Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C317/00—Sulfones; Sulfoxides
  • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
  • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D237/18—Sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• FIELD OF THE INVENTION Cancer is a disease characterized by the loss of appropriate control for cell growth.
• imatinib tosylate (marketed as Gleevec® by Novartis for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia), lapatinib ditosylate (marketed as Tykerb® by GlaxoSmithKline for the treatment of HER2 positive breast cancer in combination with other chemo therapeutic agents), sunitinib malate (marketed as Sutent® by Pfizer and approved for the treatment of renal cancer) and sorafenib (marketed as Nexavar by Bayer for the treatment of renal cancer).
• ⁇ -catenin leads to increased Wnt signaling and activation of associated nuclear transcription factors while excess axin results in the degradation of intracellular ⁇ -catenin and decreased signaling.
• Dysregulation of the canonical Wnt signaling pathway has been implicated in a range of human carcinomas such as colon cancer, hepatocellular carcinoma, endometrial ovarian cancer, pilomatricoma skin cancer, prostate cancer, melanoma and Wilms tumor.
• signaling is initiated by interaction of a Wnt ligand with a receptor complex containing a Frizzled family member and low-density lipoprotein receptor-related protein.
• Axin is the concentration limiting component of the destruction complex, and it is this complex which is formed with adenomatous polyposis coli proteins, casein-kinase la and glycogen synthase kinase 3 ⁇ which is responsible for controlling intracellular levels of ⁇ -catenin.
• ⁇ -catenin is sequentially phosphorylated by casein-kinase la and glycogen synthase kinase 3 ⁇ on a conserved set of serine and threonine residues at the amino-terminus.
• Phosphorylation facilitates binding of ⁇ -catenin to ⁇ -transducin repeat-containing protein which then mediates ubiquitination and subsequent proteasomal degradation of ⁇ -catenin.
• un-phosphorylated ⁇ - catenin is able to migrate to the cell nucleus and interact with T-cell factor proteins and convert them into potent transcriptional activators through the recruitment of co-activator proteins.
• telomeres chromosome end protection
• insulin responsiveness e.g. IL-12, 5-HT1B
• spindle assembly e.g. IL-12, 5-HT1B
• Therapeutics which are directed at and can correct dysregulation of the Wnt signaling pathway have been implicated in conditions such as bone density defects, coronary disease, late onset Alzheimer's disease, familial exudative vitreoretinopathy, retinal angiogenesis, tetra-amelia, Mullerian-duct regression and virilization, SERKAL syndrome, type 2 diabetes, Fuhrmann syndrome, skeletal dysplasia, focal dermal hypoplasia and neural tube defects.
• Tankyrase 1 and 2 comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I.
• R 1 is phenyl, phenyl-lower alkyl, cycloalkyl, or cycloalkylllower alkyl, each optionally substituted with one or more R 1 ; each R 1 is independently lower alkyl, halo, lower alkoxy, lower haloalkyl, lower alkyl sulfonyl, trifluoromethoxy, or cyano;
• the application provides a method for treating a Tankyrase-mediated condition comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I.
• the application provides a method for treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I.
• the application provides a pharmaceutical composition comprising the compound of
• a or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound.
• a compound refers to one or more compounds or at least one compound.
• the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.
• the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”.
• the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
• the term “comprising” means that the compound or composition includes at least the recited features or components, but may also include additional features or components.
• a bond drawn into a ring system indicates that the bond may be attached to any of the suitable ring atoms.
• cyano alone or in combination with other groups, refers to N ⁇ C-(NC-).
• halogen alone or in combination with other groups, denotes chloro (CI), iodo
• Tautomeric compounds can exist as two or more interconvertable species.
• Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
• Tautomers generally exist in equilibrium and attempts to isolate an individual tautomer usually produce a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of the equilibrium is dependent on chemical features within the molecule and the environment to which it is exposed e.g. solvent, temperature, pH, etc.. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates while; in phenols, the enol form predominates.
• alkylaryl haloalkylheteroaryl
• arylalkylheterocyclyl alkylcarbonyl
• alkoxyalkyl alkylcarbonyl
• phenylalkyl refers to an alkyl group having one to two phenyl substituents, and thus includes benzyl and phenylethyl.
