ardenotes phenyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, NO, CN, A and/or C(R), Ampoules OR, 0267 A solution of 1 kg of active ingredient of the Rdenotes Hoder A, formula I in 60 l of bidistilled water is sterile filtered, Cyc denotes cycloalkyl with 3, 4, 5, 6 or 7 C-atoms, transferred into ampoules, lyophilised under Sterile condi A denotes unbranched or branched alkyl with 1-6 C-at tions and sealed under sterile conditions. Each ampoule oms, wherein 1-5 H-atoms may be replaced by F. contains 10 mg of active ingredient. Hal denotes F, Cl, Br or I, 1. Compounds of the formula I p denotes 0, 1, 2, 3 or 4, in denotes 1, 2 or 3, and pharmaceutically acceptable salts, tautomers and ste reoisomers thereof, including mixtures thereof in all

ratios. 6. Compounds according to claim 1, selected from the group

No. Name A1 2-phenyl-N-phthalazin-1-yl-acetamide A2 2-(3-methoxyphenyl)-N-phthalazin-1-yl-acetamide in which A3 2-(4-methoxyphenyl)-N-phthalazin-1-yl-acetamide R" denotes H. Hal, CH, OCH or CH-OH, A4 2-(4-ethoxyphenyl)-N-phthalazin-1-yl-acetamide X denotes Ar or Cyc, A5 N-phthalazin-1-yl-2-(3-trifluoromethoxyphenyl)-acetamide A6 2-(3-cyanophenyl)-N-phthalazin-1-yl-acetamide Ardenotes phenyl, biphenyl or naphthyl, each of which is A7 2-(3-nitrophenyl)-N-phthalazin-1-yl-acetamide unsubstituted or mono-, di- or trisubstituted by Hal, A8 N-phthalazin-1-yl-2-(4-trifluoromethoxyphenyl)-acetamide NO, CN, A, C(R), OR, S(O),R, C(R), N(R) A9 2-(4-tert-butylphenyl)-N-phthalazin-1-yl-acetamide “A10' 2-(2,6-dichlorophenyl)-N-phthalazin-1-yl-acetamide 2, C(R), COOR, C(R), CONCR), C(R), “A11' 2-(4-ethoxy-phenyl)-N-(5-fluoro-phthalazin-1-yl)-acetamide SO.N(R), NRCOR, NRSO.R, NRCON(R), “A12 N-(5-fluoro-phthalazin-1-yl)-2-(4-methoxy-phenyl)-acetamide NHCOOA, OC(R), N(R), CHO and/or COA, “A13 3-cyclohexyl-N-phthalazin-1-yl-propionamide R° denotes Hoder A, “A14' 3-phenyl-N-phthalazin-1-yl-propionamide A denotes unbranched or branched alkyl with 1-10 C-at “A15' 3-cyclopentyl-N-phthalazin-1-yl-propionamide “A16' 3-(2-chloro-phenyl)-N-phthalazin-1-yl-propionamide oms, wherein two adjacent carbon atoms may form a “A17 3-(2,3-dichloro-phenyl)-N-phthalazin-1-yl-propionamide double bond and/or one or two non-adjacent CH “A18' N-(8-methyl-phthalazin-1-yl)-2-phenyl-acetamide and/or CH2-groups may be replaced by N-, O- and/or “A19 N-(5-methyl-phthalazin-1-yl)-2-phenyl-acetamide S-atoms and wherein 1-7 H-atoms may be replaced by “A20 2-(4-methoxy-phenyl)-N-(8-methyl-phthalazin-1-yl)-acetamide “A21' 2-(4-methoxy-phenyl)-N-(5-methyl-phthalazin-1-yl)-acetamide F, Cl and/or OH, “A22' 3-cyclohexyl-N-(8-methyl-phthalazin-1-yl)-propionamide Cyc denotes cycloalkyl with 3, 4, 5, 6 or 7 C-atoms, “A23 3-phenyl-N-(8-methyl-phthalazin-1-yl)-propionamide Hal denotes F, Cl, Br or I, “A24' 3-cyclopentyl-N-(8-methyl-phthalazin-1-yl)-propionamide m denotes 0, 1 or 2, “A25' 3-(2-chlorophenyl)-N-(8-methyl-phthalazin-1-yl)-propionamide in denotes 1, 2 or 3, “A26' 3-(2,3-dichlorophenyl)-N-(8-methyl-phthalazin-1-yl)- p denotes 0, 1, 2, 3 or 4, propionamide and pharmaceutically acceptable salts, tautomers and Stereoisomers thereof, including mixtures thereof in and pharmaceutically acceptable Solvates, salts, tautomers all ratios. and stereoisomers thereof, including mixtures thereof 2. Compounds according to claim 1 in which in all ratios. R" denotes H. Hal or CH, 7. Process for the preparation of compounds of the and pharmaceutically acceptable Solvates, salts, tautomers formula I according to claim 1 and pharmaceutically accept and stereoisomers thereof, including mixtures thereof able salts, Solvates, tautomers and stereoisomers thereof, in all ratios. characterised in that a compound of the formula II US 2016/0318876 A1 Nov. 3, 2016 20

thereof, including mixtures thereof in all ratios, and option

II ally an pharmaceutically acceptable carrier, excipient or vehicle. 9. Compounds of the formula I according to claim 1 and pharmaceutically acceptable salts, Solvates, tautomers and Stereoisomers thereof, including mixtures thereof in all ratios, for the use for the treatment and/or prevention of cancer, multiple Sclerosis, cardiovascular diseases, central in which R" has the meanings indicated for the compound nervous system injury and different forms of inflammation. of formula I, 10. Compounds according to claim 9 for the use for the is reacted treatment and/or prevention of diseases selected from the group cancer of head, neck, eye, mouth, throat, esophagus, with a compound of formula III bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder, uterine, cervix, breast, III ovaries, testicles or other reproductive organs, skin, thyroid, (CH2)-X blood, lymph nodes, kidney, liver, pancreas, brain, central nervous system, Solid tumors and blood-borne tumors. 11. Medicaments comprising at least one compound of the O formula I according to claim 1 and/or pharmaceutically acceptable salts, Solvates and stereoisomers thereof, includ in which X and n have the meanings indicated for the ing mixtures thereof in all ratios, and at least one further compound of formula I, medicament active ingredient. and L denotes Cl, Br, I or a free or reactively functionally 12. Set (kit) consisting of separate packs of modified OH group, (a) an effective amount of a compound of the formula I and/or according to claim 1 and/or pharmaceutically accept a base or acid of the formula I is converted into one of its able salts, Solvates, salts and stereoisomers thereof, salts. including mixtures thereof in all ratios, and 8. Medicaments comprising at least one compound of the (b) an effective amount of a further medicament active formula I according to claim 1 and/or pharmaceutically ingredient. acceptable salts, Solvates, tautomers and stereoisomers