• An "alkylaminoalkyl” is an alkyl group having one to two alkylamino substituents.
• “Hydroxyalkyl” includes 2-hydroxyethyl, 2-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, hydroxymethyl, 3-hydroxypropyl, and so forth. Accordingly, as used herein, the term "hydroxyalkyl” is used to define a subset of heteroalkyl groups defined above.
• spirocycloalkyl means a spirocyclic cycloalkyl group, such as, for example, spiro[3.3]heptane.
• spiroheterocycloalkyl as used herein, means a spirocyclic heterocycloalkyl, such as, for example, 2,6-diaza spiro[3.3]heptane.
• alkyl denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 10 carbon atoms.
• lower alkyl denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms.
• Cyno alkyl refers to an alkyl composed of 1 to 10 carbons.
• alkyl groups include, but are not limited to, lower alkyl groups including methyl, ethyl, propyl, i-propyl, n- butyl, j-butyl, i-butyl or pentyl, isopentyl, neopentyl, hexyl.
• a specific lower alkyl group is methyl.
• alkyl When the term “alkyl” is used as a suffix following another term, as in “phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkyl group, as defined above, being substituted with one to two substituents selected from the other specifically-named group.
• phenylalkyl denotes the radical R'R"-, wherein R' is a phenyl radical, and R" is an alkylene radical as defined herein with the understanding that the attachment point of the phenylalkyl moiety will be on the alkylene radical.
• arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl.
• arylalkyl or “aralkyl” are interpreted similarly except R' is an aryl radical.
• (het) arylalkyl or “(het) aralkyl” are interpreted similarly except R' is optionally an aryl or a heteroaryl radical.
• haloalkyl or “halo-lower alkyl” or “lower haloalkyl” refers to a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms wherein one or more carbon atoms are substituted with one or more halogen atoms.
• haloalkyl or “halo-lower alkyl” or “lower haloalkyl” refers to fluoroalkyl” or “fluoro-lower alkyl” or “lower fluoroalkyl”.
• alkylene or "alkylenyl” as used herein denotes a divalent saturated linear hydrocarbon radical of 1 to 10 carbon atoms (e.g. , (CH 2 ) n )or a branched saturated divalent hydrocarbon radical of 2 to 10 carbon atoms (e.g. , -CHMe- or -CH 2 CH(i-Pr)CH 2 -), unless otherwise indicated.
• alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, 1, 1-dimethyl-ethylene, butylene, 2-ethylbutylene.
• alkoxy as used herein means an -O-alkyl group, wherein alkyl is as defined above such as methoxy, ethoxy, w-propyloxy, i-propyloxy, w-butyloxy, i-butyloxy, i-butyloxy, pentyloxy, hexyloxy, including their isomers.
• Lower alkoxy as used herein denotes an alkoxy group with a "lower alkyl” group as previously defined (Ci-ealkoxy).
• Cno alkoxy as used herein refers to an-O-alkyl wherein alkyl is C 1-10 .
• Q-ealkoxy as used herein refers to an-O- alkyl wherein alkyl is C 1-6 , in particular methoxy (OMe).
• aryl denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl.
• haloalkoxy or “halo-lower alkoxy” or “lower haloalkoxy” refers to a lower alkoxy group, wherein one or more carbon atoms are substituted with one or more halogen atoms, in particular fluoro.
• hydroxyalkyl denotes an alkyl radical as herein defined wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups.
• cycloalkyl refers to a saturated or unsaturated carbocyclic ring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
• C3_7 cycloalkyl or “lower cycloalkyl” as used herein refers to an cycloalkyl composed of 3 to 7 carbons in the carbocyclic ring. Particular groups are cyclohexyl and cyclopentyl.
• carboxy-alkyl refers to an alkyl moiety wherein one, hydrogen atom has been replaced with a carboxyl with the understanding that the point of attachment is through a carbon atom.
• carboxy or “carboxyl” refers to a -C0 2 H moiety.
• heteroaryl or “heteroaromatic” as used herein means a monocyclic or bicyclic radical of 5 to 12 ring atoms in which there is at least one aromatic ring containing at least one hetero-atom drawn from the list of N, O, or S heteroatoms. Thus, for the purposes of the invention, a heteroaryl group need only have some degree of aromatic character. Heteroaryl may be optionally substituted as defined directly below.
• heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms include, but is not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazole, thiazole, isothiazole, thiadiazole and which can optionally be substituted with one or more, preferably one or two substituents selected from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo, lower haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alky
• bicyclic moieties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzoxazole, benzisoxazole, benzothiazole, naphthyridinyl, 5,6,7,8-Tetrahydro-[l,6]naphthyridinyl, and benzisothiazole.
• Bicyclic moieties can be optionally substituted on either ring.
• a particular group is pyridazinyl.
• heterocyclyl denotes a monovalent saturated or unsaturated cyclic radical, consisting of one or more rings, preferably one to two rings, including spirocyclic ring systems, of three to eight atoms per ring, incorporating one or more ring heteroatoms (chosen from N,0 or S(0)o -2 ), and which can optionally be independently substituted with one or more, preferably one or two substituents selected from hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, lower haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulf
• heterocyclic radicals include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl, and ionic forms thereof.
• PARP is used herein to mean a protein having ADP-ribosylation activity. Within the meaning of this term, PARP encompass all proteins encoded by a parp gene, mutants thereof, and alternative slice proteins thereof. Additionally, as used herein, the term “PARP” includes PARP analogues, homologues and analogues of other animals. The term “PARP”, includes but is not limited to PARP- 1.
• PARP-2 PARP 3, Vault-PARP (PARP-4), PARP-7 (TiPARP), PARP- 8.
• PARP 9 (Bal), PARP- 10, PARP-1 1, PARP- 12, PARP- 13, PARP-14, PARP- 15, PARP- 16, TNK-1, IN - 2, and may be encompassed.
• I N * or " I N S" is used to represent the word, Tankyrase.
• Compounds that inhibit tankyrase 1 and 2 can have advantageous properties in that they have growth inhibitory activity in cancer cells.
• salts refers to salts that are suitable for use in contact with the tissues of humans and animals.
• suitable salts with inorganic and organic acids are, but are not limited to acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methane-sulfonic acid, nitric acid, phosphoric acid, p-toluenesulphonic acid, succinic acid, sulfuric acid, sulphuric acid, tartaric acid, trifluoroacetic acid and the like.
• Particular acids are formic acid, trifluoroacetic acid and hydrochloric acid.
• pharmaceutically acceptable carrier and “pharmaceutically acceptable auxiliary substance” refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation.
• composition encompasses a product comprising specified ingredients in pre-determined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts.
• pharmaceutical composition encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
• inhibitor denotes a compound which competes with, reduces or prevents the binding of a particular ligand to particular receptor or which reduces or prevents the inhibition of the function of a particular protein.
• IC 50 half maximal inhibitory concentration
• IC 50 values can be converted logarithmically to pIC 5 o values (-log IC 50 ), in which higher values indicate exponentially greater potency.
• the IC 50 value is not an absolute value but depends on experimental conditions e.g. concentrations employed.
• the IC 50 value can be converted to an absolute inhibition constant (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973) 22:3099).
• Ki absolute inhibition constant
• Ki values can be converted logarithmically to pKi values (-log Ki), in which higher values indicate exponentially greater potency.
• “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state.
• the “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.
• the term “as defined herein” and “as described herein” when referring to a variable incorporates by reference the broad definition of the variable as well as in particular, more particular and most particular definitions, if any.
• aromatic denotes the conventional idea of aromaticity as defined in the literature, in particular in IUPAC - Compendium of Chemical Terminology, 2nd, A. D. McNaught & A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997).
• pharmaceutically acceptable excipient denotes any ingredient having no therapeutic activity and being non-toxic such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products. Whenever a chiral carbon is present in a chemical structure, it is intended that all stereoisomers associated with that chiral carbon are encompassed by the structure.
• R 1 is phenyl, phenyl lower alkyl, cycloalkyl, or cycloalkyl lower alkyl, each optionally substituted with one or more R 1 ; each R 1 is independently lower alkyl, halo, lower alkoxy, lower haloalkyl, lower alkyl sulfonyl, trifluoromethoxy, or cyano;
• the application provides the compound of Formula I, wherein R 1 is phenyl, optionally substituted with one or more R 1 .
• the application provides the compound of Formula I, wherein R is phenyl, optionally substituted with one or more R 2' .
• the application provides the compound of Formula I, wherein R 1 is phenyl, optionally substituted with one or more R 1 ' , and R 2 is phenyl, optionally substituted with one or more R 2' .
• the application provides the compound of Formula I, wherein R 2' is halo and R 1 is phenyl, optionally substituted with one or more R 1 .
• the application provides the compound of Formula I, wherein R 2 is phenyl, R 2' is halo, and R 1 is phenyl, optionally substituted with one or more R 1 .
• the application provides the compound of Formula I, wherein R 1 is methoxy.
• the application provides the compound of Formula I, wherein R 1 ' is methoxy and R 2 is phenyl, optionally substituted with one or more R 2' .
• the application provides the compound of Formula I, wherein R 1 ' is methoxy, R 2 is phenyl, and R 2' is halo.
• the application provides the compound of Formula I, wherein R 1 is fluoro.
• the application provides the compound of Formula I, wherein R 1 is phenyl and R 1 is fluoro.
• the application provides the compound of Formula I, wherein R 1 ' is fluoro and R 2 is phenyl, optionally substituted with one or more R 2' .
• the application provides the compound of Formula I, wherein R 1 ' is fluoro, R 2 is phenyl, and R 2' is halo.
• R 2 is phenyl, and R 2' is halo.
• R 1 is trifluoromethyl, cyano, methyl sulfonyl, or trifluoromethoxy.
• the application provides the compound of Formula I, wherein R 1 is phenyl and R 1 is trifluoromethyl, cyano, methyl sulfonyl, or trifluoromethoxy.
• R 1 is trifluoromethyl, cyano, methyl sulfonyl, or trifluoromethoxy and R is phenyl, optionally substituted with one or more R 2' .
• R 1 is trifluoromethyl, cyano, methyl sulfonyl, or trifluoromethoxy
• R 2 is phenyl
• R 2' is halo
• R 2 is phenyl, and R 2' is halo.
• the application provides the compound of Formula I, wherein R is phenyl, optionally substituted with one or more R 2' , and R 1 ' is methoxy.
• R is phenyl, optionally substituted with one or more R 2'
• R 1 is phenyl lower alkyl, cycloalkyl, or cycloalkyl lower alkyl, each optionally substituted with one or more R 1 .
• the application provides the compound of Formula I, wherein R 2 is phenyl, R 2' is halo, and R 1 is phenyl lower alkyl, cycloalkyl, or cycloalkyl lower alkyl, each optionally substituted with one or more R 1 .
• the application provides the compound of Formula I, wherein R 1 is phenyl, R 1 is methoxy, and R is napthyl, cyclohexyl, or pyridazinyl.
• the application provides a method for treating a Tankyrase-mediated condition comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I.
• the application provides a method for treating an Tankyrase-mediated condition comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I.
• the application provides a method for treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I.
• the application provides a pharmaceutical composition comprising the compound of Formula I.
• the application provides the above pharmaceutical composition, admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.
• the above pharmaceutical composition further comprises an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti- inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.
• an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti- inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.
• the application provides a use of the compound of formula I in the manufacture of a medicament for the treatment of a Tankyrase-mediated disorder.
• the application provides a compound or method as described herein.
• the compounds of formula I where Ri is aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 -cycloalkyl can be prepared by reacting commercially available 2-bromoacetyl chloride with an appropriate amine where Ri is aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 -cycloalkyl in the presence of base (see for example, Vloon, W. J., Kruk, C, Pandit, U.K., Hofs, H. P., McVie, J. G., /. Med. Chem. , 1987, 30(1 ), 20-24).
• the compounds of formula II where Ri is aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 -cycloalkyl and R 2 is aryl or substituted aryl can be prepared from the compounds of formula I by displacing the bromide of formula I where Ri is aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 -cycloalkyl with the appropriate thiol compound where R 2 is aryl, substituted aryl, or cycloalkyl (see for example, Etukala, J. R., Yadav, J. S., Heteroatom Chem., 2008, 19(2), 221-227).
• the compounds of formula III where Ri is a aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 -cycloalkyl and R 2 is aryl, substituted aryl, or cycloalkyl can be prepared from the compounds of formula II where Ri is a aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 - cycloalkyl and R 2 is aryl, substituted aryl, or cycloalkyl by oxidizing the sulfide to the corresponding sulfoxide under standard conditions (see for example, Jiang, S., Liao, C, Bindu, L., Yin, B., Worthy, K. W., Fisher, R. J., Burke, T. R., Nicklaus, M. C, Roller, P. P., Bioorg Med. Chem. Lett, 2009, 19(10), 2693-2698).
• the compounds of formula IN where R 2 is aryl, substituted aryl, or cycloalkyl can be prepared by displacing the bromide of commercially available 2-bromoacetic acid methyl ester with the appropriate thiol compound where R 2 is aryl, substituted aryl, or cycloalkyl (see for example, Etukala, J. R., Yadav, J. S., Heteroatom Chem., 2008, 19(2), 221-227).
• the compounds of formula V where R 2 is aryl, substituted aryl, or cycloalkyl can be prepared from the compounds of formula IN where R 2 is aryl, substituted aryl, or cycloalkyl by oxidizing the sulfide to the corresponding sulfoxide under standard conditions (see for example, Jiang, S., Liao, C, Bindu, L., Yin, B., Worthy, K. W., Fisher, R. J., Burke, T. R., Nicklaus, M. C, Rolller, P. P., Bioorg Med. Chem. Lett, 2009, 19(10), 2693-2698).
• the compounds of formula VI where R 2 is aryl, substituted aryl, or cycloalkyl can be prepared from the compounds of formula V where R 2 is aryl, substituted aryl, or cycloalkyl by hydrolyzing the ester to the corresponding acid using standard conditions (see for example, New, J.S., Christopher, W.L., Jass, P.A., /. Org. Chem., 1989, 54, 990-992).
• the compounds of formula III where Ri is aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 -cycloalkyl and R 2 is aryl, substituted aryl, or cycloalkyl can be prepared from the compounds of formula VI where Ri is aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 - cycloalkyl and R 2 is aryl, substituted aryl, or cycloalkyl by coupling the acid to the appropriate amines Ri is aryl, substituted aryl, CH 2 -aryl, cycloalkyl or CH 2 -cycloalkyl under standard amide bond formation conditions (see for example, Montalbetti, C. A. G. N., Falque, V., Tetrahedron, 2005, 61, 10827-10852).
• the amines can be commercially available or prepared under standard conditions to synthesize amines from various commercially available substrates.
• Compounds 5a-x can be synthesized following the reactions outlined in Scheme 2.
• Commercially available or synthetically accessible alkyl or aryl amines, la-x, and 2-bromoacetyl chloride can be reacted in the presence of base to afford compounds 2a-x (see for example, Vloon, W. J., Kruk, C, Pandit, U.K., Hofs, H. P., McVie, J. G., /. Med. Chem., 1987, 30(1 ), 20- 24).
• the bromide of compounds 2a-x can be displaced with the commercially available or synthetically accessible thiol, 3a-x, under standard conditions to afford compounds 4a-x (see for example, Etukala, J.
• the thiols, 3a- x can be commercially available or prepared from the corresponding phenol using such reagents as phosphorous pentasulfide (see for example, Ozturk, T., Ertas, E., Mert, O., Chem Rev. 2010, (110), 3419-3478).
• the resulting sulfide, 4a-x can be oxidized to the corresponding sulfoxide, 5a-x, under standard conditions to afford compounds 5a-x (see for example, Jiang, S., Liao, C, Bindu, L., Yin, B., Worthy, K.
• the resulting sulfides of compounds 6a-x can be oxidized to the corresponding sulfoxide under standard conditions to afford compounds 7a-x (see for example, Jiang, S., Liao, C, Bindu, L., Yin, B., Worthy, K. W., Fisher, R. J., Burke, T. R., Nicklaus, M. C, Rolller, P. P., Bioorg Med. Chem. Lett, 2009, 19(10), 2693-2698 and Ishibashi, H., Harada, S., Okada, M., Somekawa, M., Kido, M., Ikeda, M., Chem. Pharm. Bull, 1989, 37(4), 939-943).
• the ester of compounds 7a-x can be hydrolysed to the corresponding acid using standard conditions to afford compounds 8a-x (see for example, New, J.S., Christopher, W.L., Jass, P.A., /. Org. Chem., 1989, 54, 990- 992).
• Compounds 8a-x can be coupled to the appropriate amines, la-x, under standard amide bond formation conditions to afford compounds 5a-x (see for example, Montalbetti, C. A. G. N., Falque, V., Tetrahedron, 2005, 61, 10827-10852).
• the amines, la-x can be commercially available or prepared under standard conditions to synthesize amines from various commercially available substrates.
• the compounds of the present invention may be formulated in a wide variety of oral administration dosage forms and carriers.
• Oral administration can be in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, syrups, or suspensions.
• Compounds of the present invention maybe efficacious when administered by other routes of administration including continuous (intravenous drip) topical parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancement agent), buccal, nasal, inhalation and suppository administration, among other routes of administration.
• the preferred manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the degree of affliction and the patient's response to the active ingredient.
• a compound or compounds of the present invention, as well as their pharmaceutically useable salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages.
• the pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
• compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use.
• a typical preparation will contain from about 5% to about 95% active compound or compounds (w/w).
• preparation or “dosage form” is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the target organ or tissue and on the desired dose and pharmacokinetic parameters.
• excipient refers to a compound that is useful in preparing a pharmaceutical composition, generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.
• the compounds of this invention can be administered alone but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.
• “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
• a “pharmaceutically acceptable salt” form of an active ingredient may also initially confer a desirable pharmacokinetic property on the active ingredient which was absent in the non-salt form, and may even positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body.
• pharmaceutically acceptable salt of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
• Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- toluenesulfonic acid, cam
• an alkali metal ion an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
• Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
• a solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
• the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
• the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
• Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
• Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
• Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
• viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
• the compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi- dose containers with an added preservative.
• the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
• oily or nonaqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
• the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
• the compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch.
• Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
• Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
• Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
• the compounds of the present invention may be formulated for administration as suppositories.
• a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
• the compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
• the compounds of the present invention may be formulated for nasal administration.
• the solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray.
• the formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
• the compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
• the compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
• the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas.
• CFC chlorofluorocarbon
• the aerosol may conveniently also contain a surfactant such as lecithin.
• the dose of drug may be controlled by a metered valve.
• the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
• a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
• the powder carrier will form a gel in the nasal cavity.
• the powder composition may be presented in unit dose form for example in capsules or cartridges of e.g. , gelatin or blister packs from which the powder may be administered by means of an inhaler.
• formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
• the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial.
• Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support.
• the compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylaza- cycloheptan-2-one).
• Sustained release delivery systems are inserted subcutaneously into to the subdermal layer by surgery or injection.
• the subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polyactic acid.
• lipid soluble membrane e.g., silicone rubber
• biodegradable polymer e.g., polyactic acid.
• suitable formulations along with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania.
• a skilled formulation scientist may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity.
• the modification of the present compounds to render them more soluble in water or other vehicle may be easily accomplished by minor modifications (salt formulation, esterification, etc.), which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.
• terapéuticaally effective amount means an amount required to reduce symptoms of the disease in an individual.
• the dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved.
• a daily dosage of between about 0.01 and about 1000 mg/kg body weight per day should be appropriate in monotherapy and/or in combination therapy.
• a preferred daily dosage is between about 0.1 and about 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg body weight and most preferred 1.0 and about 10 mg/kg body weight per day.
• the dosage range would be about 7 mg to 0.7 g per day.
• the daily dosage can be administered as a single dosage or in divided dosages, typically between 1 and 5 dosages per day. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect for the individual patient is reached.
• One of ordinary skill in treating diseases described herein will be able, without undue experimentation and in reliance on personal knowledge, experience and the disclosures of this application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease and patient.
• the pharmaceutical preparations are preferably in unit dosage forms.
• the preparation is subdivided into unit doses containing appropriate quantities of the active component.
• the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
• the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
• the application provides a method for treating an PARP-mediated condition comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I.
• the application provides a method for treating an Tankyrase-mediated condition comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I.
• the application provides a method for treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I.
• the compounds of formula I and the pharmaceutically acceptable salts can be used as therapeutically active substances, e.g. in the form of pharmaceutical preparations.
• the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
• the administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
• the compounds of formula I and the pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations.
• Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.
• Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatine capsules.
• Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
• Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
• the pharmaceutical preparations can, moreover, contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
• Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
• the dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
• the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof.
• the daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
• compositions according to the invention are:
• the compound of formula I, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine.
• the mixture is returned to the mixer; the talc is added thereto and mixed thoroughly.
• the mixture is filled by machine into suitable capsules, e.g. hard gelatine capsules.
• the compound of formula I is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size.
• the filled soft gelatin capsules are treated according to the usual procedures.
• the suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to
• the compound of formula I is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water.
• the granulate is mixed with magnesium stearate and the flavoring additives and filled into sachets.
• N-(4- Methoxy-phenyl)-2-(naphthalen-2-ylsulfanyl)-acetamide was obtained as yellow solid (480 mg, 90%) .
• LC-MS: 324 [M+l] + , R t 1.623 min.
• N-(4- Methoxy-phenyl)-2-(pyridazin-3-ylsulfanyl)-acetamide was obtained as a yellow solid (400 mg, 88%).
• LC-MS: 276 [M+l] + , R t 1.303 min.
• N- (4-Methoxy-phenyl) -2-m-tolylsulf anyl- acetamide was obtained as a white solid (260 mg, 82%).
• LC-MS: 304 [M+l] + , R t 1.390 min.
• N-(4-methoxy-phenyl)-2-(naphthalen-2-ylsulfanyl)-acetamide was obtained as a white solid (180 mg, 57%).
• N-(4-methoxy-phenyl)-2-(naphthalen- 1 -ylsulfanyl)-acetamide was obtained as a white solid (210 mg, 67%).
• His6-TNKS 1 can use either His6-tankyrase 2 (construct: 934 - 1166) (His6-TNKS2) or His6-PARP1 (full length).
• Biotin-IWR2 10 mM Biotin-IWR2 stock in DMSO, stored at -20 °C.
• Positive control 10 mM XAV 939 in DMSO, stored at -20 °C
• Eu-Streptavidin 38.1 ⁇ (2.1 mg/mL) Eu-SA (Bio# Eu-2212, Lot# N 18001-BDHO2) 5.
• APC-anti-His Ab 8.50 ⁇ SL-APC, 8.26 ⁇ anti-6His antibody-SureLight APC (Columia Bioscience, Cat# D3-1711, Lot# N01010-AAH04)
• NP-40 10% NP-40 solution (PIERCE, Cat# 28324, Lot # 97101671) Assay Buffer Preparation
• Assay buffer la (ABla) for TNKS dilution 50 mM Tris, pH 7.4, 100 mM sodium chloride solution, ImM magnesium chloride solution, 1 mM DL-dithiothreitol solution, 0.2 mg/mL bovine serum albumin solution, 0.025% NP-40.
• Assay buffer lb (ABlb) for Biotin- VR2 dilution 50 mM Tris, pH 7.4, 100 mM sodium chloride solution, ImM magnesium chloride solution, 1 mM DL-dithiothreitol solution, 0.2 mg/mL bovine serum albumin solution, 0.05% NP-40
• Assay buffer lc (ABlc) for compound dilution 50 mM Tris, pH 7.4, 100 mM sodium chloride solution, ImM magnesium chloride solution, 1 mM DL-dithiothreitol solution, 0.2 mg/mL bovine serum albumin solution 4.
• Assay buffer 2 (AB2) for Eu/APC 50 mM Tris, pH 7.4, 100 mM sodium chloride solution, ImM magnesium chloride solution, 0.2 mg/mL bovine serum albumin solution

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